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EVIDENCE SUMMARY
A double-blind, double-dummy, placebo-controlled RCT comparing a combination of clopidogrel, aspirin, and omeprazole with clopidogrel, aspirin, and placebo found no increase in composite CV outcomes with the PPI (TABLE).1 Using a PPI did, however, significantly reduce gastrointestinal (GI) bleeding (hazard ratio [HR] = 0.13; 95% confidence interval [CI], 0.03-0.56).Although several meta-analyses have been conducted, they all rely on this single RCT that directly addresses the question, plus post-hoc analyses of other RCTs.
Four of 5 analyses find little or no difference in CV outcomes with a PPI
Four of 5 posthoc analyses (which weren’t themselves randomized) of RCTs found unclear or no differences in composite CV outcomes with concurrent use of a PPI and antiplatelet therapy, after multivariate adjustment for differences in populations taking or not taking a PPI.
Posthoc analysis of the largest study found worse CV outcomes for both clopidogrel and ticagrelor with concomitant PPI use.2 However, patients on any GI drugs (PPI or non-PPI) had composite outcomes similar to patients on a PPI (PPI vs non-PPI GI treatment: HR = 0.98; 95% CI, 0.79-1.23), and patients not taking GI drugs had fewer composite outcomes compared with patients on a PPI (clopidogrel vs no GI therapy: HR = 1.29; 95% CI, 1.12-1.49; ticagrelor vs no GI therapy: HR = 1.30; 95% CI, 1.14-1.49). Researchers postulated that because the rate of composite outcomes increased equally for patients on any GI drug, the higher rate of CV adverse events with a PPI might have been related to GI disease rather than PPI use.
A similar posthoc analysis found no differences with or without PPI use among patients with ACS undergoing planned percutaneous coronary intervention (PCI) and assigned to clopidogrel or prasugrel.3 Researchers performed multivariate adjustment for differences in age, gender, ethnicity, and initial presence of unstable angina/non-ST-elevation MI.
A smaller study also found no significant differences in composite CV outcomes in patients using PPIs.4 Patients did have higher rates of MI (HR = 0.62; 95% CI, 0.42-0.91), but they were more likely to be older and have a previous diagnosis of non-ST-elevation MI, higher incidence of previous coronary artery bypass graft surgery, and history of peptic ulcer disease.
The fourth posthoc analysis of an RCT found that concomitant PPI use (91% of patients on lansoprazole) didn’t alter outcomes among patients undergoing PCI and receiving dual antiplatelet therapy with clopidogrel and aspirin.5 Researchers used a multivariate adjustment for differences in age, gender, and renal function and found no difference in outcomes during the 6-month or 24-month period. PPI prescription was at physician discretion. Researchers didn’t assess for dose-dependent effects of PPI.
A fifth, flawed study finds more adverse events with PPIs
A posthoc analysis of a smaller, open-label trial found increased major adverse cardiac events with PPI use among patients taking clopidogrel after PCI.6 Researchers didn’t adjust for differences in populations at baseline, however, and patients taking PPIs were more likely to be female or older and have diabetes, GI disease, or higher serum creatinine levels.
Continue to: Editor's takeaway
Editor’s takeaway
The best evidence (a large RCT) found that adding a PPI to antiplatelet therapy didn’t alter CV outcomes in patients with ACS, but it did reduce GI bleeds. Hopefully this will give providers the confidence to use PPIs, if clinically indicated, in patients taking antiplatelet therapy with clopidogrel or prasugrel.
1. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909-1917.
2. Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation. 2012;125:978-986.
3. O’Donoghue ML, Braunwald E, Antman EM, et al. 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.
4. Nicolau JC, Bhatt DL, Roe MT, et al. Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Am Heart J. 2015;170:683-694.e3.
5. Gargiulo G, Costa F, Ariotti S, et al. Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial. Am Heart J. 2016;174:95-102.
6. Burkard T, Kaiser CA, Brunner-La Rocca H, et al. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med. 2012;271:257-263.
