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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;-:-–-) © 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; he has received speaker honoraria/

vel reimbursement from Biotronik, Medtronic, Boston Scientific, Janssen, Pfizer, and Epi EP. Dr. Swarup has served as a

sultant to Abbot Vascular and Biosense Webster; on the speakers’ bureaus for St.Jude Medical, Boston Scientific, Janssen, and

zer. Dr. Gopinathannair has served as a consultant to St. Jude Medical and Boston Scientific; has served on speaker bureaus for

American Heart Association, Pfizer, Bristol Myers Squibb, Zoll Medical, and AltaThera Pharmaceuticals; and has served on an

visory board for HealthTrust PG. Dr. Natale is a consultant for Stereotaxis, Biosense Webster, and St. Jude Medical; he has

eived speaker honoraria/travel reimbursements from Biotronik, Medtronic, Boston Scientific, Janssen, Pfizer, and Epi EP.

other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

nuscript received November 2, 2016; revised manuscript received April 5, 2017, accepted April 11, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

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

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A trial fibrillation (AF) is the most com-mon cardiac arrhythmia worldwide(1). It imparts significant stroke risk

and is associated with a >2-fold increase inthe odds of developing silent cerebral infarc-tions (2). Systemic oral anticoagulation (OAC)is currently the mainstay of therapy to reducethe thromboembolic complications associ-ated with AF (3); however, its use may belimited in patients at high risk of bleeding,particularly gastrointestinal (GI) bleeding(4–6). Arteriovenous malformations (AVMs)such as angiodysplasia and hemorrhagic

telangiectasias 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 benefitis much more profound in patients with coagulo-pathies or obligate need for OAC use (10). Currentliterature on this topic is limited to anecdotal casereports. We sought to investigate whether OCTtherapy can facilitate safe reinitiation of OAC in AFpatients with a high risk of stroke and GI bleeding dueto 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 electro-physiology clinic. Sixty patients with GI bleedingrelated to AVMs (Figure 1) or of obscure etiology (nopathology identified on endoscopy) were screened.Small-bowel AVMs are hard to identify and have beenshown to account for a large percentage of obscure GIbleeds (11). Patients with GI bleeding secondary toother causes were excluded. Patients with a ventric-ular assist device, malignancy, thrombocytopenia

(platelet count <150,000/ml), chronic liver disease,chronic kidney disease, and active infection wereexcluded. Of 60 patients screened, 55 met inclusionand exclusion criteria. Seventeen patients could notobtain OCT because of insurance coverage–relatedissues. Thirty-eight patients were ultimately enrolledin the study (Figure 2). Approval was obtained from thelocal institutional 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 theLARIAT 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. p < 0.05 was

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)

Characteristics Patients

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, 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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considered statistically significant. Statistical analysiswas performed with IBM SPSS Statistics version 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 patients werepredominantly white women (69.4%) with non-paroxysmal AF (52.8%). The mean CHA2DS2VASc score(a clinical stroke risk prediction model) was 3 � 1, andthe HAS-BLED score (which estimates risk of majorbleeding for patients receiving anticoagulation) was3 � 1. Before discontinuation of OAC, 44% of patientswere taking warfarin, 22.2% were taking apixaban,16.7% were taking rivaroxaban, and 16.7% were takingdabigatran. A left atrial appendage clot was identifiedin 5 of 36 patients (13.8%), and systemic thromboem-bolic events were reported in 8 of 36 patients (22%)before enrollment. Median left atrial size was 4.25 cm(interquartile range: 3.70 to 4.75 cm), and median leftventricle ejection fraction was 60% (interquartilerange: 55% to 65%). The most common source of GIbleed before enrollment was small intestine (42%),followed by colon (25%). Angiodysplasia was the mostcommonly identified pathology (76%). One third of thepatients (33.3%) underwent prior endoscopic inter-vention with argon plasma coagulation of identifiablelesions before enrollment.

