PLATO Analysis: PPIs Problematic with Both Ticagrelor, Clopidogrel

Download this article's Factoid in PDF (& PPT for Gold Subscribers)

Proton pump inhibitors (PPIs) are associated with increased risk of cardiovascular (CV) events not only when paired with clopidogrel but also with the newer antiplatelet agent ticagrelor, which had been thought immune to such an interaction. However, the authors of the report, from a PLATO subanalysis published online January 18, 2012, ahead of print in Circulation, caution that the association may very well not be causative.

Published in the New England Journal of Medicine in September 2009, the PLATO (PLATelet inhibition and patient Outcomes) trial randomized more than 18,000 ACS patients in 43 countries worldwide to the P2Y12 antagonist ticagrelor (AstraZeneca, Wilmington, DE; 180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). All patients also received aspirin.

Parsing Antiplatelets

For this prespecified analysis, Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital (Toronto, Canada), and fellow PLATO investigators examined the association between PPI use and 1-year CV events in the clopidogrel and ticagrelor treatment arms. At the time of randomization, 6,539 patients were taking a PPI and 12,060 were not.

Kaplan-Meier estimates found that the combined rate of CV death, MI, and stroke (primary endpoint) was higher at 1 year with PPI use in both clopidogrel and ticagrelor patients (table 1).

Table 1. CV Events at 1 Year

Yet adverse events were similarly elevated for patients taking PPIs vs. other types of gastrointestinal (GI) drugs, such as histamine H2-receptor blockers, in the clopidogrel group (HR 0.98; 95% CI 0.79-1.23) and in the ticagrelor group (HR 0.89; 95% CI 0.73-1.10). The risk was higher, meanwhile, for patients taking PPIs vs. no GI therapy whether they were on clopidogrel (HR 1.29; 95% CI 1.12-1.49) or ticagrelor (HR 1.30; 95% CI 1.14-1.49).

Prior PPI use also heightened the risk of major bleeding, though the difference did not reach significance in the ticagrelor group (table 2).

Table 2. Major Bleeding at 1 Year

“[T]he association between PPI use and adverse events appears highly confounded such that PPI use is likely a marker for, rather than a cause of, a higher rate of CV events,” the investigators conclude.

Counterintuitive Findings

In a telephone interview, Dr. Goodman told TCTMD he was surprised by his own results. “In advance, you wouldn’t think that ticagrelor would be susceptible to interference from proton pump inhibitors in the same way that clopidogrel has,” he commented. “Clopidogrel is a prodrug and requires liver metabolism before it becomes an active antiplatelet, whereas in contrast ticagrelor doesn’t require any in vivo biotransformation.”

As the paper explains, PPIs inhibit the very enzyme—cytochrome P450 2C19, or CYP2C19—responsible for clopidogrel’s conversion. Ticagrelor, meanwhile, is a direct P2Y12 inhibitor.

The fact that both drugs seem affected by PPI use suggests that “this is more likely to be a confounding issue than a true effect,” Dr. Goodman observed. “I haven’t come across anything in the literature that would explain why a ticagrelor patient on a PPI would have difficulties. And yet clearly they are at higher risk.”

Dr. Goodman would not hazard a guess as to what exactly PPI use might be a marker for, noting that it could be one factor or several working together. “Obviously, when you make attempts at statistical adjustments, you’re stuck with variables that you know about or have in a database,” he noted. “And even with statistical adjustment, it might not truly capture some company that those variables keep.”

A Non-Issue

Importantly, most of the data linking PPIs to poor outcomes in patients taking clopidogrel has come from nonrandomized trials, Dr. Goodman pointed out. As such, the warnings issued by the FDA and other regulatory bodies around the world are premature, he said, urging moderation and individualized treatment.

In an e-mail communication with TCTMD, Deepak L. Bhatt, MD, of Brigham and Women's Hospital (Boston, MA), agreed with Dr. Goodman and colleagues assessment attributing the heightened risk for both treatment arms to “classic confounding—sicker patients are on these GI agents and have worse outcomes because of their comorbidities, not because of the GI agent. Half the patients in this analysis were on omeprazole, and even with this specific PPI there was no evidence of an adverse interaction with clopidogrel (or ticagrelor). This is more reassuring information regarding the lack of any important clopidogrel-PPI interaction.”

Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), also was convinced by the results, especially the observation of increased bleeding paired with higher CV event rates, “which really show you that [patients on PPIs] are sicker people. They’re really not the same. Everything is worse.”

Dr. Brener honed in on the paper’s mention of aspirin as a possible explanation. “It’s a cool idea,” he said. “That would unify the 2 [treatment] groups. They’re both on aspirin.”

Concerns about PPI use and clopidogrel are now out of date, Dr. Brener asserted, due to the availability of alternative antiplatelet therapies and mounting evidence that the association is not real. Clinicians should instead focus on weighing whether patients need to be on PPIs in the first place, he added.

Study Details

The use of PPIs or other gastric acid suppressive drugs was at physician discretion. Patients self-reported PPI use at the time of randomization. Omeprazole (48.9%) was the most common PPI type, followed by pantoprazole (30.1%), esomeprazole (11.7%), lansoprazole (7.8%), and rabeprazole (1.5%).

Patients who received a PPI at baseline more commonly had histories of dyslipidemia, statin therapy, peripheral arterial disease, PCI, CABG, or chronic obstructive pulmonary disease. They were more likely to live in North America and to have index diagnoses of NSTEMI and higher TIMI and GRACE risk scores. They were less apt to have prior congestive heart failure and ST-segment depression. PPI use prior to randomization also was associated with history of peptic ulcer disease and lower baseline hemoglobin.

Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: Insights from PLATO. Circulation. 2012;Epub ahead of print.

Related Stories:

• Consensus Statement Supports Judicious Use of PPIs Plus Antiplatelet Therapy
• FDA Repeats Warning on Concomitant Use of Clopidogrel, Omeprazole
• COGENT Published: No Adverse Interaction Between Omeprazole, Clopidogrel