doi:10.1111/j.1440-1746.2011.07029.x
`
`J G H F M A R S H A L L A N D WA R R E N L E C T U R E jgh_7029
`Anti-platelet therapy and managing ulcer risk
`Francis K L Chan
`
`195..199
`
`Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
`
`The Marshall and Warren Lectures are educational activities sponsored by the JGH Foundation.
`
`Key words
`aspirin, clopidgrel, proton pump inhibitor, ulcer
`bleeding.
`
`Accepted for publication 23 November 2011.
`
`Correspondence
`Dr Francis KL Chan, Prince of Wales Hospital,
`30-32 Ngan Shing Street, Shatin, Hong Kong.
`Email: fklchan@cuhk.edu.hk
`
`Declaration of conflict of interest: The work
`described in this manuscript was supported
`by a funding from the JGHF. Within the last
`3 years, Dr Chan received speaker’s honoraria
`from Pfizer, AstraZeneca, and Eisai, and
`consulting fees from Pfizer. Dr Chan also
`acted as the Chairman of the steering
`committee for CONDOR study, a Pfizer
`sponsored clinical trial.
`
`Abstract
`Low-dose aspirin (ASA) has emerged as one of the most important causes of peptic ulcer
`bleeding in developed countries. Among the risk factors of ASA-associated ulcer bleeding,
`Helicobacter pylori infection is one of the few that is treatable. Recent evidence showed
`that among patients with a history of ASA-associated ulcer bleeding, the long-term inci-
`dence of recurrent bleeding with ASA use is low after eradication of H. pylori alone. Thus,
`test-and-treat H. pylori is a potentially useful strategy for ASA users with high ulcer risk.
`However, the risk of bleeding is further increased by combining other anti-platelet drugs
`(e.g. clopidogrel) with ASA in acute coronary syndromes and coronary stent placement.
`There is good evidence that co-therapy with a proton-pump inhibitor (PPI) reduces upper
`gastrointestinal bleeding with ASA alone or dual anti-platelet therapy. Recently, several
`meta-analyses of observational studies found that concurrent use of PPI and clopidogrel
`was associated with increased risk of major adverse cardiovascular events. Overall, the
`evidence does not suggest a clinically important interaction between PPIs and clopidogrel.
`However, there is a subset of patients who have reduced conversion of clopidogrel to its
`active metabolites due to genetic polymorphism of hepatic P-450 (carriers of CYP2C19
`loss-of-function alleles). Since PPIs are also metabolized by similar hepatic enzymes, it is
`uncertain whether patients carrying CY2C19 loss-of-function alleles are susceptible to
`concomitant PPI use. In the future, management of patients on dual anti-platelet therapy
`needs to be individualized according to their thrombotic and bleeding risks.
`
`Introduction
`Over the last two decades, upper gastrointestinal (GI) bleeding
`associated with low-dose aspirin (ASA) has been rising rapidly. In
`Scotland, hospitalizations for ASA-associated upper GI bleeding
`have increased from 15 patients per 100 000 in 1996 to nearly 40
`patients per 100 000 in 2005.1 Since many patients require lifelong
`ASA for prevention of atherothrombotic diseases,
`identifying
`patients at risk of upper GI bleeding and developing cost-effective
`strategies for reducing the bleeding risk is an important healthcare
`issue. However, management of patients on anti-platelet therapy
`becomes more complicated for several reasons.
`First, patients undergoing percutaneous coronary intervention
`such as coronary stent placement often require complex anti-
`platelet and anti-thrombotic therapy. These patients not only are at
`increased risk of GI bleeding but also coronary thrombosis. Bal-
`ancing the bleeding and thrombotic risks of individual patients is a
`major clinical challenge.
`Second, recent evidence suggests that concurrent use of proton-
`pump inhibitor (PPI) and clopidogrel increases the risk of major
`adverse cardiovascular events such as myocardial
`infarction.
`
`Currently, health authorities in the U.S. and in Europe have issued
`warnings against the use of PPIs in patients receiving clopidogrel.
`Whether these warnings are appropriate or clinically helpful
`remain controversial.
`Third, there is a lack of practical guidelines on balancing bleed-
`ing and thrombotic risks in patients on anti-platelet therapy. This
`lecture aims to address the above issues and provides an overview
`of managing patients on anti-platelet therapy who are at risk of
`bleeding and thrombosis.