EVIDENCE SUMMARY
A double-blind, double-dummy, placebo-controlled RCT comparing a combination of clopidogrel, aspirin, and omeprazole with clopidogrel, aspirin, and placebo found no increase in composite CV outcomes with the PPI (TABLE).1 Using a PPI did, however, significantly reduce gastrointestinal (GI) bleeding (hazard ratio [HR] = 0.13; 95% confidence interval [CI], 0.03-0.56).Although several meta-analyses have been conducted, they all rely on this single RCT that directly addresses the question, plus post-hoc analyses of other RCTs.
Four of 5 analyses find little or no difference in CV outcomes with a PPI
Four of 5 posthoc analyses (which weren’t themselves randomized) of RCTs found unclear or no differences in composite CV outcomes with concurrent use of a PPI and antiplatelet therapy, after multivariate adjustment for differences in populations taking or not taking a PPI.
Posthoc analysis of the largest study found worse CV outcomes for both clopidogrel and ticagrelor with concomitant PPI use.2 However, patients on any GI drugs (PPI or non-PPI) had composite outcomes similar to patients on a PPI (PPI vs non-PPI GI treatment: HR = 0.98; 95% CI, 0.79-1.23), and patients not taking GI drugs had fewer composite outcomes compared with patients on a PPI (clopidogrel vs no GI therapy: HR = 1.29; 95% CI, 1.12-1.49; ticagrelor vs no GI therapy: HR = 1.30; 95% CI, 1.14-1.49). Researchers postulated that because the rate of composite outcomes increased equally for patients on any GI drug, the higher rate of CV adverse events with a PPI might have been related to GI disease rather than PPI use.
A similar posthoc analysis found no differences with or without PPI use among patients with ACS undergoing planned percutaneous coronary intervention (PCI) and assigned to clopidogrel or prasugrel.3 Researchers performed multivariate adjustment for differences in age, gender, ethnicity, and initial presence of unstable angina/non-ST-elevation MI.
A smaller study also found no significant differences in composite CV outcomes in patients using PPIs.4 Patients did have higher rates of MI (HR = 0.62; 95% CI, 0.42-0.91), but they were more likely to be older and have a previous diagnosis of non-ST-elevation MI, higher incidence of previous coronary artery bypass graft surgery, and history of peptic ulcer disease.
The fourth posthoc analysis of an RCT found that concomitant PPI use (91% of patients on lansoprazole) didn’t alter outcomes among patients undergoing PCI and receiving dual antiplatelet therapy with clopidogrel and aspirin.5 Researchers used a multivariate adjustment for differences in age, gender, and renal function and found no difference in outcomes during the 6-month or 24-month period. PPI prescription was at physician discretion. Researchers didn’t assess for dose-dependent effects of PPI.
A fifth, flawed study finds more adverse events with PPIs
A posthoc analysis of a smaller, open-label trial found increased major adverse cardiac events with PPI use among patients taking clopidogrel after PCI.6 Researchers didn’t adjust for differences in populations at baseline, however, and patients taking PPIs were more likely to be female or older and have diabetes, GI disease, or higher serum creatinine levels.
Continue to: Editor's takeaway
Editor’s takeaway
The best evidence (a large RCT) found that adding a PPI to antiplatelet therapy didn’t alter CV outcomes in patients with ACS, but it did reduce GI bleeds. Hopefully this will give providers the confidence to use PPIs, if clinically indicated, in patients taking antiplatelet therapy with clopidogrel or prasugrel.
EVIDENCE SUMMARY
A double-blind, double-dummy, placebo-controlled RCT comparing a combination of clopidogrel, aspirin, and omeprazole with clopidogrel, aspirin, and placebo found no increase in composite CV outcomes with the PPI (TABLE).1 Using a PPI did, however, significantly reduce gastrointestinal (GI) bleeding (hazard ratio [HR] = 0.13; 95% confidence interval [CI], 0.03-0.56).Although several meta-analyses have been conducted, they all rely on this single RCT that directly addresses the question, plus post-hoc analyses of other RCTs.
Four of 5 analyses find little or no difference in CV outcomes with a PPI
Four of 5 posthoc analyses (which weren’t themselves randomized) of RCTs found unclear or no differences in composite CV outcomes with concurrent use of a PPI and antiplatelet therapy, after multivariate adjustment for differences in populations taking or not taking a PPI.
