Vol. 52, No. 18, 2008
`Journal of the American College of Cardiology
`© 2008 by the American College of Cardiology Foundation, American College of Gastroenterology, and the American Heart Association, Inc. ISSN 0735-1097/08/$34.00
`Published by Elsevier Inc.
`doi:10.1016/j.jacc.2008.08.002
`
`EXPERT CONSENSUS DOCUMENT
`
`ACCF/ACG/AHA 2008 Expert Consensus Document
`on Reducing the Gastrointestinal Risks of
`Antiplatelet Therapy and NSAID Use
`A Report of the American College of Cardiology Foundation Task Force
`on Clinical Expert Consensus Documents
`
`Writing
`Committee
`Members
`
`Deepak L. Bhatt, MD, FACC, FAHA, Co-Chair
`James Scheiman, MD, FACG, Co-Chair*
`
`ACCF
`Task Force
`Members
`
`Neena S. Abraham, MD, MSCE, FACG*
`Elliott M. Antman, MD, FACC, FAHA†
`Francis K. L. Chan, MD, FACG*
`Curt D. Furberg, MD, FAHA†
`
`Robert A. Harrington, MD, FACC, Chair
`
`Eric R. Bates, MD, FACC
`Charles R. Bridges, MD, MPH, FACC
`Mark J. Eisenberg, MD, MPH, FACC
`Victor A. Ferrari, MD, FACC
`Mark A. Hlatky, MD, FACC
`Sanjay Kaul, MBBS, FACC
`Jonathan R. Lindner, MD, FACC‡
`
`David A. Johnson, MD, FACG*
`Kenneth W. Mahaffey, MD, FACC
`Eamonn M. Quigley, MD, FACG*
`
`*American College of Gastroenterology Representative;
`†American American Heart Association Representative
`
`David J. Moliterno, MD, FACC
`Debabrata Mukherjee, MD, FACC
`Richard S. Schofield, MD, FACC‡
`Robert S. Rosenson, MD, FACC
`James H. Stein, MD, FACC
`Howard H. Weitz, MD, FACC
`Deborah J. Wesley, RN, BSN
`
`‡Former Task Force member during this writing effort
`
`This document was approved by the American College of Cardiology Foundation
`(ACCF) Board of Trustees in August 2008, by the American College of
`Gastroenterology (ACG) Board of Trustees in June 2008, and by the American
`Heart Association (AHA) Science Advisory and Coordinating Committee in
`August 2008.
`When citing this document, the ACCF would appreciate the following citation
`format: Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD,
`Johnson DA, Mahaffey KW, Quigley EM. ACCF/ACG/AHA 2008 expert consen-
`sus document on reducing the gastrointestinal risks of antiplatelet therapy and
`NSAID use: a report of the American College of Cardiology Foundation Task Force
`on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008:52:1502–17.
`
`This article has been copublished in the November 2008 issue of the American
`Journal of Gastroenterology and the October 28, 2008, issue of Circulation.
`Copies: This document is available on the World Wide Web sites of the American
`College of Cardiology (www.acc.org), the American College of Gastroenterology
`(www.acg.gi.org), and the American Heart Association (www.americanheart.org).
`For copies of this document, please contact Elsevier Inc. Reprint Department, fax
`212-633-3820, e-mail reprints@elsevier.com.
`Permissions: Multiple copies, modification, alteration, enhancement, and/or dis-
`tribution of this document are not permitted without the express permission of the
`American College of Cardiology Foundation. Please contact healthpermissions@
`elsevier.com.
`
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`Bhatt et al.
