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Impact of Combining Proton Pump Inhibitors and Clopidogrel
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3. 4.
5.
6.
The American Journal of Cardiology (www.AJConline.org)
implantable cardioverter defibrillators. Kidney Int 2005;68:818 – 825. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999;10:1606 –1615. Mangrum AJ, Lin D, Dimarco JP, Bolton WK, Mangrum JM. Sudden cardiac death and left ventricular function in hemodialysis patients. Heart Rhythm 2006;2:S33. Mangrum JM, Lin D, Dimarco JP, Lake DE, Bolton WK, Mangrum AJ. Prognostic value of left ventricular systolic function in renal dialysis patients. Heart Rhythm 2006;3:S154. United States Renal Data System. 2008 Annual Data Report. Bethesda, Maryland: National Institute of Diabetes and Digestive and Kidney Diseases, 2008. doi:10.1016/j.amjcard.2009.03.007
Impact of Combining Proton Pump Inhibitors and Clopidogrel Antiplatelet therapy has become the standard of care for the secondary prevention of myocardial infarction. Guidelines endorse the combined use of aspirin and clopidogrel for patients who have acute coronary syndromes or undergo percutaneous coronary intervention.1,2 The occurrence of major adverse cardiac events despite antiplatelet therapy is thought to occur because of resistance.3 In discussing resistance to antiplatelet therapy and a possible drug-drug interaction between clopidogrel and omeprazole, Angiolillo3 stated that “there is no evidence that this drug-drug interaction has any clinical impact.” However, several recent studies suggest the contrary. In 1 population-based case-control study of patients aged ⱖ66 years, the use of proton pump inhibitors in conjunction with clopidogrel was associated with an increased risk for reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03 to 1.57).4 In another cohort study of 14,383 patients who underwent stent placement, when patients with no preceding cardiovascular events were analyzed, there was a 32.5% incidence of major cardiovascular events within 1 year in the group taking proton pump inhibitors with clopidogrel compared with 21.2% in the group not taking proton pump inhibitors (adjusted OR 1.79, 95% CI 1.62 to 1.97).5 In patients with preceding cardiovascular events, the major cardiovascular event incidence was 39.8% in the group taking proton pump inhibitors compared with 26.2% in the group not taking the combination of proton pump inhibitors and clopidogrel (adjusted OR 1.86, 95% CI 1.63 to 2.12).5 The investigators concluded
that their “findings suggest that the drug interaction between proton pump inhibitors and clopidogrel may result in serious adverse outcomes within 1 year of therapy initiation.” In another study, 1-year acute myocardial infarction rates were 1.4%, 3%, and 5% in the control group and in the groups with low and high proton pump inhibitor exposure, respectively.6 Differences in acute myocardial infarction rates between the control group and the group with high proton pump inhibitor exposure remained statistically significant after adjustment (p ⬍0.05), and there was a 337% greater relative risk for acute myocardial infarction in the group with high proton pump inhibitor exposure compared with the control group.6 Finally, in a recent cohort study of 8,205 patients with acute coronary syndromes, death or rehospitalization occurred in 29.8% of patients taking the combination of clopidogrel and a proton pump inhibitor and in 20.8% of patients taking clopidogrel without proton pump inhibitors (adjusted OR 1.25, 95% CI 1.11 to 1.41).7 These data led the investigators to conclude that “concomitant use of clopidogrel and proton pump inhibitor after hospital discharge for acute coronary syndrome was associated with an increased risk of adverse outcomes than use of clopidogrel without proton pump inhibitors.”7 Although future well-controlled randomized studies are warranted, taken together, these studies suggest that a drug interaction between proton pump inhibitors and clopidogrel may indeed have a profound clinical impact, and given how frequently these medications are combined, physicians should be aware of these findings. John R. Kapoor, MD, PhD Stanford, California 15 March 2009
1. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, et al. Guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/ AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2005;2006: e1– e121. 2. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, et al. Guidelines for the management of pa-
3. 4.
5.
6.
7.
tients with unstable angina/non ST-elevation myocardial infarction. Circulation 2007;116: e148 – e304. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol 2009; 103(suppl):27A–34A. 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 –187. Aubert RE, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T, Flockhart DA. Abstract 3998: proton pump inhibitors effect on clopidogrel effectiveness: the clopidogrel Medco outcomes study. Circulation 2008;118: S_815. 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. 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. doi:10.1016/j.amjcard.2009.03.031
Drug-Eluting Stents in Heart Transplant Recipients We read with great interest the work of Gupta et al1 in which they reported on 32 heart transplant recipients at their institution who were treated with drugeluting stents (DES) for cardiac allograft vasculopathy (CAV) and retrospectively followed for 1.3 ⫾ 1.2 years. During follow-up, 12 patients (38%) died, 1 (3%) underwent retransplantation, 4 (13%) underwent revascularization, and 5 of 21 patients (24%) who underwent coronary angiography had in-stent restenosis. The investigators also compared their data with a historical control of 35 patients with CAV treated with bare-metal stents (BMS). At 1 year, survival was not different between DES (68%) and BMS (91%) after adjustments for baseline characteristics. The restenosis rate was lower with DES (19%) than BMS (49%). Gupta et al1 concluded that in this “largest single-institution series of DES use” in patients with CAV, DES were associated with lower in-stent restenosis than BMS but that the survival of these patients was particularly poor and not affected by DES use. In June 2008, we reported our experience with DES use in heart transplant recipients.2 Our population consisted of 35 patients with CAV who underwent treatment with DES on 84 de novo lesions. During a retrospective follow-up
3. 4.