`
`Risk factors for ASA-associated upper
`GI bleeding
`A number of risk factors for upper GI bleeding with ASA have
`been consistently reported. These include history of ulcer bleed-
`ing, dose of ASA, advanced age (> 70), concomitant use of non-
`steroidal anti-inflammatory drugs (NSAIDs), and Helicobacter
`pylori infection.2–4 Among survivors of myocardial infarction, a
`24-month prospective study found that the incidence of serious GI
`bleeding was very high during the first 2 months (cumulative inci-
`dence: 0.13% up to Month 2 versus 0.018% from Month 3 to
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`Managing patients on anti-platelet therapy
`
`FKL Chan
`
`Month 24). On multivariate analysis, additional risk factors for GI
`bleeding include use of dual anti-platelet therapy (hazard ratio
`[HR] 3.18, 95% confidence interval [CI], 1.91–5.29), concomitant
`anti-coagulants (HR 2.13, 95% CI, 1.28–3.52), history of alcohol
`abuse (HR 4.71, 95% CI, 2.02–11.01), New York Heart Associa-
`tion class III or IV (HR 2.27, 95% CI, 1.28–3.52), diabetes (HR
`1.76, 95% CI, 1.13–2.74), renal failure (HR 1.18, 95% CI, 1.03–
`1.34), and non-white race (HR 3.26, 95% CI, 1.89–5.61).5
`
`Strategies for reducing upper GI
`bleeding with ASA
`Patients receiving ASA should be evaluated for the presence of risk
`factors for peptic ulcer bleeding. Current strategies for reducing
`upper GI bleeding in high-risk ASA users include avoidance or
`elimination of risk factors and co-therapy with a gastroprotective
`agent. However, most of the risk factors cannot be eliminated;
`H. pylori infection is a notable exception.
`
`Can eradication of H. pylori reduce the
`risk of upper GI bleeding with ASA?
`Although H. pylori is a recognized risk factor for upper GI bleed-
`ing in ASA users, whether eradication of H. pylori can substan-
`tially reduce the risk of bleeding remains unclear. In a 6-month
`randomized trial, ASA users with H. pylori infection and previous
`ulcer bleeding were randomized to eradication therapy alone or
`maintenance treatment with a proton-pump inhibitor (PPI). Recur-
`rent ulcer bleeding occurred in 1.9% (95% CI, -0.7%, 4.5%) of
`patients in the eradication therapy group compared with 0.9%
`(95% CI, -0.8%, 2.6%) in the PPI group.6 In another 12-month
`randomized trial, ASA users with H. pylori infection and previous
`ulcer bleeding were randomized to eradication therapy alone or
`eradication therapy followed by maintenance PPI. Recurrent ulcer
`bleeding occurred in 15% (95% CI, 7%, 26%) in the eradication
`therapy group compared with 1.6% (95% CI, 0%, 9%) in the
`eradication therapy plus PPI group. Although the latter study
`found that the rate of recurrent bleeding was unacceptably high
`with eradication of H. pylori alone in high-risk ASA users, the
`majority of these patients with recurrent bleeding had failure of
`eradication or used concomitant NSAIDs.7
`Recently, a 10-year prospective cohort study reported the long-
`term incidence of ulcer bleeding in three cohorts of ASA users.
`The first cohort consisted of ASA users with previous ulcer bleed-
`ing and confirmed eradication of H. pylori (H. pylori-eradicated
`cohort). The second cohort consisted of ASA users with previous
`ulcer bleeding but no evidence of current or past H. pylori infec-
`tion (H. pylori-negative cohort). The third cohort consisted of
`asymptomatic ASA users without a history of ulcer or ulcer bleed-
`ing (average-risk cohort). The rate of ulcer bleeding was 1.08 per
`100 patient-years in the H. pylori-eradicated cohort (95% CI 0.96,
`1.96), 5.77 per 100 patient-years in the H. pylori-negative cohort
`(95% CI 3.46, 9.64), and 0.66 per 100 patient-years in the average-
`risk cohort (95% CI 0.41, 1.05).8 These findings suggest that
`among ASA users with a history of ulcer bleeding, the long-term
`risk of ulcer bleeding is low after eradication of H. pylori alone.
