Losartan in hospitalized patients with COVID-19 in North America: An individual participant data meta-analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) have been hypothesized to benefit patients with COVID-19 via the inhibition of viral entry and other mechanisms. We conducted an individual participant data (IPD) meta-analysis assessing the effect of starting the ARB losartan in recently hospitalized COVID-19 patients. METHODS: We searched ClinicalTrials.gov in January 2021 for U.S./Canada-based trials where an angiotensin-converting enzyme inhibitors/ARB was a treatment arm, targeted outcomes could be extrapolated, and data sharing was allowed. Our primary outcome was a 7-point COVID-19 ordinal score measured 13 to 16 days post-enrollment. We analyzed data by fitting multilevel Bayesian ordinal regression models and standardizing the resulting predictions. RESULTS: 325 participants (156 losartan vs 169 control) from 4 studies contributed IPD. Three were randomized trials; one used non-randomized concurrent and historical controls. Baseline covariates were reasonably balanced for the randomized trials. All studies evaluated losartan. We found equivocal evidence of a difference in ordinal scores 13-16 days post-enrollment (model-standardized odds ratio [OR] 1.10, 95% credible interval [CrI] 0.76-1.71; adjusted OR 1.15, 95% CrI 0.15-3.59) and no compelling evidence of treatment effect heterogeneity among prespecified subgroups. Losartan had worse effects for those taking corticosteroids at baseline after adjusting for covariates (ratio of adjusted ORs 0.29, 95% CrI 0.08-0.99). Hypotension serious adverse event rates were numerically higher with losartan. CONCLUSIONS: In this IPD meta-analysis of hospitalized COVID-19 patients, we found no convincing evidence for the benefit of losartan versus control treatment, but a higher rate of hypotension adverse events with losartan.

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.

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and the Risk of SARS-CoV-2 Infection or Hospitalization With COVID-19 Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: SARS-CoV-2 infects its target cells via angiotensin converting enzyme 2 receptor, a membrane-bound protein found on the surface of many human cells. Treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptors blockers (ARB) has been shown to increase angiotensin converting enzyme 2 expression by up to 5-fold. AREAS OF UNCERTAINTY: These findings coupled with observations of the high prevalence and mortality among SARS-CoV-2-infected patients with underlying cardiovascular disease have led to a speculation that ACEIs/ARBs may predispose to higher risk of being infected with SARS-CoV-2. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and the risk of SARS-CoV-2 infection or hospitalization due to COVID-19 disease. DATA SOURCES: We searched Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Medrxiv.org preprint server until June 18, 2020. THERAPEUTIC ADVANCES: Ten studies (6 cohorts and 4 case control) that enrolled a total of 23,892 patients and 853,369 controls were eligible for inclusion in our meta-analysis. One study was excluded from the analysis because of high risk of bias. Prior use of ACEIs was not associated with an increased risk of acquiring SARS-CoV-2 or hospitalization due to COVID-19 disease, odds ratio 0.98, 95% confidence interval (0.91-1.05), I2 = 15%. Similarly, prior use of ARBs was not associated with an increased risk of acquiring SARS-CoV-2, odds ratio 1.04, 95% confidence interval (0.98-1.10), I2 = 0%. CONCLUSION: Cumulative evidence suggests that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19 or hospitalization due to COVID-19 disease. Our results provide a reassurance to the public not to discontinue prescribed ACEIs/ARBs because of fear of COVID-19.

Headache medication and the COVID-19 pandemic.

The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.

Discontinuation of Renin-Angiotensin System Inhibitors During the Early Stage of the COVID-19 Pandemic.

BACKGROUND: In March and April 2020, medical societies published statements recommending continued use of renin-angiotensin system (RAS) inhibitors despite theoretical concerns that these medications could increase COVID-19 severity. Determining if patients discontinued RAS inhibitors during the COVID-19 pandemic could inform responses to future public health emergencies. METHODS: We analyzed claims data from US adults with health insurance in the Marketscan database. We identified patients who filled a RAS inhibitor and were persistent, defined by not having a ≥30-day gap without medication available, and high adherence, defined by having medication available on ≥80% of days, from March 2019 to February 2020. Among these patients, we estimated the proportion who discontinued their RAS inhibitor (i.e., had ≥30 consecutive days without a RAS inhibitor available to take) between March and August 2020. For comparison, we estimated the proportion of patients that discontinued a RAS inhibitor between March and August 2019 after being persistent with high adherence from March 2018 to February 2019. RESULTS: Among 816,380 adults who were persistent and adherent to a RAS inhibitor from March 2019 to February 2020, 10.8% discontinued this medication between March and August 2020. Among 822,873 adults who were persistent and adherent to a RAS inhibitor from March 2018 to February 2019, 11.7% discontinued this medication between March and August 2019. The multivariable-adjusted relative risk for RAS inhibitor discontinuation in 2020 vs. 2019 was 0.94 (95% CI 0.93-0.95). CONCLUSIONS: There was no evidence of an increase in RAS inhibitor discontinuation during the early stage of the COVID-19 pandemic.

