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1.
J Am Coll Emerg Physicians Open ; 1(3): 231-237, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1898668

ABSTRACT

The COVID-19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID-19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID-19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL-6 inhibitors, corticosteroids, and angiotensin-converting enzyme inhibitors.

2.
Med Clin (Engl Ed) ; 155(11): 488-490, 2020 Dec 11.
Article in English | MEDLINE | ID: covidwho-1804801

ABSTRACT

INTRODUCTION: There is controversy concerning the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) for treating hypertensive patients with Covid-19. It has been hypothesized that these drugs might increase the risk of severe Covid-19, but some authors suggested that blocking the renin-angiotensin system might actually decrease this risk. METHODS: Retrospective cohort study of all the consecutive hypertensive patients with confirmed SARS-CoV-2 infection in a health area. The outcome variable was hospitalization because of severe Covid-19. RESULTS: 539 subjects were diagnosed of SARS-CoV-2 infection. Of these, 157 (29.1%) had hypertension and were included in the study. Sixty-nine cases (43.9%) were hospitalized because of severe Covid-19. In multivariable analysis older age, diabetes and hypertensive myocadiopathy were related to a higher risk of hospital admission. ARB treatment was associated with a significantly lower risk of hospitalization (HR: 0.29, 95% CI: 0.10 - 0.88). A similar albeit not significant trend was observed for ACEI. CONCLUSION: ARB or ACEI treatment was not associated with a worse clinical outcome in consecutive hypertensive patients infected by SARS-CoV-2.


INTRODUCCIÓN: Existe controversia respecto al uso de los inhibidores de la enzima convertidora de angiotensina (IECA) o los bloqueadores de los receptores tipo I de la angiotensina II (ARA-II) para el tratamiento de la hipertensión arterial en COVID-19. Se ha sugerido que estos fármacos podrían tanto aumentar como reducir el riesgo de COVID-19 grave. PACIENTES Y MÉTODO: Estudio de cohortes retrospectivo de pacientes consecutivos de un área sanitaria, con hipertensión e infección por SARS-CoV-2. Variable de resultados: ingreso hospitalario por COVID-19 grave. RESULTADOS: Fueron diagnosticados 539 sujetos por infección por SARS-CoV-2. De estos, 157 (29,1%) eran hipertensos y se incluyeron en el estudio. Se ingresaron 69 (43,9%) pacientes por COVID-19 grave. En el análisis multivariante, la edad más elevada, la diabetes y la miocardiopatía hipertensiva se relacionaron con el riesgo de ingreso hospitalario. El tratamiento con ARA-II se asoció con un riesgo significativamente más bajo de ingreso (HR: 0,29, IC 95%: 0,10-0,88). Una tendencia similar, aunque no significativa, se encontró para los IECA. CONCLUSIÓN: el tratamiento con ARA-II o IECA no se asoció con una peor evolución clínica en pacientes hipertensos consecutivos infectados por SARS-CoV-2.

3.
Zhonghua Nei Ke Za Zhi ; 59(8): 610-617, 2020 Aug 01.
Article in Chinese | MEDLINE | ID: covidwho-1555470

ABSTRACT

Objective: To explore the feasibility of direct renin inhibitor aliskiren for the treatment of severe or critical coronavirus disease 2019 (COVID-19) patients with hypertension. Methods: The antihypertensive effects and safety of aliskiren was retrospectively analyzed in three severe and one critical COVID-19 patients with hypertension. Results: Four patients, two males and two females, with an average age of 78 years (66-87 years), were referred to hospital mainly because of respiratory symptoms. Three were diagnosed by positive novel coronavirus 2019 (2019-nCoV) nucleic acid or antibody, and the critical patient with cardiac insufficiency was clinically determined. Two patients were treated with calcium channel antagonist (CCB), one with angiotensin converting enzyme inhibitor (ACEI), and one with angiotensin Ⅱ receptor antagonist (ARB). After admission, ACEI and ARB were discontinued, one patient with heart failure was treated by aliskiren combined with diuretic.Three patients were treated with aliskiren combined with CCB among whom two withdrew CCB due to low blood pressure after 1 to 2 weeks. Based on comprehensive treatment including antiviral and oxygenation treatment, blood pressure was satisfactorily controlled by aliskiren after three to four weeks without serious adverse events. All patients were finally discharged. Conclusion: Our preliminary clinical data shows that antihypertensive effect of aliskiren is satisfactory and safe for severe COVID-19 patients complicated with hypertension.