5.
6.
The American Journal of Cardiology (www.AJConline.org)
implantable cardioverter defibrillators. Kidney Int 2005;68:818 – 825. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999;10:1606 –1615. Mangrum AJ, Lin D, Dimarco JP, Bolton WK, Mangrum JM. Sudden cardiac death and left ventricular function in hemodialysis patients. Heart Rhythm 2006;2:S33. Mangrum JM, Lin D, Dimarco JP, Lake DE, Bolton WK, Mangrum AJ. Prognostic value of left ventricular systolic function in renal dialysis patients. Heart Rhythm 2006;3:S154. United States Renal Data System. 2008 Annual Data Report. Bethesda, Maryland: National Institute of Diabetes and Digestive and Kidney Diseases, 2008. doi:10.1016/j.amjcard.2009.03.007
Impact of Combining Proton Pump Inhibitors and Clopidogrel Antiplatelet therapy has become the standard of care for the secondary prevention of myocardial infarction. Guidelines endorse the combined use of aspirin and clopidogrel for patients who have acute coronary syndromes or undergo percutaneous coronary intervention.1,2 The occurrence of major adverse cardiac events despite antiplatelet therapy is thought to occur because of resistance.3 In discussing resistance to antiplatelet therapy and a possible drug-drug interaction between clopidogrel and omeprazole, Angiolillo3 stated that “there is no evidence that this drug-drug interaction has any clinical impact.” However, several recent studies suggest the contrary. In 1 population-based case-control study of patients aged ⱖ66 years, the use of proton pump inhibitors in conjunction with clopidogrel was associated with an increased risk for reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03 to 1.57).4 In another cohort study of 14,383 patients who underwent stent placement, when patients with no preceding cardiovascular events were analyzed, there was a 32.5% incidence of major cardiovascular events within 1 year in the group taking proton pump inhibitors with clopidogrel compared with 21.2% in the group not taking proton pump inhibitors (adjusted OR 1.79, 95% CI 1.62 to 1.97).5 In patients with preceding cardiovascular events, the major cardiovascular event incidence was 39.8% in the group taking proton pump inhibitors compared with 26.2% in the group not taking the combination of proton pump inhibitors and clopidogrel (adjusted OR 1.86, 95% CI 1.63 to 2.12).5 The investigators concluded
that their “findings suggest that the drug interaction between proton pump inhibitors and clopidogrel may result in serious adverse outcomes within 1 year of therapy initiation.” In another study, 1-year acute myocardial infarction rates were 1.4%, 3%, and 5% in the control group and in the groups with low and high proton pump inhibitor exposure, respectively.6 Differences in acute myocardial infarction rates between the control group and the group with high proton pump inhibitor exposure remained statistically significant after adjustment (p ⬍0.05), and there was a 337% greater relative risk for acute myocardial infarction in the group with high proton pump inhibitor exposure compared with the control group.6 Finally, in a recent cohort study of 8,205 patients with acute coronary syndromes, death or rehospitalization occurred in 29.8% of patients taking the combination of clopidogrel and a proton pump inhibitor and in 20.8% of patients taking clopidogrel without proton pump inhibitors (adjusted OR 1.25, 95% CI 1.11 to 1.41).7 These data led the investigators to conclude that “concomitant use of clopidogrel and proton pump inhibitor after hospital discharge for acute coronary syndrome was associated with an increased risk of adverse outcomes than use of clopidogrel without proton pump inhibitors.”7 Although future well-controlled randomized studies are warranted, taken together, these studies suggest that a drug interaction between proton pump inhibitors and clopidogrel may indeed have a profound clinical impact, and given how frequently these medications are combined, physicians should be aware of these findings. John R. Kapoor, MD, PhD Stanford, California 15 March 2009
1. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O’Neill WW, Schaff HV, Whitlow PL, et al. Guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/ AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2005;2006: e1– e121. 2. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, et al. Guidelines for the management of pa-
3. 4.
5.
6.
7.
tients with unstable angina/non ST-elevation myocardial infarction. Circulation 2007;116: e148 – e304. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol 2009; 103(suppl):27A–34A. 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 –187. Aubert RE, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T, Flockhart DA. Abstract 3998: proton pump inhibitors effect on clopidogrel effectiveness: the clopidogrel Medco outcomes study. Circulation 2008;118: S_815. 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. 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. doi:10.1016/j.amjcard.2009.03.031
Drug-Eluting Stents in Heart Transplant Recipients We read with great interest the work of Gupta et al1 in which they reported on 32 heart transplant recipients at their institution who were treated with drugeluting stents (DES) for cardiac allograft vasculopathy (CAV) and retrospectively followed for 1.3 ⫾ 1.2 years. During follow-up, 12 patients (38%) died, 1 (3%) underwent retransplantation, 4 (13%) underwent revascularization, and 5 of 21 patients (24%) who underwent coronary angiography had in-stent restenosis. The investigators also compared their data with a historical control of 35 patients with CAV treated with bare-metal stents (BMS). At 1 year, survival was not different between DES (68%) and BMS (91%) after adjustments for baseline characteristics. The restenosis rate was lower with DES (19%) than BMS (49%). Gupta et al1 concluded that in this “largest single-institution series of DES use” in patients with CAV, DES were associated with lower in-stent restenosis than BMS but that the survival of these patients was particularly poor and not affected by DES use. In June 2008, we reported our experience with DES use in heart transplant recipients.2 Our population consisted of 35 patients with CAV who underwent treatment with DES on 84 de novo lesions. During a retrospective follow-up