AT ACC 2016

CHICAGO (FRONTLINE MEDICAL NEWS) – Six months of treatment with a proton pump inhibitor (PPI) is a safe way to cut the incidence of major gastrointestinal events in cardiovascular disease patients on dual-antiplatelet therapy regardless of whether they receive low-dose or high-dose aspirin, according to a post-hoc analysis of data from more than 3,700 patients enrolled in the multicenter, randomized COGENT trial.

“Short-term, prophylactic PPI therapy consistently reduced rates of adjudicated upper-gastrointestinal events without increasing cardiovascular events, regardless of the aspirin dose,” Dr. Muthiah Vaduganathan said while presenting his study at the annual meeting of the American College of Cardiology. “Gastroprotection with PPI therapy should be used in appropriately selected patients with coronary artery disease who require dual-antiplatelet therapy even if they are on low-dose aspirin.”

In addition to documenting the safety and efficacy of 6 months of PPI treatment for patients at high risk for cardiovascular disease events and low or moderate risk for a GI event, the results from the analysis also documented how common GI events are in this population, even when patients receive low-dose aspirin. Nearly two-thirds of the 3,752 patients included in the analysis took low-dose aspirin, either 75 mg or 81 mg per day. Their incidence of an adjudicated upper GI bleed, the study’s primary GI endpoint, occurred in 3.1% of patients on placebo, and in 1.2% of patients taking a prophylactic PPI. Among the other 34% of patients on high-dose aspirin – a daily dosage of at least 150 mg – the rate of adjudicated upper-GI bleeds was 2.6% without a PPI and 0.9% in those on a PPI.

In other words, even among patients deemed to have a relatively low risk for GI complications from aspirin because their entry into this study required no history of major GI bleeds or recent treatment with a gastroprotection agent, treatment with low-dose aspirin resulted in upper-GI bleeds at the same rate, about 3%, as a high-dose aspirin regimen. And in both of these aspirin subgroups 6 months of concurrent treatment with a PPI cut the incidence of major GI bleeds by more than half.

The findings are especially notable because the enrollment criteria stacked the deck toward patients with high cardiovascular disease risk and relatively low GI risk. The study enrolled “a unique population at high risk for cardiovascular disease – 71% had previously undergone a percutaneous coronary intervention, and 42% had a history of an acute coronary syndrome – and low GI risk, but even in this population enriched for cardiovascular disease risk, there was no increased rate of cardiovascular disease events” during a median follow-up while on PPI treatment of 110 days, Dr. Vaduganathan said.

Among patients on low-dose aspirin, the rate of cardiovascular disease death, MI, stroke, or coronary revascularization was 5.6% with PPI treatment and 5.5% without, and in the high-dose aspirin patients the rates were 4.2% with PPI treatment and 5.5% without. Neither of these differences between the subgroups on or off a PPI were statistically significant.

Concurrent with Dr. Vaduganathan’s report at the meeting the results also appeared online ( J Am Coll Cardiol. 2016 April 12;67[14]:661-71 ).

“There appeared to be no adverse clinical effect from PPI treatment. When used short-term, for up to 6 months, PPI treatment appears to be safe in patients with cardiovascular disease,” Dr. Vaduganathan concluded.

The analysis used data collected in COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial), a phase 3 study designed to compare a single-pill formulation of 20 mg omeprazole and 75 mg clopidogrel taken orally once daily with 75 mg clopidogrel against a background of all patients taking aspirin. COGENT stopped prematurely in late 2008 as the company developing this formulation and sponsoring the trial, Cogentus Pharmaceuticals , filed for bankruptcy. Despite its abrupt conclusion, the trial had enrolled and followed enough patients to show that treatment with omeprazole plus clopidogrel and aspirin led to a significant reduction in upper GI bleeding without increasing the rate of cardiovascular disease events, compared with clopidogrel plus aspirin ( N Engl J Med. 2010 Nov 11;363[20]:1909-17 ).

The new analysis focused on the greater than 99% of patients in the total COGENT cohort for whom information was available on whether they received high- or low-dose aspirin.

Although the primary findings from COGENT, reported in 2010, documented the safety and efficacy of concomitant PPI treatment during dual-antiplatelet therapy, and despite guidelines revised in 2010 that called for PPI treatment when appropriate, this strategy for preventing GI complications remains underused, Dr. Vaduganathan said. The most recent U.S. recommendations that address this issue called for assessing the potential risk and benefit from PPI treatment in patients receiving dual-antiplatelet therapy: “The risk reduction with PPIs is substantial in patients with risk factors for GI bleeding and may outweigh any potential reduction in the CV efficacy of antiplatelet treatment because of a drug-drug interaction ( J Am Coll Cardiol. 2010 Dec;56[24]:2051-66 ).”

The only caveat Dr. Vaduganathan placed on PPI use was that the COGENT data addressed only 6 months of PPI use; the safety of longer-term use has not been studied. But “the trend is to use PPIs for as short a period as possible,” and the risk for adverse effects from PPI treatment on cardiovascular disease events is likely greatest during the first 6 months of PPI treatment, he noted. If PPI treatment needs to continue beyond 6 months, he suggested systematically reassessing the risk-benefit balance for individual patients from continued PPI treatment every 3 months.

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