Novel oral anticoagulants in gastroenterology practice

REVIEW ARTICLE

Novel oral anticoagulants in gastroenterology practice Jay Desai, MD,1 Christopher B. Granger, MD,2 Jeffrey I. Weitz, MD,3 James Aisenberg, MD4 New York, New York

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with a 5-fold increase in the risk of ischemic stroke, and AF-related strokes have worse outcomes than those not associated with AF.1,2 Warfarin reduces the risk of stroke in patients with AF by approximately two-thirds and is more effective than aspirin or dual antiplatelet therapy with aspirin and clopidogrel.3 Although effective, warfarin has limitations that complicate its use. These include unpredictable pharmacokinetics and pharmacodynamics related to genetic polymorphisms and to variations in dietary vitamin K intake and numerous drug-drug interactions. Therefore, frequent monitoring is needed to attempt to keep the international normalized ratio (INR) within the therapeutic range. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. The limitations of warfarin contribute to its underuse in eligible patients with AF, and even when warfarin is given, the INR is frequently outside the therapeutic range. For the first time in over 50 years, novel oral anticoagulants (NOACs) are available. Instead of reducing the Abbreviations: AF, atrial fibrillation; aPTT, activated partial thromboplastin time; ARISTOTLE, apixaban for reduction in stroke and thromboembolic events in atrial fibrillation; ASGE, American Society for Gastrointestinal Endoscopy; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal antiinflammatory drug; PCC, prothrombin complex concentrate; PPI, proton pump inhibitor; PT, prothrombin time; RE-LY, randomized evaluation of long term anticoagulant therapy; ROCKET-AF, rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation; RR, relative risk. DISCLOSURES: J. Desai was supported by a grant from the Digestive Disease Research Foundation. C. Granger received grants from BristolMyers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and the Medicines Company. He received consulting fees from AstraZeneca, Boehringer Ingelhelm, Bristol-Myers Squibb, GlaxoSmithKline, HoffmannLaRoche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, Lilly, Pfizer, and the Medicines Company and travel grants from Hoffmann-La Roche, Novartis, and Pfizer. J. Weitz is a consultant for and received honoraria from BMS, Pfizer, Boehringer Ingelhelm, Bayer, Janssen Pharmaceuticals, Daiichi Sankyo, Merck, and Takeda. J. Aisenberg is a consultant for and received honoraria from Boehringer Ingelhelm. No other financial relationships relevant to this publication were disclosed. Copyright ª 2013 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.04.179

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effective levels of multiple coagulation factors, the NOACs specifically target either factor Xa or factor IIa (thrombin), thereby attenuating thrombosis. Currently, 3 NOACs are approved for stroke prevention in AF: rivaroxaban and apixaban, which target factor Xa, and dabigatran etexilate, which targets thrombin. The NOACs are at least as effective as warfarin for stroke prevention in AF, result in about half the rate of intracranial hemorrhage, and are more convenient to administer because they can be given in fixed doses without routine coagulation monitoring. Higher drug cost is one concern with NOAC treatment. A second is that the frequent measurement of effect and the associated healthcare provider interaction required with warfarin therapy likely improves medication adherence, and strategies to assure adherence to NOAC therapy are currently needed. Of particular relevance to gastroenterologists, rivaroxaban and dabigatran are associated with an increased risk of major GI bleeding compared with warfarin, and dabigatran is associated with an increased risk of non-bleeding upper GI symptoms such as dyspepsia and heartburn. Consequently, although practicing gastroenterologists may never prescribe a NOAC, they are likely to encounter NOAC-related GI adverse events, and they will need to manage NOACs around the time of endoscopy. In this review, we describe the pharmacology and GI safety profile of the NOACs and provide clinical management suggestions.

PHARMACOLOGY Whereas warfarin antagonizes vitamin K-dependent posttranslational modifications of factors II, VII, IX, and X in the liver, the NOACs directly inhibit the biologic activity of factor Xa or thrombin, which are critical proteases in the clotting cascade (Fig. 1). In contrast to warfarin, the NOACs have a rapid onset and offset of action (Fig. 2). Dietary vitamin K does not influence the anticoagulant effect of the NOACs, and there are few drug-drug interactions. Consequently, the NOACs produce a more predictable anticoagulant response than warfarin, which obviates the need for routine coagulation monitoring (Table 1). The individual NOACs have different pharmacologic properties, and an understanding of these differences is important in clinical practice (Table 2). Volume

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Figure 1. Sites of action of warfarin, apixaban, dabigatran, and rivaroxaban. Warfarin inhibits the synthesis of the vitamin K-dependent clotting factors (II, VII, IX, and X) in the liver, whereas the novel oral anticoagulants competitively inhibit the binding of factor Xa (apixaban and rivaroxaban) or thrombin (dabigatran) to their substrates in the blood. F, factor.

Dabigatran

Rivaroxaban

In order to achieve oral absorption, dabigatran is administered as a prodrug (dabigatran etexilate), which after absorption is cleaved by serum and hepatic esterases to active dabigatran.4 Absorption is increased in an acidic milieu, and therefore the drug is compounded with tartaric acid. Despite this requirement, coadministration of a proton pump inhibitor (PPI) decreases absorption but does not appear to decrease efficacy. The bioavailability of dabigatran etexilate is approximately 7%. The capsule is designed for release in the stomach, and the molecule is absorbed in the proximal small intestine. The nonabsorbed drug passes though the luminal GI tract, where the majority is converted to dabigatran and is excreted in the stool. Dabigatran reversibly binds to thrombin, inhibiting its activity (Fig. 1). Dabigatran has a half-life of 9 to 17 hours, depending on age and renal function. The drug is primarily eliminated by the kidney as unchanged drug; consequently, in patients with renal impairment, not only is there a risk of accumulation, but the half-life of the drug also is prolonged. In the United States, 2 doses of dabigatran are approved for stroke prevention in AF: 150 mg twice daily and 75 mg twice daily. Dose reduction is recommended in individuals with severe renal dysfunction,5,6 and the drug is contraindicated in individuals with a creatinine clearance !15 mL/minute. Dabigatran levels are increased by potent p-glycoprotein intestinal efflux transport inhibitors, such as fluconazole and are decreased by p-glycoprotein enhancers, such as rifampin. Modest inhibitors, like amiodarone or verapamil, increase plasma concentration modestly.

