AHA antiplatelets PPI report 2012

Antiplatelet Therapy and Proton Pump Inhibition: Clinician Update George V Moukarbel and Deepak L Bhatt Circulation 2012;125:375-380 doi: 10.1161/CIRCULATIONAHA.111.019745 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2012 American Heart Association, Inc All rights reserved Print ISSN: 0009-7322 Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/125/2/375 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services Further information about this process is available in the Permissions and Rights Question and Answer document Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/ Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 CLINICIAN UPDATE Antiplatelet Therapy and Proton Pump Inhibition Clinician Update George V Moukarbel, MD; Deepak L Bhatt, MD, MPH A 77-year-old man with history of diabetes mellitus and coronary artery disease presented with angina and evidence of ischemia despite maximal medical therapy He underwent a percutaneous coronary intervention with a drug-eluting stent and was started on long-term dual antiplatelet therapy with aspirin and clopidogrel His medical history was significant for an episode of gastrointestinal (GI) bleeding in the setting of using nonsteroidal antiinflammatory drugs Dual antiplatelet therapy, typically the addition of an ADP receptor antagonist to aspirin, has become the cornerstone of management of patients with acute coronary syndromes and after percutaneous coronary intervention However, along with the reduction of thrombotic outcomes, this therapeutic strategy has the untoward effect of increasing the risk of bleeding events, including GI bleeding.1 The use of gastroprotective strategies, most notably proton pump inhibitors (PPIs), has become a widely adopted and recommended practice in this patient population.2 Currently, the most commonly prescribed ADP receptor antagonist is clopidogrel, a prodrug that undergoes activation by the cyto- chrome P450 system, in particular CYP2C19 The importance of this reaction on the overall platelet inhibitory effects of clopidogrel is highlighted by the fact that patients with reducedfunction CYP2C19 alleles exhibit a reduced response to clopidogrel compared with those with the wild-type alleles This finding might translate into increased risk of adverse events after acute coronary syndromes and percutaneous coronary intervention Given that PPIs are inhibitors of CYP2C19, coupled with reports suggesting a clinically significant interaction,3 regulatory agencies issued a cautionary statement advising against the combined use of PPIs (specifically omeprazole and esomeprazole) and clopidogrel.4 Risk of GI Bleeding With Antiplatelet Therapy and Effect of Gastroprotective Strategies Aspirin causes direct damage to the gastric epithelium and inhibits prostaglandin production by the gastric mucosa, leading to ulcerations and an estimated 2-fold increased risk of GI bleeding with low-dose aspirin alone.1 The risk increases with the additional use of antiplatelet and antithrombotic agents, as well as steroidal and nonsteroidal antiinflammatory drugs.1,5 In patients with heart disease, several clinical characteristics that confer added risk of GI bleeding such as older age, male sex, nonwhite race, diabetes mellitus, history of alcohol abuse, heart failure symptoms, and renal insufficiency can be identified.5 History of ulcers and prior GI bleeding events are also very important risk factors.6 The risk of bleeding appears to be highest in the early period after a cardiac event but continues to be present on long-term follow-up (Figure 1) Gastroprotective strategies to reduce the risk of GI bleeding in patients taking antiplatelet agents have been tested in several settings Both H2 receptor antagonists and PPIs reduce stomach acid production, thus allowing gastric ulcers and erosions to heal Use of PPIs in patients taking antiplatelet therapy has been associated with a significant reduction in the risk of GI bleeding, ulcers, and erosions in data from observational and randomized clinical trials.7–11 Although there is no large clinical trial with a head-tohead comparison with PPIs, H2 re- From the Brigham and Women’s Hospital, Harvard Medical School (G.V.M., D.L.B.), and the VA Boston Healthcare System (D.L.B.), Boston, MA Correspondence to Deepak L Bhatt, MD, MPH, FAHA, 1400 VFW PKWY, Boston, MA 02132 E-mail DLBHATTMD@post.harvard.edu (Circulation 2012;125:375-380.) © 2012 American Heart