Use Of Angiotensin II Receptor Blockers Research Articles

Ecological Analysis of the Influence of ACEIs and ARBs on the COVID-19 Prevalence and Death from COVID-19

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) have been an arguable risk factor for COVID-19 diseases because they could upregulate Angiotensin Converting Enzyme-2 (ACE2) expression, facilitating SARS-CoV2 entry to the lungs. Several retrospective clinical studies, however, found no such effect. Here, we explore how the use of ACEIs and ARBs links to COVID-19 across all countries of the world. Methods: Data on the availability of ACEIs and ARBs for 200 countries and on the number of cases and number of deaths per country by 28 December 2020 were extracted from WHO and Worldometer website, respectively. Data on life expectancy at age 65 years as a measure of ageing were from WHO and on Gross Domestic Product Per Capita (GDP PPP) and the percentage of urbanization were from the World Bank. Excel and SPSS v 26 software were used for statistical analyses. Results: In linear regression and logistic conditional regression analysis, GDP correlates with COVID-19 prevalence (rho = 0.66, p > 0.001) and deaths from COVID-19 (rho = 0.55, p < 0.001) while urbanization and life expectancy do not when GDP influence is controlled for. After statistically removing the effects of GDP on the prevalence and mortality from COVID-19, we found that countries without ACEI and ARB availability had lower COVID-19 cases and deaths (p < 0.02). Conclusions: Our study based on the global data contradicts findings of most published clinical studies at regional levels. We found that GDP positively correlates with prevalence of and mortality related to COVID-19. ACEI and ARB use increases COVID-19 infectivity and mortality.

Association Between Angiotensin II Receptor Blockers and the Risk of Lung Cancer Among Patients With Hypertension From the Korean National Health Insurance Service-National Health Screening Cohort.

Objectives:The objective of this study was to estimate the risk of lung cancer in relation to angiotensin II receptor blocker (ARB) use among patients with hypertension from the Korean National Health Insurance Service-National Health Screening Cohort. Methods:We conducted a retrospective cohort study of patients with hypertension who started to take antihypertensive medications and had a treatment period of at least 6 months. We calculated the weighted hazard ratios (HRs) and their 95% confidence intervals (CIs) of lung cancer associated with ARB use compared with calcium channel blocker (CCB) use using inverse probability treatment weighting. Results:Among a total of 60 469 subjects with a median follow-up time of 7.8 years, 476 cases of lung cancer were identified. ARB use had a protective effect on lung cancer compared with CCB use (HR, 0.75; 95% CI, 0.59 to 0.96). Consistent findings were found in analyses considering patients who changed or discontinued their medication (HR, 0.50; 95% CI, 0.32 to 0.77), as well as for women (HR, 0.56; 95% CI, 0.34 to 0.93), patients without chronic obstructive pulmonary disease (HR, 0.75; 95% CI, 0.56 to 1.00), never-smokers (HR, 0.64; 95% CI, 0.42 to 0.99), and non-drinkers (HR, 0.69; 95% CI, 0.49 to 0.97). In analyses with different comparison antihypertensive medications, the overall protective effects of ARBs on lung cancer risk remained consistent. Conclusions:The results of the present study suggest that ARBs could decrease the risk of lung cancer. More evidence is needed to establish the causal effect of ARBs on the incidence of lung cancer.

Lack of association between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and pain improvement in patients with oral cancer.

BackgroundThere is a growing body of literature implicating angiotensin II in the modulation of tumour-associated inflammation and pain. However, the impact of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) on pain and inflammation has not yet been studied in oral cancers. The objective is to investigate the role of ACEi and ARB pharmacotherapy on preoperative pain and inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), in patients with oral cancer.MethodsWe performed a retrospective study on patients who underwent oral cancer surgery. The Wilcoxon rank-sum test or Kruskal–Wallis analysis was used to evaluate differences in demographic, tumour-related and preoperative characteristics and amongst patients using ARBs, ACEis and no treatment. Multivariable analysis was fitted to estimate the effects of important covariates on severe preoperative pain.ResultsA total of 162 patients with oral malignancies were included in the study. After adjusting for significant covariates, patients with perineural invasion were found to have higher levels of pain (p = 0.0278). Similarly, patients taking ARBs were found to have lower levels of perineural invasion (p = 0.035). The analysis did not demonstrate a significant difference in pain levels when comparing ARBs or ACEis to the no treatment group (p = 0.250). Furthermore, the use of ARB or ACEi did not significantly alter preoperative NLR (p = 0.701) or MLR (p = 0.869).ConclusionsWhen compared to no treatment, ARBs and ACEis are not associated with significant analgesic effect or decreased inflammatory scores (NLR, PLR and MLR).

Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers

Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers

The current practice of using angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in diabetic hypertensive and non-hypertensive patients. Is there a room for vitamin D?

Objectives:To determine the current pattern of using angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in diabetic nephropathy (DN), and assess physician awareness of using vitamin D in the prevention and treatment of DN.Methods:A cross-sectional study implementing a validated questionnaire, which was distributed to physicians in the aforementioned specialties in 3 hospitals in Saudi Arabia (Almanee Hospital, King Saud Medical City [KSMC], and Riyadh Care Hospital [RCH]) between April 2019 and November 2019. We used IBM SPSS 26.0 to perform descriptive statistical analyses and comparisons were based on the Chi-square test.Results:Forty-one physicians (30%) reported the use of combination therapy of ACEi and ARBs. Fifty-six (41%) physicians reported that they never used vitamin D in the treatment of DN, and 48% agreed that vitamin D can benefit patients with DN. 52% of the respondents reported the existence of guidelines. The vast majority (94%) recommended clearer guidelines on monitoring renal function in patients treated with ACEi or ARBs.Conclusion:There is a universal agreement among physicians regarding the use of ACEi and ARBs for the treatment of DN with limited awareness of the benefits of using vitamin D. Hence, the development of specific guidelines for its use are recommended.

Severity of SARS-COV-2 infection and angiotensin converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis

Background: The mechanism of entry of SARS-COV-2 into the human host cell is through the ACE2 receptor. During the pandemic, a hypothesis has been proposed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) could be risk factors for the development of severe SARS-COV-2 infection. The objective of the study was to conduct a meta-analysis of the association between ACEI or ARB use and SARS-COV-2 infection severity or mortality. Material and methods: We searched PubMed, EMBASE, Google scholar and the Cochrane Database of Systematic Reviews for observational studies published between December 2019 and August 4, 2020 Studies were included if they contained data on ACEI or ARB use and SARS-COV-2 infection severity or mortality. Effect statistics were pooled using random-effects models. The quality of included studies was assessed with the Newcastle–Ottawa Scale (NOS). Data on study design, study location, year of publication, number of participants, sex, age at baseline, outcome definition, exposure definition, effect estimates and 95% CIs were extracted. Results: Twenty-six studies (21 cohort studies and 5 case-control studies) were identified for inclusion, combining to a total sample of 361467 participants. Mean age was 61.48 (SD 8.26) years and 51.63 % were men. The mean NOS score of included studies was 7.85 (range: 7–9). Results suggested that ACEI or ARB use did not increase the risk of severe disease or mortality from SARS-COV-2 infection (OR = 0.88, 95% CI: 0.75–1.02, p &gt; 0.05). Conclusions: At present, the evidence available does not support the hypothesis of increased SARS-COV-2 risk with ACEI or ARB drugs.

Relation of Statin Use Prior to Admission to Severity and Recovery Among COVID-19 Inpatients

The impact of statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) severity and recovery is important given their high prevalence of use among individuals at risk for severe COVID-19. We studied the association between use of statin/angiotensin-converting enzyme inhibitors/ARB in the month before hospital admission, with risk of severe outcome, and with time to severe outcome or disease recovery, among patients hospitalized for COVID-19. We performed a retrospective single-center study of all patients hospitalized at University of California San Diego Health between February 10, 2020 and June 17, 2020 (n = 170 hospitalized for COVID-19, n = 5,281 COVID-negative controls). Logistic regression and competing risks analyses were used to investigate progression to severe disease (death or intensive care unit admission), and time to discharge without severe disease. Severe disease occurred in 53% of COVID-positive inpatients. Median time from hospitalization to severe disease was 2 days; median time to recovery was 7 days. Statin use prior to admission was associated with reduced risk of severe COVID-19 (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) and faster time to recovery among those without severe disease (adjusted HR for recovery 2.69, 95%CI 1.36 to 5.33, p < 0.01). The association between statin use and severe disease was smaller in the COVID-negative cohort (p for interaction = 0.07). There was potential evidence of faster time to recovery with ARB use (adjusted HR 1.92, 95%CI 0.81 to 4.56). In conclusion, statin use during the 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19, and a faster time to recovery among patients without severe disease.

Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers in Acute Coronary Syndrome and Preserved Ventricular Ejection Fraction.

Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blockers (ARB) showed comparable survival results in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). However, there is lack of evidence of the comparative effectiveness in preserved LVEF patients after an acute coronary syndrome (ACS). The aim of this study was to evaluate whether the selection between ACEi and ARB in preserved LVEF after an ACS confers a prognostic benefit, based on real life results. We analyzed a cohort of 3006 contemporary patients with LVEF ≥40% after an ACS. A propensity score matching and Cox regression analysis were performed to assess the association between treatment and events (death, acute myocardial infarction [AMI], HF, and combined event) for a mean follow-up of 3.6 ± 2.1 years. We found no significant differences between ACEi/ARB for all-cause mortality (hazard ratio [HR] for ARB: 0.95, 95% CI: 0.70-1.29), AMI (HR for ARB: 1.34, 95% CI: 0.95-1.89), HF (HR for ARB: 1.11, 95% CI: 0.85-1.45), or combined end point (death, AMI and HF: HR for ARB: 1.14, 95% CI: 0.92-1.40). In conclusion, there are no prognostic differences between the use of ACEi and ARB in patients with LVEF ≥40% after ACS. Further prospective studies are needed to confirm our results.

Re: Association of Inpatient Use of Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19.

To the Editor: We read with interest the study by Zhang et al.,1 examining the association between inpatient use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19), published in Circulation Research. The use of ACEIs or ARBs was associated with an important 58% risk reduction in all-cause mortality (hazard ratio, 0.42; 95% confidence interval, 0.19, 0.92). The association was even stronger with the use of propensity score models, resulting in a risk reduction of almost 70%. We believe that these remarkable effects are mainly driven by immortal time bias. In this study, patients were deemed exposed to ACEIs or ARBs if they had received a prescription at any time during the hospitalization period. In contrast, patients who did not receive these drugs during the hospitalization period were categorized as nonusers. This method of identifying users and nonusers can introduce immortal time bias.2 Indeed, by design, ACEI or ARB users had to survive from the date of admission to the date of an ACEI or ARB prescription to be categorized as a user. This time period was both misclassified as exposed (instead of unexposed) and immortal, as it was impossible for patients to die during this time span. In contrast, it was possible for nonusers to die at any point during the hospitalization period. This is particularly evident in Zhang et al.’s1 Figures 2A and 2B, where there were no deaths in the first 7 days of follow-up for the ACEIs/ARBs group, whereas deaths occurred as early as the second day after admission in the non-user group. Given the maximum 28-day follow-up, even a small amount of misclassified exposed person–time could lead to important bias, as was shown previously with β-blockers for patients hospitalized for chronic obstructive pulmonary disease.3 The authors also compared the risk of death among users of ACEIs/ARBs versus users of other antihypertensive drugs. In this analysis, the authors first identified ACEI/ARB users and then users of other antihypertensive drugs. This hierarchical exposure definition introduced immortal time bias,4 as the time between hospital admission and first ACEI/ARB prescription was misclassified as exposed and immortal because no events could have occurred during that period. In summary, although residual confounding is always a concern in observational studies, immortal time bias can introduce severely skewed results, though it can be avoided using proper methods of analysis.2–4 It would be informative to repeat the analyses by modeling ACEI or ARB exposure using time-dependent methods.

Outcomes Associated with the Use of Renin-Angiotensin-Aldosterone System Blockade in Hospitalized Patients with SARS-CoV-2 Infection.