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`TABLE OF CONTENTS
`
`Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1503
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1503
`
`Prevalence of Use—NSAIDs/Aspirin (ASA) . . . . . . . . . . . .1504
`
`Mechanisms of GI Injury—NSAIDs. . . . . . . . . . . . . . . . . . . . . . .1504
`
`Mechanisms of Gastroduodenal Injury—Clopidogrel . . .1504
`
`1. GI Complications of ASA and Non-ASA NSAIDs. . . . . . . .1505
`2. GI Effects of ASA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1505
`3. GI Effects of Combined ASA and Anticoagulant
`Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1506
`4. GI Effects of Clopidogrel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1507
`5. GI Effects of Combined Clopidogrel and
`Anticoagulant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1507
`6. Treatment and Prevention of ASA- and
`NSAID-Related Gastroduodenal Injury. . . . . . . . . . . . . . . . . .1508
`7. Role of H. pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1510
`A. Diagnosis of H. pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1510
`B. Tests for Active H. pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1510
`C. Treatment of H. pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1511
`8. Discontinuation of Antiplatelet Therapy
`Because of Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1511
`9. Endoscopy in Patients on Mono- or
`Dual Antiplatelet Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1511
`Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1512
`
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1512
`
`Appendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1515
`
`Appendix 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1516
`
`Preamble
`
`This document has been developed by the American Col-
`lege of Cardiology Foundation (ACCF) Task Force on
`Clinical Expert Consensus Documents, the American Col-
`lege of Gastroenterology (ACG), and the American Heart
`Association (AHA). Expert consensus documents (ECDs)
`are intended to inform practitioners, payers, and other
`interested parties of the opinion of the ACCF and docu-
`ment cosponsors concerning evolving areas of clinical prac-
`tice and/or technologies that are widely available or new to
`the practice community. Topics chosen for coverage by
`ECDs are so designed because the evidence base, the
`experience with technology, and/or the clinical practice are
`not considered sufficiently well developed to be evaluated by
`the formal American College of Cardiology/American
`Heart Association (ACC/AHA) practice guidelines pro-
`
`cess. Often the topic is the subject of ongoing investigation.
`Thus, the reader should view ECDs as the best attempt of
`the ACCF and other cosponsors to inform and guide
`clinical practice in areas where rigorous evidence may not be
`available or the evidence to date is not widely accepted.
`When feasible, ECDs include indications or contraindica-
`tions. Topics covered by ECDs may be addressed subse-
`quently by the ACC/AHA Practice Guidelines Committee
`as new evidence evolves and is evaluated.
`The Task Force on ECDs makes every effort to avoid any
`actual or potential conflicts of interest that might arise as a
`result of an outside relationship or personal interest of a
`member of the writing panel. Specifically, all members of
`the writing panel are asked to provide disclosure statements
`of all such relationships that might be perceived as real or
`potential conflicts of interest to inform the writing effort.
`These statements are reviewed by the parent task force,
`reported orally to all members of the writing panel at the
`first meeting, and updated as changes occur. The relation-
`ships with industry information for writing committee
`members and peer reviewers are listed in Appendixes 1 and
`2, respectively.
`
`Robert A. Harrington, MD, FACC
`Chair, ACCF Task Force on
`Clinical Expert Consensus Documents
`
`Introduction
`
`The use of antiplatelet therapies continues to increase as a
`result of accumulation of evidence of benefits in both
`primary and secondary treatment strategies for cardiovascu-
`lar disease (1,2). These antiplatelet agents, however, have
`recognizable risks—in particular, gastrointestinal (GI) com-
`plications such as ulceration and related bleeding. These
`risks may be further compounded by the ancillary use of
`other adjunctive medications, such as nonsteroidal anti-
`inflammatory drugs (NSAIDs), corticosteroids, and antico-
`agulants. Given the high prevalence of antiplatelet therapy
`in clinical practice, coupled with an increased emphasis on
`their extended use, especially after implantation of a drug-
`eluting stent (3,4), it is imperative that physicians know the
`potential benefits and the associated risks of antiplatelet
`therapy for primary or secondary prevention of cardiac
`ischemic events when combined with NSAID agents. Only
`with this understanding can physicians appropriately and
`fully evaluate the risk profile for each patient and either
`change medications or initiate prophylactic therapy in an
`attempt to reduce GI complications. This document pro-
`vides consensus recommendations from the ACCF, the
`AHA, and the ACG on the combined use of antiplatelets
`and NSAID agents.
