What this is
- This research analyzes the impact of corticosteroid therapy on patients with COVID-19 and pre-existing cardiovascular disease.
- It evaluates 18-month all-cause mortality and long-term symptoms in a cohort from the HOPE-2 registry.
- The study involved 1188 patients with heart disease, comparing those who received corticosteroids to those who did not.
Essence
- Corticosteroid treatment in COVID-19 patients with pre-existing heart disease showed no difference in 18-month mortality but resulted in shorter hospital stays.
Key takeaways
- Corticosteroid treatment did not lead to a higher all-cause death rate at 18 months in patients with pre-existing heart disease.
- Patients receiving corticosteroids had a shorter median hospital stay of 8 days compared to 11 days for those not treated.
- No significant association was found between corticosteroid use and long-term COVID-19 symptoms, suggesting a complex relationship in this population.
Caveats
- The observational design may introduce biases, affecting the reliability of the results.
- Variability in corticosteroid usage across centers and lack of data on dosing could influence outcomes.
- Potential confounding factors from patients with other pathologies might obscure the true effects of corticosteroid treatment.
Simplified
1. Introduction
The novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged from a zoonotic source, was initially identified in December 2019, leading to the declaration of the Coronavirus Disease 2019 (COVID-19) pandemic by the World Health Organization on 11 March 2020 [1].
While many infected individuals experience mild or no symptoms, a substantial proportion of patients develop severe disease requiring hospitalization, particularly those with underlying cardiovascular conditions [2].
In the RECOVERY study, patients hospitalized due to COVID-19 were allocated to receive either dexamethasone or standard care, with 28-day mortality as the main endpoint. Treatment with dexamethasone significantly reduced death among individuals who required invasive ventilation or supplemental oxygen, whereas no survival benefit was seen in those who did not need respiratory support or who were given higher doses [1]. Matthay et al. suggested that corticosteroid use at early disease stages or at high cumulative doses could be linked to poorer outcomes [3], a concept later examined in several observational cohorts [4,5].
Evidence of cardiac injury, reflected by increased circulating troponin concentration during COVID-19 infection, has been associated with unfavorable prognosis, particularly among individuals with prior cardiovascular comorbidities [6].
In addition, a retrospective analysis of individuals admitted for pneumonia reported that exposure to systemic corticosteroids correlated with a higher incidence of significant cardiovascular complications, especially in patients with cardiovascular risk factors or in those receiving higher doses or prolonged treatments [7].
Prior studies have shown that individuals with pre-existing cardiovascular disorders experience worse clinical outcomes and are more likely to develop persistent sequelae following SARS-CoV-2 infection. These patients exhibit both higher in-hospital and post-discharge mortality rates and report more frequent long-term symptoms after recovery. The adverse prognosis seems to stem from an exaggerated inflammatory response, dysregulated immune signaling, and endothelial impairment, which may intensify myocardial damage and tissue hypoxia [8,9]. Despite these associations, the effect of corticosteroid therapy in this population has not been clearly determined, and its clinical value continues to be debated. Figure 1 illustrates the effects of corticosteroid therapy in COVID-19 patients according to the presence or absence of pre-existing heart disease.
This study sought to analyze how corticosteroid treatment for COVID-19 influenced clinical outcomes in patients with pre-existing cardiovascular disease and to explore its potential association with persistent post-COVID-19 symptoms in a prospective multi-center registry.
2. Materials and Methods
2.1. Study Design and Participation Criteria
The HOPE-2 registry (Health Outcome Predictive Evaluation for COVID-19—2) [NCT04778020] is a prospective, investigator-initiated, multi-center study conceived under an "all-comers" approach and carried out without financial remuneration for the participating researchers. The dataset analyzed in this work can be obtained from the corresponding author upon reasonable request. Inclusion criteria encompassed all patients admitted to any participating hospital with either confirmed COVID-19 or a high clinical suspicion of infection, irrespective of survival status. COVID-19 was confirmed through nasopharyngeal or oropharyngeal swab samples processed by a real-time reverse transcriptase polymerase chain reaction (RT-PCR) according to World Health Organization recommendations. For patients who died before testing, infection was considered confirmed when there was a high clinical suspicion of infection. No specific exclusion criteria were applied except for explicit refusal to participate. Clinical management and decision-making were performed by attending physicians in accordance with each institution's local protocols and international organizations recommendations that were in effect during the study period [8,10].
