Esomeprazole, Not Rosuvastatin, Affects Clopidogrel Post-PCI

PPI and statin effects on clopidogrel probed in SPICE

Shelley Wood

October 27, 2011

October 27, 2011 (Vancouver, British Columbia) — The proton-pump inhibitor (PPI) esomeprazole (Nexium, AstraZeneca) is "at least as bad" as omeprazole in reducing the antiplatelet effects of clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb), a new randomized trial shows. In a secondary analysis, investigators for the Statins and Proton-Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial found no differences in clopidogrel effects of rosuvastatin (Crestor, AstraZeneca) and atorvastatin (Lipitor, Pfizer).

Dr Jean-Pierre Déry (Laval University, Quebec, QC) presented the SPICE results yesterday during the late-breaking clinical-trials session at the Canadian Cardiovascular Congress 2011.

Déry noted that previous trials have yielded conflicting results regarding both statins and PPIs and their effects on the antiplatelet activity of clopidogrel. Moreover, no previous randomized trials have addressed the impact of either rosuvastatin or esomeprazole, and there is very little data addressing whether CYP2C19*2 polymorphism status has an impact on the interaction of these two classes of drug and clopidogrel.

Adding SPICE

SPICE enrolled 350 post-PCI patients discharged on clopidogrel and excluded patients who were intolerant to the study drugs or who had an absolute need for a PPI. In the initial randomization, post-PCI patients were prescribed either rosuvastatin 20 mg or atorvastatin 80 mg, their CYP2C19*2 status was measured, and they were given clopidogrel but not a PPI. At 30 days, platelet-function tests were performed using both light transmittance aggregometry to test maximal platelet aggregation (MPA) and vasodilator stimulated phosphoprotein (VASP) testing to measure platelet-reactivity index (PRI). High platelet reactivity was defined as an MPA > 46% and a PRI > 50%.

At the 30-day mark, the 302 patients who'd remained in the study were further randomized to one of four gastroprotection agents: esomeprazole, pantoprazole, omeprazole, or ranitidine. Platelet-function testing was then repeated at 60 days, although only 277 remained in the study at the 60-day mark.

For the statin analysis, there were no differences in the effects of rosuvastatin and atorvastatin on antiplatelet effects at 30 days.

For the PPI analysis, there was no difference in mean change in platelet reactivity with pantoprazole as compared with ranitidine — an H2 antagonist. Esomeprazole, however, had the largest effect on platelet reactivity as measured by both MPA and PRI, with more than 35% of patients taking esomeprazole demonstrating a greater than 10% change in platelet activity by MPA, a proportion that rose to more than 50% by PRI. Omeprazole, by comparison, showed increases in mean change in platelet reactivity by PRI only, with nonsignificant increases seen on MPA.

In multivariate analyses, esomeprazole and high platelet reactivity prior to PPI therapy were the only factors independently associated with a change in MPA of greater than 10%. These two factors, as well as omeprazole use, were independently associated with a change greater than 10% when the PRI was used. PRI is a more specific marker of platelet reactivity, Déry pointed out.

Of note, an analysis of CYP2C19*2 status suggested that neither PPIs nor statins had different effects on platelet function in carriers of this polymorphism.

Not all things being equal

To heartwire, Déry explained that earlier reports have suggested that atorvastatin may have a negative impact on clopidogrel effects because of an interaction with 34A cytochromes. "Our study suggests that atorvastatin has similar effects as rosuvastatin, which is not metabolized by CYP 3A4. This is the first study comparing these two statins for clopidogrel effects."

Asked by one of the session moderators, Dr John Mancini (St Paul's Hospital, Vancouver, BC), whether the SPICE results suggest that the two statins are "equally bad or equally good," Déry replied that while both statins appeared to reduce antiplatelet activity, that effect was "very small."

While SPICE was still ongoing, Déry observed, a PROVE-IT analysis came out suggesting that "Lipitor is pretty safe, and now we show here that Crestor is probably just as safe."

As for the PPI findings, Déry emphasized that SPICE is the first randomized and adequately powered study to examine the interaction of esomeprazole and clopidogrel. It turns out "esomeprazole is at least as bad as or even worse than omeprazole in reducing the antiplatelet effect of clopidogrel," Déry told heartwire. In his practice, he says, he uses either atorvastatin or rosuvastatin, but for a PPI, he uses pantoprazole.

Asked about the high number of dropouts in the study, Déry acknowledged it was "very difficult to conduct an open-label trial at this time." Not only were an increasing number of studies raising questions about the platelet effects of statins and PPIs during the time of study enrollment, but the FDA also issued its warning about PPI use. "We were receiving all these calls from pharmacists saying, are you sure you want to put this guy on Losec [omeprazole]?" Only after the COGENT study results came out, showing no adverse effects of concomitant PPI use, was it "easier" to keep people in the study as designed, he said.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.