Subject(s)
Antihypertensive Agents , COVID-19 , Hypertension , Renin/antagonists & inhibitors , Aged , Aged, 80 and over , Amides/therapeutic use , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents/therapeutic use , COVID-19/complications , Female , Fumarates/therapeutic use , Humans , Hypertension/drug therapy , Male , Retrospective Studies
4.
Brief Bioinform ; 22(2): 1387-1401, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343660

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals that have hypertension or cardiovascular comorbidities have an elevated risk of serious coronavirus disease 2019 (COVID-19) disease and high rates of mortality but how COVID-$19$ and cardiovascular diseases interact are unclear. We therefore sought to identify novel mechanisms of interaction by identifying genes with altered expression in SARS-CoV-$2$ infection that are relevant to the pathogenesis of cardiovascular disease and hypertension. Some recent research shows the SARS-CoV-$2$ uses the angiotensin converting enzyme-$2$ (ACE-$2$) as a receptor to infect human susceptible cells. The ACE2 gene is expressed in many human tissues, including intestine, testis, kidneys, heart and lungs. ACE2 usually converts Angiotensin I in the renin-angiotensin-aldosterone system to Angiotensin II, which affects blood pressure levels. ACE inhibitors prescribed for cardiovascular disease and hypertension may increase the levels of ACE-$2$, although there are claims that such medications actually reduce lung injury caused by COVID-$19$. We employed bioinformatics and systematic approaches to identify such genetic links, using messenger RNA data peripheral blood cells from COVID-$19$ patients and compared them with blood samples from patients with either chronic heart failure disease or hypertensive diseases. We have also considered the immune response genes with elevated expression in COVID-$19$ to those active in cardiovascular diseases and hypertension. Differentially expressed genes (DEGs) common to COVID-$19$ and chronic heart failure, and common to COVID-$19$ and hypertension, were identified; the involvement of these common genes in the signalling pathways and ontologies studied. COVID-$19$ does not share a large number of differentially expressed genes with the conditions under consideration. However, those that were identified included genes playing roles in T cell functions, toll-like receptor pathways, cytokines, chemokines, cell stress, type 2 diabetes and gastric cancer. We also identified protein-protein interactions, gene regulatory networks and suggested drug and chemical compound interactions using the differentially expressed genes. The result of this study may help in identifying significant targets of treatment that can combat the ongoing pandemic due to SARS-CoV-$2$ infection.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/complications , Computational Biology , Hypertension/complications , Systems Biology , COVID-19/virology , Humans , SARS-CoV-2/isolation & purification
5.
Lancet Respir Med ; 9(8): 863-872, 2021 08.
Article in English | MEDLINE | ID: covidwho-1340915

ABSTRACT

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , COVID-19 , Hypertension , Renin-Angiotensin System , SARS-CoV-2 , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Area Under Curve , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/therapy , Female , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Male , Middle Aged , Organ Dysfunction Scores , Outcome and Process Assessment, Health Care , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Adjustment/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Severity of Illness Index , Withholding Treatment/statistics & numerical data
6.
Eur Heart J Case Rep ; 5(2): ytaa521, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1334208

ABSTRACT

BACKGROUND: Since the first documented outbreak of a novel severe acute respiratory syndrome inducing Coronavirus in China at the end of 2019 the virus has spread to all continents, leading the WHO to declare a pandemic in March 2020. While this virus primarily targets the alveoli in the lungs, multiple authors have described an increased rate of thrombo-embolic events in affected patients. We present this case of a myocardial infarction with no obstructive coronary atherosclerosis in an otherwise healthy 48-year-old patient. CASE SUMMARY: A 48-year-old female, presenting with chest pain radiating to her left shoulder with no cardiovascular risk factors other than genetic predisposition, was screened for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and tested positive. Although computed tomography angiography excluded obstructive coronary heart disease, cardiac magnetic resonance imaging showed an acute myocardial infarction with no obstructive coronary arteries of the inferior wall. The patient was treated with dual anti-platelet therapy, an angiotensin-converting-enzyme inhibitor and a statin, and assigned to a cardiac rehabilitation program. CONCLUSION: We report a serious thrombo-embolic event during an oligosymptomatic SARS-CoV-2 infection in a healthy, young patient. While these two diseases may have occurred simultaneously, by chance, it is possible that the pro-thrombotic effects of the SARS-CoV-2 infection facilitated the infarction. This case further demonstrates the significant cardiovascular morbidity potentially caused by SARS-CoV-2.

