Ticagrelor Discontinued by Many Patients Who Are Stable After MI: PEGASUS

Pam Harrison

June 21, 2016

CHICAGO, IL — Stable patients with a history of MI are significantly more likely to stop taking ticagrelor (Brilinta, AstraZeneca) of their dual antiplatelet therapy, usually soon after they start the treatment and most often due to "nonserious" bleeding or mild to moderate dyspnea, suggests an analysis based on patients in the PEGASUS-TIMI 54 trial[1].

"The tolerability of long-term antithrombotic therapy in stable populations may have an important effect on treatment adherence," write the authors, led by Dr Marc Bonaca (Brigham and Women's Hospital, Boston, MA). "The results of our analyses underscore that the adverse effects of a drug, in this case dyspnea and bleeding, regardless of their clinical severity, transience, or long-term implications, can have an immediate effect on quality of life and compliance."

Platelet inhibition with ticagrelor in unselected coronary artery disease patients is indeed associated with an increased risk of bleeding as well as the ticagrelor-specific side effect of dyspnea, and both can be expected to lead to premature discontinuation of treatment, said Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden) to heartwire from Medscape in an email.

"The protective effects of ticagrelor will therefore be attenuated in real life because of treatment cessations," said Wallentin, who was not part of the PEGASUS report, which was published June 15, 2016 in JAMA Cardiology, following the analysis' preliminary presentation at the American Heart Association 2015 Scientific Sessions.

PEGASUS-TIMI 54 randomized 21,162 patients with a history of MI and one additional high-risk feature to either 90 mg or 60 mg ticagrelor, both given twice a day, or placebo a median of 1.7 years following their acute MI. All patients received aspirin at a dose of between 75 to 150 mg a day.

At a median follow-up of 33 months, 27.4% of patients overall had discontinued ticagrelor; that combined a 21% discontinuation rate for patients on placebo but a rate of almost one-third of those in the 90-mg arm and 29% of those in the 60-mg arm (P<0.001 for both ticagrelor findings vs placebo).

"This difference was most marked in the first year after randomization and particularly in the first 90 days, with discontinuation rates at 1 year of 24.1%, 19.8%, and 12.1% in the 90-mg, 60-mg, and placebo arms, respectively," the group writes.

Patients who received 90 mg of ticagrelor twice a day were twice as likely to stop treatment during the first year and 12% more likely to stop treatment in the remaining years of the trial compared with placebo patients. The corresponding discontinuation rates for those who received 60 mg of ticagrelor were 59% and 18%, respectively.

However, for patients who tolerated ticagrelor for the first year, subsequent discontinuation rates in the second and third year were much lower and not significantly different between the three treatment arms at 7.2%, 7.5%, and 6.4% for the 90 mg, 60 mg, and placebo arms, respectively.

Effect of Adverse Events on Adherence

Discontinuation rates due to adverse events (AEs) were highest at 19% in the 90-mg arm but were almost as high at 16% for the lower, 60-mg group. Both of these rates were significantly higher than for placebo patients at 9% (P<0.001 for each dose of ticagrelor compared with placebo).

On the other hand, for patients who tolerated ticagrelor for the first year, subsequent discontinuation rates due to an AE were again much lower and not significantly different between the three treatment arms at 3.4%, 3.7%, and 2.6% for the 90 mg, 60 mg, and placebo arms, respectively.

The median time to discontinuation due to an AE was 55 days for the 90-mg dose group, compared with 103 days for those in the 60-mg dose group and 189 days for placebo. The majority of adverse events leading to discontinuation of treatment were nonserious.

Adverse Events Leading to Discontinuation in PEGASUS-TIMI 54

Outcome Ticagrelor 90-mg twice daily (%) Ticagrelor 60 mg twice daily (%) Placebo P
Nonserious AEs 80 76 63 NS
Bleeding 7.8 6.2 1.5 <0.001
Dyspnea 6.5 4.6 0.8 <0.001

That even "nonserious" AEs prompted such high discontinuation rates in PEGASUS-TIMI 54 was supported by the fact that adherence to ticagrelor was lower than it was for placebo, according to the authors. "This difference in adherence is most likely explained by tolerability," they suggest, "and highlight that patients may make decisions about treatment without telling their physician or acknowledging adverse events."

The fact that ticagrelor reduced the risk of cardiovascular death, MI, or stroke by about 15% "underscores the need for patient counseling when initiating treatment with ticagrelor to optimize shared decision making and, when appropriate, maximize adherence and improve clinical efficacy," the group concludes.

Clinical Trials vs Clinical Practice

In an accompanying editorial[2], Dr Christopher Granger (Duke University, Durham, NC) and Dr Peter Berger (Northwell Health, Great Neck, NY) point out that dyspnea is a well-documented side effect of ticagrelor and is "quickly reversible" once treatment is discontinued.

"It does, however, require a thorough conversation, because the patient and other healthcare professionals must be aware that the development of dyspnea ought not to lead to anxiety, cessation of therapy without initiation of another P2Y12 inhibitor, or an expensive evaluation of patients," they write.

As defined by PEGASUS-TIMI 54 investigators, bleeding was considered minor when hemoglobin dropped by less than 5 g/dL. However, as Granger and Berger suggest, "this definition may not be minor from a patient's perspective, especially since it was troublesome enough to lead the patient to stop a potentially lifesaving therapy."

The editorialists also point out that adherence in clinical trials and adherence in clinical practice are often hugely discrepant, adherence in clinical trials usually being much higher.

"The high frequency with which ticagrelor was discontinued in the PEGASUS-TIMI 54 trial may have been even higher if ticagrelor had been administered to patients who were similar to those found in routine clinical practice," they propose, "emphasizing the importance of taking steps to promote adherence."

The fact that slightly fewer patients discontinued ticagrelor when treated with the lower 60-mg twice-daily dose supports the use of the lower dose if the drug is used long term, they add.

Future Implications

According to Wallentin, the analysis confirms that adding ticagrelor to aspirin rather than placebo lowers the risk of CV death, MI, and stroke over the long term to a clinically relevant degree but also suggests that "even [the] moderately severe side effects of bleeding and dyspnea will be associated with increased healthcare costs related to outpatient visits and additional investigations."

To offset this additional cost, Wallentin said there is a need to develop decision support tools so as to better assess a patient's risk of having a further ischemic event along with their bleeding risk and to answer whether long-term antithrombotic therapy is appropriate for that particular patient.

"In addition, prospective studies of secondary-prevention strategies based on risk-stratification tools and also including the option to include platelet inhibitors without the risk of dyspnea are warranted," Wallentin added.

Bonaca reports receiving consulting fees from AstraZeneca, Merck, Bayer, and Roche Diagnostics. Granger reports receiving grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly during the conduct of the study and grants from Armetheon and the Medtronic Foundation. He has also received grants and personal fees from Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceuticals, the Medicines Company, Novartis, Pfizer, Sanofi, and Takeda and personal fees from Gilead, Hoffmann–La Roche, and Medtronic. Disclosures for the coauthors are listed in the article. Berger reports that, in the past 3 years, he has been the principal investigator of studies for which Northwell Health has received funding from AstraZeneca, the Medicines Company, Bristol-Myers Squibb, Sanofi, and Lilly/ Daiichi Sankyo. Wallentin reports having received institutional research grants from AstraZeneca, Bristol-Myers Squibb, MS Pharma, Boehringer-Ingelheim, GlaxoSmithKline, Pfizer, and Roche Diagnostics.

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