Data regarding the benefits or harm associated with the continuation of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs), especially the impact on inflammation, in hypertensive, hospitalized patients with COVID-19 in the United States is unclear. This is a single-center cohort study of sequentially hospitalized patients with COVID-19 at Stony Brook University Medical Center from March 7, 2020 to April 1, 2020, inclusive of these dates. Data collection included history of known comorbidities, medications, vital signs and laboratory values (admission and during the hospitalization). Outcomes include inflammatory burden (composite scores for multiple markers of inflammation), acute kidney injury (AKI), admission to the intensive care unit (ICU), need for invasive mechanical ventilation, and mortality. Of the 300 patients in the study cohort, 80 patients (26.7%) had history of ACEI or ARB use prior to admission, with 61.3% (49/80) of these patients continuing the medications during hospitalization. Multivariable analysis revealed that the history of ACEI or ARB use prior to hospitalization was not associated with worse outcomes. In addition, the continuation of these agents during hospitalization was not associated with an increase in adverse outcomes and predicted fewer ICU admissions (OR=0.25, 0.08-0.81) with a decrease in the severity of inflammatory burden (peak CRP (6.9±3.1mg/dl, p=0.03) and peak inflammation score (2.3±1.1unit reduction, p=0.04)). Use of ACEI or ARBs prior to hospitalization was not associated with adverse outcomes in COVID-19 and the therapeutic benefits of continuing ACEI or ARB in hospitalized patients with COVID-19 was not offset by adverse outcomes.

SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy.

BackgroundSARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful.Methods: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed.Findings and InterpretationSARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.

Medication use, renin-angiotensin system inhibitors, and acute care utilization after hospitalization in patients with chronic kidney disease.

Objectives:The aims of this secondary analysis were to: (a) characterize medication use following hospital discharge for patients with chronic kidney disease (CKD), and (b) investigate relationships of medication use with the primary composite outcome of acute care utilization 90 days after hospitalization.Methods:The CKD-Medication Intervention Trial (CKD-MIT) enrolled acutely ill hospitalized patients with CKD stages 3–5 not dialyzed (CKD 3–5 ND). In this post hoc analysis, data for medication use were characterized, and the relationship of medication use with the primary outcome was evaluated using Cox proportional hazards models.Results:Participants were taking a mean of 12.6 (standard deviation=5.1) medications, including medications from a wide variety of medication classes. Nearly half of study participants were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). ACE inhibitor/ARB use was associated with decreased risk of the primary outcome (hazard ratio=0.51; 95% confidence interval 0.28–0.95; p=0.03) after adjustment for baseline estimated glomerular filtration rate, age, sex, race, blood pressure, albuminuria, and potential nephrotoxin use.Conclusions:A large number, variety, and complexity of medications were used by hospitalized patients with CKD 3–5 ND. ACE inhibitor or ARB use at hospital discharge was associated with a decreased risk of 90-day acute care utilization.

Effects of ACEi and ARB on post-exercise hypotension induced by exercises conducted at different times of day in hypertensive men

ABSTRACT Background Post-exercise hypotension (PEH) is greater after evening than morning exercise, but antihypertensive drugs may affect the evening potentiation of PEH. Objective: To compare morning and evening PEH in hypertensives receiving angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). Methods Hypertensive men receiving ACEi (n = 14) or ARB (n = 15) underwent, in a random order, two maximal exercise tests (cycle ergometer, 15 watts/min until exhaustion) with one conducted in the morning (7 and 9 a.m.) and the other in the evening (8 and 10 p.m.). Auscultatory blood pressure (BP) was assessed in triplicate before and 30 min after the exercises. Changes in BP (post-exercise – pre-exercise) were compared between the groups and the sessions using a two-way mixed ANOVA and considering P < .05 as significant. Results In the ARB group, systolic BP decrease was greater after the evening than the morning exercise, while in the ACEi group, it was not different after the exercises conducted at the different times of the day. Additionally, after the evening exercise, systolic BP decrease was lower in the ACEi than the ARB group (ARB = −11 ± 8 vs −6 ± 6 and ACEi = −6 ± 7 vs. −8 ± 5 mmHg, evening vs. morning, respectively, P for interaction = 0.014). Conclusions ACEi, but not ARB use, blunts the greater PEH that occurs after exercise conducted in the evening than in the morning.

Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AngII receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Safety of ACE-I and ARB medications in COVID-19: A retrospective cohort study of inpatients and outpatients in California.