7.
Am Heart J ; 240: 46-57, 2021 10.
Article in English | MEDLINE | ID: covidwho-1316364

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are known to impact the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The association between chronic therapy with these medications and infection risk remains unclear. OBJECTIVES: The objective was to determine the association between prior ACEI or ARB therapy and SARS-CoV-2 infection among patients with hypertension in the U.S. Veteran's Affairs health system. METHODS: We compared the odds of SARS-CoV-2 infection among three groups: patients treated with ACEI, treated with ARB, or treated with alternate first-line anti-hypertensives without ACEI/ARB. We excluded patients with alternate indications for ACEI or ARB therapy. We performed an augmented inverse propensity weighted analysis with adjustment for demographics, region, comorbidities, vitals, and laboratory values. RESULTS: Among 1,724,723 patients with treated hypertension, 659,180 were treated with ACEI, 310,651 with ARB, and 754,892 with neither. Before weighting, patients treated with ACEI or ARB were more likely to be diabetic and use more anti-hypertensives. There were 13,278 SARS-CoV-2 infections (0.8%) between February 12, 2020 and August 19, 2020. Patients treated with ACEI had lower odds of SARS-CoV-2 infection (odds ratio [OR] 0.93; 95% CI: 0.89-0.97) while those treated with ARB had similar odds (OR 1.02; 95% CI: 0.96-1.07) compared with patients treated with alternate first-line anti-hypertensives without ACEI/ARB. In falsification analyses, patients on ACEI did not have a difference in their odds of unrelated outcomes. CONCLUSIONS: Our results suggest the safety of continuing ACEI and ARB therapy. The association between ACEI therapy and lower odds of SARS-CoV-2 infection requires further investigation.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , COVID-19/epidemiology , Hypertension/drug therapy , Renin-Angiotensin System/drug effects , Adrenergic beta-Antagonists/therapeutic use , Aged , Angiotensin II Type 2 Receptor Blockers , Calcium Channel Blockers/therapeutic use , Case-Control Studies , Comorbidity , Confidence Intervals , Diabetes Mellitus/epidemiology , Female , Humans , Male , Middle Aged , Odds Ratio , Propensity Score , Receptors, Virus , SARS-CoV-2 , Sodium Chloride Symporter Inhibitors/therapeutic use , United States/epidemiology , United States Department of Veterans Affairs , Veterans/statistics & numerical data
8.
Turk Kardiyol Dern Ars ; 49(4): 286-292, 2021 06.
Article in English | MEDLINE | ID: covidwho-1262654

ABSTRACT

OBJECTIVE: To compare the prevalence of hypertension and pre-existing use of renin-angiotensin-aldosterone system blockers in patients with coronavirus disease (COVID-19) and non-COVID-19 viral pneumonias. METHODS: Real-time polymerase chain reaction confirmed COVID-19 and non-COVID-19 pneumonia patients were retrospectively analyzed. The presence of hypertension, coronary artery disease (CAD), and pre-existing use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were compared between the groups. RESULTS: A total of 103 COVID-19 and 91 non-COVID-19 hospitalized viral pneumonia patients were enrolled. Hypertension and CAD were more common in patients with non-COVID-19 viral pneumonia than in patients with COVID-19 (39.6% vs 22.3%, respectively, p=0.012 and 24.2% vs 4.9%, respectively, p<0.001). In our study, 2.9% and 6.8% of patients with COVID-19 were on ACEIs and ARBs, respectively, whereas 13.2% and 19.8% of patients with non-COVID-19 viral pneumonia were on ACEIs and ARBs, respectively (p=0.009 and p=0.013). Neutrophil-to-lymphocyte ratio (p<0.001) was prominent in patients with non-COVID-19 viral pneumonia compared with patients with COVID-19. CONCLUSION: Our study results indicate that hypertension and CAD are more common among patients with non-COVID-19 viral pneumonia than patients with COVID-19. The prevalence of ACEIs and ARBs use was not higher in patients with COVID-19. Our results support that the use of ACEIs and ARBs do not play a specific role in patients with COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Hypertension , Adult , COVID-19/complications , COVID-19/epidemiology , Coronary Artery Disease/complications , Coronary Artery Disease/epidemiology , Female , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/epidemiology , Male , Middle Aged , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Prevalence , Retrospective Studies
9.
Front Med (Lausanne) ; 8: 647319, 2021.
Article in English | MEDLINE | ID: covidwho-1238868

ABSTRACT

COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed via telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance (p < 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS/BS ACE2 glycosylation and other potential beneficial effects of BS/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels.

