Combined Use of Oral Antiplatelet Agents and Gastroprotective Agents: Focus on PPIs and Clopidogrel  Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Study Group Harvard Medical School

ADP Receptors Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.

CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population 15 Placebo* Clopidogrel* 11.5% 27% RRR P=0.02 10 8.5% Combined endpoint occurrence (%) 5 The CREDO results demonstrate the benefits of long-term (1 year) administration of clopidogrel plus ASA and other standard therapies in patients undergoing PCI, with or without stent. For the entire study population, long-term clopidogrel treatment was associated with a 27% reduction in the relative risk of the combined endpoint of death, MI, and stroke at 1 year. This result was statistically significant (8.5% clopidogrel vs. 11.5% placebo, 95% CI, 3.9-44.4, p=0.02). Reference: Steinhubl S, Berger P, Tift Mann III J, et al. JAMA. 2002;Vol 288,No 19:2411-2420. 3 6 9 12 Months from randomization * Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

Multivariable Predictors of Bleeding Events Discharge to 1 Year (n=1816) Hazard Ratio (95% CI) X2 P value Clopidogrel 1.04 (0.75-1.44) 0.05 0.82 Age (per 10 years) 1.26 (1.07-1.48) 8.1 0.005 CABG discharge-1 year 32.15 (23.10-44.74) 423.6 <0.0001 Aronow HD, et al. Am Heart J 2008 (published online Nov 2008)

Kaplan Meier Estimates of Bleeding Risk Discharge to 1 Year (n=1816)

Timing of Severe or Moderate Bleeding 0.00008 0.00007 Placebo + ASA Clopidogrel + ASA 0.00006 0.00005 Hazard Function/d 0.00004 0.00003 0.00002 0.00001 15 60 135 270 450 630 810 Days Since Randomization Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Algorithm to Assess GI Risk With Antiplatelet Therapy Need for antiplatelet therapy Yes Assess GI risk factors History of ulcer complication History of ulcer disease (nonbleeding) Dual antiplatelet therapy Concomitant anticoagulant Test for H pylori; treat if infected Yes According to the consensus document: If a patient needs antiplatelet therapy, the clinician should assess the patient’s GI risk factors. [Bhatt p7] If the patient has a history of ulcer complication or of nonbleeding ulcer disease, evaluate whether H pylori infection is present and treat if indicated, before starting chronic antiplatelet tharapy. [Bhatt p7,8] Proton pump inhibitors should be prescribed if the patient has GI bleeding, is receiving dual antiplatelet therapy, or is receiving a concomitant anticoagulant. [Bhatt p7] If none of these risk factors are present, the patient should still receive a proton pump inhibitor if more than one of the following apply: [Bhatt p7] The patient is age 60 or older The patient uses corticosteroids The patient has dyspepsia or symptoms of gastroesophageal reflux disease. No Yes More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms PPI Yes Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008. 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. Circulation 2008 in press; epub Oct 3 ahead of print. 6

Clopidogrel and PPIs – The OCLA study Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite PPIs are strong inhibitors of CYP2C19 activity PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) Poor responders = 16 placebo and 39 in omeprazole PRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI rechecked Graph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically? p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

Intake of PPIs Not Associated With Impaired Response to Clopidogrel Responsiveness to clopidogrel was assessed by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 300 patients with coronary artery disease undergoing PCI. All patients received a clopidogrel loading dose (600 mg) at the start of clopidogrel treatment. Patients had been on clopidogrel (75 mg/d) and aspirin (100 mg/d) treatment for 3 months on average (at least 5 days) at the time of inclusion. The mean platelet reactivity index (PRI, assessed by the VASP assay) was similar in patients with any PPI (n=226; PRI = 51%) or without any PPI (n=74; PRI = 49%; P=.724) treatment. Likewise, the adenosine diphosphate–induced platelet aggregation did not differ significantly between patients with or without PPI treatment (45 vs 41 U; P=.619). Similarly, as shown in the figures on the slide, there was no difference in the PRI or the adenosine diphosphate–induced platelet aggregation between patients with pantoprazole (n=152; PRI = 50%; aggregation = 47 U), esomeprazole (n=74; PRI = 54%; aggregation = 42 U), or without PPI (n=74; PRI = 49%; aggregation = 40 U; P=.382). Thus, in contrast to the reported negative omeprazole-clopidogrel drug interaction, the intake of pantoprazole or esomeprazole is not associated with impaired response to clopidogrel. Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Adenosine diphosphate–induced platelet aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Data are presented as mean and 95% CI. PPI, proton pump inhibitor; VASP, vasodilator-stimulated phosphoprotein. Siller-Matula JM, et al. Am Heart J. 2009;157(1):148.e1-148.e5. 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(1):148.e1-148.e5.

Variability in Clopidogrel Responsiveness in a Diverse Population of 544 D 5mM ADP Platelet Aggregation Serebruany V, Steinhubl S et al. JACC 2005.