`Further studies are needed to determine whether test-and-treat
`H. pylori is a cost-effective strategy for reducing ulcer bleeding in
`high-risk ASA users.
`
`Co-therapy with gastroprotective
`agents
`In addition to modifying the underlying risk factors, ASA users
`with high risk of ulcer bleeding should receive cotherapy with a
`gastroprotective agent. For many years, however, the American
`College of Cardiology and the American Heart Association rec-
`ommended clopidogrel as an alternative to ASA in patients with
`major GI intolerance.9 In a 12-month, double-blind randomized
`trial of ASA plus esomeprazole versus clopidogrel alone in
`patients with previous ulcer bleeding who had healed ulcers and
`negative tests for H. pylori, recurrent ulcer bleeding occurred in
`0.7% (95% CI, 0%, 2.0%) of patients in the ASA plus esomepra-
`zole group compared with 8.6% (95% CI, 4.1%, 13.1%) in the
`clopidogrel group (P = 0.001).10 In 2008, a joint expert consensus
`report of
`the American College of Cardiology Foundation
`(ACCF), American College of Gastroenterology (ACG), and
`American Heart Association (AHA) stated that substitution of
`clopidogrel for ASA is not a recommended strategy to reduce the
`risk of recurrent ulcer bleeding in high-risk patients and is inferior
`to the combination of ASA plus PPI.11
`
`What is the risk of GI bleeding with
`dual anti-platelet therapy?
`With increasing use of dual anti-platelet therapy in patients with
`coronary stents, not only the incidence but also the complexity of
`GI bleeding is expected to increase. However, the risk of bleeding
`with dual anti-platelet therapy is largely derived from secondary
`analysis of safety data in major clinical trials. In the CURE trial of
`dual anti-platelet therapy for acute coronary syndromes, adding
`clopidogrel to aspirin increases the relative risk of GI bleeding by
`over 85% (1.3% vs 0.7% in 12 months).12 In another trial of dual
`anti-platelet
`therapy for atrial fibrillation, major GI bleeding
`occurred in 1.1%/year of patients receiving dual anti-platelet
`therapy compared with 0.5%/year in patients receiving aspirin
`(P < 0.001).13
`
`Preventing upper GI bleeding with dual
`anti-platelet therapy
`Prevention of GI bleeding associated with dual anti-platelet
`therapy is important not only because of its widespread use in
`patients with coronary artery diseases but also due to the throm-
`botic risk associated with major bleeding. In 2008, a joint consen-
`sus report of ACCF/ACG/AHA recommended routine use of
`prophylactic PPI in patients receiving dual anti-platelet therapy.11
`Subsequently, the efficacy of PPIs in preventing upper GI bleeding
`associated with dual anti-platelet therapy was confirmed by a
`double-blind randomized trial. In this study, over 3700 patients
`with an indication for dual anti-platelet therapy were randomly
`assigned to receive clopidogrel in combination with either ome-
`prazole or placebo. The primary GI end point was a composite of
`overt or occult bleeding, symptomatic gastroduodenal ulcers or
`erosions, obstruction, or perforation. The event rate was 1.1% with
`omeprazole and 2.9% with placebo in 180 days (HR with omepra-
`zole, 0.34, 95% CI, 0.18 to 0.63; P < 0.001). The rate of overt
`upper GI bleeding was also reduced with omeprazole as compared
`with placebo (HR, 0.13; 95% CI, 0.03 to 0.56; P = 0.001).14
`
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`FKL Chan
`
`Managing patients on anti-platelet therapy
`
`Can histamine-2-receptor antagonists (H2RAs) reduce upper GI
`bleeding with dual anti-platelet therapy? To date, there is only one
`retrospective study that assessed the effect of H2RAs on the risk of
`upper GI bleeding in patients on dual anti-platelet therapy. After a
`median follow-up of 5.8 months, upper GI bleeding occurred in
`3.14% in the H2RA group (n = 287) and 5.95% in the control
`group (n = 487). Thus, the benefit of H2RA is only marginal (O.R.
`0.43, 95% CI, 0.18–0.91; P = 0.04).15
`
`Interaction between PPI and
`clopidogrel: is the problem overstated?
