Long-Term DAPT with Ticagrelor Reduces Ischemic Risk, Ups Bleeding in MI Patients

SAN DIEGO, CA—Among patients who are stable more than a year after having an MI, adding ticagrelor to aspirin reduces the 3-year risk of cardiovascular death, MI, or stroke at the expense of more major bleeding, according to results of the PEGASUS-TIMI 54 trial. More serious bleeding events—intracranial hemorrhage and fatal bleeding—are not increased, however.

The findings were presented here on March 14, 2015, at the American College of Cardiology/i2 Scientific Session and simultaneously published online in the New England Journal of Medicine.

“Long–term dual antiplatelet therapy with low-dose aspirin and ticagrelor should be considered in appropriate patients with a myocardial infarction,” Marc S. Sabatine, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said during his presentation.

The trial, conducted at 1,161 sites in 31 countries from October 2010 through May 2013, included 21,162 stable patients (mean age 65 years; 24% female) who had had an MI 1 to 3 years before enrollment (median 1.7 years) and who had at least 1 additional high-risk feature: age 65 years or older, diabetes requiring medication, a second prior MI, multivessel disease, or chronic renal dysfunction. They were randomized to ticagrelor (Brilinta; AstraZeneca) 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo. All patients also were treated with low-dose aspirin 75 to 150 mg daily. Median follow-up was 33 months.

The 3-year risk of cardiovascular death, MI, or stroke (primary efficacy endpoint) was 9.04% with placebo, 7.85% with the 90-mg ticagrelor dose (HR 0.85; 95% CI 0.75-0.96), and 7.77% with the 60-mg dose (HR 0.84; 95% CI 0.74-0.95). The results were consistent in various subgroups.

There was a nonsignificant trend toward a reduction in cardiovascular death with both ticagrelor doses, a significant reduction in MI with both doses, and a significant reduction in any stroke with the lower dose. All-cause death, urgent revascularization, hospitalization for unstable angina, and TIA occurred at similar rates across groups.

Bleeding, Other Adverse Events Higher With Ticagrelor

By 3 years, TIMI major bleeding (primary safety endpoint) was higher with both the 90-mg and 60-mg doses of ticagrelor (2.60% and 2.30%, respectively) compared with placebo (1.06%). The bleeding risk also was consistent across subgroups.

In addition to TIMI major bleeding, TIMI minor bleeding, bleeding leading to transfusion, and bleeding leading to discontinuation of the study drug were more frequent in the ticagrelor groups.

However, the rate of intracranial hemorrhage or fatal bleeding did not differ between groups—0.63% and 0.71% with the higher and lower doses of ticagrelor, respectively, and 0.60% with placebo.

Among other adverse events, dyspnea and gout were more common in the ticagrelor arms. The patients on ticagrelor vs placebo were more likely to stop treatment prematurely (32% with the 90-mg dose and 28.7% with the 60-mg dose vs 21.4% with placebo; P < .001 for both).

Evidence Mounts for Long-Term Dual Antiplatelet Therapy

The benefit of dual antiplatelet therapy (DAPT) for up to 1 year after an MI has been well established, but the potential gain from extending treatment into the chronic phase has been more controversial. Although “post hoc landmark analyses from other studies have suggested a benefit to a longer duration of more-intensive antiplatelet therapy,” Dr. Sabatine and colleagues write, the overall results of the CHARISMA trial failed to support the long-term use of clopidogrel and aspirin in patients with atherosclerotic disease or multiple risk factors.

A secondary analysis looking at the subgroup of patients with prior MI, ischemic stroke, or symptomatic PAD, however, suggested a reduction in ischemic events with the addition of clopidogrel, providing support for long-term DAPT.

Expanding on those post hoc data with a newer P2Y12 inhibitor, “the results of the present trial provide prospectively defined evidence affirming the hypothesis that long-term, intensive platelet inhibition with ticagrelor reduces ischemic events in patients with prior myocardial infarction,” the authors write.