Systematic review and meta-analysis of the clinical outcomes of ACEI/ARB in East-Asian patients with COVID-19.

BACKGROUND: SARS-CoV-2 invades human cells and leads to COVID-19 by direct associating with angiotensin converting enzyme 2 (ACE2) receptors, the level of which may be increased by treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). This meta-analysis aimed to explore the impact of ACEI/ARB treatment on the clinical outcomes of patients with COVID-19 infections among population in the East-Asia region. METHODS: We collected clinical data published from January 2000 to May 2022 in the English databases including PubMed, Embase, and the Cochrane Library. Two reviewers independently screened and identified studies that met the prespecified criteria. Review Manager 5.3 software was used to perform the meta-analysis. RESULTS: A total of 28 articles were included in this analysis. The results showed that patients who were prescribed with ACEI/ARB had a shorter duration of hospital stay [MD = -2.37, 95%CI (-3.59, -1.14), P = 0.000 2] and a lower mortality rate [OR = 0.61, 95% CI (0.52, 0.70), P<0.000 01] than patients who were not on ACEI/ARB. Furthermore, there was no statistically significant difference in disease severity [OR = 0.99, 95% CI (0.83, 1.17), P = 0.90] between individuals receiving ACEI/ARB or not. CONCLUSIONS: This meta-analysis suggested that the use of ACEI/ARB was not associated with adverse clinical outcomes in East-Asian Covid-19 patients and a reduced mortality and shorter duration of hospital stay among East-Asian population (especially for female subjects) was found. Thus, ACEI/ARB should be continued in patients infected by Covid-19.

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.

The effects of hypertension on the prognosis of coronavirus disease 2019: a systematic review and meta-analysis on the interactions with age and antihypertensive treatment.

BACKGROUND: Hypertension and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) have been reported to be associated with the prognosis of COVID-19, but the findings remain controversial. Here, we conducted a systematic review to summarize the current evidence. METHODS: We retrieved all the studies by MEDLINE via PubMed, CENTRAL, and Embase using the MeSH terms until 30 April 2021. A fixed or random effect model was applied to calculate pooled adjusted odds ratio (AOR) with 95% confidence interval (CI). Interactive analysis was performed to identify the interaction effect of hypertension and age on in-hospital mortality. RESULTS: In total, 86 articles with 18 775 387 COVID-19 patients from 18 countries were included in this study. The pooled analysis showed that the COVID-19 patients with hypertension had increased risks of in-hospital mortality and other adverse outcomes, compared with those without hypertension, with an AOR (95% CI) of 1.36 (1.28-1.45) and 1.32 (1.24-1.41), respectively. The results were mostly repeated in countries with more than three independent studies. Furthermore, the effect of hypertension on in-hospital mortality is more evident in younger and older COVID-19 patients than in 60-69-year-old patients. ACEI/ARBs did not significantly affect the mortality and adverse outcomes of COVID-19 patients, compared with those receiving other antihypertensive treatments. CONCLUSION: Hypertension is significantly associated with an increased risk of in-hospital mortality and adverse outcomes in COVID-19. The effect of hypertension on in-hospital mortality among consecutive age groups followed a U-shaped curve. ACEI/ARB treatments do not increase in-hospital mortality and other poor outcomes of COVID-19 patients with hypertension.

Renin-Angiotensin Aldosterone System Inhibitors and COVID-19: A Systematic Review and Meta-Analysis Revealing Critical Bias Across a Body of Observational Research.

Background Renin-angiotensin aldosterone system (RAAS) inhibitor-COVID-19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID-19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor-COVID-19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID-19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin-converting enzyme inhibitors or angiotensin II type-I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed-effects meta-analyses, only from studies without critical risk of bias that assessed severe COVID-19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta-analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin-converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66-0.87; P<0.001; angiotensin II type-I receptor blockers: HR, 0.86; 95% CI, 0.77-0.97; P=0.015) and intubation or death (angiotensin-converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48-0.85; P=0.002; angiotensin II type-I receptor blockers: HR, 0.74; 95% CI, 0.58-0.95; P=0.019) with COVID-19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. Conclusions This study reveals the critical risk of bias that exists across almost an entire body of COVID-19 research, raising an important question: Were research methods and/or peer-review processes temporarily weakened during the surge of COVID-19 research or is this lack of rigor a systemic problem that also exists outside pandemic-based research? Registration URL: www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021237859.