Rivaroxaban directly and reversibly binds to the active site of factor Xa, thereby attenuating thrombin generation (Fig. 1). In the United States, rivaroxaban is approved at 20 mg daily, to be taken with the evening meal; the dose is reduced to 15 mg daily in patients with a creatinine clearance of !50 mL/minute. Rivaroxaban is absorbed primarily in the proximal small intestine and at the 20-mg dose has a bioavailability of approximately 66% (Table 2).7-9 The half-life is approximately 6 to 13 hours;8 one-third is excreted unchanged by the kidneys, and the remainder is metabolized by the liver in a CYP3A4-dependent fashion. Inactive metabolites are excreted equally in feces and urine. The drug is contraindicated in patients with creatinine clearance !15 mL/minute, with advanced liver disease, and with coagulopathy. At doses above 10 mg, absorption is increased by food intake and unaffected by PPIs.10 Rivaroxaban levels are increased by concomitant administration of drugs that are potent inhibitors of both p-glycoprotein and CYP3A4, such as the azole antifungal agents or protease inhibitors, and are decreased by drugs that are strong inducers of p-glycoprotein or CYP3A4.

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Apixaban Apixaban also selectively inhibits factor Xa (Fig. 1). It achieves maximum concentration within 1 hour of oral ingestion. The drug has rapid clearance, with a half-life of approximately 12 hours. The bioavailability of apixaban is approximately 50%, and approximately 35% of nonabsorbed apixaban is excreted in stool.11 Apixaban can be taken with or without food.12,13 Only 25% of apixaban is www.giejournal.org

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Novel oral anticoagulants in gastroenterology

Nonetheless, important general conclusions regarding NOAC efficacy and safety are possible, especially because they share a common comparator (adjusted-dose warfarin) (Table 4).

Efficacy: prevention of stroke and systemic embolic events In the randomized evaluation of long term anticoagulant therapy (RE-LY) trial, dabigatran at 150 mg twice daily was superior to warfarin for prevention of stroke and/or systemic embolic events (1.11% vs 1.71%/year, relative risk [RR] 0.65, 95% confidence interval [CI], 0.52-0.81; P ! .002), preventing about 6 additional events per 1000 patients per year. Likewise, in the apixaban for reduction in stroke and thromboembolic events in atrial fibrillation (ARISTOTLE) trial, apixaban 5 mg twice daily was superior to warfarin in the prevention of stroke and/or systemic embolic events (1.27% vs 1.60%/year, hazard ratio [HR] 0.79, 95% CI, 0.66-0.095; P ! .01), preventing 3 additional events per 1000 patients per year. In the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF) trial, in the intention-to-treat analysis, rivaroxaban 20 mg daily proved non-inferior to warfarin in prevention of stroke and/or systemic embolic events (2.1% vs 2.4%/year, HR 0.88, 95% CI, 0.75-1.03; P Z .12). Dabigatran 150 mg twice daily was the only drug to reduce ischemic stroke, in a secondary analysis, in comparison to warfarin (0.92% vs 1.20%/ year, RR 0.76, 95% CI, 0.60-0.98; P Z .03). Whereas each of these novel agents reduced all-cause mortality with an RR reduction of about 10%, this reduction was statistically significant and part of the prespecified primary analysis only for apixaban. Figure 2. Schematic representation of comparative pharmacodynamics (onset Fig. 2A, offset Fig. 2B) of warfarin and of the novel oral anticoagulants. The representation is based on a half-life of 10 hours for a NOAC and 40 hours for warfarin and assumes normal liver and kidney function. Note that unlike warfarin, the NOACs achieve therapeutic anticoagulation within hours of the first dose. Also unlike warfarin, full coagulation function is restored within 24 to 48 hours after the NOAC dose is held. NOAC, novel oral anticoagulant.

excreted through the kidneys; however, among patients treated with apixaban (as with warfarin, dabigatran, and rivaroxaban) renal insufficiency increases the risk of bleeding. As with dabigatran and rivaroxaban, concomitant use of potent inhibitors of p-glycoprotein and CYP3A4 increase drug exposure.

NOAC EFFICACY AND SAFETY Although similar in many respects, the pivotal NOAC trials differ in study design and study population, and their results are not directly comparable (Table 3). www.giejournal.org

Safety: major bleeding Major bleeding, the principal safety endpoint in the 3 trials, was defined as a decrease in hemoglobin of R2 g/dL or transfusion of R2 units of packed red blood cells or bleeding into a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal) or fatal bleeding. There were minor variations in protocol definitions of major bleeding among the 3 trials, but the impact of these variations on event adjudication is uncertain. In the RE-LY trial, dabigatran 150 mg twice daily (but not dabigatran 110 mg twice daily) was associated with a numerically smaller but similar rate of major bleeding as warfarin (3.32% vs 3.57%/year; P Z .32). A significant treatment-by-age interaction was noted in which the HR of major bleeding for dabigatran versus warfarin was higher in the elderly. That is, in younger patients, there was substantially less bleeding with dabigatran than with warfarin, whereas in patients Rage 75, there tended to be more bleeding with dabigatran.14 Aspirin and renal impairment increased the bleeding rate in both arms.14 In the Volume

