Discontinuation of Antihypertensive Drug Use Compared to Continuation in COVID-19 Patients: A Systematic Review with Meta-analysis and Trial Sequential Analysis.

INTRODUCTION: COVID-19 related mortality is about 2%, and it increases with comorbidities, like hypertension. Regarding management, there is debatable evidence about the benefits of continuation vs. discontinuation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB). AIM: We performed a systematic review to assess the effects and safety of in-hospital discontinuation compared to continuation of ACEI/ARB in COVID-19 patients. METHODS: We systematically searched on PubMed, Scopus, and EMBASE from inception to June 19, 2021. We included observational studies and trials that compared the effects and safety of continuing ACEI/ARB compared to discontinuing it in COVID-19 patients. Effects sizes for dichotomous variables were expressed as risk ratios (RR) and 95% confidence intervals. For continuous variables, effects were expressed as mean difference (MD). We used random effect models with the inverse variance method. We assessed certainty of evidence using the GRADE approach. RESULTS: We included three open-label randomized controlled trials and five cohort studies. We found that the continuation group had lower risk of death compared with the discontinuation group only in the cohort group (RR: 0.46, 95% CI: 0.24-0.90), but not in the RCT group (RR: 1.22, 95% CI: 0.75-2.00). The ICU admission rate was significantly lower in the continuation group (RR: 0.46, 95% CI: 0.31-0.68) in the cohort group, but not in RCT group (RR: 1.03, 95% CI: 0.67-1.59). We did not find significant differences between groups regarding hospitalization length, hypotension, AKI needing renal replacement therapy, mechanical ventilation, new or worsening heart failure, myocarditis, renal replacement therapy, arrhythmias, thromboembolic events and SOFA AUC. The GRADE approach revealed that the certainty ranged from moderate to high level. CONCLUSIONS: There is no significant difference in mortality and other outcomes between continuation and discontinuation groups.

Primary hypertension, anti-hypertensive medications and the risk of severe COVID-19 in UK Biobank.

Hypertension appears to be one of the commonest comorbidities in COVID-19 patients, although whether hypertensive individuals have a higher risk of severe COVID-19 compared with non-hypertensives is unclear. It is also unclear whether the absolute level of systolic blood pressure, or the type of anti-hypertensive medication is related to this risk. Analyses were conducted using data from the UK Biobank and linked health records. Logistic regression models were fitted to assess the impact of hypertension, systolic blood pressure (SBP) and medications on the risk of severe COVID-19. 16,134 individuals tested positive for severe acute respiratory syndrome-coronavirus, 22% (n = 3,584) developed severe COVID-19 and 40% (n = 6,517) were hypertensive. Hypertension was associated with 22% higher odds of severe COVID-19 (Odds ratio (OR) 1.22; 95% confidence interval (CI) 1.12, 1.33), compared with normotension after adjusting for confounding variables. In those taking anti-hypertensive medications, elevated SBP showed a dose-response relationship with severe COVID-19 (150-159mmHg versus 120-129mmHg (OR 1.91; 95% CI 1.44, 2.53), >180+mmHg versus 120-129mmHg (OR 1.93; 95% CI 1.06, 3.51)). SBP <120mmHg was associated with greater odds of severe COVID-19 (OR 1.40; 95% CI 1.11, 1.78). Angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers were not associated with altered risk of severe COVID-19. Hypertension is an important risk factor for COVID-19. A better understanding of the underlying mechanisms is warranted in case of more severe strains or other viruses in the future.

Angiotensin Receptor Blockers in the Management of Hypertension: A Real-World Perspective and Current Recommendations.

Hypertension represents a major common cardiovascular risk factor. Optimal control of high blood pressure levels is recommended to reduce the global burden of hypertensive-mediated organ damage and cardiovascular (CV) events. Among the first-line drugs recommended in international guidelines, renin-angiotensin-aldosterone system antagonists [angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs)] have long represented a rational, effective, and safe anti-hypertensive pharmacological strategy. In fact, current US and European guidelines recommend ACEi and ARBs as a suitable first choice for hypertension treatment together with calcium channel blockers (CCBs) and thiazide diuretics. Different studies have demonstrated that ARBs and ACEi exert a comparable effect in lowering blood pressure levels. However, ARBs are characterized by better pharmacological tolerability. Most importantly, the clinical evidence supports a relevant protective role of ARBs toward the CV and renal damage development, as well as the occurrence of major adverse CV events, in hypertensive patients. Moreover, a neutral metabolic effect has been reported upon ARBs administration, in contrast to other antihypertensive agents, such as beta-blockers and diuretics. These properties highlight the use of ARBs as an excellent pharmacological strategy to manage hypertension and its dangerous consequences. The present review article summarizes the available evidence regarding the beneficial effects and current recommendations of ARBs in hypertension. The specific properties performed by these agents in various clinical subsets are discussed, also including an overview of their implications for the current COVID-19 pandemic.

