Chelation therapy · Effect of Chelation Therapy on Endothelial Function in Patients With Coronary Artery Disease: PATCH Substudy Chelation therapy for atherosclerotic cardiovascular

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เรื่อง

Chelation therapy

สําหรับโรคหลอดเลือดหัวใจ

โดย

นายแพทยอรรถสิทธิ์ ศรีสุบัติ

สถาบันวจิัยและประเมินเทคโนโลยทีางการแพทย กรมการแพทย กระทรวงสาธารณสุข

พ.ศ.2553

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คํานํา

การรักษาภาวะที่มีโลหะหนักในรางกายโดยวิธีการ Chelation มีการใชมานานในผูปวยโรคธาลัสซีเมีย (thalassemia) ที่ไดรับเลือดจะมีธาตุเหล็กเกินในรางกาย ผูปวยจะไดรับการรักษาดวยการให deferoxamine ซึ่งเปนยามาตรฐานในการรักษา ดวยคุณสมบัติของวิธี Chelation therapy ในการจับโลหะหนักและขับออกจากรางกายได จึงเปนที่มาของแนวคิดที่วาวิธี Chelation therapy ดวยสาร EDTA (ethylenediamine tetraacetic acid) สามารถกําจัดโลหะหนักที่บริเวณผนังหลอดเลือดหัวใจไดเชนกัน ทําใหลดการเกิด atherosclerotic plaque ท่ีผนังหลอดเลือดหัวใจลงได ดวยเหตุน้ี การรักษาดวยวิธีการแพทยทางเลือกจึงมีการนํา Chelation therapy มาใชในการรักษาโรคหลอดเลือดหัวใจในปจจุบันอยางแพรหลาย อยางไรก็ตาม ยังมีขอโตเถียงและความคิดเห็นท่ีแตกตางกันของผูเชี่ยวชาญแขนงตางๆ ในประเด็นของประสิทธิผลของการใช Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจ รวมถึงผลขางเคียงที่อาจเกิดข้ึนกับผูปวย

ดังนั้น กรมการแพทย โดย สถาบันวิจัยและประเมินเทคโนโลยีทางการแพทย จึงไดดําเนินการ

ทบทวนวรรณกรรมที่มีหลักฐานนาเชื่อถือที่มีอยูในปจจุบันบนพ้ืนฐานของขอมูลท่ีสามารถสืบคนและเขาถงึได เพื่อใหทราบถึงประสิทธิผลของ Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจ

ข

บทคัดยอ

ปจจุบันมีการนํา Chelation therapy มาใชเปนการแพทยทางเลือกของการรักษา หรือใชเพื่อประกอบการรักษาภาวะ atherosclerosis และลดอาการของโรคหลอดเลือดหัวใจ ซึ่งเปนวิธีที่ทําใหมีเลือดไหลเวียนในหลอดเลือดหัวใจที่แข็งโดยไมตองผาตัด จึงสามารถปองกันอาการตางๆ ของโรคหลอดเลือดหัวใจได อาทิ อาการปวดเคนหัวใจ (angina pectoris) หรือ กลามเนื้อหัวใจตาย (myocardial infarction) เปนตน อยางไรก็ตาม การใช Chelation therapy ในปจจุบันเพื่อรักษา atherosclerosis และโรคหลอดเลือดหัวใจยังมีขอขัดแยงในดานประสิทธิผลและความปลอดภัยในกลุมผูเชี่ยวชาญแขนงตางๆ การศึกษานี้จึงมีวัตถุประสงคในการหาประสิทธิผลและผลขางเคียงจาก Chelation therapy ที่นํามารักษาโรคหลอดเลือดหัวใจ โดยการทบทวนวรรณกรรมจากการสืบคนเอกสารวิชาการท่ีเปนภาษาอังกฤษใน PubMed และ The Cochrane Library โดยผลการสืบคนได 777 เรื่อง (PubMed 615 และ The Cochrane Library 162 เรื่อง) ภายหลังจากการคัดเขาและออกตามเกณฑที่กําหนดพบวาเอกสารที่ไดเปนการทบทวนอยางเปนระบบ (systematic review) มีจํานวน 3 เรื่อง การทบทวนเชิงบรรยาย (narrative review) จํานวน 2 เรื่อง และการวิจัยคลินิกท่ีเปน randomized controlled trials จํานวน 2 เรื่อง ผลการศึกษาพบวา 6 การศึกษารายงานวาผลของการใช Chelation therapy สําหรับโรคหลอดเลือดหัวใจไมแตกตางจากกลุมเปรียบเทียบ ในขณะที่มีรายงานถึงผลอันไมพึงประสงคของ Chelation therapy จาก EDTA (ethylenediamine tetraacetic acid) ที่พบในการศึกษาเหลานี้ ไดแก พิษตอไต ชัก แคลเซียมในเลือดต่ํา น้ําตาลในเลือดต่ํา เปนตน ในขณะที่การศึกษาที่เปนการทบทวนและเผยแพรในวารสารดานการแพทยทางเลือกเพียงการศึกษาเดียวที่สนับสนุน Chelation therapy ที่ใช EDTA มีประโยชนในผูปวยที่ใสสายสวนหลอดเลือดชนิดเคลือบยา เม่ือเปรียบเทียบกับการใหยา clopidrogrel รวมกับ aspirin และไมพบผลขางเคียงที่สําคัญจาก Chelation therapy ดังนั้น ดวยขอมูลที่มีอยูในปจจุบันจึงยังไมสามารถระบุถึงประสิทธิผลของ Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจได หากแตตองระมัดระวังผลขางเคียงท่ีอาจเกิดขึ้นและเปนอันตรายตอผูปวยไวดวย การศึกษาที่เปน randomized controlled trial ดวยระเบียบวิธีวิจัยที่ถูกตอง เปนไปตามหลักการปฏิบัติการวิจัยทางคลินิกที่ดี (good clinical practice) มีจํานวนผูเขารวมโครงการเพียงพอ โปรงใส ปราศจากอคติ ตรวจสอบไดทุกข้ันตอนการวิจัย และผูวิจัยไมมีประโยชนทับซอนจะสามารถแสดงใหเห็นถึงประสิทธิผลของ Chelation therapy สําหรับโรคหลอดเลือดหัวใจตอไปไดอยางชัดเจน

ค

กิตติกรรมประกาศ

รายงานการทบทวนวรรณกรรมครั้งนี้สําเร็จลุลวงตามวัตถุประสงคทุกประการ เนื่องจากไดรับความรวมมือและการสนับสนุนการดําเนินการเปนอยางดีจากผูมีสวนเกี่ยวของทุกฝาย รวมถึง ขอขอบคุณหองสมุดกรมการแพทยที่ไดใหความชวยเหลือในการสืบคนเอกสารวิชาการจากเครือขายแหลงขอมูลตางๆ จนการดําเนนิการแลวเสร็จ ผูวิจัยจึงขอขอบคุณมา ณ โอกาสนี้

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สารบัญ

หนา

คํานํา ก บทคัดยอ ข กิตติกรรมประกาศ ค สารบัญ ง สารบัญตาราง จ สารบัญแผนภมูิ จ บทนํา 1 วัตถุประสงค 2 วิธีดําเนินการ 2 เกณฑการพิจารณาคัดเลอืกเอกสารวิจัยสําหรับการทบทวน 3 กลุมประชากรศึกษา 3 การวัดผลลัพธ 3 วิธีการสืบคนขอมูล 3 ประโยชนท่ีคาดวาจะไดรับ 5 ขอจํากัดการศึกษา 5 ผลการดําเนินการ 5 สรุปผล อภิปราย และขอเสนอแนะ 9 เอกสารอางอิง 11 ภาคผนวก

Chelation Therapy for Cardiovascular Disease Chelation therapy for coronary heart disease: An overview of all clinical investigations Chelation Therapy for Ischemic Heart Disease Effect of Chelation Therapy on Endothelial Function in Patients With Coronary Artery Disease:

PATCH Substudy Chelation therapy for atherosclerotic cardiovascular disease (The Cochrane Review) EDTA chelation therapy for cardiovascular disease: a systematic Review Should EDTA Chelation Therapy be Used Instead of Long-term Clopidogrel plus

Aspirin to Treat Patients at Risk from Drug-Eluting Stents?

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สารบัญตาราง

หนา

ตารางที่ 1 คําสืบคนและผลทีไ่ดจาก PubMed 4 ตารางที่ 2 คําสืบคนและผลทีไ่ดจาก The Cochrane Library 4 ตารางที่ 3 ประเภทและจาํนวนเอกสารวิชาการทีผ่านการคัดเลือกเพือ่ทบทวน 6

สารบัญแผนภูมิ

หนา

แผนภูมิที่ 1 ผลการสืบคนขอมูล 5

บทนํา Chelation therapy1-5เปนการกําจัดโลหะหนักโดยการใชสารบางชนิดเพ่ือเขาไปจับกับโลหะหนักแลวขับออกจากรางกาย โลหะหนักสวนใหญ ไดแก ตะกั่ว สารหนู ปรอท เหล็ก เปนตน สารท่ีใชในการกําจัดโลหะหนักมีการนํามาใชทางการแพทยตั้งแตสมัยสงครามโลกครั้งที่ 1 โดยเริ่มแรกใช dimercaprol หรือ รูจักกันในชื่อ British Anti-Lewisite (BAL) เปนยาแกพิษ (antidote) ของแกสอารเซ-นิกซึ่งเปนแกสพิษ โดย BAL จะไปจับกับอารเซนิกแลวเปลี่ยนรูปเปนสารประกอบที่ละลายน้ําได ผานเขาสูกระแสโลหิตแลวไปขับออกท่ีไตและตับ อยางไรก็ตาม BAL มีผลขางเคียงรายแรงตอรางกายเปนอยางมาก ตอมา Chelation therapy ถูกนํามาใชในประเทศอังกฤษภายหลังสงครามโลกครั้งที่ 2 เพ่ือรักษาผูที่ไดรับพิษสารหนู ตะกั่ว และโลหะหนักอ่ืนๆ การให Chelating agent สามารถใหไดทางการรับประทาน ใหทางหลอดเลือด และทางกลามเนื้อได

สารที่นิยมใชในการทํา Chelation คือ EDTA (ethylenediamine tetraacetic acid)6-7 ซึ่งเปนกรด อะมิโนสังเคราะห โดยทั่วไป EDTA ถูกนํามาใชเปนสารปองกันไมใหเลือดแข็งตัวในหองปฏิบัติการ โดยการยับยั้งการรวมตัวกันของเกล็ดเลือด Chelation therapy ไดใช EDTA โดยการใหทางหลอดเลือดดํารวมกับการรับประทานวิตามินและเกลือแร EDTA เปนสารประกอบที่ละลายน้ําได ท้ังนี้ EDTA จะชวยในการกําจัดตะกั่ว ปรอท แคดเมียม และเหล็กออกจากระบบไหลเวียนโลหิต ซ่ึงเหล็กและแคดเมียมมีความสัมพันธกับความดันโลหิตสูง ในขณะที่เหล็กปริมาณสูงมีผลตอโรคหัวใจ องคการอาหารและยาของสหรัฐอเมริกา (U.S. Food and Drug Administration, FDA) อนุญาตใหใช EDTA ในการรักษาพิษจากโลหะหนักบางชนิด อาทิ inorganic lead และใชรักษาพิษจาก digitalis เรื่อยมาจนกระทั่งมี antibody fragment มาใชรักษาพิษจาก digitalis ทดแทน อยางไรก็ตาม FDA ยังไมอนุญาตใหใช Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจโคโรนารีย8

จากคุณสมบัติของ EDTA ในการใชจับสารโลหะหนักและขับออกจากเลือดได นักวิทยาศาสตรจึงไดตั้งสมมติฐานวาหลอดเลือดแดงที่แข็งนาจะใหนิ่มลงได โดยการให EDTA เพื่อไปลด atherosclerotic plaque ท่ีผนังหลอดเลือดหัวใจ9 เนื่องจาก EDTA สามารถดึงแคลเซียมออกจากผนังหลอดเลือดแดงได และในทศวรรษท่ี 1950 มีผูสังเกตเห็นวา ผูปวยที่เปนโรคหลอดเลือดหัวใจแข็งและไดรับพิษจากตะกั่ว เมื่อได EDTA แลวพบวามีอาการของโรคหลอดเลือดแดงหัวใจดีข้ึนดวย10 ในป ค.ศ.1956 มีรายงานผูท่ีปวยเปนโรคหลอดเลือดสวนปลายอุดตัน (occlusive peripheral vascular disease) รายงานวารูสึกดีข้ึนภายหลังจากไดรับ EDTA ตอมามีรายงานผูปวยอีกหลายรายเกี่ยวกับประโยชนของ EDTA ในการรักษาผูปวยโรคหลอดเลือดหัวใจแข็ง11

อยางไรก็ตาม ยังไมมีการประเมินผลขางเคียงที่รุนแรงในการศึกษาขนาดใหญท่ีมีการสุมกลุมศึกษาและกลุมเปรียบเทียบ แตมีรายงานพิษท่ีเกิดขึ้นจากการรายงานผูปวย พบวา EDTA มีพิษตอไต พิษอ่ืนๆ ที่

2 อาจเกิดขึ้นจาก EDTA ไดแก แคลเซียมในเลือดต่ําทําใหเกิดการชักเกร็ง ซ่ึงทําใหเสียชีวิตได ภาวะน้ําเกินในรางกายทําใหเกิดหัวใจลมเหลว คาการทํางานของตับสูงขึ้น น้ําตาลในเลือดต่ําในผูปวยเบาหวานชนิดท่ีตองพ่ึงอินซูลิน9, 12-13

แพทยจํานวนมากนําวิธีการรักษาดวย EDTA ดังกลาวมาใชรักษาผูปวยโรคหลอดเลือดหัวใจและสมองอุดตัน โดยใหเหตุผลวาเปนการบําบัดแบบแพทยทางเลือกที่นิยมและยอมรับในตางประเทศ โดย EDTA ชวยใหการไหลเวียนของเลือดในหลอดเลือดแดงที่เลี้ยงกลามเนื้อหัวใจกลับเปนปกติไดโดยไมตองผาตัด และใชเปนการรักษาเชิงปองกัน ซึ่ง American College of Advancement in Medicine ใหการสงเสริมและสนับสนุน Chelation therapy14

ปจจุบันมีการนํา Chelation therapy มาใชเปนทางเลือกของการรักษา หรือใชเพ่ือประกอบการรักษาภาวะ atherosclerosis และลดอาการของโรคหลอดเลือดหัวใจ (coronary artery disease) ซึ่งมีการแนะนําวาปลอดภัย และเปนวิธีท่ีไมตองผาตัดเพื่อใหมีเลือดไหลเวียนในหลอดเลือดแดงที่แข็ง ดังนั้นจึงสามารถปองกันอาการตางๆ ของโรคหัวใจ อาทิ อาการปวดเคนหัวใจ (angina pectoris) อาการปวดขาเปนระยะเพราะขาดเลือด (claudication) กลามเนื้อหัวใจตาย (myocardial infarction) และโรคหลอดเลือดสมอง (stroke) เปนตน ดวยเหตุนี้ องคกรท่ีเปนการแพทยทางเลือกหลายแหงจึงไดมีการนํา Chelation therapy มาใชอยางกวางขวางกับผูที่มีหลอดเลือดแดงแข็ง และโรคหัวใจ อยางไรก็ตาม การใช Chelation therapy ในปจจุบันเพื่อรักษา atherosclerosis และโรคหัวใจยังมีขอขัดแยงในดานประสิทธิผลของ EDTA ซ่ึงขอมูลสนับสนุนยังมีไมเพียงพอ องคการอาหารและยาของสหรัฐอเมริกา (FDA) พิจารณาวา disodium EDTA ไมไดบรรจุอยูในรายการยา และไมมีหลักฐานเพียงพอที่แสดงถึงความปลอดภัยและประสิทธิผลท่ีเกิดขึ้นในการนํามาใชรักษาโรคหลอดเลือดหัวใจโคโรนารีย14 ดังนั้น การทบทวนวรรณกรรมในดานประสิทธิผล และภาวะแทรกซอนของ Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจ โดยใชขอมูลจากงานวิจัยที่นาเชื่อถือเทาที่มีอยู ณ ปจจุบัน จะทําใหทราบขอมูลเกี่ยวกับ Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจไดชัดเจนยิ่งขึ้น

วัตถุประสงค ทบทวนองคความรูเกีย่วกับประสิทธิผล และผลขางเคียงของ Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจ

วิธีดําเนินการ 1. กําหนดขอบเขตของการศกึษา 2. กําหนดกลยุทธการสืบคน

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3. คัดเลือกเอกสารที่เกีย่วของ 4. วิเคราะหเอกสารทีผ่านการคัดเลือก

เกณฑการพิจารณาคดัเลือกเอกสารวิจัยสําหรับการทบทวน

เกณฑการคัดเขา (inclusion criteria) • Chelation therapy ในผูปวยโรคหลอดเลือดหัวใจ • เอกสารวิชาการประเภทการทบทวนอยางเปนระบบ (systematic review) การวิจยัคลนิิกชนิด

randomized controlled trial (RCT) การวจิยัคลินิกชนดิ non-randomized controlled trial และการทบทวน (review)

เกณฑการคัดออก (exclusion criteria) • เอกสารประเภทรายงานผูปวย • การศึกษาในสตัวทดลอง

กลุมประชากรศึกษา

ผูปวยโรคหลอดเลือดหวัใจที่ไดรับการรกัษาดวย Chelation therapy

การวัดผลลัพธ

ประสิทธิผลและผลแทรกซอนของ Chelation therapy ในการรกัษาโรคหลอดเลือดหัวใจ

วิธีการสืบคนขอมูล

กําหนดกลวธิกีารสืบคน (search strategy) ดังตารางที่ 1-2

การสืบคนขอมูลทางอิเล็กทรอนิกส

1. สืบคนจากฐานขอมูล MEDLINE โดยใช PubMed ซึ่งจํากัดการสืบคนเพื่อใหไดเอกสารการศึกษาในมนุษยเปนภาษาอังกฤษที่เปนการวิเคราะหอภิมาน (meta-analysis) หรือ การทบทวนอยางเปนระบบ (systematic review) หรือการวิจัยทางคลินิก (clinical trial) หรือแนวทางปฏิบัติ (practice guideline) หรือการวิจัยแบบสุมท่ีมีกลุมควบคุม (randomized controlled trial) หรือการทบทวน (review) โดยการกําหนดกอนการสืบคนใหจํากัดดวย Humans, Clinical Trial, Meta-Analysis, Practice Guideline, Randomized Controlled Trial, Review, English

2. สืบคนจากฐานขอมูล The Cochrane Library

4 ตารางที่ 1 คําสืบคนและผลที่ไดจาก PubMed

ลําดับ คําที่ใชสืบคน ผลการสืบคน 1 chelation[ti] 1567 2 chelat*[ti] 7632 3 chelat*[tw] 46255 4 EDTA[tw] 26454 5 (((EDTA[tw]) OR (#3)) OR (#2)) OR (#1) 68381 6 coronary artery disease[tw] 58267 7 coronary heart disease[tw] 31563 8 CAD[tw] 14831 9 CHD[tw] 11786

10 cardiovascular[tw] 256515 11 ischemic heart disease[tw] 16402 12 (((((ischemic heart disease[tw]) OR (#10)) OR (#9)) OR (#8)) OR (#7)) OR (#6) 345057

13 ((((((ischemic heart disease[tw]) OR (#10)) OR (#9)) OR (#8)) OR (#7)) OR (#6)) AND (#5)

615

ตารางที่ 2 คําสืบคนและผลที่ไดจาก The Cochrane Library

ลําดับ คําท่ีใชสืบคน ผลการสืบคน 1 MeSH descriptor Chelating Agents explode all trees 1555 2 MeSH descriptor Cardiovascular Diseases explode all trees 56984 3 (chelation):ti,ab,kw or (EDTA):ti,ab,kw 732 4 (coronary artery disease):ti,ab,kw or (coronary heart disease):ti,ab,kw or

(ischemic heart disease):ti,ab,kw or (CAD):ti,ab,kw or (CHD):ti,ab,kw 11160

5 (#1 OR #3) 2036 6 (#2 OR #4) 60517 7 (#5 AND #6) 162

ประโยชนที่คาดวาจะไดรับ

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1. ขอมูลประสิทธิผลของการรกัษาโรคหลอดเลือดหัวใจดวยวิธี Chelation โดยอิงหลักฐานเชิงประจักษ

2. ขอมูลสําหรับการศกึษาวิจยัตอไป ขอจํากัดการศึกษา

การศึกษาอยูบนพื้นฐานการสืบคนขอมูลเฉพาะการศึกษาวิจยัที่เปนภาษาอังกฤษ และปรากฏอยูในฐานขอมูลท่ีสามารถเขาถึงได ผลการดําเนินการ

1. ผลการสืบคนขอมลู จากการสืบคนขอมูลตาม Search strategy ไดเอกสารทั้งสิ้น 777 เรื่อง โดยไดจาก PubMed 615 เรื่อง

และ The Cochrane library 162 เรื่อง เมื่อพิจารณาตามเกณฑการคัดเขาและคัดออก ไดเอกสารที่ตรงตามขอกําหนดจํานวน 7 เรื่องเปนการทบทวนอยางเปนระบบ (systematic review) จํานวน 3 เรื่อง randomized controlled trial จํานวน 2 เรื่อง การทบทวนเชิงบรรยาย (narrative vreview) จํานวน 2 เรื่อง ทั้งนี้ ไมพบการวิเคราะหอภิมาน (meta-analysis) ดังแผนภูมิที่ 1 และตารางที่ 3

แผนภูมิท่ี 1 ผลการสืบคนขอมูล

Search strategy results: 777 PubMed: 615 CENTRAL: 162

Studies excluded: 770

Full text analysis: 7

Studies included: 7

6 ตารางที่ 3 ประเภทและจาํนวนเอกสารวิชาการทีผ่านการคัดเลือกเพือ่ทบทวน

ลําดับ ประเภทเอกสารวชิาการ ผลการสืบคน 1 Systematic review 3 2 Randomized controlled trial 2 3 Narrative review 2

2. ผลการศกึษา 2.1 การทบทวนวรรณกรรมเผยแพรในป 1997 ของ Lewin15 พบวามากกวา 3 ทศวรรษมาแลวที่มี

การนําเอา EDTA มาทดลองใชรักษาภาวะหัวใจเสียจังหวะ (arrhythmias) และภาวะพิษจาก digitalis ในป ค.ศ.1964 เปนที่ยอมรับในวงกวางวา EDTA มีประโยชนในการแกไขภาวะพิษจาก digitalis และกดการบีบตัวของหัวใจหองลางผิดปรกติแบบ ventricular premature contraction ในกรณีฉุกเฉิน อยางไรก็ตาม ขอมูลสนับสนุนการนํามาใชทางคลินิกยังมีจํานวนนอย ในการใหขอมูล Chelation therapy กับผูปวยนั้น แพทยควรทราบขอมูลเกี่ยวกับสารที่เปน chelators ตางๆ อาทิ ประวัติความเปนมา การออกฤทธิ์ รวมถึงขอแนะนํา และไมแนะนําในการนําไปใชทางการแพทย นอกจากนี้ ผลการศึกษารายงานวา EDTA เปนพิษตอไต บางกรณีเกิดการความเสียหายที่หลอดไตฝอยสวนตน (proximal tubule) รวมถึง EDTA มีความสัมพันธกับภาวะนํ้าตาลในเลือดต่ํา ความรูสึกไมสบาย (malaise) อาการทางระบบทางเกิดอาหาร T-wave inversion ผิวหนังอักเสบ และอาการของภาวะแคลเซียมในเลือดต่ํา เชน ชัก เปนตน

2.2 การทบทวนอยางเปนระบบของ Ernst16 เพื่อใหไดขอมูลทางคลินิกที่สนับสนุน และคัดคานประสิทธิผลและสัมฤทธิผลของ Cheletion therapy สําหรับโรคหลอดเลือดหัวใจ โคโรนารีย ซึ่งเผยแพรในป 2000 ผูวิจัยสืบคนขอมูลโดยใชคอมพิวเตอรจํานวน 4 เครื่องท่ีเปนอิสระในการสืบคนขอมูลจาก MEDLINE, EMBASE, Cochrane Library และ CISCOM (a database specialized in complementary/ alternative medicine) ตั้งแตป 1998 เปนตนมา จากการสืบคนพบวา 22 การศึกษาที่สวนใหญเปน case reports และ case series ซึ่งไมมีกลุมควบคุม การรายงานผลสวนใหญเปนการรายงานอาการที่เปนนามธรรมที่ดีข้ึนของคนไขสวนใหญ มีการศึกษา 2 รายที่รายงานผลอยางเปนรูปธรรมจากภาพถายหลอดเลือด ซึ่งไมพบหลักฐานวา Cheletion therapy มีประโยชน มี 2 การศึกษาที่เปน clinical controlled trials ท่ีไมมีหลักฐานเพียงพอในการสนับสนุนประสิทธิผลของ Chelation therapy เมื่อเทียบกับยาหลอก (placebo) อยางไรก็ตาม ตองคํานึงถึงความเสี่ยงที่เกิดขึ้น ไดแก โรคไตเรื้อรัง (renal failure) หัวใจเตนผิดจังหวะ (arrhythmias) การชักเกร็ง (tetany) แคลเซียมในเลือดต่ํา (hypocalcemia) น้ําตาลในเลือดต่ํา (hypoglycemia) ความดันโลหิตต่ํา (hypotension) ไขกระดูกทําหนาที่ลดลง (bone marrow depression) ระยะเวลาเลือดออกนานขึ้น (prolonged bleeding time) ชัก (convulsions) หยุดหายใจ (respiratory arrest) โรคระบบภูมิคุมกัน (autoimmune diseases)

7

2.3 Knudtson17 และคณะ (ป 2002) ไดศึกษาการใช Chelation therapy ดวย EDTA เพื่อดูการทนตอภาวะขาดเลือด และวัดคุณภาพชีวิตของผูปวยโรคหัวใจขาดเลือดชนิดคงที่ (stable ischemic heart disease) โดยผูปวยมีอายุตั้งแต 21 ปข้ึนไปและเปนโรคหลอดเลือดหัวใจ ซ่ึงไดรับการวินิจฉัยดวยการถายภาพทางรังสีของหลอดเลือดหัวใจ หรือมีหลักฐานวาเปนกลามเนื้อหัวใจตาย หรือ stable angina ที่ไดรับการรักษาดวยยา ผูวิจัยใช blocks of 10 ในการสุมแยกผูปวยเปน 2 กลุม กลุมศึกษาไดรับ 5% dextrose ในน้ํารวมกับ disodium EDTA ในขนาด 40 มิลลิกรัม/กิโลกรัม โดยมีขนาดยาสูงที่สุดไมเกิน 3 กรัม ท้ังนี้ ในสารละลายยังประกอบไปดวยแมกนีเซียมซัลเฟต 750 มิลลิกรัม กรดแอสคอบิค 5 กรัม และโซเดียม ไบคารบอเนต 5 กรัมในสารละลาย 5% dextrose รวมถึงใส lidocaine 80 มิลลิกรัม เพ่ือลดความปวดบริเวณที่ไดรับสารละลาย ในกลุมควบคุมจะไดรับสารละลายในลักษณะเดียวกัน แตใชน้ําเกลือ 0.9% จํานวน 20 มิลลิลิตร แทน EDTA ลักษณะของสารละลายจะไมสามารถแยกไดดวยสี หรือฉลาก ผูปวยทั้งหมดไดรับการรักษาสัปดาหละ 2 ครั้งเปนเวลา 15 สัปดาห และเพิ่มเดือนละครั้งเปนเวลา 3 เดือน ดังนั้นผูปวยจะไดรับการรักษาทั้งสิ้น 33 ครั้ง อยางไรก็ตามผูปวยทั้งสองกลุมยังไดรับวิตามินรวมชนิดรับประทานครั้งละ 2 เม็ดวันละ 3 ครั้ง ยกเวนวันที่ไดรับการรักษา ผูวิจัยประเมินผลการศึกษาเมื่อไดรับการรักษาเปนระยะเวลา 15 และ 27 สัปดาห สิ้นสุดการศึกษาเมื่อคลื่นไฟฟาหัวใจมีการเปลี่ยนแปลง โดยพิจารณาจาก ST-segment depression อยางนอยที่สุด 1 มิลลิเมตรที่ 27 สัปดาห ผลการศึกษาพบวาผูปวยที่ผานเกณฑการทดสอบดวย treadmill จํานวน 84 คน ผานกระบวนการสุมแลวไดกลุมที่ไดรับ Chelation therapy จํานวน 41 ราย ไดรับ placebo therapy จํานวน 43 ราย คุณภาพชีวิตและคาตางๆ ท่ีเกี่ยวกับการออกกําลังกายของผูปวยทั้งสองกลุมไมตางกันอยางมีนัยสําคัญทางสถิติ กลุม Chelation therapy จํานวน 1 รายมีคา creatinine ในเลือดสูงขึ้น แตไมพบความผิดปรกติของระดับเกลือแรในรางกาย

2.4 Anderson18 และคณะไดทําการศึกษาวิจัยแบบ randomized controlled trial ซึ่งไดรับการเผยแพรในป 2003 การศึกษามีวัตถุประสงคในการประเมินผลของ Chelation therapy ที่ใช EDTA เปรียบเทียบกับยาหลอกเพื่อดูการตอบสนองของ endothelium-dependent vasomotor ในผูปวยโรคหลอดเลือดหัวใจโคโรนารีย โดยทําการคัดเลือกผูปวยจํานวน 53 รายเขารวมโครงการ PATCH (Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health) ผูปวยมีอายุต้ังแต 21 ปข้ึนไปที่ไดรับการตรวจวาเปนโรคหัวใจโคโรนารียดวยวิธีถายภาพทางรังสีของหลอดเลือดหัวใจ หรือมีหลักฐานแสดงวาเปนกลามเนื้อหัวใจตาย (myocardial infarction) หรือมีอาการเจ็บเคนหนาอกแบบคงที่ (stable angina) ที่ไดรับการรักษาดวยยา ผูปวยไดรับการสุมดวย block of 10 โดยผูปวยจะไมทราบวาอยูในกลุมทดลอง หรือกลุมควบคุม ผูปวย 6 คนถูกคัดออกจากการศึกษา กลุมทดลองจํานวน 24 คนจะไดรับ 5% dextrose in water ซึ่งมี EDTA เกลือแรและวิตามินรวมอยูดวย ในขณะที่กลุมควบคุมจํานวน 23 คนไดรับ 0.9% โซเดียมคลอไรด 20 มิลลิลิตรแทน EDTA ในสารละลาย ผูวิจัยวัดผลการศกึษาจากการขยายของหลอดเลือดแดง brachial จากการใชเครื่องอัลตราซาวดที่มีความคมชัดสูงวัดเสนผานศูนยกลางของ brachial artery โดยผูปวยจะไดรับ