There is significant interest in the use of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) in coronavirus disease 2019 (COVID-19) and concern over potential adverse effects since these medications upregulate the severe acute respiratory syndrome coronavirus 2 host cell entry receptor ACE2. Recent studies on ACE-I and ARB in COVID-19 were limited by excluding outpatients, excluding patients by age, analyzing ACE-I and ARB together, imputing missing data, and/or diagnosing COVID-19 by chest computed tomography without definitive reverse transcription polymerase chain reaction (RT-PCR), all of which are addressed here. We performed a retrospective cohort study of 1023 COVID-19 patients diagnosed by RT-PCR at Stanford Hospital through April 8, 2020 with a minimum follow-up time of 14 days to investigate the association between ACE-I or ARB use with outcomes. Use of ACE-I or ARB medications was not associated with increased risk of hospitalization, intensive care unit admission, or death. Compared to patients with charted past medical history, there was a lower risk of hospitalization for patients on ACE-I (odds ratio (OR) 0.43; 95% confidence interval (CI) 0.19-0.97; P = 0.0426) and ARB (OR 0.39; 95% CI 0.17-0.90; P = 0.0270). Compared to patients with hypertension not on ACE-I or ARB, patients on ARB medications had a lower risk of hospitalization (OR 0.09; 95% CI 0.01-0.88; P = 0.0381). These findings suggest that the use of ACE-I and ARB is not associated with adverse outcomes and may be associated with improved outcomes in COVID-19, which is immediately relevant to care of the many patients on these medications.

Coronavirus disease 2019 (COVID-19): angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and cardiovascular disease.

Coronavirus disease 2019 (COVID-19): angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and cardiovascular disease.

Comparisons of Staphylococcus aureus infection and other outcomes between users of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers: lessons for COVID-19 from a nationwide cohort study

Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus ( S. aureus). We sought to investigate whether humans using ACEI were at increased risk of S. aureus infection, comparing them to users of Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEI to periods with ARB prescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis, hip fracture and herpes zoster) and one that we did (dry cough). Results: We identified 445,341 new users of ACEI (mean age 64.0±14.0, male 51.7%) and 41,824 new users of ARB (mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEI vs. ARB) was 1.18 (95% CI 1.10–1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARB users appear an ideal control for analyses of ACEI effects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection.

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)

The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. History of taking ACEIs or ARBs at the time of COVID-19 testing. Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.

Comparisons of Staphylococcus aureus infection and other outcomes between users of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers: lessons for COVID-19 from a nationwide cohort study.

Background: Mice receiving angiotensin converting enzyme inhibitor (ACEI) drugs show increased susceptibility to infection by Staphylococcus aureus ( S. aureus). We sought to investigate whether humans using ACEI were at increased risk of S. aureus infection, comparing them to users of Angiotensin II Receptor Blockers (ARB) with multiple control outcomes to assess the potential for residual confounding. Methods: Using the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics between 1997 and 2017, we identified adults starting ACEI or ARB (as an active comparator drug). We regarded prescription of ACEI or ARB as time-dependent exposure and used a Cox regression model to compare incidence of first hospitalisation with infection due to S. aureus in periods with ACEI to periods with ARB prescriptions. We repeated the analysis using control outcomes that we did not expect to be associated with use of ACEI versus ARB (Gram-negative sepsis, hip fracture and herpes zoster) and one that we did (dry cough). Results: We identified 445,341 new users of ACEI (mean age 64.0±14.0, male 51.7%) and 41,824 new users of ARB (mean age 64.1±14.0, male 45.5%). The fully adjusted hazard ratio for S. aureus infection (ACEI vs. ARB) was 1.18 (95% CI 1.10-1.27), consistent across sensitivity analyses. However, we also found associations with all control outcomes; rates of Gram-negative sepsis, hip fracture and dry cough were also increased during periods of time treated with ACEI compared to ARB while herpes zoster was more common during time treated with ARB. Conclusions: Our results suggest that although ARB users appear an ideal control for analyses of ACEI effects, there is residual confounding even after multivariable adjustment. This has implications for observational analyses comparing users of these drug classes, in particular the effect of these drugs in relation to COVID-19 infection.