key: cord-0959136-04hqulge
authors: Oh, Tak Kyu; Cho, Hyoung-Won; Suh, Jung-Won; Song, In-Ae
title: Incidence and Mortality Associated with Cardiovascular Medication among Hypertensive COVID-19 Patients in South Korea
date: 2021-07-01
journal: Yonsei Med J
DOI: 10.3349/ymj.2021.62.7.577
sha: 69e16ad1dac525442aa1ea3bca3da0fd31f0a3f6
doc_id: 959136
cord_uid: 04hqulge

PURPOSE: We aimed to investigate whether the use of cardiovascular drugs in coronavirus disease 2019 (COVID-19) patients with hypertension as a comorbidity has a significant effect on the incidence and associated mortality rate of COVID-19. MATERIALS AND METHODS: Data covering the period between January 1, 2020 and June 4, 2020 were extracted from The National Health Insurance Service-COVID-19 (NHIS-COVID-19) database in South Korea and analyzed as a population-based cohort study. RESULTS: A total of 101657 hypertensive adults aged 20 years or older were included for final analysis. Among them, 1889 patients (1.9%) were diagnosed with COVID-19 between January 1, 2020 and June 4, 2020, and hospital mortality occurred in 193 patients (10.2%). In a multivariable model, the use of beta-blockers was associated with an 18% lower incidence of COVID-19 [odds ratio (OR): 0.82, 95% confidence interval (CI): 0.69–0.98; p=0.029]. Among 1889 hypertensive patients diagnosed with COVID-19, the use of a calcium channel blocker (CCB) was associated with a 42% lower hospital mortality rate (OR: 0.58, 95% CI: 0.38–0.89; p=0.012). The use of other cardiovascular drugs was not associated with the incidence of COVID-19 or hospital mortality rate among COVID-19 patients. Similar results were observed in all 328374 adults in the NHIS-COVID-19 database, irrespective of the presence of hypertension. CONCLUSION: In South Korea, beta-blockers exhibited potential benefits in lowering the incidence of COVID-19 among hypertensive patients. Furthermore, CCBs may lower the hospital mortality rate among hypertensive COVID-19 patients. These findings were also applied to the general adult population, regardless of hypertension.

sis of COVID-19. [13] [14] [15] However, other reports suggest that ACEis and ARBs may be used safely in COVID-19 patients 16 and may even result in better outcomes, including lower all-cause mortality. 17 One popular type of cardiovascular medication, namely calcium channel blockers (CCBs), has been reported to improve outcomes in COVID-19 patients by inhibiting the postentry replication events of SARS-CoV-2. 18 Beta-blockers have also been reported to decrease the severity of COVID-19 symptoms in patients 14 because they may reduce the activity of the renin-angiotensin-aldosterone system and ACE2, which may decrease the rate of SARS-CoV-2 entry into host cells. 19 Thus, the association of cardiovascular drugs with the risk of mortality among COVID-19 patients remains controversial.

Accordingly, we aimed to investigate whether the use of cardiovascular drugs among hypertensive patients is associated with the incidence of COVID-19 and its related mortality rate in South Korea.

We conducted this population-level cohort study according to the Reporting of Observational Studies in Epidemiology guidelines. 20 The need for approval of the study protocol was exempted upon deliberation by the Institutional Review Board of Seoul National University Bundang Hospital (X-2004-604-905) and the National Health Insurance Service (NHIS) (NHIS-2020-1-424). Also, the need for informed consent was waived because data analyses were performed retrospectively using anonymized data derived from the South Korean NHIS database.

In this study, we utilized data from the NHIS-COVID-19 cohort database, which was created for medical research in a collaborative effort between the Korea Centers for Disease Control and Prevention (KCDC) and the NHIS. The KCDC provided data on individuals who had tested positive for COVID-19 between the dates of January 1, 2020 and June 4, 2020. The data included the COVID-19 confirmation date, demographic information, and treatment results. In the NHIS-COVID-19 database, COVID-19 patients included all individuals who had tested positive to a COVID-19 polymerase chain reaction (PCR) test; therefore, the database included both COVID-19 patients with severe symptoms, such as pneumonia, who had been admitted to a hospital for treatment and COVID-19 patients with no or mild symptoms. COVID-19 patients who are currently undergoing in-hospital treatment have not been included in the database because the results of in-hospital treatment have not yet been determined.

Using stratification methods, the NHIS has also provided a control population with regard to age, sex, and place of residence as of February 2020 using the COVID-19 patients' infor-mation from the KCDC. The database contains all disease diagnoses using International Classification of Diseases (ICD)-10 codes and prescription information concerning drugs and/or procedures from 2015 to 2020. It also contains data on individuals who had undergone a COVID-19 PCR test, but tested negative. Therefore, the NHIS-COVID-19 database comprises data for three groups: COVID-19 patients, a control population, and individuals who have tested negative. For the hypertensive cohort, we included adults (20 years or older) in the NHIS database who had been diagnosed with hypertension (I10* according to ICD-10 codes) between 2015 and 2019.

