Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis

Published:November 02, 2020DOI:https://doi.org/10.1016/j.jjcc.2020.10.015

      Highlights

      • The usage of antihypertensive drugs is not associated with the risk and severity of COVID-19.
      • Hypertensive patients with COVID-19 benefit from prior usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

      Abstract

      Background

      The association of antihypertensive drugs with the risk and severity of COVID-19 remains unknown.

      Methods and Results

      We systematically searched PubMed, MEDLINE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and medRxiv for publications before July 13, 2020. Cohort studies and case-control studies that contain information on the association of antihypertensive agents including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCBs), β-blockers, and diuretics with the risk and severity of COVID-19 were selected. The random or fixed-effects models were used to pool the odds ratio (OR) with 95% confidence interval (CI) for the outcomes.
      The literature search yielded 53 studies that satisfied our inclusion criteria, which comprised 39 cohort studies and 14 case-control studies. These studies included a total of 2,100,587 participants. We observed no association between prior usage of antihypertensive medications including ACEIs/ARBs, CCBs, β-blockers, or diuretics and the risk and severity of COVID-19. Additionally, when only hypertensive patients were included, the severity and mortality were lower with prior usage of ACEIs/ARBs (overall OR of 0.81, 95% CI 0.66−0.99, p < 0.05 and overall OR of 0.77, 95% CI 0.66−0.91, p < 0.01).

      Conclusions

      Taken together, usage of antihypertensive drugs is not associated with the risk and severity of COVID-19. Based on the current available literature, it is not recommended to abstain from the usage of these drugs in COVID-19 patients.

      Registration

      The meta-analysis was registered on OSF (https://osf.io/ynd5g).

      Keywords

      Introduction

      The 2019 coronavirus disease (COVID-19) pandemic is caused by the novel and highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of August 30, 2020, there were 25,099,237 confirmed cases globally and 844,176 deaths from the disease [
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      ].
      Viral infection occurs when the S protein of SARS-CoV-2 binds to the host angiotensin-converting enzyme 2 (ACE2) receptor to gain entry into the cells [
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      SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
      ]. ACE2 serves a crucial role in the counter regulation of the blood pressure regulating system—the renin-angiotensin-aldosterone system (RAAS) pathway—by primarily degrading angiotensin II to angiotensin-(1-7), thereby attenuating the effects of angiotensin II [
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      Role of the ACE2/Angiotensin 1–7 Axis of the renin–Angiotensin system in heart failure.
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      Previous evidence has suggested that antihypertensive drugs such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) can elevate ACE2 expression [
      • Ferrario Carlos M.
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      • Brosnihan K.B.
      • Tallant E.A.
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      Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
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      • Tallant E.A.
      • Brosnihan K.B.
      • Ferrario Carlos M.
      Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors.
      ,
      • Fang L.
      • Karakiulakis G.
      • Roth M.
      Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.
      ], which may increase susceptibility to and worsen the prognosis of COVID-19. Due to the high prevalence of COVID-19 in patients with preexisting cardiovascular conditions such as hypertension [
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      Patients with arterial hypertension and COVID-19 are at higher risk of ICU admission.
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      ], coronary artery disease, and congestive heart failure [
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      ], the usage of these antihypertensive drugs warrants great concerns. Indeed, controversy remains regarding the usage of these antihypertensive medications on the vulnerable population. We postulated that there may be an association between the usage of antihypertensive medications and the incidence and severity of COVID-19 due to the high mortality of patients with cardiovascular comorbidities.
      To this end, we designed a meta-analysis to address whether there is an association of antihypertensive medications and the incidence and severity of COVID-19. In addition to ACEIs and ARBs, we also investigated other antihypertensive drugs [calcium channel blockers (CCBs), β-blockers, and diuretics] to evaluate whether these drugs may potentially be better substitutes for ACEIs/ARBs in the event that ACEIs/ARBs had a significant, negative association with COVID-19. We comprehensively searched through large databases to acquire relevant studies. We performed meta-analyses on 53 studies, 39 of which were cohort studies and the remaining 14 were case-control studies.

      Methods

      The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.

       Literature search and inclusion criteria

      A comprehensive search strategy was designed to retrieve relevant data from published literature. Our objective was to identify all randomized controlled trials (RCTs), cohort studies, and case-control studies that contain information on the association of antihypertensive agents including ACEIs, ARBs, CCBs, β-blockers, and diuretics, with the risk and severity of COVID-19. We systematically searched PubMed, MEDLINE, The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and medRxiv for publications before July 13, 2020. We also searched conference proceedings and performed manual reference list searching to acquire relevant papers.
      Medical subject headings (MeSH) terms and keywords including randomized controlled trial, case-control study, cohort study, angiotensin-converting enzyme inhibitor, angiotensin II receptor blockers, calcium-channel blockers, beta-blockers, diuretics, anti-hypertensive agents, ACEIs, ARBs, coronavirus, 2019-nCoV, COVID-2019, and SARS-COV-2 were used. This review was not restricted to studies conducted in the English language; it includes reports from any countries that satisfy the inclusion criteria.
      To be included in the analysis, the study had to fulfill the following criteria: 1) RCTs (open-label, single-blind, double-blind, or parallel group studies); 2) Cohort studies; 3) Case-control studies; 4) Studies that report anti-hypertensive medication data.
      Studies were excluded from meta-analysis if they were: 1) Animal studies or in vitro studies; 2) Studies that did not report the usage of anti-hypertensive medications; 3) Full texts that could not be sourced; 4) Review papers; 5) Case reports; 6) Studies with unrelated outcomes or unreported outcomes; 7) Cross-sectional studies; 8) Clinical Trial Registries.