`Many NSAIDs, both selective and nonselective, increase the
`risk of cardiovascular and cerebrovascular events. This issue
`was addressed in a scientific statement from the AHA (5). In
`terms of cardiovascular, GI, renal, and hypertension-inducing
`
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`risks, there are important differences among the NSAIDs
`(especially the cyclo-oxygenase-2 [COX-2] inhibitors), which
`should also be understood and considered in managing patients
`in need of these agents (6). The AHA statement introduces a
`stepped-care approach for selection of drugs to manage mus-
`culoskeletal discomfort in patients with known cardiovascular
`disease or risk factors for ischemic heart disease, based on the
`risk/benefit balance from a cardiovascular perspective. A fur-
`ther discussion of the cardiovascular and cerebrovascular risks
`of NSAIDs is beyond the scope of this report but may be
`found in several reviews (5,7).
`
`Prevalence of Use—NSAIDs/Aspirin (ASA)
`
`The use of NSAIDs, including ASA, is common in the
`treatment of pain, inflammation, and fever. Additionally,
`low-dose ASA is used routinely in primary and secondary
`prophylaxis of cardiovascular and cerebrovascular events.
`These agents, both through prescription and over-the-
`counter (OTC) use, are the most widely used class of
`medications in the United States (8). Not surprisingly,
`NSAID use increases among the elderly. In a survey of
`people 65 years of age and older, 70% used NSAIDs at least
`once weekly, and 34% used them at least daily. The prevalence
`of at least weekly ASA usage was 60% (9). More than 111
`million NSAID prescriptions were written in 2004 (10).
`Recognizably, much of this usage comes from noncardiac
`indications, such as arthritis and related musculoskeletal
`complaints, in particular. In 1990, the estimated prevalence
`of self-reported arthritis in the United States was 37.9
`million cases, or 15% of the population. By 2020, it is
`projected that 59.4 million will be affected—a 57% increase
`from 1990 (11). As the incidence of arthritis complaints
`increases, the use of prescription and OTC NSAIDs is also
`expected to increase.
`
`Mechanisms of GI Injury—NSAIDs
`
`A complete discussion of the pathogenesis of ASA- and
`NSAID-associated injury is beyond the scope of this article;
`however, ASA, like all NSAIDs, injures the gut by causing
`topical injury to the mucosa and systemic effects induced by
`prostaglandin depletion. Tissue prostaglandins are produced
`via 2 pathways: a COX-1 and a COX-2 pathway. The
`COX-1 pathway is the predominant constitutive pathway;
`prostaglandins derived from this enzyme mediate many
`effects, most notably facilitating gastroduodenal cytoprotec-
`tion, renal perfusion, and platelet activity. The COX-2
`pathway, in contrast, is inducible by inflammatory stimuli
`and mediates effects through prostaglandins, which result in
`inflammation, pain, and fever.
`Inhibition of the COX-1 pathway blocks production of
`prostaglandins that play an important protective role in the
`stomach by increasing mucosal blood flow and stimulating
`the synthesis and secretion of mucus and bicarbonate, as
`
`well as promoting epithelial proliferation. Accordingly, the
`inhibition of these prostaglandins impairs these protective
`factors, resulting in a gastric environment that is more
`susceptible to topical attack by endogenous factors, such as
`acid, pepsin, and bile salts (12). A major consequence of
`prostaglandin depletion is to create an environment that is
`conducive to peptic ulcer formation and serious GI compli-
`cations. Since prostaglandins are essential to both the
`maintenance of intact GI defenses and normal platelet
`function, nonselective NSAIDs such as ASA promote ulcer
`formation as well as bleeding (13).
