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NEW RESEARCH PAPERS

Systemic Octreotide Therapy inPrevention of Gastrointestinal BleedsRelated to Arteriovenous Malformationsand Obscure Etiology in Atrial Fibrillation

Venkat Vuddanda, MD,a Mohammad-Ali Jazayeri, MD,a Mohit K. Turagam, MD,b Madhav Lavu, MD,a

Valay Parikh, MD,a Donita Atkins, BS,a Sudharani Bommana, MPHIL,a Madhu Reddy Yeruva, MD,a

Luigi Di Biase, MD, PHD,c Jie Cheng, MD,d Vijay Swarup, MD,e Rakesh Gopinathannair, MD,f Mojtaba Olyaee, MD,a

Vijay Ivaturi, PHD,g Andrea Natale, MD,c Dhanunjaya Lakkireddy, MDa

ABSTRACT

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OBJECTIVES The present study describes the use of octreotide (OCT) in patients with atrial fibrillation (AF) receiving

oral anticoagulation (OAC) who have gastrointestinal (GI) bleeding related to arteriovenous malformations (AVMs), as

well as its effect on OAC tolerance and subsequent rebleeding.

BACKGROUND AVMs cause significant GI bleeding, especially in patients with AF who are receiving OAC for stroke

prevention. OCT has been shown to minimize recurrent GI bleeds related to AVMs.

METHODS In a multicenter, observational study, 38 AF patients with contraindications to OAC because of AVM-related

GI bleeding were started on 100 mg of subcutaneous OCT twice daily. OAC was resumed in all patients within 48 h.

Incidence of recurrent GI bleeds was calculated, and hemoglobin levels were recorded at enrollment and at 3 and

6 months’ follow-up.

RESULTS After a median follow-up of 8 months, 36 patients (mean age 69 � 8.0 years; mean CHA2DS2-VASc score

3 � 1 and mean HAS-BLED score 3 � 1) were available for analysis. All were able to successfully resume OAC, and 28 of

36 (78%) remained on OAC at the conclusion of the study, whereas 8 underwent left atrial appendage closure with

subsequent OAC discontinuation. No systemic thromboembolic events occurred in follow-up. Of the 28 patients who

continued receiving OAC, 19 (68%) were free of recurrent GI bleed, 4 had minor GI bleeds, 4 required transfusion,

and 1 required colectomy for GI bleeding. Mean hemoglobin levels in all patients receiving OAC were significantly higher

at 3- and 6-month follow-up than at baseline (p < 0.001).

CONCLUSIONS Subcutaneous OCT therapy is an attractive option in AF patients receiving OAC who have AVM-related

GI bleeds. It allows successful reinitiation of OAC as a bridge to left atrial appendage exclusion or short-term relief

from bleeding. (J Am Coll Cardiol EP 2017;3:1390–9) © 2017 Published by Elsevier on behalf of the American College of

Cardiology Foundation.

m the aCardiovascular Research Institute, University of Kansas Hospital, Kansas City, Kansas; bDivision of Cardiology,

iversity of Missouri, Columbia, Missouri; cTexas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas; dTexas

art Institute, St. Luke’s Hospital, Houston, Texas; eArizona Heart Rhythm Center, Phoenix, Arizona; fDivision of Cardiology,

iversity of Louisville, Louisville, Kentucky; and the gDepartment of Pharmacy Practice and Science University of Maryland,

ltimore. Dr. Di Biase is a consultant to Stereotaxis, Biosense Webster, and St. Jude Medical; and has received speaker honoraria/

vel reimbursement fromBiotronik,Medtronic,BostonScientific, Janssen, Pfizer, andEpiEP.Dr. Swaruphas servedas a consultant

AB BR E V I A T I O N S

AND ACRONYM S

AF = atrial fibrillation

AVM = arteriovenous

malformation

CF-LVAD = continuous-flow

left ventricular assist device

GI = gastrointestinal

LAAC = left atrial appendage

closure

OAC = oral anticoagulation

OCT = octreotide

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 2 , 2 0 1 7 Vuddanda et al.D E C E M B E R 1 1 , 2 0 1 7 : 1 3 9 0 – 9 OCT to Prevent AVM-Related GI Bleeds in AF Patients