       Data collection and outcome measures

      Bibliographic details and abstracts of all citations retrieved by the literature search were downloaded to Endnotes X9. All studies were screened and evaluated by two independent reviewers (LR, PNT), which were then checked by a third reviewer (SY). Discrepancies were resolved by discussion in group conferences. Completed data were then thoroughly checked by two additional reviewers (WX, JLO). Data including first author, year of publication, country where studies took place, study type, number of participants, number of hypertensive patients, age, sex, follow-up duration, type of antihypertensive drugs, and outcomes were extracted using a standardized form and presented in table format. We used the adjusted OR if the information was available from the studies. If the reports did not provide adjusted OR, we used the crude OR. We calculated all the crude ORs when not provided. We were unable to adjust for age, sex, and/or underlying conditions, due to lack of information from the studies. Additionally, some of the studies used hazard ratio (HR) or adjusted HR. Table 1 provides further information on which information was used for each study.
      Table 1Study Characteristics.
      StudyCountryStudy TypeNumber of ParticipantsNumber of Hypertension PatientsAge (years)MaleStudy Duration (days)DrugsOutcomesOdds Ratio (OR)
      Andrea et al. (2020) [
      • Andrea C.
      • Francesco M.
      • Antonio N.
      • Evgeny F.
      • Marzia S.
      • Fabio C.
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      Renin-angiotensin-Aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study.
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      ItalySingle-Center Cohort Study1919663.468.6%28ACEI, ARBAll-cause mortalityCrude OR
      Ayed et al. (2020) [
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      • Borahmah A.
      • Yazdani A.
      • Sultan A.
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      • Rawdhan H.
      Assessment of clinical characteristics and mortality-associated factors in COVID-19 Critical cases in Kuwait.
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      KuwaitCohort Study103365385.580ACEI, β-blockersMortalityCrude OR
      Bean et al. (2020) [
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      • Folarin A.
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      ACE-inhibitors and Angiotensin-2 Receptor Blockers are not associated with severe SARS- COVID19 infection in a multi-site UK acute Hospital Trust.
      ]
      UKCohort Study120064567.9657.2%21ACEI, ARBDeath or transfer to ICUAdjusted OR
      Bravi et al. (2020) [
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      Predictors of severe or lethal COVID-19, including Angiotensin converting Enzyme Inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens.
      ]
      ItalyCase-Control Study160354358.047.3%24ACEI, ARBMortality and severityAdjusted OR
      Chang et al. (2020) [
      • Chang T.S.
      • Ding Y.
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      • Yabu J.M.
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      Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles Health System.
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      USACase-Control Study2660244%98ACEI, ARBCOVID-19 Infection, hospitalization and severityCrude OR
      Choi et al. (2020) [
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      • Seok H.
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      ARB/ACEI use and severe COVID-19: a nationwide case-control study.
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      KoreaRetrospective Case-control Study158515856542.7%116ACEI, ARBSevere infection or all-cause mortalityAdjusted OR
      De Abajo et al. (2020) [
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      Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.
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      SpainCase-Control Study113961769.161%24RAAS inhibitorsAdmission to hospitalAdjusted OR
      De Spiegeleer et al. (2020) [
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      BelgiumRetrospective Multi-Center Cohort Study1543985.933.1%47ACEI, ARBSerious COVID-19 or deathAdjusted OR
      Dublin et al. 2020 [
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      USACohort study322044664435146%106ACEI, ARB, CCB, β-blockers, diureticsCOVID-19 Infection and hospitalizationAdjusted OR
      Ebinger et al. (2020) [
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      USACase-control Study44216152.758%25ACEI, ARBCOVID-19 illness severityAdjusted OR
      Felice et al. (2020) [
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      ItalyCohort study1331337328%22ACEI, ARBMortality, ICU admission, hospital admissionAdjusted OR
      Feng Yun et al. (2020) [
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      ChinaCase-Control Study4761135356.9%45ACEI, ARBSeverity of COVID-19Crude OR
      Feng Zhichao et al. (2020) [
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      ChinaRetrospective, Observational, Multi-Center Cohort Study564824750.4%15-57ACEI, ARBCOVID-19 illness severityAdjusted OR
      Fosbøl et al. (2020) [
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      Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality.
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      DenmarkRetrospective Cohort Study448084354.755.1%30ACEI, ARBMortality and severityAdjusted HR
      Fosbøl et al. (2020) [
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      Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality.
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      DenmarkCase-control Study6281628173.954.3%94ACEI, ARB, CCBIncidence rate of COVID-19Adjusted HR
      Gao et al. (2020) [
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      • Cai Y.
      • Zhang K.
      • Zhou L.
      • Zhang Y.
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      Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study.
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      ChinaRetrospective Cohort Study28778505851%30-50RAAS inhibitorsAll-cause mortalityAdjusted HR
      Golpe et al. (2020) [
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      Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors.
      ]
      SpainCohort Study53915770.445.8%23ACEI, ARBHospitalizationAdjusted OR
      Huh et al. (2020) [
      • Huh K.
      • Ji W.
      • Kang M.
      • Hong J.
      • Bae G.H.
      • Lee R.
      • et al.
      Association of previous medications with the risk of COVID-19: a nationwide claims-based study from South Korea.
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      South KoreaRetrospective case-control cohort study651492137044.649.44%NAACEI, ARBDrug association with risk of COVID-19Adjusted OR
      Imam et al. (2020) [