`for
`Because COX-2 is the primary intended target
`anti-inflammatory drug therapy, agents that selectively
`block COX-2, while having little to no effect on COX-1,
`should result
`in effective pain relief with reduced GI
`toxicity. This concept, called the “COX-2 hypothesis,” has
`been challenged by data from animal studies, which indi-
`cated that both COX-1 and COX-2 must be inhibited for
`gastric ulceration to occur. Interestingly, while the selective
`inhibition of either COX-1 or COX-2 alone failed to cause
`gastric damage, inhibition of both COX isoforms produced
`gastric ulceration (14). Thus, the explanation for reduced
`GI toxicity for COX-2–specific inhibitors may be their lack
`of dual COX inhibition rather than their COX-1–sparing
`effects.
`In this framework, taking both a cardioprotective dose of
`ASA (primarily a COX-1 inhibitor at low dose [i.e., 325 mg
`or less]) and a COX-2 inhibitor creates the ulcer risk of a
`traditional NSAID. A high percentage of individuals re-
`quiring cardioprotective doses of ASA have chronic pain
`and receive a traditional NSAID or a COX-2–selective
`NSAID (coxib). A survey that queried chronic coxib users
`found that 50% or more users were also taking ASA (15).
`Moreover, because coxibs were heralded as having an
`improved safety profile, related primarily to a lower rate of
`GI toxicity than traditional NSAIDs, the potential loss of
`this safety advantage when a COX-2 inhibitor is combined
`with ASA or an OTC NSAID remains underappreciated by
`clinicians. Heightened attention to the cardiovascular risks
`of NSAIDs has likely further increased the rate of addition
`of ASA to anti-inflammatory therapy (16).
`
`Mechanisms of
`Gastroduodenal Injury—Clopidogrel
`
`Platelet aggregation plays a critical role in healing through
`the release of various platelet-derived growth factors that
`promote angiogenesis. Angiogenesis, in turn, is critical for
`the repair of GI mucosal disruptions. Experimental animals
`with thrombocytopenia have been shown to have reduced
`ulcer angiogenesis and impaired ulcer healing (17). Addi-
`tionally, adenosine diphosphate-receptor antagonists impair
`the healing of gastric ulcers by inhibiting platelet release of
`pro-angiogenic growth factors, such as vascular endothelial
`growth factor, which promotes endothelial proliferation and
`
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`accelerates the healing of ulcers. GI bleeding is also a major
`toxic effect of chemotherapeutic agents that use monoclonal
`antibodies directed at circulating vascular endothelial
`growth factor (18). Although clopidogrel and other agents
`that impair angiogenesis may not be a primary cause of
`gastroduodenal ulcers, their anti-angiogenic effects may
`impair healing of gastric erosions or small ulcerations that
`develop because of other medications or Helicobacter pylori
`infection. This may then, in the presence of acid, lead to
`clinically significant ulceration and related complications.
`
`1. GI Complications of ASA and Non-ASA NSAIDs
`Recommendation: As the use of any NSAID, including
`COX-2–selective agents and OTC doses of traditional
`NSAIDs, in conjunction with cardiac-dose ASA, sub-
`stantially increases the risk of ulcer complications, a
`gastroprotective therapy should be prescribed for at-risk
`patients.
`Upper gastrointestinal events (UGIE), symptomatic or
`complicated ulcers, occur in 1 of every 20 NSAID users and
`in 1 of 7 older adults using NSAIDs (19), accounting for
`30% of UGIE-related hospitalizations and deaths (20–22).
`Dyspepsia, defined as upper abdominal pain or discomfort,
`may occur in individuals taking NSAIDs, including ASA.