Association, Inc Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.019745 Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 375 376 Circulation January 17, 2012 nonrandomized studies and could lead to erroneous association of PPI use with increased cardiac events.13 PPIs and Aspirin Interaction Figure Cumulative incidence of gastrointestinal (GI) bleeding during the Valsartan in Acute Myocardial Infarction (VALIANT) follow-up The dotted lines represent the 95% confidence intervals (CIs) of the estimated rate The monthly incidence rates of GI bleeding in the first months and between months and years are noted Reprinted from Moukarbel et al5 with permission from the publisher © 2009, European Society of Cardiology ceptor antagonists appear to confer a more modest protection from GI events in this setting according to observational and retrospective studies.10,12 Clinical characteristics can be used to guide the need for PPIs in patients taking antiplatelet therapy (Figure 2) The weight of the evidence for and against a clinically significant interaction between antiplatelet agents and PPIs comes mostly from retrospective cohort studies or secondary analyses of randomized controlled trials Inherent to the design of such studies, the main issue is the inability to adjust for residual confounding factors that might drive the decision to initiate PPI therapy in patients who are at high risk Additionally, patients could have been prescribed PPIs for symptoms that were misdiagnosed as having a GI rather than a cardiac origin Such an occurrence would be captured in these Figure Proposed algorithm for use of proton pump inhibitors (PPIs) in patients requiring antiplatelet therapy GI indicates gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; and GERD, gastroesophageal reflux disease There have been recent concerns that PPIs may interfere with the absorption and bioavailability of aspirin by altering gastric acidity Small platelet aggregation studies in patients treated with low-dose aspirin (75–100 mg) and concomitant PPI showed opposing results 14,15 A propensity score– matched study in Ϸ20 000 patients with first myocardial infarction who were not treated with clopidogrel showed that treatment with a PPI was associated with up to 60% increased risk of cardiovascular death, myocardial infarction, or stroke There was no increased risk noted with H2 receptor antagonists.16 This study had major specific limitations: it relied on prescription-filling data from a national registry, and it was uncertain why these patients were not treated with dual antiplatelet therapy PPIs and Clopidogrel: Evidence for and Against a Clinically Significant Interaction Only randomized controlled trial, Clopidogrel and the Optimization of Gastrointestinal Events (COGENT), has addressed treatment with PPIs in patients with coronary artery disease treated with dual antiplatelet therapy.8 Unfortunately, the trial was stopped prematurely owing to loss of funding by the sponsor Nevertheless, important lessons can be learned from the results In the 3761 patients analyzed, treatment with omeprazole was associated with a significant 66% reduction in the incidence of GI events at months (Figure 3A) COGENT was the first large randomized trial to find that prophylactic PPI use reduced clinical (as opposed to endoscopic) GI end points Additionally, there was no difference in the occurrence of cardiovascular events in the groups in the early period after acute coronary syndromes or percutaneous coronary intervention, Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 Moukarbel and Bhatt Antiplatelets and PPI 377 gested Pantoprazole and rabeprazole interfere minimally with the cytochrome P450 system and may potentially not exhibit a similar interaction.19,34 The use of prasugrel instead of clopidogrel in acute coronary syndromes patients undergoing percutaneous coronary intervention can be considered and has been shown to cause platelet inhibition even in the face of clopidogrel nonresponsiveness, albeit at the expense of increased bleeding Newer antiplatelet agents that are not dependent on the cytochrome P450 isoenzymes such as ticagrelor could be used in acute coronary syndromes treated invasively or conservatively Administration of the PPI at a different time than the administration of clopidogrel showed inconsistent results in the studies that evaluated this strategy It is unclear whether the release pharmacokinetics of the particular omeprazole formulation used in COGENT had any