Temporal Risk of Nonfatal Cardiovascular Events After Chronic Obstructive Pulmonary Disease Exacerbation: A Population-based Study

Abstract

Rationale: Cardiovascular events after chronic obstructive pulmonary disease (COPD) exacerbations are recognized. Studies to date have been post hoc analyses of trials, did not differentiate exacerbation severity, included death in the cardiovascular outcome, or had insufficient power to explore individual outcomes temporally.Objectives: We explore temporal relationships between moderate and severe exacerbations and incident, nonfatal hospitalized cardiovascular events in a primary care-derived COPD cohort.Methods: We included people with COPD in England from 2014 to 2020, from the Clinical Practice Research Datalink Aurum primary care database. The index date was the date of first COPD exacerbation or, for those without exacerbations, date upon eligibility. We determined composite and individual cardiovascular events (acute coronary syndrome, arrhythmia, heart failure, ischemic stroke, and pulmonary hypertension) from linked hospital data. Adjusted Cox regression models were used to estimate average and time-stratified adjusted hazard ratios (aHRs).Measurements and Main Results: Among 213,466 patients, 146,448 (68.6%) had any exacerbation; 119,124 (55.8%) had moderate exacerbations, and 27,324 (12.8%) had severe exacerbations. A total of 40,773 cardiovascular events were recorded. There was an immediate period of cardiovascular relative rate after any exacerbation (1-14 d; aHR, 3.19 [95% confidence interval (CI), 2.71-3.76]), followed by progressively declining yet maintained effects, elevated after one year (aHR, 1.84 [95% CI, 1.78-1.91]). Hazard ratios were highest 1-14 days after severe exacerbations (aHR, 14.5 [95% CI, 12.2-17.3]) but highest 14-30 days after moderate exacerbations (aHR, 1.94 [95% CI, 1.63-2.31]). Cardiovascular outcomes with the greatest two-week effects after a severe exacerbation were arrhythmia (aHR, 12.7 [95% CI, 10.3-15.7]) and heart failure (aHR, 8.31 [95% CI, 6.79-10.2]).Conclusions: Cardiovascular events after moderate COPD exacerbations occur slightly later than after severe exacerbations; heightened relative rates remain beyond one year irrespective of severity. The period immediately after an exacerbation presents a critical opportunity for clinical intervention and treatment optimization to prevent future cardiovascular events.

Keywords: COPD; cardiovascular disease; electronic health records; epidemiology.

Figure 1.

Study timeline with exclusion criteria and periods of covariate measurement. *Upon index date: “acceptable” data quality; age 40 years; chronic obstructive pulmonary disease (COPD) diagnosis; former or current smoker; HES, Office for National Statistics, and Index of Multiple Deprivation (IMD) linkage eligibility; and continuous 1-year GP registration. ^†Two-year window covariates: Medical Research Council dyspnea score, Global Initiative for Chronic Obstructive Lung Disease grade, COPD and CV medications, venous thromboembolism, and chronic kidney disease. ^‡Other covariates defined as all time unless specified: age, sex, IMD, ethnicity, recent smoking history, body mass index (previous 5 yr), type 2 diabetes, current asthma (period of 3 years before a 2-year period before COPD diagnosis), depression or depressive symptoms, anxiety, and hypertension. ACS = acute coronary syndrome; CV = cardiovascular; GP = general practitioner; HES = Hospital Episode Statistics; HF = heart failure; PH = pulmonary hypertension.

Figure 2.

(A and B) Cumulative incidence for composite cardiovascular events for the chronic obstructive pulmonary disease population for exacerbation dichotomized (A) and stratified by severity (B). (A) Moderate or severe exacerbation: unadjusted hazard ratio (HR), 2.36 (95% confidence interval [CI], 2.30–2.42); adjusted HR, 1.84 (95% CI, 1.79–1.90). (B) Moderate exacerbation: unadjusted HR, 2.11 (95% CI, 2.06–2.17); adjusted HR, 1.67 (95% CI, 1.62–1.72). Severe exacerbation: unadjusted HR, 4.07 (95% CI, 3.94–4.21); adjusted HR, 3.18 (95% CI, 3.06–3.29). See Figures E2A and E2B for any exacerbation and exacerbation by severity, respectively, for identical but subset plots focusing on the first 100 days of follow-up to illustrate cumulative incidence in the immediate exacerbation aftermath. AECOPD = acute exacerbation of chronic obstructive pulmonary disease.

Figure 3.

Forest plot illustrating the association between exacerbation and composite cardiovascular event, overall and by prespecified subperiod of clinical interest. N refers to the number of patients at risk in the respective period (i.e., the denominator). Events (i.e., the numerator) are available in Tables E2.1–E2.3. *The reference estimate representing patients without exacerbations for overall and subperiod effect estimates is an HR of 1.00 regardless of time strata. **Adjusted for all core set covariates. adj. = adjusted; CI = confidence interval; CVD = cardiovascular disease; HR = hazard ratio; unadj. = unadjusted.

Figure 4.

Forest plot illustrating the association between exacerbation by severity and composite cardiovascular event, overall and by prespecified subperiod of clinical interest. N refers to the number of patients at risk in the respective period (i.e., the denominator). Events (i.e., the numerator) are available in Tables E2.1–E2.3. *Reference estimate representing patients without exacerbations for overall and subperiod effect estimates is an HR of 1.00 regardless of time strata. **Adjusted for all core set covariates. For definition of abbreviations, see Figure 3.

Figure 5.

Forest plot illustrating the association between exacerbation by each secondary cardiovascular endpoint, overall and by prespecified subperiod of clinical interest. N refers to the number of patients at risk in the respective period (i.e., the denominator). Events (i.e., the numerator) are available in Appendix E9 tables. *Reference estimate representing patients without exacerbations for overall and subperiod effect estimates is an HR of 1.00 regardless of time strata. **Adjusted for all core set covariates. ACS = acute coronary syndrome; adj. = adjusted; CI = confidence interval; CVD = cardiovascular disease; HR = hazard ratio; PH = pulmonary hypertension; unadj. = unadjusted.