The exposure variable in this cohort study was the prescription of cardiovascular drugs. To evaluate this, the prescription data from 2019 to 2020 were extracted from the NHIS database. Individuals were defined as cardiovascular drug users if they were prescribed regular cardiovascular drugs from 2019 for over 90 days until the date of diagnosis of COVID-19 in 2020 for COV-ID-19 patients or until June 4, 2020 for individuals who were not diagnosed with COVID-19. The cardiovascular drugs included ACEi, aspirin, ARB, beta-blocker, CCB, clopidogrel, and thiazide.

The primary endpoint of our study was the development of CO-VID-19. COVID-19 positivity was evaluated by a COVID-19 PCR test during the period between January 1, 2020 and June 4, 2020. The secondary endpoint was hospital mortality among patients who were diagnosed with COVID-19. Hospital mortality was evaluated among COVID-19 patients until August 27, 2020.

The following data were extracted and collected as confounders in this study: 1) demographic characteristics (age and sex), 2) annual income level in 2020, 3) place of residence (Seoul, Gyeonggi-do, Daegu, Gyeongsangbuk-do, and other areas), 4) underlying disabilities (mild degree and moderate-to-severe degree), and 5) comorbidity information using Charlson comorbidity index scores, which were calculated using the registered ICD-10 diagnostic codes (Supplementary Table 1 

The baseline characteristics of the participants in this study are presented as numbers with percentages for categorical variables and mean values with their respective standard deviations for continuous variables. First, we fitted a multivariable logistic regression model for the diagnosis of COVID-19 among hypertensive individuals in the NHIS-COVID-19 cohort to investigate whether cardiovascular drug use was associated with the incidence of COVID-19. All seven cardiovascular drugs (ACEi, aspirin, ARB, beta-blocker, CCB, clopidogrel, and thiazide) were included in the multivariable logistic regression model simultaneously. In the model, the reference value for each drug was obtained from non-users of that drug. In addition, a separate multivariable logistic regression model was fitted to investigate whether the use of any of the cardiovascular drugs was associated with the incidence of COVID-19, compared to non-use of the drug. All covariates were included for multivariable adjustment, although the Charlson comorbidity index was included in the other model to avoid multicollinearity with other underlying diseases that were used to calculate the Charlson comorbidity index. Next, we fitted a multivariable logistic regression model for hospital mortality among hypertensive COVID-19 patients to investigate whether cardiovascular drug use was associated with hospital mortality among COVID-19 patients.

For sensitivity analysis, we constructed two multivariable logistic regression models for 1) COVID-19 diagnosis and 2) hospital mortality among COVID-19 patients to identify whether the results obtained from hypertensive patients in the NHIS-COVID-19 cohort were generalizable to the entire NHIS-CO-VID-19 cohort, including individuals without hypertension. Hosmer-Lemeshow statistics were used to confirm the goodness of fit of the multivariable models at p>0.05, and it was confirmed that there was no multicollinearity in any of the multivariable models, with a variance inflation factor of <2.0. The results of the logistic regression models are presented as odds ratios (ORs) with 95% confidence intervals (CIs). R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria) was used for all analyses, and a p-value<0.05 was considered statistically significant.

A flowchart depicting participant selection in this study is presented in Fig. 1 . The NHIS-COVID-19 cohort comprised 8070 COVID-19 patients, 121050 individuals in the control population, and 222257 negative-tested individuals. In total, 351377 individuals were initially reviewed. After excluding 23003 individuals aged <20 years, 328374 adults were further reviewed. Of these, 101657 adults were diagnosed with hypertension and included in the final analysis. The clinically relevant baseline characteristics of these individuals are presented in Table  1 . 83215 individuals (81.9%) had been prescribed cardiovascular medication for treatment. In addition, 1889 (1.9%) were diagnosed with COVID-19 between January 1, 2020 and June 4, 2020. The incidence of hospital mortality among COVID-19 patients was 193 (10.2%). Table 2 shows the results of the multivariable logistic regression model for the diagnosis of hypertensive COVID-19 patients. In multivariable model 1, the use of beta-blockers was associated with an 18% lower incidence of COVID-19 (OR: 0.82, 95% CI: 0.69-0.98; p=0.029), while other cardiovascular drugs, such as ACEi (p=0.269), aspirin (p=0.354), ARB (p=0.580), CCB (p= 0.707), clopidogrel (p=0.220), and thiazide (p=0.249), were not associated with the incidence of COVID-19. In multivariable model 2, compared with non-users, the use of cardiovascular medication was not associated with the incidence of COVID-19 (p=0.215). The results of multivariable logistic regression analysis of hospital mortality among COVID-19 patients with hypertension are presented in Table 3 . In multivariable model 1, among the 1889 hypertensive COVID-19 patients, CCB use was associated with a 42% lower hospital mortality (OR: 0.58, 95% CI: 0.38-0.89; p=0.012). However, other cardiovascular drugs, such as ACEi (p=0.728), aspirin (p=0.825), ARB (p=0.440), beta-blockers (p=0.793), clopidogrel (p=0.373), and thiazide (p=0.393), were not associated with hospital mortality among hypertensive COVID-19 patients. In multivariable model 2, compared to non-users, the use of cardiovascular medication was not associated with hospital mortality among hypertensive COVID-19 patients (p=0.352). 

