Ticagrelor Results Suggest Patients Decide What's a "Serious Event"

Results show that bleeding was the most common reason patients stopped taking the drug in this study of long-term tolerability.

New findings for long-term tolerability of ticagrelor, a dual antiplatelet therapy to treat acute coronary syndrome, show that how scientists define a “serious event” really doesn’t matter—ultimately, it’s the patients taking the drug who have the last word.

Results presented Tuesday at the American Heart Association Scientific Sessions in Orlando, Florida, showed that in a cohort followed for an average of 33 months, 32% of patients stopped taking a 90 mg dose of ticagrelor and 29% stopped a 60 mg dose, compared with 21% who stopped placebo. Both doses are given twice a day to patients who have had heart attacks to prevent a subsequent heart attack or stroke.1

In 11% of the cases, patients stopped taking the drug for personal choice or administrative reasons. Adverse events—bleeding and shortness of breath—accounted 19% of those who stopped taking the 90 mg dose and 16.4% of those who quit the 60 mg dose.

Most who did so stopped did so for what physicians would deem “non-serious” events (only 14% of the bleeds and only 12% of the shortness of breath cases were found to be severe). But as the study’s lead author and a commentator noted during a press conference ahead of Tuesdays’ presentation, what might not seem serious from a scientist’s point of view is still key to a patient.

Lead author Marc Bonaca, MD, of the TIMI Study Group at Brigham and Women’s Hospital said the fact that a sizable number of patients stopped taking the drug cannot be taken lightly, since the therapeutic benefits of ticagrelor are considerable. “Often in trials we categorize events as nonserious, but they have importance for patients,” he said.

Bonaca was the lead author of the major PEGASUS-TIMI study that was presented in March at the American College of Cardiology and simultaneously published in the New England of Medicine. Those results, which were presented by TIMI Study Group Chair and Brigham and Women’s senior physician Marc A. Sabatine, MD, MPH, found that long-term use of ticagrelor with aspirin reduced the likelihood of those who had suffered a heart attack from dying later of cardiovascular disease, another heart attack or stroke by 15% at the 90 mg dose and 16% at the 60 mg dose.2

There were questions about adverse events when those results were presented, but Sabatine made a distinction between major events, such as intracranial hemorrhage, and minor bleeding.

Patients, it turns out, may be less likely to make such distinctions. But Bonaca and Costa both found much to learn from the results.

Bonaca noted that when patients stopped taking the study drug, it tended to happen early on, and those taking the 90 mg dose quit earlier than those on the 60 mg dose. The average number of days to discontinuation due to bleeding was 56 for the 90 mg dose, 156 days for the 60 mg dose and 344 days on placebo.

Commenter Marco A. Costa, MD, PhD, MBA, professor of medicine at Case Western Reserve University, said there was plenty to learn from the results.

“If you have a bleed in your nose every morning, that’s serious,” he said. There might also be non-biological reasons for discontinuation, and it’s important for researchers to ask those questions.

Since there appears to be a relationship between the level of the dose and how many people quit the drug, Costa suggested there might be a lower dose that is optimal for long-term term use that might be more tolerable.

“These are good questions that a trial like this raises.”

Ticagrelor is marketed as Brilinta by Astra Zeneca.

References

1. Bonaca MP, Bhatt DL, Ophius TO, et al. Long-term tolerability of ticagrelor in the PEGASUS-TIMI 54 trial. Presented at the American Heart Association Scientific Sessions; Orlando, Florida; November 10, 2015; abstract 19689.

2. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction [published online March 14, 2015]. N Engl J Med. doi: 10.1056/MEJMoa500857.