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TABLE 1. Comparison of pharmacologic and clinical characteristics of warfarin and the novel oral anticoagulants as a class Warfarin

NOAC

Route of administration

Oral

Oral

Food and drug interactions

Many

Few

Narrow

Wide

Yes

No

Hepatic

Renal and hepatic

Reduces synthesis of factors II, VI, IX and X

Directly inhibit factor Xa or thrombin

Days

Hours

O36 hours

9-17 hours

Frequent

Rare

Valvular and nonvalvular AF Prevention and treatment of VTE

Nonvalvular AF Prevention and treatment of VTE

Yes (vitamin K, FFP, PCC)

No

Yes (PT, INR)

Yes (PT, aPTT, anti-Xa, Hemoclot)

Therapeutic window Need for routine monitoring Site of elimination Mechanism of action Time to peak onset Half-life Need for “bridging” Approved indication (USA) Antidote Monitoring

NOAC, Novel oral anticoagulant; AF, atrial fibrillation; VTE, venous thromboembolism; FFP, fresh-frozen plasma; PCC, prothrombin complex concentrate; PT, prothrombin time; INR, international normalized ratio; aPTT, activated partial thromboplastin time.

TABLE 2. Comparison of the absorption and elimination of warfarin, apixaban, dabigatran, and rivaroxaban Bioavailability

Active anticoagulant present in GI tract

Renal excretion

Hepatic metabolism

100%

None

None

High

Dabigatran

7%

High

High

Low

Rivaroxaban

66%

Moderate

Moderate

Moderate

Apixaban

50%

Moderate

Moderate

Moderate

Warfarin

ROCKET-AF trial, the major bleeding rate was comparable for rivaroxaban and warfarin (3.6% vs 3.4%/year; P Z .58). Concomitant aspirin or thienopyridine usage was associated with a higher rate of major bleeding in both the warfarin and the rivaroxaban arms.15 In the ARISTOTLE trial, the rate of major bleeding was significantly lower with apixaban as compared with warfarin (2.13% vs 3.09%/year, HR .69; CI, 0.60-0.80; P ! .001), preventing about 10 major bleeding events per 1000 patients per year. Although only 25% of apixaban is cleared through the kidneys, bleeding risk increased in patients with estimated glomerular filtration rate (eGFR) !50 with both warfarin and with apixaban, and the bleeding advantage of apixaban is consistent 4 GASTROINTESTINAL ENDOSCOPY Volume

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regardless of renal dysfunction.16 Major bleeding was higher with concurrent aspirin use. Notably, all 3 NOACs demonstrated marked superiority versus warfarin with respect to causing intracranial hemorrhage.

Safety: major GI bleeding The AF population is elderly and medically complex and therefore at increased risk for GI bleeding, even in the absence of anticoagulation.17 The underlying major GI bleeding rate in this population has been estimated to be 0.3% to 0.5% annually.18 Meta-analysis suggests that the administration of warfarin to patients with AF increases the odds ratio (OR) of major GI bleeding compared with www.giejournal.org

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TABLE 3. Comparison of the characteristics of the 3 pivotal trials of the novel oral anticoagulants RE-LY

ROCKET-AF

ARISTOTLE

Dabigatran etexilate

Rivaroxaban

Apixaban

Warfarin

Warfarin

Warfarin

Design

Multicenter randomized

Multicenter randomized

Multicenter randomized

Blinding

Open label

Blinded

Blinded

Primary endpoint

Stroke/SEE

Stroke/SEE

Stroke/SEE

Bleeding

Bleeding

Bleeding

150 mg twice daily 110 mg twice daily

20 mg daily

5 mg twice daily

No. of patients

18,113

14,264

18,201

No. of countries

44

45

39

No. of trial sites

951

1178

1034

Publication date

Sept 17, 2009

Sept 8, 2011

Sept 15, 2011

2 years

2 years

2 years

NOAC Comparator

Primary safety endpoint Dose

Trial duration

RE-LY, Randomized evaluation of long term anticoagulant therapy; ROCKET-AF, rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation; ARISTOTLE, apixaban for reduction in stroke and thromboembolic events in atrial fibrillation; NOAC, novel oral anticoagulant; SEE, systemic embolic events.

TABLE 4. Major efficacy and safety event rates of novel oral anticoagulant compared to warfarin* Dabigatrany

Rivaroxaban

Apixaban

Stroke and systemic embolism

Risk

d

d/=

d

Major bleeding

=

=

d

Major GI bleeding

c

c

=

Intracranial hemorrhage

d

d

d

Ischemic stroke

d

=

=

All-cause mortality

dz

dz

d

*The arrow indicates increased (c) or decreased (d) rate of event with NOAC as compared with warfarin in pivotal trial. The equal symbol (=) indicates that the event rates were not significantly different with the NOAC and warfarin. Note that these data compare each NOAC with warfarin; there are no data directly comparing the NOACs. yFDA-approved dose of 150 mg twice daily (BID) is depicted. zNot statistically significant, but a consistent approximately 10% reduction across the trials.

placebo approximately 3-fold18 and that adding aspirin to warfarin approximately doubles the bleeding risk of warfarin given alone.18 Data from the warfarin era suggest that 8% to 10% of all acute GI bleeding is related to systemic anticoagulation,19,20 and that the most common causes of upper and lower GI bleeding in the anticoagulated patient are peptic ulcer disease (18%-25%) and diverticular disease, respectively.21-24