8 การวัด 3 ระยะ ไดแก baseline หลังจากไดรับ Chelation therapy ครั้งแรก และครั้งสุดทายหลังจากไดรับการรักษาดวยวิธี Chelation ครบ 33 ครั้ง แลวจึงนําผลที่ไดมาคํานวณหา flow-mediated vasodilation (FMD) ผลการศึกษาไมพบความแตกตางอยางมีนัยสําคัญของ FMD ระหวางกลุมที่ไดรับ Chelation therapy กับกลุมควบคุม กลุมท่ีได Chelation therapy จํานวน 2 คนตองออกจากการศึกษาเนื่องจากระดับ creatinine ในเลือดสูง 1 คน และเกิดอาการเจ็บเคน unstable angina 1 คน

2.5 จาก Cochrane review ของ Dans19 และคณะที่ไดทําการทบทวนอยางเปนระบบในป 2002 และ update ในป 2005 จากฐานขอมูล MEDLINE, EMBASE และ CENTRAL (Cochrane Controlled Trials Register) โดยทําการทบทวนการศึกษาที่เปน randomized controlled trial (RCT) ของการใช Chelation therapy โดยการให EDTA เขาทางหลอดเลือดดําในการรักษาโรคหลอดเลือดแดงหัวใจแข็ง (atherosclerotic cardiovascular disease) เปรียบเทียบกับสารละลายไอโซทอนิก (isotonic solution) หรือน้ํากลั่น (distilled water) ซึ่งวัดผลการรักษาจากทุกสาเหตุท่ีทําใหสียชีวิต การตายจากโรคหัวใจโคโรนารีย (coronary heart disease) และการตายจากโรคของหลอดเลือด (vascular disease) รวมถึงกรณีที่ไมเสียชีวิตแตเกิดอาการของกลุมโรคหัวใจขาดเลือดเฉียบพลัน (acute coronary syndrome) อาทิ โรคกลามเนื้อหัวใจตาย และ อาการเจ็บเคนหนาอกแบบไมคงท่ี (unstable angina pectoris) ทั้งนี้ รวมถึงอาการของโรคหลอดเลือดสมอง เชน โรคหลอดเลือดสมอง (stroke) เปนตน ผลการทบทวนพบวาขอมูลที่สนับสนุน และไมสนับสนุนประสิทธิผลของ Chelation therapy ในการใชรักษา atherosclerotic cardiovascular disease ยังมีไมเพียงพอ ควรทําการศึกษาวิจัยแบบ RCT เพ่ิมขึ้น โดยเฉพาะในกลุมเสี่ยงโรคหัวใจโคโรนารีย และโรคหลอดเลือดสมอง รวมถึงการวัดผลลัพธควรวัดใหถึงคุณภาพชีวิตของผูปวย ผลขางเคียงจากการทํา Chelation therapy ที่พบ ไดแก วิงเวียนเปนลม อาการทางระบบทางเดินอาหาร (gastrointestinal symptoms) พบโปรตีนในปสสาวะ (proteinuria) แคลเซียมในเลือดต่ํา (hypocalcemia) รวมถึงผลขางเคียงจากการทําหัตถการ ไดแก หลอดเลือดดําอักเสบ (phlebitis) และปวดบริเวณที่ใหสารละลายเขาหลอดเลือด

2.6 Seely20 และคณะทําการทบทวนอยางเปนระบบในป 2005 เพื่อประเมิน Chelation therapy ในการรักษาโรคหลอดเลือดหัวใจจาก 7 ฐานขอมูล ไดแก MEDLINE, EMBASE, CENTRAL (Cochrane Controlled Trials Register), AMED (Alternative Medicine), Alt HealthWatch, Pre-CINAHL, CINAHL และ the Nursing and Allied Health Collection รวมถึงการสืบคนขอมูลท่ีไมไดเผยแพร และการศึกษาที่อยูระหวางการดําเนินการโดยผานทางเว็บไซต clinicaltrials.gov และ National Research Register ของประเทศอังกฤษ การศึกษาทั้งหมดเปนชนิด randomized controlled trial ที่ใช EDTA ในผูที่มีความเสี่ยงตอโรคหลอดเลือดหัวใจ การศึกษาที่เปน non-randomized trials และการวิจัยดานเภสัชจลศาสตร (pharmacokinetic studies) จะถูกคัดออก การศึกษาที่ผานการคัดเลือกเขามาจํานวน 7 เรื่องโดยเปนการศึกษาที่สามารถนํามาทบทวนอยางเปนระบบได 5 เรื่อง (2 เรื่องเปนการนําขอมูลจากการศึกษาใหญมาแยกวิเคราะห) การศึกษาวิจัยที่คัดเขามาในการทบทวนอยางเปนระบบดําเนินการในประเทศสหรัฐอเมริกา แคนาดา เดนมารก

9 นิวซีแลนด และเยอรมัน ผลการศึกษาพบวามี 2 การศึกษา (n = 19) ที่แสดงวาการใช EDTA เปน Chelation agent ไดประโยชนในโรคหลอดเลือดหัวใจ ขณะที่อีก 3 การศึกษา (n = 269) ใหผลตรงขาม ผลขางเคียงที่เชื่อวาเกิดจาก EDTA คือ พิษตอไต (kidney toxicity) 1 ราย วิงเวียนเปนลม 8 ราย (อยูในกลุมควบคุม 2 ราย) แคลเซียมในเลือดต่ํา 12 ราย (อยูในกลุมควบคุม 1 ราย)

2.7 Chappell21 ไดทบทวนวรรณกรรมเผยแพร (ป 2007) ในประเด็นการใช EDTA ที่ใชเปน Chelation therapy แทนท่ีการใช clopidogrel รวมกับ aspirin ในการรักษาผูปวยที่มีความเสี่ยงจากการใสสายสวนหลอดเลือดชนิดเคลือบยา (drug-eluting stents) ภายหลังการทําหัตถการ PTCA (percutaneous transluminal coronary angioplasty) เพื่อปองกันการจับตัวของ thrombin ซึ่งจะทําใหหลอดเลือดหัวใจกลับมาตีบไดอีก ผลการทบทวนพบหลักฐานการทํา Chelation therapy ดวย EDTA อาจปองกันการจับเปนลิ่มเลือดซ่ึงเปนผลมาจากการใส stent ได อยางไรก็ตามขอมูลในสวนนี้ยังมีจํากัด บางการศึกษาเปนลักษณะ retrospective การศึกษาที่เปน meta-analysis ไมไดใชขอมูลที่เปน RCT ทําใหความนาเชื่อถือของการศึกษาลดลง ผูวิจยัระบุวาไมพบผลท่ีไมพึงประสงคจากการให EDTA

สําหรับขอมูลการศึกษามีท่ีสนับสนุนวาการให EDTA ทางหลอดเลือดดําแลวเกิดประโยชนในการรักษาโรคหลอดเลือดหัวใจ ในขณะที่อีกหลายการศึกษาใหผลในทางตรงขาม ผูวิจัยใหความเห็นวาการศึกษาวิจัยตางๆ เหลานี้วามีอํานาจการทดสอบต่ํา หลายการศึกษาไมมีการควบคุม รวมถึงการสุมกลุมตัวอยางไมมีคุณภาพ และบางการศึกษามีการเลือกรายงานผล ซึ่งไมไดตามเกณฑกําหนดของโครงการวิจัยท่ีไดรับทุนสนับสนุนจาก National Institutes of Health (NIH) เพ่ือประเมิน Chelation therapy (Trial to Access Chelation Therapy, TACT)

สรุปผล อภิปรายและขอเสนอแนะ

การศึกษาตางๆ มีทั้งสนับสนุนและคัดคานประสิทธิผลของ Chelation therary สําหรับโรคหลอดเลือดหัวใจ ประเด็นที่นาสนใจคือเอกสารวิชาการที่ระบุวา Chelation therapy ไมเกิดประโยชนจะเปนลักษณะการศึกษาที่เปนการทบทวนอยางเปนระบบ (systematic review) จากเอกสารที่เปน RCT และเอกสารที่เปนการวิจัยทางคลินิกท่ีมีการสุมเลือกกลุมศึกษาและกลุมเปรียบเทียบ (randomized controlled trial, RCT)15-20 ในขณะที่มีรายงานถึงผลอันไมพึงประสงคของ Chelation therapy จาก EDTA ที่พบในการศึกษาเหลานี้ ไดแก พิษตอไต ชัก แคลเซียมในเลือดต่ํา น้ําตาลในเลือดต่ํา เปนตน ในขณะที่เอกสารที่สนับสนุนวา Chelation therary เกิดประโยชนนั้น เปนการทบทวนเชิงบรรยาย (narrative review) และลักษณะการรายงานผูปวยเปนสวนใหญ21-23 และเปนท่ีนาสังเกตวาผูที่รายงานไวในการศึกษาวา EDTA ไดผลในการปองกันโรคหัวใจเปนผูรวมวิจัยอยูใน TACT ดวย21 ซ่ึงตองพิจารณาประเด็น conflict of interest ของผูวิจัยรวมดวยไวดวย นอกจากนี้เอกสารขอมูลการศึกษาวิจัยเกี่ยวกับประสิทธิผลของ Chelation therapy

10 มีการวัดผลลัพธของการปองกัน/ รักษาโรคหัวใจท่ีแตกตางกัน ซ่ึงไมไดเปนการวัดผลของ EDTA ที่มีผลตอหัวใจโดยตรง การเปรียบเทียบผลระหวางการศึกษาจึงทําไดยาก และการวัดผลลัพธดวยวิธีตางๆ อาจไมสะทอนความจริงในส่ิงที่ตองการวัดได

การศึกษาวิจัยเกี่ยวกับ Chelation therapy ในลักษณะ RCT ดวยระเบียบวิธีวิจัยท่ีดี มีผูเขารวมโครงการจํานวนเพียงพอ เพื่อใหไดขอมูลที่ถูกตองถึงประสิทธิผลและผลขางเคียงของ Chelation therapy ไดแก การศึกษา Trial to Access Chelation Therapy (TACT)24-25 ซ่ึงไดรับทุนสนับสนุนการวิจัยจาก National Institutes of Health (NIH) ดําเนินการวิจัยในหนวยงานประมาณ100 แหงในประเทศสหรัฐอเมริกาโดยเริ่มการศึกษาในป ค.ศ. 2003 และคาดการณวาจะแลวเสร็จสมบูรณในป ค.ศ. 2012 การวิจัยเปนลักษณะ RCT โดยใหผูปวยจะไดรับ Na2EDTA (disodium ethylenediamine tetraacetic acid) เขาทางหลอดเลือดดําเพิ่มจากการรักษามาตรฐาน เพื่อศึกษาวาผูปวยที่มีภาวะกลามเนื้อหัวใจตายมากอนจะเกิดอาการของโรคหัวใจและเสียชีวิตในกลุมใดมากกวากันระหวางกลุมที่ไดรับ Chelation therapy รวมกับการรักษาตามมาตรฐานเปรียบเทียบกับการรักษาตามที่กําหนดในมาตรฐานการรักษาเพียงอยางเดียว การศึกษานี้ยังไมแลวเสร็จสมบูรณ แตมีรายงานเบื้องตนวา EDTA อาจมีประสิทธิผลในการปองกันภาวะผิดปรกติของหัวใจในผูที่เปนโรคหลอดเลือด21 อยางไรก็ตาม Atwood26 และคณะไดรายงานไวในป ค.ศ.2008 วา American College Advanced of Medicine (ACAM) ใชความสัมพันธดานการเมืองกดดันให NIH ใหทุนในสนับสนุนการศึกษาวิจัย TACT ในโครงรางวิจัย (protocol) ใหเหตุผลและความจําเปนในการศึกษาบนพื้นฐานการแสดงรายงานการศึกษาผูปวยผิดพลาด โดยมองขามความเสี่ยงที่มีหลักฐานชัดเจน ผูวิจัยรวมในโครงการประมาณ 100 คนไมมีความเหมาะสม การศึกษาขาดการแจงถึงความเสี่ยงขั้นต่ําท่ีสําคัญ แบบแสดงความจํานงการเขารวมโครงการสะทอนใหเห็นขอบกพรองและความลมเหลวในการเปดเผยการมีสวนไดสวนเสียจากการวิจัย รวมถึงผลลัพธของการศึกษาไมมีความนาเชื่อถือ และสวนใหญยังมีขอนากังขา ในประเด็นตรงขาม Clay27 ใหความเห็นวา TACT สมควรดําเนินการตอไป หากจะหยุดการศึกษาวิจัยควรเปนเหตุผลที่วา Chelation therapy ไมสามารถชวยชีวิตผูปวยไวไดจริง อยางไรก็ตาม หากการวิจัยเปนไปตามหลักการปฏิบัติการวิจัยทางคลินิกที่ดี (good clinical practice, GCP) 28 เปนมาตรฐานสากลดานจริยธรรมและดานวิชาการ โดยมีการตรวจสอบอยางเปนระบบ ท้ังการกํากับ (monitor) การตรวจสอบ (audit) และการตรวจตรา (inspection) ซึ่งในแตละขั้นตอนอาจแสดงใหเห็นถึงคุณภาพของการศึกษาวิจัยวาถูกตองและเหมาะสมตาม GCP ผลการวิจัยทางคลินิกก็นาจะเชื่อถือได การวิจัยที่ดีตองสามารถตรวจสอบได

คําแนะนําสําหรับการศึกษาสวนใหญระบุวา ยังไมมีเอกสารทางวิทยาศาสตรที่ชัดเจนในการแนะนําใหผูปวยเลือก Chelation therapy ในการรักษาโรคหัวใจ ดังนั้น แพทยควรใหขอมูลที่ถูกตองนาเชื่อถือเทาที่มีอยูในปจจุบันโดยปราศจากผลประโยชนแอบแฝง อาทิ การไดคาตอบแทนในการสงผูปวยไปรักษาดวยวิธีดังกลาว หรือแพทยเปนเจาของ/ หุนสวนของ Chelation therapy เปนตน ผูปวยควรไดรับทราบถึง

11 ประสิทธิผลของ Chelation therapy คาใชจายที่ผูปวยตองเสียไป รวมถึงภาวะแทรกซอนที่อาจเกิดขึ้นเนื่องจากการทํา Chelation therapy จัดไดวาเปนวิธีการที่อาจกอใหเกิดอันตรายตอผูปวยได

เอกสารอางอิง

1. Wikipedia. Chelation therapy. URL: http://en.wikipedia.org/wiki/Chelation_therapy. (accessed 21/06/2010).

2. American Cancer Society. Chelation therapy. Available from: URL:http://www.cancer.org/docroot/eto/content/eto_5_3x_chelation_therapy.asp. (accessed 21/06/2010).

3. Tabangcura D, Daubert GP. British anti-Lewisite. Available from: URL:http://www.chm.bris.ac.uk/motm/bal/index.html. (accessed 21/06/2010).

4. Wisegeek. What is chelation therapy? Available from: URL:http://www.wisegeek.com/what-is-chelation-therapy.htm. (accessed 21/06/2010).

5. Green S. Chelation therapy: unproven claims and unsound theories. Available from: URL:http://www.quackwatch.org/01QuackeryRelatedTopics/chelation.html. (accessed 21/06/2010).

6. Healthline. Chelation Therapy. Available from: URL:http://www.healthline.com/natstandardcontent/alt-edta-therapy?print=true. (accessed 21/06/2010).

7. Wellness.com. Chelation (EDTA) therapy. Available from: URL:http://www.wellness.com/reference/healthwellness/chelation-edta-therapy/general-information. (accessed 21/06/2010).

8. American Heart Association. Chelation therapy: AHA recommendation. Available from: URL:http://www.americanheart.org/presenter.jhtml?identifier=4493 (accessed June 14, 2010).

9. Anand A, Evans MF. Dose chelation therapy work for ischemic heart disease? Can Fam Physician. 2003 Mar;49:307-9.

10. Assistant Secretary of Legislation (ALS). Department of Health and Human Services. Statement on chelation therapy. Available from: URL:http://www.hhs.gov/asl/testify/t990310a.html. (accessed 21/06/2010).

11. Lamas GA, Hussein SJ. EDTA chelation therapy meets evidence-based medicine. Complement Ther Clin Pract 2006;12:213-5.

12 12. Center of Disease Control and Prevention. Deaths associated with hypocalcemia from chelation

therapy --- Texas, Pennsylvania, and Oregon, 2003—2005. Available from: URL:http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5508a3.htm. (accessed 21/06/2010).

13. The Medical News. Chelation therapy side effects. Available from: URL:http://www.news-medical.net/health/Chelation-Therapy-Side-Effects.aspx. (accessed 21/06/2010).

14. Chappell LT. Applications of EDTA chelation therapy. Altern Med Rev 1997;2(6):426-32. 15. Lewin MR. Chelation therapy for cardiovascular disease. Tex Heart Inst J 1997;24(2):81-9. 16. Ernst E. Chelation therapy for coronary heart disease: An overview of all clinical investigations. Am

Heart J 2000;140:139-41. 17. Knudtson ML, Wyse DG, Galbraith PD, Brant R, Hildebrand K, Paterson D, et al. Chelation therapy

for ischemic heart disease: a randomized controlled trial. JAMA 2002;287(4):481-6. 18. Anderson TJ, Hubacek J, Wyse G, Knudtson ML. Effect of chelation therapy on endothelial function

in patients with coronary artery disease: PATCH substudy. J Am Coll Cardiol 2003;41(3):420-5. 19. Dans AL, Tan FN, Villarruz-Sulit EC. Chelation therapy for atherosclerotic cardiovascular disease.

Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002785. DOI: 10.1002/14651858.CD002785.

20. Seely DMR, Wu P, Mills EJ. EDTA chelation therapy for cardiovascular disease: a systematic review. BMC Cardiovascular Disorders 2005,5:32.

21. Chappell LT. Should EDTA chelation therapy be used instead of long-term clopidogrel plus aspirin to treat patients at risk from drug-eluting stents. Altern Med Rev 2007;12(2):152-8.

22. Quan H, Galbraith PD, Norris CM, Southern DA, King K, Verhoef MJ, et al. Opinions on chelation therapy in patients undergoing coronary angiography: cross-sectional survey. Can J Cardiol. 2007;23(8):635-40.

23. Quan H, Ghali WA, Verhoef MJ, Norris CM, Galbraith PD, Knudtson ML. Use of chelation therapy after coronary angiography. Am J Med 2001;111:686-91.

24. U.S. National Institute of Health. Trial to Assess Chelation Therapy (TACT). Available from: URL:http://clinicaltrials.gov/ct2/show/NCT00044213. (accessed 21/06/2010).

25. NIH Guide. EDTA chelation therapy for coronary artery disease. Available from: URL:http://grants.nih.gov/grants/guide/rfa-files/RFA-AT-01-004.html. (accessed 21/06/2010).

26. Atwood KC, Woeckner E, Baratz RS, Sampson WI. Why the NIH trial to assess chelation therapy (TACT) should be abandoned. Medscape J Med 2008;10(5):115.

13 27. Clay B. Study of chelation therapy should not be abandoned. Journal of American Physicians and

Surgeons 2009;14(2):52-7. 28. สํานักงานคณะกรรมการอาหารและยา กระทรวงสาธารณสุข. ICH Good clinical practice (ฉบับ

ภาษาไทย); 2543.

ภาคผนวก

Chelation Therapy for Cardiovascular Disease Review and Commentary

Matthew R. Lewin

Chelation Therapy forCardiovascular DiseaseReview and Commentary

Matthew R. Lewin T wo years ago, C. Richard Conti, in his capacity as editor-in-chief of Clini-cal Cardiology, wrote a brief editorial on chelation therapy for athero-sclerosis.' His conclusion ("I counsel all patients who ask me about this

therapy not to seek out individuals who prescribe it") was not startling, given thealmost total absence of scientific evidence in support of the treatment. What didsurprise me was the need for such an editorial in 1995, after the adoption of a

dozen formal position statements by medical organizations* and the federal gov-

ernment. Dr. Conti acted, he explained, at the request of a cardiology colleague,and after having been asked by a number of his patients about the value of che-lation therapy for coronary heart disease.A surprisingly large number of people in the United States seek out unproven

and potentially harmful alternative therapies. A 1993 study published in the NewEnglandJournal ofMedicine7 suggested that each year Americans make more

than 400 million visits to providers of unconventional therapies, a number greaterthan the total number of visits to all primary care physicians. The annual out-of-pocket expenditure has been estimated to be $10 billion.8

In order to answer patients' questions about chelation therapy, a physicianshould know a few things about chelators: their history, their method of action,and their confirmed (and unconfirmed) medical applications.

Background

Mr. Lewin is in his 5th yearof training in the combinedMD/PhD Program of theUniversity of Texas MedicalSchool at Houston. Hereceived his BS degree inentomology (1991) from theUniversity of Californiaat Berkeley.

Key words: Alternativemedicine/utilization; athero-sclerosis/drug therapy;chelation therapy; chelatingagents; edetic acid/adminis-tration & dosage; edetic acid/adverse effects; edetic acid/therapeutic use; history ofmedicine, modern; Versene

Address for reprints:Matthew R. Lewin,Department of IntegrativeBiology, MSB 4. 100,University of TexasMedical School,6431 Fannin Street,Houston, TX 77030

Chelation therapy usually involves a series of slow-drip, intravenous infusions ofthe synthetic amino acid EDTA (ethylenediamine tetraacetic acid).** For many

years, EDTA has been approved by the Food and Drug Administration for use inthe treatment of some types of heavy metal poisoning (e.g., inorganic lead); andit was used in the treatment of digitalis poisoning until antibody fragments tookits place. The term chelate was coined by analytical chemist G.T. Morgan in 1920;10it comes from the Greek chela, or "claw," which refers to the claw-like chemical

structure of the compound (Fig. 1). In chelation, a metallic ion is sequesteredand firnnly bound into a ring within the chelating molecule. Alfred Werner was

awarded the 1913 Nobel Prize in chemistry for developing this concept."Natural Chelators. Naturally occurring chelating agents, such as citrate, were

among the 1st used in medicine. According to Jones,'2 the 1st modern medicalexploitation of the properties of chelation occurred in 1917, with the use of tar-trate'2-and then, in 1925, of tironl3-to reduce the toxicity of antimonial-basedantiparasitic agents used against diseases such as schistosomiasis.'3 In a 1938 pub-

lication, Health Hazards in the Plating Shop: Some Suggestionsfor TheirElimina-tion,'4 F.M. Carlsen proposed the empiric use of "fruit juices" for the treatment ofnickel-induced eczema. In 1943, Kety and Letonoff"5 explored the use of sodiumcitrate to reduce the lead burden in human beings.

Synthetic Chelators. Synthetic chelators are abundant and serve as useful ana-

lytical and biochemical tools. By the time chemist Ferdinand Munz, at the Ger-

There have been, for example, statements (advising against chelation therapy for cardiovascular dis-ease) by the American Medical Association (1984),2 the American College of Cardiology (1984),3 theAmerican Heart Association (1985),4 the American Osteopathic Association (1990),5 and the Ameri-can Academy of Family Physicians (1993).6

"Also called Versene (or calcium disodium versenate9).

Chelation Therapy for Cardiovascular Disease 81

GuestEditorial

Texas Heart Instituteiournal

0 0

NaOCCH2 C-C CH2CONa

k ECaX

Fig. 1 Ethylenediamine tetraacetic acid effectively binds di-and trivalent cations, forming a stable ring. Here it has boundcalcium, to form edetate calcium disodium.

man company General Aniline, received the U.S.patent for the structure, synthesis, and applicationof EDTA in 1938 (Fig. 2),16 there was already a richtradition in analytical chemistry surrounding chelat-ing compounds. Synthetic methods such as the onesdeveloped by Manz16 in the 1930s and Bersworth'7'18in the 1940s ameliorated the chief disadvantages ofearlier synthetic methods, i.e., low yields and therelease of free hydrogen cyanide.19 Applications forchelating compounds already considered or in useby the late 1930s included the study of metal ions inbiochemical systems such as chlorophyll and hemo-globin. Such compounds helped settle questions re-lated to stereochemistry in organic systems, to thetheory and practice of mordant dyeing, and to phar-maceutical preparations.20

Medical Applications of Chelation. A syntheticcompound, dimercaprol (Fig. 3), better known asBritish antilewisite (BAL), was introduced in 1945 byPeters and coworkers21 as a remedy for military ar-senical blisters and systemic arsenic poisoning fromthe war gas lewisite.21'22 It was soon found to beuseful against other heavy metal poisonings, such asthat caused by mercury. The introduction of EDTA-based chelating agents to combat heavy metal poi-soning was a tremendous advance in toxicology. Toput the impact of this new technology in perspec-tive, one has only to remember that the 1st editionof Goodman and Gilman's The PharmacologicalBasis of Therapeutics, published in 1941, states thefollowing objective in the treatment of lead poison-ing: "the main objective ... is to drive the lead fromthe circulation and deposit it in the bones.... 23

In the 1950s and 1960s, there was an explosion ofpublications on the effects of various chelatingagents in animals and human beings. By 1951, EDTAwas being used for the treatment of inorganic leadpoisoning24'25 and was under investigation as a toolto treat hypercalcemia26-28 and even radiation poison-ing from plutonium.29 Contemporary discoveries inthe field of cancer chemotherapy spawned an im-mense body of investigation (over 600 papers30) on

the potential of chelation-based therapies, includingEDTA.Two new areas in which chelating agents are of

interest in the medical community today are cere-brovascular physiology and neurobiology. The in-vention of membrane-permeant analogs of EDTAand related compounds (e.g., BAPTA-AM and EGTA-AM*) has opened new frontiers in these areas ofresearch. First synthesized in 1975 by Roger Tsien31as an analytical reagent, BAPTA-AM has since beenstudied by Tymianski and coworkers to determinethe mechanisms by which calcium ion chelators re-duce early excitotoxic and ischemic neuronal injuryin vitro and in vivo.32'33 As in the past, EDTA-basedchelating agents are interesting and powerftil ana-lytical and research tools. Applications for cell-permeant analogs of calcium ion chelators may inthe future have a major impact on a wide range ofmedical specialties, including neurosurgery, traumacare, cardiology, and (especially) cardiovascularsurgery. I anticipate that a significant applicationfor membrane-permeant calcium chelators will beprophylactic reduction in the activity of calcium-dependent enzymes thought to be important in post-ischemic pathology, especially iatrogenic types. Thesehypotheses will need to be tested rigorously, in acontrolled scientific setting.

CardiovascularApplications of EDTA

This brings us to the cardiovascular applications ofchelators. At present, the clinically proven applica-tions are few. Over 3 decades ago, EDTA was exam-ined as a tool to treat certain arrhythmias anddigitalis poisoning. By 1964, there was widespreadagreement that EDTA was useful in the managementof digitalis poisoning and in the suppression of ven-tricular premature contractions in the emergencysetting.34-36

In 1955, Clarke, Clarke, and Mosher introducedthe possibility that EDTA could be used as a treat-ment for atherosclerotic heart disease.37 Twenty-twopatients were treated with EDTA for a variety ofreasons; these included several patients who werereceiving EDTA experimentally in an effort to deter-mine its effects on serum calcium. Particular atten-tion was given to the case history of 1 patient undertreatment for progressively worsening bilateral neph-rocalcinosis. The apparent salutary effects of EDTAon this patient included improved hearing and im-provement of digestive symptoms. The authors pre-sented radiographic evidence of improvement in this

* 1,2-bis-(2-amino-phenoxy)ethane-N,N,N'N'-tetraacetic acid ace-toxymethyl ester (BAPTA-AM) and ethylene glycol-bis(heta-aminoethyl ether)-N,N,N'.N'-tetraacetic acid acetoxymethyl ester(EGTA-AM)

82 Chelation Therapy for Cardiovascular Disease Voltime 24, Ntiniber 2, 1997

Patented Sept. 20, 1938 2130,505

UNITED STATES PATENT OFFICE239,505

IOLYAMO CAPDOZThIC ACIDS ANDPROCESS OF WANING SAME

FeeUnnad MAns, Framkort-on-the-M-l- Ger-nan. amdsut to Genera A Works, Inc.,Nw YoTrk N. T.. corporatim of Ieawar

No Drawing. aplicton October 22.1936. Ser We 107.020. Divided and this ap-flcadon April 2, 1927, SerIa No. 134,737. In

Germany October 30, 19352 (CL 260-634)

This applicaton is a dlvision of my copendlUgapplication Ser. No. 107,020, fWed October 22.1936, whlch relates to the use of amino poly-carboxylic acids for avoidlng and rendering

* harmess the precipitates of water-inoluble metalsalts, particularly formed owing to the hardnessof water.My present Imvention relates to PolYamino car-

boxyllc ac-ids and a Drocess of making same." Trbey are obtainable by actIng with monochoro

acetic acld on a poly-mine.As a Dolyamine from which the carboxylic acids

are derived, there may be mentioned partcularlyethylene dlamrine.

US In thi manner polyamlno-polycarboxyllc acidsare obtained which correspond to the gent siformula:

HOOCHEC CHSCOOX20 --

HOOCHI,C ,cHCOoMwhereia R stands for a lower al lene radlcle.The following exa&npe wi further Illustrate

how the said invention may be carried out in25 practice, but the invenUon is not rtricted to thi

example. The parts are by wreightzampte

60 parts of ethylene diam_lne in an aquec-"

solutlon of 10% strent are mixed with 466 partsof the sodium sat of monochloraceUc acld and212 parts of sodum carbonate and the mixture isheated at 90 to 95 C. for 8 to 10 hours. Then 470parts of a hydrochloric acid of 20' BE. are added.Whe cool an acid of the formula:

HOOC.U3OCH, ICO0H

RoOC.n.C-11 CHOCOOB tprecipitates, which is scarcely soluble in waterand may be recrystallied from water.I claim:1. Polyam.ino polycarboylic acsds correspond-

lng to the formula: isEOoCI:K,O C8.COOH

\N-R

HIOOCH3C CHICOOHwherein R standx for a lower alIylene radicle. 20

2. A polycarboxyc acJd of the formula:HOOC-HgC CHSCO,OBI

aOOCHaC CHculcooH 25which Is scarcely soluble ln water and may be re-crystallized from water.

PERDNAND MtZN.

Fig. 2 United States patent for ethylenediamine tetraacetic acid.

patient's kidney stones and implied that this wasdirect evidence of the removal of metastatic calcium.Their protocol included intravenous administrationof 5 grams of EDTA in 500 cc of normal saline or 5%glucose over a period of 4 hours. Each patient wasgiven 12 to 20 infusions over a 2- or 3-week period.The authors anticipated a mechanism by whichEDTA might preferentially remove metastatic cal-

H H HI I

H-C-C-C-Hl ISH SH OH

Fig. 3 Structure of the metal complexing agent dimercaprol(BAL).

cium, and their discussion focused on the possibleinterrelationship between the calcium and the cho-lesterol found in atheromatous plaques. They con-cluded that EDTA was worthy of further study andmentioned that they were investigating the effect ofEDTA on angina pectoris in some patients from thissame group and in additional patients. These resultswould be published later.

