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Marked Global Differences in Mortality in Male Patients with COVID-19: An

Analysis of the CARDIO COVID 19-20 and WHF COVID-19 CVD Studies

Article in Global Heart · February 2025

DOI: 10.5334/gh.1403

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Marked Global Differences
in Mortality in Male Patients
with COVID-19: An Analysis
of the CARDIO COVID 19–20
and WHF COVID-19 CVD
Studies ORIGINAL RESEARCH

JUAN ESTEBAN GÓMEZ-MESA JESSICA MERCEDES

JUAN PABLO ARANGO-IBANEZ CLARA INÉS SALDARRIAGA-
GIRALDO
PABLO PEREL
MARÍA JULIANA RODRÍGUEZ-
DORAIRAJ PRABHAKARAN GONZÁLEZ
HOOVER O. LEÓN-GIRALDO ARMANDO ALVARADO
ALEJANDRO TORO-PEDROZA JUAN CARLOS ORTEGA
RICARDO ENRIQUE LARREA GÓMEZ MIGUEL QUINTANA DA SILVA CORRESPONDING AUTHOR:
Juan Esteban Gómez-Mesa
CÉSAR J. HERRERA KAVITA SINGH Fundación Valle del Lili, Cra. 98
JULIÁN LUGO-PEÑA KAREN SLIWA #18–49, Cali, Valle del Cauca,
Colombia
LILIANA PATRICIA CÁRDENAS ALAZ ON BEHALF OF THE CARDIO COVID [email protected]
VICTOR ROSSEL 19–20 AND WHF CVD COVID-19
RESEARCH GROUPS
DANIEL SIERRA-LARA
*Author affiliations can be found in the back matter of this article KEYWORDS:
COVID-19; SARS-CoV-2 virus;
men; male; mortality; global
differences; Africa; America;
Asia; Europe
ABSTRACT
Background: COVID-19 has led to nearly seven million deaths and male sex has been TO CITE THIS ARTICLE:
reported as one of the main risk factors for mortality. Few studies have analyzed cohorts Gómez-Mesa JE, Arango-
of male patients, especially in underrepresented regions in the medical literature, such Ibanez JP, Perel P, Prabhakaran
D, León-Giraldo HO, Toro-
as low and middle-income nations. To address this gap, we conducted large-scale,
Pedroza A, Gómez REL,
male-specific, multinational analyses, to improve understanding of factors associated
Herrera CJ, Lugo-Peña J, Alaz
with mortality in this high-risk population and global variations. LPC, Rossel V, Sierra-Lara
D, Mercedes J, Saldarriaga-
Methods: This is a prospective, multicenter study that includes data from the CARDIO
Giraldo CI, Rodríguez-González
COVID-19–20 registry and the WHF COVID-19 CVD study. A multiple Poisson regression MJ, Alvarado A, Ortega JC,
model was performed to evaluate differences in factors associated with in-hospital Quintana Da Silva M, Singh K,
mortality among male COVID-19 patients across different regions. Sliwa K, On behalf of the
CARDIO COVID 19–20 and
Results: We analyzed 4,899 hospitalized male COVID-19 patients from 32 countries: WHF CVD COVID-19 research
Africa (11.2%), the Americas (44.7%), Asia (33.8%), and Europe (10.2%). Median age groups. Marked Global
was 59 years (IQR: 47–69), with 50.5% aged 40–64. ICU admission was 42.4%, and Differences in Mortality in Male
mortality was 19.2%, with marked regional differences (ranging from 6% in Europe to Patients with COVID-19: An
Analysis of the CARDIO COVID
26.9% in the Americas). Poisson regression showed age >80 years (aRR = 4.21) and IMV
19–20 and WHF COVID-19 CVD
(aRR = 3.80) as the strongest factors associated with mortality. Other factors included Studies. Global Heart. 2025;
diabetes, chronic kidney disease, myocarditis, and decompensated heart failure. 20(1): 21. DOI: https://doi.
Mortality risk was higher in Africa (aRR = 3.86), Asia (aRR = 2.72), and the Americas org/10.5334/gh.1403
 (aRR = 2.23) compared to Europe (p < 0.001). Anticoagulation/Antiplatelet therapy Gómez-Mesa et al. 2
Global Heart
showed a potential correlation with survival. DOI: 10.5334/gh.1403

Conclusion: This study reflects the complexity of factors influencing COVID-19 mortality
among male patients hospitalized with COVID-19, emphasizing global variability. The
substantial differences in mortality noted across countries are likely due to differences
in disease severity, comorbidities, clinical care, and health system factors. Age remains
a primary risk factor, with older populations particularly vulnerable. Our findings
underscore the need for targeted and tailored regional approaches to manage male
COVID-19 patients.

BACKGROUND
The SARS-CoV-2 virus, responsible for Coronavirus Disease 2019 (COVID-19), triggered a
pandemic that caused one of the most significant challenges faced by healthcare systems (1).
As of August 2024, more than seven million deaths caused by COVID-19 have been reported (2).
Most patients experienced a mild course; however, the associated mortality can be substantial
in severe forms, with reports indicating general case-fatality rates of up to 10% (3). Mortality in
patients with COVID-19 is highly dependent on risk factors such as advanced age and chronic
comorbidities like diabetes mellitus (DM), obesity, and chronic kidney disease (CKD), among
many others (4).

