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CLINICAL REVIEW: Doson Chua and Andrew Ignaszewski Clopidogrel in acute coronary syndromes BMJ 2009; 338: b1180 [Full text]

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NNTs and NNHs, and PPIs and H2RAs

Peter D Burrill   (16 April 2009)

Re: NNTs and NNHs, and PPIs and H2RAs

L Sam Lewis   (17 April 2009)

PPIs may differ in effects

Ian L.. Beales   (28 April 2009)

Vital missing information

Jonathan Ball   (28 April 2009)

Bleeding clopidogrel!

Gareth J Sadler, Andrew P. Poullis, Consultant Gastroenterologist, St Georges Hospital, London.   (5 May 2009)

Authors' reply

Doson Chua, Andrew Ignaszewski   (20 May 2009)

NNTs and NNHs, and PPIs and H2RAs 16 April 2009
Peter D Burrill, Specialist Pharmaceutical Adviser for Public Health Derbyshire County PCT, Chesterfield, S41 7PF Send response to journal: Re: NNTs and NNHs, and PPIs and H2RAs	Drs Chua and Ignaszewski provide us with a useful review of the evidence base for clopidogrel. It would have been helpful if the results of the individual trials had been presented as number-needed-to-treat (NNT) and number-needed-to-harm (NNH) to enable discussion with patients and more informed decision making. For example, in the CURE trial the NNT for the primary composite outcome was 48 and the NNH for major bleeding (disabling, requiring transfusion) was 100. In other words, for every 100 patients treated for an average of 9 months with clopidogrel plus aspirin instead of aspirin alone, 2 non-fatal MIs would be prevented at the expense of one major bleed caused. Overall then, one positive outcome occurs for every 100 patients so treated. Is this explained to patients so a joint decision can be made (concordance) on whether to take clopidogrel as well as aspirin? The tips for non-specialists section includes using a PPI prophylactically to reduce the risk of bleeding. Two recent case-control studies (1,2) suggest that co-prescribing a PPI and clopidogrel increases the risk of re-infarction. It is unclear if any of the PPIs is safe in this respect. Use of H2RAs does not seem to be a risk. As double-dose H2RA (e.g. ranitidine 300mg bd) appears to be as effective as PPI at prevention of NSAID-induced gastroduodenal ulcers (3), this would seem to be the better option. 1) CMAJ 2009. Published early online 28/1/09 2) JAMA 2009; 301: 937-44 3) Cochrane review 2002. Issue 4 Competing interests: None declared
Re: NNTs and NNHs, and PPIs and H2RAs 17 April 2009
L Sam Lewis, GP Surgery, Newport, Pembrokeshire, SA42 0TJ Send response to journal: Re: Re: NNTs and NNHs, and PPIs and H2RAs	So - 9 months Clopidogrel will prevent 2 MIs in 100 people treated , but cause 1 major bleed. IF the risk of harm remains level throughout the 9 months treatment, but the benefits are high early, and fall away exponentially over time.. then to balance harm vs. benefit maybe we should treat for just the first 3 months only ? Competing interests: None declared
PPIs may differ in effects 28 April 2009
Ian L.. Beales, Clinical Senior Lecturer in Gastroenterology Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR4 7UZ Send response to journal: Re: PPIs may differ in effects	Chua and Ignaszewski state that all patients taking aspirin and clopidogrel should also be treated with a proton pump inhibitor (PPI) to reduce the risk of gastrointestinal bleeding. Whist this is consistent with guidelines(1), this recommendation requires reconsidering in the light of recent data on the interactions between PPIs and clopidogrel and a greater awareness of risk stratification for gastrointestinal bleeding. The addition of clopidogrel to aspirin is associated with a modest increase in risk of gastrointestinal haemorrhage in average risk patients (0.3 to1.4%)(2). Proton pump inhibitors do reduce the risk of GI bleeding to around baseline (3,4) but may significantly impair the beneficial effects of clopidogrel. Reductions in the anti-platelet effects of clopidogrel have been shown in patients taking omeprazole but not pantroprazole or esomeprazole (5-7). This effect is believed to due to inhibition of CYP2C19 preventing biotransfomation and activation of clopidogrel. Cohort studies have shown that PPI co-prescription after acute coronary syndrome increased the risk of recurrent myocardial infarction by 40% (8) and either death or revasularisation by 27% (9). In the latter study the absolute increase in adverse effects was 8%, suggesting that the gastrointestinal benefits would be offset by