Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research.

were adjusted for age, ethnicity, cardiovascular disease (CVD) history, medication use and CVD risk factors (hypertension, diabetes, dyslipidemia, peripheral arterial disease and body mass index).

Supplementary Figure 9
Sensitivity analyses with patients from selective recruitment sites excluded: Female-to-male odds ratios (ORs, with 95% confidence intervals [CIs]) in the cohorts without and with pre-existing cardiovascular disease (CVD), and the corresponding ratio of OR (with 95% CI). Unadjusted and adjusted estimates are presented. In adjusted analyses, models were adjusted for age, ethnicity, CVD history, medication use and CVD risk factors (hypertension, diabetes, dyslipidemia, peripheral arterial disease and body mass index).

Supplementary Material
Supplementary Table 1 List of relevant medications or interventions for each outcome. Myocarditis, pericarditis, endocarditis and acute coronary syndrome were defined according to the diagnostic criteria of the corresponding European Society of Cardiology (ESC) guidelines. [5][6][7][8] For arrhythmias, definitions were based on the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) 2006 data standards. 9  Table 3 Percentage of participants receiving treatment with cardiovascular medications or procedures, by sex. Information on baseline medication use was missing for 0.1% of participants. The number of participants with missing information on prior procedures was 1080 (9.7%) overall, 499 (11.2%) in females and 581 (8.6%) in males. S = suppressed due to small numbers <20. PCI = percutaneous coronary intervention, CABG = coronary artery bypass graft.     Figure 4 Summary statistics of vital measurements (temperature, respiratory rate, heart rate, blood pressure and oxygen saturation) and laboratory measurements (C-reactive protein, white blood cell count, lymphocyte count, haemoglobin, platelets and creatinine), by sex.  Figure 5 Odds ratios (ORs, with 95% confidence intervals [CIs]) for the association between sex and the outcomes, using four sets of model adjustments: (i) no adjustment, (ii) age and ethnicity, (iii) age, ethnicity, cardiovascular disease (CVD) history and medication use, and (iv) age, ethnicity, CVD history, medication use and CVD risk factors (hypertension, diabetes, dyslipidemia, peripheral arterial disease and body mass index).     Figure 9 Sensitivity analyses with patients from selective recruitment sites excluded: Female-to-male odds ratios (ORs, with 95% confidence intervals [CIs]) in the cohorts without and with pre-existing cardiovascular disease (CVD), and the corresponding ratio of OR (with 95% CI). Unadjusted and adjusted estimates are presented. In adjusted analyses, models were adjusted for age, ethnicity, CVD history, medication use and CVD risk factors (hypertension, diabetes, dyslipidemia, peripheral arterial disease and body mass index).

Lay Summary
Compared to men, women with COVID-19 have a lower risk of severe disease, including respiratory failure, hospitalisation and death. It is less clear whether this is also true for cardiovascular complications associated with COVID-19, for example, irregular heartbeat (arrhythmia), decreased blood flow and oxygen to the heart muscle (cardiac ischemia) and lack of blood flow to the brain (stroke). It is also unclear whether differences in COVID-19 severity between women and men is simply explained by the latter having a higher prevalence of pre-existing cardiovascular diseasea known risk factor for severe COVID-19.
In this study, we analysed data from 11,167 patients who were hospitalised with COVID-19 between March 2020 and May 2021. We compared the risk of a range of cardiovascular complications between women and men and also according to whether patients had pre-existing cardiovascular disease or not.
We found that 13 of every 100 women and 17 of every 100 men developed some form of cardiovascular complication during their hospital admission. This corresponds to a 30% lower risk in women compared to men. Arrhythmia was the most common cardiovascular complication, observed in 5 and 8 of every 100 women and men, respectively. Other cardiovascular complication sub-types, such as cardiac ischemia and pulmonary embolism, were less common overall and were similarly found to occur less frequently in women compared to men. There were also some complications, such as heart failure and stroke, for which women and men had a similar risk.
Importantly, we found that differences between the genders were present irrespective of whether they had pre-existing cardiovascular disease. This suggests that the higher risk in men may not only be explained by their higher prevalence of pre-existing cardiovascular disease. Further research is needed to understand why men are at higher risk of severe COVID-19.