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Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System

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

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Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System

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  1. 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

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

  3. 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 0 0 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.

  4. Multivariable Predictors of Bleeding EventsDischarge to 1 Year (n=1816) Aronow HD, et al. Am Heart J 2008 (published online Nov 2008)

  5. Kaplan Meier Estimates of Bleeding RiskDischarge to 1 Year (n=1816)

  6. Timing of Severe or Moderate Bleeding 0.00008 Placebo + ASA Clopidogrel + ASA 0.00007 0.00006 0.00005 Hazard Function/d 0.00004 0.00003 0.00002 0.00001 0 135 270 450 630 810 15 60 Days Since Randomization Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

  7. 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 therapyConcomitant anticoagulant Test for H pylori; treat if infected Yes No Yes PPI More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms Yes Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.

  8. 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 Clopidogrel and PPIs – The OCLA study PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

  9. Intake of PPIs Not Associated With Impaired Response to Clopidogrel Adenosine diphosphate–induced platelet aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Platelet reactivity index in the VASP phosphorylation assay 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.

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

  11. Genetic Variations and Clopidogrel Response Pharmacokinetic Response -50 -40 -30 -20 -10 0 10 20 30 Relative Percent Difference Pharmacodynamic Response -15 -10 -5 0 5 10 25 Absolute Difference Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.

  12. Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 Proportion of Deaths or Recurrent ACS 90 180 270 360 450 540 630 720 810 900 990 1080 0 Days Since Discharge Ho PM, et al. JAMA. 2009;301(9):937-944.

  13. Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI Unadjusted OR (95% CI) Adjusted OR (95% CI) Outcome Without PPI With PPI Without PPI With PPI Ho PM, et al. JAMA. 2009;301(9):937-944.

  14. 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 16.2 15 No PPI at baseline (N=1742) 14.8 13.2 10 10.8 9.2 7.7 5 0 All N=2116 Placebo N=1063 Clopidogrel N=1053 Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  15. Results – Clopidogrel Group Adjusted Data * 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

  16. Results – Placebo Group Adjusted Data * 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

  17. Results – 1 Year Primary Endpoint PPI at Baseline P-value for interaction between randomized therapy and baseline PPI P=0.69 No PPI at Baseline Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  18. THE LANCET

  19. 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

  20. Risk of CV Events with Different Types of PPIs Rabeprazole not included due to small sample size (n=66)

  21. Clopidogrel and the Optimization of GI Events Trial –COGENT

  22. 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

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