A Population-Based Registry Analysis on Hospitalized COVID-19 Patients with Previous Cardiovascular Disease: Clinical Profile, Treatment, and Predictors of Death

A high percentage of patients with COVID-19 (coronavirus disease 2019) have previous cardiovascular disease (CVD). The findings presented here came from an epidemiological population-based registry study (real-world data) that enrolled all in-hospital COVID-19 patients with previous CVD from 1 March to 31 May 2020. Death, other comorbidities, hospital stay variables, ventilation type, and main clinical outcomes were evaluated. In Castile and Leon, 35.83% of the 7307 in-hospital COVID-19 patients who participated in this study had previous CVD, particularly arrhythmias (48.97%), cerebrovascular disease (25.02%), ischemic heart disease (22.8%), and chronic heart failure (20.82%). Of the patients, 21.36% were men and more than 90% were over 65 years of age, and the mortality rate achieved 32.93%. The most used medicines were antibiotics (91.41%), antimalarials (73.3%), steroids (46.64%), and antivirals (43.16%). The main predictors of death were age over 65 years (OR: 5), ventilation needs (OR: 2.81), treatment with anti-SIRS (systemic inflammatory response syndrome) medicines (OR: 1.97), antivirals (OR: 1.74) or steroids (OR: 1.68), SIRS (OR: 5.75), SARS (severe acute respiratory syndrome) (OR: 2.44), or AKI (acute kidney injury) (OR: 1.63) occurrence. Chronic heart failure and cerebrovascular disease were associated with a worse clinical course of COVID-19, especially in men older than 65 years with diabetes who developed SIRS, SARS, or AKI.


Variables
The main study outcome was in-hospital patient death. Hospital stay variables were considered such as hospitalization period (in days) and length of stay in the intensive care unit (ICU) (in days). Furthermore, ventilation type data were obtained: oxygenation, non-invasive positive pressure ventilation (NIPPV), and invasive ventilation (IV). Finally, the following clinical outcomes were evaluated: severe acute respiratory syndrome (SARS), acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), acute heart failure, bacterial and fungal superinfection, and DIC.

Statistical Analysis
For all analyses, the gender and age distribution of the population were considered, establishing two groups with a cut-off age of 65 years. The findings related to the prevalence of previous CVD, comorbidities, pharmacological treatment, and clinical outcomes are expressed in frequencies (percentage) with their corresponding 95% confidence intervals (95% CI) and as means accompanied by their standard deviations (SDs) or as medians accompanied by their interquartile range (IQR).
For comparisons between groups, the Student's t-test or the Mann-Whitney U test for continuous variables and Pearson's chi-square test or Fisher's exact test for categorical variables were used, as appropriate. The normal data distribution was evaluated using the Kolmogorov-Smirnov and Shapiro-Wilk tests.
To identify the predictors of in-hospital patients' death with previous CVD, a multivariate logistic regression with a forward selection approach was performed. The results are expressed in terms of adjusted odds ratio (OR) and 95% CI, and the following variables were included in the model: age (≥65), gender, ventilation, type of previous CVD (aneurysms, arrhythmias, atherosclerosis, heart dysfunction, cerebrovascular disease, ischemic heart disease, chronic heart failure, cardiomyopathy, and thrombosis-thrombophlebitis), other comorbidities (hypertension, diabetes, chronic kidney diseases, obesity, chronic respiratory disease, neoplasia, and autoimmune disease), obesity, medication use (antibiotics, anti-malarials, steroids, antivirals, tocilizumab, and anti-SIRS), and clinical outcomes (SARS, SIRS, DIC, acute heart failure, and bacterial and fungal superinfections).
The level of significance was set at p ≤ 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 24.0., SPSS Inc., Chicago, IL, USA).
The mortality rate has decreased from 1 March 2020 and 15 March 2020, (69.05%) to 15 May 2020 and 31 May 2020 (16.55%). The hospital and ICU length of stay also decreased throughout the study period, from a median of 19.5 to 9 days and 26.5 to 8 days, respectively ( Figure 1).
The level of significance was set at p ≤ 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 24.0., SPSS Inc., Chicago, IL, USA).