Male sex is a risk factor for higher COVID-19 severity, ICU admission rates, and mortality rates
(5). This may stem from men’s tendency to delay seeking healthcare, higher rates of risky
behaviors such as smoking and alcohol use, and greater prevalence of comorbidities such as
cardiovascular disease and DM (6). Biological sex differences may also explain the mortality
gap. For example, men tend to have a more intense inflammatory response than women when
infected with COVID-19 (6, 7). Together, these factors contribute to worse COVID-19 outcomes
in men than women.

Regional disparities further complicate the interplay of risk factors for COVID-19 outcomes.
Factors such as the timing and location of virus introduction, population density, hospital beds
per 100,000 people, COVID-19 cases per 100,000 people, community mitigation measures,
diagnostic testing capacity, and public health reporting practices have all been identified as
influential determinants of mortality (8–10). Notably, infection fatality rates are roughly twice
as high in developing countries compared to high-income countries, likely due to socioeconomic
factors (11). These regional factors may interact with male-specific risks, amplifying the
challenges faced by men in lower-resource settings. For example, limited healthcare access
could exacerbate men’s delayed healthcare-seeking behaviors, while regional variations in the
prevalence of comorbidities like obesity and diabetes may further compound the risk of severe
outcomes.

Despite these insights, no reported studies have specifically examined the factors associated
with mortality in a stratified group of male patients across different countries. Investigating
these factors in a global context is critical, as it allows for identifying male-specific risks without
the confounding or modifying effects of sex-based differences. The importance of this research
persists, even with the decline in COVID-19 cases, as it provides vital insights for future health crisis
preparedness and the implementation of strategies tailored to the needs of these populations. By
understanding mortality-associated factors in male patients globally, we can better prepare for
potential recurrences of COVID-19 and strengthen our responses to similar infectious diseases.
To this end, we conducted a study evaluating mortality factors in hospitalized male patients with
COVID-19 across multiple countries from different World Health Organization (WHO) regions.

METHODS
STUDY DESIGN AND SETTING
This observational, prospective, multicenter study utilized two existing databases of hospitalized
COVID-19 patients: CARDIO COVID 19–20 (12) and WHF COVID-19 CVD and study (13). The
first is a prospective study of patients diagnosed with COVID-19 who required in-hospital
management between June 01, 2020, and June 30, 2021. This registry included 3,260 patients Gómez-Mesa et al. 3
Global Heart
from 14 countries in Latin America. This study was coordinated by the Scientific Committee DOI: 10.5334/gh.1403
of the Council for Heart Failure and Pulmonary Hypertension (CIFACAH) of the Inter-American
Society of Cardiology (SIAC).

The WHF COVID-19 and CVD study was a prospective cohort study that included 5,313
hospitalized patients between June 06, 2020, and September 15, 2021, from 40 hospitals across
23 countries in four continents. The World Heart Federation and Public Health Foundation of
India coordinated this study.

Figure 1 displays participating countries and their percentage of patient recruitment by

participating hospital sites. It is important to note that Latin American countries contributed Figure 1 Participating
the majority of patients in the Americas. Although North American countries participated in countries and contribution to
patient recruitment, their representation was lower compared to Latin America. patient recruitment.

The integration of the two studies was performed to ensure consistency in data. A detailed
examination of the variable lists in both records was conducted to identify similar or equivalent
variables while distinguishing exclusive variables unique to each record. An alignment of
variables across both records was accomplished. Duplicated patients were found and excluded
from the analysis. A standardization process of clinical parameter units was implemented to
ensure data comparability and consistency.

STUDY PARTICIPANTS
Male patients aged 18 years or older with a laboratory diagnosis of COVID-19 were included.
Exclusion criteria for the CARDIO COVID 19–20 registry encompassed: patients hospitalized for
less than 24 hours and those who died within 24 hours of consultation. Exclusion criteria for
the WHF COVID-19 study were: patients without complete follow-up at 30 days, and those
unlikely to stay at the participating center (e.g. transfers). For this sub-analysis, we excluded
female patients.

STATISTICAL ANALYSIS
Exposure was hospitalization due to COVID-19. The primary outcome was in-hospital mortality.
The distribution of continuous variables was assessed using the Kolmogorov-Smirnov test.
Median and interquartile range (IQR) were used for non-normally distributed data. Qualitative
data are displayed with absolute frequencies and percentages.
Univariate and multivariate analyses were conducted to calculate relative risks and their 95% Gómez-Mesa et al. 4
Global Heart
confidence intervals (CI). For the effect-size multivariate analysis, we used a Poisson regression DOI: 10.5334/gh.1403
model with robust variance to account for the intrinsic variability of the study (data from multiple
centers in different countries) and the high prevalence of the primary outcome. Variables were
selected based on their statistical significance in the univariate analysis (p < 0.25) and their
clinical relevance from previous literature. The influence of variables was assessed, and those
lacking statistical significance were sequentially removed (backward elimination) to obtain the
final model. Multicollinearity was evaluated using the generalized variance-inflation factor, and
variables with a value greater than two were removed one by one.

Next, we included the continents (Africa, America, and Asia) as variables to evaluate potential
differences in risks across the complete dataset. These variables were not included in the final
model but were used to assess potential continental differences in risks after adjusting for
multiple variables. Europe was used as the reference.

We then evaluated the model for each continent, resulting in five models (one global and one
for each continent). This approach aimed to facilitate the comparison of factors associated
with mortality across different regions. The statistical analysis was conducted using RStudio
V.1.4.1717. Figures were created with Python version 3.13.1. MapChart was used to create a
global map to highlight countries with participating institutions.

