Brief observation
Efficacy and Safety of Proton-Pump Inhibitors in High-Risk Cardiovascular Subsets of the COGENT Trial

https://doi.org/10.1016/j.amjmed.2016.03.042Get rights and content

Abstract

Background

Proton-pump inhibitors (PPIs) have been demonstrated to reduce rates of gastrointestinal events in patients requiring dual antiplatelet therapy (DAPT). Data are limited regarding the efficacy and safety of PPIs in high-risk cardiovascular subsets after acute coronary syndrome or percutaneous coronary intervention.

Methods

All patients enrolled in COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) were initiated on DAPT (with aspirin and clopidogrel) for various indications within the prior 21 days. These post hoc analyses of the COGENT trial evaluated the efficacy and safety of omeprazole compared with placebo in subsets of patients requiring DAPT for the 2 most frequent indications: 1) patients undergoing percutaneous coronary intervention (for any indication) within 14 days of randomization (n = 2676; 71.2%); and 2) patients presenting with acute coronary syndrome managed with or without percutaneous coronary intervention (n = 1573; 41.8%). Unadjusted Cox proportional hazards models were used to estimate effect sizes through final follow-up.

Results

Median follow-up duration was 110 days (interquartile range 55-167). In percutaneous coronary intervention-treated patients, omeprazole significantly reduced rates of composite gastrointestinal events at 180 days (1.2% vs 2.7%; hazard ratio [HR] 0.43; 95% confidence interval [CI], 0.22-0.85; P = .02) without increasing composite cardiovascular events (5.4% vs 6.3%; HR 1.00; 95% CI, 0.67-1.50; P = 1.00). Similarly, omeprazole lowered risk of the primary gastrointestinal endpoint at 180 days in patients presenting with acute coronary syndrome (1.1% vs 2.7%; HR 0.37; 95% CI, 0.13-1.01; P = .05) without a significant excess in cardiovascular events (5.6% vs 4.5%; HR 1.40; 95% CI, 0.77-2.53; P = .27).

Conclusions

PPI therapy attenuates gastrointestinal bleeding risk without significant excess in major cardiovascular events in high-risk cardiovascular subsets, regardless of indication for DAPT. Future studies will be needed to clarify optimal gastroprotective strategies for higher-intensity and longer durations of DAPT.

Section snippets

Methods

As previously described,2 COGENT was a phase-3, multicenter, global, placebo-controlled, double-blind, double-dummy randomized controlled trial of a fixed combination of clopidogrel 75 mg and omeprazole 20 mg compared with clopidogrel 75 mg alone. Enteric-coated aspirin was provided to all study patients. Patients initiated on DAPT within the prior 21 days without use of recent gastroprotection, oral anticoagulation, or fibrinolytic therapy, were eligible for enrollment. The ethics committee

Results

COGENT was terminated early due to the sponsor filing for bankruptcy. In the final intention-to-treat population (n = 3759), risks of gastrointestinal and cardiovascular events were assessed in 2 non-mutually exclusive groups (the 2 most common indications for DAPT): 1) patients undergoing percutaneous coronary intervention within 14 days of randomization (n = 2676; 71.2%) and 2) patients presenting with acute coronary syndrome managed with or without percutaneous coronary intervention

Discussion

COGENT enrolled a high-risk cardiovascular cohort with over 70% of patients having undergone percutaneous coronary intervention and over 40% presenting with acute coronary syndrome. Approximately 2%-3% of patients experienced major gastrointestinal events during 6 months of DAPT after acute coronary syndrome or percutaneous coronary intervention. Consistent with the overall trial results,2 this post hoc analysis demonstrates that PPI therapy safely attenuates this gastrointestinal risk without

References (17)

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Funding: The COGENT trial was funded by Cogentus Pharmaceuticals, however, this post hoc analysis was conducted independently with biostatistical support from an independent team at Harvard Clinical Research Institute (HCRI). The study investigators had full access to the trial database and retained complete control on the decision to pursue publication. The sponsor did not have right to review or approve the final manuscript.

Conflict of Interest: MV has no relevant disclosures; CPC has served on advisory boards of Bristol-Myers Squibb, Lipimedix, and Pfizer, and has received research funding from Accumetrics, Arisaph, AstraZeneca, Boehringer-Ingelheim, CSL Behring, Essentialis, GlaxoSmithKline, Janssen, Merck Regeneron, Sanofi, and Takeda; BLC has served as a consultant to Cogent Pharmaceuticals; YL has no relevant disclosures; W-HH has no relevant disclosures; GD has no relevant disclosures; MC has no relevant disclosures; AL has received an investigator-initiated grant from Bayer Pharma AG and has served on advisory boards for Bayer Pharma AG; TJS has no relevant disclosures; TLS is an employee of PAREXEL International; PL is an employee of Lexicon Pharmaceuticals; MAG is an employee of Constellation Pharmaceuticals; LL has served on the Data Safety Monitoring Boards for studies sponsored by Bayer and Bristol-Myers Squibb. DLB discloses the following relationships—Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Vice-Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: Cogentus (Chair of COGENT), FlowCo, PLx Pharma, Takeda.

Authorship: All authors had access to the data and a role in writing the manuscript.

1

A full list of investigators can be found in Bhatt DL, Cryer BL, Contant CF, et al. N Engl J Med. 2010;363:1909-1917.2

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