Effect of ACEi and ARBs vs Non ACEi/ ARBs in Hypertension with Respect to Renal Outcomes in COVID-19 Infection: A Retrospective Cohort Study

Introduction: The Acute Kidney Injury (AKI) is one of the most common complications following Coronavirus Disease-2019 (COVID-19) infection. The presence of high density of Angiotensin Converting Enzyme 2 (ACE2) receptors in Type 2 alveolar epithelial cells, vascular endothelium and proximal convoluted tubules explains the involvement of systemic organs in COVID-19 infection. Systemic hypertension is one of the most common co-morbidities associated with COVID-19 infection with high mortality, specially in patients of severe disease with AKI. The antihypertensives, which work by Renin Angiotensin Aldosterone System (RAAS) inhibition like ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) can upregulate the enzyme ACE2, so the incidence and risk of AKI in hypertensive patients who have COVID-19 infection is common. Aim(s): To determine the risk of developing AKI and mortality in hypertensive patients, with COVID-19 infection, on ACEi or ARBs as compared to non ACEi and non ARBs. Material(s) and Method(s): This was a retrospective cohort study conducted on 116 admitted hypertensive patients, who were positive for COVID-19 infection from the month of April 2021 to September 2021. The study patients were divided into two groups- group A and group B. The group A was on ACEi or ARBs and group B was on non ACEi/ARBs. The patients baseline history, clinical examination and the blood investigations like Renal Function Test (RFT), Liver Function Test (LFT), Echocardiography (ECG), Chest X-ray, 2 Dimensional ECHO (2D-ECHO), Arterial Blood Gases (ABG) were done for all the patients. The normal Blood Pressure (BP) was less than 140/90 mmHg.The normal creatinine was 0.6 to 1.5 mg/dL and normal urea was 19 to 45 mg/dL. The RFT was repeated on every day of hospital stay duration. The patients were followed-up for one month from day of starting the study. The parameters were recorded, assessed on day 7th and day 30th of the study. All parameters were compared between the final outcome of the patients by 30th day of study and the class of antihypertensives used to control hypertension. The Pearson's Chi-square test, Fisher's exact and Analysis of Variance (ANOVA) were used for testing the significance of relationship and outcome between group A and group B study patients. Result(s): The mean duration of hypertension in both the groups was 7.6 years. In group A 53 (45.7%) were on ACEi and ARBs, in group B, 63 (54.3%) were on non ACEi/ARBs. In the group A, the serum creatinine of more than >1.5 mg/dL at 7th day of study was found in 28 (52.8%) patients and on 30th day it was found in 8 (15.09%) patients (p-value=0.065). Again in the group A, blood urea of more than 45 mg/dL on 7th day of study was found in 30 (56.6%) patients and on 30th day it was found in 9 (16.98%) patients (p-value=0.064). In the group B, the serum creatinine >1.5 mg/dL on day 7th of study was found in 36 (57.14%) patients and on day 30th it was in 24 (38.09%) patients (p-value=0.061). Again in group B, the blood urea of >45 mg/dL on day 7th was found in 35 (55.55%) patients and on day 30th it was found in 16 (25.39%) patients (p-value=0.074). Of the patients on group A (ACEi and ARBs) 28 (52.83%) were on supplemental oxygen, 12 (22.6%) were on Non Invasive Ventilation (NIV), one was intubated and 12 (22.6%) did not require oxygen (p-value=0.727). Of the patients on group B (non ACEi/ARBs) 33 (52.4%) were on supplemental oxygen, 12 (19.04%) were on NIV, 5 (7.93%) were intubated and 13 (20.63%) did not require oxygen. In the patients of group A, 35 (66.03%) were recovered and 18 (33.96%) died, in the group B 40 (63.49%) cases were recovered, while 23 (36.50%) died (p-value=0.781). Conclusion(s): There was no significant and demonstrable association between specific groups of antihypertensives with renal outcomes and mortality in hypertensive patients with COVID-19 infection. By above observations this study concludes that, there is no pecific role of ACE2 receptors in renal outcome and mortality in hypertension with COVID-19 infection. Copyright © 2022 Journal of Clinical and Diagnostic Research. All rights reserved.