Indeed, in "Treatment of Angina Pectoris with Di-sodium EDTA" (1956),38 Clarke, Clarke, and Mosherreported that anginal symptoms, following treatmentin accordance with their EDTA protocol, improvedin 19 of 20 patients with coronary artery and periph-eral occlusive disease. They cited 2 chest radio-graphs (1 showing mitral valve calcification) asevidence in support of their hypothesis, but they didnot publish the radiographic images. At physiologic

Chelation Therapy for Cardiovascular Disease 83Te-vas Heart Institidejournal

pH, the sodium salt of EDTA is an effective chelatorof calcium. It was this observation, and the observa-tion by others that calcium and cholesterol are asso-ciated in the structure of atherosclerotic plaques,that led Clarke, Clarke, and Mosher to hypothesizethat EDTA could dissolve disease-causing plaques inthe coronary systems of human beings.38The 1st controlled clinical trial of EDTA chelation

therapy for cardiovascular disease, conducted byKitchell and associates in 1963,39 was subtitled "AReappraisal," in reference to their earlier (1961) workwith EDTA in human subjects.40 In 1961, they hadexamined 10 patients with angina and reportedsubjective improvement of anginal symptoms in 9patients. In the 1963 clinical study, the authors per-formed follow-up on 28 patients with angina whoreceived EDTA for at least 20 treatments. Nine otherpatients were in a double-blinded, cross-over wingof the study. Of these 9, 4 were treated with EDTAand 2 of the treated patients reported subjectiveimprovement of their symptoms after 3 months. Af-ter 18 months, 7 (25%) of the 28 patients receivingEDTA were dead, 2 (7%) were "worse," 6 (22%) were"the same," and the remaining 13 (46%) were "im-proved." They concluded, "At present we believethat chelation as used in this study did not benefitpatients more than other commonly used therapeu-tic methods. It is not a useful clinical tool in the treat-ment of coronary heart disease at the present time."To date, in the English-language medical litera-

ture, there has been only 1 other controlled clinicaltrial evaluating the efficacy of EDTA in cardiovascu-lar disease. The trial conducted by Guldager andcolleagues4' is the only placebo-controlled, double-blind study with random patient allocation. One ofthe endpoints studied was symptomatic relief ofstable, intermittent claudication. Other endpointswere pain-free walking distance on the treadmill andmaximum walking distance. One hundred fifty-threepatients who averaged 65 ± 9 years in age were ran-domized to receive 20 infusions of EDTA over a 5-to 9-week period, in accordance with a regimensimilar to those used by Clarke's group and others'3839in the 1950s and 1960s. No difference between theplacebo and treatment groups was noted in any cat-egory investigated.

Although there has been a paucity of controlledclinical trials, case-report series are abundant, andthere have been 2 open-label longitudinal studiesand 1 open-label clinical trial. I surveyed 12 consecu-tive case reports3 "'42-50 that specifically examinedthe apparent effect of EDTA on the symptoms andsigns of peripheral vascular disease, coronary arterydisease, or both. There were a total of 2,217 patientstreated with EDTA. Improvement was reported for2,060 (93%) of patients. Of these, the most notableis the open-label clinical trial published by Olszewer

and Carter47 in 1988. This study enrolled 1,974consecutive patients and reported its results in quali-tative terms, such as "marked" or "good" improve-ment. Ninety-four percent of patients with ischemicheart disease treated with EDTA chelation therapyhad marked or good improvement (77% and 17%,respectively), and 97% with peripheral vascular dis-ease had marked or good improvement (91% and6%, respectively). An excellent, detailed review of allcase reports and trials was published by Grier andMeyers in 1993.5lCommon criticisms of the data that appear to sup-

port EDTA chelation therapy for cardiovascular dis-ease have included: small sample sizes, open-labelformats, and the qualitative rather than quantitativemeans by which most studies have evaluated treat-ment outcomes. In addition, while there have beenrelatively few fatalities directly attributable to EDTAinfusions,"5 other adverse effects have been manyand varied.9 The most commonly reported adverseeffect is pain or burning at the site of infusion.41Moreover, EDTA has been reported to have toxiceffects on the kidney,9'51'52 sometimes causing proxi-mal tubule damage, and has been associated withhypoglycemia, malaise, gastrointestinal symptoms,T-wave inversion, dermatitis, and hypocalcemicsymptoms such as tetany.9'41'51The 1963 clinical trial by Kitchell39 was the 1st

published study that was critical of the EDTA proto-col for atherosclerosis. In fact, other than the Kitchellstudy, there appears to have been little enthusiasmor interest in this experimental therapeutic modalityin the 1960s, when only 2 small case report serieswere published (by Lamar, in 1964 and 1966).4445 Bythe early 1970s, interest in EDTA chelation therapyfor cardiovascular disease had pretty much fadedamong most members of the medical and scientificcommunity.

In 1973, however, the American College for Ad-vancement in Medicine (ACAM) was founded withthe purpose, in part, of promoting chelation ther-apy.53 This group, which comprises about 750 li-censed physicians, sponsors certification programsand publishes the Journal ofAdvancement in Medi-cine. It also has an easily accessible web site on theInternet. The ACAM organization has published pro-tocols for the administration of EDTA, which call forinfusions of 50 mg per kilogram of body weight. Thisis similar to doses used in early studies.37'8 However,ACAM has made many modifications and additions.These include the use of heparin, B-complex vita-mins, and megadoses of vitamin C and other vita-min and mineral supplements. Infusions are givenseveral times per week, and a complete course oftherapy can include 20 to 40 trips to the doctor at acost ranging from $1,600 to $4,000, or $80 to $100dollars per treatment. These are not covered by any

84 Chelation Therapy for Cardiovascular Disease Volume 24, Number 2, 1997

insurance companies. Additionally, lifestyle- and diet-modification programs (not dissimilar to those de-veloped, published, and validated by Dean Ornish,Larry Scherwitz, and Lance Gould and coworkersduring the last 2 decades) are encouraged to com-plete this therapy.5455

Claims regarding the benefits of EDTA havegrown since the 1950s and 1960s. Dozens of bookshave been published by proponents of chelationtherapy. These claims include, but are not limited to,the treatment and prevention of atherosclerosis,coronary heart disease, angina, and peripheral vas-cular disease, the reduction of blood viscosity andfree-radical formation, and the slowing of the agingprocess. Claims also include "increased" sexual func-tion,5657 improved mental and other nervous systemfunction, and relief of all types of arthritis and evenlupus.56 Seldom are there claims of directly antineo-plastic activities.

Proposed Mechanisms ofAction. Since the intro-duction of EDTA as a potential treatment for cardio-vascular disease, proponents of this therapy haveput forward several hypotheses to explain its mecha-nism of action. Among the earliest was the conceptthat if calcium were removed from the atheroscle-rotic plaque, the plaque would disintegrate, thus im-proving the patency of the arteries. In The ChelationAnswer (1982)58 and The Chelation Way (1990),59Morton Walker explains that parathyroid dysfunctioncauses precipitation of calcium into the vasculatureand other tissue. Chelation removes this calcium.Leading chelation therapy proponent Elmer Crantonproposes in his 1990 book, Bypassing Bypass,60 thatEDTA blocks the generation of free radicals impli-cated both in lipid peroxidation and in the chain ofevents leading to atherogenesis. Because free radi-cals have been implicated as a final common path-way in so many pathological processes, the expan-sion of claims regarding EDTA's applications hasbeen dramatic.

patent on the compound ran out in the 1940s.5' (Infact, there are several thousand patents on the medi-cal and pharmaceutical uses of EDTA.) Other pro-ponents accuse surgeons of suppressing chelationtherapy in order to keep their wards filled with rev-enue-generating bypass patients. The Internet hasbecome an efficient and cheap way for practitionersof alternative medicine to promote their therapieswith no regulation.

In 1954, Irvine H. Page6" outlined several meth-ods of combating atherogenesis that he deemedworthy of further investigation. He described mostothers as "tentative thrusts into the unknown, somecapable of being built upon, most too weak to sup-port a superstructure." He followed with a warningabout the growing open market for preventivehealth products: "none are of proved value and fewhave even any semblance of experimental evidenceto support their use as a treatment or prophylacticin atherosclerosis. Their recommendation is basedon the philosophy that they do no harm and mightdo good. This is an expensive and elusive philoso-phy, seldom contributing to the advancement ofsound therapeutics, and greatly contributing to logi-cal delinquency in the minds of the prescribing phy-sician...." His words were prophetic.

TABLE 1. Excerpts from a Popular Booklet on ChelationTherapy56

A Partial List of the Benefits of Chelation Therapy

Improves liver function

Lowers blood cholesterolLowers blood fatsReduces blood pressureImproves coronary circulationReduces heart irritabilityReduces strong heart beatsRelieves signs of senility

Removes excessive irondeposits

Heals poor circulation ulcersReduces leg crampsImproves visionImproves varicose veins,

pigmentationRelieves angina pectoris

Commentary Diseases Aided by Chelation Therapy

None of the claims listed above has been publishedin peer-reviewed scientific literature, but they arelegion in books and flyers published by the alterna-tive medicine community (Table I). Moreover, a cur-sory search of World Wide Web sites on any ofseveral servers will pull up several hundred chela-tion therapy web sites. Of the hundred or so that Ivisited (Table II), only 2 sites were for skeptics and1 was a statement from the American Heart Associa-tion (Fig. 4). Indeed many of the sources that I re-viewed have a common complaint: the existence ofa conspiracy to suppress EDTA-based treatments.Many cite the lack of financial incentive for phar-maceutical companies to produce EDTA, since the

Angina pectorisCoronary arteriosclerosisPsoriasisThrombophlebitisVenom bitesParkinson's diseaseLead toxicity

SclerodermaHypoglycemiaCerebral degenerationLupusDiabetic gangreneArteriosclerosis

[The inside front cover, however, bears the following caveat:"This booklet is intended only for informational purposes. Itonly advises people to question and learn for themselves thatthere are other treatments and methods available. The authorand publisher make no medical claim direct or implied. Thereader should consult a licensed physician for any conditionthat requires his services. "561

Chelation Therapy for Cardiovascular Disease 85Texas Heart Institutejournal

TABLE 11. This is a sample of the web sites available simply by typing "chelation therapy" when using any of themore common Internet search engines, such as Alta Vista, Yahoo, or Web Crawler.

http://www.pathwaysdc.com/9-96baer.htmlhttp://www.macontel.com/data/health/thera8l 7.htmhttp://www.coos.or.us/-signal/chel2.htmhttp://www.acam.org/cict.htmlhttp://www.abchealth.com/chelatio.htmhttp://www.idsweb.com/ahma/josephs/therapy.htmhttp://www.adcomtek.com/veins/chelo.htmhttp://www.chelation.com/http://www.hrt.org/wellfac3.htmlhttp://www.ssnow.com/med2life/chelation.htmhttp://www.eurohost.com/docwelln/chelat.htmlhttp://healthy.net/clinic/therapy/chelat/intro/

Chelation therapy for cardiovascular disease hasbeen embraced by the alternative medicine commu-nity for over 30 years, despite its lack of support byclinical evidence or by logic. Grier and Meyers5'point out that almost all clinical studies of chelationtherapy are subjective and do not apply measure-ments of endpoints uniformly. Nor are there anycontrols. Such criticisms do not intimidate the pro-ponents of chelation. In The Chelation Way,59 Walkercites 2 authorities, H. Richard Casdorph, MD, PhD,and Elmer Cranton, MD, both ofwhom contend thatdouble-blind studies are unnecessary, "since eachpatient legitimately receiving chelation therapy servesas his own control."

There are many reasons for believing that thelogic of chelation therapy for atherosclerotic diseaseis flawed. Calcification of plaques is a late manifes-tation of the disease process. Moreover, the plaqueis an integral part of the arterial wall and cannot bereached by EDTA, which is water soluble and doesnot pass freely through cell membranes. The targetion for chelation therapy, Ca2l, is not the ion moststrongly bound by EDTA, which has a much greateraffinity for heavier metal ions. Although EDTA doesincrease the urinary excretion of calcium, there aresources of calcium much more abundant than ath-erosclerotic plaques-the 2 most obvious beingbone and serum.

*Then there is the newer claim that EDTA chela-tion therapy prevents the generation of free radicalsand, thereby, lipid peroxidation. This also does notmake sense, unless chelation is combined with theadministration of antioxidant vitamins such as ascor-bic acid. Even chelated, ferric iron has 2 free elec-trons available to help catalyze the formation offree radicals by participating in oxidation-reductionchemical reactions. At best, this treatment might dono harm; but at worst, it might actually generate agreater quantity of free radicals."3 (This has not been

http://www.newagemall.com/prac/WA/yelm.htmIhttp://www.envprevhealthctratl.com/chelther.htmhttp://www.acam.org/biblio.htmlhttp://www.vitawise.com/chethe.htmhttp://www.acam.org/pospaper.htmlhttp://www.acam.org/edtapapr.htmlhttp://www.acam.org/schedule.htmlhttp://mel.lib.mi.us/health/health-chelation.htmlhttp://www.amhrt.org/hs96/chelate.htmlhttp://wheel.ucdavis.edu/-btcarrol/skeptic/chelate.htmlhttp://www.quackwatch.com/01 QuackeryRelatedTopics/

chelation.html

substantiated either way.) These are but a few rea-sons, in addition to the absence of supporting clini-cal data, that chelation therapy with EDTA has facedsuch skepticism.The overwhelming majority of chelation thera-

pists promote their therapies as exceptionally safe,natural, and nontoxic. As we've already seen, this is(in the case of EDTA) patently untrue. However, therisks of serious harm from this therapy are relativelylow when the drug is administered properly to apatient with healthy kidneys.62 This has enhanced itsappeal for promoters, who incur little liability by itsuse.

In 1993, Monaco and Green63 noted that manypromoters of unproven alternative therapies warnpatients not to tell their regular doctors because"they won't understand" and will "interfere withyour trust in our program." Moreover, these practi-tioners' liberal use of recognized (but little-under-stood) scientific and medical terms creates an auraof scientific expertise that is hard to resist.63

Dozens of physicians have been disciplined bystate boards for using chelation therapy in unaccept-able ways. In Texas, for example, an osteopath usedchelation therapy in the treatment of Alzheimer'sdisease and was disciplined in 1990 for a "profes-sional failure to practice medicine in an acceptablemanner consistent with public health and welfare."*In Washington, DC, a medical doctor had his licenserevoked for using EDTA-based therapy to treat ath-erosclerosis and was told, "EDTA therapy is not anaccepted treatment modality used by competentphysicians.... the use of invalidated treatment mo-dalities demonstrates a willful or careless disregardfor the health, welfare and safety of patients...."*Many of these censured doctors are considered mar-tyrs in their professional circles.* Personal communication, Saul Green, PhD, Zol Consultants, Inc.August 1996.

86 Chelation Therapy for Cardiovascular Disease Volume 24, Number 2, 1997

*I

Heart & StrokeA-Z Guide

American HeartAssociationFigt.w et

and Sfo

CHELATION THERAPY

AHA Recommendation

The American Heart Association's Task Force on New and UnestablishedTherapies reviewNed the available literature on the use of chelation (E.D.T.A.,ethvlenediamine tetraacetic acid) in treating arteriosclerotic heart disease.They found no scientific evidence to demonstrate any benefit from this formof therapy.

The task force recoanized that there have been no adequate published trials usingcurrentlv approved scientific methodology to support this therapy.

Furthermore. usingy this form of unpro-en treatment may deprive patients of thewxell-established benefits from the many7 other valuable methods of treating thesediseases.

Fig. 4 An excerpt from the American Heart Association's recommendation in regard to chelation for the treatment of arterioscle-rotic heart disease, as it appears on the World Wide Web. Copyright © 1996 American Heart Association. Used by permission.

The Appeal ofAlternative Medicine. Unorthodoxpractitioners are not entirely to blame. The marketfor alternative medicine is a void that cries to befilled. In "Aequenimitas," his famous valedictoryaddress at the University of Pennsylvania (1889),William Osler urged new graduates to ". . restrainyour indignation when you find your pet person hastriturates of the 1000th potential in his pocket, oryou discover a case of Warner's Safe Cure in thebedroom of your favorite patient. It must needs bethat offenses of this kind come; expect them and donot be vexed." That the desperately ill will seek analternative after conventional therapies have failedis clear. But contrary to the common belief of physi-cians in the United States, most seekers of alterna-tive therapies are not terminally ill.7'64 One reason,cited by Holohan,64 for the proliferation of alterna-tive therapies among the relatively healthy is thesimple lack of professional vigilance among physi-cians: the absence of "clear, consistent, and activeopposition to such approaches" is "perceived as atleast tacit support of unorthodoxy." Perhaps evenmore significantly, people have sought alternative

therapies because they have experienced costly andimpersonal care by conventional practitioners.'65A New Zealand editorial66 regarding medicine on

the fringes commented that what is fringe to some iscentral to others and (again) cited William Osler: "Agood doctor may have practice and no theory, artand no science." Certainly science has become agreater part of the medical equation than it was acentury ago, but Osler's point should be consideredseriously in attempting to understand why manypeople prefer alternatives to conventional medicine.Some unorthodox remedies have been found to beeffective in controlled clinical trials,66 either becauseof their inherent therapeutic qualities or because oftheir elaborate placebo effects, which can help pa-tients alter their lifestyles in ways that are beneficial.

However, there are to date no scientific data tosupport the claims made by chelationists in regardto cardiovascular cures. Unfortunately, the sloppyscience behind the original assumptions and obser-vations-bolstered by the natural appeal of thehypothesis-has evolved step by step from goodintention to the cascade of poor medicine and sci-

Chelation Therapy for Cardiovascular Disease 87Texas Heart Institulejournal

air.,-g-tI rff-.Wff- "TM-A.-mr-M

ence that envelops chelation therapy today. Al-though some patients do ask their physicians aboutthis debunked therapy, most are not so forthcomingabout their interest in chelation. It is, therefore, in-cumbent upon physicians to ask patients about theiruse of alternative therapies and to discuss thesetherapies in a constructive manner.

It is probable that the majority of chelation thera-pists who uncritically advocate the purported car-diovascular applications of EDTA believe in theirpractices, just as conventional practitioners believein theirs. However, as it is practiced today, chelationtherapy for cardiovascular disease at best defies rec-ommendation and, at worst, is a direct or indirectdanger to patients. How many patients have beendeprived of safer, more efficacious therapies becausethey have sought unproven and potentially danger-ous alternative therapies? The maintenance of goodhealth, good patient care, and good scientific under-standing requires perpetual vigilance.

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11. Kauffman GB. Alfred Werner: Founder of coordinationchemistry. Berlin: Springer-Verlag, 1966.

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13. Schmidt H. Antimon in der Arzeimittelsynthese. Z AngnewChem 1930;43:963.

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29. Foreman H, Fuqua PA, Norwood WD. Experimental admin-istration of ethylenediamine-tetraacetic acid in plutoniumpoisoning. AMA Arch Ind Hyg Occup Med 1954;10:226-31.

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31. Tsien R. Special report: fluorescence imaging creates a win-dow on the cell. Chem Eng News 1994;72(July 18):34.

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36. Gubner RS, Kallman H. Treatment of digitalis toxicity bychelation of serum calcium. Am J Med Sci 1957;234:136-43.

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40. Kitchell JR, Meltzer LE, Seven MJ. Potential uses of chelationmethods in the treatment of cardiovascular diseases. ProgCardiovasc Dis 1961;3(4):338-49.

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Chelation Therapy for Cardiovascular Disease 89Texas Heart InstituteJournaI

Chelation therapy for coronary heart disease: An overview of all clinical investigations E.Ernst,MD,PhD,FRCP (Edin)Exeter.United Kingdom

MethodsFour independent, computerized literature searches were

performed, all from earliest possible available data to the endof 1998 (Medline, Embase, Cochrane Library, and CISCOM [adatabase specialized in complementary/alternative medicine]).The aim was to identify all clinical investigations of chelationtherapy for cardiovascular disease. The key words used werechelation, EDTA, ethylenediamine tetraacetic acid, edeteate,edeteate sodium, edetic acid, vascular disease, and controlledclinical trials. Publications found were screened for further rele-vant articles in their bibliographies. In particular, 2 criticalreviews5,6 and 1 meta-analysis of (mostly uncontrolled) clinicaltrials7 proved to be useful sources for further references. Inaddition, leading experts and national societies were contactedand asked for further material. Finally, my own extensive fileswere searched for relevant publications. There were norestrictions according to language of publication.

Initially, it was intended that studies would be admitted ifthey related to controlled, clinical trials of intravenous chela-tion therapy for CHD. Because of the extreme paucity of suchpublications it was subsequently decided also to include allclinical investigations into this systematic review. Data wereextracted in a predefined, standardized format (Tables I and II).

ResultsTwenty-two studies8-29 without control groups were

located (Table I). The majority of these studies werepublished in the 1960s and report subjective symptomaticimprovements in most patients. The 2 case reports thatincluded objective angiographic results25,26 showed noevidence of benefit.

Only 2 controlled clinical trials were located.17,30

Kitchell et al17 conducted a placebo-controlled, double-

See related Editorial on page 4.

Chelation therapy can be defined as the use of repeatedintravenous administration of ethylenediamine tetraaceticacid (EDTA), usually in combination with vitamins, traceelements, and iron supplements, as a treatment for a vari-ety of diseases.1

The treatment is of proven efficacy for heavy metalpoisoning.2 In “alternative” medicine it is also advocatedfor the treatment of vascular disease.3 This approach ispopular in the United States. Hundreds of thousands ofpeople currently undergo chelation therapy every year.More than 1000 US physicians support chelation ther-apy. The average cost for a course of 20 to 30 treat-ments is around $3000.4 A recent systematic review ofall randomized trials1 concluded that chelation therapyfor peripheral arterial occlusive disease is not superiorto placebo. This article addresses the question ofwhether chelation therapy is effective as a treatment forcoronary heart disease (CHD).

From the Department of Complementary Medicine, School of Postgraduate Medi-cine and Health Sciences, University of Exeter.Submitted August 16, 1999; accepted December 17, 1999.Reprint requests: E. Ernst, MD, Department of Complementary Medicine, School ofPostgraduate Medicine and Health Sciences, University of Exeter, 25 Victoria ParkRd, Exeter EX2 4NT, United Kingdom.E-mail: [email protected] © 2000 by Mosby, Inc.0002-8703/2000/$12.00 + 0 4/1/107548doi:10.1067/mhj.2000.107548

Chelation therapy for coronary heart disease: Anoverview of all clinical investigationsE. Ernst, MD, PhD, FRCP (Edin) Exeter, United Kingdom

Background Chelation therapy is popular in the United States. The question of whether it does more good than harmremains controversial.

Aim The aim of this systematic review was to summarize all the clinical evidence for or against the effectiveness and effi-cacy of chelation therapy for coronary heart disease.

Methods A thorough search strategy was implemented to retrieve all clinical investigations regardless of whether theywere controlled or uncontrolled.

Results The most striking finding is the almost total lack of convincing evidence for efficacy. Numerous case reports andcase series were found. The majority of these publications seem to indicate that chelation therapy is effective. Only 2 con-trolled clinical trials were located. They provide no evidence that chelation therapy is efficacious beyond a powerfulplacebo effect.

Conclusion Given the potential of chelation therapy to cause severe adverse effects, this treatment should now be con-sidered obsolete. (Am Heart J 2000;140:139-41.)

blind, crossover study on 9 patients with “historicallyunquestionable” CHD.17 Patients were allocated toreceive 20 injections of placebo or EDTA over 3-monthperiods. The authors fail to mention the dosage used inthis study. Therapeutic success or failure was assessedthrough performance on a treadmill. The authors didnot analyze their results statistically but explain that 2of the 4 patients receiving EDTA in the first treatmentphase “benefitted after 6 and 12 weeks.” Only 2 patientsvolunteered to be treated with EDTA in the secondtreatment phase. None of them showed any benefit.

The second controlled trial was published as anabstract only.30 16 male patients with angiographicallyverified CHD were randomly assigned to receive EDTAor placebo injections. Twenty treatments were givenevery third day and consisted of 3 to 4 g sodium EDTAor saline. In the course of this series, subjective improve-ments and an increase in physical performance were notedin both groups with no intergroup differences (numericallythe increase was larger in the placebo group). Angio-graphically there was a slow progression of the coronarysclerosis in both groups, again with no intergroupdifferences.

DiscussionThese reports collectively provide no reliable evi-

dence to suggest that chelation therapy is of benefit inCHD. Most of the uncontrolled data imply that chelation

has positive effects. These reports are consistent with apowerful placebo effect of chelation treatment. Thepower of the placebo responses in CHD is perhaps besthighlighted by the fact that sham surgery has been shownto yield symptomatic benefit in the vast majority ofCHD patients.31 When angiographic verification issought in case studies of chelation therapy,25,26 theresults are negative.

The most impressive, albeit disappointing, findingof this systematic review is the almost total lack of con-trolled clinical trials. In view of the claims made forchelation therapy and the often aggressive marketing ofthis therapy,32 this void seems embarrassing. The 2reports of controlled trials are far from being fully satis-factory. One study17 was extremely small and lackedsufficient detail for an objective assessment. The sec-ond trial30 seems to be of high methodologic standardbut has not been reported in sufficient detail to allow afair evaluation.

The risks associated with chelation therapy are sub-stantial: renal failure, arrhythmias, tetany, hypocal-cemia, hypoglycemia, hypotension, bone marrowdepression, prolonged bleeding time, convulsions,respiratory arrest, and autoimmune diseases have allbeen described.1,3,5,26,33-35 Several deaths have beenreported with little doubt about the causal role ofchelation therapy.36 Proponents of chelation therapymight argue that, with more refined treatment regimens,the problems of the early days have been overcome.

American Heart JournalJuly 2000Ernst140

Sample OutcomeReference size measures Result

Clarke et al (1955)8 22 Symptoms Some improvementsClarke et al (1956)9 20 Symptoms 19 improved, 1 diedBoyle et al (1957)10 20 Symptoms, ECG Significant improvementsClarke (1960)11 700 Symptoms 87% improvedMeltzer (1960)12 10 Symptoms, ECG 9 improved, 5 improvedClarke et al (1960)13 76 Symptoms 58 improvedKitchell et al (1961)14 10 Symptoms 9 improvedBoyle et al (1961)15 10 Symptoms, ECG 9 improvedMeltzer et al (1961)16 81 Not stated “Therapeutically effective”Kitchell et al (1963)17 28 Symptoms, ECG 18 improved, 1 died, 13 improvedLamar (1964)18 15 Symptoms 15 improvedLamar (1966)19 3 Symptoms 1 improved, 1 diedEvers (1979)20 3000 Symptoms >90% improvedAAMP (1981)21 18 Symptoms 17 improvedCasdorph (1981)22 18 Ejection fraction 17 improvedRobinson (1982)23 248 Symptoms, ECG Significant improvementsOlszewer and Carter (1988)24 844 Symptoms 821 improvedMcGillen (1988)25 1 Angiography No evidence of benefitWinebaugh et al (1990)26 1 Angiography No evidence of benefitDeycher (1992)27 215 Symptoms 70% improvementHancke and Flytlie (1992)28 42 Necessity of surgery 39 were able to cancel their surgeryHancke and Flytlie (1993)29 470 Symptoms Significant improvements

AAMP, American Academy of Medical Preventics; ECG, electrocardiogram.

Table I. Uncontrolled studies and case reports of chelation therapy for CHD

Yet, with the absence of reliable data to support it, thisnotion is unconvincing.

On balance, therefore, chelation therapy cannot berecommended as a useful treatment for CHD. Numerousuncontrolled investigations report symptomatic improve-ment, whereas the only 2 controlled trials suggest thatthese benefits are caused by placebo effects. In view ofits potential risks, chelation therapy for CHD should bediscarded in favor of therapies of proven efficacy.37

References1. Ernst E. Chelation therapy for peripheral arterial occlusive disease.

Circulation 1997;96:1031-3.2. Lin J-L, Ho H-H, Yu C-C. Chelation therapy for patients with elevated

body lead burden and progressive renal insufficiency. A randomized,controlled trial. Ann Intern Med 1999;130:7-13.

3. Chappell LT, Janson M. EDTA chelation therapy in the treatment ofvascular disease. J Cardiovasc Nurs 1996;10:78-86.

4. Holmes NH. Chelation therapy. In: Nurse’s handbook of alternativeand complementary therapies. Springhouse; 1999. p. 378.

5. Grier MT, Meyers DG. So much writing, so little science: a reviewof 37 years of literature on edetate sodium chelation therapy. AnnPharmacother 1993;27:1504-9.

6. Rathmann KL, Golightly LK. Chelation therapy of atherosclerosis.Drug Int Clin Pharm 1984;18:1000-3.

7. Chappell LT, Stahl JP. The correlation between EDTA chelation ther-apy and improvement in cardiovascular function: a meta-analysis. JAdvancement Med 1993;6:139-60.

8. Clarke NE, Clarke CN, Mosher RE. The “in vivo” dissolution ofmetastatic calcium: an approach to atherosclerosis. Am J Med Sci1955;229:142-9.

9. Clarke NE, Clarke CN, Mosher RE. Treatment of angina pectoriswith disodium EDTA. Am J Med Sci 1956;232:654-66.

10. Boyle AJ, Jasper JJ, McCormick H. Studies in human and inducedatherosclerosis employing EDTA. Bull Schw Akad Wiss1957;13:408-25.

11. Clarke NE. Arteriosclerosis, occlusive vascular disease and EDTA.Am J Cardiology 1960;2:233-6.

12. Meltzer LE. Chelation therapy. In: Seven MJ, Johnson LA, editors. Metal-binding in medicine. Philadelphia: JB Lippincott; 1960. p. 132-48.

13. Clarke NE Sr, Clarke NE Jr, Mosher RE. Treatment of occlusivevascular disease with disodium EDTA. Am J Med Sci 1960;239:732-44.

14. Kitchell JR, Meltzer LE, Seven MJ. Potential uses of chelation methodsin the treatment of cardiovascular diseases. Prog Cardiovasc Dis1961;3:338-49.

15. Boyle AJ, Clarke NE, Mosher RE, McCann DS. Chelation therapyin circulatory and sclerosing diseases. Fed Proc 1961;29:243-51.

16. Meltzer LE, Kitchell JR, Palmon F. The long-term use, side-effects,and toxicity of disodium EDTA. Am J Med Sci 1961;245:51-7.

17. Kitchell JR, Palmon F, Ayton N, Meltzer LE. The treatment of coronaryartery disease with disodium EDTA. Am J Cardiol 1963;11:501-6.

18. Lamar CP. Chelation therapy of occlusive arteriosclerosis in diabeticpatients. Angiology 1964;15:379-94.

19. Lamar CP. Chelation endarterectomy for occlusive atherosclerosis. JAm Geriatr Soc 1966;14:272-94.

20. Evers R. Chelation of vascular atheromatous disease (experiencewith 3000 patients). Laguna Hills (CA): American College forAdvancement in Medicine; 1979.