Following Dr. Sabatine’s presentation, panelist Robert Harrington, MD, of Stanford University School of Medicine (Stanford, CA), said, “Now that we’ve seen the [DAPT Study] results with the long-term benefit of dual antiplatelet therapy in stented patients [and] now that we see this, it seems pretty clear that there’s probably not a time you should ever come off of dual antiplatelet therapy if you have a certain risk of atherosclerosis.”

Dr. Sabatine agreed that for patients like the ones enrolled in PEGASUS-TIMI 54—who were treated for a minimum of 16 months and a maximum of nearly 4 years—“you would continue such therapy as long as it was well tolerated.” Given the data from the PLATO trial and the evidence of similar efficacy but better tolerability of the 60-mg vs the 90-mg dose of ticagrelor in the current trial, he added that he would start patients on the higher, recommended dose and titrate down after about a year.

Ticagrelor Has Benefits, But Impact Questionable

Panelist Valentin Fuster, MD, PhD, of Mount Sinai Hospital (New York, NY), acknowledged that adding ticagrelor yielded a reduction in clinical events, but he urged caution in interpreting the impact of the findings, pointing out that the absolute reduction in the primary endpoint was of a magnitude similar to the absolute increase in major bleeding.

The researchers calculated that for every 10,000 patients treated, adding the 90-mg dose of ticagrelor would prevent 40 primary endpoint events at the cost of 41 TIMI major bleeds, whereas the 60-mg dose would prevent 42 primary endpoint events at the expense of 31 major bleeds.

Therefore, clinicians need to balance the ischemic benefit with the risks of bleeding and other adverse events, like dyspnea, when deciding how to treat individual patients, Dr. Fuster said. He noted that he has been using long-term DAPT with clopidogrel and aspirin in about 70% of his patients based on the CHARISMA findings, and said that he would take a closer look at using ticagrelor based on the PEGASUS-TIMI 54 results.

The current trial “adds to the evolving trend of using two platelet inhibitors in long-term coronary artery disease, but I think we should be a little bit cautious …,” he said.

Dr. Sabatine countered by saying that most clinicians and patients would consider the hard ischemic endpoints as more important than TIMI major bleeding and noted that there was no difference in more serious bleeding events. “From my calculus … I would much rather prevent the CV death, MI, and stroke, at the expense of causing reversible nonfatal bleeding events, but that’s a reasonable discussion for each practitioner to have [with a patient].”

Reaching the ‘Point of Diminishing Returns’?

In an editorial accompanying the paper, John F. Keaney Jr., MD, of the University of Massachusetts Medical School (Worcester, MA), says the new data “prompt speculation as to whether dual platelet inhibition with high-potency agents is approaching the point of diminishing returns,” pointing to the balance between a reduction in ischemic events and an increase in major bleeding.

“Granted, one could argue that major bleeding events do not have the same effect on patients as ischemic cardiovascular events,” he writes. “Nevertheless, the patient population studied … was at particularly high risk for ischemic events (eg, diabetes, renal disease, multivessel disease, and recurrent myocardial infarction) and had had no recent bleeding episodes or indication for anticoagulation.

“Thus, not all patients who have a myocardial infarction will fit these same criteria and, as a consequence, may not be appropriate candidates for long-term treatment with ticagrelor,” he continues. “Patients without high-risk features for ischemia, or with higher bleeding risks, will probably not realize as much net benefit as those included in the study….”

 

 

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Sources:
1. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;Epub ahead of print.
2. Keaney JF. Balancing the risks and benefits of dual platelet inhibition [editorial]. N Engl J Med. 2015;Epub ahead of print.

 

Disclosures:

 

• The trial was funded by AstraZeneca.
• Dr. Sabatine reports receiving grant support from AstraZeneca during the conduct of the study, and grant support and personal fees from multiple pharmaceutical companies. In addition, he reports having pending patents related to the results of this study.
• Dr. Harrington reports relationships with multiple pharmaceutical and device companies.
• Dr. Fuster reports no relevant conflicts of interest.
• Dr. Keaney reports being an associate editor of the New England Journal of Medicine.

 

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