`Although the joint consensus report of the ACCF/ACG/AHA in
`2008 recommended routine prophylaxis with a PPI in patients
`requiring dual anti-platelet therapy, subsequent observational data
`found that patients receiving concomitant PPI and clopidogrel
`had significantly higher risk of major cardiovascular adverse
`events including death, myocardial infarction, stroke, and urgent
`revascularization.16,17
`Pharmacodynamic
`interaction
`exists
`between PPIs and clopidogrel because both drugs share similar
`metabolic pathways in the liver. Clopidogrel is a prodrug that
`requires conversion by hepatic cytochrome P450 isoforms, notably
`CYP2C19, into active metabolites. These active metabolites then
`irreversibly antagonize the adenosine diphosphate receptor on
`platelets. On the other hand, proton-pump inhibitors are prodrugs
`that are also bioactivated by CYP2C19. PPIs compete with clopi-
`dogrel for CYP2C19, thereby reducing conversion of clopidogrel
`to active metabolites for platelet inhibition.18 The negative impact
`of PPIs on the platelet inhibitory effect of clopidogrel has been
`confirmed by double-blind randomized trials using platelet reac-
`tivity index as the study endpoint.19 In vitro studies found that
`different PPIs have different degrees of inhibitory effects on clo-
`pidogrel. Omeprazole and lansoprazole have the strongest inhibi-
`tory effect, whereas pantoprazole and rabeprazole are the
`weakest.20 Whether there is a good correlation between in vitro
`findings and clinical outcome remains controversial.
`In a meta-analysis of cardiovascular outcomes in patients
`receiving clopidogrel with or without concomitant PPI, there was
`a significant
`increase in the risk of myocardial
`infarction in
`patients receiving concomitant PPI (risk ratio 1.43, 95% CI, 1.16–
`1.77).21 However, substantial heterogeneity was detected. On
`subgroup analysis, observational studies showed a significant
`association (risk ratio 1.54, 95% CI, 1.23–1.92) whereas data from
`randomized trial or propensity-matched participants showed no
`such association (risk ratio 1.15, 95% CI, 0.89–1.48).
`How to account for these inconsistent data? In observational
`studies, patients receiving concomitant PPIs were older and had
`more severe concurrent illnesses than patients receiving clopi-
`dogrel alone. It is likely that PPIs were more often prescribed to
`patients with high GI risk or those with anticipated high cardio-
`vascular mortality should bleeding complication develop. Thus,
`concomitant PPI may be a surrogate marker for, rather than a cause
`of, serious cardiovascular events among clopidogrel users. When
`baseline imbalance between patients with and without concomi-
`tant PPI use was eliminated in randomized trials, PPI use was not
`associated with increased incidence of major adverse cardiovas-
`cular events.
`To date, there is only one double-blind randomized trial that was
`designed to determine whether concomitant PPI use would
`
`adversely affect the cardiovascular outcome of patients on clopi-
`dogrel. Patients with an indication for dual anti-platelet therapy
`were randomly assigned to receive clopidogrel in combination
`with either omeprazole or placebo. The primary cardiovascular
`end point was a composite of death from cardiovascular causes,
`nonfatal myocardial infarction, revascularization, or stroke. The
`study planned to enroll 5000 patients, and 3873 were randomized.
`The event rates were 4.9% with omeprazole and 5.7% with
`placebo (H.R. with omeprazole, 0.99; 95% CI, 0.68–1.44;
`P = 0.96). Unfortunately, the trial was terminated prematurely
`when the sponsor lost financing.14 Because of premature termina-
`tion, this study was not powered to detect a small difference in the
`primary cardiovascular endpoint.
