Incidence of Dyspnea and Assessment of Cardiac and Pulmonary Function in Patients With Stable Coronary Artery Disease Receiving Ticagrelor, Clopidogrel, or Placebo in the ONSET/OFFSET Study
Key result
Ticagrelor increases dyspnea to ~39% without causing cardiac or pulmonary dysfunction.
- P<0.001
- n=123
Why the study?
Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function in stable CAD patients.
Does ticagrelor cause adverse changes in cardiac or pulmonary function in patients with stable CAD who develop dyspnea?
Key Points
- To evaluate whether ticagrelor-induced dyspnea is associated with adverse changes in cardiac or pulmonary function in patients with stable coronary artery disease.
- A multicenter, randomized, double-blind, double-dummy trial (ONSET/OFFSET; NCT00528411) evaluating 123 stable aspirin-treated CAD patients assigned to ticagrelor (180 mg loading dose, then 90 mg twice daily; n=57), clopidogrel (600 mg loading dose, then 75 mg daily; n=54), or placebo (n=12) for 6 weeks.
- Electrocardiography, echocardiography, serum NT-proBNP, and pulmonary function tests were measured at baseline, at 6 weeks, and/or upon dyspnea onset.
- Dyspnea occurred in 38.6% of ticagrelor, 9.3% of clopidogrel, and 8.3% of placebo patients (p<0.001); most episodes were mild, lasted <24 hours, and began within 1 week of therapy initiation.
- No significant changes in cardiac or pulmonary function parameters occurred from baseline to 6 weeks across any treatment group or among ticagrelor-treated patients experiencing dyspnea.
Study Design
Type
RCT (n=123)
Blinding
Double-blind, double-dummy
Randomization
Parallel group
Multicenter
Yes
Structured PICO
Does ticagrelor cause adverse changes in cardiac or pulmonary function in patients with stable CAD who develop dyspnea?
P
Population
123 stable aspirin-treated patients with coronary artery disease randomized to ticagrelor, clopidogrel, or placebo for 6 weeks.
I
Intervention
Ticagrelor (180 mg load, then 90 mg twice daily) added to aspirin background therapy for 6 weeks
C
Comparator
Clopidogrel (600 mg load, then 75 mg daily) or placebo, added to aspirin background therapy for 6 weeks
O
Outcome
Changes in cardiac or pulmonary function parameters (electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests) between baseline and 6 weeks or after development of dyspneasafety
Main Result
Absolute Event Rate: 38.6% vs 9.3%
p-value: p=<0.001
Ticagrelor-associated dyspnea is common in stable CAD patients but is not associated with adverse changes in cardiac or pulmonary function.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“Pointing to a lack of discontinuance of drug doesn't make me feel any more confident when the dyspneic patient is sitting in front of me in the exam room.”
EREric R. BatesCardiologist, University of Michigan Medical Center
“But the clinical benefit in the trial was [late not early]. You're given this drug constantly and the dyspnea goes away, then the mortality benefit comes on later.”
Implication
Ticagrelor may be continued despite dyspnea in stable CAD; this RCT confirms no associated cardiac or pulmonary dysfunction.
Abstract
OBJECTIVES We prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study. BACKGROUND Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function. METHODS In all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n=57), clopidogrel (600 mg load, then 75 mg daily; n=54), or placebo (n=12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea. RESULTS After drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p<0.001). Most instances were mild and/or lasted<24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters. CONCLUSIONS Dyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411).
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Cite This Study
Storey et al. (2010) conducted an RCT in Stable coronary artery disease (n=123). Ticagrelor vs. Clopidogrel or placebo was evaluated on Incidence of dyspnea (p=<0.001). Ticagrelor therapy resulted in a higher incidence of dyspnea compared to clopidogrel and placebo (38.6% vs 9.3% and 8.3%, p<0.001), without adverse changes in cardiac or pulmonary function.