10.
Am J Health Syst Pharm ; 78(24): 2245-2255, 2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1236214

ABSTRACT

PURPOSE: To provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone. METHODS: PubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I2. Risk of bias was assessed using the revised Cochrane risk of bias tool. RESULTS: From the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%). CONCLUSION: Treatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia.


Subject(s)
Angiotensin Receptor Antagonists , Spironolactone , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Humans , Potassium , Reproducibility of Results , Spironolactone/adverse effects
11.
Front Cardiovasc Med ; 8: 609857, 2021.
Article in English | MEDLINE | ID: covidwho-1226973

ABSTRACT

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share a target receptor with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The use of ACEIs/ARBs may cause angiotensin-converting enzyme 2 receptor upregulation, facilitating the entry of SARS-CoV-2 into host cells. There is concern that the use of ACEIs/ARBs could increase the risks of severe COVID-19 and mortality. The impact of discontinuing these drugs in patients with COVID-19 remains uncertain. We aimed to assess the association between the use of ACEIs/ARBs and the risks of mortality and severe disease in patients with COVID-19. A systematic search was performed in PubMed, EMBASE, Cochrane Library, and MedRxiv.org from December 1, 2019, to June 20, 2020. We also identified additional citations by manually searching the reference lists of eligible articles. Forty-two observational studies including 63,893 participants were included. We found that the use of ACEIs/ARBs was not significantly associated with a reduction in the relative risk of all-cause mortality [odds ratio (OR) = 0.87, 95% confidence interval (95% CI) = 0.75-1.00; I 2 = 57%, p = 0.05]. We found no significant reduction in the risk of severe disease in the ACEI subgroup (OR = 0.95, 95% CI = 0.88-1.02, I 2 = 50%, p = 0.18), the ARB subgroup (OR = 1.03, 95% CI = 0.94-1.13, I 2 = 62%, p = 0.48), or the ACEI/ARB subgroup (OR = 0.83, 95% CI = 0.65-1.08, I 2 = 67%, p = 0.16). Moreover, seven studies showed no significant difference in the duration of hospitalization between the two groups (mean difference = 0.33, 95% CI = -1.75 to 2.40, p = 0.76). In conclusion, the use of ACEIs/ARBs appears to not have a significant effect on mortality, disease severity, or duration of hospitalization in COVID-19 patients. On the basis of the findings of this meta-analysis, there is no support for the cessation of treatment with ACEIs or ARBs in patients with COVID-19.

12.
Br J Clin Pharmacol ; 87(12): 4598-4607, 2021 12.
Article in English | MEDLINE | ID: covidwho-1205938

ABSTRACT

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.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , COVID-19 Testing , Case-Control Studies , Humans , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , SARS-CoV-2
13.
Curr Pharmacol Rep ; 7(3): 102-106, 2021.
Article in English | MEDLINE | ID: covidwho-1202878

ABSTRACT

COVID-19 represents the biggest health challenge. Although the mortality rate of COVID-19 is low, the high numbers of infected people and those with post-COVID-19 symptoms represent a real problem for the health system. A high number of patients with COVID-19 or people recovered from COVID-19 suffer from a dry cough and/or myalgia. Interestingly, an imbalance in bradykinin was observed in COVID-19 patients, which might be due to the accumulation of bradykinin as a result of a reduction in the degradation of bradykinin. This finding inspired the idea of possible similitude between the dry cough that is induced by angiotensin-converting enzyme inhibitors and the COVID-19-induced dry cough. Both of these types of cough are mediated, at least partially, by bradykinin. They both manifested as a persistent dry cough that is not responded to traditional dry cough remedies. However, several drugs were previously investigated for the treatment of angiotensin-converting enzyme inhibitor-induced dry cough. Here, we hypothesized that such treatment might be useful in COVID-19-induced dry cough and other bradykinin-related symptoms such as generalized pain and myalgia. In this article, evidence was presented to support the use of indomethacin as a potential treatment of COVID-19-induced dry cough. The choice of indomethacin was based on its ability to suppress the cyclooxygenase enzyme while also lowering the level of the inflammatory mediator bradykinin. Furthermore, indomethacin has been shown to be effective in treating angiotensin-converting enzyme inhibitor-induced dry cough. Moreover, indomethacin is a long-established, low-cost, effective, and readily available medication.

