ADAPT-DES Analysis Reopens Debate Over Possible PPI, Clopidogrel Interaction

Renewing talk of a possible interaction between proton pump inhibitors (PPIs) and clopidogrel, new data from ADAPT-DES show that PPI use by PCI-treated patients at discharge is associated with greater risk of adverse events 2 years later. A range of experts, however, downplayed the likelihood that PPIs played a causal role.

The results, from a prespecified study of the trial, “support both the existence of a clinically meaningful interaction and the postulated mechanism of the increased hazard for MACE with PPI therapy by demonstrating an associated attenuation of clopidogrel antiplatelet activity,” Giora Weisz, MD, of Shaare Zedek Medical Center (Jerusalem, Israel), and colleagues write. The paper was published in the October 2015 issue of Circulation: Cardiovascular Interventions.

“There is no question that there is a pharmacodynamic interaction. That’s 100% certain.” Sorin J. Brener, MD, of New York Methodist Hospital (Brooklyn, NY), commented in an interview. However, any apparent relationship between concomitant clopidogrel/PPI use and clinical outcomes likely stems from confounding, he continued. “PPIs are a marker of patients with more advanced disease.”

The actual question is whether there are clinical consequences, Brener said, noting that the answer is “almost certainly not.”

In 2009, the US FDA updated the labeling for clopidogrel, at that time sold exclusively as Plavix (Bristol-Myers Squibb), to warn providers against concomitant use of the drug with the PPI omeprazole. Two years later, the agency added another PPI, esomeprazole. In the years since, several published studies have affirmed or refuted the link.

Higher Reactivity on Clopidogrel, Increased Risk at 2 Years

Out of 8,582 patients enrolled in ADAPT-DES, 2,697 (31.4%) received a PPI at the time of PCI. Patients receiving PPIs were older, more often female, had a higher burden of established cardiovascular disease, and were more likely to present with hypertension, diabetes, PAD, and chronic kidney disease.

After clopidogrel loading, PPI-treated patients had a higher mean P2Y12 reactivity unit (PRU) value according to the VerifyNow assay (Accriva Diagnostics). They also were more likely to meet the definition of high platelet reactivity, whether defined as PRU value > 208 or ≥ 230. PPI use was independently associated with high platelet reactivity at hospital discharge (adjusted OR 1.38; 95% CI 1.25-1.52).

Taking a PPI at the time of revascularization had no significant impact on in-hospital outcomes including mortality, MI, stent thrombosis, and clinically relevant bleeding.

In all, 25.2% of patients were prescribed a PPI when discharged from the hospital, again with many differences in baseline characteristics between those who did and did not receive the drugs. Patients discharged on PPIs had higher 2-year risks of MACE (death, MI, stent thrombosis, or clinically driven TVR) as well as death and clinically driven TVR. Risks of MI, stent thrombosis, and clinically relevant bleeding did not differ by PPI use (table 1).

“Additional studies are warranted to determine the risk–benefit ratio of PPI use in patients with DES in whom clopidogrel is used to inhibit the P2Y12 platelet receptor,” the researchers conclude.

Muthiah Vaduganathan, MD, MPH, and Deepak L. Bhatt, MD, MPH, both of Brigham and Women’s Hospital (Boston, MA), summarize the evidence base “from bench to bedside” in an accompanying editorial. “Despite new data generated in this space and increased attention from regulatory and research fronts, it remains unclear whether the pharmacokinetic and pharmacodynamics interaction between clopidogrel and PPIs has any real-world clinical implications,” they say.

Nevertheless, the editorialists predict that clinicians will continue to be concerned about a potential interaction. The aging cardiovascular disease population has numerous comorbidities that necessitate PPI use, while prolonged dual antiplatelet therapy for ACS patients is gaining traction.  Additionally, they cite the “advent of newer, more potent antithrombotic combinations which amplify bleeding risk.”

Adding NSAIDs to the Mix

Another recent study, published October 19 in the BMJ, adds some insights into the bleeding issue in a real-world context.

Researchers led by Anne-Marie Schjerning Olsen, MD, PhD, of Copenhagen University Hospital Herlev, conducted a nationwide cohort study using registry data from all hospitals in Denmark between 1997 and 2011. Employing claimed prescriptions to document medication use, they assessed GI bleeding in 82,955 patients with first-time MI who were more than 30 years old and on aspirin and/or clopidogrel (45.3% dual therapy and 54.7% monotherapy). Simultaneous NSAID and PPI exposure occurred in 12.8% of patients.

Over a mean follow-up period of 5.1 years, there were 3,229 GI bleeding events (8.7% fatal). Crude incidence of GI bleeds was lower for patients with concurrent PPI and nonsteroidal anti-inflammatory drug (NSAID) use than for those not taking the 2 drugs at the same time (1.8 vs 2.1 per 100 person-years; adjusted HR 0.72; 95 CI% 0.54-0.95).

“Our data suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well,” Schjerning Olsen and colleagues advise.

Describing the Danish observational study as “well done,” Bhatt told TCTMD in an email that “[i]nterest in reducing GI bleeding among cardiac patients remains high, as this is an important and relatively frequent complication in our patients.” Current US guidelines, he said, “support use of PPIs in patients at high GI bleeding risk, such as those in this study.”

Brener emphasized, however, that both European and US guidelines agree “it’s a class III indication to administer NSAIDs in patients after an MI. So it’s really a nonissue. It shouldn’t be done. We know that it’s not good. … If you do use [an NSAID] it should be for a very short period of time.”

Note: Weisz and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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Sources: 
1. Weisz G, Smilowitz NR, Kirtane AJ, et al. Proton pump inhibitors, platelet reactivity, and cardiovascular outcomes after drug-eluting stents in clopidogrel-treated patients: the ADAPT-DES study. Circ Cardiovasc Interv. 2015;8:e001952.
2. Vaduganathan M, Bhatt DL. Revisiting the clopidogrel–proton pump inhibitor interaction: from bench to bedside. Circ Cardiovasc Interv. 2015;8:e003208.
3. Schjerning Olsen A-M, Lindhardsen J, Gislason GH, et al. Impact of proton pump inhibitor treatment on gastrointestinal bleeding associated with non-steroidal anti-inflammatory drug use among post-myocardial infarction patients taking antithrombotics: nationwide study. BMJ. 2015;351:h5096.

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