Most Drug Discontinuations in PEGASUS-TIMI 54 Related to Dyspnea, Bleeding

ORLANDO, FL—The higher rate of premature discontinuation of ticagrelor vs placebo in the PEGASUS-TIMI 54 trial of stable outpatients with prior MI is attributed largely to more frequent dyspnea and bleeding, a new study shows.

Implications:  	 Most Drug Discontinuations in PEGASUS-TIMI 54 Related to Dyspnea, Bleeding

Even so, dyspnea was considered non-serious in more than 95% of cases and rated as mild-to-moderate in intensity by more than 80% of affected patients. Bleeds were generally mild or required medical attention without rising to the threshold for TIMI minor or major bleeding, Marc Bonaca, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), reported here at the American Heart Association 2015 Scientific Sessions.

Among patients who tolerated therapy for the first year, rates of discontinuation related to adverse events were relatively low at about 3% per year going forward. Moreover, an on-treatment analysis showed that both the 90-mg and 60-mg twice-daily doses of ticagrelor (Brilinta; AstraZeneca) reduced the risk of cardiovascular death, MI, or stroke (primary composite endpoint) by a relative 20% through 3 years of follow-up, a slightly larger magnitude of benefit compared with the intention-to-treat analysis from the main trial results.

“Non-serious bleeding and other adverse events have very important consequences, including discontinuation of therapy,” Bonaca said. “And these data underscore the need for patient counseling when initiating antithrombotic therapies in order to maximize adherence and improve outcomes.”

The researchers took a closer look at treatment discontinuations in the trial, which included 21,162 patients who were stable 1 to 3 years after an MI. All received low-dose aspirin in addition to their assigned study drug or placebo. Overall, premature discontinuation at 3 years was higher with the 90-mg and 60-mg bid doses of ticagrelor (32% and 29%, respectively) than with placebo (21%). Most stoppages were due to adverse events.

In the first year, 1,669 and 1,367 patients discontinued treatment for any reason in the 90-mg and 60-mg bid ticagrelor groups compared with 908 in the placebo group. Those numbers fell considerably in the second and third years, when 564 and 632 patients dropped out in the 2 ticagrelor groups and 588 stopped treatment in the placebo group. Still, the risks of discontinuation remained higher with ticagrelor.

When looking specifically at drug discontinuation due to adverse events, rates for the higher and lower doses of ticagrelor were elevated compared with placebo in the first year (16% and 13% vs 6%). Rates remained higher with ticagrelor in the second and third years among patients who tolerated the first year of treatment, but the disparity was much smaller (6.5% and 6.0% vs 4.5%; P < .01 for all comparisons with placebo).

Much of the difference in adverse event-related discontinuations was the result of higher rates of dyspnea and bleeding with ticagrelor. At 3 years, dyspnea rates were 6.5%, 4.6%, and 0.8% and bleeding rates were 7.8%, 6.2%, and 1.5% in the 90-mg bid ticagrelor, 60-mg bid ticagrelor, and placebo groups, respectively. Other adverse events were relatively balanced across the 3 arms of the trial.

Stoppages for both dyspnea and bleeding tended to occur shortly after the initiation of ticagrelor, with substantially longer times to discontinuation in the placebo group.

Call for Personalized Therapy

In a commentary following Bonaca’s presentation, Marco Costa, MD, PhD, of University Hospitals Case Medical Center (Cleveland, OH), said that the findings of the analysis “made us realize that discontinuation and noncompliance to dual antiplatelet therapy in the long term is actually real.” He added that discontinuation is probably higher outside of the carefully controlled clinical trial setting.

The study “points us toward the need for more personalized dual antiplatelet therapy for our patients that [accounts for] the risk of bleeding, the benefits of ischemia prevention, and also balances the needs of our patients and providers,” he said.

Costa noted that an important finding from the analysis is that more than one-third of discontinuations were not related to a biological event. The other reasons for stopping therapy are incompletely understood, he said, highlighting the discrepancy between the major advances made in drugs and devices and the little progress that has been made in understanding human behavior and why patients choose to stop taking a therapy with proven benefits.

Bonaca MP, Bhatt DL, Ophuis TO, et al. Long-term tolerability of ticagrelor for secondary prevention: insights from PEGASUS-TIMI 54 trial. Presented at: American Heart Association Scientific Sessions; November 10, 2015; Orlando, FL.

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  • PEGASUS-TIMI 54 was funded through a research grant to Brigham and Women’s Hospital.
  • Bonaca reports serving as a consultant for AstraZeneca, Bayer, Merck, and Roche Diagnostics.
  • Costa reports receiving honoraria from CardioKinetix, Edwards Lifesciences, Medtronic, and St. Jude Medical.

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