Dyspnea With Ticagrelor Is "Common, But Mild and Self-Limiting"

July 08, 2010

July 8, 2010 (Sheffield, United Kingdom) — A new analysis looking at the incidence of dyspnea in a small study of the investigational antiplatelet agent ticagrelor (Brilanta, AstraZeneca) shows that although this is a relatively common side effect with the drug, it resolves quickly and does not appear to be associated with any serious cardiac or pulmonary sequelae [1].

Ticagrelor is one of the most eagerly anticipated new drugs for some time, with many predicting it will replace clopidogrel as the antiplatelet agent of choice. The impressive results of the phase 3 PLATO study with the drug were first reported last summer and showed that ticagrelor reduced the rate of MI/stroke/CV death in ACS patients, as compared with clopidogrel. Subset analyses of PLATO data also resurfaced in late-breaking clinical-trial sessions in at least two additional meetings. Ticagrelor is awaiting approval and is due to be discussed by the US FDA Cardiovascular and Renal Drugs Advisory Committee later this month, on July 28.

But there has been lingering concern about dyspnea with ticagrelor, which has occurred more frequently with the drug than in active comparison or placebo arms in clinical trials--in PLATO, for instance, 14.2% of patients on ticagrelor experienced dyspnea compared with 9.2% of those taking clopidogrel (p<0.001). Now scientists have taken a prospective look at this adverse effect and its consequences in ONSET/OFFSET, a small six-week trial looking at the pharmacokinetics of ticagrelor.

The report is published in the July 13, 2010 issue of the Journal of the American College of Cardiology.

Lead investigator of the new analysis, Dr Robert F Storey (University of Sheffield, UK), told heartwire : "The data we have from the ONSET/OFFSET study are reassuring; they show us that dyspnea is a common side effect of ticagrelor, and it's usually mild and often self-limiting, but if it persists then it seems to go away when the drug is stopped."

Pulmonary and left ventricular function was also prospectively studied in ONSET/OFFSET, and Storey said: "We didn't find any abnormality in pulmonary function or left ventricular function in any of the patients, including the cohort that developed dyspnea."

More Dyspnea With Ticagrelor in ONSET/OFFSET Than Prior Trials

The six-week ONSET/OFFSET study was first presented at the American Heart Association meeting last year and also published simultaneously in Circulation [2]. It showed a much more rapid and potent platelet inhibition with ticagrelor (180-mg loading dose, 90 mg twice daily, n=57) compared with clopidogrel (600 mg, then 75 mg per day, n=54) in 123 stable coronary disease patients, and the turning off, or "offset" effect, of ticagrelor was also significantly faster than that for clopidogrel. The study also randomized a few patients to placebo (n=12).

Of the 57 (38.6%) patients taking ticagrelor, 22 experienced dyspnea, compared with five taking clopidogrel and one in the placebo group. This is a higher incidence than reported in previous studies, say Storey et al, and "could be due to chance or could reflect the fact that both investigators and patients were informed of the potential occurrence of dyspnea and the reasons for the cardiac and pulmonary investigation, thus increasing their awareness of this symptom and the probability of recording it as a side effect."

Storey said dyspnea, if it was going to occur in the ticagrelor group, tended to manifest early, in the first week of treatment. And the pattern of dyspnea "varied widely, from brief episodes lasting minutes to sustained or intermittent episodes occurring over several weeks, with most episodes being reported as mild but some leading to discontinuation of study medication," he and his colleagues explain.

"Most people tolerate it; occasionally people need to discontinue ticagrelor because of [dyspnea]," Storey said. Of the 22 patients who developed dyspnea while taking ticagrelor, three patients had to discontinue the medication (5.3% of all those patients taking ticagrelor).

Most of the sustained episodes of dyspnea in the ticagrelor group resolved upon cessation of ticagrelor, and there was little difference between the two active-treatment groups in the proportions of patients who had persistent dyspnea despite discontinuation of the study medication. "These observations provide reassurance about the reversibility of ticagrelor-related dyspnea with decline in plasma levels of ticagrelor," he and his colleagues say.

No Cardiac or Pulmonary Sequelae; But Studies Needed in Lung Disease

Cardiac and pulmonary function were prospectively assessed in everybody in the study before treatment and again in everybody who remained in the study at the end, after six weeks of treatment; ad hoc additional measurements were also performed in those who developed dyspnea during the course of the study, Storey explained.

They found no significant differences in cardiac function--heart rate and electrical activity, BP, LV ejection fraction, and serum N-terminal pro-BNP--or pulmonary function--including markers for presence and severity of bronchoconstriction and interstitial lung disease--between the treatment groups, even among patients who had dyspnea after commencing ticagrelor.

"We didn't find any abnormality in pulmonary function or LV function in any of the patients, including the cohort who developed dyspnea, and so that confirmed what we believed from previous studies: there was no asthmatic response, there was no more sinister pulmonary disease arising as a result of this dyspnea, and no impact on LV function," Storey says. And there was no evidence that metabolic acidosis, a cause of dyspnea, was induced by ticagrelor, as judged by serum bicarbonate levels.

However, the authors note that the patients in ONSET/OFFSET were free of active lung disease at the start of the study; "further studies of ticagrelor in patients with active lung disease are now warranted," they note.

More Analysis of PLATO Data Required

The authors also say that further analysis of the PLATO study data is needed to explore what clinical factors may contribute to ticagrelor-related dyspnea.

And Storey told heartwire there will be more data presented at the European Society of Cardiology meeting in Stockholm in a couple of months "on the clinical outcomes in PLATO in those patients who did and did not develop dyspnea in the ticagrelor and clopidogrel groups, so there will be more data on any prognostic implications of dyspnea."

Storey has received honoraria, consultancy fees, and/or institutional research grants from AstraZeneca, Eli Lilly, Daiichi-Sankyo, Schering-Plough, the Medicines Company, Novartis, and Teva Pharmaceuticals. Disclosures for the coauthors are listed in the paper.