ETHICAL CONSIDERATIONS
The Comité de ética en Investigación Biomédica (Institutional Review Board) of the Fundación Valle
del Lili in Cali, Colombia, approved this study. The WHF COVID-19 study received ethics approval
from the University of Cape Town (South Africa), the Centre for Chronic Disease Control (India),
and the Public Health Foundation (India). Each participating institution required ethics committee
approval before patient recruitment. National regulatory clearances were also obtained for the
WHF COVID-19 study. This study follows the guidelines of the Declaration of Helsinki.

In the WHF CVD study, informed consent was obtained following local ethical guidelines, either
from participants or their legal representatives if they were unable to provide consent. In the
CARDIO COVID Study, informed consent was not required due to its observational nature, but a
validated consent form was used when mandated by institutional policies.

RESULTS
We included 4,899 male patients hospitalized with COVID-19, distributed across 32 countries
spanning 4 continents. The patient distribution across the WHO region was: 551 patients
(11.2%) from Africa, 2,188 patients (44.7%) from the Americas, 1,654 patients (33.8%) from
Asia, and 506 patients from Europe (10.2%).

The overall median age was 59 years (IQR: 47–69), and most patients (n = 2,476, 50.5%)
were aged between 40 and 64 years. The most common comorbidities included hypertension
(n = 2,284, 46.6%), DM (n = 1,458, 29.8%), and obesity (n = 761, 23.4%). Data regarding
demographics and comorbidities is shown in Table 1.

VARIABLE OVERALL, n = 4899, AFRICA, n = 551, AMERICAS, n = 2188, ASIA, n = 1654, EUROPE, n = 506, p-VALUE
(%) (%) (%) (%) (%)

Age, years, median, IQR 59 (47–69) 55 (43–67) 60 (48–70) 58 (46–68) 60 (48–70) <0.001

Age <40, years 679 (13.9%) 98 (17.8%) 240 (11%) 264 (16%) 77 (15.2%) <0.001

Age 40–64, years 2476 (50.5%) 292 (53%) 1127 (51.5%) 819 (49.5%) 238 (47%) <0.001

Age 65–79, years 1376 (28.1%) 130 (23.6%) 626 (28.6%) 483 (29.2%) 137 (27.1%) <0.001

Age ≥80, years 368 (7.5%) 31 (5.6%) 195 (8.9%) 88 (5.3%) 54 (10.7%) <0.001

Hypertension 2284 (46.6%) 269 (48.8%) 1021 (46.7%) 711 (43.0%) 283 (55.9%) <0.001

Diabetes Mellitus 1458 (29.8%) 137 (24.9%) 586 (26.8%) 618 (37.4%) 117 (23.1%) <0.001

Obesity 761 (23.4%) 66 (28%) 455 (31.1%) 114 (9.6%) 126 (34.3%) <0.001

(Contd.)
 VARIABLE OVERALL, n = 4899, AFRICA, n = 551, AMERICAS, n = 2188, ASIA, n = 1654, EUROPE, n = 506, p-VALUE
(%) (%) (%) (%) (%)

Chronic Kidney Disease 401 (8.2%) 37 (6.7%) 183 (8.4%) 113 (6.8%) 68 (13.4%) <0.001

Coronary Artery Disease 552 (11.3%) 25 (4.5%) 183 (8.4%) 253 (15.3%) 91 (18%) <0.001

Atrial Fibrillation 144 (2.9%) 3 (0.5%) 76 (3.5%) 19 (1.1%) 46 (9.1%) <0.001

Heart Failure 271 (5.5%) 18 (3.3%) 121 (5.5%) 63 (3.8%) 69 (13.6%) <0.001

Cancer 121 (2.5%) 3 (0.5%) 74 (3.4%) 19 (1.1%) 25 (4.9%) <0.001

Smoking* 1201 (24.5%) 81 (14.7%) 396 (18.1%) 479 (29.0%) 245 (48.4%) <0.001

Table 2 shows the clinical characteristics of the patients including vital signs at admission, Table 1 Demographics and
acute cardiovascular complications, pulmonary findings on chest imaging, medical treatment, comorbidities by continent.
and outcomes. Overall ICU admission was 42.4%, and mortality was 19.2%. Figure 2 represents IQR = Interquartile range.
mortality and ICU admission by continent. *Smoking History or Current
Smoking Status.

VARIABLE n FOR OVERALL, n AFRICA, n (%)/ AMERICAS, n ASIA, n (%)/ EUROPE, n (%)/ p-VALUE
ANALYSIS (%)/MEDIAN MEDIAN (%)/MEDIAN MEDIAN MEDIAN
(IQR) (IQR) (IQR) (IQR) (IQR)

Vital signs at admission

Respiratory rate (respirations 4050 22 (20–26) 24 (21–28) 23 (20–28) 22 (20–24) 20 (18–22) <0.001
per minute)

Heart rate (beats per minute) 4821 92 (80–105) 94 (81–105) 93 (81–107) 91 (80–104) 88 (80–99) <0.001

Systolic blood pressure 4828 128 (115–140) 133 (121–148) 127 (113–140) 125 (114–140) 130 (120–140) <0.001
(mmHg)

Diastolic blood pressure 4829 79 (70–85) 83 (72–91) 75 (69–84) 80 (70–85) 80 (70–86) <0.001
(mmHg)

Temperature (Celcius) 4683 37 (36.5–38) 36.6 (36.2–37.1) 37 (36.4–37.9) 37.1 (36.6–38) 37.6 (37.0–38.2) <0.001