Initiation of antihypertensive drugs to patients with confirmed COVID-19-A population-based cohort study in Sweden.

PURPOSE: Hypertension is an important risk factor for severe outcomes in patients with COVID-19, and antihypertensive drugs may have a protective effect. However, the pandemic may have negatively impacted health care services for chronic diseases. The aim of this study was to assess initiations of antihypertensive medicines in patients infected by COVID-19. METHODS: A cohort study including all Swedish residents 20-80 years old with a COVID-19 positive test compared with an unexposed group without COVID-19 matched for age, sex, and index date (date of confirmed COVID-19). Data were collected within SCIFI-PEARL, a study including linked data on COVID tests, hospital diagnoses, dispensed prescriptions, and socioeconomic data from Swedish national registers. Initiations of different antihypertensive drugs were studied from March 2020 until October 2020. Associations between COVID-19 and initiation of antihypertensives were assessed by a multivariable Cox proportional hazards model. RESULTS: A total of 224 582 patients (exposed and unexposed) were included. After adjusting for cardiovascular comorbidities and education level, ACEi was the most commonly initiated antihypertensive agent to patients with COVID-19. Hazard ratio and 95% confidence interval for initiation of drug therapy was 1.83 [1.53-2.19] for ACEi, followed by beta-blockers 1.74 [1.55-1.95], calcium channel blockers 1.61 [1.41-1.83], angiotensin receptor blockers 1.61 [1.40-1.86], and diuretics 1.53 [1.32-1.77]. CONCLUSION: All antihypertensive medicines were initiated more frequently in COVID-19 patients. This can either be associated with hypertension caused by the COVID-19 infection, more frequent diagnosis of hypertension among people with COVID-19 since they consult health care, or residual confounding factors not adjusted for in the study.

Interaction of ACEI antihypertensive agent's administration with the inflammatory status at admission concerning COVID-19 clinical stay outcomes.

Interactions between anti-hypertensive agents (ACEI), comorbidities, inflammation, and stress status may impact hospital stay duration in COVID-19 patients. This retrospective study analyzed epidemiological data, comorbidities, metabolic/inflammatory markers, and clinical information from 165 SARS-CoV-2 positive patients. In a multiple linear regression model, an IL-6 higher than 100 mg/L, glucose at admission (baseline levels at the hospital entry), and the interaction between ACEI administration and LDH predicted the days of hospital admission (P < 0.001). In conclusion, hypertensive patients suffering more severe inflammatory condition assessed by LDH levels clinically benefited more and reduced the hospital stay when prescribed ACEI agents than those with lower systemic baseline inflammation at admission.

Data mining methodology for response to hypertension symptomology-application to COVID-19-related pharmacovigilance.

Background: Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. Methods: Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO. Results: Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy. Conclusions: We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness. Funding: GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.

White Coat Uncontrolled Hypertension in Teleconsultation: A New and Frequent Entity.

INTRODUCTION: Cardiovascular risk seems not to be greater in patients with white coat uncontrolled hypertension (WUCH) than in patients with sustained blood pressure (BP) control. Therefore, its detection is important to avoid overtreatment. The COVID-19 pandemic determined a massive migration of hypertension consultations from the face-to-face modality to teleconsultations, and it is unknown whether WUCH exists in this context. AIM: We aimed to evaluate the prevalence of WUCH through home BP monitoring (HBPM) in treated hypertensive patients evaluated by teleconsultation. METHODS: We included treated hypertensive patients that owned a digital BP monitor. During teleconsultation, patients were asked to perform two BP measurements and then a 7-day HBPM, using the same device. Patients were classified as having WUCH if BP was ≥ 140 and/or 90 mmHg in teleconsultation and < 135/85 mmHg on HBPM. The prevalence of WUCH and its 95% confidence interval were estimated. One-way ANOVA, the Chi-square test or Fisher's exact test were used to compare the characteristics of these patients with the other groups. RESULTS: We included 341 patients (45.2% male, mean age 62.3 years). The prevalence of WUCH was 33.1% (95% CI 28.3-38.3%). Significant differences were found in terms of age, the number of antihypertensive drugs and the use of calcium channel blockers, all lower in the WUCH group as compared with the groups with elevated BP on HBPM. CONCLUSION: WUCH exists in teleconsultation and is very frequent. It can be easily detected though HBPM, thus avoiding overmedication, and its potential impact on side-effects and health costs.