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A trial fibrillation (AF) is the most common car-diac arrhythmia worldwide (1). It imparts sig-nificant stroke risk and is associated with a

>2-fold increase in the odds of developing silent cere-bral infarctions (2). Systemic oral anticoagulation(OAC) is currently the mainstay of therapy to reducethe thromboembolic complications associated withAF (3); however, its use may be limited in patientsat high risk of bleeding, particularly gastrointestinal(GI) bleeding (4–6). Arteriovenous malformations(AVMs) such as angiodysplasia and hemorrhagictelangiectasias of the GI tract account for 40% to60% of lower GI bleeds (7,8). GI bleeding often forceswithdrawal of OAC and places patients at high risk ofsystemic thromboembolism. First-line managementoptions for AVMs include endoscopic therapy withargon plasma coagulation, fluoroscopy-guidedvascular embolization, and surgery. Most of theaforementioned options can be limited by patientfactors, procedural risks, and anatomic factors suchas the multifocal nature of the AVMs or poor accessi-bility of the culprit lesion, resulting in recurrent GIbleeds in 30% to 40% of cases despite the above inter-ventions (9).

There is some evidence that pharmacotherapy withsomatostatin analogues such as octreotide (OCT) is aneffective and well-tolerated option to prevent recur-rent GI bleeds in cases where endoscopic or surgicaltherapy is not feasible or is unsuccessful. The benefit ismuch more profound in patients with coagulopathiesor obligate need for OAC use (10). Current literatureon this topic is limited to anecdotal case reports.We sought to investigate whether OCT therapy canfacilitate safe reinitiation of OAC in AF patients with ahigh risk of stroke and GI bleeding due to AVMs.

METHODS

In this multicenter, observational study, 150 AFpatients with contraindication to OAC because of GIbleeding (defined as the appearance of melena, hem-atochezia, or guaiac-positive stool and a new drop inhemoglobin) were identified at the cardiac

to Abbot Vascular and BiosenseWebster; and is on the speakers bureaus for St

Dr. Gopinathannair has served as a consultant to St. Jude Medical and Bost

the American Heart Association, Pfizer, Bristol-Myers Squibb, Zoll Medical,

an advisory board for HealthTrust PG. Dr. Natale is a consultant for Stereota

received speaker honoraria/travel reimbursements from Biotronik, Medtro

All other authors have reported that they have no relationships relevant t

All authors attest they are in compliance with human studies committe

institutions and Food and Drug Administration guidelines, including

information, visit the JACC: Clinical Electrophysiology author instructions

Manuscript received November 2, 2016; revised manuscript received April 5

electrophysiology clinic. Sixty patients withGI bleeding related to AVMs (Figure 1) or ofobscure etiology (no pathology identified onendoscopy) were screened. Small-bowelAVMs are hard to identify and have beenshown to account for a large percentage ofobscure GI bleeds (11). Patients with GIbleeding secondary to other causes wereexcluded. Patients with a ventricular assistdevice, malignancy, thrombocytopenia(platelet count <150,000/ml), chronic liverdisease, chronic kidney disease, and activeinfection were excluded. Of 60 patientsscreened, 55 met inclusion and exclusion

criteria. Seventeen patients could not obtain OCTbecause of insurance coverage–related issues. Thirty-eight patients were ultimately enrolled in the study(Figure 2). Approval was obtained from the localinstitutional review boards.

Patients were started on OCT therapy (100 mg twicedaily given subcutaneously). Although monthlyintramuscular injection of a long-acting OCT formu-lation is available, daily injections were chosenbecause of cost implications. There were no signifi-cant differences between the 2 formulations in termsof efficacy or safety. OAC was resumed 48 h afterinitiation of OCT therapy. Choice of OAC was based onphysician preference.

Baseline demographic information, patient char-acteristics, medical history, medication details, dataon recurrent GI bleed and systemic thromboembolism(stroke, transient ischemic attack, and splenicinfarct), and hemoglobin levels at baseline and at3 and 6 months’ follow-up were collected.

