Time-Dependent Risk of Cardiovascular Events Following an Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Post Hoc Analysis From the IMPACT Trial

Abstract

Background The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08-3.32]) or severe (HR, 21.84 [95% CI, 17.71-26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28-2.08]; severe: HR, 1.75 [95% CI, 0.99-3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53-3.97]; severe: HR, 41.29 [95% CI, 30.43-56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://ichgcp.net/clinical-trials-registry/NCT02164513; Unique identifier: NCT02164513.

Keywords: LAMA/LABA; cardiovascular disease; chronic obstructive pulmonary disease; exacerbations; triple therapy.

Figures

Figure 1. Graphic representation of analysis of order of exacerbation and CVAESIs.

Black bars start at study randomization for all patients and indicate exacerbation‐free on study treatment periods. Blue arrows indicate exacerbation start and end dates. Purple bars indicate exacerbation duration. Blue, green, and yellow bars indicate fixed‐length postexacerbation risk periods of 1 to 30 days, 31 to 90 days, and 91 days to 1 year after exacerbation, respectively. Red stars indicate cardiovascular events, no further risk periods are applicable after a cardiovascular event. The representations depict scenarios of event patterns in this analysis. (1) No exacerbation and no cardiovascular event; (2) no exacerbation, but cardiovascular event in exacerbation‐free period; (3) exacerbation (start and end date indicated with blue arrows) with cardiovascular event in the fixed‐length postexacerbation risk period; (4) exacerbation with cardiovascular event during exacerbation period; and (5) multiple exacerbations with no cardiovascular event – the fixed‐length postexacerbation events are reset following each exacerbation. CVAESI indicates cardiovascular adverse events of special interest.

Figure 2. Risk of a first cardiovascular event during and following a moderate exacerbation (primary analysis method) ***P<0.001; **P<0.01 versus exacerbation‐free period.

The hazard for a CVAESI was compared assuming that for exacerbations and CVAESIs that occurred on the same day, the exacerbation occurred first. Serious CVAESI are CVAESI resulting in or prolonging hospitalization or resulting in death. CVAESI indicates cardiovascular adverse events of special interest.

Figure 3. Risk of a first cardiovascular event during and following a severe exacerbation (primary analysis method) ***P<0.001 versus exacerbation‐free period.

The hazard for a CVAESI was compared assuming that for exacerbations and CVAESIs that occurred on the same day, the exacerbation occurred first. Serious CVAESI are CVAESI resulting in or prolonging hospitalization or resulting in death. CVAESI indicates cardiovascular adverse events of special interest.