The study protocol received ethical approval from the Ethics Committee of Hospital Clínico San Carlos (reference 21/128-E) and was subsequently endorsed by the ethics committees or institutional review boards of all participating sites. Given its anonymized and observational design, the coordinating ethics committee granted a waiver of written informed consent, in line with Spanish law and international ethical principles for health-related research. Data were collected electronically through a secure online platform, starting on 15 March 2021, and the present manuscript includes analyses performed up to 31 December 2021. Data integrity and manuscript validation were overseen by the principal investigators at each center. Detailed study definitions and the full list of collaborators have been reported previously [8].
2.2. Data Acquisition and Study Definitions
Eligible participants were those with a documented history of cardiovascular disease who experienced either confirmed or clinically suspected COVID-19 infection during any hospital admission. The presence and type of cardiac disease were identified from medical records or ongoing treatments and were pragmatically classified by site investigators as arrhythmic, ischemic, heart failure or cardiomyopathy, valvular, combined or unspecified, and other forms such as congenital heart disease [8].
The administration of corticosteroids was conducted at the discretion of the attending clinicians, guided by the patient's condition and indications such as pneumonia, sepsis, systemic inflammatory response syndrome, requirement for invasive or non-invasive ventilation, circulatory or extracorporeal membrane oxygenation (ECMO) support, or high-flow oxygen therapy. Outcomes during follow-up were documented locally according to predefined registry criteria. The overall patient selection process is illustrated in Figure 2.
2.3. Study Follow-Up and Outcomes
The present analysis included hospitalized individuals with confirmed COVID-19 infection and a documented history of cardiovascular disease. The primary outcome was all-cause mortality at 18 months, whereas secondary endpoints addressed the occurrence of long-term post-COVID-19 symptoms. Follow-up data were gathered through standardized telephone assessments conducted with patients or their relatives and were complemented by information provided by attending clinicians and reviews of medical records.
2.4. Statistical Analysis
Continuous variables were summarized as the mean ± standard deviation when normally distributed or as the median with the interquartile range otherwise. Categorical variables were expressed as counts and percentages. Comparisons between groups were performed with Student's t-test or the Mann–Whitney U test for continuous variables and with Pearson's chi-square or Fisher's exact test for categorical variables.
Within the subgroup of patients presenting pre-existing cardiac disease, a propensity score for corticosteroid treatment was constructed based on baseline variables showing a p-value < 0.05 in the univariable analysis (including renal impairment, chronic pulmonary disease, and immunosuppression). The model was additionally adjusted for clinical factors defining severe SARS-CoV-2 and potential indication for corticosteroid therapy (pneumonia, sepsis, respiratory failure, and systemic inflammatory response syndrome [SIRS]). Subsequently, a 1:1 matched sample was generated by pairing treated and untreated individuals using nearest-neighbor matching with a caliper width of 0.5.
Survival was assessed through Kaplan–Meier curves with log-rank testing. The survival period was calculated from the date of hospital admission to the 18-month follow-up. Mortality comparisons were carried out with chi-square testing. A post hoc sensitivity analysis using the log-rank test was performed as well to explore a possible association between all-cause death and invasive mechanical ventilation as well as statin therapy in the post-PSM population. The length of hospital stay was analyzed with the Mann–Whitney U test.
All statistical analyses were conducted with IBM SPSS Statistics v26.0 (SPSS Inc., Chicago, IL, USA) and R v4.4.1. Two-tailed tests were applied, and a p-value < 0.05 was considered statistically significant. A pre-specified sensitivity analysis was also performed to assess whether the timing of corticosteroid initiation (within ±7 days of symptom onset) influenced overall mortality.