Recurrent GI bleed was defined as any clinicallysuspected or documented bleeding from the GI tractas indicated by a new drop in hemoglobin and theappearance of melena, hematochezia, or guaiac-positive stools. All GI bleeding events were furthercharacterized based on the need for blood transfusionor invasive intervention. GI bleeds that requiredblood transfusion or colectomy were considered forleft atrial appendage closure (LAAC) using the

. JudeMedical, Boston Scientific, Janssen, and Pfizer.

on Scientific; has served on the speakers bureau for

and AltaThera Pharmaceuticals; and has served on

xis, BiosenseWebster, and St. JudeMedical; and has

nic, Boston Scientific, Janssen, Pfizer, and Epi EP.

o the contents of this paper to disclose.

es and animal welfare regulations of the authors’

patient consent where appropriate. For more

page.

, 2017, accepted April 11, 2017.

FIGURE 1 Arteriovenous Malformation

(Left) Endoscopic view of an arteriovenous malformation (AVM). (Right) AVM on mesenteric angiography.

FIGURE 2 Flow Diagram of Patient Enrollment

AF ¼ atrial fibrillation; AVM ¼ arteriovenous malformation; GI ¼ gastrointestinal; OAC ¼ oral anticoagulation.

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TABLE 1 Baseline Characteristics of the Study Population (n ¼ 36)

Age (yrs) 69.8 � 08

Sex

Men 9 (25)

Women 27 (75)

Race

White 33 (91.7)

African American 2 (5.6)

Other 1 (2.8)

BMI (kg/m2) 31 � 12

Type of AF

Paroxysmal 17 (47.2)

Persistent 19 (52.8)

CHADS2VASc score 3 � 1

HAS-BLED score 3 � 1

Type of OAC used prior to discontinuation for GI bleed

Rivaroxaban 6 (16.7)

Apixaban 8 (22.2)

Dabigatran 6 (16.7)

Warfarin 16 (44.4)

Source of GI bleed

Stomach 2 (5.6)

Duodenum 1 (2.8)

Small intestine 15 (41.7)

Colon 9 (25)

Unidentified 9 (25)

Pathology

Angiodysplasia 19 (52.8)

Vascular ectasia 2 (5.6)

Vascular nevus 3 (8.3)

Hemorrhagic telangiectasia 1 (2.8)

Hemangioma 1 (2.8)

N/A 10 (27.8)

Prior endoscopic therapy 12 (33.3)

LAA clot identified before intervention 5 (13.8)

Systemic thromboembolism before intervention

Stroke 5 (13.8)

TIA 2 (5.6)

Splenic infarct 1 (2.8)

Hypertension 22 (61.1)

Diabetes mellitus 7 (19.4)

Systolic heart failure 3 (8.3)

Valvular heart disease 9 (25)

Coronary artery disease 5 (13.8)

Peripheral vascular disease 17 (47.2)

Obstructive airway disease 1 (2.8)

Obstructive sleep apnea 8 (22.2)

LVEF (%) 60 (55–65)

LA size (cm) 4.25 (3.70–4.75)

Values are n mean � SD, n (%), or median (interquartile range).

AF ¼ atrial fibrillation; BMI ¼ body mass index; GI ¼ gastrointestinal; LA ¼ leftatrial; LAA ¼ left atrial appendage; LVEF ¼ left ventricular ejection fraction;N/A ¼ not available; OAC ¼ oral anticoagulation; TIA ¼ transient ischemic attack.

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LARIAT Suture delivery system (SentreHEART Inc.,Palo Alto, California) or WATCHMAN endocardialocclusion device (Boston Scientific, Marlborough,Massachusetts). If patients were not candidates forLAAC, their OCT dose was up-titrated to either 200 or300 mg at the physician’s discretion, and OAC therapywas continued. If patients experienced recurrent GIbleeding despite the above interventions, their OACtherapy was discontinued.

STATISTICAL ANALYSIS. Categorical variables arepresented as a frequency (n) or percentage, andcontinuous variables are expressed as mean � SD ormedian (interquartile range). Categorical variableswere compared with chi-square test or Fisher exacttest. Repeated-measures data analysis was performedwith a mixed-effects regression model in the entirecohort who continued receiving OAC, and cohortswere stratified by presence or absence of GI bleed ifassumptions for normality were met. If assumptionsof normality were not met, continuous variables werecompared with the Friedman test. A value of p < 0.05was considered statistically significant. Statisticalanalysis was performed with IBM SPSS Statisticsversion 23.0 (IBM, Armonk, New York).

