Use of ticagrelor ( Brilinta; AstraZeneca), an antiplatelet agent commonly associated with dyspnea, in patients with stable coronary artery disease (CAD) did not adversely affect either cardiac or pulmonary function, according to the ONSET/OFFSET trial published July 13 in the Journal of the American College of Cardiology.
Robert F. Storey, MD, of the University of Sheffield in Sheffield, England, and colleagues conducted the ONSET/OFFSET (A Multi-Centre Randomized, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of antiplatelet Effects of AZD60140 Compared with Clopidogrel and Placebo with Aspirin as Background Therapy in Patients with Stable Coronary Artery Disease) trial on 123 patients with stable CAD between Oct. 17, 2007, and March 5, 2009.
The authors selected patients who had stable CAD and were being treated with 75 to 100 mg of aspirin daily. Researchers then studied the onset and offset action of ticagrelor compared to clopidogrel (Plavix; Sanofi-Aventis/ Bristol-Myers Squibb) to uncover its effect on cardiac and pulmonary function.
To do so, the researchers split patients into three groups: 57 patients received a 180 mg load of ticagrelor and were administered 90 mg of the drug twice daily; 54 received a 600 mg of clopidogrel and an additional 75 mg daily; and 12 received a placebo. All patients were continued on aspirin during the trial.
While the researchers used the onset and offset of the antiplatelet effect of ticagrelor compared to clopidogrel as the primary outcome, they also documented and graded adverse effects as mild, moderate or severe. During the study, the researchers also collected serum samples and assessed plasma levels.
Results showed that incidence of dyspnea occurred at rates of 38.6, 9.3 and 8.3 percent in the ticagrelor, clopidogrel and placebo arms, respectively. Investigators at the various study sites estimated that 24.6, 3.7 and 0 percent of these rates were directly associated with the study drug.
The researchers found that there were no statistically significant changes in patients’ blood pressure, heart rates, ejection fractions or N-terminal pro-brain natriuretic peptide between baseline and week six of follow-up. Additionally, researchers found no significant events involving pulmonary parameters including ventilation and respiratory rate, spirometry, lung volume, lung diffusion capacity or blood oxygen saturation.
Dyspnea did not affect either cardiac or pulmonary measurements. “The reversible nature of ticagrelor-related dyspnea and the lack of any evidence of cardiac or pulmonary pathology associated with this provide reassurance about the nature of this side effect,” the authors wrote.
In addition, after looking at serum levels the researchers found no significant evidence of metabolic acidosis developing after drug treatment and no significant differences between either group regarding pharmacokinetic parameters at either drug onset of offset.
“Although the mechanism for the dyspnea is unproven, a number of observations support the hypothesis that adenosine may mediate it,” the authors wrote.
“Ticagrelor treatment was not associated with any adverse changes in cardiac or pulmonary function after six weeks of treatment in this study of patients who were free of active lung disease at commencement of the study, including patients who had dyspnea during therapy,” they concluded. “Further studies of ticagrelor in patients with active lung disease are now warranted.”