Platelet Inhibitors, PPIs, and Adverse CV Events Not Linked

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Platelet Inhibitors, PPIs, and Adverse CV Events Not Linked

By David Douglas

NEW YORK (Reuters Health) Feb 27 – There is no need to avoid proton pump inhibitors (PPIs) in patients on the platelet inhibitors clopidogrel or ticagrelor, according to a new paper.

In a prespecified analysis of the PLATO trial, which compared the two antiplatelet drugs, higher rates of cardiovascular events were tied to baseline status rather than any PPI interaction, researchers reported online January 18 in Circulation.

The findings, said lead author Dr. Shaun Goodman in email to Reuters Health, «are a good reminder to clinicians that we always need to be cautious in the interpretation of observational studies describing associations between treatment (in this case proton pump inhibitors together with clopidogrel) and outcomes (in this case cardiovascular death/myocardial infarction/stroke at 1 year) and not jump to cause-and-effect conclusions.»

In PLATO, patients with acute coronary syndromes were randomly assigned to clopidogrel or ticagrelor. PPIs or other gastric acid suppressive therapy such as histamine H2 receptor blockers were used at the discretion of the patient’s physician. According to reports from that trial, ticagrelor reduced the rate of the primary endpoint (death from vascular causes, myocardial infarction, or stroke) without increasing the rate of major bleeding.

In the current study, Dr. Goodman, from the University of Toronto, and colleagues analyzed the effects of PPIs in 6,539 study subjects who received them and 12,060 who did not

Ticagrelor, they say, «is a P2Y12 inhibitor that does not require biotransformation and has no known pharmacokinetic or pharmacodynamic interaction with PPIs.»

On the other hand, some PPIs, in particular omeprazole, can «inhibit the CYP2C19 isoenzyme, and thus modulate conversion of clopidogrel into its active metabolite.»

With a median follow-up of about one year, the risk of reaching the primary endpoint was significantly increased both with clopidogrel (hazard ratio 1.20) and ticagrelor (hazard ratio 1.24). But the risk was similarly increased in patients on non-PPI gastrointestinal treatments.

Thus, the authors write, «The 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 cardiovascular events.»

PPI use was also associated with an increased rate of major bleeding in both the clopidogrel and ticagrelor group.

«If PPIs interfered with the metabolism of clopidogrel and ticagrelor such that their reduced antiplatelet efficacy resulted in a higher risk of subsequent ischemic events,» the researchers point out, «it is otherwise difficult to explain why these patients would also experience a higher rate of bleeding.»

«However, if the use of PPIs simply identifies those patients at increased risk of cardiovascular events, it is not surprising that these patients are also at higher risk of major bleeding.»

In fact, they wrote, at baseline «patients on a PPI are at higher risk compared to those not on a PPI.» More are older, have prior comorbidities and have a higher mortality risk. Thus, «the increased rate of cardiovascular events in patients who receive a PPI seems mainly explained by differences in baseline characteristics.»

«Even statistical attempts at adjusting for differences in the characteristics of patients who do or do not take a PPI cannot replace a proper randomized clinical trial,» Dr. Goodman said.

«We can use observational studies to generate hypotheses,» he noted – for instance, that some PPIs interfere with the metabolism and therefore the antiplatelet effect of clopidogrel («already demonstrated in multiple studies,» he added, although «the clinical impact remains uncertain»).

But, Dr. Goodman continued, «In general, we should NOT change our clinical practice in the absence of randomized trial data confirming or refuting our findings of association.»


Circulation 2012.

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