Posthoc analysis of the largest study found worse CV outcomes for both clopidogrel and ticagrelor with concomitant PPI use.2 However, patients on any GI drugs (PPI or non-PPI) had composite outcomes similar to patients on a PPI (PPI vs non-PPI GI treatment: HR = 0.98; 95% CI, 0.79-1.23), and patients not taking GI drugs had fewer composite outcomes compared with patients on a PPI (clopidogrel vs no GI therapy: HR = 1.29; 95% CI, 1.12-1.49; ticagrelor vs no GI therapy: HR = 1.30; 95% CI, 1.14-1.49). Researchers postulated that because the rate of composite outcomes increased equally for patients on any GI drug, the higher rate of CV adverse events with a PPI might have been related to GI disease rather than PPI use.
A similar posthoc analysis found no differences with or without PPI use among patients with ACS undergoing planned percutaneous coronary intervention (PCI) and assigned to clopidogrel or prasugrel.3 Researchers performed multivariate adjustment for differences in age, gender, ethnicity, and initial presence of unstable angina/non-ST-elevation MI.
A smaller study also found no significant differences in composite CV outcomes in patients using PPIs.4 Patients did have higher rates of MI (HR = 0.62; 95% CI, 0.42-0.91), but they were more likely to be older and have a previous diagnosis of non-ST-elevation MI, higher incidence of previous coronary artery bypass graft surgery, and history of peptic ulcer disease.
The fourth posthoc analysis of an RCT found that concomitant PPI use (91% of patients on lansoprazole) didn’t alter outcomes among patients undergoing PCI and receiving dual antiplatelet therapy with clopidogrel and aspirin.5 Researchers used a multivariate adjustment for differences in age, gender, and renal function and found no difference in outcomes during the 6-month or 24-month period. PPI prescription was at physician discretion. Researchers didn’t assess for dose-dependent effects of PPI.
A fifth, flawed study finds more adverse events with PPIs
A posthoc analysis of a smaller, open-label trial found increased major adverse cardiac events with PPI use among patients taking clopidogrel after PCI.6 Researchers didn’t adjust for differences in populations at baseline, however, and patients taking PPIs were more likely to be female or older and have diabetes, GI disease, or higher serum creatinine levels.
Continue to: Editor's takeaway
Editor’s takeaway
The best evidence (a large RCT) found that adding a PPI to antiplatelet therapy didn’t alter CV outcomes in patients with ACS, but it did reduce GI bleeds. Hopefully this will give providers the confidence to use PPIs, if clinically indicated, in patients taking antiplatelet therapy with clopidogrel or prasugrel.
1. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909-1917.
2. Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation. 2012;125:978-986.
3. O’Donoghue ML, Braunwald E, Antman EM, et al. 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.
4. Nicolau JC, Bhatt DL, Roe MT, et al. Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Am Heart J. 2015;170:683-694.e3.
5. Gargiulo G, Costa F, Ariotti S, et al. Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial. Am Heart J. 2016;174:95-102.
6. Burkard T, Kaiser CA, Brunner-La Rocca H, et al. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med. 2012;271:257-263.
1. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909-1917.
2. Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation. 2012;125:978-986.
3. O’Donoghue ML, Braunwald E, Antman EM, et al. 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.
4. Nicolau JC, Bhatt DL, Roe MT, et al. Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Am Heart J. 2015;170:683-694.e3.
5. Gargiulo G, Costa F, Ariotti S, et al. Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial. Am Heart J. 2016;174:95-102.
6. Burkard T, Kaiser CA, Brunner-La Rocca H, et al. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med. 2012;271:257-263.
EVIDENCE-BASED ANSWER:
No. Adding a proton pump inhibitor (PPI) in patients taking antiplatelet medications such as clopidogrel for acute coronary syndrome (ACS) doesn’t increase the composite risk of cardiovascular (CV) events: CV death, myocardial infarction (MI), and cerebrovascular accident (CVA) (strength of recommendation: B, randomized, controlled trial [RCT] and prepon-derance of posthoc analyses of large RCTs).