cardiovascular events. It remains unclear whether all PPIs share this effect. Omeprazole and rabeprazole have been implicated in the clinical studies (8, 9) and one subgroup analysis showed no adverse effects with pantoprazole (9) and reported numbers are too small for lansoprazole or esomeprazole to draw conclusions. Whilst the benefits for primary prevention of GI bleeding are questionable, Chua and Ignaszewski should have emphasized the importance of a prior history of peptic ulcer as a risk factor for recurrent bleeding whilst on anti-platelets (odds ratio 10.6 – 16)(3) and these patients do require acid suppressive therapy. Although H2 receptor antagonists do not affect CYP2C19, it remains to be proven they reduce clinically important end points in these high risk patients. Double dose ranitidine and famotidine reduce endoscopically detectable ulcers induced by non- steroidal anti-inflammatory drugs but have not been shown to reduce ulcer complications (10). Proton pump inhibitor co-therapy did reduce the excess risk of bleeding associated with all anti-platelet therapies, but H2 antagonists were infective without any dose-response relationship (3). Thus PPI prophylaxis for the highest risk patients taking aspirin and clopidogrel is indicated: on limited data the choice is between esomeprazole (which does reduce rebleeding (4) and pantoprazole (which has the greater body of data showing no interaction with clopidogrel). References 1 Bhatt DL, Scheiman J, Abraham NS, et al. 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. J Am Coll Cardiol 2008;52:1502-17. 2 Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2009;157:369-74. 3 Ibanez L, Vidal X, Vendrell L, Moretti U, Laporte JR. Upper gastrointestinal bleeding associated with antiplatelet drugs. Aliment Pharmacol Ther 2006;23:235-42. 4 Lai KC, Chu KM, Hui WM, et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol 2006;4:860-5. 5 Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-60. 6 Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714-9. 7 Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-5. 8 Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44. 9 Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8. 10 Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;CD002296. Competing interests: None declared
Vital missing information 28 April 2009
Jonathan Ball, Consultant in Intensive Care St George's Hospital, London SW17 0QT, UK Send response to journal: Re: Vital missing information	Three critical issues are missing from this review. Firstly, in the penultimate section of this review the authors state, "Gastrointestinal prophylactic treatment should be initiated in all patients at high risk for gastrointestinal bleeding who are on dual antiplatelet treatment." However, no mention is made of the emerging concerns regarding the drug interaction between clopidogrel and proton pump inhibitors [reference Ho P.M.,Maddox T.M.,Wang L. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA Mar 2009, vol./is. 301/9(937-944)]. The current evidence suggests that proton pump inhibitors adversely affect the cardioprotective actions of clopidogrel. Whether they merely reduce the bioavailability or have other interactions is unknown. It is not known whether other gastric mucosal protectants have a similar effect. The second issue that is missing from this review is a paragraph or even a reference to the management of bleeding in patients taking clopidrogel. Unlike aspirin, whose antiplatelet effects can be predictably overcome by platelet transfusion, clopidogrel has no reliable antidote. The third issue is that of clopidogrel resistance which has been the subject of a recent review [reference Dominick J. Angiolillo MD. Variability in Responsiveness to Oral Antiplatelet Therapy. The American Journal of Cardiology Volume 103, Issue 3, Supplement 1, 2 February 2009, Pages 27A-34A] Competing interests: None declared
Bleeding clopidogrel! 5 May 2009
