Possible "class effect" for proton-pump inhibitors on top of clopidogrel therapy
Las Vegas, NV - One-year risk of cardiovascular events is increased more than 50% in patients taking a proton-pump inhibitor (PPI) on top of clopidogrel, as compared with patients not taking a PPI, and the risk seems to be a class effect, according to a retrospective cohort study of more than 16 700 patients who received clopidogrel poststenting.
The study is the latest in an inconsistent series of reports trying to assess the clinical impact of combining the two classes of drugs. Professional society guidelines recommend the use of PPIs to treat and prevent gastrointestinal ulcers and bleeding in patients on antiplatelet therapy, but increasing use of PPIs in this setting has raised questions as to whether PPIs may attenuate clopidogrel's antiplatelet response by interfering with CYP2C19-mediated clopidogrel metabolism.
Dr Erick J Stanek (Medco Health Solutions, Franklin Lakes, NJ) presented the results of the Clopidogrel Medco Outcomes study as a late-breaking clinical trial during the first day of the Society for Cardiovascular Angiography and Interventions (SCAI) 2009 Scientific Sessions. The study compared major adverse cardiovascular events (MACE) among members of the Medco Health Solutions pharmacy and medical claims database. In all, 9862 patients never made a prescription claim for a PPI over the 12 months post-PCI and were classified as no PPI therapy for the purposes of the study, while 6828 filed prescription claims for a PPI: esomeprazole (Nexium, AstraZeneca), omeprazole, pantoprazole (Protonix, Wyeth), lansoprazole, or rabeprazole (Aciphex, Eisai/Ortho-McNeil-Janssen Pharmaceuticals).
Prescription status was then correlated with hospitalization for stroke/TIA, ACS, cardiovascular death, or coronary revascularization, based on ICD-9 or CPT-4 codes.
Higher MACE with PPIs
As Stanek showed here, one-year risk of MACE was significantly higher in PPI-treated subjects, at 25.1%, as compared with patients who did not take a PPI, at 17.9% (hazard ratio 1.51 [95% CI 1.39-1.64]; p<0.0001). According to investigators, PPI effect was "consistent across subgroups," with no single patient subset being significantly more likely to develop an adverse cardiovascular event.
They also looked at the CV risk associated with individual PPIs, restricting their analysis to PPIs with sufficient patient numbers to detect a difference in risk similar to that seen in the overall population, with adequate statistical power. Due to low numbers, rabeprazole, taken by just 298 patients, could not be addressed in this analysis.
According to Stanek, each of the PPIs, individually, was associated with a higher risk of major cardiovascular events vs no PPI use, ranging from a 24.3% increased risk with lansoprazole to a 29.2% risk with pantoprazole.
"There was considerable overlap between agents, suggesting this is somewhat a class effect," Stanek commented.
Of note, hospitalization rates for upper-GI bleeding were low across all groups of PPI use, in the range of 1.1%. Also of interest, investigators looked at PPI use among patients who were not treated with clopidogrel and found no increased risk of CV events in this group, as compared with patients taking neither a PPI nor clopidogrel.
"These results provide further support for the hypothesis that PPIs attenuate the effects of clopidogrel," Stanek concluded. "More data are needed to establish if newer PPIs . . . have similar effects. Considering all available evidence, PPI use should be limited to situations clearly indicated in patients on clopidogrel after coronary stenting."
Following Stanek's presentation and during a morning press conference, Dr Steven Bailey (University of Texas Health Sciences Center, San Antonio) confirmed with Stanek that the nature of the Medco analysis made it impossible to take into account whether patients were taking nonprescription medications, including aspirin as well as over-the-counter PPIs or other gastrointestinal agents, information that Bailey emphasized to be vitally important.
Bailey also emphasized that physicians need to do a better job of discriminating between patients who are just at risk of GI symptoms or who may have had previous GI disease and patients who actually have current GI problems—it is the latter group in whom concomitant PIs are likely to be useful, he said.
Stanek and colleagues are continuing to look at their data set, hoping to determine whether there are any signals of increased risk based on timing or duration of drug overlap. But Stanek hinted that based on information he's seen so far, "any length of exposure seems to be a problem."
Both Stanek and Bailey stressed, however, that the study was retrospective and "hypothesis-generating."
As Bailey put it: "This is not a cause for concern or alarm, but a cause for consultation." He urged physicians to take the time to discuss the risks and benefits with patients and also to emphasize that patients should not, by any means, stop clopidogrel therapy—a point also hammered by Stanek
More questions needing answers
Asked to comment on the study for heartwire, Dr Peter Berger (Geisinger Health, Danville, PA) observed that it is impossible to know from a retrospective cohort study the full reasons for why patients are put on PPIs in the first place and whether these factors were key to their subsequent cardiovascular events. "In this study, as in nearly all others, patients on PPIs are older and sicker than patients who are not. All statistical methods are imperfect at adjusting for differences when the groups are so different, as they are in this analysis."
Berger pointed out that there are other reasons to question whether PPIs truly adversely affect clopidogrel efficacy. In the TRITON study, he notes, the reduction in cardiovascular risk seen with prasugrel over clopidogrel was identical in patients on and not on PPIs.
"Since PPIs are not believed to influence the efficacy of prasugrel, that suggests that clopidogrel was equally effective in both groups," he said. "And paradoxically, in TRITON, patients on clopidogrel and a PPI bled even more than patients on clopidogrel and not on a PPI; in fact, they bled almost as much as patients treated with prasugrel. If the clopidogrel wasn't working because the PPI prevented clopidogrel prodrug from being metabolized to its active compound, patients on both shouldn't have bled so much more."
SCAI issues statement urging caution with PPIs
SCAI believes more research is needed on this topic. However, given the thousands of patients who receive stents each year, coupled with the significant risks demonstrated in this study, SCAI recommends the use of alternative medications for GI symptoms in patients with stents when appropriate. Other effective treatments for heartburn and ulcers include histaminergic (H2) blockers (Zantac [ranitidine, Boehringer Ingelheim], Tagamet [cimetidine, GlaxoSmithKline]) or antacids. In some patients the use of PPIs may still be warranted, based on the patient's medical problems, and should be taken at the direction of the patient's cardiologist, gastroenterologist, or primary physician."
Θέμα: Clopidogrel: Σε κάποιους δεν έχει αποτέλεσμα... (Αναγνώστηκε 27991 φορές)
8 Ιουλίου 2010, 22:57:44