Major GI bleeding event rates Dabigatran (RE-LY). Dabigatran 150 mg given twice daily was associated with a higher rate of major GI bleeding www.giejournal.org

than warfarin (1.85% vs 1.36%/year; P Z .002; RR 1.49 [1.21-1.84]), resulting in about 5 additional events per 1000 patients per year. Dabigatran usage resulted in major GI bleeding particularly during the first few months of treatment and also with more life-threatening GI bleeding (0.76% vs 0.48%/year).14,25 The rate of fatal GI bleeding related to dabigatran in the RE-LY trial has not been reported. Dabigatran-related major GI bleeding was higher with the concomitant administration of aspirin and/or clopidogrel (4.08% vs 2.85%/year) and with decreasing creatinine clearance.14,25 There was a significant age interaction for major GI bleeding: in patients O75 years, the Volume

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risk of major GI bleeding was higher with dabigatran given at a dose of 150 mg twice daily than with warfarin, whereas in patients aged !65 years, the risk of major GI bleeding was higher with warfarin.14 In a post-hoc analysis, the anatomic level of GI bleeding was “lower GI” in 53% in the dabigatran arm versus 25% in the warfarin arm.14 The specific bleeding lesion was not reported. Major GI bleeding event rates are shown in Figure 3. Rivaroxaban (ROCKET-AF). Compared with the RELY and ARISTOTLE trial populations, the ROCKET-AF trial population was older and had more comorbidity at baseline, and thus it was at higher risk of GI bleeding. As compared with warfarin, rivaroxaban was associated with an increased rate of major GI bleeding (2.00% vs 1.24%/ year; HR 1.61 [CI, 1.30-1.99]), resulting in 8 additional events per 1000 patients per year.26,27 The incidence of life-threatening bleeding was similar between the 2 arms (n Z 49 and n Z 47, respectively), and fatal GI bleeding was uncommon, and there were fewer fatal bleeding events with rivaroxaban than with warfarin (1 and 5, respectively). The anatomic location of the GI bleeding was not specified. In the entire study population (ie, pooled warfarin plus rivaroxaban), an increased rate of GI bleeding was noted in individuals receiving concurrent antiplatelet therapy,15 older individuals, individuals with lower creatinine clearance, those with anemia at baseline, current and/or prior smokers, individuals with history of GI bleeding, males, and those who had experienced a prior stroke. Apixaban (ARISTOTLE). The major GI bleeding rates were numerically but not statistically significantly lower in the apixaban compared with the warfarin arm (0.76% vs 0.86%/year; HR 0.89 [CI, 0.70-1.15]; P Z .37). In the AVERROES trial of apixaban compared with low-dose aspirin involving 5600 patients deemed not suitable for warfarin, major GI bleeding rates were comparable in the apixaban and aspirin arms (0.35% vs 0.4%/year).28

Postmarket safety data Post-market safety data have been obtained from voluntary adverse event reporting, treatment registries, and claims databases. Although these data are derived from “real world” experience, clinicians are more likely to report adverse events with the new agents than with warfarin. Consequently, it is difficult to compare rates of adverse events with the NOACs with those expected with warfarin. Nonetheless, based on the limited data available, rates of major bleeding events in patients receiving NOACs do not appear to exceed those reported in the pivotal trials.29-31

Major GI bleeding: pathophysiology It is uncertain why, compared with warfarin, dabigatran and rivaroxaban preferentially increase major GI bleeding but not major bleeding in other organs, specifically causing less intracranial hemorrhage. One hypothesis is that non-absorbed, active anticoagulant drug within the GI 6 GASTROINTESTINAL ENDOSCOPY Volume

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Figure 3. The rate of major GI bleeding in the 3 pivotal novel oral anticoagulant trials (NOAC compared with warfarin). Note that in the ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban) trials, definition of major bleeding required bleeding to be clinically overt, whereas in the RE-LY (dabigatran) trial, this was not required. MGI, major GI; NOAC, novel oral anticoagulant.

tract lumen promotes GI bleeding (eg, from vulnerable mucosal erosions or angiectasias).4 The absorption of warfarin in contrast is O95%, and intraluminal drug has no anticoagulant activity. A second hypothesis is that the drugs directly injure the GI tract. Specifically, it has been proposed that tartaric acid in dabigatran capsules may be responsible; however, rivaroxaban also promotes GI bleeding, and Aggrenox (Boehringer Ingelheim, Germany), which also contains tartaric acid, does not. It is also uncertain why apixaban and rivaroxabandboth factor Xa inhibitorsdappear to differ in their GI bleeding safety profiles. Possible explanations include (1) the fact that rivaroxaban is dosed once daily, thereby leading to higher peak-to-trough anticoagulant activity than apixaban, which is dosed twice daily; (2) functional differences related to the different chemical structures of the 2 molecules; and (3) differences between the study populations. It remains to be established why dabigatrandrelative to warfarin or heparindincreases lower GI bleeding in particular and whether this is true of rivaroxaban and apixaban as well. Furthermore, the association of dabigatran with lower GI bleeding requires confirmation in postmarket studies.

Prevention of NOAC-related GI bleeding Early case reports of NOAC-related GI hemorrhage involved instances in which the drugs were prescribed outside of the recommended indications or dosing, highlighting the importance of physician and patient education.32-34 In order to minimize NOAC-related bleeding, prescribing physicians should adhere to administration guidelines, and GI bleeding risk factors should be minimized when possible. For example, the risk of GI bleeding related to dabigatran is 30% to 50% higher when it is coadministered with antiplatelet agents.14 Use of concomitant aspirin www.giejournal.org

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should be reserved for patients with a clear indication, such as recent myocardial infarction, particularly among patients at risk for GI bleeding. In patients taking chronic nonsteroidal anti-inflammatory drugs (NSAIDs) for analgesic or anti-inflammatory effects, coadministration of a gastric protective agent (eg, a PPI) should be strongly considered.35 The HAS-BLED score,36 initially created to predict bleeding risk, serves as a tool to identify other modifiable bleeding risk factors, such as excessive alcohol intake and uncontrolled hypertension. There are no data relating Helicobacter pylori serologic status to the risk of NOAC-related GI bleeding.