Gareth J Sadler, Specialist Registrar, Gastroenterology St George's Hospital, London, SW17, Andrew P. Poullis, Consultant Gastroenterologist, St Georges Hospital, London. Send response to journal: Re: Bleeding clopidogrel!	Gastroenterologists are very aware of the potential for upper gastrointestinal haemorrhage in patients receiving dual antiplatelet therapy. However, we would flag up caution against Chua’s recommendation for using any proton pump inhibitor (PPI) therapy in all patients with acute coronary syndromes (ACS) receiving dual antiplatelet therapy (1). Although the efficacy of PPIs in significantly reducing the rates of gastrointestinal bleeding in this group of patients has been well demonstrated, recent evidence points to sinister and potentially far more injurious side effects. In the study by Juurlink and colleagues (2), co-prescription of PPIs known to inhibit hepatic cytochrome P450 2C19 (omeprazole, lansoprazole and rabeprazole) with clopidogrel, resulted in a 40% relative increase in the risk of recurrent myocardial infarction. Evidence from Ho and colleagues corroborates this finding (3), with greater risks of re- hospitalisation, revascularization procedures and death for ACS observed in patients receiving PPI and clopidogrel. The risk of adverse outcome does not appear to be class-dependent, however, as trials of pantoprazole and esomeprazole have shown no negative effects on the cardioprotective action of clopidogrel (2,4), an effect likely due to their differing metabolic pathways (5). Many UK patients currently receive PPI therapy with clopidogrel, and in the USA, recently published guidelines advocate routine prescription of PPIs to ACS patients receiving dual antiplatelet therapy (6). In light of these recent findings it should not be assumed that all PPIs are ‘born equal’, and further studies are urgently required to establish the safest combination. References 1 Chua D, Ignaszewshi A. Clopidogrel in acute coronary syndromes. BMJ 2009;338(7701):998-1002. 2 Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009 Mar 31;180(7):713-8. 3 Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301(9):937-944. 4 Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009 Apr;101(4):714-9. 5 Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009 Jan;157(1):148.e1-5. 6 Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. Am J Gastroenterol 2008 Nov;103(11):2890-907. Competing interests: None declared
Authors' reply 20 May 2009
Doson Chua, Clinical Pharmacotherapeutic Specialist, Cardiology St. Paul’s Hospital, Vancouver, BC Canada V6Z 1Y6, Andrew Ignaszewski Send response to journal: Re: Authors' reply	Coadministration of a proton pump inhibitor (PPI) with clopidogrel increases the risk of recurrent myocardial infarction and adverse cardiovascular outcomes, thought due to inhibition of the cytochrome P450 2C19 pathway. Pantoprazole may be devoid of this interaction with clopidogrel based on its lack of cytochrome P450 2C19 inhibition and subgroup analyses of two recent retrospective cohort studies.(1) (2) However, translating the results of subgroup analysis of these retrospective cohort studies into clinical recommendations is premature at this time. Emerging data regarding the interaction between clopidogrel and PPI contradict the suggestion that pantoprazole shows no negative effects on the cardioprotective action of clopidogrel. Dunn et al performed a post hoc analysis of the CREDO trial of patients on clopidogrel and assessed concurrent PPI use.(3) PPI use was associated with increased cardiovascular events regardless if the patient was on clopidogrel or placebo and was independently associated with increased adverse cardiac outcomes. Similarly, Stanek et al recently presented the results of the Clopidogrel Medco Outcomes Study, which is the largest trial to date investigating the interaction between clopidogrel and PPI in 16,690 patients. (4) In this retrospective study, the use of any PPI concurrently with clopidogrel was shown to be associated with an increased risk of major adverse cardiovascular events, with pantoprazole having the highest risk of cardiac events compared to other PPIs. Thus, clinical studies have consistently shown that PPI use concurrently with clopidogrel is associated with higher cardiovascular events rates. However, whether one particular PPI is safer remains unclear and the evidence to date is conflicting. 1. Juurlink DN, Gomes T, Ko DT et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8 2. Ho PM, Maddox TM, Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44 3. Dunn SP, Macaulay TE, Brennan DM et al. Baseline proton pump inhibitor use is associated with increase cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circ 2008;118:S815 4. Stanek EJ, Aubert RE, Flockhart DA et al. A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: The Clopidogrel in Medco Outcomes Study. Presented at 32nd Annual Scientific Sessions. Society of Cardiovascular Angiography and Intervention, May 6 2009. http://www.scai.org/pdf/20090506Medcoabstract.pdf