JACC: New P2Y12 inhibitors improve mortality, meta-analysis shows
Compared with clopidogrel, new P2Y12 inhibitors, such as prasugrel and ticagrelor, better decrease mortality after PCI and are particularly favorable for STEMI patients, according to a meta-analysis in the November issue of the Journal of the American College of Cardiology.

No trials of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) have shown an effect on mortality, and trials of the new P2Y12 inhibitors have not been powered to show a mortality benefit.

In that regard, Anne Bellemain-Appaix, MD, from Institut de Cardiologie, Pitié-Salpêtrière University Hospital in Paris, and colleagues—in an effort to increase the statistical power—analyzed the combined effect of eight randomized, placebo-controlled trials that compared new P2Y12 antagonists with clopidogrel in PCI.

"The newly developed P2Y12 inhibitors are more potent and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for PCI," the authors wrote.

The four agents that have been tested in several clinical studies are:
  • Prasugrel (Effient, Sanofi-Aventis/Daiichi-Sankyo), an oral pro-drug leading to irreversible blockade of the P2Y12 receptor;
  • Ticagrelor (Brilinta, AstraZeneca), a direct-acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects;
  • Cangrelor (The Medicines Company), an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition; and
  • Elinogrel (Novartis), an intravenous and oral P2Y12 antagonist with a direct and reversible action.

The eight studies included 48,599 patients, 94 percent of whom had acute coronary syndrome and 84 percent who underwent PCI.

The primary efficacy endpoint was all-cause death and the researchers also examined CV death, major adverse cardiac events (MACE), MI, stroke and stent thrombosis.

The new P2Y12 inhibitors significantly decreased death for the whole cohort, for any PCI and for STEMI patients (odds ratio: 0.83, 0.85 and 0.78, respectfully). The P2Y12 antagonists also significantly decreased MACE rates by 18 percent and stent thrombosis by 40 percent in PCI patients.

The researchers noted an increase in thrombolysis In MI (TIMI) major bleeding for any PCI, but no difference in PCI for STEMI or primary PCI for STEMI. They confirmed these results in sensitivity analyses that removed the largest study (PLATO).

Although the STEMI patients comprised smaller groups overall, they are at a "higher risk and, therefore, theoretically obtained greater benefit from rapid platelet inhibition for PCI," Bellemain-Appaix and colleagues concluded.

The authors cautioned that they cannot confirm that survival effect is a real class effect because the four agents have individual properties and differ from one another. However, when they removed the large PLATO study, which evaluated ticagrelor, they still found a significant 22 percent decrease in mortality in STEMI patients treated with PCI.

They also cautioned that mortality in the clopidogrel group could have been confounded by varying the loading doses between 300 mg and 600 mg. A subanalysis, however, found similar results in MACE and mortality when comparing the 600 mg dose of clopidogrel with the new P2Y12 agents.

Another factor to consider is that none of the trials genotyped for the CYP2C19 gene variant that affects platelet inhibition in up to 30 percent of the population. "It is possible that the enhanced efficacy of newer agents is mostly or only confined to those individuals with clopidogrel-resistant alleles," the authors said.

They also suggested that the higher cost of the newer agents compared with generic forms of clopidogrel "might temper enthusiasm for these agents in the greater population with the exception of individuals with STEMI."