3. Results
The baseline clinical profile of patients with pre-existing heart disease who were hospitalized with or without corticosteroid therapy is summarized in. Individuals receiving corticosteroids more frequently presented a history of chronic lung disease, chronic kidney disease, or immunosuppression and were less often treated with statins. During hospitalization, these patients exhibited a higher incidence of pneumonia, respiratory failure, and systemic complications such as sepsis, acute kidney injury, and systemic inflammatory response syndrome (). Supplementary Table S1 Table S1
The clinical characteristics of both groups after propensity score matching on baseline and outcome variables are detailed in Table 1.
In the matched cohort, patients with corticosteroid treatment experienced a higher frequency of in-hospital bleeding events and the need for invasive mechanical ventilation. Additionally, the proportion of individuals on statin therapy remained higher among those treated with corticosteroids.
Table 2 shows the distribution of the different types of heart disease in the matched population. No significant differences were found in the distribution of heart disease types between the two groups (p = 0.83).
Survival analysis is presented by Kaplan–Meier curves in Figure 3, demonstrating no differences in all-cause mortality at 18 months in the log-rank test (p = 0.52) in patients with previous heart disease treated with corticosteroids compared to those without corticosteroid treatment. The comparison of hospital stay and categorical mortality analysis (Table 1) indicated a shorter length of hospitalization in the corticosteroid group, while overall mortality remained similar. In-hospital mortality, assessed through a chi-squared test, also revealed no statistically significant differences between the two treatment groups.
We conducted a pre-specified sensitivity analysis to assess whether the timing of corticosteroid initiation had a significant influence on all-cause mortality, and no significant differences were found. Additionally, we performed a post hoc sensitivity analysis to assess the association between all-cause death and invasive mechanical ventilation in the matched population, as well as statins. We generated Kaplan–Meier curves for patients with and without each of the aforementioned therapies, comparing survival according to corticosteroid use in both subgroups, with no significant differences observed.
A comparison of long-term post-COVID-19 symptoms across groups is summarized in Table 3. No significant relationship was observed between corticosteroid therapy and the occurrence of persistent symptoms in patients with pre-existing cardiac disease, except for major bleeding events, which were more frequent among corticosteroid users. The number of reports of dizziness tended to be higher in the steroid-treated group, whereas myalgia was more common among those who did not receive corticosteroids, although these differences did not reach statistical significance.
4. Discussion
In this study, we evaluate the effect of corticosteroid treatment in patients with previous heart disease who were hospitalized with a COVID-19 infection on mortality and long-term COVID-19 symptoms.
The main findings in terms of patients with previous heart disease are as follows: (1) Systemic corticosteroid use was not associated with a higher all-cause death rate at 18 months. (2) Patients who underwent corticosteroid treatment had a shorter in-hospital stay. (3) No association was found between corticosteroid treatment and long-term COVID-19 symptoms.
Several prior investigations have characterized the distinctive clinical features of COVID-19 infection among individuals with pre-existing cardiac disease [1], and others have suggested that corticosteroid therapy may exert harmful cardiovascular effects [10,11]. However, no previous study has specifically examined the impact of corticosteroid use in patients with underlying heart disease and COVID-19 infection. The present work aimed to determine whether the response to corticosteroid treatment differs in this subgroup of patients with underlying heart disease.
The mechanisms underlying myocardial involvement likely include the direct viral invasion of cardiomyocytes together with indirect contributors such as hypoxia-related damage, local inflammatory activity, and increased prothrombotic signaling [1]. Angiotensin-converting enzyme 2 (ACE2), which serves as the binding receptor for the viral spike protein, has been shown to be upregulated in cardiac tissue from patients with heart failure, prior myocardial infarction, and diabetes [12,13,14].
Although a mortality benefit of corticosteroid treatment has been observed in the general population, this study did not find a significant association between corticosteroid treatment and mortality in our cohort of patients with heart disease.
