Adding a Second Bronchodilator in COPD: A Meta-Analysis on the Risk of Specific Cardiovascular Serious Adverse Events of Tiotropium/Olodaterol Fixed-Dose Combination

Dual bronchodilation therapy represents the cornerstone for the treatment of COPD. A large retrospective study reports that adding a second long-acting bronchodilator in patients with COPD significantly increases the risk of heart failure. Nevertheless, retrospective studies are characterized by limitations including misdiagnosis and inaccuracy of recordkeeping. This study aimed to ascertain whether tiotropium/olodaterol (T/O) 5/5 μg fixed-dose combination (FDC) may modulate the risk of main cardiovascular outcomes in COPD patients enrolled in randomized controlled trials (RCTs). A meta-analysis (CRD42017070100) was performed by selecting RCTs reporting raw data from the ClinicalTrials.gov database concerning the impact of T/O 5/5 µg FDC vs. monocomponents on the occurrence of specific cardiovascular serious adverse events: arrhythmia, heart failure, myocardial infarction, and stroke. Data were reported as relative risk and 95% Confidence Interval, and the risk of publication bias assessed via Egger's test. Eighty six full text articles were identified, and 10 RCTs published in 7 studies between 2015 and 2018 were included into the analysis. Data obtained from 12,690 COPD patients (44.47% T/O FDC, 55.53% monocomponents) were extracted. T/O 5/5 μg FDCs did not significantly modulate (p-value > 0.05) the risk of arrhythmia (1.02, 0.55 - 1.92), heart failure (0.88, 0.41 - 1.92), myocardial infarction (1.15, 0.70 - 1.87), and stroke (0.98, 0.44 - 2.16) vs. monocomponents. No significant publication bias affected the effect estimates of this meta-analysis. The results of this quantitative synthesis indicate that dual bronchodilation with T/O 5/5 μg FDC is characterized by an acceptable cardiovascular safety profile in COPD patients.