[Retrospective analysis of clinical outcomes of patients with COVID-19 depending on receiving antihypertensive, lipid-lowering and antihypertensive therapy].

BACKGROUND: The main factors that increase the risk of cardiovascular accidents and mortality among patients with COVID-19 include hyperglycemia, arterial hypertension and dyslipidemia. Therefore, all patients with COVID-19 and metabolic syndrome should receive antihypertensive (AHT), hypolipidemic (GLT) and hypoglycemic therapy (GGT). Currently, there is a limited number of studies regarding the effectiveness and safety of this therapy in patients with COVID-19. AIM: Evaluate the clinical outcomes of patients with COVID-19, depending on the recipient of AHT, GLT and GGT. MATERIALS AND METHODS: A retrospective analysis of the clinical outcomes "discharged/died" of 1753 patients with COVID-19 was carried out depending on the received AHT, GLT and GGT. RESULTS: A significant reduction in the risk of mortality among patients with COVID-19 was observed during therapy with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers ACE inhibitors/ARBs (OR 0.39, 95% CI 0.210.72; p0.05) and b-adrenergic blockers b-AB (OR 0.53, 95% CI 0.281; p0.05). At the same time, against the background of therapy with ACE inhibitors/ARBs and b-ABs, the chance of mortality decreased more significantly among patients with type 2 diabetes mellitus (T2DM) compared with patients without T2DM. Diuretic therapy was associated with a 3-fold increase in the chances of death: OR 3.33, 95% CI 1.884.79; p0.05. Statin therapy did not affect clinical outcomes in COVID-19 patients. On the background of therapy with oral hypoglycemic drugs, the risk of mortality decreased 5-fold (OR 0.19, 95% CI 0.070.54; p0.05). Against the background of insulin therapy, there was an increase in mortality risk by 2.8 times (OR 2.81, 95% CI 1.55.29; p0.05). CONCLUSION: A significant reduction in mortality among patients with COVID-19 was observed during therapy with ACEI/ARB, b-AB, and oral hypoglycemic therapy. Increased risk of death was associated with insulin therapy and diuretic therapy.

[Tactics of antihypertensive therapy during COVID-19 pandemic].

Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.

Effects of renin-angiotensin system blockers on the risk and outcomes of severe acute respiratory syndrome coronavirus 2 infection in patients with hypertension.

BACKGROUND/AIMS: There are concerns that the use of renin-angiotensin system (RAS) blockers may increase the risk of being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or progressing to a severe clinical course after infection. This this study aimed to investigate the influence of RAS blockers on the risk and severity of SARS-CoV-2 infection. METHODS: We conducted a retrospective cohort study analyzing nationwide claims data of 215,184 adults who underwent SARS-CoV-2 tests in South Korea. The SARS-CoV-2 positive rates and clinical outcomes were evaluated according to the use of RAS blockers in patients with hypertension (n = 64,243). RESULTS: In total, 38,919 patients with hypertension were on RAS blockers. The SARS-CoV-2 positive rates were significantly higher in the RAS blocker group than in the control group after adjustments (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 1.10 to 1.36; p < 0.001), and matching by propensity score (adjusted OR, 1.16; 95% CI, 1.03 to 1.32; p = 0.017). Among the 1,609 SARS-CoV-2-positive patients with hypertension, the use of RAS blockers was not associated with poor outcomes, such as mortality (adjusted OR, 0.81; 95% CI, 0.56 to 1.17; p = 0.265), and a composite of admission to the intensive care unit and mortality (adjusted OR, 0.95; 95% CI, 0.73 to 1.22; p = 0.669). Analysis in the propensity scorematched population showed consistent results. CONCLUSION: In this Korean nationwide claims dataset, the use of RAS blockers was associated with a higher risk to SARS-CoV-2 infection but not with higher mortality or other severe clinical courses.

Hydralazine-induced liver injury: a review and discussion.

