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News Author: Fran Lowry
CME Author: Laurie Barclay, MD


CME Released: 09/27/2010; Valid for credit through 09/27/2011

September 27, 2010 — Proton pump inhibitors (PPIs) are associated with an increased risk for adverse cardiovascular outcomes independent of clopidogrel use in patients who have had a myocardial infarction (MI), according to a new study published in the September 21 issue of the Annals of Internal Medicine.

The study, by Mette Charlot, MD, from Copenhagen University Hospital Gentofte, Hellerup, Denmark, and colleagues, also found that concomitant PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.

"...PPIs are often given in combination with clopidogrel and aspirin to reduce the risk for upper gastrointestinal bleeding," write Dr. Charlot and colleagues. "Clinical studies involving selected populations show conflicting results regarding risk for adverse cardiovascular events associated with the dual use of clopidogrel and PPIs."

The study authors note that the US Food and Drug Administration and the European Medicines Agency have discouraged the combined use of these drugs unless strongly indicated and emphasize the need for further studies.

In this study, the investigators sought to examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel vs use of PPIs alone in a large, unselected cohort of patients who were hospitalized with first-time MI.

They used Danish national administrative databases to identify all consecutive patients 30 years and older who were hospitalized with acute MI between 2000 and 2006 and who survived for at least 30 days.

The primary outcome was a composite of rehospitalization for MI or stroke or cardiovascular death. Patients were examined 7, 14, 21, and 30 days after MI and were then observed for 1 year.

Of the 56,406 patients in the analysis, 9137 (16.2%) died from cardiovascular causes or were rehospitalized for MI or stroke. Clopidogrel was associated with lower event rates, and PPIs were associated with higher event rates. The event rates were highest among patients who received a PPI but not clopidogrel (26.3%), the study authors report.

Overall, 43.8% of the study cohort received clopidogrel, and 27.3% also received concomitant PPIs. The hazard ratio (HR) for the primary endpoint for concomitant use of a PPI and clopidogrel at day 30 after discharge from the hospital was 1.29 (95% confidence interval [CI], 1.17 - 1.42; P < .001). The HR for use of a PPI without clopidogrel was 1.29 (95% CI, 1.21 - 1.37; P < .001). There was no statistically significant interaction between a PPI and clopidogrel (P = .72).

However, there was a statistically significant interaction between percutaneous coronary intervention (PCI) and PPIs in the group that received clopidogrel. In this group, there was a statistically significant higher risk for cardiovascular death or rehospitalization for MI or stroke in patients who had PCI (HR, 1.40; 95% CI, 1.19 - 1.64) vs patients who did not have PCI (HR, 1.21; 95% CI, 1.07 - 1.38).

"Our study furthers the research in this area by investigating the risk for cardiovascular events in a nationwide, unselected population that represents the average patient who has had a myocardial infarction," the study authors write. "We suspect that the increased cardiovascular risk in all patients who received a PPI can be explained by differences in baseline comorbid conditions that were unmeasured or measured imperfectly," they add.

The study authors caution that these data from a mostly white study population may not be generalizable to other racial and ethnic groups. Also, information on the indications for PPI therapy was lacking.

"In conclusion, PPIs seem to be associated with an increased risk for adverse cardiovascular outcomes regardless of clopidogrel use, but concomitant PPI and clopidogrel use was not associated with any additional increase in risk over that observed for patients who received a PPI alone," the study authors write, adding: "These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy."

Editorial: Reflection on Regulatory Decisions

In an accompanying editorial, João Paulo de Aquino Lima, MD, from the Federal University of Ceará School of Medicine, Fortaleza, Brazil, and James M. Brophy, MD, PhD, from McGill University, Montreal, Canada, write that regulatory and cardiovascular specialists may be less convinced of the intrinsic value of PPIs. They also point out that the role of clopidogrel "is no longer sacrosanct" as the expiration of its patent approaches and as more potent antiplatelet agents such as prasugrel and ticagrelor come on the market.