Associations Between Gastrointestinal Symptoms and COVID-19 Severity Outcomes Based on a Propensity Score-Weighted Analysis of a Nationwide Cohort.

Background and Aims: Gastrointestinal (GI) symptoms are well-recognized manifestations of coronavirus disease 2019 (COVID-19). Our primary objective was to evaluate the association between GI symptoms and COVID-19 severity. Methods: In this nationwide cohort of US veterans, we evaluated GI symptoms (nausea/vomiting/diarrhea) reported 30 days before and including the date of positive SARS-CoV-2 testing (March 1, 2020, to February 20, 2021). All patients had ≥1 year of prior baseline data and ≥60 days follow-up relative to the test date. We used propensity score (PS)-weighting to balance covariates in patients with vs without GI symptoms. The primary composite outcome was severe COVID-19, defined as hospital admission, intensive care unit admission, mechanical ventilation, or death within 60 days of positive testing. Results: Of 218,045 SARS-CoV-2 positive patients, 29,257 (13.4%) had GI symptoms. After PS weighting, all covariates were balanced. In the PS-weighted cohort, patients with vs without GI symptoms had severe COVID-19 more often (29.0% vs 17.1%; P < .001). When restricted to hospitalized patients (14.9%; n=32,430), patients with GI symptoms had similar frequencies of intensive care unit admission and mechanical ventilation compared with patients without symptoms. There was a significant age interaction; among hospitalized patients aged ≥70 years, lower COVID-19-associated mortality was observed in patients with vs without GI symptoms, even after accounting for COVID-19-specific medical treatments. Conclusion: In the largest integrated US health care system, SARS-CoV-2-positive patients with GI symptoms experienced severe COVID-19 outcomes more often than those without symptoms. Additional research on COVID-19-associated GI symptoms may inform preventive efforts and interventions to reduce severe COVID-19.

Lack of Correlation Between Soluble Angiotensin-Converting Enzyme 2 and Inflammatory Markers in Hospitalized COVID-19 Patients with Hypertension.

Purpose: This study aimed to investigate the correlation of plasma soluble angiotensin-converting enzyme 2, sACE2, and several inflammatory markers in COVID-19 patients requiring hospitalization with hypertension. Additionally, we analyzed the effects of renin-angiotensin-aldosterone-system, RAAS, inhibitors on the levels of sACE2 and inflammatory marker levels in patients with COVID-19. Patients and Methods: This cross-sectional study involved patients with COVID-19 who required hospitalization on a stable dose of antihypertensive drugs. The study included three hospitals in Jakarta and Tangerang, Indonesia, between December 2020 and June 2021. We classified eligible subjects into two groups: patients with COVID-19 treated with antihypertensive RAAS inhibitors or non-RAAS inhibitors. Results: We found no correlation between sACE2 and all the inflammatory and coagulation markers studied (high-sensitivity C-reactive protein, IL-6, IL-10, IL6/IL10, tumor necrosis factor-α, neutrophil-to-lymphocyte ratio, and D-dimer) in COVID-19 patients with hypertension. Further analysis showed lower sACE2 concentrations and IL-6/IL-10 ratio in patients treated with RAAS inhibitors vs those treated with non-RAAS inhibitors. Conclusion: We found no correlation between ACE2 and inflammatory markers. Using RAAS inhibitors resulted in a lower sACE2 and IL-6/IL-10 ratio. The type of antihypertensive treatments has a neutral effect on disease severity and outcome in COVID-19 patients with hypertension. However, to firmly-established these effects, our findings should be confirmed in a much larger population.

