PPIs May Lower Gastrointestinal Events After DAPT, Regardless of Aspirin Dosing

Deborah Brauser

March 29, 2016

BOSTON, MA — Proton-pump inhibitors (PPIs) convey gastroprotection in coronary artery disease (CAD) patients who take dual antiplatelet therapy (DAPT) of clopidogrel and aspirin—even when the latter is prescribed in low doses, new research suggests[1].

A subanalysis of the phase 3 COGENT trial showed that in the high-dose aspirin group of DAPT patients with CAD, those randomly assigned to receive the PPI omeprazole had fewer composite upper-gastrointestinal (GI) events up to 180 days posttreatment than those receiving placebo (0.9% vs 2.6%, respectively, P=0.05). There were also fewer GI events in the low-dose-aspirin/PPI group vs the low-dose-aspirin/placebo group (1.2% vs 3.1%, respectively, P=0.003).

Although the original COGENT trial showed significant mean reductions in upper-GI events for all of the participants receiving omeprazole vs those who received placebo (1.1% vs 2.9%, respectively; P<0.001), there's long been a question of whether this association is affected by aspirin dosing, report the investigators, led by Dr Muthiah Vaduganathan (Brigham and Women's Hospital, Boston, MA).

However, the new results show that, as long as this patient population is "appropriately selected," most can benefit from taking PPIs, they write.

"I think a lesson here is that cardiologists and primary-care physicians need to pay more attention to gastrointestinal bleeding in these sorts of patients," senior author Dr Deepak L Bhatt (Brigham and Women's Hospital) told heartwire from Medscape.

"Based on COGENT, one could make an argument to consider routine [PPIs] in these patients. But that does go beyond what the current guidelines and expert consensus state," he said.

The findings were published online March 21, 2016 in the Journal of the American College of Cardiology and will be presented at the upcoming American College of Cardiology 2016 Scientific Sessions.

Premature Termination

As reported at the time by heartwire , the 15-country COGENT trial was prematurely terminated back in December 2008 after its sponsor filed for bankruptcy. Despite enrollment being stopped before reaching the planned 4000 participants, the findings showed significant GI-event reductions for the omeprazole group, without a significant increase in major adverse cardiac events (MACE).

The investigators had randomized about half of its patients to receive clopidogrel 75 mg once daily, whereas the other half received a single pill that combined 75-mg clopidogrel with 20-mg omeprazole.

In the current analysis, they assessed 2480 of COGENT participants who were taking low-dose aspirin (<100 mg) and 1272 who were taking high-dose aspirin (>100 mg) for a mean follow-up of 110 days.

The number needed to treat (NNT) to prevent one major upper-GI event within 6 months of PPI treatment was 52 and 58 in the low- and high-dose aspirin groups, respectively.

"Aspirin dosing did not appear to modify the benefit of PPI therapy in reducing rates of the primary GI end point," note the researchers, adding that this benefit could be related to PPIs' "potent effects on gastric-acid suppression."

In addition, pain intensity scores on the Severity of Dyspepsia Assessment (SODA) questionnaire were significantly reduced after PPI treatment in both aspirin groups.

Routine Use?

The primary composite CV end point for the main COGENT trial and this new subanalysis combined CV death, nonfatal MI, coronary revascularization, and ischemic stroke. Neither aspirin-dosing group had a significant increase in this end point after PPI therapy (low dose 5.6% in the PPI group vs 5.5% in the non-PPI group; high dose 4.2% vs 5.55, respectively).

In addition, "180-day Kaplan-Meier estimates of adjudicated composite GI events" were similar, at 2.1% in the low-dose group and 1.7% in the high-dose group. MACE estimates were 5.5% and 4.8%, respectively.

"These were patients who had relatively high cardiovascular risk, with many having acute coronary syndromes but with low perceived gastrointestinal risk," said Bhatt. "Even within that context, it appeared that routine prophylactic proton-pump inhibition reduced [GI] bleeding without any significant CV or other major adverse effects."

However, he added that the trial didn't examine very long-term clinical benefit. "The safety and efficacy is true for 6 months but we don't know about a longer duration of follow-up."

Overcomes a "False Sense of Security"

In an accompanying editorial[2], Dr Michael E Farkouh (Mount Sinai Hospital) writes that although the new report offers several important findings, including that patients taking low-dose as well as high-dose aspirin can be at risk for GI events such as symptomatic gastroduodenal ulcers, the results "must be placed in proper context."

Farkouh points out that Kaplan-Meier estimates were presented as 180-day event rates but the trial's mean follow-up was actually only 110 days. So "the long-term reduction in bleeding risk with PPIs for low-dose-aspirin–treated patients is not definitive." In addition, although use of clopidogrel was the focus of the main study, GI events after the use of other P2Y12 inhibitors would have been "of clinical interest."

Still, he notes that the new results suggest that a change in practice may be needed when it comes to prescribing low-dose aspirin.

"The COGENT investigators should be commended for bringing this important GI safety issue to the forefront, because it has been long overshadowed by both the concern about a PPI–clopidogrel interaction and by the false sense of security in the belief that low-dose aspirin, as opposed to high-dose aspirin, does not warrant a GI protective strategy," he concludes.

Although COGENT was initially funded by Congentus Pharmaceuticals, the new analysis was conducted independently. Bhatt serves on the advisory boards of Cardax, Elsevier Practice Update Cardiology, and Regado Biosciences; serves on the boards of directors of the Boston VA Research Institute and the Society of Cardiovascular Patient Care; chairs the American Heart Association Quality Oversight Committee; is vice chair of the ACTION Registry Steering Committee; serves on data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology, Belvoir Publications, HMP Communications, Journal of the American College of Cardiology , Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, and WebMD; is deputy editor of Clinical Cardiology; has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and the Medicines Company; is a site coinvestigator for Biotronik, Boston Scientific, and St Jude Medical; is a trustee of the American College of Cardiology; and performs unfunded research for Cogentus as chair of COGENT and for FlowCo, PLx Pharma, and Takeda. Vaduganathan reports no relevant financial relationships. Disclosures for the coauthors are listed in the article. Faroukh reports no relevant financial relationships.


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