impact on the results of the trial Finally, different gastroprotective drugs such as H2 receptor antagonists can be used, although they have been shown to confer a somewhat more modest protective effect than PPIs Figure Efficacy (A) and safety (B) of concomitant proton pump inhibitor (PPI) (omeprazole) treatment in patients on dual antiplatelet therapy in Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) A, Kaplan-Meier estimates of the probability of remaining free of primary gastrointestinal events according to study group The event rate for the primary gastrointestinal end point at day 180 was 1.1% in the omeprazole group and 2.9% in the placebo group B, Kaplan-Meier estimates of the probability of remaining free of primary cardiovascular events according to study group The event rate for the primary cardiovascular end point at day 180 was 4.9% in the omeprazole group and 5.7% in the placebo group Reprinted from Bhatt et al8 with permission from the publisher © 2010, Massachusetts Medical Society when risk of cardiac events would be expected to be highest (Figure 3B) The Table summarizes the large nonrandomized published studies examining this issue in different patient populations These studies vary in terms of patient inclusion criteria, outcomes measured, and analysis methods In general, studies reporting a positive association found Ϸ25% to 80% increased risk of cardiovascular events in patients treated with a PPI in addition to dual antiplatelet therapy Interestingly, recent meta-analyses of published studies found no association between PPI use and mortality.32,33 A significant association with cardiovascular events was found in observational studies but not in those using propensity matching or participants of randomized trials The presence of significant heterogeneity again indicates the biased and confounded nature of the evidence Strategies to Avoid the Effects of an Interaction Several approaches to circumvent the potential for significant interference with clopidogrel effect have been sug- Conclusions and Summary of Recommendations The totality of evidence available to date does not support a clinically significant impact of any pharmacokinetic or pharmacodynamic interactions between PPIs and the current widely used antiplatelet agents Further evidence that will shed more light on this matter should come only from randomized clinical trials because new retrospective studies, no matter how statistically sound, will only add confusion to the matter Until then, the benefit of PPIs in reducing bleeding events (and treating GI symptoms) must be factored into decision making when faced with patients with high GI bleeding risk requiring antiplatelet therapy Our patient was treated with 20 mg omeprazole once per day, given the history of prior GI bleeding events, other risk factors, and the need for Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 378 Circulation January 17, 2012 Table Summary of Recent Large (n >1000), Nonrandomized Studies Looking at Clinical Evidence of an Interaction Between Clopidogrel and Proton Pump Inhibitors Reference (Year) Design Population Treatment, n Follow-Up End Point Results Pezalla et al17 (2008) Retrospective cohort Heart disease and or risk factors PPI, 626; no PPI, 384 1y MI OR, 4.3 (95% CI, 2.2–8.4) Ho et al18 (2009) Retrospective cohort Post-MI, ACS PPI, 5244; no PPI, 2961 Death, ACS OR, 1.25 (95% CI, 1.11–1.41) Nested case-control Post-MI Cases, 734 (PPI, 194); controls, 2057 (PPI, 424) Death, MI OR, 1.27 (95% CI, 1.03–1.57) Kreutz et al20 (2010) Retrospective cohort Poststenting PPI, 6828; no PPI, 9862 1y CVA, ACS, Revascularization, CV death HR, 1.51 (95% CI, 1.39–1.64) Huang et al21 (2010) Registry Post-PCI PPI, 572; no PPI, 2706 6y ACS; death HR, 1.23 (95% CI, 1.07–1.41) and 1.65 (95% CI, 1.35–2.01) Stockl et al22 (2010) Retrospective propensity matching Post-MI or stent PPI, 1033; no PPI, 1033 1y MI, stent HR, 1.64 (95% CI, 1.16–2.32) Van Boxel et al23 (2010) Retrospective cohort Clopidogrel use PPI, 5734; no PPI, 12 405 2y Death, ACS, CVA HR, 1.75 (95% CI, 1.58–1.94) Registry Vascular disease PPI, 519; no PPI, 703 15 mo MI, CVA, CLI, death HR, 1.8 (95% CI, 1.1–2.7) Post hoc analysis of RCT ACS and PCI PPI, 2257; no PPI, 4,538 Up to 15 mo MI, CVA, CV death No effect Rassen et al26 (2009) Retrospective cohort ACS or PCI PPI, 3996; no PPI, 14 569 mo MI, death, revascularization No effect Ray et al7 (2010) Retrospective cohort MI, revascularization, UA PPI, 7593; no PPI, 