Effects of Renin-Angiotensin System Inhibitors on Mortality and Disease Severity of COVID-19 Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: There is controversy over the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on the prognosis in patients with coronavirus disease 2019 (COVID-19), therefore, we aim to further explore the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19-associated disease severity and mortality. METHODS: We systematically searched PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv from inception to 6 September 2021. The primary outcome was all-cause mortality. Secondary outcome was severe disease which was defined as admission to the intensive care unit, the use of noninvasive or invasive mechanical ventilation, or death. RESULTS: A total of 7 randomized controlled trials involving 1,321 COVID-19 patients were included. Fixed-effects meta-analysis demonstrated that the use of ACEI/ARB was not associated with higher risk of mortality (risk ratio [RR] = 0.84, 95% confidence interval [CI] 0.57-1.22, P = 0.10, I2 = 43%) and disease severity (RR = 0.86, 95% CI 0.71-1.05, P = 0.11, I2 = 47%). However, the subgroup analysis showed that compared with no ACEI/ARB use, the use of ARB was associated with a significant reduction of mortality (RR = 0.23, CI 0.09-0.60, P = 0.55, I2 = 0%) and disease severity (RR = 0.38, CI 0.19-0.77, P = 0.007). CONCLUSIONS: In conclusion, based on the available data, ACEI/ARB is not associated with the risk of mortality and disease severity in COVID-19 patients. And ACEI/ARB medications, especially ARB, should not be discontinued for patients with COVID-19.

COVID-19 and RAAS inhibitors: is there a final conclusion?

Coronavirus disease 2019 (COVID-19), the first pandemic caused by a human infecting coronavirus, has drawn global attention from the first time it appeared in Wuhan city of China in late December 2019. Detection of the responsible viral pathogen, named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by WHO, and its possible pathogenesis lead to the forming of many hypotheses about the factors that may affect the patients' outcome. One of the SARS-CoV-2 infection concerns was the potential role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19 patients' morbidity and mortality. Studies demonstrated that because SARS-CoV-2 uses human ACE2 cell receptors as an entry receptor to invade the cells, there might be an association between antihypertensive drugs such as RAAS inhibitors (specifically ACEIs and ARBs) and the COVID-19 disease. Data are scarce and conflicting regarding ACEI or ARB consumption and how it influences disease outcomes, and a single conclusion has not been reached yet. According to the literature review in our article, the most evidentially supported theory about the use of RAAS inhibitors in COVID-19 is that these medications, including ACEI/ARB, are not associated with the increased risk of infection, disease severity, and patient prognosis. However, further studies are needed to support the hypothesis.

Safety and Efficacy of Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19 Population.

INTRODUCTION: The safety of renin-angiotensin-aldosterone system inhibitors (RAASi) among COVID-19 patients has been controversial since the onset of the pandemic. METHODS: Digital databases were queried to study the safety of RAASi in COVID-19. The primary outcome of interest was mortality. The secondary outcome was seropositivity improvement/viral clearance, clinical manifestation progression, and progression to intensive care units. A random-effect model was used to compute an unadjusted odds ratio (OR). RESULTS: A total of 49 observational studies were included in the analysis consisting of 83,269 COVID-19 patients (RAASi n = 34,691; non-RAASi n = 48,578). The mean age of the sample was 64, and 56% were males. We found that RAASi was associated with similar mortality outcomes as compared to non-RAASi groups (OR 1.07; 95% CI 0.99-1.15; p > 0.05). RAASi was associated with seropositivity improvement including negative RT-PCR or antibodies, (OR 0.96; 95% CI 0.93-0.99; p < 0.05). There was no association between RAASi versus control with progression to ICU admission (OR 0.99; 95% CI 0.79-1.23; p > 0.05) or higher odds of worsening of clinical manifestations (OR 1.04; 95% CI 0.97-1.11; p > 0.05). Metaregression analysis did not change our outcomes for effect modifiers including age, sex, comorbidities, RAASi type, or study type on outcomes. CONCLUSIONS: COVID-19 is not a contraindication to hold or discontinue RAASi as they are not associated with higher mortality or worsening symptoms. Continuation of RAASi might be associated with favorable outcomes in COVID-19, including seropositivity/viral clearance.

The age again in the eye of the COVID-19 storm: evidence-based decision making.

BACKGROUND: One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data. RESULTS: Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/µL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve. CONCLUSION: Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.

Antihypertensive medications and COVID-19 diagnosis and mortality: Population-based case-control analysis in the United Kingdom.