In this study, we found that beta-blocker use was associated with a lower incidence of COVID-19 among hypertensive patients, while CCB use was associated with a decreased hospital mortality rate among hypertensive COVID-19 patients. These findings were also applied to the general adult population, regardless of hypertension diagnosis, in the NHIS-COVID-19 database. Since the relationship between cardiovascular drugs and the risk of COVID-19 is currently undetermined, 6 our findings have potential clinical benefits. It was recently reported that beta-adrenergic receptors might be involved in SARS-CoV-2 entry into the cell by acting as a coreceptor via its interaction through surface vimentin and ACE2 receptor. 21 Thus, the potential role of beta-blockers in treatment for COVID-19 was suggested in September 2020. 19 Furthermore, recent evidence has shown that treatment with beta-blockers reduces mortality in septic shock patients 22 and has beneficial effects in individuals with acute respiratory distress syndrome or respiratory failure. 23 However, at the time of writing this report, no study has described clinical effects for beta-blockers in COVID-19 patients. 14, 24 We report, for the first time, that prior beta-blocker therapy might be associated with a reduced risk of COVID-19 among both hypertensive patients and the general adult population in South Korea. However, the hospital mortality rate among COVID-19 patients was not associated with beta-blocker therapy, and more clinical research is needed in this regard.

We also found that CCB use was associated with decreased mortality among both hypertensive and non-hypertensive CO-VID-19 patients. A previous in vitro study reported that SARS-CoV-2 requires Ca2+ ions for host cell entry 25 and that CCBs are efficacious in inhibiting the spread of SARS-CoV-2 in cell cultures. 26 CCB (amlodipine besylate) administration has been found to be associated with better outcomes among COVID-19 patients. 18 However, other studies, including a meta-analysis conducted among older COVID-19 patients 14 and a prospective cohort study in Italy, did not demonstrate benefits for CCB use on the prognosis of COVID-19 patients. 27 Notwithstanding, the sample size in the latter study was small (69), 27 while we included 101657 hypertensive adults and 328374 adults from the general population. Considering the mixed results of previous studies regarding the effect of CCB on COVID-19 patients, 14, 18, 27 our results might provide rationale and evidence on which to consider the administration of CCB among COV-ID-19 patients in the future.

Interestingly, in our sensitivity analysis, aspirin showed potential benefits in lowering COVID-19 incidence among adults in general, but not in the hypertensive population. As one of the most common and important cardiovascular drugs, aspirin has been prescribed for adults to reduce the risk of acute cardiovascular events, suggesting it has a broader indication than that of anti-hypertensive drugs. 28 Currently, there is emerging evidence on the benefits of using aspirin to treat COVID-19 patients. 29 SARS-CoV-2 is known to cause lung and systemic inflammation, 30 which can cause severe respiratory failure, multiorgan dysfunction, and mortality. 31 The main pathological features of COVID-19 are micro-and macrovascular thromboses due to the activation of the immune response with the release of pro-inflammatory cytokines and the overactivation of the coagulation cascade and platelet aggregation. 32 Therefore, aspirin has been suggested as a new treatment option for CO-VID-19 patients as it has anti-inflammatory, antithrombotic, and antiviral effects. 33 The potential benefits of aspirin in reducing COVID-19 incidence in our study need further research.

The current study has a few limitations. First, some clinically important variables, such as body mass index, were not included in the analysis because they were not available in the NHIS database. Second, multivariable adjustment is known to reduce known and measured confounders. Thus, there might be some residual confounders that affect the results of this study. Third, we defined comorbidities using ICD-10 codes to calculate the Charlson comorbidity index, but the diseases specified by the ICD-10 codes might not reflect actual comorbidities in our study population. Furthermore, our analysis was based on prescription data in the NHIS database; we did not assess compliance among those classified as cardiovascular drug users. Fourth, we did not consider the daily dosage of cardiovascular drugs because the NHIS database provides this prescription information with masking of type and dosage. Finally, we did not consider the possibility of combining any of the seven cardiovascular drugs in this study because there were too many possible combinations of cardiovascular drugs to reflect in the multivariable model. Therefore, combinations of cardiovascular drugs might affect the results in this study and should be interpreted carefully.

Using the NHIS-COVID-19 database cohort, we showed that beta-blockers may have potential benefits in lowering the incidence of COVID-19 in hypertensive patients in South Korea. Among these hypertensive COVID-19 patients, we also found that CCB may lower hospital mortality rates. These findings were also applied to the general adult population, regardless of the presence of hypertension as a variable, in the NHIS-COV-ID-19 database.

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Tak Kyu Oh https://orcid.org/0000-0002-4027-4423 Hyoung-Won Cho https://orcid.org/0000-0001-6095-8569 Jung-Won Suh https://orcid.org/0000-0002-0397-6071 In-Ae Song https://orcid.org/0000-0002-7814-4253