Oxygen saturation (%) 4592 93 (88–96) 93 (88–96) 91 (85–95) 95 (92–97) 94 (91–96) <0.001

Cardiovascular complications

Arrhythmia 4899 299 (6.1%) 11 (2%) 216 (9.9%) 24 (1.5%) 48 (9.5%) <0.001

Myocarditis 4899 48 (1%) 5 (0.9%) 27 (1.2%) 14 (0.8%) 2 (0.4%) 0.3

Pulmonary embolism 4899 156 (3.2%) 6 (1.1%) 98 (4.5%) 29 (1.8%) 23 (4.5%) <0.001

Acute coronary syndrome 4899 113 (2.3%) 5 (0.9%) 69 (3.2%) 27 (1.6%) 12 (2.4%) 0.002

Acute heart failure 4899 286 (5.8%) 20 (3.6%) 183 (8.4%) 61 (3.7%) 22 (4.3%) <0.001

Pulmonary findings

Lung Infiltrates 3188* 2730 (85.6%) 127 (90.7%) 1790 (88.0%) 647 (80.8%) 166 (77.6%) <0.001

Pleural effusion 3188* 288 (9%) 20 (14.3%) 215 (10.6%) 29 (3.6%) 24 (11.2%) <0.001

In-hospital treatment

Inotropes/Vasopressors 4899 795 (16.2%) 17 (3.1%) 685 (31.3%) 60 (3.6%) 33 (6.5%) <0.001

Corticosteroid 4899 3438 (70.2%) 364 (66.1%) 1586 (72.5%) 1096 (66.3%) 392 (77.5%) <0.001

Anticoagulant/Antiplatelet 4899 3346 (68.3%) 195 (35.4%) 1955 (89.4%) 814 (49.2%) 382 (75.5%) <0.001

Invasive mechanical 4899 919 (18.8%) 26 (4.7%) 784 (35.8%) 74 (4.5%) 35 (6.9%) <0.001
ventilation

Clinical outcomes

ICU admission 4899 2075 (42.4%) 102 (18.5%) 1303 (59.6%) 589 (35.6%) 81 (16%) <0.001

In-hospital mortality 4899 934 (19.2%) 91 (16.9%) 587 (26.9%) 226 (13.7%) 30 (6%) <0.001

Using the World Health Organization data on hospital beds/10,000 population (14), we Table 2 Clinical characteristics
by continent.
estimated the weighted mean value of this parameter for each continent, adjusting for the
percentage contribution of patients from each participating country. We found that the mean ICU = Intensive care
unit. IQR = Interquartile
number of beds per 10,000 population was 13.13 in Africa, 17.49 in the Americas, 31.98 in Asia,
range. *Missing data due to
and 53.73 in Europe. unavailability of radiological
imaging in 1,711 patients.
Figure 3 represents five Poisson regression models with robust variance of factors associated Gómez-Mesa et al. 6
Global Heart
with mortality. In the global model, the risk for mortality was higher for the three age groups DOI: 10.5334/gh.1403
in ascending order, a finding consistently seen in all continents. The biggest factor associated
with mortality was an age greater than 80 years (aRR = 4.21; 95% CI: 3.09–5.72) followed by
IMV (aRR = 3.80 95% CI: 3.37–4.29). The use of an anticoagulant/antiplatelet had an effect Figure 2 Intensive care unit
associated with decreased mortality, although the 95% CI included the unit (P = 0.058). This admission rate and mortality
variable was still included in the model due to its clinical significance and the prominent effect rate by continent.
direction it demonstrated. ICU: Intensive care unit.

Figure 3 Heatmap of factors

associated with in-hospital
COVID-19 mortality by
continent.
aRR: adjusted relative risk.
For each value, the aRR is
presented along with its
95% confidence interval. In
these statistical models,
4,873 (99.4%) patients were
included in the ‘Global’ model,
537 in Africa, 2,180 in the
Americas, 1,652 in Asia, and
504 in Europe.

We conducted an exploratory analysis to evaluate the differences between continents in

mortality; we added Africa, the Americas, and Asia as independent variables to the final global
model and used Europe as the reference. We found the following adjusted relative risks (aRR):
Africa 3.86 (CI 95 2.67–5.57, p < 0.001), Americas 2.23 (CI 95 1.58–3.15, p < 0.001), and Asia
2.72 (CI 95 1.92–3.84, p < 0.001). Including the continents in the model did not affect the
magnitude of the effects of all other variables by more than 10% except for anticoagulation/
antiplatelet, which showed an aRR of 1.01 (CI 0.86–1.19, p = 0.893).
In Africa, IMV was associated with higher mortality (aRR = 4.35; 95% CI: 3.03–6.27), along with Gómez-Mesa et al. 7
Global Heart
corticosteroid use (aRR = 1.76; 95% CI = 1.03–3.03). As observed in Europe and Asia, the highest DOI: 10.5334/gh.1403
aRR is seen in patients over 80 years old.

In Americas, a high risk of mortality was observed in patients with CKD (aRR = 1.30; 95% CI:
1.07–1.57); DHF (aRR = 1.52; 95% CI: 1.32–1.76); pleural effusion (aRR = 1.24; 95% CI: 1.05–1.47);
and IMV (aRR = 4.44; 95% CI: 3.78–5.22). No significance was observed in DM, myocarditis, lung
infiltrates, corticosteroids, and anticoagulation/antiplatelet use. The variable with the highest
risk was IMV, followed by age over 80 years.