RESULTS

Thirty-eight patients who met the inclusion criteriawere enrolled in the study. Two patients were lost tofollow-up, whereas 8 underwent LAAC and had OACand OCT discontinued before the 3-month follow-upvisit. Baseline characteristics of the study popula-tion are shown in Table 1.

The mean age was 69 � 8.0 years, and patientswere predominantly white women (69.4%) withnonparoxysmal AF (52.8%). The mean CHA2DS2VAScscore (a clinical stroke risk prediction model) was 3 �1, and the HAS-BLED score (which estimates risk ofmajor bleeding for patients receiving anticoagulation)was 3 � 1. Before discontinuation of OAC, 44% ofpatients were taking warfarin, 22.2% were takingapixaban, 16.7% were taking rivaroxaban, and 16.7%were taking dabigatran. A left atrial appendage clotwas identified in 5 of 36 patients (13.8%), and sys-temic thromboembolic events were reported in 8 of36 patients (22%) before enrollment. Median leftatrial size was 4.25 cm (interquartile range: 3.70 to4.75 cm), and median left ventricle ejection fractionwas 60% (interquartile range: 55% to 65%). The mostcommon source of GI bleed before enrollment wassmall intestine (42%), followed by colon (25%).Angiodysplasia was the most commonly identifiedpathology (76%). One third of the patients (33.3%)

underwent prior endoscopic intervention with argonplasma coagulation of identifiable lesions beforeenrollment.

Median follow-up duration was 8 months (range 6to 13 months). Among the study population, 8 of 36

FIGURE 3 GI Bleeds During Study Period

Recurrent GI bleeds after OAC was restarted with octreotide therapy in patients who

underwent LAAC with subsequent discontinuation of OAC (right) compared with patients

who continued receiving OAC (left). GI bleeding events in the LAAC group happened

before the LAAC procedure while patients were receiving OAC plus octreotide therapy

(n ¼ 36). LAAC ¼ left atrial appendage closure; req. ¼ requiring; other abbreviations as

in Figure 2.

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patients (22%) underwent LAAC for stroke prevention(LARIAT in 4 patients, WATCHMAN in 3 patients, andAtriClip [AtriCure, West Chester, Ohio] in 1 patient)with subsequent discontinuation of OAC and OCTtherapy. Before LAAC, while still receiving OAC/OCTtherapy, 4 of 8 (50%) had recurrent GI bleeds, and ofthese, 3 (37.5%) were major bleeds that requiredblood transfusion, whereas 1 was a minor bleed thatrequired no intervention (Figure 3).

The remaining 28 of 36 patients (77.8%) continuedOAC with apixaban in 15 cases (53.5%), rivaroxaban in11 (39.3%), and warfarin in 2 (7.1%). Among the 28patients who continued to receive OAC, 19 (67.8%)had no recurrent GI bleeds, whereas 4 (14.2%) hadminor GI bleeds and 4 (14.2%) had major GI bleedsthat required blood transfusion. In 1 other case, apatient had a major GI bleed that ultimately requiredcolectomy (Figure 4, Table 2).

In those patients who remained on OACthroughout the study period (n ¼ 28), the mean he-moglobin levels were significantly higher at 3 months(9.33 g/dl vs. 7.49 g/dl; p < 0.001) and 6 months(11.10 g/dl vs. 7.49 g/dl; p < 0.001) than at baseline(Figure 5). In 19 of the 28 patients free of recurrent GIbleeding while receiving OAC/OCT therapy (68%),mean hemoglobin levels were significantly higher at3 months (9.62 � 0.87 g/dl) and 6 months (11.69 �0.91 g/dl) than at baseline (7.55 � 1.08 g/dl). Anonparametric Friedman test of differences amongmean hemoglobin levels at baseline and 3- and6-month follow-up was conducted and rendered a

chi-square value of 36, which was significant(p < 0.01) (Figure 6). In 9 of the 28 patients withrecurrent GI bleeding while undergoing OAC/OCTtherapy (32%), mean hemoglobin levels were notsignificantly higher at 3-month follow-up than atbaseline (8.72 g/dl vs. 7.55 g/dl; p ¼ 0.56), but therewas a statistically significant difference at 6-monthfollow-up (9.84 g/dl vs. 7.55 g/dl; p ¼ 0.02). Of 28patients who remained on OAC, 8 had no identifiablecause on endoscopy and were labeled as having“obscure etiology.” Because the majority of thesepatients were clinically similar to patients withconfirmed AVMs, we included them as a singlecohort. The results discussed herein retained statis-tical significance even in the cohorts stratified on thebasis of the cause of GI bleed (AVMs vs. obscureetiology). Please see the Online Appendix for furtherdetails and comparisons.