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      USACohort Study13057346153.8%32ACEI, ARBMortalityAdjusted OR
      Ip et al. (2020) [
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      • Parikh K.
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      Hypertension and renin-angiotensin-Aldosterone system inhibitors in patients with Covid-19.
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      USACase-Control Study30171584NANANAACEI, ARB, non-ACEI/ARB drugsSeverity and mortalityCrude OR
      Jung et al. (2020) [
      • Jung S.-Y.
      • Choi J.C.
      • You S.-H.
      • Kim W.-Y.
      Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study.
      ]
      South KoreaCohort Study5179115744.644%Before April 8RAAS inhibitorsMortality rateAdjusted OR
      Jurado et al. (2020) [
      • Jurado A.
      • Martin M.C.
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      • Orduna A.
      • Martinez A.
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      SpainCase-Control Study57429063.259.4%21ACEI, ARBCOVID-19 illness severityCrude OR
      Khawaja et al. (2020) [
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      UKProspective Cohort Study4067931356046845%30ACEI, ARB, CCB, β-blockers, diureticsHospitalization with COVID-19Adjusted OR
      Khera et al. (2020) [
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      • Clark C.
      • Lu Y.
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      USACohort Study101961019669 and 7747.5% and 45.4%59 and 127ACEI, ARBCOVID-19 infection and mortalityHazard ratio
      Li Juyi et al. (2020) [
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      ChinaCase-Control Study117836255.546.3%51ACEI, ARB, CCB, β-blockersCOVID-19 mortality and severity in patients with hypertensionCrude OR
      Li Xiaochen et al. (2020) [
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      ChinaCohort Study5481666050.9%26-36ACEI, ARBSeverityCrude OR
      Liabeuf et al. 2020 [
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      FranceCohort Study2681527358%44ACEI, ARB, diureticsICU admission, deathAdjusted OR
      Liu et al. (2020) [
      • Liu Y.
      • Huang F.
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      • Yang P.
      • Qin Y.
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      ChinaRetrospective Cohort Study787865.255.1%26-64ACEI, ARB, CCB, β-blockers, thiazideCOVID-19 illness severityAdjusted OR
      Lo ́pez-Otero et al. (2020) [
      • Lopez-Otero D.
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      SpainCohort Study96529859.543.9%28ACEI, ARBMortality, hospitalization and ICU admissionAdjusted OR
      Mancia et al. (2020) [
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      ItalyCase–Control Study37031NA8663%20ACEI, ARB, CCB, β-blockers, diureticsCOVID-19 illness severityAdjusted OR
      Mehta et al. (2020) [
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      USARetrospective Cohort Study18472NA4940%36ACEI, ARBCOVID-19 infection; hospitalizations, ICU admissions, mechanical ventilationAdjusted OR
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      ChinaCohort Study4175164.557.10%43ACEI, ARB, non-ACEI/ARB drugsCOVID-19 InfectionCrude OR
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      MultinationalCohort Study1.1 M1.1M92ACEI, ARB, CCB, diureticsCOVID-19 InfectionAdjusted HR
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      USACohort Study6893725543%71ACEI, ARB, CCB, β-blockers, diureticsMortality and hospitalizationAdjusted OR
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      FranceCohort Study149756561%31ACEI, ARBMortality rateAdjusted OR
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      Severe obesity is associated with higher in-hospital mortality in a cohort of patients with COVID-19 in the Bronx, New York.
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      USARetrospective Cohort Study2001526449%21ACEI, ARBIn-hospital deathAdjusted OR
      Raisi-Estabragh et al. (2020) [
      • Raisi-Estabragh Z.
      • McCracken C.
      • Ardissino M.
      • Bethell M.S.
      • Cooper J.
      • Cooper C.
      • et al.
      NON-WHITE ethnicity, male sex, and higher body mass index, but not medications acting on the RENIN-ANGIOTENSIN system are associated with coronavirus disease 2019 (COVID-19) hospitalisation: review of the first 669 cases from the UK BIOBANK.
      ]
      UKCohort Study147472869.353.40%29ACEI, ARBCOVID-19 infectionCrude OR
      Regina et al. (2020) [
      • Regina J.
      • Papadimitriou-Olivgeris M.
      • Burger R.
      • Filippidis P.
      • Tschopp J.
      • Desgranges F.
      • et al.
      Epidemiology, risk factors and clinical course of SARS-CoV-2 infected patients in a Swiss university hospital: an observational retrospective study.
      ]
      SwitzerlandRetrospective Observational Study200877060%≥14ACEI, ARBNeed for mechanical ventilation at day 14Crude OR
      Rentsch et al. (2020) [
      • Rentsch C.T.
      • Kidwai-Khan F.
      • Tate J.P.
      • Park L.S.
      • King J.T.
      • Skanderson M.
      • et al.
      Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years.
      ]
      USARetrospective Cohort Study3789246365.790.2%50ACEI, ARBInfection, hospitalization, ICU admissionAdjusted OR
      Reynolds et al. (2020) [
      • Reynolds H.R.
      • Adhikari S.
      • Pulgarin C.
      • Troxel A.B.
      • Iturrate E.
      • Johnson S.B.
      • et al.
      Renin–Angiotensin–Aldosterone system inhibitors and risk of Covid-19.
      ]
      USARetrospective Cohort Study1259443574941.50%45ACEI, ARB, CCB, β-blockers, thiazide diureticsSeverity and mortalityAdjusted OR
      Rossi et al. (2020) [
      • Giorgi Rossi P.
      • Marino M.
      • Formisano D.
      • Venturelli F.
      • Vicentini M.
      • Grilli R.
      Characteristics and outcomes of a cohort of SARS-CoV-2 patients in the Province of Reggio Emilia, Italy.
      ]
      ItalyProspective Cohort Study265343063.250.1%14-28ACEI, ARBHospitalization and mortalityHazard ratio
      Sardu et al. (2020) [
      • Sardu C.
      • Maggi P.
      • Messina V.
      • Iuliano P.
      • Sardu A.
      • Iovinella V.
      • et al.
      Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? Data from centers of southern Italy.
      ]
      ItalyCohort Study62625841%NAACEI, ARB, CCBMortality and ICU admissionCrude OR
      Şenkal et al. (2020) [
      • Senkal N.
      • Meral R.
      • Medetalibeyoglu A.
      • Konyaoglu H.
      • Kose M.
      • Tukek T.
      Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19.
      ]
      TurkeyCohort Study6112495759.4%64ACEI, ARBSeverityAdjusted OR
      Solaimanzadeh et al. (2020) [
      • Solaimanzadeh I.
      Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19.
      ]
      USARetrospective Study652275.349.2%45CCBSurvival to discharge, severity, mechanical ventilation, and mortalityCrude OR
      Tan et al. (2020) [