In Asia, factors associated with mortality included CKD (aRR = 1.75; 95% CI: 1.24–2.46); the
presence of myocarditis (aRR = 2.33; 95% CI: 1.24–4.38); DHF (aRR = 2.55; 95% CI: 1.82–3.57);
lung infiltrates (aRR = 2.02; 95% CI: 1.56–2.61); IMV (aRR = 2.71; 95% CI: 2.03–3.61) and use of
steroids (aRR = 2.25; 95% CI: 1.57–3.24). The variables most strongly associated with mortality
were ages over 80 years and ages between 65 and 79 years.

In Europe, a significant risk of mortality was identified in patients aged over 80 years (aRR =
7.11; 95% CI: 1.53–33.01), and a smaller effect was observed in the two other age groups. Other
factors associated with mortality included DM (aRR = 2.65; 95% CI: 1.47–4.79), myocarditis
(aRR = 6.59; 95% CI: 1.70–25.58), and IMV (aRR = 6.96; 95% CI: 3.16–15.31). The variables
most strongly associated with mortality were ages over 80 years, followed closely by IMV and
myocarditis. The use of anticoagulant/antiplatelet presented an aRR and CI consistent with a
potential effect associated with mortality, in contrast to the findings of the global model.

Table 3 (Supplementary Material) presents a logistic regression model of factors associated

with in-hospital COVID-19 mortality by continent for sensitivity analysis. Variables were
selected using the same approach described in the Statistical Analysis section of this
manuscript. This analysis yielded similar patterns to those observed in the Poisson model
with robust variance.

DISCUSSION
This study presents an analysis of the factors associated with COVID-19 in-hospital mortality
among men from Africa, the Americas, Asia, and Europe. To the best of our knowledge,
this is the first study conducting a continent-stratified regression analysis on male patients
hospitalized with COVID-19. The most notable finding is the high mortality in the Americas
(predominantly Latin America) and, to a lesser extent, in Africa, compared to Asia and Europe.
Additionally, we found an association with mortality in factors including age, comorbidities
(DM, CKD), cardiovascular complications (myocarditis, DHF), lung infiltrates, pleural effusion,
corticosteroids, and IMV.

Overall mortality in our study (19.2%) is consistent with a meta-analysis that found a mortality
rate of 16% (95% CI 12–21, I2 = 100%) in hospitalized COVID-19 patients (15). However, the
mortality in the Americas (26.9%) was substantially higher. Age does not appear to drive the
global differences in mortality in our study, as the continents with the highest (Americas) and
lowest (Europe) mortality rates had a comparable proportion of patients over 65 years (37.5%
vs 37.8%, respectively). The substantial differences in mortality cannot be adequately explained
by the impact of comorbidities, such as DM and CKD, the only comorbidities associated with
mortality in our model. In the regression analysis, they showed only modest associations
in terms of magnitude and diverse patterns of aRR across continents. The vaccination rate
among patients in the WHF COVID-19 registry was substantially low, and there were no
vaccinated patients in the CARDIO COVID 19–20 registry; thus vaccination is also not a potential
explanation (16, 17). These findings indicate that other unaccounted variables may have had a
higher impact on mortality differences across continents. This hypothesis is further supported
by our analysis incorporating continent as a variable in the final global model, which revealed
that Africa, the Americas, and Asia were independently associated with increased mortality risk
compared to Europe, even after adjusting for other factors.

The higher ICU admission rates in the Americas and Africa suggest a greater proportion of
patients with severe illness in our cohort for these regions, which could partially explain the
difference in mortality (18, 19). This is also supported by data showing more frequent abnormal Gómez-Mesa et al. 8
Global Heart
vital signs at admission, lung infiltrates, cardiovascular complications, and the need for IMV in DOI: 10.5334/gh.1403
these regions. Additionally, differences in the number of hospital beds/10,000 population may
partially explain this, as it has been identified as a country-level predictor of COVID-19 mortality
(10). The weighted average of beds/10,000 habitants was substantially lower in Africa and the
Americas compared with Asia and Europe. Other factors that could explain the differences
in mortality include comorbidity burden, quality of care, hospital resources, and treatment
protocols (20–22). Thus, regions with stronger healthcare systems may be more effective in
managing pandemics and reducing mortality rates.

Previous studies have explored factors associated with mortality in men. One study included
294 hospitalized male patients and found that pulmonary disease and connective tissue
disease were significant factors, along with age over 70 years, quick Sequential Organ
Failure Assessment (qSOFA) score, and laboratory markers such as C-reactive protein,
lymphocytopenia, and thrombocytopenia (23). Another study, which included 2,757 male
patients, found that age (>64) and hypoxia (oxygen saturation <92%) were associated
with increased mortality. No significant effects were observed in different ethnic groups
(e.g., Hispanic, Asian, non-Hispanic White) or various comorbidities (e.g., DM, CDK, heart
failure) (24).

In this study, age was the primary factor linked to mortality, demonstrating a direct
proportionality across age ranges (40–64, 65–79, ≥80 years). Individuals aged 80 years or
older exhibited the highest risks. These findings align consistently with those of extensive
studies (4, 25). However, one key observation in our study is that while Europe had the largest
proportion of patients aged ≥80, the Americas exhibited higher overall mortality. This suggests
that although age is a significant factor in mortality, many other factors also play crucial roles
in determining outcomes. CKD and DM were associated with in-hospital mortality, although
notable differences can be seen across continents; these diseases are well-established major
risk factors for COVID-19 mortality in the literature (4, 18, 26, 27). Interestingly, we found that
CKD had a non-significant effect in Europe, which aligns with results from a meta-analysis
and is thought to be related to lifestyle or treatment modalities (28). The magnitude of its
risk is similar to the one reported in a study incorporating multiple systematic reviews (27).
Notably, Europe exhibited the highest risk associated with DM, despite having the lowest DM
prevalence among all continents. Regional differences in how comorbidities affect COVID-19
outcomes likely stem from variations in healthcare, population traits, pandemic factors, and
statistical power, among other factors.

