Dyspnea, Minor Bleeds Led Causes for Stopping Ticagrelor in PEGASUS TIMI 54

Marlene Busko

November 17, 2015

ORLANDO, FL — One in five stable outpatients with a prior MI on dual antiplatelet therapy with aspirin and the nonthienopyridine P2Y12 inhibitor ticagrelor (Brilinta, AstraZeneca) to lower the risk of future ischemic events discontinued the drug due to adverse events—mainly "nonserious" (not TIMI minor or TIMI major) bleeding or dyspnea[1].

"Often in trials we categorize adverse events as nonserious or nonmajor, but these events can drive treatment adherence," said Dr Marc P Bonaca (Brigham and Women's Hospital, Boston, MA), presenting these drug-discontinuation findings from the PEGASUS TIMI 54 trial, in a press briefing at the American Heart Association (AHA) 2015 Scientific Sessions.

Patients stopped taking ticagrelor within 11 days if they were bothered by dyspnea and within 5 months if they were bothered by mild or moderate bleeding, he reported. However, patients who tolerated the drug for a year were much less likely to discontinue it in the next 2 years.

Moreover, the drug effectively lowered the overall risk of CVD death, MI, or stroke by about 20% during a median 33-month follow-up, and the benefit was greatest in patients who remained on the drug.

Dr Mark Bonaca

"As clinicians we shouldn't underestimate the impact on patients of nosebleeds and bruising . . . and we have to talk to patients about [adverse effects] vs the benefit and make sure they have both sides of the equation to decide if they are going to continue [on therapy]," he told heartwire from Medscape.

This study should reassure clinicians that tolerability improves in patients who have already been on ticagrelor a year after their MI, he said. It will provide more information for clinicians when they "have that conversation with the patient [about balancing] the efficacy and tolerability."

Dr Marco Costa (Case Western Reserve University School of Medicine, Cleveland, OH), who discussed the paper on behalf of his colleague Dr Daniel Simon (Case Western Reserve University School of Medicine), who was unable to attend the meeting, said that the findings "made us realize that discontinuation and noncompliance of long-term dual antiplatelet therapy is real" and would be even higher outside a clinical trial. This trial provides important insights into this therapy discontinuation and raises questions for future research.

Why Such a High Rate of Drug Discontinuation?

As reported previously, PEGASUS TIMI 54 randomized 21,162 patients who had an MI within the past 1 to 3 years and were taking low-dose aspirin, to three treatment arms: 90-mg twice-daily (high-dose) ticagrelor, 60-mg twice-daily (low-dose) ticagrelor, or placebo. The patients were followed for a median of 33 months.

At study end, 32% and 29% of patients on high- and low-dose ticagrelor vs 21 % of patients on placebo had discontinued the drug (or placebo), mostly due to adverse events.

The current study aimed to look at the reasons, rates, and timing of ticagrelor discontinuation as well as the drug's efficacy in patients who continued on treatment.

In the first year, 16% of patients taking high-dose ticagrelor and 13% of patients taking low-dose ticagrelor vs 6% of patients taking placebo discontinued treatment.

In years 2 and 3, the rate of therapy discontinuation fell to 3.3%, 3.0%, and 2.3% per year, among patients taking high-dose ticagrelor, low-dose ticagrelor, or placebo, respectively.

In the first year, among patients taking the study drug, the main reasons for discontinuation were adverse events/serious adverse events (65%), followed by patient decisions (30%), administrative reasons (4%), and other reasons (1%). The percentages were similar in years 2 and 3.

"Nonserious" Bleeding and Dyspnea Drive Discontinuation

Drilling down revealed that the main adverse events leading to discontinuation of therapy were bleeding, closely followed by dyspnea, then other reasons, and less often, arrhythmia.

Among patients who received 90-mg twice-daily ticagrelor, 19% discontinued therapy due to an adverse event (bleeding in 7.8% of cases and dyspnea in 6.5% of cases). Similarly, among patients who received 60-mg twice-daily ticagrelor, 16.4% discontinued therapy due to an adverse event (bleeding in 6.2% of cases and dyspnea in 4.6% of cases).

Among patients who received placebo, 8.9% discontinued due to an adverse event (1.5% discontinued due to bleeding and 0.8% discontinued due to dyspnea).

Patients who discontinued therapy due to dyspnea did so very quickly (within 8 days and 11 days for high-dose or low-dose ticagrelor, respectively, vs 53 days for placebo).

Patients who discontinued therapy due to bleeding did so later on (within 56 days and 156 days for high-dose or low-dose ticagrelor, respectively, vs 344 days for placebo).

Although the cases of dyspnea were significant enough to prompt discontinuation, most cases were not serious (>95%), and most participants classified their bleeding as being mild to moderate (>80%). Similarly, most bleeds were classified as "needing medical attention," or less often, "minimal" bleeding.

At 3 years, among patients who did not discontinue the study drug, 6.6% of patients taking 90-mg twice-daily ticagrelor and 6.8% of patients taking 60-mg ticagrelor twice daily vs 8.4% of patients taking placebo had an MI or stroke or died from CVD (HR 0.79, 95% CI 0.70–0.88; P<0.001 for the pooled ticagrelor group vs placebo).

"There is no question that this medication has a positive effect on the primary end point and outcomes of CV death and MI and stroke," Costa said. And "obviously we are excited . . . about the ability to personalize dual antiplatelet therapy."

But the trial raises important questions, he continued. For example, why do people who aren't extremely bothered by side effects decide to stop taking a drug that improves survival? To reduce the risk of bleeding, should patients be on monotherapy with ticagrelor without aspirin? Would dyspnea be improved with a dose of ticagrelor below 60 mg?

The group is continuing this research and is working on a study looking at how caffeine might lower the rate of dyspnea with ticagrelor.

Bonaca is a member of the TIMI study group that receives research grant support from AstraZeneca and Merck. He is an advisory board consultant for AstraZeneca, Merck, Bayer, and Roche Diagnostics; disclosures for the coauthors are listed in the abstract. Costa received honoraria from Edwards Lifesciences, Medtronic, St Jude Medical, and Cardiokinetix. Simon receives grants and research support from the Medtronic Foundation and consulting fees/honoraria from Medtronic and HeartFlow; he is the owner and founder of and holds intellectual property rights for Sujana Biotech.


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