      Tan N-D, Qiu Y, Xing X-B, Ghosh S, Chen M-H, Mao R. Associations between angiotensin converting enzyme inhibitors and angiotensin ii receptor blocker use, gastrointestinal symptoms, and mortality among Patients with COVID-19. Gastroenterology.

      ]
      ChinaRetrospective Cohort Study204100NANA72ACEI, ARBMortality rateCrude OR
      Tedeschi et al. (2020) [
      • Tedeschi S.
      • Giannella M.
      • Bartoletti M.
      • Trapani F.
      • Tadolini M.
      • Borghi C.
      • et al.
      Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19.
      ]
      ItalyCohort Study6093116868%41ACEI, ARBMortality rateAdjusted HR
      Trecarichi et al. (2020) [
      • Trecarichi E.M.
      • Mazzitelli M.
      • Serapide F.
      • et al.
      Characteristics, outcome and predictors of in-hospital mortality in an elderly population from a SARS-CoV-2 outbreak in a long-term care facility.
      ]
      ItalySingle-Center Cohort Study508057.1%41ACEI, ARBMortality rateAdjusted OR
      Yan et al. (2020) [
      • Yan H.
      • Valdes A.M.
      • Vijay A.
      • Wang S.
      • Liang L.
      • Yang S.
      • et al.
      Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China.
      ]
      ChinaCase-Control Study49277999249.948.3%49ACEI, ARB, CCB, β-blockers, diureticsRisk and severity of COVID-19Adjusted OR
      Yang et al. (2020) [

      Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J., et al. Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes in COVID-19 patients with hypertension: a single center retrospective study. Hypertension. 0.

      ]
      ChinaRetrospective Cohort Study25112666.149.1%57ACEI, ARB, non-ACEI/ARB drugsDischarge, mortality, length of stayCrude OR
      Zeng et al. (2020) [
      • Zeng Z.
      • Sha T.
      • Zhang Y.
      • Wu F.
      • Hu H.
      • Li H.
      • et al.
      Hypertension in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study.
      ]
      ChinaRetrospective, Single-Center, Observational Study274756055%14-62ACEI, ARB, non-ACEI/ARB drugsSeverity and mortalityCrude OR
      Zhang et al. (2020) [

      Zhang P, Zhu L, Cai J, Lei F, Qin J-J, Xie J, et al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circulation Research. 0.