The presence of pulmonary infiltrates in chest imaging was associated with increased mortality
in our cohort. Previous research has established a correlation between lung infiltrates and
severe COVID-19. This suggests that extensive pulmonary involvement, as indicated by this
imaging finding, is linked to increased disease severity in COVID-19 patients (29, 30). Pleural
effusion was found to be associated with mortality, being consistent with a meta-analysis,
including 6,234 patients, which found that this finding is associated with both severity and
mortality (31).

Regarding cardiac complications during hospitalization, we found evidence of myocarditis as

an important factor for mortality, especially in Asia and Europe. This complication has received
attention given its association with both the virus and vaccines and has been shown to have
a higher impact on men than on women (32, 33). DHF was associated with mortality; this was
also found in a large study that included 42,225 patients with DHF and COVID-19 (34).

The use of corticosteroids was associated with higher mortality. Corticosteroids have played
a critical role in the treatment of COVID-19, with multiple early studies highlighting their
potential to reduce mortality (35, 36). However, their effectiveness appears to be modified
by the severity of the disease. A meta-analysis, which included five randomized trials and
one propensity score-matched study, suggested that corticosteroids might increase the risk
of mortality in COVID-19 patients who are not receiving oxygen therapy (37). Our findings
likely result from a combination of factors, including indication bias, in which corticosteroids
were more frequently prescribed to patients with greater disease severity, and a potential true
association with increased mortality. During the early pandemic, corticosteroids were widely
used among hospitalized patients, as seen in this study, many of whom did not have severe Gómez-Mesa et al. 9
Global Heart
disease. DOI: 10.5334/gh.1403

We found a trend toward a protective effect with the use of anticoagulant/antiplatelet therapy.
Evidence supports the decrease in mortality associated with therapeutic anticoagulation in
moderate cases of COVID-19 (38). On the other hand, the use of antiplatelet therapies has
inconsistent evidence on decreasing mortality (39). However, a recent propensity-scored-
match cohort study demonstrated that antiplatelet therapy before COVID-19 decreases
mortality (40). We evidenced differences in the effect direction in our study when analyzing
the models by region: while an effect associated with decreased mortality was seen in the
Americas and Africa, Europe, and Asia showed a trend towards higher risk. This suggests that
other variables could have confounded the potential protective effects associated with using
anticoagulation/antiplatelet.

Lastly, IMV was found to be consistently associated with mortality in all continents. Its use
is highly related to COVID-19 severity and has been described as one of the leading factors
associated with mortality in patients with severe disease (41). The global differences in the
effects of the mentioned interventions could be explained by distinct prescription policies, and
medications used, among other not accounted factors.

STRENGTHS/LIMITATIONS
The strengths of this study include its considerably large sample size, geographic representation,
and inclusion of patients recruited from underrepresented countries of Sub-Saharan Africa,
Asia, and Latin America. Additionally, it included a significant number of male patients from
low- and middle-income countries, where there is limited information on COVID-19 health
outcomes (42).

One key limitation of this study is the exclusion of patients with short hospital stays or those
who passed away within 24 hours. This exclusion may have omitted critically severe cases,
potentially introducing bias into the assessment of mortality risk. Therefore, our findings
should be interpreted with caution and are most applicable to patients who do not meet these
exclusion criteria. Another limitation of this study is the limited number of patients recruited
from Europe and Africa. Our findings cannot be generalized to entire continents due to the
underrepresentation or absence of certain countries within some regions. Nevertheless, we
believe that stratifying data by continent offers valuable insights into global differences
evidenced in our study.

Some variables had missing data that were not available in the electronic health records (e.g.,
radiological studies) and we did not perform imputation of missing data. Moreover, since a
considerable amount of data comes from unvaccinated individuals given the early stage of
the COVID-19 pandemic during which the patients were recruited, COVID-19 vaccination may
alter the effect of risk factors regarding COVID-19 mortality in patients (43). Another limitation
is the creation of composite variables (e.g. anticoagulant/antiplatelet), making it challenging
to draw specific conclusions about one without the other. Additional studies with greater
representation from all continents are needed to provide more robust and comprehensive
conclusions regarding the aim of our research.