Management of acute GI bleeding in patients receiving NOACs The 2009 American Society for Gastrointestinal Endoscopy (ASGE) Guidelines for Management of Antithrombotic Agents for Endoscopic Procedures provide recommendations regarding the interruption of anticoagulation therapy and the timing and techniques of endoscopy during acute GI bleeding in the setting of warfarin-based anticoagulation.37,38 These guidelines state that the decision to reverse anticoagulation should “be individualized based on the potential risk of thrombosis and continued bleeding.” Early endoscopy is encouraged, especially if an upper GI bleeding source is likely.22 However, these guidelines are based on low-quality evidence and are not closely followed.20 Instead, a case-by-case approach, weighing the relative risks of thrombosis and of bleeding, is practiced.37,38 The management of GI bleeding in patients receiving NOACs follows the general principles used in management of acute GI bleeding during warfarin-based anticoagulation, including (1) education of patients and prescribers regarding the increased risk of GI bleeding during anticoagulation, (2) education of patients regarding the signs and symptoms of acute GI bleeding and the actions to take if it should occur, (3) timely recognition of subacute GI bleeding (eg, through periodic hemoglobin measurement or fecal occult blood testing), (4) prompt hospital emergency department admission for major GI bleeding, followed by administration of standard in-patient supportive and/or resuscitative care and monitoring, and (5) urgent or semiurgent endoscopic evaluation as dictated by the local protocols and by the clinical circumstances. However, because of the novel pharmacology of the NOACs, the approach to acute GI bleeding in the setting of NOACs will differ from that in the setting of warfarin in several specific ways (Fig. 4).

NOAC pharmacokinetics In patients with normal kidney and liver function, NOAC clearance and the loss of the anticoagulation effect is rapid and predictable (Fig. 2). In patients taking dabigatran who have significant renal impairment, the anticoagulant effect is prolonged. If the patient is supported and www.giejournal.org

Novel oral anticoagulants in gastroenterology

stabilized during the first 12 hours of GI bleeding, the native hemostatic mechanisms recover, and bleeding may spontaneously cease. Therefore, an early “watch and support” strategy is a more attractive option with NOACs than with warfarin, and a reversal agent less important. The time of the last dose of NOAC should be used in order to predict the duration of anticoagulant effect.

Interdisciplinary management and education of consultants Because of the novel pharmacology of the NOACs, management of major GI bleeding will benefit from the collaboration of gastroenterologists, emergency department physicians, cardiologists, hematologists, and in rare instances, nephrologists. Implementation of NOAC-specific institutional protocols and educational programs for GI bleeding will promote optimal management.

Laboratory monitoring of anticoagulation Coagulation studies provide qualitative information related to the level of anticoagulation.39 The prothrombin time (PT), activated partial thromboplastin time (aPTT), and (when available) thrombin time should be determined. Dabigatran has a greater effect on the aPTT than on the PT, whereas the reverse is true for the factor Xa inhibitors. Rivaroxaban has a greater effect on the PT than does apixaban.40-42 Thus, if the aPTT is normal in a patient taking dabigatran, it is reasonable to conclude that there is little ongoing anticoagulation effect. Likewise, if the PT is normal in a patient taking rivaroxaban, there is likely to be little anticoagulant effect. In the case of apixaban, which does not affect the PT to a significant extent, an anti-Xa assay is needed to assess drug levels. Dabigatran is the only NOAC to affect the thrombin time. If quantitative drug levels are needed, these can be obtained by using a dilute thrombin time (Hemoclot assay, Aniara, West Chester, Ohio) for dabigatran (this is not approved in the United State) and chromogenic anti-Xa assays for rivaroxaban and apixaban. Appropriate drugspecific calibrators must be used in each of these assays.43

Interrupting anticoagulation The decision to interrupt NOAC therapy requires weighing the risk of thrombosis versus the risk of ongoing bleeding, and decision-making must be made on a case-by-case basis. The more precise “titratability” of the NOACs as compared to warfarin is a significant advantage in this setting: if the NOAC is held, the return of the ability to coagulate is generally rapid (12-24 hours and 5 drug half-lives for near complete recovery). When the decision to reinitiate is made, anticoagulation is restored within hours of the first dose, unlike with warfarin, where full effect takes days. In most cases, the risk of interrupting therapy temporarily (ie, !1 week) in patients with nonvalvular AF is associated with a low risk of thrombotic adverse events (!0.5%/day); however, the thrombosis and/or stroke risk Volume

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Figure 4. Suggested algorithm for GI bleeding management in the patient receiving novel oral anticoagulant therapy. Figure 4 modified from van Ryn et al.47 NOAC, novel oral anticoagulant; CBC, complete blood count; ED, emergency department; LGIB, lower GI bleeding; PCC, prothrombin complex concentrate.

of anticoagulation interruption in the acutely bleeding patient is not known.44-46

Reversing anticoagulation Acute bleeding into a closed space (eg, the brain) in the anticoagulated patient can have catastrophic results. In contrast, the GI lumen is an open space, and thus there is less urgency to reverse the anticoagulation in the setting of NOAC-related acute GI bleeding in the hemodynamically stable patient. In practice, in the patient with preserved drug clearance and active GI bleeding, the need to acutely reverse the NOAC is unusual, largely because of the short drug half-life. During the pivotal NOAC trials, 8 GASTROINTESTINAL ENDOSCOPY Volume