`Dyspepsia is not clearly predictive of the presence of an
`ulcer, as it is far more prevalent. Some patients may also
`experience an increase in symptoms of gastroesophageal
`reflux disease on NSAIDs as well (23). Endoscopic ulcers
`are used as a surrogate marker in clinical trials for risk of
`medications and in treatment trials; this document focuses
`on patients with dyspepsia and an ulcer (symptomatic ulcer)
`or those with serious (life threatening) ulcer complications
`such as bleeding or perforation. The annual incidence of
`NSAID-related UGIE is 2.0% to 4.5% (19), and the risk of
`bleeding, perforation, or obstruction is 0.2% to 1.9%
`(19,24). NSAIDs contribute to 10–20/1000 hospitaliza-
`tions per year and are associated with a 4-fold increase in
`mortality (20). In the United States alone, NSAID use has
`been extrapolated to account for approximately 107 000
`hospitalizations and 16 500 deaths per year among patients
`with arthritis (25). More recent information regarding these
`estimates related to NSAIDs suggests that these numbers
`may be too high, but increasing use of antiplatelet medica-
`tions may contribute to an increased burden of GI bleeding
`(26–28). According to these reports, GI hospitalization
`rates markedly declined (from 1.5% to 0.5%) between 1992
`and 2000. Four potential explanations were given: use of
`lower doses of NSAIDS, less use of “more toxic” NSAIDs,
`increased use of “safer” NSAIDs, and increased use of
`proton pump inhibitors (PPIs).
`Among elderly veterans, NSAID exposure has been
`shown to increase risk of UGIE-related mortality 3-fold,
`even after adjustment for advancing age, comorbidity, and
`proportion of time spent on a traditional or COX-2–
`selective NSAID (26). In fact, if deaths resulting from
`NSAID-associated upper GI complications were tabulated
`
`separately, it would represent the 15th most common cause
`of death in the United States (29). National data from the
`Department of Veterans Affairs reveal that 43.0% of the
`veterans prescribed NSAIDs are considered to be at high
`risk for UGIE and that patients 65 years or older constitute
`the largest high-risk subset (87.1%) (8). Among elderly veter-
`ans, the risk of NSAID-related UGIE has been estimated as
`2753 UGIE in 220 662 person-years of follow-up (30).
`Those who combine an NSAID with ASA represent
`another high-risk group. When patients combine an
`NSAID with ASA, the annual risk of UGIE is 5.6%, with
`coxibs providing no additional gastroprotection (7.5%
`UGIE/year). A number of observational studies have noted
`a 2- to 4-fold increased risk of UGIE associated with the
`concomitant prescription of NSAIDs with low-dose ASA.
`Data from Scandinavia indicated an annual incidence of
`hospital admission for UGIE of 1.4% related to use of
`NSAIDs plus low-dose ASA versus 0.6% for low-dose
`ASA. Estimates of the relative risk (RR) of UGIE for
`NSAID plus ASA range from 3.8 (95% confidence interval
`[CI]: 1.8 to 7.8) (14) to 5.6 (95% CI: 4.4 to 7.0) when
`compared with ASA alone (30).
`Endoscopic trials suggest that the GI toxicity of a coxib
`plus ASA is additive, resulting in an overall risk of endo-
`scopic ulcer formation that parallels that seen with a
`nonselective NSAID (25,31). Additionally, evidence from
`observational studies and randomized controlled trials
`(RCTs) reveals that the risk of an NSAID plus ASA
`exceeds that of a coxib plus ASA, although both were
`markedly increased by ASA (9,27,29). In this context,
`whether one chooses a nonselective NSAID or a selective
`COX-2 inhibitor has a minimal, and perhaps clinically
`insignificant, impact on the likelihood of serious adverse GI
`outcomes. Thus, the selection of anti-inflammatory drug
`therapy in such patients must involve consideration of
`overall GI and cardiovascular risk of NSAIDs (32). The
`ongoing PRECISION (Prospective Randomized Evalua-
`tion of Celecoxib Integrated Safety vs Ibuprofen or
`Naproxen; NCT00346216) study, which is randomizing
`arthritis patients with or at risk of cardiovascular disease to
`ibuprofen, naproxen, or celecoxib, should provide more data
`to help clarify these issues.
`
`2. GI Effects of ASA
`Recommendation: The use of low-dose ASA for cardio-
`prophylaxis is associated with a 2- to 4-fold increase in
`UGIE risk. Enteric-coated or buffered preparations do
`not reduce the risk of bleeding. For patients at risk of
`adverse events, gastroprotection should be prescribed.