21. The American Academy of Medical Preventics. Chelation therapy.Med Lett 1981;23:51.

22. Casdorph MR. EDTA chelation therapy, efficacy in arterioscleroticdisease. J Holistic Med 1981;3:53-9.

23. Robinson DM. Chelation therapy. NZ Med J 1982;95:750.24. Olszewer E, Carter JP. EDTA chelation therapy in chronic degener-

ative disease. Med Hypothesis 1988;4:91-5.25. McGillen MJ, Mancini GBJ. Inefficacy of EDTA chelation therapy

for coronary atherosclerosis. N Engl J Med 1988;318:1618-9.26. Winebaugh SR, Geraets DR. Apparent failure of edetic acid chela-

tion therapy for the treatment of coronary atherosclerosis. DICPAnn Pharmacother 1990;24:22-5.

27. Deycher GP. Antioxidant therapy in the ageing process. In: Emerit I,Charles B, editors. Free radicals in aging. Basel: Birkauser Verlag;1992. p. 93-117.

28. Hancke C, Flytlie K. Manipulation with EDTA. Ugeskar Laeger 1992;154:2213-5.

29. Hancke C, Flytlie K. Benefits of EDTA chelation therapy in arterioscle-rosis: a retrospective study of 470 patients. J Advancement Med1993;6:161-71.

30. Hopf R, Gleußner M, Babej-Dölle R, et al. Wirksamkeit von chelatbei patienten mit koronarer herzkrankheit [abstract]. Z Kardiol1997;76(suppl 2):31.

31. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammaryligation and sham operation for angina pectoris. Am J Cardiol1960;5:483-6.

32. Chappell LT, Wilson J. Chelation therapy for vascular disease. Dallas:American Heart Association; 1999. p. 164.

33. Anonymous. Chelation therapy. JAMA 1983;250:672.34. Peterson GR. Adverse effects of chelation therapy. JAMA 1983;

250:2926.35. Meyer FP. Über die omnipotenz der chelattherapie. Forschende

Komplementär 1998;5:226-71.36. Magee R. Chelation treatment of atherosclerosis. Med J Aust 1985;

142:514-5.37. Haskell WL, Luskin FM, Marvasti FF. Complementary/alternative

therapies in general medicine: cardiovascular disease. In: Comple-mentary/alternative medicine, an evidence-based approach. SpencerJW, Jacobs JJ, editors. St Louis (MO): Mosby; 1999. p. 94.

American Heart JournalVolume 140, Number 1 Ernst 141

Chelation Therapy for Ischemic Heart Disease A Randomized Controlled Trial

Merril L.Knudtson,D.George Wyse,P.Diane Galbraith,et al.

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Merril L. Knudtson; D. George Wyse; P. Diane Galbraith; et al.

Randomized Controlled TrialChelation Therapy for Ischemic Heart Disease: A

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ORIGINAL CONTRIBUTION

Chelation Therapy for Ischemic Heart DiseaseA Randomized Controlled TrialMerril L. Knudtson, MDD. George Wyse, MD, PhDP. Diane Galbraith, BNRollin Brant, PhDKathy Hildebrand, BNDiana Paterson, BScNDeborah Richardson, RNConnie Burkart, BNEllen Burgess, MDfor the Program to Assess AlternativeTreatment Strategies to AchieveCardiac Health (PATCH)Investigators

ISCHEMIC HEART DISEASE CONTINUES

to be the leading cause of death anddisability among North Americanadults. Testimonials of symptom-

atic improvement frequently lead pa-tients with ischemic heart disease to seekalternative therapies that have not beenscrutinized in clinical trials. One suchtherapy is the repeated intravenous ad-ministration of the chelating agent EDTAin combination with oral vitamins andminerals. Two small randomized con-trolled clinical trials showed no benefitof EDTA in patients with peripheral ar-terial disease,1,2 and the few available tri-als in ischemic heart disease are unin-formative.3-5 Although the recent reviewby Ernst6 concluded that chelationtherapy for coronary heart diseaseshould be considered “obsolete,” manypatients continue to seek alternativetherapy.7

There are no current data on thenumber of patients seeking chelationtherapy. In 1993, Grier and Meyers8 es-timated that more than 500000 peoplein the United States are treated withEDTA therapy each year. In a recent Ca-

nadian study, 8% of patients who hadundergone cardiac catheterization andresponded to a survey had used chela-tion therapy.9 Assuming 8% of the 1.25million US residents who have under-gone cardiac catheterization10 have triedchelation therapy, we project that100000 have tried chelation therapy.Estimating a cost of $4000 for the usualseries of treatment sums to an annualexpenditure of approximately $400 mil-

lion. The actual amount is likely higherbecause these estimates do not in-clude all the cardiac patients who do

Author Affiliations: Division of Cardiology, Univer-sity of Calgary and Calgary Regional Health Author-ity, Calgary, Alberta.A list of the PATCH Investigators appears at the endof this article.Corresponding Author and Reprints: Merril L. Knudt-son, MD, Foothills Medical Center, 140329th St NW,Calgary, Alberta, Canada T2N 2T9 (e-mail :[email protected]).

Context Chelation therapy using EDTA is an unproven but widely used alternativetherapy for ischemic heart disease.

Objective To determine if current EDTA protocols have a favorable impact on ex-ercise ischemia threshold and quality of life measures in patients with stable ischemicheart disease.

Design Double-blind, randomized, placebo-controlled trial conducted between Janu-ary 1996 and January 2000.

Setting Participants were recruited from a cohort of cardiac catheterization patientsand the practices of cardiologists in Calgary, Alberta.

Participants We screened 3140 patients, performed a qualifying treadmill test in171, and enrolled 84. Entry criteria included age at least 21 years with coronary arterydisease proven by angiography or a documented myocardial infarction and stable an-gina while receiving optimal medical therapy. The required treadmill test used a gradualramping protocol and patients had to demonstrate at least 1-mm ST depression.

Interventions Patients were randomly assigned to receive infusion with either weight-adjusted (40 mg/kg) EDTA chelation therapy (n=41) or placebo (n=43) for 3 hoursper treatment, twice weekly for 15 weeks and once per month for an additional 3 months.Patients in both groups took oral multivitamin therapy as well.

Main Outcome Measure Change from baseline to 27-week follow-up in time toischemia (1-mm ST depression).

Results Thirty-nine patients in each group completed the 27-week protocol. Onechelation patient had therapy discontinued for a transient rise in serum creatinine. Themean (SD) baseline exercise time to ischemia was 572 (172) and 589 (176) seconds inthe placebo and chelation groups, respectively. The corresponding mean changes intime to ischemia at 27 weeks were 54 seconds (95% confidence interval [CI], 23-84seconds; P�.001) and 63 seconds (95% CI, 29-95 seconds; P�.001), for a differenceof 9 seconds (95% CI, −36 to 53 seconds; P=.69). Exercise capacity and quality of lifescores improved by similar degrees in both groups.

Conclusion Based on exercise time to ischemia, exercise capacity, and quality of lifemeasurements, there is no evidence to support a beneficial effect of chelation therapy inpatients with ischemic heart disease, stable angina, and a positive treadmill test for ischemia.JAMA. 2002;287:481-486 www.jama.com

©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, January 23/30, 2002—Vol 287, No. 4 481



not undergo catheterization and allother noncardiac patients who seek che-lation therapy.

We undertook a randomized, double-blind, placebo-controlled clinical trialof chelation therapy using the Ameri-can College for Advancement in Medi-cine (ACAM) protocol11 to determinethe efficacy of EDTA with respect to ex-ercise ischemia threshold, symptoms,and quality of life in patients with stableischemic heart disease.

METHODSStudy Subjects

Patients were recruited from the Al-berta Provincial Project for OutcomeAssessment in Coronary Heart Dis-ease (APPROACH) cohort of cardiaccatheterization patients12 and the prac-tices of community cardiologists in Cal-gary. Participants had to be aged 21years or older and have coronary ar-tery disease proven by coronary angi-ography or a documented myocardialinfarction and stable angina while re-ceiving optimal medical therapy. Toqualify for randomization patients wererequired to have a treadmill test, us-ing a gradual ramping protocol, dem-onstrating at least 1 mm of horizontalor downsloping ST-segment depres-sion from the isoelectric line 80 milli-seconds after the J point. The study pro-tocol required detection of ST-segment depression between 2 and 14minutes from the onset of exercise.

Exclusion criteria included plannedrevascularization, previous chelationtherapy, evidence of heart failure, in-ability to walk on the treadmill, rest-ing electrocardiographic (ECG) changesthat would interfere with ischemic as-sessment, abnormal renal or liver func-tion, or untreated lipid abnormality atthe time of randomization.

Treadmill TestingTreadmill testing was done at baselineand at 15 and 27 weeks after random-ization. The protocol began with a levelof exercise equivalent to 2 metabolicequivalents (METs) and increasedslowly every 10 to 15 seconds, reach-ing an equivalent of 13 METs at 14 min-

utes. A 12-lead ECG was recorded ev-ery 20 seconds. Maximum oxygenconsumption (V· O2max) and anaero-bic thresholds were determined by con-tinuous measurement of expired gasesusing a gas analyzer (MedGraphicsmodel CPX/D; MedGraphics Corpora-tion, St Paul, Minn) calibrated online.

Randomization and TreatmentPatients were randomized in blocks of10. Investigators were blinded to treat-ment assignment. The hospital phar-macy assigned the randomized therapyand prepared solutions for blinded ad-ministration of infusions. The 500-mLinfusion solution of 5% dextrose in wa-ter for the active treatment containingdisodium EDTA (Endrate; Abbott Labo-ratories, Abbott Park, Ill) was weightadjusted (40 mg/kg), with a maxi-mum total dose for each treatment of3 g. Each treatment solution also con-tained 750 mg of magnesium sulfate,5 g of ascorbic acid, and 5 g of sodiumbicarbonate (titrated to physiologic pH)in the 5% dextrose. Lidocaine, 80 mg,was added to relieve pain at the admin-istration site. In the placebo infusion so-lution the EDTA was replaced by 20 mLof 0.9% sodium chloride. The infu-sion solutions were indistinguishableby color and labeling. The infusion so-lution was administered over 3 hoursto minimize the potential unblindingeffect of infusion-related adverse ef-fects. All patients received treatmentstwice weekly for 15 weeks and oncemonthly for an additional 3 months, fora total of 33 treatments. In accordancewith the ACAM protocol, patients inboth groups took oral multivitamintherapy, 2 tablets 3 times daily as tol-erated, except on treatment days. All pa-tients were seen at the University of Cal-gary Cardiovascular Risk ReductionClinic and had treatment of their riskprofile optimized according to Ameri-can Heart Association guidelines (in-cluding management of diet, lipid lev-els, angina, stress, and exercise).

Other Tests and Safety MonitoringDipstick urine testing was performedat each visit. Urinalysis and serum cre-

atinine were measured at every fifthvisit. Hematology, electrolyte, and cho-lesterol panels were measured at base-line and at 15 and 27 weeks. The studynurse supervised patients throughoutthe duration of therapy, and hourlypulse and blood pressure measure-ments were obtained.

Study End PointsExercise parameters and quality of lifequestionnaires were collected at 15 and27 weeks after randomization. The pri-mary end point was the change in timeto reach at least 1 mm of ST-segment de-pression at the 27-week evaluation. Pa-tients who did not achieve ischemicchanges at 27 weeks had the test pe-riod truncated at 14 minutes, and 14minutes was recorded as their “time toischemia.” Functional reserve was alsomeasured by determination of V· O2maxand time to reach anaerobic threshold.Quality of life instruments included theDuke Activity Status Index,13 Health Sta-tus Survey Short Form-36,14 and Se-attle Angina Questionnaire.15

Follow-up and Clinical EventsAll patients were followed up for 1 yearfrom randomization. During this time,all clinical events were tabulated, includ-ing death, myocardial infarction, coro-nary artery bypass graft surgery, and per-cutaneous coronary intervention.

All patients signed an informed con-sent form. The Conjoint Ethics Com-mittee of the University of Calgary andthe Calgary Regional Health Author-ity approved this study and its con-sent form. All clinical events were re-ported to an independent safetymonitoring committee.

Statistical AnalysisA sample size of 40 per group was cho-sen to provide 90% power to detect a60-second difference in mean changein exercise time from baseline to the 27-week follow-up, assuming an SD of 80seconds within each group. The 60-second difference was based on a mini-mally important difference deter-mined by a consensus of Calgarycardiologists. Statistical analysis was

CHELATION THERAPY FOR ISCHEMIC HEART DISEASE

482 JAMA, January 23/30, 2002—Vol 287, No. 4 (Reprinted) ©2002 American Medical Association. All rights reserved.



performed using S-plus, version 6.0(Mathsoft, Seattle, Wash). Categoricalvariables were analyzed with the �2 orFisher exact test, as appropriate. Con-tinuous variables were examined withpaired and unpaired t tests. Graphicalexamination of the data showed thatnormal assumption was viable. All re-ported significance levels are 2-sided,and P�.05 was set as the significancelevel. All analyses of exercise and qual-ity of life data were conducted usinglast-observation-carried forward.

RESULTSPatients

A total of 3140 patients (FIGURE) werescreened and 171 of these agreed to un-dergo a qualifying exercise test. Eighty-four patients met the treadmill test cri-teria, consented, and were randomizedbetween January 1996 and January 2000.Baseline characteristics according totreatment assignment are shown inTABLE 1. There were no important dif-ferences between the groups. Of the 84patients randomized, 78 completedtreatment, the final treadmill test, andthe final quality of life assessments (39in each group). Four placebo patientsand 2 chelation patients were unable tocomplete the treatment phase (Figure).

Exercise End PointsAt baseline, mean (SD) treadmill testtimes to ischemic ECG changes were572 (172) seconds in the placebo and589 (176) seconds in the chelationgroups. Both groups were able to sig-nificantly (P<.001) increase their ex-ercise time to ischemia at the 27-weektreadmill test (TABLE 2). Changes in ex-ercise measurements of functional re-serve (time to anaerobic threshold andV· O2max) are shown in Table 2. Themagnitude of the increases in time toischemic changes and to anaerobicthreshold were not statistically differ-ent in the 2 groups. The increase inV· O2max was not significant at the 27-week treadmill test in the placebo groupbut the increase in the chelation groupwas significant (P=.03). However, thedifference between these 2 results wasnot significant (P=.46).

Quality of LifeThe changes in quality of life scoresbetweenbaselinemeasurementandthoseobtained at the 27-week evaluation areshown in Table 2. There was a tendencyfor modest increases in quality of lifescores inbothgroupswithsignificantbutsimilar improvements in the exertionalcapacitycomponentof theSeattleAnginaQuestionnaire. Differences between thegroups were not significant.

Ischemia and Other Clinical EventsClinical events are presented on an in-tention-to-treat basis (all 84 patients in-cluded). The duration of follow-up was1 year from randomization for each pa-tient. There were no deaths during thattime. One patient in the placebo grouphad a documented myocardial infarc-tion and 6 other patients were admit-

ted at least once for worsening angina.Four of these 7 patients had angio-plasty and none had coronary artery by-pass graft (CABG) surgery for theseevents, although 1 other patient hadelective surgery (CABG was planned bythe cardiologist after randomizationwithout investigators’ knowledge).There was 1 myocardial infarction inthe chelation group and 9 patients wereadmitted at least once for worsening an-gina. None of these had angioplasty orCABG surgery associated with theseevents.

One of the chelation patients waswithdrawn from therapy because of anelevation in serum creatinine. Duringthe first 10 treatments the patient’s se-rum creatinine level increased from 1.5to 2.1 mg/dL (129 to 186 µmol/L,respectively). Treatment was stopped

Figure. Flow of Patients in the Trial

2969 Excluded 690 Refused Consent 576 Were Unable to Perform Treadmill/ECG

470 Had Nonsignificant Disease 412 Had Planned Revascularization

296 Had Comorbidity Factors137 Were Unavailable for Follow-up 31 Had Previous EDTA Therapy 21 Died336 Other

3140 Patients Screened

87 Did Not Meet Treadmill Test Criteria

84 Randomized

171 Eligible for Treadmill Test

43 Assigned to ReceivePlacebo Therapy

41 Assigned to ReceiveEDTA Therapy

43 Included in Analysis

39 Completed Trial andTreadmill Test at 27 Weeks

39 Completed Trial andTreadmill Test at 27 Weeks

4 Unable to Complete Protocol1 Cancer1 Pneumothorax1 Unstable Angina

and Angioplasty1 Coronary Artery

Bypass Graft Surgery

2 Unable to Complete Protocol1 Creatinine Elevated

Above Study Limit1 Hospitalization for

Unstable Angina and Withdrawal of Consent

41 Included in Analysis

ECG indicates electrocardiogram.





and the serum creatinine level de-creased to 1.6 mg/dL (138 µmol/L) af-ter 10 weeks. No other cause for the el-evation in creatinine was found. Inaddition to the nonischemic eventsshown in the Figure leading to discon-tinuation of therapy, 3 additional pla-cebo patients were hospitalized fornonischemic events: gout, lumbar backpain from a herniated disk, and gastro-intestinal bleeding. These events did notinterfere with completion of the treat-ment phase. There were no electrolyteresults out of normal range during thestudy.

COMMENTThe main finding of this study was thatchelation therapy had no beneficialeffect on exercise time to ischemia,functional reserve for exercise, andquality of life in patients with provenischemic heart disease, stable angina,and evidence of ischemia on treadmillexamination. Accordingly, chelationtherapy remains unproven in the treat-ment of ischemic heart disease.

EDTA is an amino acid complex witha high affinity for divalent and triva-lent cations such as lead, magnesium,zinc, iron, and calcium. Conventional

chelation therapy involves multiple in-fusions of EDTA to chelate lead, iron,copper, calcium, and other metal ionsin a redox inactive state. Chelated metalions are then excreted from the bodyin the urine. For this reason EDTA hasbeen used as a chelating agent in clini-cal situations in which these elementsare found in excess.16

Because calcium is often found inatheromatous plaques, early propo-nents hypothesized that EDTA mightbe effective in treating ischemic heartdisease by liberating plaque calciumwith a subsequent favorable change inthe properties of the plaque.3,4,17,18 Otherhypotheses possibly accounting for thesymptomatic improvement reported bymany patients with ischemic heart dis-ease include a free radical–scavengingfunction, inhibition of lipid oxidation(antioxidant), reduction of total bodyiron stores, cell membrane stabiliza-tion, arterial dilation due to possible cal-cium channel blocking actions, orstimulation of prostacyclin produc-tion and improvement in arterial wallelasticity.3,4,17-21 Oxidized cholesterolplays an important role in endothelialfunction and the formation of athero-sclerotic plaque.22 There is at least someevidence, albeit controversial, that in-creased total body iron stores are asso-ciated with increased ischemic heartdisease.23 Therefore, some of these hy-potheses about chelation having a po-tential mechanism for benefit in ische-mic heart disease have plausibility. Inthe absence of studies confirming sucheffects and, more importantly, confirm-ing a definite clinical benefit of chela-tion therapy, it remains possible that an-ecdotally reported improvements aresimply due to the spontaneous fluctua-tions in symptoms frequently seen inischemic heart disease.24-27 In our trial,the 1-minute increase in exercise timeto ischemia and the improvement in theexertional capacity component of theSeattle Angina Questionnaire in bothgroups is consistent with a combina-tion of placebo24-27 and training ef-fects28-30 commonly seen in studies ofangina patients. Another potential ex-planation for improvement is that both

Table 1. Baseline Characteristics of Patients Completing Treatment*

VariablePlacebo(n = 43)

Chelation(n = 41) P Value

Age, mean (SD), y 65 (8.5) 66 (9.1) .86

Male sex, No. (%) 32 (83.7) 33 (85.4) .93

Left ventricular ejection fraction, mean (SD), % 58 (13.1) 62 (11.2) .11

Extent of CAD, No. (%)Single vessel 17 (39.5) 21 (51.2)

.39Multivessel 26 (60.5) 20 (48.8)

CCS angina class, No. (%)Asymptomatic 14 (32.6) 12 (29.3)

I 17 (39.5) 22 (53.7)

II 9 (20.9) 5 (12.2) .53

III 2 (4.7) 2 (4.9)

IV 1 (2.3) 0 (0)

Previous cardiac events, No. (%)Myocardial infarction 12 (27.9) 20 (48.8) .08

Percutaneous coronary intervention 19 (44.2) 19 (46.3) .98

Coronary artery bypass graft surgery 12 (27.9) 10 (24.4) .91

Comorbid conditions, No. (%)Diabetes 6 (14.0) 7 (17.1) .93

Hypertension 28 (65.1) 23 (56.1) .53

Hyperlipidemia 34 (79.1) 34 (82.9) .86

Laboratory values, mean (SD), mg/dL†Total cholesterol 185 (34.7) 185 (30.9) .77

HDL cholesterol 43 (8.9) 45 (13.1) .54

LDL cholesterol 106 (27.0) 107 (22.4) .97

Triglycerides 177 (132.7) 177 (79.6) .97

Creatinine 1.0 (0.20) 1.1 (0.23) .19

Medication use, No. (%)�-Blockers 32 (74.4) 30 (73.2) .90

Calcium channel blockers 23 (53.5) 19 (46.3) .51

Nitrates 19 (44.2) 10 (24.4) .06

Triple therapy‡ 11 (25.6) 5 (12.2) .12

ACE inhibitors 13 (30.2) 11 (26.8) .73

Aspirin 41 (95.3) 38 (92.7) .61

Lipid-lowering agents 37 (86.0) 28 (68.3) .05

*CAD indicates coronary artery disease; CCS, Canadian Cardiovascular Society; HDL, high-density lipoprotein; LDL,low-density lipoprotein; and ACE, angiotensin-converting enzyme. The CCS scale is measured from I to IV, with ahigher score indicating greater severity.

†To convert cholesterol values to mmol/L, multiply values by 0.0259. To convert triglycerides to mmol/L, multiply val-ues by 0.0113. To convert creatinine to µmol/L, multiply values by 88.4.

‡Triple therapy includes �-blockers, calcium channel blockers, and nitrates.





groups were treated with optimal riskreduction therapy.

Chelation therapy is practiced andpromoted as a form of complementaryor alternative medicine in many devel-oped countries. Additional vitamins andmineral supplements are recom-mended for patients undergoing che-lation therapy. In our study, bothgroups received multivitamins; we can-not exclude the possibility that thesesupplements could be partially respon-sible for the improvement that we sawin both groups.

In the literature, numerous authorshave reported positive results in uncon-trolled studies.3-5,31 Very few random-ized clinical trials have been publishedon the effects of chelation therapy, andthose that have been published were per-formed in patients with peripheral ar-terial disease.1,2 Olszewer et al32 pub-lished a small trial of 10 men withperipheral arterial disease in which im-provement was demonstrated in walk-ing distance after 20 treatments, butthere were only 5 patients in each groupand therapy was not blinded. Guldagerand colleagues1 published a random-ized, double-blind, placebo-controlledtrial of 153 male patients with periph-eral arterial disease (75 EDTA and 78placebo), and during the 6-month fol-low-up no effect of EDTA on walkingtime or ankle-brachial blood pressure in-dex was demonstrated. That trial has

been criticized for the high dropout rate(123 completed 6-month follow-up).van Rij et al2 published the results of asimilar randomized, double-blind, pla-cebo-controlled trial of walking time andankle-brachial blood pressure indices in32 patients (15 EDTA and 17 placebo)with claudication, which also showed noeffect of EDTA therapy.

There is even less evidence in pa-tients with ischemic heart disease.Kitchell et al5 conducted a placebo-controlled, double-blind, crossoverstudy of 9 patients with coronary heartdisease and assessed performance on atreadmill. The authors documented that2 of 4 EDTA-treated patients ben-efited at 12 weeks but only 2 patientsvolunteered to be treated in the sec-ond phase, and neither patient showedimprovement. No statistical analyseswere presented in that study.

As with all randomized clinical tri-als, our results can be applied to fit onlya similar population to that studied: pa-tients with stable angina who are notcandidates for revascularization and canexercise on a treadmill. Our studyshowed that following 33 treatmentswith EDTA therapy, there was no evi-dence of any benefit compared with pla-cebo in either objective measurementsof exercise capacity or in measure-ments of patient-perceived well-being.One patient receiving EDTA had a tran-sient increase in serum creatinine. There

was no difference in the number of clini-cal ischemic events, but our study wasnot powered to detect any such differ-ences. According to our findings, the useof chelation therapy to increase ische-mic threshold and improve quality of lifecannot be supported for patients with is-chemic heart disease. Larger trials witha broader range of patients will beneeded to assess the safety and impactof EDTA therapy on clinical event rates.

Author Contributions: Study concept and design:Knudtson, Wyse, Galbraith, Brant, Hildebrand.Acquisition of data: Knudtson, Wyse, Galbraith,Hildebrand, Paterson, Richardson, Burkart, Burgess.Analysis and interpretation of data: Knudtson, Wyse,Galbraith, Brant, Burgess.Drafting of the manuscript: Knudtson, Wyse,Galbraith, Brant, Hildebrand, Burgess.Critical revision of the manuscript for important in-tellectual content: Knudtson, Wyse, Galbraith, Brant,Hildebrand, Paterson, Richardson, Burkart.Statistical expertise: Wyse, Galbraith.Obtained funding: Knudtson, Wyse, Galbraith, Brant,Hildebrand.Administrative, technical, or material support: Knudt-son, Wyse, Galbraith, Hildebrand, Paterson, Richard-son, Burgess.Study supervision: Knudtson, Wyse, Galbraith, Pat-erson, Burkart, Burgess.Funding/Support: This study was supported by theAlberta Health Services Research and Innovation Fund,Medical Services Incorporated Research Foundation,and the Calgary Regional Health Authority.PATCH Investigators: Clinical Steering CommitteeMembers: Merril L. Knudtson, MD, D. George Wyse,MD, PhD, Rollin Brant, PhD, Ellen Burgess, MD, JamesStone, MD, James Mayhew, MD, Jeanette Soriano,MD, Janet Hammond, P. Diane Galbraith, BN. SafetyMonitoring Committee Members: Paul Armstrong,MD, University of Alberta; Koon Teo, MD, McMas-ter University; G. B. John Mancini, MD, University ofBritish Columbia. Substudy Committee: Merril L.Knudtson, MD, D. George Wyse, MD, PhD, RollinBrant, PhD, P. Diane Galbraith, BN, Todd Anderson,MD, Ellen Burgess, MD, and Derek Exner, MD, MPH.

Table 2. Exercise Times, Oxygen Consumption, and Quality of Life Scores at Baseline and 27 Weeks*

Measurement

Placebo Group Chelation Group Group Comparison

Baseline,Mean (SD)

27 Weeks,Mean (SD)

Change,Mean (95% CI)

PValue

Baseline,Mean (SD)

27 Weeks,Mean (SD)

Change,Mean (95% CI)

PValue

Difference inMean Change

PValue

Time to ischemia, s 572 (172) 626 (186) 54 (23 to 84) �.001 589 (176) 652 (174) 63 (29 to 95) �.001 9 (−36 to 53) .69

Time to anaerobicthreshold, s

555 (151) 571 (195) 16 (−27 to 59) .45 555 (164) 585 (140) 31 (−11 to 72) .14 15 (−44 to 73) .63

V̇o2max, mL/min 1606 (484) 1646 (419) 40 (−53 to 134) .39 1591 (468) 1675 (432) 84 (10 to 159) .03 44 (−74 to 162) .46

DASI 37.4 (13.4) 39.3 (14.5) 1.9 (−0.6 to 4.5) .13 42.2 (12.5) 41.9 (14.2) −0.2 (−3.2 to 2.7) .87 −2.1 (−6.0 to 1.6) .26

SAQ exertion 64.8 (20.3) 73.2 (17.8) 8.3 (3.9 to 12.8) �.001 69.9 (22.5) 77.2 (18.2) 7.3 (2.2 to 12.5) .006 −1.0 (−7.7 to 5.7) .77

SF-36 mentalcomponentsummary

48.3 (10.4) 50.4 (9.2) 2.1 (−0.4 to 4.5) .09 52.6 (7.6) 54.6 (6.7) 2.1 (−0.4 to 4.6) .10 0.01 (−3.4 to 3.4) .99

SF-36 physicalcomponentsummary

39.9 (11.0) 44.9 (10.7) 5.0 (2.7 to 7.3) �.001 42.9 (10.1) 45.1 (10.0) 2.2 (−0.5 to 4.9) .11 −2.8 (−6.3 to 0.6) .11

*CI indicates confidence interval. Maximum score on the Duke Activity Status Index (DASI) is 58.2, with a higher score indicating better physiologic reserve. Scores on the SeattleAngina Questionnaire (SAQ) range from 1-100, with a higher score indicating better levels of functioning. Scores on the Short-Form 36 (SF-36) range from 0-100, with a higherscore indicating better health-related quality of life. Mean change values were rounded.





Acknowledgment: We gratefully acknowledge DavidGoodhart, MD, for his supervision during many ex-ercise tests. We thank Cliff Simpson for his computerprogramming expertise, the University of Calgary LipidClinic personnel, Heritage Medical Research Clinic per-sonnel, the Foothills Medical Center pharmacy per-sonnel, and Lu Mann, BN, for her help with the tread-mills. Joyce Forster helped with preparation of themanuscript.

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1. Guldager B, Jelnes R, Jorgensen SJ, et al. EDTA treat-ment of intermittent claudication: a double-blind, pla-cebo-controlled study. J Intern Med. 1992;231:261-267.2. van Rij AM, Solomon C, Packer SG, Hopkins WG.Chelation therapy for intermittent claudication: adouble-blind, randomized, controlled trial. Circula-tion. 1994;90:1194-1199.3. Clarke NE, Clarke CN, Mosher RE. Treatment ofangina pectoris with disodium ethylene diamine tet-raacetic acid. Am J Med Sci. 1960;232:654-656.4. Casdorph RH. EDTA chelation therapy: efficacy inatherosclerotic heart disease. J Hol Med. 1981;3:53-59.5. Kitchell JR, Palmon F, Aytan N, Meltzer L. The treat-ment of coronary artery disease with disodium EDTA.Am J Cardiol. 1963;11:501-506.6. Ernst E. Chelation therapy for coronary heart dis-ease: an overview of all clinical investigations. Am HeartJ. 2000;140:139-141.7. Eisenberg DM, Davis RB, Ettner SL, et al. Trendsin alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA.1998;280:1569-1575.8. Grier MT, Meyers DG. So much writing, so littlescience: a review of 37 years of literature on edetatesodium chelation therapy. Ann Pharmacother. 1993;27:1504-1509.9. QuanH,GhaliWA,VerhoefMJ,NorrisCM,GalbraithPD, Knudtson ML. Use of chelation therapy after coro-nary angiography. Am J Med. 2001;111:686-691.

