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Exercise rehabilitation associates with lower mortality and hospitalisation in cardiovascular disease patients with COVID-19

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, William Henry Duncan Building, Liverpool L7 8TX, UK; TriNetX Inc, Cambridge, MA, USA; TriNetX Inc, London, UK; Liverpool Centre for Cardiovascular Science, Liverpool John Moores University, Liverpool, UK; Department of Primary Care and Mental Health, University of Liverpool, UK; and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

The COVID-19 pandemic has caused global health, social, and economic system challenges. In an effort to try and reduce transmission rates, most countries have varying levels of societal 'lockdowns' and social restrictions in place. This creates a unique challenge for the promotion of physical activity and exercise, which we know has profound physical and mental health benefits. Although there was initial promise of increased population interest in physical activity and exercise at the beginning of the COVID-19 pandemic, 1 recent large-scale data from over 455 000 people has demonstrated a 27% decrease in average daily steps within 30 days of the pandemic declaration. 2 It may therefore be more important now than ever to facilitate physical activity and exercise promotion during and post-COVID-19. Despite, recent collaborative efforts developing post-COVID-19 guidelines for athletes returning to exercise, 3 limited evidence is available for the impact of exercise and cardiac rehabilitation (CR) on clinical outcomes following-COVID-19. Secondary prevention through comprehensive CR has been recognized as the most costeffective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular diseases. 4 Given there is a high prevalence of cardiovascular disease among patients with COVID-19, and >7% experience COVID-19 induced myocardial injury, 5 CR following COVID-19 infection warrants investigation. The objective of this study was therefore to compare mortality, hospitalization, and cardiovascular comorbidity between patients with cardiovascular disease and COVID-19 with and without an electronic medical record (EMR) of CR or exercise programmes.
This retrospective observational study was conducted in October 2020 with anonymized data provided by TriNetX, a global federated health research network with access to EMRs from participating academic medical centres, specialty physician practices, and community hospitals, predominantly in the USA. Patients with COVID-19 were identified via Centers for Disease Control and Prevention (CDC) coding using ICD-10-CM codes, or specific laboratory Logical Observation Identifiers Names and Codes. 6 All patients were aged > _18 years with COVID-19 recorded in EMRs between 20 January 2020 (date COVID-19 first confirmed in the USA) 7 and 26 May 2020 (to allow 4-month follow-up). Cardiac rehabilitation was identified from ICD-10-CM codes Z71.82 (Exercise counselling), HCPCS code S9472 (CR programme, non-physician provider, per diem), or CPT code 1013171 (physician or other qualified healthcare professional services for outpatient CR). Correspondingly, these CR and exercise programme codes were excluded in the propensity score-matched controls. At the time of the search, 33 participating healthcare organizations had data available for patients meeting the study inclusion criteria. Thus, following propensity score matching, the cohort consisted of patients with cardiovascular disease and a diagnosis of COVID-19; who either were referred for CR and exercise programmes (due to cardiovascular disease) within 3 months of a COVID-19 diagnosis (intervention) or were not referred (control).
Baseline characteristics were compared using v 2 tests or independent-sample t-tests. Using logistic regression, CR and exercise patients were 1:1 propensity score matched with controls for age, sex, race, acute myocardial infarction (AMI), heart failure, hypertensive disease, diabetes mellitus, chronic kidney disease, cerebrovascular disease, cardiovascular procedures (e.g. cardiography, echocardiography, cardiac catheterization, cardiac devices, electrophysiological procedures), and cardiovascular medications (e.g. betablockers, antiarrhythmics, diuretics, antilipemic agents, antianginals, calcium channel blockers, angiotensin-converting enzyme inhibitors). These variables were chosen because they are established risk factors for cardiovascular disease and/or mortality or were significantly different between the two cohorts. Logistic regression produced odds ratios (OR) with 95% confidence intervals (CI) for mortality, hospitalization, AMI, stroke, and heart failure at 4 months following a COVID-19 diagnosis, comparing exercise-based CR with propensity score-matched controls. Statistical significance was set at P < 0.05. In total, 400 383 patients with COVID-19 met the inclusion criteria for the control group and 643 patients with COVID-19 met the inclusion criteria for the exercise-based CR cohort. Compared with controls, the exercise-based CR cohort were generally older, had less females, and more cardiovascular comorbidities ( Table 1). Following propensity score matching, cohorts were well balanced for age, race, sex, comorbidities, cardiovascular medications, and cardiovascular procedures (P > 0.05; Table 1).
Several limitations are of note. Firstly, the characterization of COVID-19, health conditions, and CR and exercise programmes were based on ICD codes from EMRs, and reporting of conditions with ICD codes may vary by patient characteristics and healthcare organizations. 8 Indeed, we do not know the severity of individual COVID-19 cases, which may have affected the results. However, before propensity score matching, there was no difference in relative mortality between the cohorts. Thus, it may not be illness severity that differentiated patients receiving CR or not within this cohort. We also do not know details of the CR interventions, including whether they were comprehensive, multicomponent or exercise-only, which limits the ability to identify active 'intervention ingredients'. Due to closures in many traditional (centre-based) CR programmes, evaluation of different types of CR is needed, particularly frameworks that are adapted to COVID-19 delivery such as 'cardiac telerehabilitation'. 9 Another important caveat, an EMR of CR and exercise does not necessarily provide information as to whether a patient attended, the intervention type and dose, or intervention adherence. We could also not determine the influence of attending different healthcare organizations due to data privacy restrictions. Finally, although we were able to match patients for important comorbidities and demographic factors, residual confounding may present.
In summary, the present study of over 1200 patients with cardiovascular disease demonstrated that exercise-based CR programmes following COVID-19 associated with significantly lower odds of mortality and re-hospitalization at 4 months, when compared to propensity score-matched patients without CR. The provision of exercise rehabilitation for cardiovascular patients following a COVID-19 diagnosis is therefore a promising entity and warrants further investigation.

Funding
There was no specific funding received for this study. TriNetX LLC funded the acquisition of data.  Data are taken from structured fields in the electronic medical record systems of the participating healthcare organizations, therefore, there may be regional or countryspecific differences in how race categories are defined. c Cardiovascular procedures include cardiography, echocardiography, catheterization, cardiac devices, and electrophysiological procedures. d Cardiovascular medications include beta-blockers, antiarrhythmics, diuretics, antilipemic agents, antianginals, calcium channel blockers, and angiotensin-converting enzyme inhibitors.