Newer P2Y12 inhibitors reduce all-cause mortality compared with clopidogrel (Plavix), the older member of the class, a meta-analysis showed.
Pooled data from trials of prasugrel (Effient) and three investigational drugs showed that the newer medications significantly decreased death during follow-up by 17% (OR 0.83, 95% CI 0.75 to 0.92), according to Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière University Hospital in Paris, and colleagues.
The results were similar for patients undergoing percutaneous coronary intervention (PCI) for any reason (OR 0.85, 95% CI 0.75 to 0.96) and those undergoing PCI for ST-segment elevation MI (OR 0.78, 95% CI 0.66 to 0.92), the researchers reported online in the Journal of the American College of Cardiology.
Action Points
- Explain that newly developed P2Y12 inhibitors are more potent and have a faster onset of action than clopidogrel.
- Point out that the utility of these agents may be diminished because of the increased likelihood of major bleeding in patients undergoing PCI except for STEMI patients.
They noted that the risk-benefit ratio was especially favorable with the newer drugs for patients undergoing PCI for STEMI because there was no increased likelihood of TIMI major bleeding in that population.
Even so, clopidogrel may not be pushed aside for the newer P2Y12 inhibitors, according to Montalescot and his colleagues.
That's because there was an increased likelihood of major bleeding overall in patients undergoing PCI for any indication (OR 1.23, 95% CI 1.04 to 1.46).
In addition, the authors noted, "the high number needed to treat for benefit from the newer agents and their financial cost compared with clopidogrel's generic copies might temper enthusiasm for these agents in the greater population, with the exception of individuals with STEMI."
Although clopidogrel prevents major adverse cardiovascular events, it has never been shown to reduce mortality in the PCI setting, according to Montalescot and his colleagues.
The newer P2Y12 inhibitors -- prasugrel and the investigational agents ticagrelor (which was recently endorsed by an FDA panel), cangrelor, and elinogrel -- result in greater platelet inhibition and act faster than clopidogrel. But whether they resulted in a reduction in mortality compared with clopidogrel had been unknown.
The researchers identified eight randomized placebo-controlled trials (three were phase II) comparing the newer P2Y12 inhibitors with clopidogrel in a population in which more than 70% of patients underwent PCI. They included 48,599 patients, of which 94% had acute coronary syndrome and 84% underwent PCI.
All-cause mortality and TIMI major bleeding were the primary efficacy and safety endpoints, respectively.
In addition to significant reductions in death during follow-up, the new drugs reduced rates of cardiovascular death by 16%, major adverse cardiovascular events by 13%, and stent thrombosis by 40% among patients undergoing PCI for any indication (P<0.05 for all).
There was no difference in the occurrence of stroke between groups for the overall cohort or for patients undergoing PCI for any indication, but there was an increase in stroke with the newer P2Y12 inhibitors in patients undergoing PCI for STEMI (1.54% versus 1.13% with clopidogrel; OR 1.48, 95% CI 1.07 to 2.07).
This "may challenge the net clinical benefit of these agents," the researchers wrote.
"However," they added, "the heterogeneity in stroke definitions across studies and the absence of such an effect in other subgroups also suggest a play of chance for this finding."
Montalescot and his colleagues noted that two factors could have worked against clopidogrel in this comparison, including the variation in loading dose from 300 mg to 600 mg. The inclusion of the lower dose may have had a negative effect on mortality rates.
The second factor potentially influencing the results is the fact that randomization to the clopidogrel arms of the trials did not include genotyping for hepatic cytochrome gene variants, which confer resistance to clopidogrel.
"It is possible that the enhanced efficacy of newer agents is mostly or only confined to those individuals with clopidogrel-resistant alleles," the authors wrote.
They acknowledged that meta-analyses in general are limited by differences between trials, particularly the length of follow-up. The current meta-analysis was limited also by differences in agent characteristics and results that were not based on individual data.
Disclosures
Montalescot reported financial relationships with Bristol-Myers Squibb, sanofi- aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie, Société Française de Cardiologie, The Medicines Company, Schering-Plough, Merck Sharpe & Dohme, and GlaxoSmithKline. His co-authors reported relationships with sanofi-aventis, Eli Lilly, Merck/Schering-Plough, Boehringer Ingelheim, AstraZeneca, Roche, Pfizer, Astellas, Daiichi- Sankyo, INSERM, Fédération Française de Cardiologie, Société Française de Cardiologie, CLS Behring, Abbott, Servier, Bristol-Myers Squibb, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, and Fondation de France.
Primary Source
Journal of the American College of Cardiology
Bellemain-Appaix A, et al "New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis" J Am Coll Cardiol 2010; DOI: 10.1016/j.jacc.2010.07.012.