Hydralazine is a commonly prescribed antihypertensive agent. Some of its labelled adverse reactions include lupus-like syndrome, tachycardia, headache and fever. Despite its well-known side effects, little is known about hydralazine's hepatotoxic effects. We report the case of a 54-year-old female patient who was started on hydralazine for hypertension management but later presented with hydralazine-induced liver injury. Her initial presentation consisted of non-specific symptoms and a hepatocellular injury pattern. Liver biopsy revealed hepatic steatosis. Three weeks after discontinuation of hydralazine, the patient's liver enzymes normalised, and her symptoms resolved. Few studies have examined the incidence and mechanism by which hydralazine induces a liver injury pattern. With this case, we review the literature, the pathogenesis involved and the eventual management of hydralazine-induced liver injury. We propose close monitoring of liver enzymes for patients on hydralazine throughout their treatment course.

Sex Differences in Association Between Anti-Hypertensive Medications and Risk of COVID-19 in Middle-Aged and Older Adults.

BACKGROUND: There is ongoing debate about the associations between drug therapies targeting the renin-angiotensin-aldosterone system (RAAS) and adverse outcomes in coronavirus disease 2019 (COVID-19). OBJECTIVE: This study aims to examine the associations between using medications for the cardiovascular system and the risks associated with COVID-19 in middle-aged and older adults. METHODS: A total of 77,221 participants (aged 50-86 years) from UK Biobank were tested for SARS-CoV-2 RNA. The medications included angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), ß-blockers, calcium channel blockers (CCB), statins, and aspirin. COVID-19 outcomes comprised a positive test result and severity of COVID-19 (defined as mild, hospitalization or death). We evaluated the risk among total participants and for sub-groups based on sex. Propensity score matching was performed 1:1 and logistic regression models were used. RESULTS: Among the middle- and older aged participants, no significant associations between any class of medications and the likelihood of COVID-19 infection were observed. ACEI were associated with a higher mortality risk from COVID-19 (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01-1.32) and CCB were associated with a lower hospitalization risk for COVID-19 (OR 0.87, 95% CI 0.79-0.96) among the male patients with COVID-19, while a lower mortality risk from COVID-19 (OR 0.67, 95% CI 0.47-0.96) was observed with ARB among the female patients with COVID-19. CONCLUSIONS: The study suggested sex differences in the risk of death from COVID-19 with the use of ACEI and ARB among middle-aged and older adults. Sex differences in the risk of hospitalization for COVID-19 with the use of CCB was observed as well. It is of clinical importance that clinicians adopt different CVD treatment approaches for female and male patients with COVID-19.

[The RAAS and SARS-CoV-2: A riddle to solve]. / El SRAA y el SARS-CoV-2: el acertijo a resolver.

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.

Pulmonary adverse drug event data in hypertension with implications on COVID-19 morbidity.

Hypertension is a recognized comorbidity for COVID-19. The association of antihypertensive medications with outcomes in patients with hypertension is not fully described. However, angiotensin-converting enzyme 2 (ACE2), responsible for host entry of the novel coronavirus (SARS-CoV-2) leading to COVID-19, is postulated to be upregulated in patients taking angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Here, we evaluated the occurrence of pulmonary adverse drug events (ADEs) in patients with hypertension receiving ACEIs/ARBs to determine if disparities exist between individual drugs within the respective classes using data from the FDA Spontaneous Reporting Systems. For this purpose, we proposed the proportional reporting ratio to provide a statistical summary for the commonality of an ADE for a specific drug as compared to the entire database for drugs in the same or other classes. In addition, a statistical procedure, multiple logistic regression analysis, was employed to correct hidden confounders when causative covariates are underreported or untrusted to correct analyses of drug-ADE combinations. To date, analyses have been focused on drug classes rather than individual drugs which may have different ADE profiles depending on the underlying diseases present. A retrospective analysis of thirteen pulmonary ADEs showed significant differences associated with quinapril and trandolapril, compared to other ACEIs and ARBs. Specifically, quinapril and trandolapril were found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs as well as ARBs (P < 0.0001) for group comparison (i.e., ACEIs vs. ARBs vs. quinapril vs. trandolapril) and (P ≤ 0.0007) for pairwise comparison (i.e., ACEIs vs. quinapril, ACEIs vs. trandolapril, ARBs vs. quinapril, or ARBs vs. trandolapril). This study suggests that specific members of the ACEI antihypertensive class (quinapril and trandolapril) have a significantly higher cluster of pulmonary ADEs.

Comparison of renin-angiotensin-aldosterone system inhibitors with other antihypertensives in association with coronavirus disease-19 clinical outcomes.