Genetic Variations and Clopidogrel Response Percent Difference in AUC0-t P Value CYP2C19 −32.4 .001 CYP2C9 −6.8 .59 CYP2B6 −15.7 .03 CYP3A5 5.6 CYP1A2 11.2 .45 Pharmacokinetic Response -50 -40 -30 -20 -10 10 20 30 Relative Percent Difference Gene Percent Difference in ΔMPA P Value CYP2C19 −9.0 .001 CYP2C9 −0.6 .86 CYP2B6 −5.7 .012 CYP3A5 7.5 CYP1A2 0.5 .90 Pharmacodynamic Response -15 -10 -5 5 10 25 Absolute Difference Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.

Deaths or Recurrent ACS Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI 0.70 0.60 0.50 0.40 0.30 0.20 0.10 90 180 270 360 450 540 630 720 810 900 990 1080 Days Since Discharge Deaths or Recurrent ACS Proportion of Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI In this retrospective cohort study by Ho and colleagues, concomitant use of clopidogrel and a proton pump inhibitor (PPI) after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without a PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS. Of 8205 patients with ACS taking clopidogrel after hospital discharge, 63.9% (n=5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n=2961) were not prescribed PPI. Median follow-up after hospital discharge was 521 days (interquartile range, 305-779 days). Death or rehospitalization for ACS occurred in 20.8% (n=615) of patients prescribed clopidogrel without PPI and 29.8% (n=1561) of patients prescribed clopidogrel plus PPI. In multivariable analysis, use of clopidogrel plus PPI at any point in time was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio, 1.25; 95% CI, 1.11-1.41). In multivariable analyses with medication use as a time-varying covariate, periods of use of clopidogrel without PPI were associated with a significantly lower risk of adverse events compared with periods without the use of either clopidogrel or PPI (P<.001). However, this association appeared to be attenuated when comparing periods of use of clopidogrel plus PPI use with periods without use of either clopidogrel or PPI (shown in figure on slide). Ho PM, et al. JAMA. 2009;301(9):937-944. 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.

Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI Unadjusted OR (95% CI) Adjusted OR (95% CI) Outcome Primary outcome Death or rehospitalization for ACS Secondary outcomes Rehospitalization for ACS Revascularization procedures Death (all-cause) Without PPI With PPI Without PPI With PPI Ho PM, et al. JAMA. 2009;301(9):937-944.

Results – 1 Year Endpoint from CREDO Unadjusted Data Primary 1-Year Endpoint: Death, MI or Stroke 20 P=0.45 PPI at baseline (N=374) P=0.001 15 16.2 No PPI at baseline (N=1742) 14.8 13.2 10 10.8 9.2 No PPI p-value is 0.035 7.7 5 All N=2116 Placebo N=1063 Clopidogrel N=1053 Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD 13

One Year Death/MI/Stroke Results – Clopidogrel Group Adjusted Data 28 Days Death/MI/ UTVR Adjusted OR (95% CI) p-value* One Year Death/MI/Stroke Adjusted HR (95% CI) p-value† Clopidogrel / PPI (n=179) 18/179 (10.2) 1.8 (0.99, 3.23) 0.051 23/179 (13.2) 1.6 (1.02, 2.63) 0.043 Clopidogrel / No PPI (n=874) 47/874 (5.4) 66/874 (7.7) * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum † Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD 14

One Year Death/MI/Stroke Results – Placebo Group Adjusted Data 28 Days Death/MI/UTVR Adjusted OR (95% CI) p- value* One Year Death/MI/Stroke Adjusted HR (95% CI) p-value† Placebo / PPI (n=195) 19/195 (9.8) 1.4 (0.81, 2.41) 0.221 31/195 (16.2) 1.6 (1.03, 2.34) 0.035 Placebo / No PPI (n=868) 64/868 (7.4) 91/868 (10.8) * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum † Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

Results – 1 Year Primary Endpoint PPI at Baseline Randomized Therapy Death, MI or Stroke Adjusted HR (95% CI) P-value Placebo (N=195) 16.2% 0.77 (0.45, 1.33) 0.35 Clopidogrel (N=179) 13.2% P-value for interaction between randomized therapy and baseline PPI P=0.69 No PPI at Baseline Randomized Therapy Death, MI or Stroke Adjusted HR (95% CI) P-value Placebo (N=868) 10.8% 0.75 (0.55, 1.03) 0.08 Clopidogrel (N=874) 7.7% Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

THE LANCET

Primary endpoint stratified by use of a PPI PPI use at randomization (n= 4529) Clopidogrel Prasugrel CV death, MI or stroke CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Days 18

Risk of CV Events with Different Types of PPIs Type of PPI Clopidogrel HR (95% CI) CV death, MI or stroke Prasugrel Omeprazole (n=1675) 0.91 (0.72-1.15) 1.04 (0.81-1.34) Pantoprazole (n=1844) 0.94 (0.74-1.18) 1.09 (0.86-1.39) Esomeprazole (n=613) 1.07 (0.75-1.52) 0.86 (0.55-1.33) Lansoprazole (n=441) 1.00 (0.63-1.59) 0.98 (0.61-1.57) Rabeprazole not included due to small sample size (n=66) 19

Clopidogrel and the Optimization of GI Events Trial – COGENT 20

Conclusions Dual antiplatelet therapy reduces important ischemic events after PCI, ACS GI bleeding is the most common form of major bleeding that occurs Logical, though not proved, that prophylactic PPI reduces this GI bleeding Patients prescribed PPI are a higher risk than those who are not While pathways for an interaction exist, unclear degree of clinical relevance