Risk Factor for Clinical Outcomes and Medication Prescribed
The multiple logistic regression analysis for all in-hospital COVID-19 patients showed that previous CVD impact on death (OR: 1.57; 95% CI: 1.39-1.79). Furthermore, in patients with previous CVD, the presence of comorbidities, such as diabetes mellitus, was associated with a higher probability of death compared to those patients with previous CVD without comorbidities (OR: 1.27, 1.05-1.55). In patients with previous CVD, it was observed that patients with chronic heart failure (OR: 1.27, 1.02-1.58) and with cerebrovascular disease (OR: 1.35, 1.09-1.66) were most likely to die than those who had other types of previous CVD.
In addition, among in-hospital COVID-19 patients, death was more likely to occur in those over 65 years of age (OR: 5, 3.

Risk Factor for Clinical Outcomes and Medication Prescribed
The multiple logistic regression analysis for all in-hospital COVID-19 patients showed that previous CVD impact on death (OR: 1.57; 95% CI: 1.39-1.79). Furthermore, in patients with previous CVD, the presence of comorbidities, such as diabetes mellitus, was associated with a higher probability of death compared to those patients with previous CVD without comorbidities (OR: 1.27, 1.05-1.55). In patients with previous CVD, it was observed that patients with chronic heart failure (OR: 1.27, 1.02-1.58) and with cerebrovascular disease (OR: 1.35, 1.09-1.66) were most likely to die than those who had other types of previous CVD.
In addition, among in-hospital COVID-19 patients, death was more likely to occur in those over 65 years of age (

Discussion
Approximately one out of three in-hospital COVID-19 patients had previous CVD, mainly arrhythmias, cerebrovascular disease, ischemic heart disease, and chronic heart failure. The mortality rate of these patients was the third highest, after those who developed AKI (46.1%) and SARS (42.53%). As in other studies conducted by our team [32,33], the use of antibiotics and steroids remained stable, while the use of antimalarials, antivirals, tocilizumab, and other anti-SIRS decreased between 1 March 2020 and 31 May 2020. Our results show that males with previous CVD, especially chronic heart failure or cerebrovascular diseases, older than 65 years, who needed some type of ventilation, and who developed SIRS, SARS, and AKI had a higher risk of death. In addition, the use of anti-SIRS medicines, antivirals, and steroids was related to a worse prognosis of the disease.
At this point, it is convenient to clarify the dual role of ACE2. First, COVID-19 symptoms were more severe in patients with CVD, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals [3]. Second, the