"The unflattering episodes of cardiovascular drug safety with rofecoxib and rosiglitazone may also account for a regulatory willingness to accept less stringent evidence and to be perceived as proactive," they write.

The study indicates that the existing regulatory decisions are based on a lack of quality clinical studies and rely instead on in vitro platelet inhibition studies, which can be unreliable in cardiovascular medicine. "Unbiased science should be the final arbiter in determining the risk for any putative drug interaction, but the modulating role that the social, cultural, economic, and political context in which medicine and clinical research is practiced should be appreciated," the editorialists conclude.

The Danish Medical Research Council and the Danish Heart Foundation supported this study. A complete description of disclosure information for the study authors is available here . Dr. Lima and Dr. Brophy have disclosed no relevant financial relationships.

Ann Intern Med. 2010;153:378-386, 413-415. Abstract

Clinical Context

Clopidogrel, a platelet inhibitor that lowers the risk for new ischemic cardiovascular events when given with aspirin, is often prescribed to patients after an MI. To lower the risk for upper gastrointestinal tract bleeding, PPIs are often prescribed along with clopidogrel and aspirin.

Whether the concomitant use of clopidogrel and PPIs affects the clinical efficacy of clopidogrel is unclear. Because of concerns regarding the risk for MI and other adverse cardiovascular reactions, the US Food and Drug Administration and the European Medicines Agency recently warned against the combined use of PPIs and clopidogrel except for patients in whom the indication for simultaneous use of these drugs is very strong.

Study Highlights

• The goal of this nationwide cohort study was to assess the risk for adverse cardiovascular outcomes associated with concomitant use of PPIs and clopidogrel vs PPIs alone in adults hospitalized for MI.
• Using linked administrative registry data from all hospitals in Denmark, the investigators identified all patients discharged from 2000 to 2006 after first-time MI.
• The main study endpoint was a composite of rehospitalization for MI or stroke or cardiovascular death.
• Follow-up evaluations were performed at 7, 14, 21, and 30 days after MI and at various other time points through 1 year.
• Rehospitalization for MI or stroke or cardiovascular death occurred in 9137 (16.2%) of 56,406 included patients.
• Concomitant PPIs were prescribed to 6753 (27.3%) of 24,702 patients (43.8%) who received clopidogrel.
• There was a reduction in the risk for gastrointestinal tract bleeding related to PPI therapy for patients who received clopidogrel, but this reduction was not statistically significant.
• Among the participants evaluated at day 30 after discharge, the HR for cardiovascular death or rehospitalization for MI or stroke associated with concomitant use of a PPI and clopidogrel was 1.29 (95% CI, 1.17 - 1.42; P < .001).
• For use of a PPI in patients who did not receive clopidogrel, the corresponding HR was 1.29 (95% CI, 1.21 - 1.37; P < .001).
• There was no statistically significant interaction between use of a PPI and use of clopidogrel (P = .72).
• There was no evidence of differences in risk among the subtypes of PPIs, with or without clopidogrel.
• There was also no evidence of differences in risk related to heart failure, diabetes, age, hospitals, or PPI dosages.
• However, there was a statistically significant interaction between PCI and PPIs in the group that received clopidogrel.
• In this group, there was a statistically significant higher risk for cardiovascular death or rehospitalization for MI or stroke in patients who had PCI (HR, 1.40; 95% CI, 1.19 - 1.64) vs patients who did not have PCI (HR, 1.21; 95% CI, 1.07 - 1.38).
• On the basis of these findings, the investigators concluded that regardless of clopidogrel use for MI, PPIs seem to be linked to an increased risk for adverse cardiovascular outcomes after discharge but that dual use of PPIs and clopidogrel was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.
• Limitations of this study include possible unmeasured and residual confounding, time-varying measurement errors of exposure, lack of data on adherence or over-the-counter drug use, and biases from survival effects.

Clinical Implications

Regardless of clopidogrel use, PPI use was linked to an increased risk for adverse cardiovascular outcomes after hospital discharge for a first MI, based on a nationwide Danish cohort study.
In a nationwide Danish cohort study, dual use of PPIs and clopidogrel was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.