New Analysis of COGENT Supports PPI Use in Patients on Low-Dose Aspirin

Omeprazole, a proton pump inhibitor (PPI), protects patients on dual antiplatelet therapy (DAPT) against gastrointestinal events regardless of whether their regimen involves low-dose or high-dose aspirin, according to a post-hoc analysis of the COGENT trial.

Implications. New Analysis of COGENT Supports PPI Use in Patients on Low-Dose Aspirin

Clinicians ought to take the findings to heart, said Matthew W. Sherwood, MD (Duke Clinical Research Institute, Durham, NC), who was not involved in the study. In patients who need to take DAPT and are at risk for bleeding, “there should be a real push, honestly, to put them on PPI therapy to reduce their risk. And I think this paper [offers] good evidence that it is in fact effective at reducing the risk of GI bleeding across aspirin doses,” he commented to TCTMD.

The findings were published online yesterday in the Journal of the American College of Cardiology.

For the analysis, researchers led by Muthia Vaduganathan, MD (Brigham and Women’s Hospital, Boston, MA), looked at outcomes according to whether patients in COGENT had received aspirin at a low dose (≤ 100 mg; n = 2,480) or high dose (> 100 mg; n = 1,272).

They found that high- and low-dose aspirin each carried similar 180-day risks of composite upper GI events (overt upper GI bleeding of known or unknown origin, bleeding of presumed GI origin with a clinically significant reduction in hematocrit, symptomatic gastroduodenal ulcer, persistent GI pain with evidence of endoscopy-confirmed gastroduodenal erosions, obstruction, or perforation) and of MACE (cardiovascular death, nonfatal MI, coronary revascularization, or ischemic stroke).

Randomization to omeprazole 20 mg versus placebo was associated with a significant reduction in GI events for patients in both the high- and low-dose aspirin groups, with no difference between those groups. The PPI had no apparent effect on MACE in either group.

COGENT Analysis: Kaplan-Meier Estimated Outcomes at 180 Days

“The consistency of PPI benefit across aspirin doses may be related to its potent effects on gastric acid suppression,” Vaduganathan and colleagues suggest.

Low-Dose Aspirin Favored

Current guidelines back the use of low-dose aspirin, Sherwood said, as it “seems certainly sufficient to prevent cardiovascular events, and it likely has less risk for GI bleeding, though that wasn’t seen here.” Thus, the COGENT analysis provides a clinically relevant message, he confirmed.

Indeed, as the study authors say: “Despite recent shifts towards utilizing lower-dose aspirin therapy, higher-dose aspirin is still used in more than 60% of ‘real-world’ patients discharged after acute myocardial infarction in the United States, and it continues to be supported by guideline committees for select high-risk settings.”

The current analysis also brings to mind the “controversial issue” of a potential adverse interaction between omeprazole and clopidogrel, Sherwood said.

Observational studies had hinted that omeprazole might dampen the antiplatelet effects of clopidogrel, leading the US Food and Drug Administration to add a “black box” warning to the clopidogrel’s labeling in May 2009 that discouraged use of the combo. Later that year, COGENT, though halted early due to loss of funding, partially quelled those concerns when researchers presented results at TCT 2009 showing no increase in cardiovascular events—and in fact protection against GI bleeding—among omeprazole-treated patients. The full findings were subsequently published in the New England Journal of Medicine.

It is unclear whether practice patterns have been altered by the concerns over omeprazole. In fact, based on the COGENT data, the FDA’s warning “may have been premature,” Sherwood said, though some clinicians have chosen to substitute another PPI for omeprazole or to prescribe H2 blockers.

At the moment, “PPI use appears to be underutilized for prevention of GI events,” the study authors say, adding, “Prophylactic PPI therapy is a data-driven, expert-recommended, and cost-effective approach to gastroprotection in appropriately selected patients, even those on low-dose aspirin.”

  • Vaduganathan M, Bhatt DL, Cryer BL, et al. Proton-pump inhibitors reduce gastrointestinal events regardless of aspirin dose in patients requiring dual antiplatelet therapy. J Am Coll Cardiol. 2016;Epub ahead of print.

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  • The COGENT trial was funded by Cogentus Pharmaceuticals. The current, post hoc analysis was conducted independently with biostatistical support from an independent team from Harvard Clinical Research Institute.
  • Bhatt reports serving on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors of Boston VA Research Institute, Society of Cardiovascular Patient Care; as chair of the AHA Quality Oversight Committee; on the data monitoring committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; as site co-investigator of Biotronik, Boston Scientific, and St. Jude Medical; and as a trustee of the American College of Cardiology (ACC). He also reports receiving honoraria from the ACC (Senior Associate Editor, Clinical Trials and News,, 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), and WebMD (CME steering committees); research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; and royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). He additionally reports being involved in unfunded research with FlowCo, PLx Pharma, and Takeda.
  • Vaduganathan reports no relevant conflicts of interest.
  • Sherwood reports receiving honoraria for consulting from Boehringer-Ingelheim and an education grant from AstraZeneca.

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