In addition, 13 of 36 patients (36%) underwent suc-cessful cardioversion and were given antiarrhythmicdrugs for maintenance of sinus rhythm and continuedreceiving OAC/OCT. Throughout the follow-up period,there were no reported events of systemic thrombo-embolism or intracranial hemorrhage. OCT therapyenabled systemic thromboembolism prevention byeither continued OAC use (78%) or LAAC (22%). Amongthe patients in whom OAC was continued, 68%remained free of recurrent GI bleeding during thestudy period. Patients reported no side effects fromOCT (hypothyroidism, bradycardia, or gallbladderdysfunction) during the study period.

DISCUSSION

GI bleeding is a common side effect of OAC (odds ratio:1.45; 95% confidence interval: 1.07 to 1.97) (4–6).Often, diagnostic endoscopy reveals either no identi-fiable pathology or intestinal pathology such as AVMs.In such situations, continued OAC use can result inhigher rebleeding rates. No clinical trials currentlyaddress the safety of reinitiating OAC after major GIbleeding (12–16). Our study is the first multicenter,observational study evaluating the safety of reinitia-tion of OAC in AF patients with AVM-related GI bleedsusing concomitant OCT therapy. We showed thatmean hemoglobin levels were significantly higher at3 and 6 months compared with baseline.

AVM-RELATED GI BLEEDS. AVMs account for w5% ofupper GI bleeds and 40% to 60% of lower GI bleeds(17). They are pathologically dilated communicationsbetween thin-walled veins, venules, and capillarieslocated in the mucosa and submucosa of the GIsystem (18). Their pathogenesis remains unclear.

FIGURE 4 Outcomes of Patients Enrolled in the Study

A ¼ apixaban; pt ¼ patient; R ¼ rivaroxaban; W ¼ warfarin; other abbreviations as in Figures 2 and 3.

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Increased expression of angiogenic factors (basicfibroblast growth factor and vascular endothelialgrowth factor [VEGF]) is likely to play a major role(19). Acquired von Willebrand disease due to valvular

TABLE 2 Outcomes in Patients on OAC/OCT Therapy at

6-Month Follow-Up (n ¼ 28)

Type of OAC continued

Apixaban 15 (53.5)

Rivaroxaban 11 (39.3)

Warfarin 2 (07.1)

Recurrent GI bleeding after restartingOAC þ OCT therapy

9 (32.1)

Minor bleeds 4 (14.2)

Major bleed requiring transfusion 4 (14.2)

Major bleed requiring colectomy 1 (03.5)

Hemoglobin (g/dl)

Baseline 7.49 � 1.07

At 3-month follow-up 9.33 � 1.12

At 6-month follow-up 11.10 � 1.50

Values are n (%) or mean � SD.

OCT ¼ octreotide; other abbreviations as in Table 1.

heart disease (e.g., aortic stenosis) in elderly patientsis considered to be another possible mechanism andis mediated by negative modulation of the VEGFreceptor (20,21). Increased expression of VEGF exertsdirect action on endothelial cells, resulting inincreased production of tissue factor or plasminogenactivators. This increase in local fibrinolytic activitycould contribute to the increased bleeding tendencyand high rebleeding rates despite interventions (22).Rebleeding might be higher in patients who requireOAC therapy.

Pharmacotherapy with somatostatin analogues(OCT), hormone therapy (estrogen analogues), andthalidomide has emerged as a treatment optionfor refractory AVM-related GI bleeds. Data fromhormone therapy trials showed no significant dif-ferences compared with placebo in rates of recurrentGI bleeds and transfusion requirements (8). Datafrom OCT and thalidomide studies showed prom-ising results, but thalidomide use was limited by itshigh incidence of central nervous system side effects(71%) (23).