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reversal was attempted rarely and primarily in patients with impaired drug elimination and/or closed-space bleeding. There are no specific antidotes for the NOACs, other than passage of time. In the case of severe, ongoing GI bleeding, several options are available: (1) If the last dose of NOAC was given within 1 to 2 hours of presentation, orally administered activated charcoal may limit absorption of residual drug in the stomach or duodenum.47 This potential benefit must be weighed against decreasing the effectiveness of upper endoscopy and risk of aspiration. It is plausible that rapid administration of a balanced electrolyte lavage could accelerate the excretion of the intraluminal NOAC anticoagulant effect, but there www.giejournal.org

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are no data regarding this method. (2) In patients with lifethreatening bleeding, procoagulants such as prothrombin complex concentrate (PCC) or recombinant activated factor VII may be effective.48-50 In one small study, healthy volunteers were given rivaroxaban or dabigatran for several days and then randomized to either 50 IU/kg of a 4-factor PCC (not available in the United States) or placebo. Although PCC administration normalized the PT in participants taking rivaroxaban, it had no effect on the prolonged aPTT in those given dabigatran.48 No studies have tested PCC in actively bleeding patients on NOACs and/or shown that PCCs improve clinical outcomes in this setting.48 (3) A mouse antibody against dabigatran has been developed and is under investigation for dabigatran reversal.51 For factor Xa inhibitors, a recombinant, functionally inactive form of factor Xa that serves as a competitive decoy to lessen the inhibition of native factor Xa is under investigation.52 (4) In patients with acute renal failure and life-threatening bleeding with dabigatran, hemodialysis or hemoperfusion may be effective.47 Dialysis is less likely to hasten the elimination of rivaroxaban or apixaban because these drugs are O90% protein bound, although such studies are ongoing. In one small trial, when otherwise-healthy volunteers with ESRD underwent hemodialysis 4 hours after a single dose of dabigatran, approximately two-thirds of the serum drug concentration was removed.53,54 (5) Patients with life-threatening bleeding who are also taking aspirin might benefit from platelet transfusion.

Endoscopic management of GI bleeding There are scant data related to the diagnostic and therapeutic utility of urgent endoscopy in the management of patients receiving systemic anticoagulation and experiencing GI bleeding.21,23,55 Therefore, guidelines concerning the timing and techniques for endoscopy in this setting are based primarily on expert opinion.38 In the patient taking a NOAC and presenting with acute GI bleeding, decisions regarding the timing and techniques of endoscopy will be determined by the severity of the bleeding and by local protocols. For acute hemorrhage, associated with persistent or recurrent hypotension or signs of end-organ hypoperfusion and a failure to respond to supportive measures, emergent upper and lower endoscopy may be appropriate. When hemodynamics are stable and/or respond to resuscitation, it may be reasonable to defer endoscopy for 12 to 24 hours, when the effect of the NOAC will be attenuated. These recommendations are consistent with existing ASGE guidelines for timing of endoscopy for nonvariceal upper GI bleeding.56 The theoretical advantages of this approach are increased effectiveness of endoscopic therapy in the patient who has recovered normal coagulation function; increased safety of endoscopy in the semielective rather than the emergency setting; increased time to achieve colon cleansing; and perhaps enhanced endoscopic visualization related to spontaneous attenuation of bleeding. www.giejournal.org

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Given the relative tendency of NOAC to induce lower tract bleeding,57 rapid colon purging followed by rapid colonoscopy (and perhaps small-bowel enteroscopy) may be useful. Treatment of a bleeding lesion with mechanical compression (eg, endo-clipping) in addition to a thermal modality is reasonable but of unproven benefit.

Reinitiating anticoagulant therapy after an episode of major GI bleeding In most instances it will be desirable to resume systemic anticoagulation for stroke prevention in AF as soon as it is safe. There are scant data to guide timing: in general, anticoagulation should be resumed after hemostasis is secure, and some healing has occurred.38 Decision-making should reflect the cause and severity of the GI bleeding and the interventions that occurred as well as the stroke risk. In some instances (eg, after resection of a bleeding GI tract tumor) the patient’s bleeding risk after intervention returns to baseline; in others (eg, the patient with multiple small-intestine angiectasias, one of which was cauterized), the risk of recurrent major GI bleeding remains high despite the intervention. In patients receiving NOACs who have experienced major GI bleeding, stroke prevention options include the following: (1) resuming the NOAC at the same dose, (2) resuming the NOAC at a reduced dose (eg, switching from dabigatran 150 mg twice daily to 75 mg twice daily, which may have a lower risk of major GI bleeding), (3) switching NOAC (which may in theory lower the major GI bleeding risk in the individual patient, eg, because of pharmacogenomics), (4) switching to warfarin (with the attendant increased risk of intracranial hemorrhage), (5) eliminating concurrent antiplatelet agents and modify other bleeding risk factors (if present), (6) using pharmacologic therapy to reduce rebleeding risk (eg, administration of long-term PPI therapy or Helicobacter pylori eradication), and (7) using another strategy in hope of reducing the stroke risk (eg, amputation or occlusion of the left atrial appendage).

Management of occult GI bleeding Occult GI bleeding in the individual receiving NOACs should be systematically evaluated. It is generally not adequate to ascribe the bleeding to the effect of the anticoagulant. During the pivotal trials of the NOACs, GI tract malignancies were identified during investigations of occult GI bleeding (the number and location of these malignancies are not yet reported); it is plausible but untested that the high intraluminal anticoagulant activity present during NOAC therapy could function as a “GIbleeding stress test.”