Median follow-up duration was 8 months (range 6to 13 months). Among the study population, 8 of 36patients (22%) underwent LAAC for stroke prevention(LARIAT in 4, WATCHMAN in 3, and AtriClip [Atri-Cure, West Chester, Ohio] in 1 patient) with subse-quent discontinuation of OAC and OCT therapy.Before LAAC, while still receiving OAC/OCT therapy,4 of 8 (50%) had recurrent GI bleeds, and of these,3 (37.5%) were major bleeds that required bloodtransfusion, 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

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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(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 g/dl � 0.87 g/dl) and 6 months(11.69 g/dl � 0.91 g/dl) than at baseline (7.55 g/dl �1.08 g/dl). A nonparametric Friedman test of differ-ences among mean hemoglobin levels at baseline and3- and 6-month follow-up was conducted andrendered a chi-square value of 36, which was signifi-cant (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%) underwentsuccessful cardioversion and were given antiar-rhythmic drugs for maintenance of sinus rhythm andcontinued receiving OAC/OCT. Throughout thefollow-up period, there were no reported events ofsystemic thromboembolism or intracranial hemor-rhage. OCT therapy enabled systemic thromboembo-lism prevention by either continued OAC use (78%) orLAAC (22%). Among the patients in whom OAC wascontinued, 68% remained free of recurrent GIbleeding during the study period. Patients reportedno side effects from OCT (hypothyroidism, brady-cardia, or gallbladder dysfunction) during the studyperiod.

DISCUSSION

GI bleeding is a common side effect of OAC (oddsratio: 1.45; 95% confidence interval: 1.07 to 1.97)(4–6). Often, diagnostic endoscopy reveals either noidentifiable pathology or intestinal pathology such asAVMs. In such situations, continued OAC use canresult in higher rebleeding rates. No clinical trialscurrently address the safety of reinitiating OAC aftermajor GI bleeding (12–16). Our study is the firstmulticenter, observational study evaluating thesafety of reinitiation of OAC in AF patients with

AVM-related GI bleeds using concomitant OCTtherapy. We showed that mean hemoglobin levelswere significantly higher at 3 and 6 months comparedwith 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.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 valvularheart 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

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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differences compared with placebo in rates ofrecurrent GI bleeds and transfusion requirements(8). Data from OCT and thalidomide studies showedpromising results, but thalidomide use was limited

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.

by its high incidence of central nervous system sideeffects (71%) (23).

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). Somestudies demonstrated decreased incidence of recur-rent GI bleeding and an increase in hemoglobin levelsin a sustained fashion (26–29). However, in most ofthese studies, only a small number of patients (#10)were receiving concomitant antithrombotic therapy.

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 was

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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preferred 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 andhyperkalemia, 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 the dose-time-response relationship of its safety and efficacyprofiles in the AF population. In addition, with thecurrent choice of monthly OCT injections available,differences in the drug’s safety and efficacy profilesbased on route of delivery need to be further inves-tigated 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 therapy

PERSPECTIVES

COMPETENCY IN PATIENT CARE: Pharmaco-

therapy 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 prospective 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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showed 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 therapy forAVM-related GI bleeding, in the novel setting of AFpatients with high stroke risk warranting OAC use. Bymitigating the risk of rebleeding, OCT enabled thesafe continuation of OAC in more than half of thepatients (52.8%), as evidenced by the steadyimprovement of their hemoglobin levels whilereceiving OCT plus OAC therapy. Even in patientswith GI bleeding while undergoing therapy, OCThelped enable the continuation of short-termperiprocedural OAC for LAAC. Nevertheless, beforethis therapy is considered as a long-term measure, thebenefits of the treatment must be weighed against therisk of adverse effects such as hepatobiliarydysfunction associated with long-term therapy.

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 sizes

and 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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infarctions: a systematic review and meta-analysis.Ann Intern Med 2014;161:650–8.

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

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