FIGURE 5 Mean Hemoglobin Levels During Follow-up

Mean hemoglobin levels in patients who remained on oral anticoagulation therapy

throughout the study period (n ¼ 28) were significantly higher at 3 months (9.33 g/dl vs.

7.49 g/dl; p < 0.001) and 6 months (11.10 g/dl vs. 7.49 g/dl; p < 0.001) of follow-up than

at baseline. Box plot shows median hemoglobin level (thick black line) with interquartile

range (yellow box); whiskers represent 1.5 � interquartile range; circles represent outliers.

FIGURE 6 Mean Hemoglobin Levels During Follow-up in Patients With and Without

Recurrent GI Bleed

In the group with no recurrent GI bleeding (NGIB; n ¼ 19), mean hemoglobin levels were

significantly higher at 3 months (9.62 � 0.87 g/dl) and 6 months (11.69 � 0.91 g/dl) than

at baseline (7.55 � 1.08 g/dl; p < 0.01). In the group with recurrent GI bleeding (GIB

group; n ¼ 9), no statistically significant difference was noted at 3-month follow-up

(8.72 g/dl vs. 7.36 g/dl; p ¼ 0.56), but the mean hemoglobin level at 6-month follow-up

was significantly higher than at baseline (9.84 g/dl vs. 7.36 g/dl; p ¼ 0.02).

GI ¼ gastrointestinal.

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OCT THERAPY. OCT, a synthetic analogue ofsomatostatin, has been studied in AVM-related GIbleeding. It acts by inhibition of angiogenesis (24).Indeed, disappearance or decrease in the size ofAVMs has been reported with OCT therapy (25).Some studies demonstrated decreased incidence ofrecurrent GI bleeding and an increase in hemoglobinlevels in a sustained fashion (26–29). However, inmost of these studies, only a small number of patients(#10) were receiving concomitant antithrombotictherapy.

DOSAGE AND FORMULATIONS. OCT is available in 2injectable formulations for long-term use (i.e., twice-daily subcutaneous injection and monthly intramus-cular injection). Oral formulation of the drug is notyet approved but could be available soon (30). Thetherapeutic dose ranges from 100 to 500 mg twicedaily for the subcutaneous formulation and 10 to30 mg monthly for the intramuscular formulation. Inthe present study, the subcutaneous formulation waspreferred because of cost. Although the maximumdaily dose was 500 mg thrice daily, this dose wasassociated with higher adverse events in prior studies(31). In light of this, we decided to limit patients to amaximum daily dose of 300 mg twice daily.

SIDE EFFECTS PROFILE. The most frequently re-ported side effects included pain at the injectionsite (10% to 20%) and mild to moderate GI distur-bances (5% to 15%) such as nausea, flatulence, loosestools, and abdominal cramping that were transientand self-limiting (32–38).

Long-term therapy (>12 months) had been reportedto result in hepatobiliary dysfunction, most commonlythrough asymptomatic gallstone formation (20% to40%) that usually requires no therapeutic interven-tion. Etiopathogenesis of these gallstones is unclearbut might involve change in bile composition, inhibi-tion of gallbladder emptying, hepatic bile secretion,and sphincter of Oddi motility. Timing of OCT injec-tion in relation to meals might mitigate this risk to acertain extent (39,40). Anecdotal case reports ofOCT-induced biliary hepatitis and pancreatitis havealso been published (41,42).

Cardiovascular side effects include conductiondisturbances (w2%) ranging from sinus bradycardiato complete heart block, more prominently withintravenous rather than subcutaneous or intramus-cular injection (43–45). Intravenous infusions werereported to have systemic and pulmonary vaso-pressor effects (46). Long-term subcutaneous OCTtherapy has been reported to cause injection-sitelipoatrophy (47). Other rare laboratory abnormalities(<1%) include reversible thrombocytopenia and

PERSPECTIVES

COMPETENCY IN PATIENT CARE: Pharmacotherapy with

somatostatin analogues such as octreotide is an attractive option

in people with lower GI bleeds related to vascular malformations

(AVMs) and an obligate need for OAC use. This enables

successful reinitiation of OAC with a decreased risk of recurrent

GI bleeds and provides a window to explore options such as

rhythm control strategy and LAAC in people with atrial

fibrillation.

