Long-term cardiovascular outcomes of COVID-19

Abstract

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

Fig. 1. Flowchart of cohort construction.

Cohort construction for COVID-19 group (blue), contemporary control group (yellow) and historical control group (orange). Comparisons between groups are presented in green.

Fig. 2. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes compared with the contemporary control cohort.

Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. COVID-19 cohort (n = 153,760) and contemporary control cohort (n = 5,637,647). Adjusted HRs and 95% CIs are presented. The length of the bar represents the excess burden per 1,000 persons at 12 months, and associated 95% CIs are also shown.

Fig. 3. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes compared with the contemporary control cohort.

Composite outcomes consisted of cerebrovascular disorders (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias and atrial flutter), inflammatory heart disease (pericarditis and myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis and superficial vein thrombosis), MACE (all-cause mortality, stroke and myocardial infarction) and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. COVID-19 cohort (n = 153,760) and contemporary control cohort (n = 5,637,647). Adjusted HRs and 95% CIs are presented. The length of the bar represents the excess burden per 1,000 persons at 12 months, and associated 95% CIs are also shown.

Fig. 4. Subgroup analyses of the risks of incident post-acute COVID-19 composite cardiovascular outcomes compared with the contemporary control cohort.

Composite outcomes consisted of cerebrovascular disorders (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias and atrial flutter), inflammatory heart disease (pericarditis and myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis and superficial vein thrombosis), MACE (all-cause mortality, stroke and myocardial infarction) and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. COVID-19 cohort (n = 153,760) and contemporary control cohort (n = 5,637,647). Adjusted HRs and 95% CIs are presented.

Fig. 5. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes compared with the contemporary control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising non-hospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 d) of COVID-19 (blue). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. The contemporary control cohort served as the referent category. Within the COVID-19 cohort, non-hospitalized (n = 131,612), hospitalized (n = 16,760), admitted to intensive care (n = 5,388) and contemporary control cohort (n = 5,637,647). Adjusted HRs and 95% CIs are presented. The length of the bar represents the excess burden per 1,000 persons at 12 months, and related 95% CIs were also presented.

Fig. 6. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes compared with the contemporary control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising non-hospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 d) of COVID-19 (blue). Composite outcomes consisted of cerebrovascular disorders (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias and atrial flutter), inflammatory heart disease (pericarditis and myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis and superficial vein thrombosis), MACE (all-cause mortality, stroke and myocardial infarction) and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. The contemporary control cohort served as the referent category. Within the COVID-19 cohort, non-hospitalized (n = 131,612), hospitalized (n = 16,760), admitted to intensive care (n = 5,388) and contemporary control cohort (n = 5,637,647). Adjusted HRs and 95% CIs are presented. The length of the bar represents the excess burden per 1,000 persons at 12 months, and related 95% CIs were also presented.

Extended Data Fig. 1. Standardized mean difference of predefined and algorithmically selected high dimensional variables.

a. between COVID-19 and contemporary control cohorts; b. between COVID-19 categorized by care setting of the acute infection (non-hospitalized, hospitalized, and admitted to intensive care) and contemporary control cohorts; c. between COVID-19 and historical control cohorts; d. between COVID-19 categorized by care setting of the acute infection (non-hospitalized, hospitalized, and admitted to intensive care) and historical control cohorts. Standardized difference less than 0.15 is considered good balance.

Extended Data Fig. 2. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes in participants without any history of cardiovascular outcomes prior to COVID-19 exposure compared to the contemporary control cohort.

Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort without any history of cardiovascular outcomes (N = 126,575) and contemporary control cohort without any history of cardiovascular outcomes (N = 5,010,542). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. TIA, transient ischemic attack.

Extended Data Fig. 3. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes in participants without any history of cardiovascular outcomes prior to COVID-19 exposure compared to the contemporary control cohort.

Composite outcomes consisted of cerebrovascular (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias, and atrial flutter), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy, and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis, and superficial vein thrombosis), MACE (all-cause mortality, stroke, and myocardial infarction), and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort without any history of cardiovascular outcomes (N = 126,575) and contemporary control cohort without any history of cardiovascular outcomes (N = 5,010,542). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. MACE, major adverse cardiac events; TIA, transient ischemic attack.