13 003 1y MI, CVA, CV death No effect Charlot et al27 (2010) Registry MI PPI, 6753; no PPI, 17 949 1y MI, CVA, CV death No effect Sarafoff et al28 (2010) Retrospective cohort Poststent PPI, 698; no PPI, 2640 mo Stent thrombosis No effect Tentzeris et al29 (2010) Registry; propensity matching Poststent PPI, 691; no PPI, 519 1y Death, ACS No effect Banerjee et al13 (2011) Retrospective propensity matching Post-PCI PPI, 867; no PPI, 3678 6y MACE No effect Simon et al30 (2011) Registry MI PPI, 1453; no PPI, 900 1y MI, CVA, Death No effect Harjai et al31 (2011) Registry; propensity matching Post-PCI PPI, 751; no PPI, 1900 mo MACE No effect Evidence for Juurlink et al19 (2009) Munoz-Torrero et al24 (2011) Ϸ3 y mo Evidence against O’Donoghue et al25 (2009) ACS indicates acute coronary syndrome; CI, confidence interval; CLI, chronic limb ischemia; CV, cardiovascular; CVA, cerebrovascular accident; HR, hazard ratio; MACE, major adverse cardiac events (death, myocardial infarction, revascularization); MI, myocardial infarction; OR, odds ratio; RCT, randomized controlled trial; and UA, unstable angina long-term dual antiplatelet therapy For this patient, omeprazole was the cheapest option because it was on the hospital formulary If cost were not an issue, it would have been reasonable to initiate therapy with a PPI that has less effect on CYP2C19 in case future studies show that the pharmacokinetic and pharmacodynamic interactions with clopidogrel translate into clinical events cines Company He has collaborated with Takeda and PLx Pharma on research studies He was the chair of the COGENT trial Dr Moukarbel reports no conflicts Disclosures References Dr Bhatt receives research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-aventis, and The Medi- Garcia Rodriguez LA, Lin KJ, HernandezDiaz S, Johansson S Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 Moukarbel and Bhatt acid alone and in combination with clopidogrel and other medications Circulation 2011;123: 1108–1115 Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM 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 Circulation 2008;118: 1894 –1909 Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J 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 –260 US Food and Drug Administration Follow-up to the January 26, 2009, early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC) November 17, 2009.http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatient sandProviders/DrugSafetyInformationfor HeathcareProfessionals/ucm190784.htm Accessed July 15, 2011 Moukarbel GV, Signorovitch JE, Pfeffer MA, McMurray JJ, White HD, Maggioni AP, Velazquez EJ, Califf RM, Scheiman JM, Solomon SD Gastrointestinal bleeding in high risk survivors of myocardial infarction: the VALIANT Trial Eur Heart J 2009;30: 2226 –2232 Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF ACCF/ ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the 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 Expert Consensus Documents Circulation 2010;122:2619 –2633 Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study Ann Intern Med 2010;152:337–345 Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP Clopidogrel with or without omeprazole in coronary artery disease N Engl J Med 2010;363: 1909 –1917 Lanas A, Garcia-Rodriguez LA, Arroyo MT, Bujanda L, Gomollon F, Forne M, Aleman S, Nicolas D, Feu F, Gonzalez-Perez A, Borda A, Castro M, Poveda MJ, Arenas J 10 11 12 13 14 15 16 17 18 19 20 Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants Am J Gastroenterol 2007;102:507–515 Lin KJ, Hernandez-Diaz S, Garcia Rodriguez LA Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy Gastroenterology 2011;141:71–79 Scheiman JM, Devereaux PJ, Herlitz J, Katelaris PH, Lanas A, Veldhuyzen van Zanten S, Naucler E, Svedberg LE Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON) Heart 2011;97:797– 802 Ng FH, Lam KF, Wong SY, Chang CM, Lau YK, Yuen WC, Chu WM, Wong BC Upper gastrointestinal bleeding in patients with aspirin and clopidogrel co-therapy Digestion 2008;77:173–177 Banerjee S, Weideman RA, Weideman MW, Little BB, Kelly KC, Gunter JT, Tortorice KL, Shank M, Cryer B, Reilly RF, Rao SV, Kastrati A, de Lemos JA, Brilakis ES, Bhatt DL Effect of concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention Am J Cardiol 2011;107:871– 878 Adamopoulos AB, Sakizlis GN, Nasothimiou EG, Anastasopoulou I, Anastasakou E, Kotsi P, Karafoulidou A, Stergiou GS Do proton pump inhibitors attenuate the effect