10. Laine C, Venditti L, Localio R, Wickenheiser L, Mor-ris DL. Combined cardiac catheterization for uncom-plicated ischemic heart disease in a Medicare popu-lation. Am J Med. 1998;105:373-379.11. Rozema TC. Protocols for chelation therapy. J AdvMed. 1997;10:1-100.12. Ghali WA, Knudtson ML, for the APPROACH In-vestigators. Overview of the Alberta Provincial Projectfor Outcome Assessment in Coronary Heart Disease.Can J Cardiol. 2000;16:1225-1230.13. Hlatky MA, Boineau RE, Higginbotham MB, et al.A brief self-administered questionnaire to determinefunctional capacity (the Duke Activity Status Index).Am J Cardiol. 1989;64:651-654.14. Ware JE Jr, Kosinski M, Keller SD. SF-36 Physicaland Mental Health Summary Scales: A User’s Manual.Boston, Mass: Health Assessment Lab, New EnglandMedical Center; 1994.15. Spertus JA, Winder JA, Dewhurst TA, et al. De-velopment and evaluation of the Seattle Angina Ques-tionnaire: a new functional status measure for coro-nary artery disease. J Am Coll Cardiol. 1995;25:333-341.16. Dudley H, Ritchie A, Schilling A, Baker WH. Patho-logical changes associated with the use of sodium eth-ylene diamine tetraacetic acid. N Engl J Med. 1955;52:331-337.17. Clarke NE, Clarke CN, Mosher RE. The “in vivo”dissolution of metastatic calcium: an approach to ath-erosclerosis. Am J Med Sci. 1955;229:142-149.18. Cranton EM, Frackelton JP. Free radical pathol-ogy in age associated diseases: treatment with EDTAchelation, nutrition and antioxidants. J Hol Med. 1984;6:6-37.19. Koen A, McCann D, Boyle A. Some in vivo ef-fects of chelation-II: animal experimentation. J ChronicDis. 1963;16:329-333.20. McCann D, Koen A, Zdybek G. Effect of chela-tion on phosphorus metabolism and experimental ath-erosclerosis. Circ Res. 1962;9:880-884.21. Lamas GA, Ackermann A. Clinical evaluation ofchelation therapy: is there any wheat amidst the chaff?Am Heart J. 2000;140:4-5.

22. Adams MR, Kinlay S, Blake GJ, Orford JL, GanzP, Selwyn AP. Atherogenic lipids and endothelial dys-function: mechanisms in the genesis of ischemic syn-dromes. Annu Rev Med. 2000;51:149-167.23. Salonen JT, Nyyssonen K, Korpela H, Tu-omilehto J, Seppanen R, Salonen R. High stored ironlevels are associated with excess risk of myocardial in-farction in eastern Finnish men. Circulation. 1992;86:803-811.24. Bienenfeld L, Frishman W, Glasser SP. The pla-cebo effect in cardiovascular disease. Am Heart J. 1996;132:1207-1221.25. Weber JR. Problems associated with clinical evalu-ation of antianginal medications. Am J Cardiol. 1985;56:14I-18I.26. Benson H, McCallie DP Jr. Angina pectoris andthe placebo effect. N Engl J Med. 1979;300:1424-1429.27. Folli G, Radice M, Beltrami A, Potenza S, Mari-otti G. Placebo effect in the treatment of angina pec-toris. Acta Cardiol. 1978;33:231-239.28. Romano M, Carella G, Cotecchia MR, et al. Ex-ercise time: a possible source of misleading results dur-ing long-term pharmacological studies by multiple stresstestings in coronary artery disease. Clin Cardiol. 1989;12:39-41.29. Laslett LJ, Paumer L, Amsterdam EA. Increasein myocardial oxygen consumption indexes byexercise training at onset of ischemia in patientswith coronary artery disease. Circulation. 1985;71:958-962.30. Ades PA, Grunvald MH, Weiss RM, Hanson JS.Usefulness of myocardial ischemia as predictor of train-ing effect in cardiac rehabilitation after acute myo-cardial infarction or coronary artery bypass grafting.Am J Cardiol. 1989;63:1032-1036.31. Olszewer E, Carter JP. EDTA chelation therapy:a retrospective study of 2,870 patients. J Adv Med.1989;2:197-211.32. Olszewer E, Sabbag FC, Carter JP. A pilot double-blind study of sodium-magnesium EDTA in periph-eral vascular disease. J Natl Med Assoc. 1990;82:173-177.





Effect of Chelation Therapy on Endothelial Function in Patients With Coronary Artery Disease: PATCH Substudy

Todd J. Anderson,Jaroslav Hubacek,D.George Wyse, Merril L.Knudtson

Effect of Chelation Therapy onEndothelial Function in Patients WithCoronary Artery Disease: PATCH SubstudyTodd J. Anderson, MD, FRCP(C), Jaroslav Hubacek, MD, MSC, D. George Wyse, MD, PHD, FRCP(C),Merril L. Knudtson, MD, FRCP(C)Calgary, Canada

OBJECTIVES The purpose of this study was to evaluate the effect of chelation therapy with ethylenediaminetetraacetic acid (EDTA) on endothelium-dependent vasomotor responses in patients withdocumented coronary artery disease (CAD).

BACKGROUND Oxidative stress plays an important role in the dysfunction of endothelium and developmentof atherosclerosis. Modification of cardiac risk factors and employment of antioxidants havebeen shown to improve endothelial function. Ethylenediamine tetraacetic acid chelationtherapy is considered to be a complementary therapy for patients with CAD and is proposedto have antioxidant properties.

METHODS A total of 47 patients enrolled in the Program to Assess Alternative Treatment Strategies toAchieve Cardiac Health (PATCH) participated in this substudy and had complete data.High-resolution ultrasound was used to assess endothelium-dependent brachial arteryflow-mediated vasodilation (FMD) in patients with CAD in a randomized, double-blind,and placebo-controlled fashion. Patients were randomized to chelation therapy or placebo.The primary end point was the absolute difference in FMD after the first and 33rd treatments(6 months) of study groups compared with their baselines.

RESULTS At the baseline, the study population had mild impairment of FMD (7.2 � 3.4%). The firstchelation treatment did not change FMD as compared with placebo (chelation 6.5 � 3.5%vs. placebo 7.4 � 2.9%; p value � 0.371). The brachial artery studies at six months did notdemonstrate significant differences in FMD between study groups (placebo 7.3 � 3.4% vs.chelation 7.3 � 3.2%; p value � 0.961).

CONCLUSIONS Our results suggest that EDTA chelation therapy in combination with vitamins and mineralsdoes not provide additional benefits on abnormal vasomotor responses in patients with CADoptimally treated with proven therapies for atherosclerotic risk factors. (J Am Coll Cardiol2003;41:420–5) © 2003 by the American College of Cardiology Foundation

Chelation therapy or intravenous infusion of ethylenedia-mine tetraacetic acid (EDTA) in combination with oralvitamins and minerals is considered an “alternative” or“complementary” therapy for patients with coronary arterydisease (CAD). It has been suggested that patients withCAD might benefit from this complementary therapeuticapproach (1–4). However, definitive evidence that chelationis beneficial has been lacking in randomized trials. Severalmechanisms for the potential beneficial effects of chelationtherapy in patients with atherosclerosis have been postu-lated. Lamas and Ackermann (5) suggested that an antiox-idant effect of EDTA, in combination with vitamins andminerals, might be the most plausible.

Over the past decade, emerging data have demonstratedthat cardiovascular risk factors and oxidative stress play acrucial role in abnormal vasomotor responses (6). Abnormalvasomotor responses are probably one of the first events inthe atherosclerosis process and have been shown to be an

important cause of ischemia in patients with establishedatherosclerosis (7). Furthermore, modification of cardiacrisk factors and employment of antioxidants have beenshown to improve endothelial function (8). On the basis ofpreviously proposed antioxidant, antihypertensive, andcholesterol-lowering properties of chelation therapy (9), wehypothesized that EDTA in combination with vitamins andminerals may have a beneficial effect on endothelial functionin patients with established CAD.

The purpose of this study was to evaluate the effect ofchelation therapy with EDTA on endothelium-dependentvasomotor responses in patients with documented CAD ina randomized, double-blind, and placebo-controlled fash-ion.

METHODS

Study subjects. A total of 53 patients enrolled in theProgram to Assess Alternative Treatment Strategies toAchieve Cardiac Health (PATCH) study participated inthis substudy. The main PATCH study has been previouslyreported (10). Briefly, patients �21 years old with CADproven by coronary angiography or a documented myocar-dial infarction and stable angina on optimal medical therapywere studied. To qualify for randomization, patients were

From the Faculty of Medicine, University of Calgary and Calgary Health Region,Calgary, Canada. Supported by the Alberta Health Services Research and InnovationFund, the Medical Services Incorporated Research Foundation, and the CalgaryRegional Health Authority. Todd J. Anderson is a Medical Scholar of the AlbertaHeritage Foundation for Medical Research.

Manuscript received June 7, 2002; revised manuscript received October 2, 2002,accepted October 17, 2002.

Journal of the American College of Cardiology Vol. 41, No. 3, 2003© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00Published by Elsevier Science Inc. doi:10.1016/S0735-1097(02)02770-5

required to have a treadmill test using a gradual rampingprotocol and demonstrating �1 mm horizontal ordownsloping ST depression from the isoelectric line 80 msafter the J point. The study required detection of STdepression between 2 and 14 min from the onset of exercise.Patients were excluded for the following reasons: plannedrevascularization, previous chelation therapy, evidence ofheart failure, inability to walk on the treadmill, restingelectrocardiogram changes that would interfere with isch-emic assessment, abnormal renal or liver function, or un-treated lipid abnormality at the time of randomization.Study protocol. RANDOMIZATION AND TREATMENT.

Written informed consent was obtained from all partici-pants. The Conjoint Ethics Committee of the University ofCalgary and the Calgary Regional Health Authority ap-proved this study and its consent form. All clinical eventswere reported to an independent Safety Monitoring Com-mittee. The present study was a double-blind, randomized,and placebo-controlled trial. Patients were randomized inblocks of 10 using S-plus version 3.4 (Statistical ScienceInc., Seattle, Washington). The Foothills Medical CenterPharmacy assigned the randomized therapy and preparedsolutions for blinded administration of infusions. The 500ml infusion solution of 5% dextrose in water for the activetreatment containing disodium EDTA (Endrate, AbbottLaboratories) was weight adjusted (40 mg/kg), with amaximum total dose for each treatment of 3 g. Eachtreatment solution also contained 750 mg of magnesiumsulfate, 5 g of ascorbic acid (Mega C), and 5 g sodiumbicarbonate (titrated to physiologic pH) in the D5W.Lidocaine (Xylocaine ) 80 mg was added to relieve pain atthe administration site and mask taste. In the placeboinfusion solution, the EDTA was replaced by 20 ml of 0.9%sodium chloride. The infusion solutions were indistinguish-able by color, taste, and labeling. All infusion solutions wereprepared following manufacturers’ instructions and wereadministered immediately after mixing. The infusion solu-tion was administered over 3 h to minimize the potentialunblinding effect of infusion-related side effects. All patientsreceived treatments twice weekly for 15 weeks and once permonth for an additional three months, for a total of 33treatments. In accordance with the American College ofAdvancement in Medicine protocol, patients in both groups

took oral multivitamin therapy (FLW, Douglas Labs, Pitts-burgh, Pennsylvania), two tablets three times daily astolerated, except on treatment days. The components ofFLW were as follows: vitamin A 4,000 IU, vitamin E 65IU, vitamin C 400 mg, vitamin B1 20 mg, vitamin B2 5 mg,vitamin B6 15 mg, vitamin B12 25 �g, niacin 5 mg,niacinamide 5 mg, pantothenic acid 50 mg, folic acid 0.04mg, biotin 10 �g, choline 72.5 mg, inositol 5 mg, methio-nine 24 mg, magnesium 40 mg, potassium 40 mg, manga-nese 0.5 mg, zinc 3 mg, chromium 20 �g, and selenium 25�g. All patients were seen at the University of CalgaryCardiovascular Risk Reduction Clinic and had treatment oftheir risk profile optimized.

BRACHIAL ENDOTHELIAL FUNCTION STUDIES. A recentlydescribed technique employing high-resolution ultrasoundto measure brachial artery diameter was used to study thevasodilator responses induced by reactive hyperemia after 5min of upper arm occlusion (11). Assessment of brachialartery endothelial function was performed at baseline, afterthe first chelation therapy (acute), and at the end of study(after the completion of 33 chelation treatments) by apreviously validated technique (12,13). Patients underwenteach of three brachial artery ultrasound studies after anovernight fast (12 h), and all vasoactive medications, includ-ing angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium-channel blockers, long-acting nitrites, andstatins were stopped for 24 h. Studies were performed in aquiet clinical laboratory with the temperature maintained at21 to 23°C. A 7.5 MHz linear phase-arrayed ultrasoundtransducer attached to a Hewlett-Packard 5500 ultrasoundmachine was used. Pulsed-wave Doppler was used to recordbrachial artery velocity for each of the interventions.Data analysis. BRACHIAL ARTERY ANALYSIS. Brachial ar-tery analysis was performed at a core laboratory at theUniversity of Calgary by a single technician blind to thestudy group assignment or study sequence. Three sequentialsystolic frames (taken at the end of the T-wave on theelectrocardiogram) were digitized via an analog-to-digitalconverting board. A software algorithm automatically cal-culates the average diameter (100 points) over the operator-selected segment. Flow-mediated vasodilation (FMD) wascalculated from the diameters as (reactive hyperemia �baseline)/baseline � 100%. The intra- and inter-observervariability in our laboratory is 1%. Systolic frames were usedas previously validated (13). In 20 studies selected randomly,measurements were made at both end-diastole and systole,and the FMD was exactly the same. Brachial artery flow wascalculated as the product of velocity and cross-sectionalarterial area.

STATISTICS. Data are expressed as mean � SD for contin-uous variables and as counts and percentage for discretevariables. Statistical analyses were conducted with a com-mercially available software package (SPSS version 10.0;SPSS Inc, Chicago, Illinois). The sample size was deter-mined to detect a clinically important absolute improvement

Abbreviations and AcronymsACE � angiotensin-converting enzymeCAD � coronary artery diseaseEDTA � ethylenediamine tetraacetic acideNOS � endothelial nitric oxide synthaseFMD � flow-mediated vasodilationNO � nitric oxideNTG � nitroglycerinPATCH � Program to Assess Alternative Treatment

Strategies to Achieve Cardiac Health

421JACC Vol. 41, No. 3, 2003 Anderson et al.February 5, 2003:420–5 Effect of EDTA Chelation on Endothelial Function

in FMD of 3% (with a SD of 3% to 4%) in the chelationgroup when compared with placebo. This assumes an alphaof 0.05 and beta 0.2. Categorical variables were analyzedwith the Mann-Whitney U-test. Continuous variables wereexamined with paired and unpaired t tests, as appropriate.All reported significance levels are two-sided.

RESULTS

Patient characteristics. A total of 53 patients agreed andconsented to participate in the study between January 1996and January 2000. Of the 53 patients, 47 completedtreatment and final brachial artery ultrasound study. Fourplacebo patients were unable to finish the treatment phasebecause of: 1) cancer of the hip; 2) hospitalization withpneumothorax in the setting of previous asbestosis andchronic obstructive pulmonary disease; 3) unstable anginafollowed by angioplasty and coronary artery bypass graftsurgery; and 4) coronary artery bypass graft surgery that hadbeen planned as an elective procedure by the primarycardiologist after randomization without the knowledge ofthe investigators. Two EDTA patients were unable tocomplete the study: one because of a serum creatinine levelincrease above preset study limit (175 �mol/l) and the otherbecause of hospitalization for unstable angina followed bywithdrawal of consent. There was no difference in thedemographics of these patients and those who completedthe study. Data presented in this report are from the 47patients with complete information. The baseline charac-teristics of the 47 randomized patients are shown in Table 1.There were no important differences at baseline between thetwo groups. The mean age of the study population was 68� 9 years, with 85% men. Risk factors were as follows:hypercholesterolemia 80%, hypertension 43%, and diabetesmellitus 10%. All patients had treatment of their risk profileoptimized. Among all 47 patients, 95% were treated with

aspirin, 80% with lipid-lowering therapies, 70% with beta-blockers, 34% with ACE inhibitors, and 30% with long-acting nitrates. The use of medication was comparablebetween the randomization groups. During the course ofthe study, there was no statistically significant difference inlipid profile or in blood pressure between the groups.Treatment effect on brachial artery characteristics. Flow-mediated vasodilation was inversely related to baselinebrachial artery diameter in this study (baseline 4.1 � 0.7mm vs. FMD diameter 4.3 � 0.8 mm; p value �0.001) andin other studies (13–15). The baseline brachial arterydiameter was the same for both study groups, and the studymedications had no significant effect on baseline brachialdiameter after six months of treatment. Upper arm occlu-sion resulted in an increase in forearm blood flow ofapproximately 450%, which was the same at baseline forboth groups and was not affected by drug treatment.Treatment effect on FMD. At the baseline, the studypopulation had FMD of 7.2 � 3.4% and nitroglycerin(NTG)-mediated dilation of 13.2 � 5.7%. These values aresimilar to what we have reported previously in patients withCAD (14) and less than those of normal controls in our lab(16). Baseline FMD and NTG-mediated vasodilations weresimilar in both groups (Table 2). Short-term treatment withEDTA in combination with vitamins and minerals did notchanged FMD and NTG-mediated vasodilation (Table 2).The brachial artery studies at six months, after the comple-tion of 33 treatments, did not demonstrate significantdifferences in FMD between placebo and chelation therapygroups (placebo 7.3 � 3.4% vs. chelation 7.3 � 3.2%; pvalue � 0.961) (Table 2). There was no significant effect ofchelation therapy on NTG-induced vasodilation (placebo12.4 � 6.4% vs. chelation group 15.3 � 7.1%; p value �0.148) (Table 2). Furthermore, we did not observe anystatistically significant changes within either study groupover time (Fig. 1).

Table 1. Baseline Demographics

Placebo(n � 23)

Chelation(n � 24) p Value

Age 64 � 9 64 � 9 0.939*Male 19 (83%) 21 (88%) 0.641Female 4 (17%) 3 (13%) 0.641Postmenopausal 4 (17%) 3 (13%) 0.641Diabetes mellitus 1 (4%) 4 (17%) 0.176Hypertension 11 (48%) 9 (38%) 0.479Smoker 1 (4%) 1 (4%) 0.976CHF 1 (4%) 1 (4%) 0.976PVD 3 (13%) 2 (8%) 0.605Lipids (mmol/l)Total cholesterol 5.0 � 1.1 4.9 � 0.8 0.760*LDL-C 3.0 � 0.7 2.9 � 0.7 0.639*HDL-C 1.1 � 0.2 1.1 � 0.3 0.975*Triglycerides 2.0 � 1.1 2.8 � 3.9 0.356*

CHF � history of congestive heart failure; HDL-C � high-density lipoproteincholesterol; LDL-C � low-density lipoprotein cholesterol; p value � chelationtherapy versus placebo group; unpaired t test and Mann-Whitney U-test (*); PVD �peripheral vascular disease

Table 2. Brachial Artery Parameters

Placebo Chelation p Value

BaselineBaseline diameter (mm) 4.1 � 0.7 4.0 � 0.8 0.974FMD (%) 7.6 � 3.4 6.7 � 3.5 0.355NTG (%) 12.8 � 5.0 13.5 � 6.3 0.664

Short-termBaseline diameter (mm) 4.1 � 0.8 4.1 � 0.7 0.769FMD (%) 7.4 � 2.9 6.5 � 3.5 0.371NTG (%) 12.0 � 4.9 12.8 � 4.1 0.516

6-monthBaseline diameter (mm) 4.1 � 0.5 4.0 � 0.8 0.625FMD (%) 7.3 � 3.4 7.3 � 3.2 0.961NTG (%) 12.4 � 6.4 15.3 � 7.1 0.148

baseline � measurement performed before the treatment, after the first chelationtherapy (short-term) and after the completion of 33 chelation treatments; datapresented in millimeters as mean � SD for baseline diameter and in % � SD increasefrom baseline diameter for FMD and NTG; FMD � flow-mediated vasodilation;NTG � nitroglycerin-mediated vasodilation; p value � chelation therapy versusplacebo group; unpaired t test.

422 Anderson et al. JACC Vol. 41, No. 3, 2003Effect of EDTA Chelation on Endothelial Function February 5, 2003:420–5

DISCUSSION

This randomized, double-blind, and placebo-controlledstudy demonstrates that short- and long-term treatment (33infusions) with EDTA in combination with vitamins andminerals did not improve impaired endothelium-dependentFMD in the brachial artery circulation of patients withestablished CAD and optimized treatment of risk profile.

There is ample evidence that the endothelium plays animportant role in maintaining vascular integrity through therelease of a variety of paracrine and autocrine factors,including nitric oxide (NO). In health, NO causes vasodi-lation, inhibits platelet aggregation and adhesion, and in-hibits smooth muscle cell proliferation and white celladhesion (17). Endothelial dysfunction has been observed inpatients with established CAD or coronary risk factors, both

in coronary and peripheral circulation (12,18). Oxygen freeradicals, generated by a number of pathways in the body,play an important role in the dysfunction of endotheliumand development of atherosclerosis (19). Modification ofcardiac risk factors and employment of antioxidants havebeen shown to improve endothelial function (8).

Chelation therapy is considered to be complementarytherapy for patients with CAD. In fact, the beneficial effectof EDTA therapy in this setting remains unproven (5,10).Originally, liberation of plaque calcium with a subsequentfavorable change in the properties of the plaque (20–23) wasthought to be the underlying mechanism of action. Later,EDTA was proposed to lower low-density lipoprotein andvery-low-density lipoprotein levels and iron stores, inhibitplatelet aggregation, relax vascular tone, and “scavenge” free

Figure 1. Changes in vasomotor responses in study groups over time. (A) placebo group; (B) chelation therapy group; *p value � 0.05 (baseline vs. acutevs. 6 months) paired t test. FMD � flow-mediated vasodilation; NTG � nitroglycerin.


radicals (5,20–29). Ethylenediamine tetraacetic acid reducesiron and copper levels from cell membrane. Both thesemetals are important catalysts in the peroxidation of unsat-urated fatty acids and the oxidation of low-density lipopro-tein, which generate free radicals with subsequent disrup-tion of membrane architecture, promoting cellular injuryand progression of atherosclerosis (30). The beneficial effectof iron chelation on endothelial function has been previouslydemonstrated. Deferoxamine, an iron chelator, improvedNO-mediated, endothelium-dependent vasodilation in pa-tients with CAD (31) and in diabetics with angiographicallynormal coronary arteries (32). On the other hand, in anon-randomized and non-blinded study (33), EDTA alonedid not significantly improve either endothelium or NO-dependent vasodilation in patients with CAD after 10chelation infusions over 60 days. However, EDTA incombination with predominantly B vitamins improved va-somotor responses and was associated with a significantreduction in homocysteine levels. The patients in our studyhad documented CAD and impaired endothelial function inperipheral circulation at baseline. An improvement in ab-normal vasomotor responses has not been observed inpatients randomized to EDTA therapy compared withpatients randomized to placebo, either in the short term orat six months. Furthermore, we have not demonstrated anystatistically significant changes in FMD or NTG-mediatedvasodilation within the study groups over time. One possi-ble explanation might be that EDTA, unlike deferoxamine,is too small to bind entire iron ions and it creates a seventhcoordination site (34). As a result, iron remains in itscatalytically active form, and EDTA-iron complex cancatalyze the formation of the hydroxyl radical in a superox-ide generating system (35).

In our study, “placebo treatment” contained a high doseof intravenous vitamin C and multivitamin oral supplemen-tation. Therefore, we cannot exclude a beneficial effect oftreatment with vitamins and minerals alone. Vitamin C is awater-soluble antioxidant that inhibits lipid peroxidation invitro (36) and in vivo (37) by directly scavenging aqueousfree radicals, by reducing the chain-carrying alpha-tocopheroxyl radical, and by stabilization of tetrahydrobiop-terin, which prevents uncoupling of eNOS (38,39). Inclinical studies, vitamin C has been shown to reverseimpaired endothelial function in patients with establishedCAD (40,41). However, long-term vitamin C supplemen-tation did not show a consistent beneficial effect on theendothelial function of treated patients (42). The reasonwhy our patient population, either in the EDTA or placebogroup, did not respond to vitamin C treatment is not clear.All our patients were aggressively treated for atheroscleroticrisk factors. The majority of our study population wastreated with lipid-lowering therapy and 34% of patientsused ACE inhibitors. Lipid-lowering therapies and ACEinhibition have been shown to augment endothelial NOsynthesis, to inhibit endothelial superoxide anion in animalstudies (43–46), and to have beneficial effects on abnormal

vasomotor responses in humans (47–50). Therefore, it canbe speculated that free radical production was suppressedbelow the level at which free radical scavengers used in thepresented study (EDTA and vitamin C) could demonstratetheir beneficial effect on vasomotor responses. It was alimitation of our study that we did not have a measure ofoxidative stress or vitamin C levels.

In conclusion, our results suggest that chelation therapywith EDTA in combination with vitamins and mineralsdoes not provide any additional benefit on abnormal vaso-motor responses in patients with CAD optimally treated foratherosclerotic risk factors with proven therapies.

Reprint requests and correspondence: Dr. Todd J. Anderson,1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada.E-mail: [email protected].

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18. Drexler H. Endothelial dysfunction: clinical implications. Prog Car-diovasc Dis 1997;39:287–324.

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20. Casdorph RH. EDTA chelation therapy: efficacy in atheroscleroticheart disease. J Holistic Med 1981;3:53–9.

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21. Clarke NE, Clarke CN, Mosher RE. The “in vivo” dissolution ofmetastic calcium: an approach to atherosclerosis. Am J Med Sci1955;229:142–9.

22. Clarke NE, Clarke CN, Mosher RE. Treatment of angina pectoriswith disodium ethylene diamine tetraacetic acid. Am J Med Sci1960;232:654–6.

23. Cranton EM, Frackelton JP. Free radical pathology in age associateddiseases: treatment with EDTA chelation, nutrition and antioxidants.J Holistic Med 1984;6:6–37.

24. Frishman WH. Chelation therapy for coronary artery disease: panaceaor quackery? Am J Med 2001;111:729–30.

25. Kindness G, Frackelton JP. Effect of ethylendiaminetetraacetic acid(EDTA) on platelet aggregation in human blood. J Adv Med1989;2:519–29.

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27. McCann D, Koen A, Zdybek G. Effect of chelation on phosphorusmetabolism and experimental atherosclerosis. Circ Res 1962;9:880–4.

28. Olszewer E, Carter JP. EDTA chelation therapy in chronic degener-ative disease. Med Hypotheses 1988;27:41–9.

29. Olszewer E, Sabbag FC, Carter JP. A pilot double-blind study ofsodium-magnesium EDTA in peripheral vascular disease. J Natl MedAssoc 1990;82:173–7.

30. Deucher DP. EDTA chelation: an antioxidant strategy. J Adv Med1988;1:182–90.

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33. Green DJ, O’Driscoll JG, Maiorana A, Scrimgeour NB, WeerasooriyaR, Taylor RR. Effect of chelation with EDTA and vitamin B therapyon nitric oxide-related endothelial vasodilator funstion. Clin ExpPharmacol Physiol 1999;26:853–6.

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43. Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediatedhypertension in the rat increases vascular superoxide production viamembrane NADH/NADPH oxidase activation. Contribution to al-terations of vasomotor tone. J Clin Invest 1996;97:1916–23.

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Chelation therapy for atherosclerotic cardiovascular disease (The Cochrane Review)

Dans AL,Tan FN,Villarruz-Sulit EC

Chelation therapy for atherosclerotic cardiovascular disease

(Review)

Dans AL, Tan FN, Villarruz-Sulit EC

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2009, Issue 3

http://www.thecochranelibrary.com

Chelation therapy for atherosclerotic cardiovascular disease (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 EDTA versus placebo, Outcome 1 Ankle-brachial pressure index at 20th infusion. . . 14

Analysis 1.2. Comparison 1 EDTA versus placebo, Outcome 2 Ankle-brachial pressure index at 3 months post-treatment. 15

Analysis 1.3. Comparison 1 EDTA versus placebo, Outcome 3 Ankle-brachial pressure index at 6 months post-treatment. 15

Analysis 1.4. Comparison 1 EDTA versus placebo, Outcome 4 Walking distance (m) at 10th infusion. . . . . . 16

Analysis 1.5. Comparison 1 EDTA versus placebo, Outcome 5 Walking distance (m) at 20th infusion. . . . . . 16

Analysis 1.6. Comparison 1 EDTA versus placebo, Outcome 6 Walking distance (m) at 3 months post-treatment. . 17

Analysis 1.7. Comparison 1 EDTA versus placebo, Outcome 7 Walking distance (m) at 6 months post-treatment. . 17

Analysis 1.8. Comparison 1 EDTA versus placebo, Outcome 8 Pain-free walking distance (m) at 10th infusion. . . 18

Analysis 1.9. Comparison 1 EDTA versus placebo, Outcome 9 Pain-free walking distance (m) at 20th infusion. . . 18

Analysis 1.10. Comparison 1 EDTA versus placebo, Outcome 10 Pain-free walking distance (m) at 3 months post-

treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Analysis 1.11. Comparison 1 EDTA versus placebo, Outcome 11 Pain-free walking distance (m) at 6 months post-

treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Analysis 1.12. Comparison 1 EDTA versus placebo, Outcome 12 Subjective walking distance (m) at 20th infusion. . 20

Analysis 1.13. Comparison 1 EDTA versus placebo, Outcome 13 Subjective walking distance (m) at 3 months post-

treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Analysis 1.14. Comparison 1 EDTA versus placebo, Outcome 14 Subjective evaluation - aggravation. . . . . . . 21

Analysis 1.15. Comparison 1 EDTA versus placebo, Outcome 15 Subjective evaluation - unchanged. . . . . . . 21

Analysis 1.16. Comparison 1 EDTA versus placebo, Outcome 16 Subjective evaluation - mild improvement. . . . 22

Analysis 1.17. Comparison 1 EDTA versus placebo, Outcome 17 Subjective evaluation - moderate improvement. . 22

Analysis 1.18. Comparison 1 EDTA versus placebo, Outcome 18 Subjective evaluation - great improvement. . . . 23

Analysis 1.19. Comparison 1 EDTA versus placebo, Outcome 19 Plasma low density lipoprotein (LDL)-cholesterol levels

(mmol/litre). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Analysis 1.20. Comparison 1 EDTA versus placebo, Outcome 20 Plasma triglyceride levels (mmol/litre). . . . . 24

Analysis 1.21. Comparison 1 EDTA versus placebo, Outcome 21 Plasma high density lipoprotein (HDL)-cholesterol levels

(mmol/litre). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Analysis 1.22. Comparison 1 EDTA versus placebo, Outcome 22 Plasma cholesterol levels (mmol/litre). . . . . . 25

Analysis 1.23. Comparison 1 EDTA versus placebo, Outcome 23 Adverse event - stroke. . . . . . . . . . . 25

Analysis 1.24. Comparison 1 EDTA versus placebo, Outcome 24 Adverse event - hypocalcaemic symptoms. . . . 26

Analysis 1.25. Comparison 1 EDTA versus placebo, Outcome 25 Adverse event - fatigue. . . . . . . . . . . 26

Analysis 1.26. Comparison 1 EDTA versus placebo, Outcome 26 Adverse event - faintness. . . . . . . . . . 27

Analysis 1.27. Comparison 1 EDTA versus placebo, Outcome 27 Adverse event - gastrointestinal symptoms. . . . 27

Analysis 1.28. Comparison 1 EDTA versus placebo, Outcome 28 Adverse event - serum-creatinine increase. . . . 28

Analysis 1.29. Comparison 1 EDTA versus placebo, Outcome 29 Adverse event - proteinuria. . . . . . . . . 28

Analysis 1.30. Comparison 1 EDTA versus placebo, Outcome 30 Adverse event - phlebitis at infusion site. . . . . 29

Analysis 1.31. Comparison 1 EDTA versus placebo, Outcome 31 Adverse event - pain at infusion site. . . . . . 29

Analysis 1.32. Comparison 1 EDTA versus placebo, Outcome 32 Adverse event - headache. . . . . . . . . . 30

Analysis 1.33. Comparison 1 EDTA versus placebo, Outcome 33 Adverse event - Raynaud’s phenomenon. . . . . 30

iChelation therapy for atherosclerotic cardiovascular disease (Review)


Analysis 1.34. Comparison 1 EDTA versus placebo, Outcome 34 Adverse event - metallic taste. . . . . . . . . 31

Analysis 1.35. Comparison 1 EDTA versus placebo, Outcome 35 Adverse event - dermatitis. . . . . . . . . . 31

31APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiChelation therapy for atherosclerotic cardiovascular disease (Review)


[Intervention Review]


Antonio L Dans2, Flordeliza N Tan3, Essie C Villarruz-Sulit1

1Section of Adult Medicine & Medical Research Unit, Department of Medicine, Ermita, Philippines. 2Section of Adult Medicine,

College of Medicine, University of the Philippines, Ermita, Philippines. 3Manila, Philippines

Contact address: Essie C Villarruz-Sulit, Section of Adult Medicine & Medical Research Unit, Department of Medicine, 1st Floor,

Philippine General Hospital, Taft Avenue, Ermita, Manila, Philippines. [email protected]. [email protected]. (Editorial group:

Cochrane Peripheral Vascular Diseases Group.)