`The risk of UGIE increases with ASA dose escalation;
`thus, for the chronic phase of therapy, doses greater than
`81 mg should not be routinely prescribed.
`The AHA recommends low-dose ASA use among pa-
`tients with a 10-year cardiovascular risk that is greater than
`or equal to 10% (33,34), and the U.S. Preventive Services
`Task Force recommends ASA cardioprophylaxis for pa-
`
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`tients with a 5-year risk of greater than or equal to 3% (35).
`It has been estimated that 50 million Americans use
`low-dose ASA (i.e., 325 mg/day or less) regularly for
`cardioprophylaxis (36). The use of low-dose ASA is asso-
`ciated with a 2- to 4-fold increased risk of UGIE (37,38),
`which is not reduced by the use of buffered or enteric-coated
`preparations
`(39,40). Fourteen randomized placebo-
`controlled trials have presented data on UGIE with cardiac-
`dose ASA (75 to 325 mg per day) in adults. When these
`data are pooled, the absolute increased risk per year of
`UGIE with ASA is 0.12% when compared with placebo
`(number needed to harm⫽833), with conflicting evidence
`of risk reduction with lower doses (75 to 162.5 mg) versus
`higher doses (greater than 162.5 to 325 mg) (41).
`The estimated average excess risk of UGIE related to
`cardioprophylactic doses of ASA is 5 cases per 1000 ASA
`users per year (42). Among elderly patients, the odds ratios
`(ORs) of bleeding with daily doses of ASA of 75, 150, and
`300 mg are 2.3, 3.2, and 3.9, respectively (37). Dose
`reduction does not appear to reduce antithrombotic bene-
`fits; however, dose escalation does seem to increase bleeding
`complications (43). Additionally, case series implicate OTC
`use of low-dose ASA in over one-third of the patients
`admitted for GI hemorrhage (44), suggesting that patients
`who self-medicate may be unaware of the significant in-
`crease in their risk of UGIE.
`The complexities of confirming a significant difference
`across the range of the low doses of ASA used for cardio-
`protection are discussed below. Meta-analyses have been
`contradictory in demonstrating a significant difference in
`the risk of GI bleeding (45,46). Observational studies are
`somewhat contradictory, supporting evidence of a trend for
`an association between higher ASA dose and risk of upper
`GI complications (37,47). The ACC and AHA recommend
`lowering the dose from 325 to 81 mg among those with a
`high risk of UGIE (2). However, some experts feel it may be
`prudent to use up to 325 mg a day of ASA for 1 month after
`a stent procedure, although it is not clear from the data
`whether this dose is really necessary (2). While this low-
`dose ASA approach makes sense intuitively because of the
`lack of demonstrated additional cardiovascular benefits at
`the higher dose (with certain limited exceptions, such as
`acute coronary syndrome [ACS]), coupled with a likelihood
`of increased risk of GI harm at the higher dose, the key
`point is that the benefit,
`in terms of GI bleeding risk
`reduction with the lower dose, remains insufficient
`to
`protect high-risk patients and mandates the addition of
`other GI bleeding risk-reduction approaches. However, it is
`unknown what the optimal dose of ASA really is. The
`Antithrombotic Trialists’ Collaboration meta-analysis pro-
`vides indirect evidence that higher doses of ASA are not
`more effective, at least at a population level (48). There are
`observational data from the CURE (Clopidogrel in unstable
`angina to prevent recurrent events) trial that suggest no
`benefit from higher doses of ASA but a greater risk of
`bleeding (49). The CURRENT/OASIS-7 (Clopidogrel
`
`Optimal Loading Dose Usage to Reduce Recurrent
`EveNTs/Optimal Antiplatelet Strategy for InterventionS-7;
`NCT00335452)
`trial
`is randomizing ACS patients to
`higher (300 to 325 mg) or lower (75 to 100 mg) ASA doses
`in the range used for cardiovascular disease and may help to
`clarify this issue once the results are known.