AIMS: Antihypertensive drugs have been implicated in coronavirus disease 2019 (COVID-19) susceptibility and severity, but estimated associations may be susceptible to bias. We aimed to evaluate antihypertensive medications and COVID-19 diagnosis and mortality, accounting for healthcare-seeking behaviour. METHODS: A population-based case-control study was conducted including 16 866 COVID-19 cases and 70 137 matched controls from the UK Clinical Practice Research Datalink. We evaluated all-cause mortality among COVID-19 cases. Exposures were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (B), calcium-channel blockers (C), thiazide diuretics (D) and other antihypertensive drugs (O). Analyses were adjusted for covariates and consultation frequency. RESULTS: ACEIs were associated with lower odds of COVID-19 diagnosis (adjusted odds ratio [AOR] 0.82, 95% confidence interval [CI] 0.77-0.88) as were ARBs (AOR 0.87, 95% CI 0.80-0.95) with little attenuation from adjustment for consultation frequency. C and D were also associated with lower odds of COVID-19 diagnosis. Increased odds of COVID-19 for B (AOR 1.19, 95% CI 1.12-1.26) were attenuated after adjustment for consultation frequency (AOR 1.01, 95% CI 0.95-1.08). Patients treated with ACEIs or ARBs had similar odds of mortality (AOR 1.00, 95% CI 0.83-1.20) to patients treated with classes B, C, D or O or patients receiving no antihypertensive therapy (AOR 0.99, 95% CI 0.83-1.18). CONCLUSIONS: There was no evidence that antihypertensive therapy is associated with increased risk of COVID-19 diagnosis or mortality; most classes of antihypertensive therapy showed negative associations with COVID-19 diagnosis.

Association between renin-angiotensin-aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million patient nationwide registry analysis.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) improve outcomes in cardiorenal disease but concerns have been raised over increased risk of incident hospitalization and death from coronavirus disease 2019 (COVID-19). We investigated the association between use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs) and COVID-19 hospitalization/death in a large nationwide population. METHODS AND RESULTS: Patients with hypertension, heart failure, diabetes, kidney disease, or ischaemic heart disease registered in the Swedish National Patient Registry until 1 February 2020 were included and followed until 31 May 2020. COVID-19 cases were defined based on hospitalization/death for COVID-19. Multivariable logistic and Cox regressions were fitted to investigate the association between ACEi/ARB and MRA and risk of hospitalization/death for COVID-19 in the overall population, and of all-cause mortality in COVID-19 cases. We performed consistency analysis to quantify the impact of potential unmeasured confounding. Of 1 387 746 patients (60% receiving ACEi/ARB and 5.8% MRA), 7146 (0.51%) had incident hospitalization/death from COVID-19. After adjustment for 45 variables, ACEi/ARB use was associated with a reduced risk of hospitalization/death for COVID-19 (odds ratio 0.86, 95% confidence interval 0.81-0.91) in the overall population, and with reduced mortality in COVID-19 cases (hazard ratio 0.89, 95% confidence interval 0.82-0.96). MRA use was not associated with risk of any outcome. Consistency analysis showed that unmeasured confounding would need to be large for there to be harmful signals associated with RAASi use. CONCLUSIONS: In a 1.4 million nationwide cohort, use of RAASi was not associated with increased risk of hospitalization for or death from COVID-19.

COVID-19 and cardiovascular diseases.

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the second pandemic of the XXI century after influenza A in 2009. As of mid-June 2020, more than 4,40,000 fatal cases of SARS-CoV-2-related disease (COVID-19) have occurred worldwide. Besides its prominent expression at the level of the respiratory apparatus, COVID-19 is also characterized by a substantial degree of cardiovascular involvement, both in terms of deterioration of pre-existing conditions, and as the effect of inflammation-facilitated acute events. They include ischemic/inflammatory heart disease, ventricular arrhythmias, conduction disturbances, thrombotic events at the level of the lungs, and systemic activation of the coagulation cascade, configuring the scenario of disseminated intravascular coagulation. Herein, we summarize the main COVID-19 features of relevance for the clinicians in the cardiovascular field. The rationale, concerns, and possible side effects of specific therapeutic measures, including anticoagulants, renin-angiotensin-aldosterone system inhibitors, and anti-inflammatory/antiviral medications applied to the treatment of COVID-19 are also discussed.