of aspirin on platelet aggregation? A randomized crossover study J Cardiovasc Pharmacol 2009;54:163–168 Wurtz M, Grove EL, Kristensen SD, Hvas AM The antiplatelet effect of aspirin is reduced by proton pump inhibitors in patients with coronary artery disease Heart 2010;96:368 –371 Charlot M, Grove EL, Hansen PR, Olesen JB, Ahlehoff O, Selmer C, Lindhardsen J, Madsen JK, Kober L, Torp-Pedersen C, Gislason GH Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study BMJ 2011;342:d2690 Pezalla E, Day D, Pulliadath I Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors J Am Coll Cardiol 2008;52: 1038–1039; author reply 1039 Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome JAMA 2009;301:937–944 Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM A population-based study of the drug interaction between proton pump inhibitors and clopidogrel CMAJ 2009;180: 713–718 Kreutz RP, Stanek EJ, Aubert R, Yao J, Breall JA, Desta Z, Skaar TC, Teagarden JR, Frueh FW, Epstein RS, Flockhart DA Antiplatelets and PPI 21 22 23 24 25 26 27 28 29 30 379 Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: the Clopidogrel Medco Outcomes study Pharmacotherapy 2010; 30:787–796 Huang CC, Chen YC, Leu HB, Chen TJ, Lin SJ, Chan WL, Chen JW Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention Am J Cardiol 2010;105:1705–1709 Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor Arch Intern Med 2010;170:704 –710 van Boxel OS, van Oijen MG, Hagenaars MP, Smout AJ, Siersema PD Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study Am J Gastroenterol 2010;105:2430 –2437 Munoz-Torrero JF, Escudero D, Suarez C, Sanclemente C, Pascual MT, Zamorano J, Trujillo-Santos J, Monreal M Concomitant use of proton pump inhibitors and clopidogrel in patients with coronary, cerebrovascular, or peripheral artery disease in the Factores de Riesgo y ENfermedad Arterial (FRENA) registry J Cardiovasc Pharmacol 2011;57:13–19 O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials Lancet 2009;374:989 –997 Rassen JA, Choudhry NK, Avorn J, Schneeweiss S Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome Circulation 2009;120:2322–2329 Charlot M, Ahlehoff O, Norgaard ML, Jorgensen CH, Sorensen R, Abildstrom SZ, Hansen PR, Madsen JK, Kober L, TorpPedersen C, Gislason G Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study Ann Intern Med 2010;153:378 –386 Sarafoff N, Sibbing D, Sonntag U, Ellert J, Schulz S, Byrne RA, Mehilli J, Schomig A, Kastrati A Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors Thromb Haemost 2010; 104:626 – 632 Tentzeris I, Jarai R, Farhan S, Brozovic I, Smetana P, Geppert A, Wojta J, SillerMatula J, Huber K Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation Thromb Haemost 2010;104:1211–1218 Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, Lardoux H, Coste P, Lefevre T, Drouet E, Mulak G, Bataille V, Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 380 Circulation January 17, 2012 Ferrieres J, Verstuyft C, Danchin N Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry Circulation 2011;123: 474–482 31 Harjai KJ, Shenoy C, Orshaw P, Usmani S, Boura J, Mehta RH Clinical outcomes in patients with the concomitant use of clopi- dogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators Circ Cardiovasc Interv 2011;4:162–170 32 Kwok CS, Loke YK Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel Aliment Pharmacol Ther 2010;31:810 – 823 33 Siller-Matula JM, Jilma B, Schror K, Christ G, Huber K Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis J Thromb Haemost 2010;8:2624–2641 34 Ferreiro JL, Ueno M, Tomasello SD, Capodanno D, Desai B, Dharmashankar K, Seecheran N, Kodali MK, Darlington A, Pham JP, Tello-Montoliu A, Charlton RK, Bass TA, Angiolillo DJ Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study Circ Cardiovasc Interv 2011;4:273–279 Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 ... Post-PCI PPI, 867; no PPI, 3678 6y MACE No effect Simon et al30 (2011) Registry MI PPI, 1453; no PPI, 900 1y MI, CVA, Death No effect Harjai et al31 (2011) Registry; propensity matching Post-PCI PPI, ... 10.1161/CIRCULATIONAHA.111.019745 Downloaded from http://circ.ahajournals.org/ by guest on June 26, 2014 375 376 Circulation January 17, 2012 nonrandomized studies and could lead to erroneous association of PPI. .. cohort Heart disease and or risk factors PPI, 626; no PPI, 384 1y MI OR, 4.3 (95% CI, 2.2–8.4) Ho et al18 (2009) Retrospective cohort Post-MI, ACS PPI, 5244; no PPI, 2961 Death, ACS OR, 1.25 (95% CI,