`The use of enteric-coated or buffered formulations does
`not appear to reduce the risk of GI bleeding complications
`(39,40,50), a finding that suggests that the upper GI
`side-effects of ASA are a result of a systemic effect, in
`addition to its potent topical action to induce chemical
`injury. Anecdotal reports of reduced dyspepsia with these
`products likely contribute to their uptake in practice (51).
`While the risk factors for NSAID-related UGIEs have
`been well characterized, there are much less data on the risk
`of antiplatelet therapy. The synergism between ASA and
`NSAIDs was reviewed in detail in the previous section. A
`history of peptic ulcer, particularly with associated bleeding,
`appears to be the most important risk factor. Age is an
`important risk factor as well, with the relative increase
`beginning at age 60 years and rising in a nonlinear fashion
`with age. Gender is a less important concern, although the
`risk of men is slightly higher than that of women (42). The
`risk associated with combination antiplatelet and anticoag-
`ulant therapies is substantial as well, and each is discussed
`below given their importance in cardiology clinical practice.
`
`3. GI Effects of Combined ASA and
`Anticoagulant Therapy
`Recommendation: The combination of ASA and antico-
`agulant therapy (including unfractionated heparin, low-
`molecular-weight heparin, and warfarin) is associated
`with a clinically meaningful and significantly increased
`risk of major extracranial bleeding events, a large pro-
`portion from the upper GI tract. This combination
`should be used with established vascular, arrhythmic, or
`valvular indication; patients should receive concomitant
`PPIs as well. When warfarin is added to ASA plus
`clopidogrel, an international normalized ratio (INR) of
`2.0 to 2.5 is recommended (52).
`The use of antiplatelet drugs for the initial management
`of ACS is common and known to be effective (1,2). In some
`clinical settings, such as the initial and long-term manage-
`ment of ACS, the combination of anticoagulant and anti-
`platelet therapy is superior to antiplatelet therapy alone (53)
`but is associated with a substantial increase in UGIE, as
`shown in observational studies (54–56) and multiple RCTs.
`A meta-analysis of 4 RCTs of unfractionated heparin
`plus ASA versus ASA alone for ACS demonstrated a 50%
`increase in major bleeds (57), representing an excess of 3
`major bleeds per 1000 patients. Low-molecular-weight
`heparin given in conjunction with ASA also increases major
`bleeding, as demonstrated in the FRISC-1 (Fragmin during
`Instability in Coronary Artery Disease-1) study (58) and
`CREATE (Clinical Trial of Reviparin and Metabolic Mod-
`ulation in Acute Myocardial Infarction Treatment Evalua-
`
`
`Page 5 of 16
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`Patent Owner Ex. 2002
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`JACC Vol. 52, No. 18, 2008
`October 28, 2008:1502–17
`
`Bhatt et al.
`ACCF/ACG/AHA Expert Consensus Document: Antiplatelets, NSAIDs, and GI Risk
`
`1507
`
`tion) (59). A comprehensive meta-analysis of over 25 307
`patients demonstrated that the benefits of adding warfarin
`to ASA in the treatment of ACS must be weighed against
`a 2-fold increased risk in major extracranial bleeding (OR
`2.4; 95% CI: 1.4 to 4.1), suggesting that as few as 67
`additional patients would need to be treated with ASA plus
`warfarin to result in 1 additional major extracranial bleeding
`event (60).
`Conditions such as venous thromboembolism or me-
`chanical heart valves may necessitate long-term anticoagu-
`lation. With certain mechanical heart valves, an INR target
`of 2.0 to 2.5 may not be appropriate, and a higher INR may
`be required. Depending on the patient’s specific bleeding
`and thrombotic risks, consideration may be given to stop-
`ping the antiplatelet agent, as warfarin also has cardiopro-
`tective effects (61).
`
`4. GI Effects of Clopidogrel
`Recommendation: Substitution of clopidogrel for ASA is
`not a recommended strategy to reduce the risk of recur-
`rent ulcer bleeding in high-risk patients and is inferior to
`the combination of ASA plus PPI.