Cochrane Database of Systematic Reviews, Issue 3, 2009 (Status in this issue: Unchanged)


DOI: 10.1002/14651858.CD002785

This version first published online: 21 October 2002 in Issue 4, 2002.

Last assessed as up-to-date: 10 May 2005. (Help document - Dates and Statuses explained)

This record should be cited as: Dans AL, Tan FN, Villarruz-Sulit EC. Chelation therapy for atherosclerotic cardiovascular disease.

Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002785. DOI: 10.1002/14651858.CD002785.

A B S T R A C T

Background

Chelation therapy is being promoted and practiced all over the world as a form of alternative medicine in the treatment of atherosclerotic

cardiovascular disease. It has been recommended as a safe, relatively inexpensive and non-surgical method of restoring blood flow in

atherosclerotic vessels. At present the benefit of chelation therapy remains controversial at best.

Objectives

To assess the effects of ethylene diamine tetraacetic acid (EDTA) chelation therapy on clinical outcomes among people with atheroscle-

rotic cardiovascular disease.

Search strategy

The Cochrane Peripheral Vascular Diseases Group Trials Register was searched, (last searched May 2005), the Cochrane Controlled

Trials Register, (The Cochrane Library Issue 2, 2005), MEDLINE and EMBASE for published articles and other relevant articles. Studies

were also requested through correspondence with known Filipino practitioners of the procedure.

Selection criteria

Studies were included if they were randomized controlled trials of EDTA chelation therapy versus placebo or no treatment in participants

with atherosclerotic cardiovascular disease. Main outcome measures considered included either total or cause-specific mortality, non-

fatal cardiovascular events, direct or indirect measurement of disease severity, subjective measures of improvement or adverse events.

Data collection and analysis

Two authors (MVV, FT) extracted data and assessed trial quality independently. Unresolved issues were considered by a third author

(ALD). Discrepancies were discussed until a consensus was reached. Authors were contacted for additional information.

Main results

A total of five studies were included in the review. Mortality, non-fatal events, and cerebrovascular events were not reported in any of the

studies. Four of the studies, with a total recruitment rate of 250 participants, showed no significant difference in the following outcomes:

direct or indirect measurement of disease severity and subjective measures of improvement. One of the studies, which included only

1Chelation therapy for atherosclerotic cardiovascular disease (Review)




http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdf

10 participants, was interrupted prematurely, because of an apparent treatment effect. However, relevant data were not available in the

report and have been requested from the authors.

Authors’ conclusions

At present, there is insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical

outcomes of people with atherosclerotic cardiovascular disease. This decision must be preceded by conducting randomized controlled

trials that would include endpoints that show the effects of chelation therapy on longevity and quality of life among people with

atherosclerotic cardiovascular disease.

P L A I N L A N G U A G E S U M M A R Y


Not enough evidence about the effects of chelation therapy to reduce blockages in the blood vessels of people with atherosclerotic

cardiovascular (heart and circulation) disease. Atherosclerosis is caused by fatty deposits sticking to the inside of people’s arteries and

restricting blood flow. People with blocked arteries are more likely to have strokes and heart attacks, and can often only walk short

distances before their legs begin to ache. Chelation therapy involves infusions into the bloodstream of substances believed to remove

metals from the blood. This is promoted to people with atherosclerotic heart and circulation disease as a way of breaking down the

blockages in their blood vessels. However, the review found there is not enough evidence from trials about the effects of this treatment.

B A C K G R O U N D

Chelation therapy is being promoted and practiced as a form of

alternative medicine to treat atherosclerosis and relieve symptoms

of cardiovascular disease (Hiatt 1997). It has been recommended

as a safe, relatively inexpensive and non-surgical method of restor-

ing blood flow in atherosclerotic vessels, thus preventing chronic

symptoms such as angina pectoris and claudication, or acute symp-

toms such as myocardial infarction or stroke. Several clinics have

been set up worldwide advocating its use in people with atheroscle-

rotic cardiovascular disease.

Chelation therapy consists of a series of intravenous infusions con-

taining disodium ethylene diamine tetraacetic acid (EDTA) in

combination with other substances. EDTA, a water soluble com-

pound, has been found to be effective in chelating and removing

toxic metals from the blood (Green 1993). It is capable of com-

bining with polyvalent cations, such as calcium ions, to form a

soluble non-ionic complex that can be excreted (Wilder 1962).

Proponents of chelation believe that this mechanism, taking place

at the arterial wall, can lead to regression of atherosclerotic plaques

(Clarke 1960; Green 1993; Meltzer 1960). There have been case

reports suggesting that EDTA chelation therapy in people with

angina may lead to alleviation of symptoms (Clarke 1956; Meltzer

1960). On the other hand, a recent review on chelation therapy

for peripheral arterial occlusive disease has shown that chelation

therapy is not superior to placebo and is associated with consider-

able risks (Ernst 1997).

At present, the benefit of chelation therapy in people with

atherosclerosis has not been fully documented. In a book by Drs.

Walker and Shah on chelation therapy (Walker 1997), the authors

correctly noted that, “all possible mechanisms of action of chela-

tion therapy for producing the observed beneficial effects are still

incompletely documented. And this incomplete understanding of

why and how it works becomes a useful argument employed by

medical opponents of the method....There has, in fact, been no

full-scale study of the technique.”

Thus, the authors decided to perform a systematic review of avail-

able information on this treatment in order to discuss implications

for clinical practice and research.

O B J E C T I V E S

To determine whether EDTA chelation therapy is better than no

treatment or placebo in terms of improving clinical outcomes in

people with atherosclerotic cardiovascular disease.

M E T H O D S

Criteria for considering studies for this review

Types of studies



All randomized controlled trials of chelation therapy compared to

placebo or no treatment were included in this review.

Types of participants

Trials on people with atherosclerotic cardiovascular disease - either

cerebrovascular disease, coronary artery disease, or peripheral vas-

cular disease. Most trials were on people with intermittent claudi-

cation.

Types of interventions

Trials evaluating intravenous infusions containing EDTA com-

pared to placebo infusions or no treatment.

Types of outcome measures

The following outcome measures were considered: all cause mor-

tality, coronary heart disease (CHD) deaths, and vascular deaths.

Non-fatal events including acute coronary syndromes such as my-

ocardial infarction and unstable angina pectoris as well as cere-

brovascular events such as stroke were also considered. Effects on

direct measurement of disease severity (e.g. digital subtraction an-

giograms for peripheral arterial disease), indirect tests of disease

severity (e.g. ankle-brachial pressure index (ABPI)) and subjective

measures of severity such as walking distance for claudicants were

also evaluated. Adverse events were also included.

Search methods for identification of studies

The Cochrane Peripheral Vascular Diseases Group searched

their Specialised Register (last searched May 2005) and the

Cochrane Central Register of Controlled Trials (CENTRAL) in

The Cochrane Library (last searched Issue 2, 2005) for publications

describing (or which might describe) randomized controlled trials

(RCTs) of chelation therapy against placebo, or reference medi-

cations, for atherosclerotic cardiovascular disease. See Appendix 1

for details of the search strategy used to search CENTRAL.

The Specialised Register is constructed from electronic searches

of MEDLINE (1966 to date), EMBASE (1980 to date), and

CINAHL (1982 to date), and through handsearching relevant

journals. The full list of journals that have been handsearched, as

well as the search strategies used are described in the ’Search strate-

gies for the identification of studies’ section within the editorial

information about the Cochrane PVD Group in The Cochrane

Library,

http:/ / www.mrw.interscience.wiley.com/ cochrane/ clabout/

articles/ PVD/ frame.html

Other terms were sought by visiting chelation clinics and deter-

mining the names of the manufactured agents used, particularly

for chelation therapy on people with atherosclerotic cardiovascular

disease. Studies were also requested through correspondence with

known Filipino “experts” in the procedure, and through reading of

other published materials such as books and conference proceed-

ings. The bibliographies of the studies thus retrieved were searched

for further trials. There were no restrictions on language.

Data collection and analysis

Selection of trials

All identified trials were checked by two authors (MVV, FT), to

determine relevant articles for full text retrieval. Retrieved studies

were then assessed for eligibility by the same two authors, accord-

ing to the inclusion criteria specified. Issues that were unresolved

in the assessment and data extraction process were passed on to

the third author (ALD). Discrepancies were discussed until a con-

sensus was reached.

Quality of trials

For each trial fulfilling the inclusion requirements, an assessment

of methodological quality was undertaken independently by two

authors (MVV, FT). A quality assessment instrument developed

by the Philippine Cardiovascular Research Group was used. This

instrument classifies study quality according to selection, detec-

tion, performance and exclusion biases. Specific features evaluated

in this instrument were allocation concealment, balance in base-

line characteristics, blinding, drop-out rates, and analysis by in-

tention-to-treat. Issues that were unresolved in the assessment and

data extraction process were passed on to the third author (ALD).

Discrepancies were discussed until a consensus was reached.

Data extraction

Data for the specified outcomes were extracted independently by

two authors (MVV, FT). The information collected from each trial

included study design, participant characteristics, interventions

compared and outcomes measured. Discrepancies were discussed

until a consensus was reached.

Statistical analysis

Statistical pooling of outcomes was conducted. Heterogeneity be-

tween trials was tested. Analysis was performed using the statis-

tical guidelines set by the Cochrane Peripheral Vascular Disease

Group. For dichotomous outcomes, relative risk (RR) was used as

a measure of effect. Continuous scales of measurements used were

analysed as weighted mean difference (WMD).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

A total of seven randomized controlled trials were retrieved (

Guldager 1992; Guldager (Dan) 1992; Guldager 1993; Guldager

1996; Olszewer 1990; Sloth-Nielsen 1991; Van Rij 1994). None



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PVD/frame.html








of the studies evaluated people with coronary or cerebrovascular

disease. All seven studies recruited participants with peripheral

vascular disease, particularly those with intermittent claudication.

A double publication was noted as the Guldager study in 1992 was

also published in Danish (Guldager (Dan) 1992). Two of the seven

studies (Guldager 1993; Guldager 1996), were actually substud-

ies of another (Guldager 1992). One of the substudies (Guldager

1996), focused on mechanistic outcomes such as urinary metal

excretion and magnesium retention and was eventually excluded.

Thus, only five studies eventually underwent appraisal and data

extraction.

The following outcomes were monitored: digital subtraction an-

giogram, walking distance based on onset of pain or disabling

claudication, subjective walking distance, ankle brachial pressure

index (ABPI), lifestyle measures (i.e. quality of life and physical

well-being), blood lipid levels, pain-free maximal walking distance

measured on treadmill, or walking and bicycle stress tests.

Mortality was not reported in any of the trials. Non-fatal events

such as myocardial infarction, unstable angina pectoris and cere-

brovascular events were not included as endpoints in any of the

studies.

All studies compared EDTA to placebo. The placebo was either

an isotonic solution or distilled water.

Risk of bias in included studies

The quality of the included studies ranged from A to C, based on

the Philippine Cardiovascular Research Group assessment scale.

Allocation concealment and double-blinding were stated or im-

plied in all of the studies. However, in the study by Olszewer (

Olszewer 1990), the code was broken before the study’s comple-

tion, thereby opening the study to performance, exclusion, and al-

location bias. Only the study by Van Rij (Van Rij 1994) described

an intention-to-treat type of analysis at three months follow-up.

Effects of interventions

All the studies evaluated the use of EDTA on people with periph-

eral arterial disease. The study by Sloth-Nielsen analyzed a group

of 30 participants (Sloth-Nielsen 1991). The outcome reported

focused on digital subtraction angiograms. The result showed no

significant difference between EDTA chelation and placebo. Other

outcomes were measured such as walking distance, ABPI and tran-

scutaneous tension of oxygen diffusion on the skin. Exact data for

analysis could not be extracted from the article. Further informa-

tion was requested but none has been forthcoming. However, the

trial authors concluded that EDTA chelation therapy has no ben-

eficial effect on objective parameters or on subjective evaluations

on participants with claudication in the lower extremities caused

by arteriosclerosis.

Van Rij recruited 32 participants in the study (Van Rij 1994).

Fifteen participants were randomized to chelation and 17 to the

control group. The major endpoints monitored were walking dis-

tance (based on onset of pain or disabling claudication), subjective

walking distance, or ABPI at rest, and on exertion. There was no

significant difference between the control and treatment groups

for these major endpoints. Other endpoints included lifestyle mea-

sures (i.e. quality of life and physical well-being). Again, results

showed no significant difference.

There were two studies authored by Guldager et al that re-

cruited participants with intermittent claudication (Guldager

1992; Guldager 1993). However, one of these was a substudy that

monitored the effect of EDTA on blood lipids (Guldager 1993).

In this study, treatment with EDTA did not alter total cholesterol,

high density lipoprotein (HDL), low density lipoprotein (LDL) or

triglycerides. Guldager’s main trial of 153 participants monitored

pain-free and maximal walking distance measured on treadmill, as

well as ABPI (Guldager 1992). The results failed to demonstrate

any significant effect. There was no significant difference as well, in

terms of subjective evaluation by participants. Adverse events were

reported but not subjected to statistical analysis. These potential

side effects were as follows: stroke, hypocalcemic symptoms, fa-

tigue, faintness, gastrointestinal symptoms, serum creatinine in-

crease, proteinuria, phlebitis at infusion site, pain at infusion site,

headache, Raynaud’s phenomenon, metallic taste and dermatitis.

Only one article reported improvement in the application of chela-

tion therapy (Olszewer 1990). The study by Olszewer, et al. started

with a randomized, double-blind method, but was eventually com-

pleted as a single-blind study with no control group. Ten partici-

pants were recruited and initially received either EDTA or placebo.

The study was arbitrarily stopped because, according to the in-

vestigators, “after 10 treatments it was apparent that some partic-

ipants were improving substantially but others were not ..... we

therefore, decided to break the code.” The investigators then de-

cided to finish the study on a single-blind basis with no control

group, convinced with the improvements obtained from EDTA

treatment. Data from this study cannot be included in the statisti-

cal analysis as standard deviations were not reported in the article.

We asked the trial authors for more data but have not received any

response to date.

Overall, there were no significant changes in ABPI, walking dis-

tance, or pain-free walking distance. Weighted mean difference

(WMD) for ABPI was 0.01 (95% confidence interval (CI) -0.03

to 0.06) at the 20th infusion (Guldager 1992; Van Rij 1994), and

0.02 (95% CI -0.03 to 0.06) at three months post-treatment (

Guldager 1992; Van Rij 1994). WMD for walking distance was -

37.93 (95% CI -90.32 to 14.45) at the 20th infusion (Guldager

1992; Van Rij 1994), and -31.46 (95% CI -87.63 to 24.71) at three

months post-treatment (Guldager 1992; Van Rij 1994). Lastly,

WMD for pain-free walking distance was -16.4 (95% CI -31.99

to -0.81) at the 20th infusion (Guldager 1992; Van Rij 1994) and

-7.73 (95% CI -22.59 to 7.13) at three months post-treatment.



The side effects of chelation noted included faintness, relative risk

(RR) 11.44 (95% CI 1.51 to 86.45) and possibly gastrointestinal

symptoms, RR 1.63 (95% CI 0.67 to 3.99), proteinuria RR 2.60

(95% CI 0.85 to 7.93), and hypocalcemia, RR 3.12 (95% CI 0.65

to 14.98) (Guldager 1992). Procedure-related side effects were also

noted including phlebitis and pain at the infusion site (Guldager

1992).

D I S C U S S I O N

Treatment with EDTA for metal poisoning has been established

for decades (Guldager 1996). However, since the 1950s chelation

therapy has been suggested for the treatment of coronary disease

and other vascular diseases (Clarke 1955; Clarke 1956). Based on

the premise that since metastatic calcium deposits can be removed

by this technique, the calcium involved in atheromata could be

evacuated in a similar way. This mechanism would eventually

lead to an improvement in outcome of participants with coronary

disease. Initial claims on the effect of EDTA in lowering serum

calcium levels were based on animal experiments (Clarke 1956).

However, it was the result of active administration of EDTA to

people at that time that provided encouragement for the use of

this form of therapy. The continued use and promotion of chela-

tion therapy, however, is hampered by the limited availability of

randomized controlled trials that have shown benefit.

The studies published to date have failed to demonstrate signif-

icant benefit with the use of EDTA chelation therapy in people

with peripheral vascular disease. A single study showed benefit,

but conclusions were weak because of serious methodological flaws

seen upon review (Olszewer 1990). Although a meta-analysis of

unpublished data reported a high correlation between improve-

ment in cardiovascular function and treatment with EDTA, a ran-

domized controlled method was not used by the various investiga-

tors in their recruitment of participants (Chappel 1994). There-

fore, contrary to circulating claims, no published randomized con-

trolled trials have evaluated the use of EDTA in participants with

coronary or cerebrovascular disease. The meta-analysis by Chappel

(Chappel 1994) may be indicative of a treatment effect, however,

benefit is still questionable in the absence of a large randomized

controlled trial.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

At the present time, there is insufficient evidence to decide on the

effectiveness or ineffectiveness of chelation therapy in improving

clinical outcomes among people with atherosclerotic cardiovascu-

lar disease. Wider acceptance of this treatment in clinical practice

must be preceded by conducting more randomized clinical trials,

especially among people at risk for coronary or cerebrovascular

disease.

Implications for research

To date, there are no trials on the effectiveness of chelation therapy

on coronary and cerebrovascular disease. Trials have centered on

peripheral vascular disease, more specifically treatment of inter-

mittent claudication. Therefore, it is important that randomized

trials be conducted in people for whom the treatment is intended

and supposed to benefit, i.e. people with coronary and cerebrovas-

cular disease. It is also important that future trials using chelation

therapy include endpoints that show its effects on longevity and

quality of life rather than monitoring mechanistic outcomes.

A C K N O W L E D G E M E N T S

The authors wish to thank their family, friends and colleagues in

the profession for all the support. We are also grateful for the en-

couragement given by the following people: Prof. Shah Ebrahim,

Theresa Moore and Katherine Wornell of the Cochrane Heart

Group. Our deepest appreciation goes to the Cochrane Periph-

eral Vascular Disease Group, especially to Dr. Elizabeth Royle and

Heather Maxwell for the technical support, encouraging words

and reminders.

R E F E R E N C E S

References to studies included in this review

Guldager 1992 {published data only}

Guldager B, Jelnes R, Jorgensen SJ, Nielsen JS, Klaerke A, Mogensen

K, et al.EDTA treatment of intermittent claudication - a double-

blind, placebo-controlled study. Journal of Internal Medicine 1992;

231(3):261–7.

Guldager B, Jelnes R, Jorgensen SJ, Sloth-Nielsen J, Klaerke A, Mo-

gensen K, et al.EDTA versus placebo treatment in intermittent clau-

dication. A double-blind randomized trial [EDTA versus placebobe-

handling af claudicatio intermittens]. Ugeskrift for Laeger 1992;154

(23):1618–21.


Guldager B, Faergeman O, Jorgensen SJ, Nexo E, Jelnes R. Dis-

odium-ethylene diamine tetraacetic acid (EDTA) has no effect on

blood lipids in atherosclerotic patients. A randomized, placebo-con-

trolled study. Danish Medical Bulletin 1993;40(5):625–7.



Olszewer 1990 {published data only}

Olszewer E, Sabbag FC, Carter JP. A pilot double-blind study of

sodium magnesium EDTA in peripheral vascular disease. Journal of

the National Medical Association 1990;82(3):173–7.

Sloth-Nielsen 1991 {published data only}

Sloth-Nielsen J, Guldager B, Mouritzen C, Lund EB, Egebland M,

Norregaard O, et al.Arteriographic findings in EDTA chelation ther-

apy on peripheral arteriosclerosis. American Journal of Surgery 1991;

162(2):122–5.

Van Rij 1994 {published data only}

Van Rij AM, Solomon C, Packer SGK, Hopkins WG. Chelation

therapy for intermittent claudication: A double-blind, randomized,

controlled trial. Circulation 1994;90(3):1194–9.

References to studies excluded from this review

Anderson 2003 {published data only}

Anderson TJ, Hubacek J, Wyse DG, Knudtson ML. Effect of chela-

tion therapy on endothelial function in patients with coronary artery

disease: PATCH substudy. Journal of the American College of Cardi-

ology 2003;41(3):420–5.


Guldager B, Jorgensen PJ, Grandjean P. Metal excretion and mag-

nesium retention in patients with intermittent claudication treated

with intravenous disodium EDTA. Clinical Chemistry 1996;42(12):

1938–42.

References to ongoing studies

TACT 2003 {published data only}

Trial to Assess Chelation Therapy (TACT). http:

//www.clinicaltrials.gov/ct/show/NCT00044213?order=1.

Additional references

Chappel 1994

Chappel LT, Stahl JP, Evans R. EDTA chelation treatment for vas-

cular disease: a meta-analysis using unpublished data. Journal of Ad-

vancement in Medicine 1994;7(3):131–42.

Clarke 1955

Clarke NE, Clarke CN, Mosher RE. The “in vivo” dissolution of

metastatic calcium. An approach to atherosclerosis. American Journal

of Medical Sciences 1955;229(2):142–9.

Clarke 1956

Clarke NE, Clarke CN, Mosher RE. Treatment of angina pectoris

with disodium ethylene diamine tetraacetic acid. American Journal

of Medical Sciences 1956;232(6):654–66.

Clarke 1960

Clarke N. Atherosclerosis, occlusive vascular disease and EDTA. The

American Journal of Cardiology 1960;6(2):1–3.

Ernst 1997

Ernst E. Chelation therapy for peripheral arterial occlusive disease: a

systematic review. Circulation 1997;96(3):1031–3.

Green 1993

Green S. Chelation Therapy: unproven claims and unsound theories.

Nutrition Forum 1993.

Guldager (Dan) 1992

Guldager B, Jelnes R, Jorgensen SJ, Sloth-Nielsen J, Klaerke A, Mo-

gensen K, et al.EDTA versus placebo treatment in intermittent clau-

dication. A double-blind randomized trial [EDTA versus placebobe-

handling af claudicatio intermittens]. Ugeskrift for Laeger 1992;154

(23):1618–21.

Hiatt 1997

Hiatt WR. Current and future drug therapies for claudication. Vas-

cular Medicine 1997;2(3):257–62.

Meltzer 1960

Meltzer LE, Ural ME, Kitchell JR. The treatment of coronary artery

disease with disodium EDTA. Metal-Binding in Medicine, edited by

Seven MJ. Philadelphia: Lippincott, 1960.

Walker 1997

Walker M, Shah H. Everything you should know about chelation ther-

apy. New Canaan, Connecticut: Keats Publishing, 1997.

Wilder 1962

Wilder LW, De Jode LR, Milstein SW, Howard JM. Mobilization

of atherosclerotic plaque calcium with EDTA utilizing the isolation-

perfusion principle. Surgery 1962;52(5):793–5.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Guldager 1992

Methods Study design: Randomized, double-blind trial.

Method of randomization: patients randomized in blocks of 10.

Exclusions post-randomization: 6 (5 EDTA, 1 placebo).

Losses to follow up: 4 (2 deteriorations leading to vascular surgery, 1 death, 1 patient started chelation

therapy at a private clinic).

Participants Country: Denmark.

Setting: Outpatient clinic.

No. of patients: 159 (80 EDTA, 79 placebo).

Age: 64 ± 7 years EDTA, 66 ± 9 years placebo.

Gender: 48M : 32F EDTA, 55M : 24F placebo.

Inclusion criteria: stable intermittent claudication for at least 12 months; pain-free walking distance range

of 50 to 200 m measured on treadmill at a speed of 3.6 km/hr with 10 degree inclination; ABPI of worse

leg < 0.8.

Exclusion criteria: Vascular surgery within last 12 months, ischaemic rest pain or gangrene, moderate or

severe venous insufficiency, renal insufficiency, diabetes mellitus, thyroid or parathyroid disorders, hepatic

dysfunction, significant cardio-pulmonary failure, eg acute myocardial infarction within last 12 months,

tuberculosis, pregnancy, other conditions which could limit the patient’s walking distance or reliable

interpretation of the study, patients receiving anticoagulants, nitroglycerine or lithium, EDTA chelation

therapy within last 24 months.

Interventions Treatment: EDTA 3 g + NaCl 8.4 g in 1 litre normal saline solution x 20 infusions.

Control: 1 litre normal saline solution x 20 infusions.

Duration of treatment: 5-9 weeks.

Follow up: 3 and 6 months.

Outcomes 1. Subjective evaluation.

2. Pain-free and maximal walking distances.

3. ABPI (6 months duration of observation).

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate



Guldager 1993

Methods Study design: Randomized, double-blind trial or parallel group design.

Method of randomization: not stated but presumably as per Guldager 1992, patients randomized in blocks

of 10.

Exclusions post-randomization: Not stated.

Losses to follow up: Not stated.



No. of patients: 29 (14 EDTA, 15 placebo).

Age: over 40 years.

Gender: Not stated.

Inclusion criteria: stable intermittent claudication for 1 year; systolic ABPI < 0.8; pain-free walking distance

50 to 200 m.

Exclusion criteria: Diabetes mellitus, rest pain, ulcers or gangrene, kidney or liver disease, alcoholism.

Interventions Treatment: EDTA 3 g in

1 litre isotonic solution x 20 infusions.

Control: 1 litre isotonic saline x 20 infusions.

Patients also received daily vitamins, minerals and trace elements.


Follow up: Not stated.

Outcomes Plasma concentration of cholesterol, LDL, HDL, or triglycerides,

(5-9 weeks duration of observation).

Notes Substudy of Guldager 1992.

Risk of bias



Olszewer 1990

Methods Study design: Randomized,

double-blind for 10 treatments, then completed in an open single treatment fashion.

Method of randomization: Ampules numbered 1 to 10, patients randomly and equally divided; identifi-

cation of contents of each vial in a sealed envelope held by the manufacturer of the ampules.

Exclusions post-randomization: Not stated.

Losses to follow up: Not stated.



Olszewer 1990 (Continued)

Participants Country: Brazil/USA.


No. of patients: 10.

Age: Mean 47 years (range 41 to 53).

Gender: Male.

Inclusion criteria: peripheral vascular disease (Fontaine Stage II) - intermittent claudication; walking test

- claudication between 100 and 300 m; master exercise test - claudication with < 40 steps; bicycle stress

test

- claudication before 3 minutes at 50 km/hr.

Exclusion criteria: Pain at rest or at night, gangrene.

Interventions Treatment: EDTA 10 ml (1.5 g).

Control: Distilled water 10 ml.

Duration of treatment: 20 infusions (no time length specified).

Follow up: Not stated.

Outcomes 1. Walking distance measured by Walking Test.

2. Number of steps measured by Master Exercise Test.

3. Cycling time at 25 km/hr by Bicycle Test,

(observations made after 10 infusions and after 20 infusions).

Notes Adequate allocation concealment initially, but the code was broken before end of study.

Risk of bias



Sloth-Nielsen 1991


Method of randomization: Blocks of 10 according to a randomization code.

Exclusions post-randomization: None.

Losses to follow up: None.



No. of patients: 30.

Age: > 40 years old.

Gender: Not stated.

Inclusion criteria: (+) stable intermittent claudication; walking range of 50 to 200 m; ABPI < 0.8.

Exclusion criteria: vascular surgery within the last 12 months, ischaemic rest pain or gangrene, moderate

or severe venous insufficiency, renal insufficiency, diabetes mellitus, thyroid or parathyroid disorders,



Sloth-Nielsen 1991 (Continued)

hepatic dysfunction, significant cardio-pulmonary failure (eg. acute myocardial infarction within last year),

coexistent carcinomas, tuberculosis, pregnancy, other conditions that could limit the patient’s walking

distance or the full understanding of the study, patients receiving anticoagulants, nitroglycerin or lithium,

EDTA chelation therapy within the last 24 months.

Interventions Treatment: EDTA 3 g + NaCl 8.4 g in sterile water; 1 litre isotonic solution x 20 infusions.

Control: 1 litre isotonic solution x 20 infusions.

Patients also received oral viatmins, minerals and trace elements.


Follow up: 3 months.

Outcomes Digital subtraction angiograms,

(6 to 10 weeks duration of observation).

Notes Substudy of a larger trial not specified within the article.

Risk of bias



Van Rij 1994


Method of randomization: blocks of 10.

Exclusions post-randomization: None up to 3 month assessment.

Losses to follow up: None up to 3 month assessment.

Participants Country: New Zealand.


No. of patients: 32 (15 treatment, 17 control).

Age: 67.7 ± 7.0 years EDTA, 66.9 ± 6.7 years control.

Gender: 13M : 2F EDTA, 15M : 2F control.

Inclusion criteria: Intermittent claudication < 20% variation in measured walking distance over 3 consec-

utive assessments performed on different days, older than 45 years.

Exclusion criteria: Other debilitating disease that affected walking, significant renal disease, diabetes

mellitus.