Peri-endoscopic NOAC management for elective endoscopy There are a paucity of outcome data to guide perendoscopic anticoagulation management in the patient with nonvalvular AF.38 Therefore, both U.S. and Canadian Volume

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guidelines primarily reflect expert opinion.45,58 Canadian guidelines provide more specific recommendations regarding the optimal timing for NOAC discontinuation and resumption around the time of invasive procedures, graduated based on creatinine clearance, risk of bleeding associated with the procedure, risk of stroke, and extent of hemostasis after the procedure.40-42,59-61 Clinical studies are required in order to determine which practices provide the greatest overall clinical benefit. Case-by-case assessment of patient-specific and procedure-specific thrombotic and hemorrhagic risk factors is recommended. Because of their short half-life, NOACs can generally be continued until shortly before the procedure, and because of their rapid onset of action, therapeutic anticoagulation is achieved within a few hours of reinstituting treatment.62 This obviates the costs and inconveniences of parenteral unfractionated or low molecular weight heparin bridging therapy and of laboratory testing of coagulation parameters. In the case of low-risk elective GI procedures such as endoscopy or colonoscopy with biopsy, the NOAC may be continued, or the morning dose could be held. Ideally, the procedure should be performed when the NOAC is at trough levels, and the anticoagulant effect is relatively low.62 For the drugs given twice daily (dabigatran and apixaban) this means O10 hours after the last dose, whereas for rivaroxaban this might mean O20 hours after the last dose. Thus, if the patient is scheduled to undergo a morning colonoscopy, the patient is instructed to withhold the NOAC dose the evening before and the morning of the procedure. During higher-risk elective procedures (eg, colonoscopic polypectomy, percutaneous endoscopic gastrostomy tube placement, EUS-guided pseudocyst drainage, or biliary sphincterotomy) anticoagulation should be interrupted. The NOAC should be held for 2 to 3 half-lives (Fig. 2), which, in patients with normal drug elimination, corresponds to approximately 24 to 48 hours.63 In the setting of impaired elimination, an appropriate adjustment is made; for example, in a patient receiving dabigatran who has a creatinine clearance of 30 to 50 mL/minute, the drug is held for 3 to 5 days.62 Because the drug is cleared by the kidney, vigorous oral hydration and use of split-dose, iso-osmotic bowel preparations should be encouraged to support volume status and maintenance of optimal drug clearance. The optimal time to resume the NOAC after endoscopy will depend on the nature of the endoscopic intervention and the patient’s thrombotic risk. Decision making may benefit from collaboration with a cardiologist and hematologist. It is important to recognize that resuming NOACs results in peak plasma concentrations within 2 to 3 hours of the first doseda distinctly different timeline than with warfarin reinitiationdwhich achieves the full effect days later. The endoscopist should weigh the relative risk of postprocedural bleeding: for example, it is reasonable to resume the NOAC immediately following cold resection 10 GASTROINTESTINAL ENDOSCOPY Volume

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of a !5-mm polyp, but to wait O3 days in the case of a 2.5-cm, flat, right-sided polyp that was resected after submucosal injection of saline solution (the use of prophylactic endo-clipping in this latter setting is advocated by some experts and is plausible, but to date has unproven clinical benefit and cost effectiveness). A reasonable compromise in patients at higher risk for postprocedure bleeding from the endoscopic surgical site is to resume the NOAC within 24 to 48 hours, after hemostasis is secure and the risk of early bleeding is low.45 Patients must be warned of the risk of delayed bleeding (eg, 7-14 days after “hot” polypectomy, related sloughing of devitalized mucosa). Limited data suggest that the rate of postprocedure bleeding in patients receiving NOACs is comparable to that seen with warfarin. In the RE-LY trial, dabigatran was stopped 1 to 5 days before elective procedures, depending on the patient’s renal function and the nature of the intervention and was restarted once hemostasis was achieved.57 During the RE-LY trial, 4591 patients underwent at least 1 surgical procedure (of which 8.6% were colonoscopy).64 The last dose of dabigatran was ingested a mean of 2 days before the surgical intervention, versus 5 days in the warfarin arm. Overall, the rate of periprocedural major bleeding was comparable between dabigatran and warfarin arms (4%-5%), as was the rate in the subset of patients undergoing elective procedures (2%-3%), urgent procedures (17%-20%), and minor procedures (2%-3%).64 (Data related to bleeding after endoscopic procedures in particular are not provided.) In fact, there was less major bleeding in dabigatran patients who underwent surgery or intervention within 24 hours of the last drug dose than there was in the warfarin group.

NOACs and acute coronary syndrome Despite the use of dual antiplatelet therapy, the risk of ischemic coronary events in the postacute coronary syndrome setting is approximately 11%, in part because of the importance of platelet-independent thrombotic mechanisms.65 The addition of warfarin to antiplatelet agents in this setting is not routine, largely because the risk of major bleeding events appears to negate the cardiac-protective advantage.66 Seven randomized clinical trials provide data assessing the effects of adding a NOAC to dual antiplatelet drugs in the post-acute coronary syndrome setting.67-73 A meta-analysis of these trials demonstrated that this practice was associated with a 2-fold to 3-fold higher risk of major bleeding events (OR 3.03 [2.204.16]) but only a very small reduction in ischemic coronary events (OR 0.86 [0.79-0.94]) and no significant overall mortality benefit.65 Thus, the addition of a NOAC to dual antiplatelet therapy in this setting is not recommended, nor are the drugs approved for this indication. In a subgroup of post-acute coronary syndrome patients (ie, those with both coronary stent placement and concurrent AF and substantial risk of stroke) “triple” antithrombotic therapy is recommended. Patients with AF who www.giejournal.org

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develop acute coronary syndrome are difficult to manage because the use of an anticoagulant in addition to dual antiplatelet therapy confers an increased risk of bleeding, including major GI bleeding.74 To reduce this risk, clinicians should attempt to limit the duration of exposure to triple therapy. This can best be accomplished by using bare metal stents whenever possible so that clopidogrel can be stopped after 4 to 6 weeks, using low-dose aspirin, and adding a proton pump inhibitor if appropriate.

