Caffeinated Beverage Intake, Dyspnea With Ticagrelor, and Cardiovascular Outcomes: Insights From the PEGASUS-TIMI 54 Trial

Abstract

Background A proposed cause of dyspnea induced by ticagrelor is an increase in adenosine blood levels. Because caffeine is an adenosine antagonist, it can potentially improve drug tolerability with regard to dyspnea. Furthermore, association between caffeine and cardiovascular events is of clinical interest. Methods and Results This prespecified analysis used data from the PEGASUS TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial, which randomized 21 162 patients with prior myocardial infarction to ticagrelor 60 mg or 90 mg or matching placebo (twice daily). Baseline caffeine intake in cups per week was prospectively collected for 9694 patients. Outcomes of interest included dyspnea, major adverse cardiovascular events (ie, the composite of cardiovascular death, myocardial infarction, or stroke), and arrhythmias. Dyspnea analyses considered the pooled ticagrelor group, whereas cardiovascular outcome analyses included patients from the 3 randomized arms. After adjustment, caffeine intake, compared with no intake, was not associated with lower rates of dyspnea in patients taking ticagrelor (adjusted hazard ratio (HR), 0.91; 95% CI, 0.76-1.10; P=0.34). There was no excess risk with caffeine for major adverse cardiovascular events (adjusted HR, 0.78; 95% CI, 0.63-0.98; P=0.031), sudden cardiac death (adjusted HR, 0.98; 95% CI, 0.57-1.70; P=0.95), or atrial fibrillation (adjusted odds ratio, 1.07; 95% CI, 0.56-2.04; P=0.84). Conclusions In patients taking ticagrelor for secondary prevention after myocardial infarction, caffeine intake at baseline was not associated with lower rates of dyspnea compared with no intake. Otherwise, caffeine appeared to be safe in this population, with no apparent increase in atherothrombotic events or clinically significant arrhythmias. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT01225562.

Keywords: arrhythmias; caffeine; cardiovascular outcomes; dyspnea; ticagrelor.

Figures

Figure 1. Median caffeinated beverages consumption in cups per week according to regions of the world.

Figure 2. Proportion of patients with dyspnea according to randomized groups.

P values are shown for comparison of proportions across the 3 groups for each adverse event.

Figure 3. Association between dyspnea and baseline caffeine intake in the pooled ticagrelor group (n=6363).

Adjusted for age, sex, race, body mass index, hypercholesterolemia, heart failure, diabetes mellitus, presence of multivessel coronary artery disease history of percutaneous coronary intervention, type of qualifying myocardial infarction (ST‐segment–elevation myocardial infarction vs non–ST‐segment–elevation myocardial infarction), glomerular filtration rate 2, smoking, region of the world, and use of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers at baseline. Adj HR indicates adjusted hazard ratio.

Figure 4. Association between major adverse cardiovascular events (MACE) and its components and baseline caffeine intake in the overall population (N=9694).

MACE was defined as the composite of cardiovascular (CV) death, myocardial infarction, or stroke. Adjusted for age, sex, race, body mass index, hypercholesterolemia, heart failure, diabetes mellitus, presence of multivessel coronary artery disease, history of percutaneous coronary intervention, type of qualifying myocardial infarction (ST‐segment–elevation myocardial infarction vs non–ST‐segment–elevation myocardial infarction), glomerular filtration rate <60 mL/min per 1.73 m2, smoking, region of the world, and use of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers at baseline. Adj HR indicates adjusted hazard ratio.

Figure 5. Association between clinically meaningful arrhythmias (reported as serious adverse events) and baseline caffeine intake in the overall population (N=9694).

Adjusted for age, sex, race, body mass index, hypercholesterolemia, heart failure, diabetes mellitus, presence of multivessel coronary artery disease, history of percutaneous coronary intervention, type of qualifying myocardial infarction (ST‐segment–elevation myocardial infarction vs non–ST‐segment–elevation myocardial infarction), glomerular filtration rate 2, smoking, region of the world, and use of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers at baseline. Adj HR indicates adjusted hazard ratio; and OR, odds ratio.

Figure 6. Hazards for dyspnea with ticagrelor vs placebo stratified by quartiles of caffeine intake.

HR indicates hazard ratio; and Q, quartile.