Statin therapy has previously been associated with a favorable prognosis in the context of COVID-19 infection [15]. In our cohort, the use of statins was more frequent among patients who did not receive corticosteroid therapy. This finding could be related to a higher prevalence of comorbidities in this subgroup, having led clinicians to be more cautious or reluctant to prescribe corticosteroids due to concerns about potential adverse effects in fragile patients. However, after further analysis, this imbalance did not influence the association between steroid treatment and mortality.
Corticosteroid use has been related to several unfavorable cardiovascular outcomes. Observational data indicate that oral corticosteroid therapy may elevate the risk of acute myocardial infarction, particularly within the first month of exposure, and has also been associated with the onset of atrial fibrillation [16,17]. Among patients hospitalized for pneumonia, systemic corticosteroid administration has been correlated with a higher rate of cardiovascular complications, with the likelihood increasing proportionally to both treatment duration and cumulative dose [7].
Glucocorticoid therapy is recognized as elevating blood pressure, an effect that frequently manifests soon after treatment initiation [18]. Although the precise mechanisms remain incompletely clarified, available data point toward an imbalance between vasoconstrictive and vasodilatory responses, mediated by alterations in vasoactive mediators, oxidative stress, and the stimulation of the renin–angiotensin system [17]. Moreover, corticosteroids promote renal sodium and water retention, potentially worsening fluid overload and contributing to adverse outcomes in patients with heart failure [19]. Consistent with volume overload, several studies examining the link between glucocorticoid exposure and cardiovascular risk have described stronger associations with heart failure than with other cardiac complications [20,21,22].
In our matched analysis, corticosteroid administration was significantly linked to a higher incidence of in-hospital bleeding events. This observation may reflect the well-documented association between corticosteroid exposure and an elevated risk of gastrointestinal hemorrhage [23]. Although the underlying mechanism has not been fully elucidated, corticosteroids are thought to interfere with tissue regeneration, potentially delaying mucosal healing [23]. Prophylactic anticoagulation during the acute phase of COVID-19 has been reported to reduce 30-day mortality in observational cohorts [24]. Additionally, Santoro et al. demonstrated that the combination of aspirin and prophylactic anticoagulation conferred a lower mortality risk compared with anticoagulation alone in hospitalized COVID-19 patients, suggesting a synergistic antithrombotic effect [25]. While these interventions appear to improve short-term prognosis, they simultaneously increase bleeding susceptibility. In our study, the distribution of these therapies was comparable between groups, supporting a potential contribution of corticosteroid therapy itself to the observed excess of bleeding events.
Interestingly, we observed an increased risk of clinically relevant bleeding during follow-up among individuals who received corticosteroids in the acute phase of infection. Yao et al. reported that hemorrhagic complications related to short corticosteroid "bursts" peak during the first month after exposure and, although they decline over time, remain slightly elevated for up to 90 days after therapy initiation [26]. This temporal pattern may account for the greater number of bleeding episodes identified in the corticosteroid-treated subgroup during follow-up.
These pathophysiological mechanisms, when acting in a population with pre-existing heart disease, where the baseline risk of such complications is already elevated, may partly explain why corticosteroid treatment did not confer a survival benefit in our cohort of patients with underlying cardiovascular disease. The lack of a statistically significant relationship between steroid use and mortality emphasizes the need for additional research focused on this specific population.
Nevertheless, we did not observe detrimental cardiovascular consequences among corticosteroid-treated patients, as long-term mortality was comparable between groups. Interestingly, corticosteroid treatment was associated with a shorter duration of hospitalization, suggesting a potential advantage in recovery time and clinical stabilization, as noted in previous reports [2,27,28].
Long-term COVID-19 symptoms are common, particularly in patients who were hospitalized or have a history of heart disease [29]. Such manifestations tend to occur more frequently and resolve more slowly in individuals with cardiovascular comorbidities [30]. Freund et al. linked the severity of acute infection with greater respiratory symptom burden and reduced diffusing capacity (DLCO) at three-month follow-up, reinforcing the role of acute disease severity in the development of long-term sequelae [31].