`Despite the inconsistent data, the Food and Drug Administration
`in the U.S. issued a warning in November 2009 that “healthcare pro-
`viders should re-evaluate the need for starting or continuing treat-
`ment with a PPI in patients taking clopidogrel,” and that “concomi-
`tant use of drugs that inhibit CYP2C19 (e.g. omeprazole) should be
`discouraged.”22 The European Medicines Agency adopts a more
`conservative standpoint and “discourages concomitant use of PPI
`and clopidogrel-containing drugs unless absolutely necessary.”23
`While the overall evidence does not suggest a clinically impor-
`tant interaction between PPIs and clopidogrel for most patients, it
`remains uncertain as to whether there are certain subgroups of
`patients who are at risk of this drug interaction. Recently, another
`meta-analysis of 23 studies also found that patients who are on
`concurrent PPI and clopidogrel are at higher risk of major adverse
`cardiovascular events (odds ratio (OR) 1.41, 95% CI, 1.34–1.48,
`P < 0.001).24 Statistical testing for heterogeneity was again signifi-
`cant for the analysis (P = 0.001). Differences between trials in
`terms of how elements of the composite endpoint were recorded,
`together with the unintentional inclusion of CYP2C19 genetic
`polymorphism in the PPI studies may explain why the variability
`between trials is higher than what can be expected from chance
`alone. Interestingly, secondary analysis found that underlying high
`cardiovascular risk (defined as an annual rate of major adverse
`cardiovascular events > 10%) was the only factor that predicted
`serious cardiovascular outcomes with concurrent use of PPI and
`clopidogrel. If this observation is confirmed by prospective trials,
`we may need to evaluate the cardiovascular risk of patients on
`clopidogrel before prescribing PPI in the future.
`Another uncertainty is whether
`clopidogrel users with
`CYP2C19 loss-of-function alleles using concomitant PPIs are at
`increased risk of serious cardiovascular events. Recent studies
`reported that certain genetic variants of hepatic cytochrome P-450
`system that are involved in the conversion of clopidogrel into its
`active metabolites are associated with increased risk of recurrent
`cardiovascular events.18,25,26 In particular, patients who carry
`CYP2C19 loss-of-function alleles have reduced conversion of clo-
`pidogrel to its active metabolites, leading to decreased platelet
`inhibition. In a meta-analysis of cardiovascular events according to
`the genetic variants of CYP2C19, it was found that carriers of the
`CYP2C loss-of-function alleles (CYP2C19*2) showed a signifi-
`cant increased risk of major adverse cardiovascular events com-
`pared with noncarriers (9.7% vs 7.8%; OR, 1.29; 95% CI, 1.12–
`1.49; P < 0.001). This genetic variant was also associated with an
`excess of mortality (1.8% vs 1.0%; OR, 1.79; 95% CI, 1.10–2.91;
`P = 0.019) and of stent thrombosis (2.9% vs 0.9%; OR, 3.45; 95%
`CI, 2.14–5.57; P < 0.001).24
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`Managing patients on anti-platelet therapy
`
`FKL Chan
`
`Table 1 Risk factors for coronary stent thrombosis (modified from
`Becker et al.30)
`
`Table 2 Balancing bleeding and thrombotic risks in patients with coro-
`nary stents
`
`Clinical risk factors
`1. History of stent thrombosis†
`2. Acute coronary syndrome or ST-segment elevation myocardial
`infarction
`3. Diffuse coronary artery disease
`4. Diabetes mellitus
`5. Renal failure
`6. Depressed ejection fraction
`Procedural risk factors
`1. Multi-vessel PCI
`2. Multiple stents
`3. Coronary dissection
`4. Bifurcation stents
`Reduced responsiveness to clopidogrel
`1. CYP2C19 genetic polymorphism
`
`†History of stent thrombosis is the most important risk factor.
`
`Since patients carrying CYP2C19*2 alleles (i.e. poor metabo-
`lizers) will have reduced platelet inhibitory effect with clopi-
`dogrel, will concomitant PPI use increase their risk of recurrent
`cardiovascular events by further reducing the conversion of clopi-
`dogrel to its active metabolites? This question is particularly rel-
`evant to Asia because the prevalence of carriers of CYP2C19
`loss-of-function alleles is between 15% and 25% in Chinese, Japa-
`nese and Thai, whereas it is less than 5% in Caucasians.27,28 To
`date, there is only one study providing indirect data on the inter-
`action between PPI use and CYP2C19 loss-of-function alleles. In
`a large-scale French registry of acute myocardial infarction, sub-
`group analysis of propensity-matched cohorts found that the rate
`of in-hospital death, recurrent myocardial infarction, or stroke
`among clopidogrel users with two loss-of
`function alleles
`(homozygotes) was 5% and 12% with and without concomitant
`PPI, respectively. Despite a more than twofold difference in the
`event rates, the difference did not reach statistical significance
`(OR, 1.05, 95% CI, 0.03–34.6) because of the small number of
`patients involved (n = 44).29
`Overall, current evidence suggests that concomitant PPI use
`does not increase the risk of major adverse cardiovascular events in
`patients on clopidogrel. However, the safety of PPI in patients with
`high baseline cardiothrombotic risk and those carrying CYP2C19
`loss-of-function alleles (15–25% of Asians) remain to be explored.