14.
Int J Mol Sci ; 22(9)2021 Apr 26.
Article in English | MEDLINE | ID: covidwho-1201474

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of Coronavirus Disease-2019 (COVID-19) in humans. ACE-2 is a type I transmembrane metallocarboxypeptidase expressed in vascular endothelial cells, alveolar type 2 lung epithelial cells, renal tubular epithelium, Leydig cells in testes and gastrointestinal tract. ACE2 mediates the interaction between host cells and SARS-CoV-2 spike (S) protein. However, ACE2 is not only a SARS-CoV-2 receptor, but it has also an important homeostatic function regulating renin-angiotensin system (RAS), which is pivotal for both the cardiovascular and immune systems. Therefore, ACE2 is the key link between SARS-CoV-2 infection, cardiovascular diseases (CVDs) and immune response. Susceptibility to SARS-CoV-2 seems to be tightly associated with ACE2 availability, which in turn is determined by genetics, age, gender and comorbidities. Severe COVID-19 is due to an uncontrolled and excessive immune response, which leads to acute respiratory distress syndrome (ARDS) and multi-organ failure. In spite of a lower ACE2 expression on cells surface, patients with CVDs have a higher COVID-19 mortality rate, which is likely driven by the imbalance between ADAM metallopeptidase domain 17 (ADAM17) protein (which is required for cleavage of ACE-2 ectodomain resulting in increased ACE2 shedding), and TMPRSS2 (which is required for spike glycoprotein priming). To date, ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) treatment interruption in patients with chronic comorbidities appears unjustified. The rollout of COVID-19 vaccines provides opportunities to study the effects of different COVID-19 vaccines on ACE2 in patients on treatment with ACEi/ARB.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Cardiovascular Diseases/pathology , SARS-CoV-2/physiology , ADAM17 Protein/metabolism , COVID-19/complications , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , Cardiovascular Diseases/complications , Humans , Receptors, Virus/metabolism , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism
15.
PLoS One ; 16(4): e0248080, 2021.
Article in English | MEDLINE | ID: covidwho-1199975

ABSTRACT

BACKGROUND: Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses. METHODS AND FINDINGS: In this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days). CONCLUSIONS: This observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/pathology , Hypertension/drug therapy , Aged , COVID-19/mortality , COVID-19/virology , Female , Hospitalization/statistics & numerical data , Humans , Hypertension/pathology , Male , Middle Aged , Propensity Score , Proportional Hazards Models , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Survival Rate , Veterans
16.
Clin Sci (Lond) ; 135(8): 1009-1014, 2021 04 30.
Article in English | MEDLINE | ID: covidwho-1195632

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the leading player of the protective renin-angiotensin system (RAS) pathway but also the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAS inhibitors seemed to interfere with the ACE2 receptor, and their safety was addressed in COVID-19 patients. Pedrosa et al. (Clin. Sci. (Lond.) (2021), 135, 465-481) showed in rats that captopril and candesartan up-regulated ACE2 expression and the protective RAS pathway in lung tissue. In culture of pneumocytes, the captopril/candesartan-induced ACE2 up-regulation was associated with inhibition of ADAM17 activity, counterbalancing increased ACE2 expression, which was associated with reduced SARS-CoV-2 spike protein entry. If confirmed in humans, these results could become the pathophysiological background for justifying RAS inhibitors as cornerstone cardiovascular protectives even during COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , COVID-19 , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Benzimidazoles , Biphenyl Compounds , Captopril/pharmacology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Rats , Renin-Angiotensin System , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tetrazoles
17.
Curr Opin Cardiol ; 36(4): 436-443, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1191524

ABSTRACT

PURPOSE OF REVIEW: Hypertension (HTN) is the most prevalent risk factor for cardiovascular disease (CVD) worldwide, affecting 1.39 billion people. This review discusses recent literature regarding the global burden of HTN and emerging concepts in prevalence, treatment, and control in different regions around the globe. RECENT FINDINGS: Community-based interventions and telemedicine may be useful in increasing access to care and identifying/assisting patients with HTN, especially in populations with geographical and economic barriers to healthcare. Home blood pressure monitoring is beneficial for HTN control in diverse regions. Polypills have proven benefits to decrease HTN and CVD risk. Continuation of treatment with angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers in high risk COVID-19 patients appears appropriate. SUMMARY: Extensive research demonstrates that early screening/treatment, lifestyle modification, and pharmacotherapy are essential to control HTN worldwide. This review highlights recent research and novel concepts on effective interventions being used globally.