Although some studies have suggested that corticosteroid therapy during the acute phase of COVID-19 may lower the risk of post-COVID-19 syndrome, our results did not confirm this benefit in patients with underlying heart disease [32].
Corticosteroid therapy has been linked to a higher likelihood of developing long-term cardiovascular complications related to COVID-19, including hypertension, acute coronary syndromes, and atrial fibrillation [17]. In our cohort, however, the frequency of these events during follow-up was comparable between steroid-treated patients and those who did not receive such therapy. This finding may be explained by the overall low incidence of cardiovascular events, which could have reduced the statistical power to identify differences, and by the short-lived nature of corticosteroid-induced cardiovascular effects. Furthermore, the slower recovery trajectory typical of cardiovascular patients may obscure potential differences between treatment groups.
Clinical Implications
Our study tried to analyze the clinical response to corticosteroid therapy in COVID-19 patients with previous heart disease. We found an association between corticosteroid use and shorter hospital stay, likely related to the impact of these drugs on symptom duration. However, no clear association was demonstrated with long-term symptoms or reduced in-hospital or 18-months mortality.
Although corticosteroid therapy is generally advised for patients with COVID-19-related respiratory failure who lack prior cardiac disease, its administration in individuals with established heart conditions remains complex due to the potential adverse cardiovascular effects of these agents. Consequently, in such cases, treatment decisions should be carefully tailored, balancing possible therapeutic benefits against cardiovascular risks.
In our study, patients were categorized according to the presence of pre-existing heart disease; however, in everyday clinical practice, it is essential to recognize that cardiovascular disorders are heterogeneous and cannot be approached uniformly. Each patient should therefore be assessed individually to ensure that management strategies are adapted to the specific cardiac substrate and overall clinical context.
5. Limitations
The main limitation of this study lies in its design (i.e., observational, all-comer approach, electronic data collection), which may introduce relevant biases that could influence the results. It is also important to note that, to balance the two groups, patients were matched using variables known to influence prognosis. While this approach aims to reduce confounding factors, it may also make it more difficult to detect potential differences between groups.
Patients with a highly suspicious COVID-19 diagnosis who died before confirmation were included in this study, which raises the possibility of inadvertently including patients with other pathologies that could confound the results.
Given our study design, we cannot affirm that the observed results were attributable to corticosteroid treatment, as the influence of uncontrolled or unmeasured factors cannot be excluded.
There might be considerable variability in the indications and use of corticosteroids across different centers as well as an absence of data regarding the dose and duration of corticosteroid treatment, which represents a source of potential bias. Moreover, there are no data collected regarding some pharmacological therapies (e.g., antidiabetic drugs) that are frequently used in this subgroup of patients and could have prognostic impact.
A higher proportion of patients requiring invasive mechanical ventilation was present in the corticosteroid subgroup after propensity score matching, which may have obscured a potential beneficial effect of corticosteroid treatment. However, an additional Cox regression analysis did not demonstrate an association between invasive mechanical ventilation and mortality in our population.
Heart disease is a concept that includes a wide range of cardiovascular conditions. Different responses to corticosteroids across the different pathologies could influence the results.
6. Conclusions
This study provides an analysis of the effects of corticosteroid treatment in a cohort of patients with COVID-19 and pre-existing heart disease. The results showed no clear mortality benefit in this subgroup; however, no harmful effects were observed either, and a potential benefit in terms of hospital stay was appreciated. These findings highlight the need for further research to clarify the effects of corticosteroids in patients with pre-existing heart disease and to evaluate the safety of their use in this population, which is at higher risk of complications. Future studies should aim to determine whether specific subgroups of cardiac patients could benefit from tailored corticosteroid regimens and to identify potential biomarkers that may help guide individualized therapeutic decisions.