`Because of their alternative molecular targets and inhibi-
`tion of platelet activation, thienopyridines (i.e., clopidogrel,
`ticlopidine) taken on their own, or in combination with
`ASA, have been compared with ASA. The ACC/AHA
`practice guidelines recommend the use of clopidogrel for
`hospitalized patients with ACS who are unable to take ASA
`because of major GI intolerance (Class I, Level of Evidence:
`A recommendation) (2). This recommendation was largely
`based on the safety data of the CAPRIE (Clopidogrel
`Versus Aspirin in Patients at Risk of Ischaemic Events)
`study (62). This study compared clopidogrel 75 mg daily
`with a relatively high cardioprotective dose of ASA (325 mg
`daily) for the prevention of ischemic events,
`including
`myocardial infarction, stroke, and peripheral arterial disease.
`After a median follow-up of 1.91 years, the incidence rate of
`major GI bleeding was lower in the clopidogrel group
`(0.52%) when compared with the ASA group (0.72%; p less
`than 0.05). The rate of hospitalization for GI bleeding was
`0.7% with clopidogrel versus 1.1% with ASA (p⫽0.012)
`(63). Although the risk of GI bleeding with clopidogrel was
`lower than that with ASA, the difference was small (0.2%).
`Clopidogrel with ASA for at least 1 month is also recom-
`mended for patients with a recent non–ST-segment
`elevation-ACS, with a preference of 12 months if the
`bleeding risk is not high (2,64). In patients who have
`received drug-eluting stents, at least 12 months of uninter-
`rupted dual antiplatelet therapy is recommended (65). Data
`from the CURE (66), MATCH (Management of Athero-
`thrombosis with Clopidogrel in High-Risk Patients) (67),
`and CHARISMA (Clopidogrel for High Atherothrom-
`botic Risk and Ischemic Stabilization, Management, and
`Avoidance) studies (68) provide confirmatory evidence that
`combined ASA and clopidogrel therapy is associated with
`significantly increased risk of UGIE complications when
`
`compared with either agent alone (69). In patients at high
`risk of bleeding who require a stent, a bare-metal stent, with
`its shorter requisite duration of dual antiplatelet therapy,
`may be preferable (4,70).
`Concomitant use of clopidogrel and an NSAID (includ-
`ing low-dose ASA) has been associated with impaired
`healing of asymptomatic ulcers (17) and disruption of
`platelet aggregation (71), with a consequent increase in
`serious UGIE (OR 7.4; 95% CI: 3.5 to 15) (28). Few
`human studies document clopidogrel’s potential for inde-
`pendent injury to the GI mucosa. A single endoscopic study
`with limited follow-up failed to demonstrate mucosal injury
`in humans (72). In a hospital-based, case-control study of
`2777 consecutive patients with major upper GI bleeding and
`5532 controls, it was found that non-ASA antiplatelet drugs
`(clopidogrel, ticlopidine) had a similar risk of upper GI
`bleeding (adjusted RR 2.8; 95% CI 1.9 to 4.2) to ASA, at a
`dose of 100 mg/day (adjusted RR 2.7; 95% CI: 2.0 to 3.6), or
`anticoagulants (adjusted RR 2.8; 95% CI: 2.1 to 3.7) (73).
`A prospective, double-blind RCT comparing ASA plus
`esomeprazole against clopidogrel among H. pylori–negative
`patients with recent UGIE secondary to low-dose ASA
`demonstrated a significantly higher proportion of recurrent
`UGIE in the clopidogrel arm versus the ASA plus esome-
`prazole (20 mg twice daily) arm during the 12 months of
`study (8.6% versus 0.7%; 95% CI on the difference: 3.4% to
`12.4%) (74). A subsequent randomized trial with very
`similar design has shown virtually identical results (13.6%
`UGIE in the clopidogrel group versus 0% in the ASA plus
`esomeprazole group [20 mg daily]; 95% CI on the differ-
`ence: 6.3% to 20.9%) (75). These data suggest that use of
`clopidogrel alone to redu