P2Y12 Inhibitor Monotherapy Edges Out Aspirin for Secondary Prevention

For long-term secondary prevention of MI, the use of P2Y12 monotherapy has a borderline advantage over aspirin alone and does not affect bleeding, according to a meta-analysis of nine randomized trials.

But this advantage is of “debatable clinical relevance, in view of the high number needed to treat to prevent a myocardial infarction and the absence of any effect on all-cause and vascular mortality,” according to the authors.

The new data are “complementary” to both the TWILIGHT and GLOBAL LEADERS trials, which looked at short-term prevention in a high-risk group of post-PCI patients, according to senior author Giulio Stefanini, MD, PhD (Humanitas University, Milan, Italy). “Monotherapy is a very valuable alternative to the standard [dual antiplatelet therapy],” he told TCTMD. “The issue is when this 12-month period finishes, what shall we do? Shall we continue with ticagrelor or go back to therapy with aspirin as is recommended by guidelines? Our answer is [that] going back to aspirin is very reasonable.”

The meta-analysis, published in the May 9, 2020, issue of the Lancet, was jointly led by Mauro Chiarito, MD, Jorge Sanz-Sánchez, MD, PhD, and Francesco Cannata, MD (all of Humanitas University, Milan, Italy).

Minimal Advantage With P2Y12 Inhibitor

For the study, the researchers included data from more than 40,000 patients with cerebrovascular, coronary, or peripheral artery disease randomized to P2Y12 inhibitor (n = 21,043) or aspirin (n = 21,065) monotherapy for secondary prevention as part of nine randomized trials published between 1989 and 2019. The P2Y12 inhibitors used included ticlopidine, clopidogrel, and ticagrelor, and follow-up ranged between 3 and 36 months.

Overall, those allocated to P2Y12 inhibitor versus aspirin monotherapy saw a slight reduction in the risk of MI (OR 0.81; 95% CI 0.66-0.99) with a number needed to treat of 244. There were no differences in the risks of stroke (OR 0.93; 95% CI 0.82-1.06), all-cause death (OR 0.98; 95% CI 0.89-1.08), or vascular death (OR 0.97; 95% CI 0.86-1.09).

Also, the risks of any (OR 1.08; 95% CI 0.91-1.29) or major bleeding (OR 0.90; 95% CI 0.74-1.10) did not differ between the P2Y12 inhibitor and aspirin arms. GI bleeding, however, was lower in the P2Y12 inhibitor group (OR 0.59; 95% CI 0.39-0.89).

The approach for long-term secondary prevention is not going to be a uniform approach. I think we'll have to tailor it. Usman Baber

Meta-regression analyses confirmed the results did not vary by type of P2Y12 inhibitor. Nor was there any interaction between the qualifying disease and treatment effect.

Stefanini said he was partly surprised by the results given that he expected “a more marked advantage in favor of a P2Y12 inhibitor monotherapy as compared to aspirin monotherapy.”

However, the study findings highlight the importance of not only focusing on the post-PCI period, when patients are at highest risk for ischemic events, he said. “We [need to] focus on secondary prevention in general—so the broad population that requires an antiplatelet treatment because of established atherosclerosis. It might be patients that underwent a PCI several years before.” The issue of cost could also factor in over the long term given that aspirin is cheaper than P2Y12 inhibitors, Stefanini added.

What could be interesting going forward, he said, would be to look at whether there exists a subset of patients “who have the more pronounced benefit if treated with a P2Y12 inhibitor alone as compared to aspirin. Because they have a higher risk, we might expect the number needed to treat to be way lower than what we observed in the overall population,” Stefanini said. “To do this, we need individual patient data.”

Heterogeneity, Study Age as Limitations

Commenting on the study for TCTMD, Usman Baber, MD (University of Oklahoma Health Sciences Center, Oklahoma City), noted that one potential confounding issue is that the patient population is heterogeneous. “You've got patients with cerebrovascular disease and coronary disease, and really those I think are two fundamentally different phenotypes,” he said. “The approach for long-term secondary prevention is not going to be a uniform approach. I think we'll have to tailor it.”

For example, Baber noted, the COMPASS study supported a therapeutic regimen involving an anticoagulant for patients with cerebrovascular disease to prevent stroke. However, PEGASUS showed that more-intense antiplatelet therapy was beneficial for preventing recurrent MI in a population of patients with coronary disease.

Additionally, he said, “perhaps the toxicity with respect to aspirin exposure was not as apparent from these data. . . . We've seen TWILIGHT and other studies have clearly shown when we add aspirin to P2Y12 inhibition, you pay a large penalty in bleeding, and I don't think that a lot of these studies were done at a time when there were standardized approaches to quantifying and measuring bleeding.”

Hence, it’s possible that bleeding was underestimated here, according to Baber. “That’s an important point because the whole concept of why we're talking about aspirin withdrawal is fundamentally driven by avoiding bleeding, in particular GI bleeding.”

Ultimately, this meta-analysis adds to the literature but doesn’t firmly answer any open questions about secondary prevention, Baber said. “But I do think it's incremental and it's an important piece of evidence that does give us some insight on head-to-head comparison between whether or not aspirin monotherapy or a P2Y12 inhibitor may be optimal. I don't think this analysis itself is going to change practice or should change practice. I think it adds to the evidence base, and I think there are going to be many more studies examining this for long-term secondary prevention.”

In addition to what has been gleaned from both COMPASS and PEGASUS, he said, “it would be great to have a study where we look at long-term secondary prevention with just P2Y12 inhibitor monotherapy, which we haven't done yet, and try to understand if we can maintain efficacy and avoid aspirin-related bleeding.”

Extrapolating what has been seen in studies like MATCH and TWILIGHT to the long term, Baber said he suspects that P2Y12 inhibitor monotherapy will give protection from ischemic events without increasing bleeding. But “we don't have the aspirin-free strategy tested for long-term secondary prevention yet, and ideally we would want to test conventional [dual antiplatelet therapy] versus an aspirin-free strategy and perhaps a third arm where we look at a low-dose direct oral anticoagulant. Those are all the three regimens that are currently really being used in clinical practice, and so a study that tries to evaluate those head-to-head would be very helpful to move the field.”

Not Robust Evidence

In an accompanying editorial, Robert Byrne, MBBCh, PhD, and Róisín Colleran, MBBCh (both of Mater Private Hospital, Dublin, Ireland), also point to the age of many of the included trials and the heterogeneity of the population as limitations, and they note that the quality of data on bleeding was not high enough.

“Although the authors found no difference between the two treatments with respect to overall or major bleeding, the analysis does not provide robust evidence on this important element of the treatment effect,” Byrne and Colleran write. “Nevertheless, the observed lower risk of gastrointestinal bleeding with P2Y12 inhibitor monotherapy could be important information for patients with heightened risk of this complication.”

As for the overall clinical implications of the study, they say their impression “is that the absence of substantial difference between the two approaches supports the use of aspirin—the drug is easier to take, associated with less noncompliance, fewer off-target side effects (compared with ticagrelor in particular), and less variation in treatment response (compared with clopidogrel), and is likely to be more cost-effective.”