Extended Data Fig. 4. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes compared to the historical control cohort.

Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort (N = 153,760) and historical control cohort (N = 5,859,411). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. TIA, transient ischemic attack.

Extended Data Fig. 5. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes compared to the historical control cohort.

Composite outcomes consisted of cerebrovascular (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias, and atrial flutter), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy, and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis, and superficial vein thrombosis), MACE (all-cause mortality, stroke, and myocardial infarction), and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort (N = 153,760) and historical control cohort (N = 5,859,411). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. MACE, major adverse cardiac events; TIA, transient ischemic attack.

Extended Data Fig. 6. Subgroup analyses of the risks of incident post-acute COVID-19 composite cardiovascular outcomes compared to the historical control cohort.

Composite outcomes consisted of cerebrovascular (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias, and atrial flutter), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy, and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis, and superficial vein thrombosis), MACE (all-cause mortality, stroke, and myocardial infarction), and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort (N = 153,760) and historical control cohort (N = 5,859,411). Adjusted hazard ratios and 95% confidence intervals are presented. MACE, major adverse cardiac events; TIA, transient ischemic attack.

Extended Data Fig. 7. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes in participants without any history of cardiovascular outcomes prior to COVID-19 exposure compared to the historical control cohort.

Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort without any history of cardiovascular outcomes (N = 126,575) and historical control cohort without any history of cardiovascular outcomes (N = 5,188,992). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. TIA, transient ischemic attack.

Extended Data Fig. 8. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes in participants without any history of cardiovascular outcomes prior to COVID-19 exposure compared to the historical control cohort.

Composite outcomes consisted of cerebrovascular (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias, and atrial flutter), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy, and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis, and superficial vein thrombosis), MACE (all-cause mortality, stroke, and myocardial infarction), and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. COVID-19 cohort without any history of cardiovascular outcomes (N = 126,575) and historical control cohort without any history of cardiovascular outcomes (N = 5,188,992). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and associated 95% confidence intervals are also shown. MACE, major adverse cardiac events; TIA, transient ischemic attack.

Extended Data Fig. 9. Risks and 12-month burdens of incident post-acute COVID-19 cardiovascular outcomes compared to the historical control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising non-hospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange), and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 days) of COVID-19 (blue). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. The historical control cohort served as the referent category. Within the COVID-19 cohort, non-hospitalized (N = 131,612), hospitalized (N = 16,760); admitted to intensive care (N = 5,388); and historical control cohort (N = 5,859,411). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and related 95% confidence intervals were also presented. TIA, transient ischemic attack.

Extended Data Fig. 10. Risks and 12-month burdens of incident post-acute COVID-19 composite cardiovascular outcomes compared to the historical control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising non-hospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange), and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 days) of COVID-19 (blue). Composite outcomes consisted of cerebrovascular (stroke and TIA), dysrhythmias (atrial fibrillation, sinus tachycardia, sinus bradycardia, ventricular arrhythmias, and atrial flutter), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease (acute coronary disease, myocardial infarction, ischemic cardiomyopathy, and angina), other cardiac disorders (heart failure, non-ischemic cardiomyopathy, cardiac arrest, and cardiogenic shock), thrombotic disorders (pulmonary embolism, deep vein thrombosis, and superficial vein thrombosis), MACE (all-cause mortality, stroke, and myocardial infarction), and any cardiovascular outcome (incident occurrence of any cardiovascular outcome studied). Outcomes were ascertained 30 days after the COVID-19 positive test until the end of follow-up. The historical control cohort served as the referent category. Within the COVID-19 cohort, non-hospitalized (N = 131,612), hospitalized (N = 16,760); admitted to intensive care (N = 5,388); and historical control cohort (N = 5,859,411). Adjusted hazard ratios and 95% confidence intervals are presented. Length of the bar represents the excess burden per 1000 persons at 12 months and related 95% confidence intervals were also presented. MACE, major adverse cardiac events; TIA, transient ischemic attack.