CONCLUSIONS
This study reflects the complexity of factors influencing COVID-19 mortality in male patients,
with a distinct global variability observed. The data reveal that age remains a primary risk
factor, with older populations particularly vulnerable. Differences regarding comorbidities
demonstrate varying degrees of influence across continents, highlighting the possible role of
healthcare care and other environmental factors. This study highlights massive disparities in
mortality across continents, especially affecting Hispanics and African men, which are likely to
be highly influenced by socio-economic determinants and health system factors. The diverse
findings concerning factors for mortality in male patients from various continents emphasize
the need for region-specific strategies in patient management and further research to elucidate
regional disparities.
SUPPLEMENTARY MATERIAL

VARIABLE OVERALL, AFRICA, n = 537, AMERICAS, ASIA, n = 1652, EUROPE, n = 504,

n = 4873, aOR aOR (95% CI) n = 2180, aOR aOR (95% CI) aOR (95% CI)
(95% CI) (95% CI)

Age 40–64, years 2.22 (1.56–3.22, 1.89 (0.74–5.70, 1.87 (1.18–3.05, 3.29 (1.57–8.07, 1.13 (0.15–24.36,
p < 0.001) p = 0.212) p = 0.009) p = 0.004) p = 0.917)

Age 65–79, years 4.56 (3.18–6.68, 5.90 (2.25–18.26, 4.83 (3.01–7.98, 4.20 (1.97–10.41, 3.18 (0.47–66.34,
p < 0.001) p = 0.001) p < 0.001) p = 0.001) p = 0.318)

Age ≥80, years 7.60 (5.02–11.70, 10.76 (3.33–38.78, 10.95 (6.30–19.48, 3.98 (1.56–11.11, p 10.63 (1.45–232.01,
p < 0.001) p < 0.001) p < 0.001) = 0.005) p = 0.048)

Diabetes Mellitus 1.24 (1.03–1.48, 1.66 (0.94–2.89, 1.05 (0.81–1.36, 1.07 (0.77–1.48, 3.38 (1.37–8.52,
p = 0.019) p = 0.075) p = 0.701) p = 0.684) p = 0.008)

Chronic Kidney Disease 1.65 (1.26–2.17, 1.63 (0.68–3.66, 1.75 (1.18–2.60, 2.43 (1.45–3.99, 0.47 (0.14–1.41,
p < 0.001) p = 0.253) p = 0.006) p = 0.001) p = 0.201)

Myocarditis 2.67 (1.34–5.30, 2.67 (1.34–5.30, 1.04 (0.40–2.64, 13.70 (3.72–59.18, 14.01 (0.37–591.44,
p = 0.005) p = 0.005) p = 0.940) p < 0.001) p = 0.124)

Decompensated heart failure 3.23 (2.41–4.32, 1.19 (0.36–3.68, 3.00 (2.06–4.38, 6.76 (3.66–12.56, 1.71 (0.44–6.10,
p < 0.001) p = 0.763) p < 0.001) p < 0.001) p = 0.422)

Lung infiltrates 1.71 (1.41–2.08, 1.20 (0.62–2.27, 1.20 (0.62–2.27, 2.46 (1.78–3.41, 1.75 (0.66–4.61,
p < 0.001) p = 0.585) p = 0.585) p < 0.001) p = 0.258)

Pleural effusion 1.49 (1.11–2.00, 2.10 (0.64–6.75, 1.58 (1.11–2.23, 1.15 (0.42–2.94, 3.59 (0.72–15.70,
p = 0.008) p = 0.212) p = 0.010) p = 0.770) p = 0.100)

Invasive mechanical ventilation 8.42 (6.98–10.20, 18.32 (6.75–55.86, 11.15 (8.68–14.42, 6.59 (3.88–11.25, 12.09 (4.26–35.26,
p < 0.001) p < 0.001) p < 0.001) p < 0.001) p < 0.001)

Corticosteroid 1.53 (1.25–1.88, 2.09 (1.10–4.14, 1.16 (0.89–1.53, 3.00 (1.94–4.80, 0.85 (0.26–3.18,
p < 0.001) p = 0.028) p = 0.272) p < 0.001) p = 0.794)

Anticoagulation/Antiplatelet 0.74 (0.60–0.91, 0.68 (0.37–1.22, 0.64 (0.43–0.96, 1.16 (0.83–1.61, 2.75 (0.67–15.04,
p = 0.004) p = 0.202) p = 0.028) p = 0.393) p = 0.192)

ABBREVIATIONS Table 3 Logistic regression

analysis of factors associated
ACS: Acute coronary syndrome with in-hospital COVID-19
mortality by continent.
aRR: Adjusted relative risk
aORR = Adjusted odds ratio.
CI: Confidence interval CI = Confidence interval. First,
candidate variables were
COVID-19: Coronavirus Disease 2019 assessed using univariate
CKD: Chronic kidney disease analysis. Variables with
a p < 0.25 or considered
DHF: Decompensated heart failure clinically significant were
selected for evaluation
DM: Diabetes mellitus in the logistic regression
model. A backward selection
qSOFA: Sequential organ failure assessment
method was then applied to
ICU: Intensive care unit determine the final model
for all participants. Finally,
IMV: Invasive mechanical ventilation this analysis was stratified by
continent.
IQR: Interquartile range

PE: Pulmonary embolism

RR: Relative risk

SBP: Systolic blood pressure

WHF: World Heart Federation

DATA ACCESSIBILITY STATEMENT

The data that support the findings of this study are available from the corresponding author
upon reasonable request.
ACKNOWLEDGEMENTS Gómez-Mesa et al.
Global Heart
11

DOI: 10.5334/gh.1403
We would like to acknowledge the contributions of the following researchers to the CARDIO
COVID 19–20 study Igor Morr, Luis Carlos Santana Passos, Estevão Lanna Figueiredo, Alejandra
Ines Christen, Andrés Buitrago, Carlos Eduardo Montenegro, Franco Appiani Florit, William Millán
Orozco, Sylvia Sandoval, Wilbert German Yabar Galindo, Paula Silva, Iván Criollo, Paola Oliver,
Daniel Quesada, Andrés Ulate, Alexander Romero, Ricardo Ramírez Ramírez, Hugo Fernando
Fernández, Andrea Alejandra Arteaga, Manuela Escalante Forero, Jessica Largo Ocampo,
Andrés Gempeler, and Andrea Valencia Orozco.