Discussion
Approximately one out of three in-hospital COVID-19 patients had previous CVD, mainly arrhythmias, cerebrovascular disease, ischemic heart disease, and chronic heart failure. The mortality rate of these patients was the third highest, after those who developed AKI (46.1%) and SARS (42.53%). As in other studies conducted by our team [32,33], the use of antibiotics and steroids remained stable, while the use of antimalarials, antivirals, tocilizumab, and other anti-SIRS decreased between 1 March 2020 and 31 May 2020. Our results show that males with previous CVD, especially chronic heart failure or cerebrovascular diseases, older than 65 years, who needed some type of ventilation, and who developed SIRS, SARS, and AKI had a higher risk of death. In addition, the use of anti-SIRS medicines, antivirals, and steroids was related to a worse prognosis of the disease.
At this point, it is convenient to clarify the dual role of ACE2. First, COVID-19 symptoms were more severe in patients with CVD, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals [3]. Second, the inhibition of ACE2 may be another factor of lung injury as well as the cause of the systemic inflammation following cytokine release, which can result in acute respiratory distress syndrome (ARDS) and multiorgan dysfunction [16][17][18].
The prevalence of in-hospital COVID-19 patients with previous CVD is higher than other Spanish [34,35], European [36], and Chinese [1] cohorts, while it is lower compared to another US cohort [37]. This finding is possible in relation to the predominance of the elderly in Castile and Leon, which is demonstrated by the elevated median age observed (83 years). As in other national [34,35] and international cohorts [38][39][40][41], our findings showed a higher prevalence in males than in females. A meta-analysis carried out by Ortolan et al. [42] showed that males are 61% more likely to die from COVID-19 infection than females. This higher predisposition in males appears to be related to differences in innate immunity, steroid hormones, and factors related to sex chromosomes. In this sense, the double copy of the X chromosome in females is essential against viral infections. However, it is observed that female are at a higher risk of COVID-19 clinical manifestations in the long term than males [43].
Surprisingly, in our cohort, hospital death was not influenced by the obesity factor as was the case in other studies [44,45]. One possible explanation is that the obesity rate of our patients was lower than in other cohorts [46].
Although primarily a respiratory disease, COVID-19 also causes important systemic effects, especially on the cardiovascular and immune systems. For this reason, in patients with previous CVD, mortality rates of 5-10 times higher are observed [8]. Our findings showed that the increase in mortality was not so pronounced among patients without previous CVD (19.68%) compared to patients with previous CVD (32.93%).
As in other published studies [38,40,41,[47][48][49], hypertension and diabetes were the most observed comorbidities, followed by chronic respiratory disease and some type of neoplasia, increasing the thrombotic event risk, which is associated with a mortality increase [50].
The pharmacological treatments used for COVID-19 have significant cardiovascular toxicities and side effects. However, data on side effects come from chronic treatments for other clinical conditions such as autoimmune diseases (hydroxychloroquine, chloroquine, and tocilizumab), hepatitis (interferon), or HIV (lopinavir-ritonavir) [26].
Azithromycin was consumed mainly by patients who did not die (69.36%), although it is known that this antibiotic in combination with hydroxychloroquine prolongs the QT interval [51].
Antimalarial drugs (i.e., hydroxychloroquine and chloroquine) were used in three out of four patients. It is known that these drugs at high doses mainly cause cardiac conduction disorders, in addition to ventricular hypertrophy, hypokinesia, heart failure, pulmonary arterial hypertension, and valve dysfunction [52].
Steroids were used in half of deceased patients (51.51%) and a positive OR was observed (1.68). This may be since in the case of methylprednisolone, which was the most frequently used steroid, it has been associated with electrolyte derangements, fluid retention, and hypertension [53].
The percentage of patients treated with antivirals (43.16%) was lower than in other studies [54], but it has been related to a higher probability of death (OR: 1.74). The combination of lopinavir-ritonavir must be used with caution, since it can interact with cardiovascular medicines metabolized by cytochrome P450-3A4 such as antiarrhythmics, antiplatelets, and anticoagulants [55], in addition to causing QT and PR segment prolongation [56]. In the case of remdesevir, no associated cardiovascular adverse effects have been reported [25].
The use of tocilizumab (8.33%) has demonstrated cardiovascular safety in patients with rheumatoid arthritis, although it is not currently confirmed in patients with previous CVD [57].
The anti-SIRS medicines are associated with a greater probability of death (OR: 1.97), probably because the patients are in a more advanced and more severe phase of the disease; therefore, the probability of death is higher.
Regarding thromboprophylaxis strategies, according to different studies [58,59], initial treatment with heparin improves the prognosis of COVID-19 by increasing survival until hospital discharge compared to routine thromboprophylaxis, especially in non-critical patients.
Lastly, this study has several limitations that must be mentioned. Occasionally, the diagnosis of COVID-19 was made according to clinical and radiological criteria without microbiological confirmation. Another possible limitation was the unavailability of other variables, such as earlier lifestyle factors, physical activity level, or sleep, which can influence the results of the logistic regression model regarding the prediction of hospital death in patients with previous CVD. Regarding pharmacological treatment, only the Spanish guidelines [28,29] indicators were considered, and other possible treatments used may have been ignored. On the other hand, cardiovascular pharmacological treatments during patient admission were not available, which may be a limitation.

Conclusions
Almost one out of three in-hospital COVID-19 patients had a previous CVD, of which half had arrhythmias history. In addition, these patients had a worse disease prognosis with higher mortality than the global patient average [32].
According to our findings, men older than 65 years with diabetes who developed SIRS, SARS, or AKI had a higher probability of hospital death. Among previous CVDs, chronic heart failure and cerebrovascular disease were associated with a worse clinical course of the disease, and a greater probability of associated death was observed.
Regarding pharmacological treatment, antivirals and antimalarials, especially, have shown long-term cardiovascular toxicity, but it is too early to analyze their short-term effects. The medicines used for COVID-19 treatment were modified throughout the study period according to the availability and the national guideline recommendations [28,29].
Definitely, previous CVDs are related to a worse prognosis of COVID-19; therefore, "special attention" to these patients must be paid, especially after steroid, antiviral, and anti-SIRS administration, which are associated with a higher probability of death.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/1 0.3390/jcdd8120167/s1, Table S1: List of medicines used in the COVID-19 treatment according to Spanish guidelines; Table S2: Treatment and clinical outcome evolution of in-hospital COVID-19 patients with previous cardiovascular diseases.  Informed Consent Statement: Patient consent was waived due to the fact that this was a retrospective observational study, and anonymized databases provided by the health authorities were used.

Data Availability Statement:
Restrictions apply to the availability of these data. Data were obtained from regional health authorities (Gerencia Regional de Salud (GRS)) and may be requested from sdinvestigacion@saludcastillayleon.es (GRS).