Single-Center Study Offers Insights for Ticagrelor vs Prasugrel in Chronic CAD

Patients with chronic or acute coronary syndromes undergoing PCI have comparable safety and efficacy outcomes at 1 year no matter whether they were initially discharged on aspirin plus prasugrel or aspirin plus ticagrelor, according to new observational data.

Use of these more-potent P2Y12 inhibitors over clopidogrel has become widely accepted—and guideline supported—in clinical practice for patients following ACS, with ISAR-REACT-5 showing an advantage for prasugrel over ticagrelor. But for those with stable CAD, the data are scant, with the most recent US guidelines for revascularization continuing to give clopidogrel a class 1 recommendation for chronic coronary disease, whereas ticagrelor or prasugrel can be used in preference to clopidogrel in patients with ACS.

Senior author Samin K. Sharma, MD (Icahn School of Medicine at Mount Sinai, New York, NY), told TCTMD he has been using both prasugrel and ticagrelor—but mostly the former—in complex stable patients “off label” for several years. The main question he wanted to answer with this study, he said, was: “By using these agents, are we harming any patients or are we having more bleeding?”

The data, which show no difference in the risks of death or MI, stroke, or bleeding between the two agents but a slight advantage in terms of reduced TVR with ticagrelor, send a clear message, according to Sharma: “Do not hesitate to use potent P2Y12 inhibitors in stable CAD.”

For Usman Baber, MD (University of Oklahoma Health Sciences Center, Oklahoma City), who was not involved in the research, the study demonstrates “that clinicians seem to have made their decisions about using these potent drugs [over clopidogrel] in the stable setting,” especially for those at high ischemic risk. What would be helpful in making clinical decisions going forward, he told TCTMD, would be a randomized comparison.

Real-world Data

For the study, published in the November 28, 2022, issue of the Journal of the American College of Cardiology, Anoop N. Koshy, MBBS, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), Sharma, and colleagues included 3,858 consecutive patients (mean age 62 years; 22.7% female) undergoing PCI at their institution between 2014 and 2019 who were discharged on dual antiplatelet therapy (DAPT) consisting of aspirin and either ticagrelor (n = 2,771) or prasugrel (n = 1,087). The dosing protocol was as follows:

• Aspirin: 325 mg > 90 minutes prior to angiography with a maintenance dose of 81 mg daily
• Ticagrelor: 180-mg loading dose with a 90-mg twice daily maintenance dose
• Prasugrel: 60-mg loading dose followed by either a 10-mg daily maintenance dose for patients who had a body weight ≥ 100 kg or had three stents implanted in the same vessel or 5 mg for everyone else

Most patients (48.4%) presented with chronic coronary syndrome (CCS), while the rest had unstable angina (26.7%), NSTEMI (17.5%), and STEMI (7.0%). Notable exclusion criteria were cardiogenic shock and being on oral anticoagulants prior to PCI.

Patients receiving prasugrel had a slightly higher frequency of left main and multivessel disease as well as were more likely to undergo complex and CTO PCI. Those receiving ticagrelor tended to be female, have a history of cerebrovascular disease, and present with ACS.

At 1 year, there was no significant difference in the primary endpoint of death or MI for patients discharged on ticagrelor compared with prasugrel (3.3% vs 3.1%; adjusted HR 0.88; 95% CI 0.54-1.43). There were also no differences in stroke or stent thrombosis. However, the rate of clinically driven TVR occurred in fewer patients in the ticagrelor compared with prasugrel groups (9.3% vs 14.0%; P < 0.001), and this remained significant after risk adjustment (HR 0.71; 95% CI 0.55-0.91).

Sharma said the TVR finding was surprising for him because it hasn’t been seen in any other study, adding that he can’t fully explain the reason for it other than maybe the higher degree of complexity in the prasugrel group.

Researchers observed a trend toward more bleeding with ticagrelor, but this did not remain significant after risk adjustment (HR 1.24; 95% CI 0.79-1.93).

In propensity-score analyses, patterns for both the primary endpoint as well as clinically driven TVR remained similar. Additionally, subgroup analyses confirmed the findings when patients were stratified by ACS presentation and PCI complexity, but highlighted that TVR was only significantly lower in ACS patients prescribed ticagrelor. Lastly, the researchers found no effect of drug dose on outcomes.

Sharma noted some limitations of the study. First, they weren’t able to capture exactly how long patients stayed on DAPT, especially past 1 year, and this duration may have had an impact on outcomes. Also, he said, there was likely some degree of crossover they couldn’t account for—likely between 5% and 8%—but more likely from one of the more-potent agents to clopidogrel as opposed to from one to another.

With antiplatelet therapies constantly evolving, Sharma said he hopes “this paper will add comfort to a lot of people who are always concerned about two things.” First, he stressed, prasugrel and ticagrelor are safe in both ACS and stable CAD. Second, using a prasugrel dose of 5 mg “is good enough” for many patients and may cause less bleeding compared with the standard 10-mg dose.

Another Randomized Trial Needed

Baber said most of the study’s findings were not entirely unexpected since “what we see in registries is much different than what we see in clinical trials.” Notably, he said, the overall rates of MI were “somewhat low,” meaning that it would be hard to demonstrate a large reduction in that endpoint.

He, too, was puzzled, by the significant reduction in TVR with ticagrelor. “That finding is a bit hard to reconcile with the lack of difference in MI, and to me, that might reflect differences in the types of patients who receive prasugrel,” Baber said, echoing the point made by Sharma. “The patients who received prasugrel seemed to have a bit more complex disease, and although these [factors] were adjusted for, one can never completely adjust away confounding in an observational study.”

In an accompanying editorial, Jochen Wöhrle, MD, and Julia Seeger, MD (both Medical Campus Lake Constance, Friedrichshafen, Germany), note that “despite the lack of clear evidence for prasugrel or ticagrelor in CCS patients, the administration of these two potent P2Y12 inhibitors is continuously increasing.” As such, they say, “a prospective trial comparing both potent P2Y12 inhibitors in a PCI patient population with CCS and a high ischemic risk is eagerly awaited.”

Sharma agreed, saying, “There definitely is a need for a trial in stable CAD.” A three-arm trial comparing clopidogrel, prasugrel, and ticagrelor in complex stable CAD patients would be ideal, he continued, but it might be hard to find funding for such a study. Perhaps, he said, the National Institutes of Health or other sponsor would be interested, “because this is a field which continues to evolve, and we are investing in more and more.”

Baber agreed that a three-arm trial would answer the most questions, especially if it used a shorter DAPT duration and potentially a de-escalation strategy. “Clearly, we are seeing from this study that clinicians have already made the decision to use stronger agents to protect their patients at high ischemic risk and therefore a clinical trial would be very informative for practice and understanding the risks and benefits of these agents,” he said, adding that data from both TWILIGHT and GLOBAL LEADERS have offered some, but not enough, insight.