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.

Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial.

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Safety of ACEi and ARB in COVID-19 management: A retrospective analysis.

BACKGROUND & AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)is a highly contagious virus that has infected 260 million individuals since December 2019. The severity of coronavirus disease 2019 (COVID-19) depends upon the complex interplay between viral factors and the host's inflammatory response, which can trigger a cascadeeventually leading to multiorgan failure. There is contradictory evidence that angiotensin-converting enzyme (ACEi) or angiotensin receptor blockers (ARBs) may affect mortality in patients with severe COVID-19, theoretically due to interaction with the bradykinin pathway. Therefore, we aim to explore the association between ACEi and ARB use and mortality in severe SARS-CoV2 infection.Severe acute respiratory yndrome with coronavirus (SARS-CoV2) is a highly contagious virus that has infected 260 million individuals since December 2019. The severity of COVID-19 depends upon the complex interplay between viral factors and the host's inflammatory response, which can trigger a cascadeeventually leading to multiorgan failure. There is contradictory evidence that angiotensin-converting enzyme (ACEi) or angiotensin receptor blockers (ARBs) may affect mortality in patients with severe COVID-19, theoretically due to interaction with the bradykinin pathway. Therefore, we aim to explore the association between ACEi and ARB use and mortality in severe SARS-CoV2 infection. MATERIALS & METHODOLOGY: This multicenter retrospective observational study enrolled 2935 COVID-19 patients admitted at six hospitals in Southern California, USA, between March 2020 and August 2021. Our primary outcome was the association of pre-hospital use of ACEi and ARB on in-hospital mortality in COVID-19 patients. First, relevant deidentified patient data were extracted using an SQL program from the electronic medical record. Then, a bivariate analysis of the relationship between ACEi and ARB use and different study variables using χ2 and t test was done. Finally, we did a backward selection Cox multivariate regression analysis using mortality as a dependent variable. RESULTS: Of the 2935 patients in the study, hypertension was present in 40.6%, and congestive heart failure in 13.8%. ACEi and ARB were used by 17.5% and 11.3% of patients, respectively, with 28.8% of patients on either medication. After adjusting for confounding variables in the multivariate analysis, the use of ACEi (HR: 1.226, 95% CI: 0.989-1.520) or ARB (HR: 0.923, 95% CI: 0.701-1.216) was not independently associated with increased mortality. CONCLUSION: Our results are consistent with the clinical guidelines and position statements per the International Society of Hypertension, that there is no indication to stop the use of ACEi/ARB in COVID-19 patients.

What is the association of renin-angiotensin-aldosterone system inhibitors with COVID-19 outcomes: retrospective study of racially diverse patients?

OBJECTIVE: To describe the clinical outcomes of COVID-19 in a racially diverse sample from the US Southeast and examine the association of renin-angiotensin-aldosterone system (RAAS) inhibitor use with COVID-19 outcome. DESIGN, SETTING, PARTICIPANTS: This study is a retrospective cohort of 1024 patients with reverse-transcriptase PCR-confirmed COVID-19 infection, admitted to a 1242-bed teaching hospital in Alabama. Data on RAAS inhibitors use, demographics and comorbidities were extracted from hospital medical records. PRIMARY OUTCOMES: In-hospital mortality, a need of intensive care unit, respiratory failure, defined as invasive mechanical ventilation (iMV) and 90-day same-hospital readmissions. RESULTS: Among 1024 patients (mean (SD) age, 57 (18.8) years), 532 (52.0%) were African Americans, 514 (50.2%) male, 493 (48.1%) had hypertension, 365 (36%) were taking RAAS inhibitors. During index hospitalisation (median length of stay of 7 (IQR (4-15) days) 137 (13.4%) patients died; 170 (19.2%) of survivors were readmitted. RAAS inhibitor use was associated with lower in-hospital mortality (adjusted HR, 95% CI (0.56, (0.36 to 0.88), p=0.01) and no effect modification by race was observed (p for interaction=0.81). Among patients with hypertension, baseline RAAS use was associated with reduced risk of iMV, adjusted OR, 95% CI (aOR 0.58, 95% CI 0.36 to 0.95, p=0.03). Patients with heart failure were twice as likely to die from COVID-19, compared with patients without heart failure. CONCLUSIONS: In a retrospespective study of racially diverse patients, hospitalised with COVID-19, prehospitalisation use of RAAS inhibitors was associated with 40% reduction in mortality irrespective of race.