`
`Balancing bleeding and thrombotic
`risks: My personal view
`With increasing complexity of anti-platelet therapy for patients
`undergoing coronary intervention (e.g. intracoronary placement of
`drug-eluting stents), the management of these patients requires not
`only careful assessment of the risk of GI bleeding but also the risk
`of thrombosis. While gastroenterologists are well aware of the risk
`of bleeding with anti-platelet therapy, many are not familiar with
`assessing the cardiothrombotic risk of patients with coronary
`artery disease. Specifically, patients with coronary stents are at
`high risk of thrombosis. It is therefore important for gastroenter-
`ologists to be able to recognize the cardiothrombotic risk factors
`associated with coronary stents (Table 1) and communicate with
`
`Low thrombotic
`risk
`
`High thrombotic risk†
`
`Low bleeding
`risk
`
`High bleeding
`risk
`
`No PPI prophylaxis Avoid PPI
`Standard dual
`High-dose clopidogrel??
`anti-platelet
`Alternative anti-platelet therapy
`therapy
`(Prasugrel/Ticagrelor)
`PPI prophylaxis,
`Stagger the administration of PPI
`Standard dual
`and clopidogrel (12 h apart)
`Avoid omeprazole
`anti-platelet
`therapy
`Alternative anti-platelet therapy
`
`†High thrombotic risk. 1. Clinical/procedural risk factors for stent throm-
`bosis; 2. Genetic testing for CYP2C19 loss-of-function alleles; 3. Platelet
`reactivity test (PRU ⱖ 230, VerifyNow P2Y12 assay).
`
`cardiologists to optimize the use of anti-ulcer therapy for indi-
`vidual patients.
`In future, we should no longer focus on managing the ulcer risk
`of patients on anti-platelet therapy. Instead, we should aim at
`developing individualized therapy to balance bleeding and throm-
`botic risks. Patients with high thrombotic risk, e.g. a history of
`stent
`thrombosis or multiple clinical/procedural
`risk factors
`(Table 2) should undergo laboratory tests for reduced responsive-
`ness to clopidogrel. Commercially available tests include platelet
`reactivity test
`(e.g. VerifyNow® P2Y12 assay: cut-off at
`PRU ⱖ 230) and genetic test for CYP2C19 loss-of-function
`alleles. Patients with high thrombotic risk and low bleeding risk
`should avoid using PPI.
`High-dose clopidogrel has been advocated to overcome patients
`with high on-treatment platelet reactivity. However, recent studies
`found that high-dose clopidogrel was not effective in overcoming
`poor response to clopidogrel in CYP2C19*2 allele carriers.31 In
`another randomized trial, high-dose clopidogrel compared with
`standard-dose clopidogrel did not reduce cardiovascular deaths,
`nonfatal myocardial infarction, or stent thrombosis in patients with
`high on-treatment
`reactivity after placement of drug-eluting
`stents.32 Current evidence suggests that prasugrel, a new platelet
`P2Y12-ADP receptor antagonist, is more effective than high-dose
`clopidogrel in inhibiting platelet reactivity in patients with high
`on-treatment platelet reactivity following long-term clopidogrel
`therapy.33
`Patients with high bleeding and thrombotic risks require PPI
`prophylaxis. Because of the concern about PPI-clopidogrel inter-
`action, one potential (though unproven) strategy is to stagger the
`administration of these drugs 12 h apart. This approach can prob-
`ably avoid the drug interaction, if any, because the elimination half
`life of PPIs is only about 1–1.5 h and that of clopidogrel is 4–6 h.
`One should avoid using omeprazole because it has the strongest
`inhibitory effect on CYP2C19. Alternatively, new anti-platelet
`drugs such as prasugrel ot ticagrelor may be considered.
`
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`FKL Chan
`
`Managing patients on anti-platelet therapy
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`Journal of Gastroenterology and Hepatology 27 (2012) 195–199
`© 2011 Journal of Gastroenterology and H