      ]
      ChinaRetrospective, Multi-Center Study112811286453.4%15-66ACEI, ARBMortality rateHazard ratio
      Zhou Feng et al. (2020) [
      • Zhou F.
      • Liu Y.M.
      • Xie J.
      • Li H.
      • Lei F.
      • Yang H.
      • et al.
      Comparative impacts of ACE (Angiotensin-Converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality.
      ]
      ChinaCohort Study35726651.1%28ACEI, ARBMortality rateAdjusted HR
      Zhou Jiandong et al. (2020) [
      • Zhou J.
      • Tse G.
      • Lee S.
      • Liu T.
      • Wu W.K.
      • Cao Z.
      • et al.
      Identifying main and interaction effects of risk factors to predict intensive care admission in patients hospitalized with COVID-19: a retrospective cohort study in Hong Kong.
      ]
      ChinaCohort Study10431083554%145ACEI, ARBICU admissionAdjusted OR
      Zhou Xian et al. (2020) [
      • Zhou X.
      • Zhu J.
      • Xu T.
      Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin-angiotensin system inhibitors.
      ]
      ChinaCohort Study1103657.754.5%27ACEI, ARBMortality rateCrude OR
      Characteristics of patient population, study type, treatment intervention, and outcomes are displayed. We also indicated the type of ORs used for each study. ACEI, Angiotensin-Converting Enzyme Inhibitor; ARB, Angiotensin II Receptor Blocker; CCB, Calcium-Channel Blocker; OR: Odds Ratio; ICU, Intensive Care Unit.

       Study quality assessment

      Newcastle–Ottawa Quality Assessment Scale was used to assess the quality of cohort studies and case-control studies. The assessment was performed by two independent reviewers (WX, JLO) and further verified by two additional reviewers (LR, PNT). Discussion was performed if obvious discrepancies existed in assigning the study quality assessment. An additional reviewer was consulted when necessary (SY). The completed information is provided in Online Tables 1 and 2.

       Population selection

      This meta-analysis focuses on determining the association between taking antihypertensive drugs and the risk and severity of COVID-19 in both non-hypertensive and hypertensive patients. We first screened for studies to include (Fig. 1). Fig. 2 focuses on ACEIs/ARBs in the whole population taking these antihypertensive medications. Fig. 3 evaluates these drugs specifically on hypertensive patients. Fig. 4 extends the meta-analysis to the whole population taking other antihypertensive medications. If “hypertensive patients” was not mentioned for the patient population, then it can be assumed that the patient population includes both hypertensive and non-hypertensive patients.
      Fig. 1
      Fig. 1Process of identifying eligible studies. We searched for relevant studies using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach.
      Fig. 2
      Fig. 2Incidence and Severity of COVID-19 with ACEIs/ARBs. We pooled data from ACEIs, ARBs, and a combination of ACEIs/ARBs to perform meta-analyses on the A) incidence, B) hospitalization, C) ICU admission, D) severity, and E) mortality. Statistics are provided in the forest plots.
      ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ICU, intensive care unit.
      Fig. 3
      Fig. 3Incidence and Severity of COVID-19 with ACEIs/ARBs in Hypertensive Patients. We pooled data from ACEIs, ARBs, and a combination of ACEIs/ARBs to perform meta-analyses on the A) incidence, B) severity and C) mortality of COVID-19 in hypertensive patients. Statistics are provided in the forest plots.
      ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
      Fig. 4
      Fig. 4Incidence and Severity of COVID-19 with CCBs, β-blockers, and diuretics. Severity and mortality of COVID-19 with the usage of A) CCBs, B) β-blockers, and C) diuretics. Statistics are provided in the forest plots.
      CCB, calcium channel blocker.

       Statistical analysis

      Outcomes were summarized as odds ratio (OR). Fixed-effects or random-effects model were used to pool the OR with 95% confidence interval (CI) for the outcomes. If I2 ≤40%, studies were considered homogeneous and fixed-effects model of meta-analysis were used. If I2 ≥40%, the heterogeneity was high, so a random-effects model was used. I2 statistics was included in all the meta-analyses performed, which is a percentage of variance attributed to study heterogeneity. Sensitivity analyses were also included. Publication bias was assessed by funnel plots. Meta-analyses were performed with STATA 16 (Stata, College Station, TX, USA). Leave-one-out meta-analyses were performed with OpenMeta[Analyst] (CEBM, Brown University, Providence, RI, USA).

      Results

       Process of identifying eligible studies and assessing study quality

      The PRISMA flowchart (Fig. 1) includes the summary of the study selection process and search results. We initially screened 309 records using the studies’ titles and abstracts. A total of 140 studies were identified after removal of duplicate records. Of these remaining records, 71 studies were removed, since they were animal studies, review papers, commentaries, part of a registry, or the full texts were not available, which left us with 69 records. After the exclusion of 16 studies that were assessing unrelated outcomes and/or were cross-sectional studies and a thorough review according to the inclusion and exclusion criteria, 53 records satisfied our requirements. We included 39 cohort studies and 14 case-control studies. No RCTs were identified. The studies that were included were subjected to the Newcastle-Ottawa Quality Assessment, which is reported in Online Tables 1 and 2. Studies deemed low quality (less than or equal to 4 stars) by independent reviewers were excluded.

