Non-Severe Adverse Events With Ticagrelor Led to Premature Discontinuation in Patients With Previous Myocardial Infarction

ORLANDO, Fla. — In stable patients with prior myocardial infarction (MI), premature discontinuation of ticagrelor was primarily due to non-severe adverse events that occurred early after randomization, according to data from a PEGASUS-TIMI 54 trial substudy.

In the PEGASUS-TIMI 54 trial, Marc P. Bonaca, MD, of the Brigham and Women’s Hospital in Boston, and colleagues observed a 15% to 16% reduction in cardiovascular death, MI, or stroke in patients with prior MI who were treated with ticagrelor (AstraZenca, Wilmington, DE) compared with placebo, although the ticagrelor group had a higher rate of premature discontinuation.

The latter finding led Dr Bonaca and colleagues to conduct the present substudy, which examined rates of and reasons for drug discontinuation.

“The hypothesis was that in this population, treatment discontinuation overall [and] due to adverse events would be higher early after initiation and would be low in patients who had tolerated therapy for at least 1 year,” said Dr Bonaca  during a press conference at the American Heart Association Scientific Sessions, adding that they also wanted to explore the efficacy of ticagrelor to see whether it was robust in patients who remained on therapy.

During the trial (median, 33 months), drug discontinuation was reported in 32% of patients who received ticagrelor 90 mg, 29% of patients who received ticagrelor 60 mg, and 21% of patents in the placebo group (P<.001).

In each arm, between 10% and 11% of patients discontinued the study drug because of patient decision or administrative reason. However, rate of adverse events leading to discontinuation was 8.9% in the placebo arm compared with 19% in the ticagrelor 90 mg arm (P<.001) and 16.4% in the ticagrelor 60 mg arm (P<.001), with bleeding and dyspnea being the most common adverse events that led to discontinuation.

Among ticagrelor-treated patients, 14% of bleeds were major and 12% of dyspnea cases were severe.

After the first year, adverse events leading to drug discontinuation and the differences between groups were greatly attenuated, according to the researchers.

In addition, ticagrelor significantly decreased the 3-year risk for cardiovascular death, MI, or stroke at both 60-mg (hazard ratio [HR]=0.79; 95% confidence interval [CI], 0.68 to0.91; P<.001) and 90-mg (HR=0.78; 95% CI, 0.68 to0.90; P<.001) doses compared with placebo.

“Overall discontinuation of newly started ticagrelor was driven by adverse events … and the [adverse event] rates after 1 year in those who tolerated therapy were generally low,” Bonaca said. “The ischemic risk reduction was robust for patients who tolerated [ticagrelor] therapy.”

Bonaca added that often in trials, investigators categorize adverse events as non-serious or non-major; however, these events have a significant impact on patients.

“Bruising and epistaxis can drive treatment adherence and it’s important for us to recognize that,” he said. “We need to counsel patients in terms of adherence with antithrombotic therapies.”

Disclosures: Dr Bonaca has received research grant support from AstraZeneca and Merck, and serves as a consultant for/on the advisory board of AstraZeneca, Bayer, Merck and Roche Diagnostics.

References

1. Bonaca MP et al. LBCT.06. ACS and PCI: The Continuum of Care. Long-Term Tolerability of Ticagrelor for Secondary Prevention: Insights from PEGASUS-TIMI 54 Trial. Presented at: American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.

2. Bonaca MP, Bhatt DL, Cohen M, et al; for the PEGASUS-TIMI 54 Steering Committee and Investigators. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. New Engl J Med. 2015;372(19):1791-1800. DOI:10.1056/NEJMoa1500857.