Interventions Treatment: EDTA 3 g + MgCl 0.76 g + NaHCO3 0.84 g in

500 ml normal saline x 20 infusions.

Control: 500 ml normal saline x 20 infusions.



Van Rij 1994 (Continued)

Both groups’ infusions contained Parentrovite (thiamine hydrochloride 250 mg, riboflavine phosphate 5.5

mg, pyridoxine hydrochloride 50 mg, ascorbic acid 500 mg, nicotinamide 160 mg, sodium pantothenate

5 mg, glucose anhydrous 1000 mg, sodium metabisulphite 4 mg).

Both groups also received oral daily vitamin supplements.

Duration of treatment: 10 weeks.

Follow up: after 10 infusions, 3, 6 and 12 months (6 and 12 month assessments still in progress at time

of article).

Outcomes 1. Measured walking distance as total distance the patient was able to walk at 4 km/hr on a treadmill at

10% gradient to onset of pain or before stopping because of claudication.

2. Subjective walking distance as distance the patients considered able to walk before stopping because of

claudication.

3. Ankle/brachial indices at rest and immediately after TET,

(12 weeks duration of observation).

Notes

Risk of bias



ABPI Ankle-brachial pressure index

EDTA Ethylene diamine tetra-acetic acid

HDL High density lipoprotein

LDL Low density lipoprotein

MgCl Magnesium chloride

NaCl Sodium chloride

NaHCO3 Sodium hydrogen carbonate

TET Treadmill exercise test

Characteristics of excluded studies [ordered by study ID]

Anderson 2003 Outcome measured was flow-mediated vasodilation.

Guldager 1996 Reported only on metal excretion and magnesium retention.



Characteristics of ongoing studies [ordered by study ID]

TACT 2003

Trial name or title Trial to Assess Chelation Therapy (TACT).

Methods

Participants Patients with coronary artery disease.

Interventions 40 infusions of standard chelation solution versus 40 infusions of placebo in a 2x2 factorial design.

Outcomes Composite outcome of all cause mortality, myocardial infarction (MI), stroke, hospitalization for angina and

hospitalization for congestive heart failure.

Secondary endpoints will be:

a) combined outcome of cardiac death or nonfatal MI or nonfatal stroke;

b) individual components of the primary outcome;

c) coronary revascularisation;

d) safety of interventions including renal, hepatic and hematological function;

e) health related quality of life;

f ) cost and cost-effectiveness;

g) brachial artery flow-mediated endothelial function;

h) plasma markers of oxidative stress and anti-oxidant protection;

i) plasma markers of endothelial activation and inflammation.

Starting date March 2003.

Contact information NCCAM Clearinghouse +1 888 644 6226 or

http://www.clinicaltrials.gov/ct/show/NCT00044213?order=1

Notes



D A T A A N D A N A L Y S E S

Comparison 1. EDTA versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Ankle-brachial pressure index at

20th infusion

2 185 Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.03, 0.06]


3 months post-treatment

2 181 Mean Difference (IV, Fixed, 95% CI) 0.02 [-0.03, 0.06]


6 months post-treatment

1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

4 Walking distance (m) at 10th

infusion


5 Walking distance (m) at 20th

infusion

2 167 Mean Difference (IV, Fixed, 95% CI) -37.93 [-90.32,

14.45]

6 Walking distance (m) at 3

months post-treatment

2 165 Mean Difference (IV, Fixed, 95% CI) -31.46 [-87.63,

24.71]

7 Walking distance (m) at 6

months post-treatment


8 Pain-free walking distance (m) at

10th infusion


9 Pain-free walking distance (m) at

20th infusion

2 167 Mean Difference (IV, Fixed, 95% CI) -16.40 [-31.99, -

0.81]

10 Pain-free walking distance (m)

at 3 months post-treatment

2 165 Mean Difference (IV, Fixed, 95% CI) -7.73 [-22.59, 7.13]

11 Pain-free walking distance (m)



12 Subjective walking distance (m)

at 20th infusion


13 Subjective walking distance (m)



14 Subjective evaluation -

aggravation

1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected


unchanged


16 Subjective evaluation - mild

improvement



moderate improvement


18 Subjective evaluation - great

improvement


19 Plasma low density lipoprotein

(LDL)-cholesterol levels

(mmol/litre)


20 Plasma triglyceride levels

(mmol/litre)




21 Plasma high density lipoprotein

(HDL)-cholesterol levels

(mmol/litre)


22 Plasma cholesterol levels

(mmol/litre)


23 Adverse event - stroke 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

24 Adverse event - hypocalcaemic

symptoms


25 Adverse event - fatigue 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

26 Adverse event - faintness 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

27 Adverse event - gastrointestinal

symptoms


28 Adverse event - serum-

creatinine increase


29 Adverse event - proteinuria 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

30 Adverse event - phlebitis at

infusion site


31 Adverse event - pain at infusion

site


32 Adverse event - headache 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

33 Adverse event - Raynaud’s

phenomenon


34 Adverse event - metallic taste 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

35 Adverse event - dermatitis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Analysis 1.1. Comparison 1 EDTA versus placebo, Outcome 1 Ankle-brachial pressure index at 20th

infusion.

Review: Chelation therapy for atherosclerotic cardiovascular disease

Comparison: 1 EDTA versus placebo

Outcome: 1 Ankle-brachial pressure index at 20th infusion

Study or subgroup Treatment Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Guldager 1992 75 0.52 (0.14) 78 0.51 (0.13) 95.4 % 0.01 [ -0.03, 0.05 ]

Van Rij 1994 15 0.7 (0.36) 17 0.6 (0.15) 4.6 % 0.10 [ -0.10, 0.30 ]

Total (95% CI) 90 95 100.0 % 0.01 [ -0.03, 0.06 ]

Heterogeneity: Chi2 = 0.78, df = 1 (P = 0.38); I2 =0.0%

Test for overall effect: Z = 0.66 (P = 0.51)

-20 -10 0 10 20

Favours treatment Favours control



Analysis 1.2. Comparison 1 EDTA versus placebo, Outcome 2 Ankle-brachial pressure index at 3 months

post-treatment.



Outcome: 2 Ankle-brachial pressure index at 3 months post-treatment



Guldager 1992 73 0.54 (0.14) 76 0.53 (0.14) 82.6 % 0.01 [ -0.03, 0.05 ]

Van Rij 1994 15 0.62 (0.15) 17 0.58 (0.13) 17.4 % 0.04 [ -0.06, 0.14 ]

Total (95% CI) 88 93 100.0 % 0.02 [ -0.03, 0.06 ]



-10 -5 0 5 10


Analysis 1.3. Comparison 1 EDTA versus placebo, Outcome 3 Ankle-brachial pressure index at 6 months

post-treatment.



Outcome: 3 Ankle-brachial pressure index at 6 months post-treatment

Study or subgroup Treatment Control Mean Difference Mean Difference


Guldager 1992 57 0.56 (0.13) 66 0.53 (0.14) 0.03 [ -0.02, 0.08 ]

-10 -5 0 5 10




Analysis 1.4. Comparison 1 EDTA versus placebo, Outcome 4 Walking distance (m) at 10th infusion.



Outcome: 4 Walking distance (m) at 10th infusion



Guldager 1992 70 164 (79) 73 192 (222) -28.00 [ -82.18, 26.18 ]

-1000 -500 0 500 1000

Favours control Favours treatment

Analysis 1.5. Comparison 1 EDTA versus placebo, Outcome 5 Walking distance (m) at 20th infusion.



Outcome: 5 Walking distance (m) at 20th infusion



Guldager 1992 68 159 (99) 67 206 (239) 71.7 % -47.00 [ -108.88, 14.88 ]

Van Rij 1994 15 208 (135) 17 223 (149) 28.3 % -15.00 [ -113.41, 83.41 ]

Total (95% CI) 83 84 100.0 % -37.93 [ -90.32, 14.45 ]



-1000 -500 0 500 1000




Analysis 1.6. Comparison 1 EDTA versus placebo, Outcome 6 Walking distance (m) at 3 months post-

treatment.



Outcome: 6 Walking distance (m) at 3 months post-treatment



Guldager 1992 66 162 (101) 67 204 (248) 76.6 % -42.00 [ -106.19, 22.19 ]

Van Rij 1994 15 233 (138) 17 230 (195) 23.4 % 3.00 [ -113.06, 119.06 ]

Total (95% CI) 81 84 100.0 % -31.46 [ -87.63, 24.71 ]



-1000 -500 0 500 1000


Analysis 1.7. Comparison 1 EDTA versus placebo, Outcome 7 Walking distance (m) at 6 months post-

treatment.



Outcome: 7 Walking distance (m) at 6 months post-treatment



Guldager 1992 51 180 (150) 56 194 (127) -14.00 [ -66.93, 38.93 ]

-1000 -500 0 500 1000




Analysis 1.8. Comparison 1 EDTA versus placebo, Outcome 8 Pain-free walking distance (m) at 10th

infusion.



Outcome: 8 Pain-free walking distance (m) at 10th infusion



Guldager 1992 70 97 (41) 73 101 (53) -4.00 [ -19.49, 11.49 ]

-100 -50 0 50 100


Analysis 1.9. Comparison 1 EDTA versus placebo, Outcome 9 Pain-free walking distance (m) at 20th

infusion.



Outcome: 9 Pain-free walking distance (m) at 20th infusion



Guldager 1992 68 93 (40) 67 109 (56) 90.0 % -16.00 [ -32.44, 0.44 ]

Van Rij 1994 15 101 (50) 17 121 (89) 10.0 % -20.00 [ -69.30, 29.30 ]

Total (95% CI) 83 84 100.0 % -16.40 [ -31.99, -0.81 ]



-100 -50 0 50 100




Analysis 1.10. Comparison 1 EDTA versus placebo, Outcome 10 Pain-free walking distance (m) at 3 months

post-treatment.



Outcome: 10 Pain-free walking distance (m) at 3 months post-treatment



Guldager 1992 66 95 (48) 67 102 (42) 93.9 % -7.00 [ -22.34, 8.34 ]

Van Rij 1994 15 104 (62) 17 123 (108) 6.1 % -19.00 [ -79.17, 41.17 ]

Total (95% CI) 81 84 100.0 % -7.73 [ -22.59, 7.13 ]



-100 -50 0 50 100


Analysis 1.11. Comparison 1 EDTA versus placebo, Outcome 11 Pain-free walking distance (m) at 6 months

post-treatment.



Outcome: 11 Pain-free walking distance (m) at 6 months post-treatment



Guldager 1992 51 97 (47) 56 119 (93) -22.00 [ -49.56, 5.56 ]

-100 -50 0 50 100




Analysis 1.12. Comparison 1 EDTA versus placebo, Outcome 12 Subjective walking distance (m) at 20th

infusion.



Outcome: 12 Subjective walking distance (m) at 20th infusion



Van Rij 1994 15 413 (775) 17 327 (461) 86.00 [ -363.27, 535.27 ]

-1000 -500 0 500 1000


Analysis 1.13. Comparison 1 EDTA versus placebo, Outcome 13 Subjective walking distance (m) at 3

months post-treatment.



Outcome: 13 Subjective walking distance (m) at 3 months post-treatment



Van Rij 1994 15 448 (556) 17 381 (473) 67.00 [ -293.17, 427.17 ]

-1000 -500 0 500 1000




Analysis 1.14. Comparison 1 EDTA versus placebo, Outcome 14 Subjective evaluation - aggravation.



Outcome: 14 Subjective evaluation - aggravation

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Guldager 1992 1/75 0/78 3.12 [ 0.13, 75.37 ]

0.001 0.01 0.1 1 10 100 1000


Analysis 1.15. Comparison 1 EDTA versus placebo, Outcome 15 Subjective evaluation - unchanged.



Outcome: 15 Subjective evaluation - unchanged



Guldager 1992 38/75 39/78 1.01 [ 0.74, 1.39 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.16. Comparison 1 EDTA versus placebo, Outcome 16 Subjective evaluation - mild improvement.



Outcome: 16 Subjective evaluation - mild improvement



Guldager 1992 19/75 23/78 0.86 [ 0.51, 1.44 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.17. Comparison 1 EDTA versus placebo, Outcome 17 Subjective evaluation - moderate

improvement.



Outcome: 17 Subjective evaluation - moderate improvement



Guldager 1992 13/75 9/78 1.50 [ 0.68, 3.31 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.18. Comparison 1 EDTA versus placebo, Outcome 18 Subjective evaluation - great improvement.



Outcome: 18 Subjective evaluation - great improvement



Guldager 1992 4/75 7/78 0.59 [ 0.18, 1.95 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.19. Comparison 1 EDTA versus placebo, Outcome 19 Plasma low density lipoprotein (LDL)-

cholesterol levels (mmol/litre).



Outcome: 19 Plasma low density lipoprotein (LDL)-cholesterol levels (mmol/litre)



Guldager 1993 14 4.37 (0.21) 15 4.85 (0.26) -0.48 [ -0.65, -0.31 ]

-10 -5 0 5 10




Analysis 1.20. Comparison 1 EDTA versus placebo, Outcome 20 Plasma triglyceride levels (mmol/litre).



Outcome: 20 Plasma triglyceride levels (mmol/litre)



Guldager 1993 14 1.96 (0.17) 15 1.51 (0.18) 0.45 [ 0.32, 0.58 ]

-10 -5 0 5 10


Analysis 1.21. Comparison 1 EDTA versus placebo, Outcome 21 Plasma high density lipoprotein (HDL)-

cholesterol levels (mmol/litre).



Outcome: 21 Plasma high density lipoprotein (HDL)-cholesterol levels (mmol/litre)



Guldager 1993 14 1.03 (0.07) 15 1.43 (0.12) -0.40 [ -0.47, -0.33 ]

-10 -5 0 5 10




Analysis 1.22. Comparison 1 EDTA versus placebo, Outcome 22 Plasma cholesterol levels (mmol/litre).



Outcome: 22 Plasma cholesterol levels (mmol/litre)



Guldager 1993 14 6.29 (0.24) 15 6.97 (0.25) -0.68 [ -0.86, -0.50 ]

-10 -5 0 5 10


Analysis 1.23. Comparison 1 EDTA versus placebo, Outcome 23 Adverse event - stroke.



Outcome: 23 Adverse event - stroke



Guldager 1992 1/75 0/78 3.12 [ 0.13, 75.37 ]

0.01 0.1 1 10 100




Analysis 1.24. Comparison 1 EDTA versus placebo, Outcome 24 Adverse event - hypocalcaemic symptoms.



Outcome: 24 Adverse event - hypocalcaemic symptoms



Guldager 1992 6/75 2/78 3.12 [ 0.65, 14.98 ]

0.01 0.1 1 10 100


Analysis 1.25. Comparison 1 EDTA versus placebo, Outcome 25 Adverse event - fatigue.



Outcome: 25 Adverse event - fatigue



Guldager 1992 12/75 11/78 1.13 [ 0.53, 2.41 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.26. Comparison 1 EDTA versus placebo, Outcome 26 Adverse event - faintness.



Outcome: 26 Adverse event - faintness



Guldager 1992 11/75 1/78 11.44 [ 1.51, 86.45 ]

0.01 0.1 1 10 100


Analysis 1.27. Comparison 1 EDTA versus placebo, Outcome 27 Adverse event - gastrointestinal symptoms.



Outcome: 27 Adverse event - gastrointestinal symptoms



Guldager 1992 11/75 7/78 1.63 [ 0.67, 3.99 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.28. Comparison 1 EDTA versus placebo, Outcome 28 Adverse event - serum-creatinine increase.



Outcome: 28 Adverse event - serum-creatinine increase



Guldager 1992 7/75 9/78 0.81 [ 0.32, 2.06 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.29. Comparison 1 EDTA versus placebo, Outcome 29 Adverse event - proteinuria.



Outcome: 29 Adverse event - proteinuria



Guldager 1992 10/75 4/78 2.60 [ 0.85, 7.93 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.30. Comparison 1 EDTA versus placebo, Outcome 30 Adverse event - phlebitis at infusion site.



Outcome: 30 Adverse event - phlebitis at infusion site



Guldager 1992 35/75 28/78 1.30 [ 0.89, 1.91 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.31. Comparison 1 EDTA versus placebo, Outcome 31 Adverse event - pain at infusion site.



Outcome: 31 Adverse event - pain at infusion site



Guldager 1992 9/75 5/78 1.87 [ 0.66, 5.33 ]

0.1 0.2 0.5 1 2 5 10




Analysis 1.32. Comparison 1 EDTA versus placebo, Outcome 32 Adverse event - headache.



Outcome: 32 Adverse event - headache



Guldager 1992 7/75 7/78 1.04 [ 0.38, 2.82 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.33. Comparison 1 EDTA versus placebo, Outcome 33 Adverse event - Raynaud’s phenomenon.



Outcome: 33 Adverse event - Raynaud’s phenomenon



Guldager 1992 1/75 0/78 3.12 [ 0.13, 75.37 ]

0.01 0.1 1 10 100




Analysis 1.34. Comparison 1 EDTA versus placebo, Outcome 34 Adverse event - metallic taste.



Outcome: 34 Adverse event - metallic taste



Guldager 1992 1/75 0/78 3.12 [ 0.13, 75.37 ]

0.01 0.1 1 10 100


Analysis 1.35. Comparison 1 EDTA versus placebo, Outcome 35 Adverse event - dermatitis.



Outcome: 35 Adverse event - dermatitis



Guldager 1992 1/75 0/78 3.12 [ 0.13, 75.37 ]

0.01 0.1 1 10 100


A P P E N D I C E S

Appendix 1. Search strategy for CENTRAL

1) CARDIOVASCULAR DISEASES MeSH explode tree 1

2) (CARDIOVASCULAR next DISEASE*)

3) (PERIPHERAL next VASCULAR next DISEASE*)

4) #1 or #2 or #3

5) CHELATION THERAPY MeSH single term

6) CHELATING AGENTS MeSH explode tree 1

7) CHELATION*

8) ETHYLENEDIAMINES MeSH single term

9) (ETHYLENE next DIAMINE next TETRAACETIC next ACID*)

10) (ETHYLENE next DIAMINE next TETRA next ACETIC next ACID*)



11) (DISODIUM next ETHYLENE next DIAMINE next TETRAACETIC next ACID)

12) EDTA

13) #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12

14) (#4 and #13)

W H A T ’ S N E W

Last assessed as up-to-date: 10 May 2005.

29 May 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 4, 2000

Review first published: Issue 4, 2002

30 October 2006 Amended Minor edit

25 May 2005 New search has been performed Review updated with the addition of one ongoing study and minor style guide

changes

C O N T R I B U T I O N S O F A U T H O R S

Villarruz MVC - primary author, contact reviewer, appraised studies and extracted data.

Dans AL - author, reviewer, resolved discrepancies.

Tan F - author, reviewer, appraised studies and extracted data.

D E C L A R A T I O N S O F I N T E R E S T

None known.



S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• The Chief Scientist Office, Scottish Executive Health Directorates, The Scottish Government, UK.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Arteriosclerosis [∗therapy]; Chelating Agents [∗therapeutic use]; Chelation Therapy [∗methods]; Edetic Acid [∗therapeutic use]; Ran-

domized Controlled Trials as Topic

MeSH check words

Humans



EDTA chelation therapy for cardiovascular disease: a systematic Review Dugald MR Seely, Ping Wu and Edward J Mills

BioMed CentralBMC Cardiovascular Disorders

ss
Open AcceResearch articleEDTA chelation therapy for cardiovascular disease: a systematic reviewDugald MR Seely*1,2, Ping Wu2,3 and Edward J Mills4
Address: 1Canadian College of Naturopathic Medicine, Toronto, Canada, 2Institute of Medical Science, University of Toronto, Toronto, Canada, 3London School of Hygiene and Tropical medicine, University of London, UK and 4Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Canada

Email: Dugald MR Seely* - [email protected]; Ping Wu - [email protected]; Edward J Mills - [email protected]

* Corresponding author

AbstractBackground: Numerous practitioners of both conventional and complementary and alternativemedicine throughout North America and Europe claim that chelation therapy with EDTA is aneffective means to both control and treat cardiovascular disease. These claims are controversial,and several randomized controlled trials have been completed dealing with this topic. To addressthis issue we conducted a systematic review to evaluate the best available evidence for the use ofEDTA chelation therapy in the treatment of cardiovascular disease.

Methods: We conducted a systematic review of 7 databases from inception to May 2005. Handsearches were conducted in review articles and in any of the trials found. Experts in the field werecontacted and registries of clinical trials were searched for unpublished data. To be included in thefinal systematic review, the studies had to be randomized controlled clinical trials.

Results: A total of seven articles were found assessing EDTA chelation for the treatment ofcardiovascular disease. Two of these articles were subgroup analyses of one RCT that looked atdifferent clinical outcomes. Of the remaining five studies, two smaller studies found a beneficialeffect whereas the other three exhibited no benefit for cardiovascular disease from the use ofEDTA chelation therapy. Adverse effects were rare but those of note included a few cases ofhypocalcemia and a single case of increased creatinine in a patient on the EDTA intervention.

Conclusion: The best available evidence does not support the therapeutic use of EDTA chelationtherapy in the treatment of cardiovascular disease. Although not considered to be a highly invasiveor harmful therapy, it is possible that the use of EDTA chelation therapy in lieu of proven therapymay result in causing indirect harm to the patient.

BackgroundChelation therapy, a program of repeated intravenousadministration of ethylene diamine tetraacetic acid(EDTA), often given in combination with vitamins andminerals, has been touted as a safe alternative treatmentfor atherosclerotic vascular disease [1-3]. As this is a non-

conventional therapy, there is no universally recognizedstandard protocol. Most protocols, however, share adegree of similarity. A typical protocol might consist of 30intravenously administered solutions of 3 grams of diso-dium EDTA with concomitant administration of varyinglevels of ascorbic acid, B-vitamins, heparin, and the

Published: 01 November 2005

BMC Cardiovascular Disorders 2005, 5:32 doi:10.1186/1471-2261-5-32

Received: 08 July 2005Accepted: 01 November 2005

This article is available from: http://www.biomedcentral.com/1471-2261/5/32

© 2005 Seely et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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minerals magnesium, copper, zinc, selenium and manga-nese delivered over 1.5 to 3 hours in 500 ml to 1000 mlof normal saline. Therapy is often delivered on a weeklyor biweekly basis and may be followed up with a less fre-quent maintenance schedule.

There is a very strong market for this therapy with out-of-pocket costs for the use of EDTA to treat cardiovasculardisease estimated to range from $400 million to $3 bil-lion annually in the United States [4,5]. The use of chela-tion therapy for cardiovascular disease appears tocontradict conventional medical thought, however, asthree systematic reviews of clinical trials have concludedthat chelation therapy is not supported by the evidence[1,2,6]. In contrast, one early meta-analysis of uncon-trolled trials and unpublished data claimed that EDTAchelation therapy effectively improved the symptoms ofcardiovascular disease in over 80% of cases [7].

There is continued controversy as to the use of this therapyand a substantial amount of press given to it in popularnon-peer reviewed literature and on the Internet. Consid-ering the continued widespread usage and interest inEDTA chelation therapy we have endeavored to review themost current state of the evidence in order to provide anupdate on this contentious and clinically relevant issue.

MethodsSearch strategyWe searched the following databases, from inception toMay 2005: MedLine, EMBASE, Cochrane controlled trialsregister (CENTRAL), AMED (Alternative Medicine);AltHealthWatch;Pre-CINAHL;CINAHL;and the Nursing andAllied Health Collection. In addition we searched forunpublished and on-going trials through Clinicaltrials.gov and the National Research Register (UK). To beincluded in this review, a trial had to be a randomizedcontrolled trial assessing EDTA in humans at risk for car-diovascular disease. We excluded non-randomized trialsand pharmacokinetic studies. No limits based on lan-guage were imposed. Two reviewers (DS and PW) inde-pendently assessed the articles for inclusion and outcomedata. In the case of disagreement, arbitration was soughtfrom EM.

A more detailed description of the search strategy usedand the results are presented [see additional file 1].Authors of some of the trials were contacted to solicit theirinterpretation of the review and also to comment on anycriticism that we had found in non-peer reviewedliterature.

Data abstractionWe abstracted outcome data on ECG tests, exercise testsincluding treadmill tests, cycling time, time to ischemia,

pain free and maximal walking distances, subjectivesymptoms of angina, ankle brachial indices, digital sub-traction angiograms, transcutaneous oxygen tension,blood cholesterol levels, and quality of life measures. Weplanned to conduct a meta-analysis, however, the limitednumber of trials, their clinical heterogeneity, and the var-iability of outcomes made pooling impossible. Weabstracted quality criteria data from each of the RCTsassessed based on randomization, sample size determina-tion, dropouts, intention to treat, blinding, and allocationconcealment.

ResultsMain findingsWe found a total of fourteen studies for further analysis[4,8-20]. Of these, we excluded seven, as they were eitherreview articles or non-randomized studies [8-14]. Sevenstudies of randomized controlled trials have beenincluded in this systematic review [4,15-20]. Of the sevenmanuscripts, five were of distinct sample populations[4,16-18,20], with three of the trials analyzing data fromonly one participant sample [15,16,19]. Except for onetrial published in Danish, all trials were published in Eng-lish between 1963 and 2002. The data from the Danishtrial was also published in English, however, thereby notrequiring translation or inclusion. All included trials wereconducted in the United States, Canada, Denmark, NewZealand, or Germany.

Of the five sample populations tested, two studies (total n= 19) demonstrated a beneficial effect of EDTA chelationtherapy on cardiovascular disease measures and three(total n = 269) did not.

Study characteristics and adverse effectsSince the most recent systematic review, a Cochranereview, by Villaruz et al., 2002 [6], there has been one ran-domized controlled clinical trial on the effect of EDTA oncardiovascular disease. The conclusion found by Villaruzet al was that 'there is insufficient evidence to decide onthe effectiveness or ineffectiveness of chelation therapy inimproving clinical outcomes of patients with atheroscle-rotic cardiovascular disease' [6].

The most recent placebo-controlled trial conducted byKnudtson and colleagues in 2002 [4] explored the effectof chelation therapy on ischemic heart disease. Whencompared to placebo, a total of 33 rounds of EDTA treat-ment per patient was found to have no effect in any of theoutcomes measured [see additional file 2]. Both groupsexhibited improvements from baseline but this was inde-pendent of EDTA use.

Two of the earliest randomized controlled trials, by Kitch-ell et al., 1963 [17] and Olszewer et al., 1990 [18], found



EDTA chelation therapy to have a beneficial effect on car-diovascular risk profiles when compared to control. In thefirst trial by Kitchell et al., 50% of the active group experi-enced improved ECG readings after 6 and 12 weeks fol-lowing the final treatment. This crossover trial was haltedearly because 3 of the 5 members in the placebo groupdropped out due to a lack of improvement. In the trial byOlszewer et al. (1990), the code was broken early becausethe exercise measures and the ankle brachial blood pres-sure index all showed dramatic improvements in the che-lation group [see additional file 2]. Of all the trialsanalyzed, however, these studies used the least number ofparticipants, with sample sizes of 9 and 10 respectively.

Since the two positive trials by Kitchell and Olszewer,three larger trials have been completed. None of the morerecent trials has indicated any benefit from EDTA therapyon cardiovascular disease. One group of investigators,Guldager et al., 1992 [16], tested 153 patients with inter-mittent claudication for a number of clinical outcomes[see additional file 2]. None of these outcomes demon-strated evidence of improvement using parenteral EDTAchelation. Two subsets of this initial sample were ana-lyzed separately; one for digital angiograms and transcu-taneous oxygen profiles [19], and one for bloodcholesterol levels [15]. In neither of these outcomes wasthere any evidence of improvement dependent the inter-vention alone. In the trial by Van Rij et al., 1994 [20], 32patients were tested for similar outcomes with the same

negative findings. As described above, the most recenttrial by Knudtson et al., 2002 did not find any evidence ofefficacy in the treatment of 84 patients with coronaryartery disease through EDTA chelation therapy [4].

We assessed for adverse effects amongst the trials andfound only a few cases of adverse events that might beattributed to the EDTA [see additional file 2]. In the EDTAtreatment (vs. control) groups, one trial had a single (zerocontrols) case of potential kidney toxicity in a populationof 84 [4] and in another trial, eight cases (two controls) offaintness and 12 cases of hypocalcemia (one control) in apopulation of 153 were found [16]. No other adverseeffects were noted in any of the RCTs.

Study qualityIn an assessment of the articles for quality criteria, two ofthe trials did not describe randomization [15,17]; samplesize determination was only described in two trials [4,20];drop outs were excessive in one [17]; intention to treatanalysis was performed in four trials [4,18-20]; blindingwas inadequate in two of the trials [17,18]; and allocationconcealment was only adequate in one trial [4]. A sum-mary of quality criteria findings is listed in table 1. Thetwo trials with the highest quality [4,20] were the mostrecent and, as discussed above, found no evidence of effi-cacy for EDTA chelation therapy in the treatment ofcardiovascular disease.

Table 1: Quality criteria of the randomized controlled trials assessed

Reference Randomization Sample size determination

Drop outs Intention to treat analysis

Blinding Allocation concealment

Kitchell 1963 [17] Not described (nor stated)

Not described 33% of the treatment group upon cross-over

No Allegedly participants blinded, but impossible to adequately assess

Unclear

Olszewer 1990 [18]

Described Not described None Yes Initially double blinded but code was broken after 10 treatments and study was completed with single blind for remaining 10 treatments

Unclear

Sloth-Nielsen 1991 [19]

Described Not described None Yes Double Unclear

Guldager 1992 [16]

Described Not described 4 drop outs by 3 months; 30 drop outs by 6 months

No Double: code broken at 3 months

Unclear

Guldager 1993 [15]

Not described Not described Not mentioned No Double Unclear

Van Rij 1994 [20] Described Yes None Yes Double UnclearKnudtson 2002 [4] Described Yes 4 in placebo, 2 in

treatment groupYes Double Well described



DiscussionThe overall evidence on EDTA chelation therapy arguesagainst any clinical benefit with respect to cardiovasculardisease. The evidence that we were able to find in supportof EDTA chelation for cardiovascular disease relies almostentirely on uncontrolled trials and a large body of anecdo-tal evidence. Given the parameters of the evidence so far,and in keeping with patient values, it is encouraging thatthe NIH is funding a large simple trial. A 5-year multi-center randomized placebo-controlled trial will hopefullydeliver a conclusive answer on the question of whether ornot intravenous EDTA infusion has any role in the treat-ment of cardiovascular disease. Until such time, cliniciansshould openly discuss the use of complementary andalternative medicine and specifically chelation therapywith patients in an informed and non-judgmental man-ner. Clinicians should also discuss potential risks associ-ated with EDTA chelation therapy and the current lack ofevidence supporting it use in cardiovascular disease.