       Characteristics of studies, patients, and interventions

      Table 1 describes the overall characteristics of the studies. We included the first author, year of publication, country, study type, number of participants, number of hypertensive patients, age, sex, follow-up duration, type of antihypertensive drugs, and outcomes. We included a total of 35 studies that investigated ACEIs and ARBs, while the other 18 focused on ACEIs, ARBs, or other antihypertensive drugs (CCBs, β-blockers, and diuretics). There was a total of 2,100,587 participants across all 53 studies. Studies were conducted in a variety of countries, predominantly in the USA and China, but also included Spain, Italy, and the United Kingdom. There was an equal number of males and females for most studies, however, one study had 90.2% male participants [
      • Rentsch C.T.
      • Kidwai-Khan F.
      • Tate J.P.
      • Park L.S.
      • King J.T.
      • Skanderson M.
      • et al.
      Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years.
      ] and another had 28% male participants [
      • Felice C.
      • Nardin C.
      • Di Tanna G.L.
      • Grossi U.
      • Bernardi E.
      • Scaldaferri L.
      • et al.
      Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives.
      ]. On average, most studies included middle-aged participants, but three trended more toward elderly participants [
      • Mancia G.
      • Rea F.
      • Ludergnani M.
      • Apolone G.
      • Corrao G.
      Renin–Angiotensin–Aldosterone system blockers and the risk of Covid-19.
      ,
      • Regina J.
      • Papadimitriou-Olivgeris M.
      • Burger R.
      • Filippidis P.
      • Tschopp J.
      • Desgranges F.
      • et al.
      Epidemiology, risk factors and clinical course of SARS-CoV-2 infected patients in a Swiss university hospital: an observational retrospective study.
      ,
      • Solaimanzadeh I.
      Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19.
      ]. Study durations varied, with the shortest being 14 days and the longest being 145 days. The outcomes of these studies included incidence, hospitalization, severity, and mortality. Incidence was defined as patients who took antihypertensive medications and tested positive for COVID-19, while severity was defined as a combination of hospitalization, intensive care unit (ICU) admission, and mortality. Severity was then further broken down into their individual components for analysis.

       Incidence and severity of COVID-19 with ACEIs/ARBs

      We performed meta-analyses on the incidence (26 studies), severity (40 studies), hospitalization (23 studies), ICU admission (12 studies), and mortality (38 studies) of COVID-19 in patients with prior usage of either ACEI, ARB, or a combination of both (Fig. 2). As shown in the forest plots, there was no association with the incidence (overall OR of 0.96, 95% CI 0.86–1.08), severity (overall OR of 0.92, 95% CI 0.77–1.11), hospitalization (overall OR of 1.09, 95% CI 0.91–1.31), ICU admission (overall OR of 1.19, 95% CI 0.85–1.66), or mortality (overall OR of 0.92, 95% CI 0.74–1.13). Overall heterogeneity between trials was observed with incidence (I2 = 88.40%), severity (I2 = 83.08%), hospitalization (I2 = 70.27%), ICU admission (I2 = 56.64%), and mortality (I2 = 84.72%). Together, these data suggest that there was no association between prior drug usage and risk or severity of COVID-19 in patients taking ACEIs/ARBs.

       Incidence and severity of COVID-19 with ACEIs/ARBs in hypertensive patients

      We further conducted meta-analyses of severity and mortality of COVID-19 with prior usage of ACEIs, ARBs, or ACEI/ARBs in hypertensive patients (Fig. 3). We observed a significant decrease in severity (overall OR of 0.81, 95% CI 0.66–0.99, p < 0.05) and mortality (overall OR of 0.77, 95% CI 0.66–0.91, p < 0.01) in favor of ACEIs/ARBs. The heterogeneity between trials was observed with severity (I2 = 50.52%) and mortality (I2 = 46.96%). Together, these data suggest that prior usage of ACEIs/ARBs in hypertensive patients is associated with significantly lower severity and mortality than the control group.

       Incidence and Severity of COVID-19 with CCBs, β-blockers, and diuretics

      We next examined whether prior usage of other antihypertensive medications exhibited an association with the risk and severity of COVID-19 (Fig. 4). There was no association between usage of CCBs with incidence (overall OR of 1.15, 95% CI 0.87–1.53) or severity (overall OR of 0.94, 95% CI 0.80–1.10) of COVID-19. Heterogeneity between trials was evident for both incidence (I2 = 93.61%) and severity (I2 = 17.11%). Similarly, there was no association between the use of β-blockers with incidence (overall OR of 1.03, 95% CI 0.78–1.35) or severity (overall OR of 1.23, 95% CI 0.74–2.04). There was heterogeneity in incidence (I2 = 92.59%) and severity (I2 = 85.42%) with β-blockers. Like CCBs and β-blockers, there was no evidence that prior usage of diuretics was associated with the incidence (overall OR of 0.86, 95% CI 0.54–1.38) or severity (overall OR of 0.96, 95% CI 0.81–1.15). Heterogeneity was also observed with diuretics and the incidence of COVID-19 (I2 = 97.26%). Together, there was no evidence for an association between prior usage of these antihypertensive medications and risk or severity of COVID-19 in patients taking any of these antihypertensive medications.