NOACs and nonbleeding GI symptoms In a post hoc analysis of the RE-LY trial, an increase in the number of nonbleeding upper GI adverse events (gastroesophageal reflux, dyspepsia, dysmotility-related symptoms, or gastroduodenal mucosal injury) related to dabigatran was observed.75 These adverse events occurred in 16.9% of individuals receiving dabigatran (RR vs warfarin Z 1.81; P ! .001), and 4% of patients stopped taking dabigatran because of these adverse events (RR vs warfarin Z 2.34; P ! .001). In 91% of cases, the nonbleeding upper GI adverse events were rated as mild or moderate rather than severe. The greatest increase relative to warfarin was in symptoms suggestive of GERD (5.5% vs 1.5%, RR Z 3.71; P ! .001), and the symptoms most commonly occurred soon after dabigatran was initiated. In dabigatran-treated patients, nonbleeding upper GI adverse events slightly increased the risk of experiencing major GI bleeding, although less than in warfarin. These adverse events were more common in patients who were female, aged O75 years, of non-white ethnicity, and taking concurrent NSAIDs. The etiology of the nonbleeding upper GI adverse events related to dabigatran is uncertain. On endoscopy, localized esophagitis suggestive of a superficial caustic injury has been noted (Fig. 5). This may be the result of capsule release in the esophagus and creation of a caustic microenvironment. It has been hypothesized that the offending agent is tartaric acid, but Aggrenox is formulated with a similar coating and with similar amounts of tartaric acid and does not cause nonbleeding upper GI adverse events. Moreover, tartaric acid is a weak acid, and there is less tartaric acid in one dabigatran 150 mg capsule than in one glass of wine.76 It is believed that if dabigatran is taken in accordance with guidelines (ie, upright, with food or an 8-ounce glass of water), in many cases the nonbleeding upper GI adverse events can be avoided. It is unknown whether a PPI or cessation of concurrent NSAIDs or taking the drug with a meal will ameliorate the symptoms, but these strategies are reasonable. Neither rivaroxaban nor apixaban has been associated with an increase in the number of nonbleeding GI symptoms (eg, diarrhea or dyspepsia) versus comparator in clinical trials.

Conclusion The NOACs represent an important advance in the management of nonvalvular AF. Both dabigatran and www.giejournal.org

Figure 5. Findings of esophageal injury presumed related to novel oral anticoagulant ingestion. Several days after starting dabigatran, an elderly man complained of new odynophagia. The drug was held for several days, and the symptoms resolved. In the endoscopic image, superficial caustic-type injury with surface exudate is seen in the mid and distal esophagus.

rivaroxaban are associated with a small but increased incidence of major GI bleeding relative to warfarin, whereas dabigatran is associated with an increased incidence of nonbleeding upper GI symptoms such as dyspepsia and heartburn. Fortunately, these adverse GI events rarely represent an absolute contraindication to NOAC usage.77 NOAC-related GI bleeding can be minimized by adherence to guidelines for drug administration and by reduction of risk factors such as concurrent NSAID and aspirin administration. Management of GI bleeding in the patient receiving NOACs follows the same principles used to manage GI bleeding in the patient receiving warfarin, but with modifications that are based on an understanding of the pharmacology of the novel agents. Non-bleeding upper GI symptoms in the patient receiving dabigatran in most cases do not require drug discontinuation and may improve if the medication is taken with the patient upright and is taken with food. Regarding GI bleeding in the patient taking NOACs, further research is required regarding the effectiveness and best timing of endoscopic interventions, the effectiveness of prevention strategies, the pathophysiology of bleeding, guidelines for treatment interruption, and the role of anticoagulation reversal.

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Novel oral anticoagulants in gastroenterology 64. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation 2012;126:343-8. 65. Komocsi A, Vorobcsuk A, Kehl D, et al. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome. Arch Int Med 2013;172:1537-45. 66. Andreotti F, Testa L, Biondi-Zoccai GGL, et al. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519-26. 67. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003;362:789-97. 68. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011;32:2781-9. 69. Steg PG, Mehta SR, Jukema JW, et al. RUBY-1: a randomized, doubleblind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011;32:2541-54. 70. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. New Eng J Med 2011;365: 699-708. 71. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACSTIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38. 72. Mega JL, Braunwald E, Wiviott S, et al. Rivaroxaban in patients with a recent acute coronary syndrome. New Eng J Med 2012;366:9-19. 73. Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the apixaban for prevention of acute ischemic and safety events (APPRAISE) trial. Circulation 2009;119:2877-85. 74. Abraham N. Novel oral anticoagulants and gastrointestinal bleeding: a case for cardiogastroenterology. Clin Gastroenterol Hepatol 2013;11:324-8. Epub 2013 Jan 21. 75. Bytzer P, Connolly SJ, Yang S, et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013;11:246-52. 76. Hoffman A, Galle PR. Gastrointestinal disorders and dabigatran. Scand J Gastroenterol 2012;48:9-16. 77. Lip GYH, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 2011;13:723-46.

Received February 1, 2013. Accepted April 11, 2013. Current affiliations: Department of Medicine (Division of Gastroenterology), New York University, New York, New York (1), Duke Clinical Research Institute, Durham, North Carolina (2), Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (3), Department of Medicine (Division of Gastroenterology), Mount Sinai Medical Center, New York, New York (4).

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