Meta-analysis: Prasugrel the Best P2Y12 Inhibitor After PCI?

Among oral P2Y12 inhibitors, prasugrel appears to have the best balance between risks and benefits in patients who have undergone PCI, according to a new meta-analysis.

Compared with clopidogrel, prasugrel was associated with a lower likelihood of MACE, MI, and stent thrombosis, with no increase in major bleeding. Ticagrelor, on the other hand, was associated with a reduced odds of stent thrombosis but higher rates of major bleeding and intracranial hemorrhage.

When comparing prasugrel and ticagrelor directly, there were lower risks of MACE, MI, and stent thrombosis with the former.

Lead author M. Haisum Maqsood, MD (Houston Methodist Hospital, TX), and colleagues report the findings in a paper published online recently in JAMA Cardiology. Based on the results, they say, prasugrel provides “the optimal balance between efficacy and safety compared with ticagrelor and clopidogrel.”

The take-home message, according to Donald Cutlip, MD (Beth Israel Deaconess Medical Center, Boston, MA), who was not involved in the analysis, “is that we should consider prasugrel more often, certainly in younger patients with acute coronary syndrome.

“All things considered, prasugrel should probably move up higher in our choice of antithrombotic therapy in acute coronary syndrome,” Cutlip added.

Guidelines from the United States and Europe include class 1 recommendations to use one of the more-potent P2Y12 inhibitors, prasugrel or ticagrelor, over clopidogrel in patients undergoing PCI to reduce MACE and stent thrombosis, with the European Society of Cardiology also saying that consideration should be given to selecting prasugrel instead of ticagrelor in ACS patients based on the results of ISAR-REACT 5 (class 2a recommendation). In that study, treatment with prasugrel versus ticagrelor lowered MACE risk, with no difference in bleeding.

Additionally, ticagrelor failed to demonstrate noninferiority compared with prasugrel after PCI in patients with diabetes and multivessel disease in the TUXEDO-2 trial, with most outcomes leaning toward an advantage for prasugrel.

“Given these striking findings, it is imperative to evaluate the efficacy and safety of currently used oral [P2Y12] antiplatelet therapies,” Maqsood et al write.

Drug Comparisons

This systematic review and meta-analysis included 15 randomized trials with a total of 48,904 patients (mean age 63.2 years; 27.3% women) treated with invasive management for either ACS (93.9%) or chronic coronary syndrome (6.1%). Most trials compared either prasugrel or ticagrelor with clopidogrel; ISAR-REACT 5 and TUXEDO-2 were the only two head-to-head trials comparing the two more-potent agents.

Overall, 24.8% of patients were randomized to prasugrel, 32.8% to ticagrelor, and 42.4% to clopidogrel. More than one-quarter (28.2%) had diabetes.

Over a mean duration of 12.1 months, the primary efficacy outcome of MACE was less likely with prasugrel compared with clopidogrel (OR 0.80; 95% CI 0.69-0.93). This was driven mostly by lower likelihoods of MI (OR 0.71; 95% CI 0.62-0.82) and stent thrombosis (OR 0.48; 95% CI 0.37-0.62) with prasugrel.

Ticagrelor, on the other hand, did not significantly influence the odds of MACE (OR 0.97; 95% CI 0.84-1.12) or MI (OR 0.91; 95% CI 0.79-1.05) compared with clopidogrel, although it did come with lower rates of stent thrombosis (OR 0.73; 95% CI 0.59-0.91).

Prasugrel also bested ticagrelor when it came to the likelihoods of MACE (OR 0.83; 95% CI 0.70-0.98), MI (OR 0.78; 95% CI 0.65-0.94), and stent thrombosis (OR 0.66; 95% CI 0.49-0.88).

Risks of all-cause mortality, ischemic stroke, and cardiovascular death were not significantly different across all comparisons, although there were hints that patients were less likely to die from CV causes when treated with prasugrel or ticagrelor rather than clopidogrel.

The primary safety outcome was major bleeding, which was significantly more frequent with ticagrelor than with clopidogrel (OR 1.24; 95% CI 1.01-1.52), a difference driven by higher rates of intracranial hemorrhage (OR 1.89; 95% CI 1.08-3.33). No other between-drug comparisons for bleeding revealed significant differences.

Ticagrelor was also associated with greater odds of drug discontinuation due to adverse events compared with clopidogrel (OR 2.07; 95% CI 1.20-3.56).

When ranking treatments for efficacy, prasugrel came out on top, followed by ticagrelor and clopidogrel. Clopidogrel fared best for safety, with prasugrel in second place and ticagrelor in third.

Prasugrel Underused?

Prasugrel likely has been underused, with bleeding concerns stemming from the findings of the TRITON-TIMI 38 and ACCOAST trials and the contraindication to using the drug in patients with prior stroke likely contributing to the issue, Cutlip said.

“Both of those studies may have been overinterpreted a bit,” he said, adding that, more recently, ISAR-REACT 5 showed an advantage for prasugrel in a direct comparison with ticagrelor. Still, those results didn’t have a major impact on practice, at least in the US. “Ticagrelor became the favorite and it may take more than one or two studies to change that,” Cutlip said.

Ticagrelor became the favorite and it may take more than one or two studies to change that. Donald Cutlip

Meta-analyses generally carry less weight than randomized trials but because of the experienced investigators who conducted this one and the high-quality of the included studies, Cutlip said, “I tend to put some value on this, and I think the fact that it, in a way, is supportive of ISAR-REACT 5 is also something that’s worthy of consideration.”

Prasugrel, he said, “may not be appropriate in all-comers but . . . with dose adjustment for weight and older age, it seems that the bleeding risk of prasugrel is not any higher and might even be lower than with ticagrelor.”