TRANSLATIONAL OUTLOOK: Large-scale, multicenter pro-

spective studies and controlled trials comparing GI bleed event

rates, dose-response effect, and other clinical parameters that

influence the risk of recurrent GI bleeding are needed to validate

the above-mentioned conclusions.

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hyperkalemia, especially in patients undergoinghemodialysis (48,49).

Most of the safety data associated with long-termuse of OCT come from the acromegaly population.Going forward, more prospective studies are neededto pursue exploratory analysis to examine thedose-time-response relationship of its safety andefficacy profiles in the AF population. In addition,with the current choice of monthly OCT injectionsavailable, differences in the drug’s safety and efficacyprofiles based on route of delivery need to be furtherinvestigated in a prospective fashion.

Despite the above-mentioned side effects, OCT isoften well tolerated and is considered a valuabletherapeutic option in many hypersecretory states(acromegaly, carcinoid syndrome, VIPoma). It is alsoused as an antidote for sulfonylurea-induced hypo-glycemia, especially in patients with heart failurewho cannot tolerate intravenous dextrose infusions(50). Recent reports suggested that OCT therapyshowed a favorable response in decreasing bloodtransfusions, number of endoscopic procedures, andreadmissions because of GI bleeding in patients withcontinuous-flow left ventricular assist devices(CF-LVADs) (51,52). GI bleed is the most commoncause of readmissions in patients with end-stageheart disease treated with CF-LVADs (53). It ishypothesized that the lack of pulse pressure inCF-LVADs might lead to the development of AVMs,and the exact etiopathogenesis is multifactorial (54).

A recent phase I study by Malhotra et al. (55)evaluating the safety and tolerability of octreotideacetate long-acting release 20 mg depot injectionevery 4 weeks until week 16 after CF-LVAD placementhad 8 patients in the study. None of the patientsexperienced side effects or safety concerns relatedto OCT, nor did GI bleeding occur in the studypopulation (55).

In our study, we used OCT, a known therapyfor AVM-related GI bleeding, in the novel setting ofAF patients with high stroke risk warranting OACuse. By mitigating the risk of rebleeding, OCTenabled the safe continuation of OAC in more thanone-half of the patients (52.8%), as evidenced by thesteady improvement of their hemoglobin levelswhile receiving OCT plus OAC therapy. Even inpatients with GI bleeding while undergoing therapy,OCT helped enable the continuation of short-termperiprocedural OAC for LAAC. Nevertheless, beforethis therapy is considered as a long-term measure,the benefits of the treatment must be weighedagainst the risk of adverse effects such ashepatobiliary dysfunction associated with long-termtherapy.

STUDY LIMITATIONS. Our study presents the obviouslimitations of an observational study with medianfollow-up of only 8 months (range 6 to 13 months). Allpatients received OCT therapy, and there was nocontrol arm. It is hard to justify continued OACwithout an intervention in such a high-risk group ofpatients with GI bleeding while receiving anti-coagulation therapy. We were therefore unable tofind a control group, because most patients withrecurrent GI bleeding were not receiving OAC. Effectsof long-term OCT therapy in this population areunknown. Further studies with larger sample sizesand appropriate comparator groups, despite thestated challenges with identifying the latter, areneeded to confirm our findings. Despite these limi-tations, our study points toward a potential noveltherapy for patients with AF and a history of GIbleeding who require continued OAC.

CONCLUSIONS

Subcutaneous OCT therapy is a potential therapeuticoption in patients with AVM-related GI bleeding whorequire OAC therapy for stroke prevention. Treatmentwith OCT offers a safer way to reinitiate OAC bymitigating the risk of recurrent GI bleeds in themajority of patients. OCT therapy could serve as abridge to performing LAAC procedures and enablecontinuation of OAC after cardioversion and antiar-rhythmic drug therapy.

ADDRESS FOR CORRESPONDENCE: Dr. DhanunjayaLakkireddy, Division of Cardiovascular Diseases,Cardiovascular Research Institute, The University ofKansas Hospital, 3901 Rainbow Boulevard, KansasCity, Kansas 66160. E-mail: dlakkireddy@kumc.edu.

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KEY WORDS anticoagulation, atrialfibrillation, gastrointestinal bleed,octreotide, stroke

APPENDIX For supplemental figures, pleasesee the online version of this paper.