       Assessments of publication Bias and quality of studies and sensitivity analysis

      To assess publication bias, we constructed funnel plots of all the parameters that were tested (Online Fig. 1). Additionally, two independent reviewers performed the quality assessment, while two others confirmed results using the Newcastle-Ottawa Quality Assessment (Online Tables 1 and 2). Finally, to determine if removing a study would skew the results, we performed sensitivity analyses on all the parameters that we examined in the main text. Results can be found in Online Figs. 2–4.

      Discussion

      The pandemic has disproportionately affected the lives of patients with cardiovascular comorbidities [
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area.
      ]. Although many variables may contribute to this outcome, we sought to address whether prior usage of antihypertensive medications is associated with the risk and severity of COVID-19 in this study. Our motivation stems from two factors. First, a previous study suggests that antihypertensive drugs may increase the expression of ACE2—a protein that is paramount for SARS-CoV-2 viral infection [
      • Hoffmann M.
      • Kleine-Weber H.
      • Schroeder S.
      • Krüger N.
      • Herrler T.
      • Erichsen S.
      • et al.
      SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
      ]. Second, there is high mortality in patients with cardiovascular complications [
      • Roncon L.
      • Zuin M.
      • Zuliani G.
      • Rigatelli G.
      Patients with arterial hypertension and COVID-19 are at higher risk of ICU admission.
      ,
      • Li J.
      • He X.
      • Yuan Y.
      • Zhang W.
      • Li X.
      • Zhang Y.
      • et al.
      Meta-analysis investigating the relationship between clinical features, outcomes, and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.
      ,
      • Pranata R.
      • Lim M.A.
      • Huang I.
      • Raharjo S.B.
      • Lukito A.A.
      Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: a systematic review, meta-analysis and meta-regression.
      ,
      • Gold M.S.
      • Sehayek D.
      • Gabrielli S.
      • Zhang X.
      • McCusker C.
      • Ben-Shoshan M.
      COVID-19 and comorbidities: a systematic review and meta-analysis.
      ].
      We identified 53 studies that satisfied our inclusion criteria, which comprised 39 cohort and 14 case-control studies (Fig. 1). The characteristics for these studies are detailed in Table 1. The studies included a total of 2,100,587 patients. Meta-analyses were performed to determine the risk and severity of COVID-19 in patients with prior usage of ACEIs/ARBs. We observed no evidence of an association with regards to incidence, hospitalization, severity, and mortality.
      Since the findings in Fig. 2 included both non-hypertensive and hypertensive patients, we determined whether there was an association of prior usage of these medications and the risk and severity of COVID-19 in hypertensive patients (Fig. 3). We noted that severity (p < 0.05) was significantly lower in hypertensive patients taking ACEIs/ARBs than controls. Additionally, mortality was significantly lower in patients taking ACEIs/ARBs versus control patients (p < 0.01). These findings support the benefits of using ACEIs/ARBs in hypertensive patients. Therefore, our analyses suggest that abstaining from ACEIs/ARBs, especially in the context of hypertensive patients, will not provide benefits.
      Additionally, we examined whether other commonly prescribed antihypertensive medications are associated with the risk and severity of COVID-19. There was no evidence of an association between taking these antihypertensive medications (CCBs, β-blockers, and diuretics) and the incidence and severity of COVID-19. With the leave-one-out-meta-analysis (Online Figs. 2–4), there were no significant differences in most of the parameters except for a significant increase in ICU admission, with more ACEIs/ARBs patients being admitted, when the study of Felice et al. was excluded (Online Fig. 2) [
      • Felice C.
      • Nardin C.
      • Di Tanna G.L.
      • Grossi U.
      • Bernardi E.
      • Scaldaferri L.
      • et al.
      Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives.
      ]. However, severity, a parameter that takes into account ICU admission, mechanical ventilation, duration of hospital stay, hospital admittance, noninvasive ventilation, and organ dysfunction, was not significantly different between ACEIs/ARBs and control patients. Therefore, caution is required for the interpretation of the ICU admission findings.
      Multiple studies have reported high mortality in patients with cardiovascular complications [
      • Burrell L.M.
      • Risvanis J.
      • Kubota E.
      • Dean R.G.
      • MacDonald P.S.
      • Lu S.
      • et al.
      Myocardial infarction increases ACE2 expression in rat and humans.
      ,
      • Roncon L.
      • Zuin M.
      • Zuliani G.
      • Rigatelli G.
      Patients with arterial hypertension and COVID-19 are at higher risk of ICU admission.
      ,
      • Li J.
      • He X.
      • Yuan Y.
      • Zhang W.
      • Li X.
      • Zhang Y.
      • et al.
      Meta-analysis investigating the relationship between clinical features, outcomes, and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.
      ,
      • Pranata R.
      • Lim M.A.
      • Huang I.
      • Raharjo S.B.
      • Lukito A.A.
      Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: a systematic review, meta-analysis and meta-regression.
      ]. Our results suggest that taking antihypertensive medications did not increase the incidence or severity of COVID-19 in patients taking antihypertensive medications. In fact, ACEIs/ARBs may be beneficial in hypertensive patients. Our findings do not support abstaining from antihypertensive medications when patients are already taking them.
      Additionally, it is critical to note that data regarding ACE2 expression with the usage of antihypertensive medications remains controversial, with some studies reporting an increase [
      • Ferrario Carlos M.
      • Jessup J.
      • Chappell Mark C.
      • Averill David B.
      • Brosnihan K.B.
      • Tallant E.A.
      • et al.
      Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
      ,
      • Ishiyama Y.
      • Gallagher Patricia E.
      • Averill David B.
      • Tallant E.A.
      • Brosnihan K.B.
      • Ferrario Carlos M.
      Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors.
      ,
      • Fang L.
      • Karakiulakis G.
      • Roth M.
      Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.
      ,
      • Ocaranza M.P.
      • Godoy I.
      • Jalil J.E.
      • Varas M.
      • Collantes P.
      • Pinto M.
      • et al.
      Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat.
      ,
      • Burrell L.M.
      • Risvanis J.
      • Kubota E.
      • Dean R.G.
      • MacDonald P.S.
      • Lu S.
      • et al.
      Myocardial infarction increases ACE2 expression in rat and humans.
      ], while others show no changes [
      • Campbell D.J.
      • Zeitz C.J.
      • Esler M.D.
      • Horowitz J.D.
      Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation.
      ,
      • Burchill L.J.
      • Velkoska E.
      • Dean R.G.
      • Griggs K.
      • Patel S.K.
      • Burrell L.M.
      Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions.
      ]. Therefore, additional studies are required to test the effects of antihypertensive medications on ACE2 expression, as well as applicability of the findings across species. Current data support potential benefits compared to harms in the use of RAAS blockers in patients [
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–Angiotensin–Aldosterone system inhibitors in patients with Covid-19.
      ]. Our meta-analysis of currently available data further support the lack of an association between antihypertensive medications and the risk or severity of COVID-19.
      Our current study provides several advantages relative to previous meta-analysis studies [
      • Pranata R.
      • Permana H.
      • Huang I.
      • Lim M.A.
      • Soetedjo N.N.M.
      • Supriyadi R.
      • et al.
      The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.
      ,
      • Flacco M.E.
      • Acuti Martellucci C.
      • Bravi F.
      • Parruti G.
      • Cappadona R.
      • Mascitelli A.
      • et al.
      Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis.
      ,
      • Grover A.
      • Oberoi M.
      A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
      ,
      • Zhang X.
      • Yu J.
      • Pan L.Y.
      • Jiang H.Y.
      ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis.
      ,
      • Pirola C.J.
      • Sookoian S.
      Estimation of renin-angiotensin-Aldosterone-System (RAAS)-inhibitor effect on COVID-19 outcome: a meta-analysis.
      ,
      • Guo X.
      • Zhu Y.
      • Hong Y.
      Decreased mortality of COVID-19 with renin-angiotensin-Aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis.
      ]. In contrast to previous meta-analysis studies, which analyzed approximately 9–16 records, our study included 53 records to generate a large dataset. Additionally, while other studies primarily focused on assessing ACEIs/ARBs, our study included analyses of other antihypertensive drugs such as CCBs, β-blockers, and diuretics. New insights from the comprehensive meta-analysis in the current study have important implications in clinical decisions.

