Pantoprazole Not Necessarily a Safer PPI Choice for Patients on Dual Antiplatelet Therapy

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Controversy regarding a possible role of proton pump inhibitors (PPIs) in interfering with the efficacy of dual antiplatelet therapy continues with a new study showing that pantoprazole—thought to be less likely to interfere with clopidogrel metabolism than its counterparts—in fact increases at least 1 measure of residual platelet reactivity in patients after primary percutaneous coronary intervention (PCI). The study was published online June 22, 2012, ahead of print in the International Journal of Cardiology.

Researchers led by Maria Serena Parri, of Ospedale G. Pasquinucci (Massa, Italy), randomized 105 STEMI patients who received primary PCI to 40 mg pantoprazole (n = 54) or 150 mg ranitidine (n = 51), an H2-receptor antagonist, on top of dual antiplatelet therapy (100 mg/day aspirin and 75 mg/day clopidogrel).

Platelet function was evaluated by the Platelet Function Analyzer-100 (PFA-100) point-of-care assay and by light transmittance aggregometry (LTA) at 5 and 30 days after PCI. In addition, to evaluate a possible interference of the CYP2C19*2 polymorphism on platelet function testing, the distribution of the polymorphism also was assessed in the cohorts.

Unexpected Poor Response for PPI

The prevalence of carriers of the *2 polymorphism was lower in the PPI group than the ranitidine group, but the difference did not reach statistical significance (27% vs. 40%; P = 0.16).

Although residual platelet reactivity results were similar for the 2 LTA testing methods, there was a difference in maximal aggregation of ADP (ADP-MA) as measured by Platelet Function Analyzer at 10 µM ADP, with poorer response in the PPI group at both 5 days and 30 days after revascularization compared with the ranitidine group. Despite the higher increase in median values observed in the PPI group at the 30-day mark, this did not translate into an increase in residual platelet reactivity (P = 0.2; table 1).

Table 1. ADP Maximal Aggregation

Because the higher prevalence of the *2 polymorphism in the ranitidine group might affect the test results, the researchers compared ADP-MA values between loss-of-function carriers and normal metabolizers. Normal metabolizers receiving the PPI showed higher levels of ADP-MA than those receiving ranitidine at both 5 days and 30 days (P = 0.001 and P = 0.01, respectively), whereas in carriers of the *2 polymorphism, ADP-MA values were similar at the 2 time points (P = 0.66 and P = 0.94, respectively).

Additionally, after multivariate linear regression analysis adjusting for cardiovascular risk factors as well as procedural, clinical, and laboratory data plus the presence of *2, use of a PPI remained associated with ADP-MA at both 5 and 30 days (P = 0.05 and P = 0.03, respectively).

“Our data provide the first documentation in a randomized trial, after correction for the presence of the CYP2C19*2 polymorphism, that pantoprazole, concurrently administered with clopidogrel and aspirin in patients with acute coronary syndromes, significantly increases ADP-MA,” the authors write.

Further Clarification Needed

As to why others studies have shown pantoprazole to have less adverse effect on antiplatelet therapy than other PPIs or even to have no interaction at all, the study authors offer a possible explanation: Those studies did not evaluate the distribution of the *2 loss-of-function polymorphism, which has been shown to be a major predisposing factor toward residual platelet reactivity as well as an independent predictor of MACE and in particular of stent thrombosis.

Furthermore, they say their study also points out that platelet reactivity test data should not be analyzed independent of genetic assessment.

“Our data underscore the need for further studies on large series and clinically and genetically [well] characterized patients, in order to clarify the real role of PPIs,” they write. “This need is particularly urgent since the PPIs are more effective in preventing gastric complications compared with H2-receptor antagonists.”

Time to Move On

But in a telephone interview with TCTMD, Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), said the literature does not support any clear connection between PPIs and a significantly reduced inhibitory effect of clopidogrel.

“The differences here are subtle, and the data we have so far from the COGENT trial don’t suggest that there is any clinical implication, which you would expect if there was a real effect [of PPIs],” Dr. Kleiman said. “Frankly, I think it’s time to move beyond this. Stent thrombosis is pretty uncommon now, and if you are concerned about the possibility, there are alternative drugs available.”

But Dr. Kleiman did acknowledge that such studies, if done properly, could be useful for identifying high-risk patients in need of tailored therapy.

“If anything further needs to be done, it is to focus on subsets of patients at highest risk for stent thrombosis, such as those with kidney failure, long lesions, bifurcation stenting, etc,” he said. “It’s certainly doable to mount randomized trials including such patients, but the ability to get the resources to do so is questionable.”

 

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Source:
Parri MS, Gianetti J, Dushpanova A, et al. Pantoprazole significantly interferes with antiplatelet effect of clopidogrel: Results of a pilot randomized trial. Int J Cardio. 2012;Epub ahead of print.

 

 

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