Risk of GI Bleeding and Use of PPIs ESC 211 August 28, 211 Marc S. Sabatine, MD, MPH Chairman, TIMI Study Group Associate Physician, Cardiovascular Division, BWH Associate Professor of Medicine, Harvard Medical School
Disclosure Statement AstraZeneca: research grant support through BWH Bristol-Myers-Squibb / sanofi-aventis Joint Venture: research grant support through BWH, scientific advisory boards Daiichi-Sankyo: research grant support through BWH Daiichi-Sankyo / Lilly Partnership: scientific advisory boards Schering-Plough: research grant support through BWH
OR GI Bleeding Aspirin & the Risk of GI Bleeding 5 4 3 2.5 2 1.59 1.69 2.7 1 Derry, BMJ 2 Sanmuganathan, Weisman, McQuaid, Heart 21 Arch Int Med 22 Am J Med 26
Ulcer or erosive esophagitis (%) GI Ulcers, Bleed or Complications (%) H2RA & PPIs Reduce GI Complications for Patients on Aspirin 35 44 patients with vascular disease 33. 16 123 patients with healed PUD & H pylori 14.8 3 14 25 2 15 HR.13 (95% CI.7-.24) P<.1 12 1 8 6 HR.9 (95% CI.1-.77) P=.8 1 5 5.9 4 2 1.6 Famotidine Placebo Lansoprazole Placebo Taha et al. Lancet 29;374:119-25 Lai et al. NEJM 22;346:233-8
Risk of GI Bleeding with Clopidogrel: RCTs 2 RR 1.78 (1.25-2.54) P<.5 NNH 13 RR 1.96 (1.46-2.63) P<.1 NNH 167 1.5 1.3 1.7 1.1 Clopidogrel Placebo.5.5 CURE Yusuf S et al. NEJM 21;345:494-52 ACTIVE-A Connolly SJ et al. NEJM 29;36:266-78
Risk Factors for Hospitalization for GI bleeding in Clopidogrel Users Age 65 years History of hospitalization for upper GI disease or bleeding Recent use of anticoagulants Current use of other meds that bleeding risk (systemic steroids, NSAIDs, COX-2 inhibitors) Any hospital discharge in past year Ray W A et al. Ann Intern Med 21;152:337-345
Association of H2RA and PPI use and GI Bleeding in Observational Studies OR (95% CI) for GI Bleed Study H2RA vs placebo PPI vs placebo Lanas et al. Am J Gastroenterol 27;12:57-15 Ng et al. Digestion 28;77:173-7.83 (.2-3.51).19 (.7-.49).43 (.18-.91).4 (.2-.21)
PRI Variation (%) 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) -5-1 -15-2 -25-3 -35-4 -45-5 -32.6 p<.1-43.3 Omeprazole (n=64) Placebo (n=6) Gilard et al. J Am Coll Cardiol 28;51:256-6.
MACE through 1 year (%) Association between PPI Use & Clinical Outcomes MEDCO Database (n=14,383 on clopidogrel s/p stent) CREDO Clinical Trial (n=2166 s/p PCI w/ or w/o clopidogrel) 35 Adj OR 1.79 (1.62-1.97) 32.5 18 Adj OR 1.63 (1.2-2.63) Randomized to clopidogrel Adj OR 1.55 (1.3-2.34) Randomized to placebo 3 25 21.2 16 14 12 13.4 15. 11.1 2 15 1 8 7.7 1 6 4 5 2 n=4321 PPI n=9862 No PPI n=176 PPI n=877 No PPI n=19 PPI n=873 No PPI Aubert RE et al. AHA 28 Dunn SP et al. AHA 28
Proportion of Deaths or Recurrent ACS Clopidogrel With or Without PPI Cumulative Risk of All-Cause Mortality and Recurrent ACS.7.6.5.4.3.2.1 Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI 9 18 27 36 45 54 63 72 81 9 99 18 Period Since Discharge (days) Observational Study- VA Database Ho et al. JAMA. 29;31:937-944.
CV death, MI or stroke Risk of CV Death, MI, or Stroke by PPI use Data from TRITON-TIMI 38; PPI use (n= 4529) at discretion of physician Clopidogrel Prasugrel CLOPIDOGREL PPI vs no PPI: Adj HR.94, 95% CI.8-1.11 PRASUGREL PPI vs no PPI: Adj HR 1., 95% CI.84-1.2 Days O Donoghue M et al. Lancet 29;374:989-97.
Mean (SD) Active Metabolite H4 Concentration (ng/ml) Mean (SD) Active Metabolite H4 Concentration (ng/ml) Standard-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 3-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 45% AUC (P<.1) 4% AUC (P<.1) 6 Day 1 3 mg 25 Day 5 75 mg 5 4 Clopidogrel alone Clopidogrel + omeprazole LOQ =.5 ng/ml 2 15 Clopidogrel alone Clopidogrel + omeprazole LOQ =.5 ng/ml* 3 2 1 1 5..5 1. 1.5 2. 2.5 3. Nominal Time (h)..5 1. 1.5 2. Nominal Time (h) LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. Angiolillo DA, et al. Clin Pharmacol Ther 211;89:65-74.
Standard-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µm +8.% (4.7-11.3&) P<.1 ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. Angiolillo DA, et al. Clin Pharmacol Ther 211;89:65-74.
Relative percent decrease in AUC Absolute increase in MPA Absolute increase in VASP Effect of Different PPI Regimens on Clopidogrel PK & PD Omeprazole simultaneously Omeprazole 12 hrs later Pantoprazole simultaneously 5 47. 1 3 27.1 4 3 4. 8 6 8. 5.6 2 2.7 4.3 2 14. 4 1 1 2 3.9 AUC MPA VASP Angiolillo DA, et al. Clin Pharmacol Ther 211;89:65-74.
COGENT Trial 3761 Pts w/ ACS, PCI, or other indic for ASA + clopidogrel randomized to clopidogrel (75 mg/d) vs. clopidogrel (75 mg/d) + omeprazole (2 mg/d) CV Death, MI, Revasc, Stroke 4.9% vs. 5.7% HR =.99 (95% CI.68-1.44) P=.96 CV Death, MI, Stroke ~23 events vs. ~2 events Bhatt DL et al. NEJM 21;363:199.
COGENT Trial: Efficacy of PPI Primary GI Endpoint: 1.1% vs. 2.9% HR =.34 (95% CI.18-.63) P<.1; NNT 6mos =55 Overt Upper GI Bleed:.2% vs. 1.2% HR =.34 (95% CI.18-.63) P<.1; NNT 6mos =98 Primary GI Endpoint = overt or occult GIB, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation Bhatt DL et al. NEJM 21;363:199.
Summary & Conclusions Patients on dual antiplatelet therapy are at risk of GIB PPIs and, to a lesser extent, H2RAs, that risk PPIs inhibit CYP2C19 to varying degrees PPIs clopidogrel active metabolite levels & platelet inhibition to varying degrees In the setting of clopidogrel Rx, no clear association between PPI & CV events, but not definitely refuted If at high risk of GIB (h/o GIB, h/o PUD, advanced age, concom meds, H pylori) reasonable to treat with PPI, preferably one that minimally inhibits CYP2C19