Clopidogrel with or without omeprazole in coronary artery disease

Deepak L. Bhatt, Byron L. Cryer, Charles F. Contant, Marc Cohen, Angel Lanas, Thomas J. Schnitzer, Thomas L. Shook, Pablo Lapuerta, Mark A. Goldsmith, Loren Laine, Benjamin M. Scirica, Sabina A. Murphy, Christopher P. Cannon

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.)

Original languageEnglish (US)
Pages (from-to)1909-1917
Number of pages9
JournalNew England Journal of Medicine
Volume363
Issue number20
DOIs
StatePublished - Nov 11 2010

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clopidogrel
Omeprazole
Coronary Artery Disease
Proton Pump Inhibitors
Placebos
Confidence Intervals
Hemorrhage
Aspirin
Myocardial Revascularization
Peptic Ulcer

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bhatt, D. L., Cryer, B. L., Contant, C. F., Cohen, M., Lanas, A., Schnitzer, T. J., ... Cannon, C. P. (2010). Clopidogrel with or without omeprazole in coronary artery disease. New England Journal of Medicine, 363(20), 1909-1917. https://doi.org/10.1056/NEJMoa1007964

Clopidogrel with or without omeprazole in coronary artery disease. / Bhatt, Deepak L.; Cryer, Byron L.; Contant, Charles F.; Cohen, Marc; Lanas, Angel; Schnitzer, Thomas J.; Shook, Thomas L.; Lapuerta, Pablo; Goldsmith, Mark A.; Laine, Loren; Scirica, Benjamin M.; Murphy, Sabina A.; Cannon, Christopher P.

In: New England Journal of Medicine, Vol. 363, No. 20, 11.11.2010, p. 1909-1917.

Research output: Contribution to journalArticle

Bhatt, DL, Cryer, BL, Contant, CF, Cohen, M, Lanas, A, Schnitzer, TJ, Shook, TL, Lapuerta, P, Goldsmith, MA, Laine, L, Scirica, BM, Murphy, SA & Cannon, CP 2010, 'Clopidogrel with or without omeprazole in coronary artery disease', New England Journal of Medicine, vol. 363, no. 20, pp. 1909-1917. https://doi.org/10.1056/NEJMoa1007964
Bhatt, Deepak L. ; Cryer, Byron L. ; Contant, Charles F. ; Cohen, Marc ; Lanas, Angel ; Schnitzer, Thomas J. ; Shook, Thomas L. ; Lapuerta, Pablo ; Goldsmith, Mark A. ; Laine, Loren ; Scirica, Benjamin M. ; Murphy, Sabina A. ; Cannon, Christopher P. / Clopidogrel with or without omeprazole in coronary artery disease. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 20. pp. 1909-1917.
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abstract = "BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1{\%} with omeprazole and 2.9{\%} with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95{\%} confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95{\%} CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9{\%} with omeprazole and 5.7{\%} with placebo (hazard ratio with omeprazole, 0.99; 95{\%} CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.)",
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AU - Bhatt, Deepak L.

AU - Cryer, Byron L.

AU - Contant, Charles F.

AU - Cohen, Marc

AU - Lanas, Angel

AU - Schnitzer, Thomas J.

AU - Shook, Thomas L.

AU - Lapuerta, Pablo

AU - Goldsmith, Mark A.

AU - Laine, Loren

AU - Scirica, Benjamin M.

AU - Murphy, Sabina A.

AU - Cannon, Christopher P.

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N2 - BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.)

AB - BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.)

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