      Limitations

      There are some limitations in the current study. Only observational studies are currently available in the literature due to the urgency of the pandemic resulting in the need to rapidly gather information. There were no available RCTs. Additionally, some studies did not provide ORs, necessitating the calculation of the values without adjustment for age, sex, and underlying comorbidities. Nonetheless, by taking advantage of meta-analysis on the large available and up-to-date dataset of more than two million patients, these observational studies can be impactful to drive clinical decisions.

      Conclusions

      Based on all currently available literature, the usage of antihypertensive drugs is not associated with the risk and severity of COVID-19. It is not recommended to abstain from the use of these drugs in COVID-19 patients, especially those with hypertension. More clinical trials are needed to further validate these findings.

      Authors’ contributions

      LR and PNT designed the study. LR and PNT screened and evaluated studies. LR and SY performed statistical analyses. PNT checked statistical analyses. LR, WX, JO, and PNT performed comprehensive characterization of studies. SY and NC provided expertise. LR, PNT, and NC wrote the manuscript.

      Disclosures

      None

      Sources of funding

      This work was supported by UC Davis Dissertation-Year Fellowship and American Heart Association Predoctoral Award 18PRE34030199 (LR); Postdoctoral Fellowships from NIH/NHLBI Institutional Training Grant in Basic and Translational Cardiovascular Science (T32 NIH HL086350) and NIH F32 HL149288 (PNT); NIH R01 HL085727, HL085844, HL137228 and VA Merit Review Grant I01 BX000576 and I01 CX001490 (NC). The contents of this article do not represent the views of the funding agencies. NC is the holder of the Roger Tatarian Endowed Professorship in Cardiovascular Medicine and a part-time staff physician at VA Northern California Health Care System, Mather, CA, USA.

      Independent data access and analysis

      The corresponding authors had full access to all the data in the study and take responsibility for its integrity and the data analysis.

      Appendix A. Supplementary data

      The following are Supplementary data to this article:

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