Proposed mechanisms of action for the reversal of cardio-vascular disease by EDTA include: calcium chelationresulting in dissolution of atheromatous plaques, free rad-ical scavenging action, reduction of total body iron stores,cell membrane stabilization, arterial dilatation due to cal-cium channel blocking action, improvement of arterialwall elasticity and increased production of nitric oxide[4,21]. Critics have taken issue with some of these mech-anisms, however, claiming the use of outdated conceptson the pathophysiology of atherosclerosis and forinstance, the inability of EDTA, a water soluble com-pound, to effectively complex with plaque calcium [3].

Given the widespread usage of EDTA chelation therapy,an assessment of its safety is crucial. EDTA is responsiblefor a wide range of potential side effects including gas-trointestinal and musculoskeletal complaints, diaphore-sis, fever, leukopenia, thrombocytopenia, kidney damage,mineral depletion, and hypocalcemia [19,22-24]. With

Flow-chart detailing study selection and exclusion for systematic reviewFigure 1Flow-chart detailing study selection and exclusion for systematic review.

374 articles excluded as irrelevant or

duplicate papers based on title and/or

abstract

14 articles retrieved for further

analysis

7 articles rejected due to being

review, duplicate data, and/or o

randomized trials

f non-

7 studies included in the systematic review

(including data from 5 separate trials)

2 studies analysed data from subpopulations of

the larger study

388 articles screened for inclusion



proper dose control and assessment of kidney function,however, EDTA is not considered to be a particularly high-risk therapy and there is little doubt that it is safer thancoronary bypass surgery. However, if EDTA has no efficacybeyond placebo, then the possibility of adverse effects, thecost of treatment, and potential to avoid greater risk maywell result in unjustifiable morbidity and mortality.

There are several limitations to consider in our review. Wecannot determine to what extent publication bias hasaffected our results. Empirical evidence has shown thatnegative trials in CAM and other fields are less likely to bepublished [25]. Claims have been made however, that evi-dence in favor of EDTA chelation therapy may have beensuppressed [26]. To mitigate as much as possible againstthese circumstances, we conducted thorough systematicsearches of the literature. We contacted some, but not allof the authors of the studies to confirm our interpretationof the results. It may be that authors of original studiesexcluded important information from the publishedmanuscripts in order to reduce the page length or to fol-low reviewers' suggestions [27]. In many of the trials therewas a significant improvement in outcome measures forboth control groups and chelation groups. This is a clearindication of the need to conduct controlled trials in orderto pick up a type I error that might mistakenly attributeefficacy to the therapy in question.

There is a large body of literature to support the use ofEDTA in the treatment of cardiovascular disease; however,the vast majority of the literature relies on uncontrolledevidence. Supporters of EDTA chelation therapy have lev-ied a number of criticisms against some of the RCTsassessed in this review. These criticisms include but arenot limited to: too short of a treatment schedule, claims ofincorrect statistical manipulation of the data, improperrandomization, and high dropout rates [26,28-30]. Theearliest trials incorporated 20 treatments of chelationtherapy and the American College for Advancement inMedicine (ACAM), considered an authority in chelationtherapy, claims that at least 30 treatments may be requiredfor improvements to be noted. In the most recent study byKnudston et al., 2002, however, a protocol involving 33treatment sessions were used and no positive therapeuticeffect was found. In our review we included quality crite-ria and did not find evidence of any bias, however, we didnot obtain the raw data needed to conduct an independ-ent reanalysis.

ConclusionThe findings of this systematic review should be of interestto clinicians and patients alike. The use of EDTA bypatients as a treatment for cardiovascular disease and asan adjunct or alternative to surgery is not supported by thehighest quality of evidence. Considering the cost incurred

by patients who use EDTA chelation therapy and thepotential for harm associated with any intravenous inter-vention including the potential for adverse effects attrib-utable directly to EDTA, clinicians should inquire aboutpatient use and highlight the lack of evidence to supportits usage.

List of abbreviations usedCAM: complementary and alternative medicine

ECG: electrocardiogram

EDTA: ethylene diamine tetraacetic acid

NIH: National Institutes of Health

RCT: randomized controlled trial

Competing interestsThe author(s) declare that they have no competinginterests.

Authors' contributionsDS and EM conceived the design of the study, DS and PWconducted the searches and undertook the data extractionand analysis with assistance from EM. DS drafted themanuscript. EM edited the manuscript.

Additional material

AcknowledgementsThe Hospital for Sick Children Research Institute and the Sick Kids Foun-dation and for their support.

References1. Ernst E: Chelation therapy for coronary heart disease: An

overview of all clinical investigations. Am Heart J 2000,140(1):139-141.

2. Ernst E: Chelation therapy for peripheral arterial occlusivedisease: a systematic review. Circulation 1997, 96(3):1031-1033.

3. Lewin MR: Chelation therapy for cardiovascular disease.Review and commentary. Tex Heart Inst J 1997, 24(2):81-89.

Additional File 1(text) EDTA and cardiovascular disease systematic review search strategy employed.Click here for file[http://www.biomedcentral.com/content/supplementary/1471-2261-5-32-S1.doc]

Additional File 2(table) Randomized controlled trials assessing the therapeutic use of EDTA for atherosclerotic cardiovascular disease.Click here for file[http://www.biomedcentral.com/content/supplementary/1471-2261-5-32-S2.doc]


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4. Knudtson ML, Wyse DG, Galbraith PD, Brant R, Hildebrand K, Pater-son D, Richardson D, Burkart C, Burgess E: Chelation therapy forischemic heart disease: a randomized controlled trial. Jama2002, 287(4):481-486.

5. Lamas GA, Ackermann A: Clinical evaluation of chelation ther-apy: is there any wheat amidst the chaff? Am Heart J 2000,140(1):4-5.

6. Villarruz MV, Dans A, Tan F: Chelation therapy for atheroscle-rotic cardiovascular disease. Cochrane Database Syst Rev2002:CD002785.

7. Chappell LT, Stahl JP: The correlation between EDTA chelationtherapy and improvement in cardiovascular function: ameta-analysis. J Adv Med 1993, 6:139-160.

8. Cheraskin E: Cardiovascular dynamics and EDTA chelationwith multivitamin/trace mineral supplementation. J Orthomo-lecular Medicine 1991, 6(1):8-12.

9. Cranton EM, Misner B: Endurance performance gains followingintravenous EDTA chelation therapy in a healthy 60-year-oldathlete. Clin Pract Alternat Med 2001, 2(2):135-136.

10. Elihu N, Anandasbapathy S, Frishman WH: Chelation therapy incardiovascular disease: ethylenediaminetetraacetic acid,deferoxamine, and dexrazoxane. J Clin Pharmacol 1998,38(2):101-105.

11. Geurkink TL: Improved peripheral vascular function with lowdose intravenous ethylene diamine tetraacetic acid (EDTA).Townsend Letter for Doctors & Patients 1994:722.

12. McDonagh EW, Rudolph CJ, Cheraskin E: An oculocerebrovascu-lometric analysis of the improvement in arterial stenosis fol-lowing EDTA chelation therapy. J Holistic Med 1982, 4(1):21-23.

13. Rathmann KL, Golightly LK: Chelation therapy ofatherosclerosis. Drug Intell Clin Pharm 1984, 18(12):1000-1003.

14. Schacter MB: EDTA Chelation Therapy - 2000. Total Health2000, 22(4):42.

15. Guldager B, Brixen KT, Jorgensen SJ, Nielsen HK, Mosekilde L, JelnesR: Effects of intravenous EDTA treatment on serum parath-yroid hormone (1-84) and biochemical markers of boneturnover. Dan Med Bull 1993, 40(5):627-630.

16. Guldager B, Jelnes R, Jorgensen SJ, Nielsen JS, Klaerke A, MogensenK, Larsen KE, Reimer E, Holm J, Ottesen S: EDTA treatment ofintermittent claudication--a double-blind, placebo-control-led study. J Intern Med 1992, 231(3):261-267.

17. Kitchell JR, Palmon FJ, Aytan N, Meltzer LE: The treatment of cor-onary artery disease with disodium EDTA. A reappraisal. AmJ Cardiol 1963, 11:501-506.

18. Olszewer E, Sabbag FC, Carter JP: A pilot double-blind study ofsodium-magnesium EDTA in peripheral vascular disease. JNatl Med Assoc 1990, 82(3):173-177.

19. Sloth-Nielsen J, Guldager B, Mouritzen C, Lund EB, Egeblad M, Nor-regaard O, Jorgensen SJ, Jelnes R: Arteriographic findings inEDTA chelation therapy on peripheral arteriosclerosis. Am JSurg 1991, 162(2):122-125.

20. van Rij AM, Solomon C, Packer SG, Hopkins WG: Chelation ther-apy for intermittent claudication. A double-blind, rand-omized, controlled trial. Circulation 1994, 90(3):1194-1199.

21. Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, WeerasooriyaR, Taylor RR: Effects of chelation with EDTA and vitamin Btherapy on nitric oxide-related endothelial vasodilatorfunction. Clin Exp Pharmacol Physiol 1999, 26(11):853-856.

22. Morgan BW, Kori S, Thomas JD: Adverse effects in 5 patientsreceiving EDTA at an outpatient chelation clinic. Vet HumToxicol 2002, 44(5):274-276.

23. Wirebaugh SR, Geraets DR: Apparent failure of edetic acid che-lation therapy for the treatment of coronary atherosclerosis.Dicp 1990, 24(1):22-25.

24. Guldager B, Jorgensen PJ, Grandjean P: Metal excretion and mag-nesium retention in patients with intermittent claudicationtreated with intravenous disodium EDTA. Clin Chem 1996,42(12):1938-1942.

25. Schmidt K, Pittler MH, Ernst E: Bias in alternative medicine isstill rife but is diminishing. Bmj 2001, 323(7320):1071.

26. Cranton EM: Textbook on EDTA Chelation Therapy. 2nd edi-tion. Charlottesville, Virginia , Hampton Roads Publishing CompanyInc.; 2001.

27. Roberts JC, Fletcher RH, Fletcher SW: Effects of peer review andediting on the readability of articles published in Annals ofInternal Medicine. Jama 1994, 272(2):119-121.

28. Cranton EM: Negative Danish study of EDTA chelation biased.Townsend Letter for Doctors 1992:604-605.

29. Olmstead SF: Critique of the Patch Chelation Therapy Trial.2002.

30. Chappell LT, Wilson J: Chelation therapy for vascular disease.Circulation 1999, 99(1):164-165.

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Should EDTA Chelation Therapy be Used Instead of Long-term Clopidogrel plus Aspirin to Treat Patients at Risk from Drug-Eluting Stents?

L.Terry Chappell

Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007

Alternative Medicine Review Volume 12, Number 2 2007

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Should EDTA Chelation Therapy be Used Instead of Long-term

Clopidogrel plus Aspirin to Treat Patients at Risk from

Drug-Eluting Stents?L. Terry Chappell, MD

AbstractThe recently discovered increased risk of blood clots, leading to myocardial infarction and sudden death beginning six months after medicated stents are implanted in patients following percutaneous transluminal coronary angioplasty (PTCA), has left cardiologists pondering what course of action to take. The purpose of adding implanted medication to a stent is to prevent thrombin accumulation and restenosis. However, these stents may increase, rather than decrease, the risk. Although long-term treatment with clopidogrel bisulfate (Plavix®) plus aspirin for at least 12 months has been suggested as a preventive treatment, there is no evidence from randomized, controlled trials that this treatment is effective for more than six months. Clopidogrel also increases the risk of major bleeding episodes.The author served as the primary investigator for a study that showed cardiovascular patients treated with EDTA chelation therapy had a lower rate of subsequent cardiac events, including myocardial infarction and death, than those treated with cardiac medications, PTCA, or coronary artery bypass graft (CABG). The data also indicated chelation therapy might be effective in preventing thrombosis and cardiac events from stent implantation.There is evidence EDTA chelation therapy might prevent hypercoagulability resulting from the placement of stents, although not specifically medicated stents. Based on the limited data currently available, intravenous EDTA may be safe and effective for treating patients who have implanted medicated stents. Prospective clinical trials are needed, and EDTA should be included in those trials.(Altern Med Rev 2007;12(2):152-158)

Risk of Thrombosis from Medicated Stents

The use of drug-coated (drug-eluting) stents with percutaneous transluminal coronary angioplasty (PTCA) has come into widespread use in recent years. Sirolimus-eluting stents were approved for use in April 2003, and 1.5 million have been implanted worldwide. Paclitaxel-eluting stents were approved in March 2004, and over three million have been implanted worldwide. The purpose of these stents is to reduce restenosis. Medicated stents have become increasingly popular; for example, they account for 90 percent of all stents sold in the United States in recent years. Although this percentage has decreased since reports of unfavorable outcomes began appearing, medicated versions are still being widely used.

An analysis of the Swedish Coronary Angi-ography and Angioplasty Registry found a promising initial trend, with 13.4 fewer events per 1,000 patients treated during the first six months after the stents were inserted.1 However, after six months, patients with drug-eluting stents had 12.7 more cardiac events per thousand patients than those with bare metal stents,

L. Terry Chappell, MD – Board-certified family physician; private practice in Bluffton, Ohio; President of the International College of Integrative Medicine.; advisor for the American Board of Clinical Metal Toxicology; member of the American College for Advancement in Medicine; clinical investigator for the NIH-funded Trial to Assess Chelation Therapy. Correspondence address: 122 Thurman Street, Bluffton, OH 45817.Email: [email protected]

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due to an increase in thrombosis at the site of the stent. The risk of death increased by 0.5 percent per year and the risk of myocardial infarction (MI) increased by 0.5-1.0 percent per year. At three years, the adjusted relative risk for death was 1.32 for patients treated with medi-cated stents compared to patients with non-medicated stents.

Medicated stents have U.S. Food and Drug Administration (FDA) approval for use in patients with single-vessel blockage (no more than two stents per patient) and no other significant medical problems. In September 2006, an FDA panel concluded that pa-tients who have drug-eluting stents have a significantly increased risk for developing blood clots. The report also noted studies indicating a small but significant increased risk for myocardial infarction and stroke.2 Drug-eluting stent patients had a lesser need for reintervention; how-ever, long-term survival and myocardial infarction-free survival were not improved, compared to patients with bare metal stents.

These risks are of great concern, but an even greater concern, according to the FDA panel, is that at least 60 percent of coated-stent use was off-label, due to the simultaneous insertion of more than two stents and/or the implantation of coated stents in patients with concomitant medical problems, such as myocardial infarction, multivessel disease, and diabetes.3 For indi-viduals treated for an off-label indication, the drug-elut-ing stent patients had higher rates of death from cardio-vascular causes, more nonfatal myocardial infarctions, and more stent thromboses than bare metal stent pa-tients. One reason for the expanded use of coated stents is that Medicare pays for these off-label, non-FDA-ap-proved indications.

The Occluded Artery Trial (OAT) added more confusion by challenging the basis of the open artery theory.4 It looked at 2,166 stable patients with totally occluded arteries several days after an MI and compared those treated with angioplasty plus stent and medications to those treated with medications alone. The patients treated with medications alone did slightly better than those treated with stents, whether the stent was drug-eluting or not. The difference was statistically significant.

The dilemma about when to use medicated stents and how to treat patients who have had them inserted has been so controversial the New England

Journal of Medicine devoted virtually the entire March 8, 2007, issue to the subject. Unanswered questions re-main because, depending on the techniques of analysis, some studies concluded drug-eluting stents impose an increased cardiovascular risk and higher mortality than bare metal stents, while others detect no such increases or even a reverse trend. However, all the studies con-firmed the FDA conclusion that stents of any kind can cause thrombosis and that the risk is particularly high with drug-eluting stents used for off-label indications.

Mechanism and Evidence for the Use of Clopidogrel for Coronary Artery Disease

Clopidogrel inhibits adenosine-induced plate-let aggregation. The evidence for its use for cardiovas-cular disease is primarily based on two randomized, controlled clinical trials. Aspirin inhibits thrombox-ane A2-induced platelet aggregation. Thus, combining clopidogrel with aspirin results in two slightly differ-ent mechanisms of action. The two drugs together are thought to be more effective than either drug alone.

The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,5 compared as-pirin with clopidogrel for an average time of 1.6 years in 19,185 patients with established vascular disease. The incidence of new ischemic strokes was 4.6 percent with clopidogrel and 4.8 percent with aspirin. The incidence of new myocardial infarctions was 2.9 percent with clopidogrel and 3.5 percent with aspirin. The absolute risk was lowered only 0.2 and 0.6 percent, respectively, and the vascular death rates were identical. The relative risks showed a preference for clopidogrel, but based on death rates, the trial did not actually show clopidogrel was superior to aspirin for this broad group of patients.

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial of 12,562 patients with acute coronary syndrome compared clopidogrel plus aspirin to aspirin alone over a one-year period.6 Add-ing clopidogrel lowered the cardiovascular death rate from 5.5 to 5.1 percent, ischemic stroke incidence from 1.4 to 1.2 percent, and MI incidence from 6.6 to 5.2 percent. A small benefit was attributed to combining the two drugs, but this benefit was demonstrated only for patients with the specific vascular problem of acute coronary syndrome (either unstable angina or non-ST elevation myocardial infarction). Importantly, for pa-tients who had acute coronary syndrome, the benefit



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occurred in the first two months after the syndrome was diagnosed. The CURE trial limited stroke analysis to is-1chemic strokes; apparently patients who suffered hem-orrhagic strokes were outliers removed from the study.

The CURE study demonstrated clopidogrel had no impact in reducing the number of patients who subsequently needed a coronary artery bypass graft (CABG) or PTCA (with or without stenting). There was no reduction in cardiac deaths for patients with demonstrated vascular disease in general, and for those with acute coronary syndrome the benefit was marginal and limited to the initial two months of therapy.

Eisenstein et al conducted an observational study of patients who received angioplasty and stents at the Duke Heart Center from 2000-2005.7 They found drug-eluting stent patients who discontinued clopido-grel after six months experienced an increased rate of death and non-fatal MI compared to those treated for 12 months. For patients with bare metal stents there was no such increase. The authors concluded there was a beneficial trend for using clopidogrel for 12 months, but that a randomized clinical trial of sufficient power was needed to provide evidence to determine the opti-mal length of treatment with clopidogrel. The research-ers did not analyze bleeding complications.

The increased risk of blood clots from drug-eluting stents does not begin until six months after in-sertion. Despite the lack of major clinical benefit and the existence of a significant risk for major bleeding episodes, many cardiologists treat patients who have medicated stents with clopidogrel plus aspirin for at least 12 months, if not indefinitely. Clinical evidence to

date does not support this therapy, and there is a significant risk of brain hemorrhage.

Mechanism and Evidence for the Use of Intravenous EDTA for Coronary Artery Disease

Many studies affirm the usefulness of intravenous (I.V.) EDTA8,9 in the treatment of vascular disease, while others report negative conclusions.10 None of the studies meet the cri-teria of two National Institutes of Health (NIH) review panels for definitive proof. All have been under-powered and many studies have been un-controlled, poorly randomized, and selectively reported. The NIH has funded the Trial to As-

sess Chelation Therapy (TACT), which is in progress at more than 100 centers in the United States and Can-ada. This randomized, controlled trial is designed to de-termine whether patients treated with EDTA chelation therapy in addition to standard medications and who have had a previous MI will have fewer cardiac events and deaths than others treated with standard medica-tions alone.

Anticoagulation is a common laboratory use for and known mechanism of EDTA. Studies demon-strate EDTA inhibits platelet aggregation induced by adenosine, epinephrine, and thrombin, while preserving collagen-induced aggregation.11,12 Thus, EDTA pro-vides good therapeutic effect, with three mechanisms that reduce platelet aggregation, while it maintains a safety factor by not inhibiting collagen-induced aggre-gation. Clopidogrel inhibits only adenosine-induced aggregation.

EDTA is approved for chelating lead from the body. Recent studies have shown even small amounts of lead can be a major risk for all-cause mortality, car-diovascular mortality, and myocardial infarction.13 Lead has also been shown to increase free radical activity.14 Thus, documented mechanisms of action support the use of EDTA for coronary artery disease, whether a stent is also used or not.

The author of this article was the chief inves-tigator for a multicenter, retrospective study of 220 pa-tients with known vascular disease treated from 1992-2001 with I.V. EDTA and followed for three years.15 The purpose of the study was to compare whether

PredictedPredicted ActualActual

Myocardial infarctions 1515 00

DeathsDeaths 66 00

Subsequent angioplastiesSubsequent angioplasties 3131 22

Subsequent CABGSubsequent CABG 1616 66

Table 1. EDTA Cardiac Events Study: 220 Patients with Three-year Follow-up



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cardiac events and death rates were reduced compared to what has been reported in the literature for stan-dard therapy (Table 1). Study patients were compared to similar groups of patients reported in the literature treated primarily with PTCA, CABG, or conventional cardiac medications; both surgical groups were also treated with cardiac medications as indicated.

Rakesh Shukla of the Center for Biostatistical Services at the University of Cincinnati Medical School performed a meta-analysis on the groups treated with conventional therapies and determined the rate of sub-sequent cardiac events (MI, CABG, and PTCA) and death together and separately. From the rate of cardiac events and deaths in the meta-analysis, he predicted the 220 patients treated with EDTA chelation thera-py should have suffered 15 MIs and six deaths during the three-year follow-up period. There were no MIs and no deaths in the patients treated with EDTA che-lation therapy. Furthermore, it was predicted by the meta-analysis that there should have been 16 CABG procedures and 31 PTCAs for the comparable group of 220 patients in the chelation study. There were only six CABG procedures and two PTCAs in the EDTA treatment group.

This article focuses on the groups of patients treated primarily with angioplasty with or without stents. A literature search found seven groups of patients treated primarily with PTCA in a time period similar to the study group. The average number of patients for the PTCA groups was 226. Other characteristics of the PTCA groups were similar to the EDTA group. The average age of the EDTA group was 64 years, while the average age of the PTCA group was 58 years. The

chelation group was 72-percent male; the PTCA groups were 82-percent male. Forty-eight percent of the chela-tion group had never smoked compared to 42 percent of the PTCA groups.

Of the groups treated primarily with PTCA, 7.3 percent had an MI within three years of follow-up, while the incidence of death from any cause was 3.2 per-

cent in the PTCA groups. Of those treated with PTCA, 22.3 percent needed another angioplasty within three years, and 11.8 percent un-derwent a CABG procedure. Thus, 34.1 percent of patients treated with angioplasty required another surgi-cal procedure within three years. These statistics are comparable to other reports from the literature.

Twenty-five of 220 pa-tients in the chelation study group had been treated previously with a PTCA, mostly with stent place-

ment (Table 2). Although this is not a large group, the 25 patients did remarkably well, as only one required a repeat PTCA within the three-year follow-up. None of them had an MI or a CABG procedure, and none of them died. The data from the literature indicate these outcome numbers are less than expected from a group of patients treated primarily with PTCA and followed with conventional cardiac medications.

The chelation study group reported no ad-verse clinical effects from the intravenous use of EDTA, which was administered according to the published protocol,15 confirming many reports from the literature that EDTA is a safe treatment when used properly.9,15 Major bleeding episodes have not been a concern with a properly administered EDTA protocol.

According to the published protocol, EDTA is administered with specified additives intravenously once or twice weekly for 20-30 treatments, each lasting 1.5-3 hours, depending on the dose used. The recom-mended dose of disodium magnesium EDTA is 50 mg/kg. Some clinicians give a maximum dose of 1.5 g, oth-ers 3.0 g; the dose is adjusted based on kidney function. For maintenance, treatments are administered monthly because new platelets are formed approximately every 3.5 weeks; monthly treatments provide continued plate-let aggregation inhibition.

Table 2. Surgical Procedures Required for Patients Treated Primarily with Angioplasty and Stents with Three-year Follow-up

Control Groups EDTA Treated(25 patients)

Percent repeat angioplasties 22.3% 4%

Percent CABG required 11.8% 0%

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The Case for Using EDTA Chelation Therapy to Prevent Activated Clotting in Patients Treated Previously with Medicated Stents

The mechanism of action of I.V. EDTA argu-ably fits well as an agent to prevent clotting induced by a medicated stent. It could be theorized its inhibition of adenosine-, epinephrine-, and thrombin-induced plate-let aggregation might be more effective than mecha-nisms that inhibit platelet aggregation more narrowly, as is the case of clopidogrel, which inhibits only adenos-ine-induced aggregation. Low levels of lead, commonly

found in patients, pose a substantial risk for cardiovas-cular disease. EDTA removes lead from the body. What is needed is clinical data to confirm the assertion that chelation therapy might be a useful treatment.

Although data from a prospective, controlled trial does not exist, the data from the EDTA cardiac events study is discussed above. Twenty-five out of 220 patients treated with EDTA were treated previously with PTCA with or without stent placement. None of these patients had a myocardial infarction or ischemic stroke, and none of them died during the three-year follow-up period. Only one of the 25 patients required a repeat PTCA, and no CABG procedures were per-

formed during the follow-up period, indicating the incidence of cardiac events was apparently significantly reduced by treat-ment with EDTA from what would be expected in a group of patients with coronary artery disease treated with PTCA and stents.

Table 3 compares the albeit limited data on intrave-nous EDTA to data supporting the long-term use of clopidogrel plus aspirin to prevent clot-ting in the presence of medi-cated stents and the effect of

Table 3. Thrombosis from Drug-eluting Stents Compared to EDTA

EDTA Long-term Clopidogrel

FDA indication No No

Clinical trials No No

Platelet inhibition 3 Mechanisms 1 Mechanism

Risk of major bleeding Minimal Yes

Preliminary data showing Yes Yesclinical effectiveness

Table 4. Optimal Treatment for Coronary Artery Disease

Optimize lifestyle Yes Yes

Platelet aggregation Clopidogrel; Aspirin EDTA; Fish oils

Lipids “Statin” drug Red yeast rice; Niacin; Fish oils

Inflammation “Statin” drug Red yeast rice; Fish oils

Arrhythmias Beta-blocker Magnesium

Blood pressure Beta-blocker; ACE Magnesium; Fish oils; Garlic; inhibitor, Diuretic Medication if necessary

Removal of lead None EDTA chelation therapy

Conventional Therapy Alternative Therapy



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clopidogrel in preventing cardiac events for other con-ditions, the latter of which demonstrated virtually no reduction in death rates. Both therapies are being used off-label in the treatment of coronary artery disease.

Safety is an important factor in choosing which medication to use. Intravenous disodium magnesium EDTA has been used safely since the modern protocol was established 35 years ago. Clopidogrel carries a sig-nificant risk of hemorrhage.

Clopidogrel is often given in a loading dose followed by 75 mg daily. EDTA is usually given intra-venously once or twice per week for 20-30 treatments, followed by monthly treatments. The cost of the initial course of treatment is higher with EDTA, but the cost of maintenance treatment with EDTA is probably less than ongoing treatment with clopidogrel. Furthermore, patients receiving monthly I.V. treatments are moni-tored more closely than those given a three-month pre-scription for clopidogrel with refills up to one year. At such visits, lifestyle changes can be reinforced, resulting in better compliance, an important consideration given adherence to multiple healthy lifestyle factors might be more important than any therapeutic drug in prevent-ing cardiovascular deaths.16 An optimal integrative ap-proach to prevention and treatment of coronary artery disease is summarized in Table 4.

ConclusionNo scientific evidence supports long-term use

of clopidogrel in preventing potentially fatal clotting linked to medicated stents. Quite the contrary, there is some indication that the long-term use of clopido-grel might put the patient at risk for a major bleeding episode, especially a hemorrhagic stroke. The benefit of using clopidogrel appears to be limited to the first 60 days after diagnosing acute coronary syndrome, which applies to a minority of patients who have had stents inserted. There is also some evidence that clopidogrel plus aspirin inhibits stent thrombosis during the first 3-6 months after stent placement. The recently detected increased risk of clotting from medicated stents occurs later, at least six months after insertion. Thus, there is no proof via randomized, clinical trials that treating patients with a drug-eluting stent in conjunction with clopidogrel for more than six months is helpful or safe.

Intravenous EDTA has a documented mecha-nism of action. There is reliable evidence from the lit-erature that it may prevent clotting and subsequent car-diac events, including premature death, in patients who have had PTCA with or without stent placement. The evidence is not conclusive, but it compares favorably to the body of evidence supporting the use of clopidogrel. Neither treatment has an FDA indication for long-term use to prevent complications from the placement of medicated stents. The data in hand, however, appears to indicate that chelation therapy may be an effective component in a comprehensive program to lesson the clotting risk from drug-eluting stents. In addition, any cardiovascular rehabilitation program should include aggressive lifestyle change. While there is some evidence that treatment with clopidogrel might have benefit dur-ing the 3-6 months following the placement of a medi-cated stent, long-term use of clopidogrel has no proven benefit. EDTA appears to be safer than clopidogrel be-cause it is less likely to cause major bleeding episodes.

In a March 8, 2007, New England Journal of Medicine article, the FDA called for randomized, con-trolled trials to determine the best treatment strategies for patients with complex cardiovascular conditions, such as diabetes, acute myocardial infarction, and mul-tivessel coronary artery disease.17 The FDA emphasized that safety end points such as death and myocardial in-farction should be studied, and the duration of therapy with clopidogrel and aspirin needs to be determined. This author proposes treatment with EDTA chela-tion therapy should also be studied for use in patients treated with medicated stents because of its safety and possible effectiveness. In the article, the FDA did not address the concern that patients with occluded arteries treated with medications alone might have better out-comes than those treated with angioplasty and stents.

The limited data available indicates EDTA may be safer and more effective than clopidogrel in pre-venting clots, myocardial infarctions, additional surgical procedures, and death as complications from medicated stents placed in coronary arteries, particularly in pa-tients with complex conditions.

EDTA has the additional benefit of removing low levels of lead that add a major risk of cardiovascu-lar disease and increased mortality. EDTA chelation therapy is being examined in the TACT study. Prelimi-nary data from the study cited above, which looked at

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the same end points as TACT, indicate EDTA might be effective in preventing cardiac events for patients with known vascular disease. Since the use of angio-plasty and stents does not appear to improve outcomes in patients with totally occluded arteries, the addition of EDTA to standard medications may be a promising treatment for coronary artery disease, whether or not drug-eluting stents have been implanted.

DisclosureThe author has no financial interest in EDTA

other than its use for patients in his own office.

References1. Lagerqvist B, James SK, Stenestrand U, et.al.

Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009-1019.

2. http://www.fda.gov/cdrh/news/091406.html [Accessed May 14, 2007]

3. http://www.fda.gov/cdrh/news/010407.html [Accessed May 14, 2007]

4. Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395-2407.

5. No authors listed. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

6. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.

7. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159-168.

8. Chappell LT, Stahl JP. The correlation between EDTA chelation therapy and improvement in cardiovascular function: a meta-analysis. J Adv Med 1993;6:139-163.

9. Olmstead SF. A Critical Review of EDTA Chelation Therapy in the Treatment of Occlusive Vascular Disease. Klamath Falls, OR: Merle West Medical Center Foundaton; 1998.

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Chelation therapy · Effect of Chelation Therapy on Endothelial Function in Patients With Coronary Artery Disease: PATCH Substudy Chelation therapy for atherosclerotic cardiovascular