We would like to acknowledge the valuable contributions of the following researchers to

the WHF-COVID-19 study: Dimple Kondal, Lana Raspail, Bishav Mohan, Toru Kato, Nizal
Sarrafzadegan, Shamim Hayder Talukder, Shahin Akter, Mohammad Robed Amin, Fastone
Goma, Ntobeko Ntusi, Francisca Inofomoh, Surender Deora, Evgenii Philippov, Alla Svarovskaya,
Alexandra Konradi, Aurelio Puentes, Okechukwu S. Ogah, Bojan Stanetic, Aurora Issa, Friedrich
Thienemann, Dafsah Juzar, Ezequiel Zaidel, Sana Sheikh, Dike Ojji, Carolyn S. P. Lam, Junbo Ge,
Amitava Banerjee, L. Kristin Newby, Antonio Luiz P. Ribeiro, Samuel Gidding, and Fausto Pinto.

FUNDING INFORMATION
CARDIO COVID 19–20 institutionally funded by Fundación Valle del Lili. The WHF COVID-19
Global Cardiovascular Disease Study was funded by the WHF with additional support from
a grant provided by Pfizer and Sanofi. The funding organizations had no involvement in the
study’s design, conduct, analysis, or the reporting of the findings.

COMPETING INTERESTS
Karen Sliwa is a Senior Editorial Advisor in Global Heart. Pablo Perel is a Executive Editor in Global
Heart. Kavita Singh is supported by the National Institutes of Health, Fogarty International
Centre, USA; Emerging Global Leader grant award number: 1 K43 TW011164. We declare no
other competing interests.

AUTHOR AFFILIATIONS
Juan Esteban Gómez-Mesa orcid.org/0000-0002-6635-6224
Departamento de Cardiología, Fundación Valle del Lili, Cali, Colombia; Centro de Investigaciones Clínicas,
Fundación Valle del Lili, Cali, Colombia; Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia
Juan Pablo Arango-Ibanez orcid.org/0000-0003-3601-3279
Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia; Facultad de Ciencias de la
Salud, Universidad Icesi, Cali, Colombia
Pablo Perel orcid.org/0000-0002-2342-301X
Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine,
World Heart Federation, Switzerland
Dorairaj Prabhakaran orcid.org/0000-0002-3172-834X
Public Health Foundation India, Centre for Chronic Disease Control, World Heart Federation, London School
of Hygiene & Tropical Medicine, UK
Hoover O. León-Giraldo orcid.org/0000-0002-8854-105X
Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia; Facultad de Ciencias de la
Salud, Universidad Icesi, Cali, Colombia
Alejandro Toro-Pedroza orcid.org/0009-0009-9140-3465
Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia
Ricardo Enrique Larrea Gómez
Departamento de Cardiología, Clínica Dávila, Santiago, Chile
César J. Herrera orcid.org/0000-0002-3546-5225
Departamento de Cardiología, Centros de Diagnóstico y Medicina Avanzada y de Conferencias Médicas y
Telemedicina (CEDIMAT), Santo Domingo, Dominican Republic
Julián Lugo-Peña orcid.org/0000-0002-5867-2876
Departamento de Cardiología, Centro de Diagnóstico, Medicina Avanzada y Telemedicina (CEDIMAT),
Santo Domingo, República Dominicana
Liliana Patricia Cárdenas Alaz
Departamento de Cardiología, Hospital Eugenio Espejo, Quito, Ecuador
 Gómez-Mesa et al. 12
Victor Rossel orcid.org/0000-0002-4212-1148
Global Heart
Departamento de Cardiología, Hospital del Salvador, Santiago de Chile, Chile; Facultad de Medicina, DOI: 10.5334/gh.1403
Universidad de Chile, Santiago, Chile
Daniel Sierra-Lara
Departamento de Cardiología, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, México
Jessica Mercedes
Departamento de Cardiología, Hospital Nacional San Rafael, Santa Tecla, El Salvador
Clara Inés Saldarriaga-Giraldo orcid.org/0000-0002-5945-1127
Departamento de Cardiología Clínica y Falla Cardiaca, Clínica CardioVID, Medellín, Colombia
María Juliana Rodríguez-González orcid.org/0000-0002-6865-8031
Departamento de Cardiología, LaCardio-Fundación Cardioinfantil, Bogotá, Colombia
Armando Alvarado
Hospital Especializado de Villa Nueva, Villa Nueva, Guatemala
Juan Carlos Ortega
Departamento de Cardiología, Hospital Universitario Erasmo Meoz, Cúcuta, Colombia
Miguel Quintana Da Silva orcid.org/0009-0001-9322-629X
Departamento de Cardiología, Instituto Cardiovascular Sanatorio MIGONE, Asunción, Paraguay
Kavita Singh orcid.org/0000-0003-4330-666X
Public Health Foundation of India, Gurugram, Haryana, India; Centre for Chronic Disease Control, New
Delhi, India; Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany
Karen Sliwa orcid.org/0000-0002-8272-0911
Cape Heart Institute, Department of Medicine & Cardiology, Groote Schuur Hospital, Faculty of Health
Sciences, University of Cape Town, South Africa, World Heart Federation, Switzerland
On behalf of the CARDIO COVID 19–20 and WHF CVD COVID-19 research groups

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Submitted: 29 September 2024

Accepted: 11 February 2025
Published: 28 February 2025

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