BACKGROUND: Reports on the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on the clinical outcomes of coronavirus disease-19 (COVID-19) have been conflicting. We performed this meta-analysis to find conclusive evidence. METHODS: We searched published articles through PubMed, EMBASE and medRxiv from 5 January 2020 to 3 August 2020. Studies that reported clinical outcomes of patients with COVID-19, stratified by the class of antihypertensives, were included. Random and fixed-effects models were used to estimate pooled odds ratio (OR). RESULTS: A total 36 studies involving 30,795 patients with COVID-19 were included. The overall risk of poor patient outcomes (severe COVID-19 or death) was lower in patients taking RAAS inhibitors (OR = 0.79, 95% CI: [0.67, 0.95]) compared with those receiving non-RAAS inhibitor antihypertensives. However, further sub-meta-analysis showed that specific RAAS inhibitors did not show a reduction of poor COVID-19 outcomes when compared with any class of antihypertensive except beta-blockers (BBs). For example, compared to calcium channel blockers (CCBs), neither angiotensin-I-converting enzyme inhibitors (ACEIs) (OR = 0.91, 95% CI: [0.67, 1.23]) nor angiotensin-II receptor blockers (ARBs) (OR = 0.90, 95% CI: [0.62, 1.33]) showed a reduction of poor COVID-19 outcomes. When compared with BBs, however, both ACEIs (OR = 0.85, 95% CI: [0.73, 0.99) and ARBs (OR = 0.72, 95% CI: [0.55, 0.94]) showed an apparent decrease in poor COVID-19 outcomes. CONCLUSIONS: RAAS inhibitors did not increase the risk of mortality or severity of COVID-19. Differences in COVID-19 clinical outcomes between different class of antihypertensive drugs were likely due to the underlying comorbidities for which the antihypertensive drugs were prescribed, although adverse effects of drugs such as BBs could not be excluded.

Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes. Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19. Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020. Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs. Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs. Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19. Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007). Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.

Update on association between exposure to renin-angiotensin-aldosterone system inhibitors and coronavirus disease 2019 in South Korea.

BACKGROUND/AIMS: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, there have been concerns about the association between exposure to renin-angiotensin-aldosterone system (RAAS) inhibitors and the risk and severity of COVID-19. METHODS: We performed a case-control study that utilized up-to-date data on the South Korean population provided by the Korean National Health Insurance System. Of the 62,909 patients with hypertension or heart failure tested for COVID-19, there were 1,644 (2.6%) confirmed cases. After case-control matching, multivariable-adjusted conditional logistic regression analysis was performed. RESULTS: Comparison between patients exposed to RAAS inhibitors and those not exposed to RAAS inhibitors revealed that the adjusted odds ratio (OR) and 95% confidence interval (CI) for COVID-19 infection and death were 0.981 (95% CI, 0.849 to 1.135) and 0.875 (95% CI, 0.548 to 1.396), respectively. Subgroup analysis for the major confounders, age and region of diagnosis, resulted in OR of 0.912 (95% CI, 0.751 to 1.108) and 0.942 (95% CI, 0.791 to 1.121), respectively. CONCLUSION: The present study demonstrated no evidence of association between RAAS inhibitor exposure and risk and severity of COVID-19.

Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies.

Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.

Renin-angiotensin system inhibitors and susceptibility to COVID-19 in patients with hypertension: a propensity score-matched cohort study in primary care.

INTRODUCTION: Renin-angiotensin system (RAS) inhibitors have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This study investigated whether there is an association between their prescription and the incidence of COVID-19 and all-cause mortality. METHODS: We conducted a propensity-score matched cohort study comparing the incidence of COVID-19 among patients with hypertension prescribed angiotensin-converting enzyme I (ACE) inhibitors or angiotensin II type-1 receptor blockers (ARBs) to those treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 in each drug exposure group. We used Cox proportional hazards models to produce adjusted hazard ratios for COVID-19. We assessed all-cause mortality as a secondary outcome. RESULTS: The incidence rate of COVID-19 among users of ACE inhibitors and CCBs was 9.3 per 1000 person-years (83 of 18,895 users [0.44%]) and 9.5 per 1000 person-years (85 of 18,895 [0.45%]), respectively. The adjusted hazard ratio was 0.92 (95% CI 0.68 to 1.26). The incidence rate among users of ARBs was 15.8 per 1000 person-years (79 out of 10,623 users [0.74%]). The adjusted hazard ratio was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of RAS inhibitors and all-cause mortality. CONCLUSION: Use of ACE inhibitors was not associated with the risk of COVID-19 whereas use of ARBs was associated with a statistically non-significant increase compared to the use of CCBs. However, no significant associations were observed between prescription of either ACE inhibitors or ARBs and all-cause mortality.