Subject(s)
COVID-19 , Hypertension , Angiotensin-Converting Enzyme Inhibitors , Blood Pressure Monitoring, Ambulatory , Humans , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , SARS-CoV-2
18.
CJC Open ; 3(7): 965-975, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1174145

ABSTRACT

BACKGROUND: Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users. METHODS: We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis. RESULTS: In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 [95% confidence interval: 0.62, 0.96]). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 [95% confidence interval: 0.71, 1.08]). CONCLUSIONS: ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias.


INTRODUCTION: Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA. MÉTHODES: Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l'âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l'étude durant la synthèse des données. RÉSULTATS: Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 [intervalle de confiance à 95 % : 0,62, 0,96]). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 [intervalle de confiance à 95 % : 0,71, 1,08]). CONCLUSIONS: L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l'âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.

19.
Mol Cell Endocrinol ; 529: 111263, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1164193

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19). The main organ affected in this infection is the lung and the virus uses the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the target cells. In this context, a controversy raised regarding the use of renin-angiotensin system (RAAS) blockers, as these drugs might increase ACE2 expression in some tissues and potentially increase the risk for SARS-CoV-2 infection. This is specially concerning in diabetic patients as diabetes is a risk factor for COVID-19. METHODS: 12-week old diabetic mice (db/db) were treated with ramipril, or vehicle control for 8 weeks. Non-diabetic db/m mice were included as controls. ACE2 expression and activity were studied in lung, kidney and heart of these animals. RESULTS: Kidney ACE2 activity was increased in the db/db mice as compared to the db/m (143.2% ± 23% vs 100% ± 22.3%, p = 0.004), whereas ramipril had no significant effect. In the lung, no differences were found in ACE2 when comparing db/db mice to db/m and ramipril also had no significant effect. In the heart, diabetes decreased ACE2 activity (83% ± 16.8%, vs 100% ± 23.1% p = 0.02), and ramipril increased ACE2 significantly (83% ± 16.8% vs 98.2% ± 15%, p = 0.04). CONCLUSIONS: In a mouse model of type 2 diabetes, ramipril had no significant effect on ACE2 activity in either kidneys or in the lungs. Therefore, it is unlikely that RAAS blockers or at least angiotensin-converting enzyme inhibitors increase the risk of SARS-CoV-2 infection through increasing ACE2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Diabetes Mellitus, Experimental/drug therapy , Kidney/metabolism , Lung/metabolism , Myocardium/metabolism , Ramipril/pharmacology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/enzymology , COVID-19/genetics , COVID-19/pathology , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Kidney/pathology , Kidney/virology , Lung/pathology , Lung/virology , Male , Mice , Mice, Mutant Strains , Organ Specificity/drug effects , Organ Specificity/genetics , SARS-CoV-2/genetics
20.
Adv Ther ; 38(5): 2709-2716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1163169

ABSTRACT

INTRODUCTION: At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, controversial data were reported concerning angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) that induced a number of physicians to stop using them in patients with COVID-19. Although large-scale studies have ruled out this concern, it is common experience that patients with COVID-19 taking ACE inhibitors or ARBs are at increased risk of death. The aim of this study was to investigate the reasons for this apparently high mortality rate. METHODS: During the first wave of the pandemic, we conducted a field study of 427 consecutive patients with COVID-19 upon their admission to the emergency department of a hospital in one of the most severely hit cities in northern Italy, and 30 days later. The disease was defined as being mild, moderate or severe on the basis of clinical, laboratory and imaging data, and a multivariate model was used to analyse the determinants of mortality. RESULTS: Within 30 days of admission, 31.6% of the patients treated with ACE inhibitors or ARBs and 15.2% of those not treated with these drugs had died. Multivariate analysis showed that the determinants of mortality were age (p = 0.0001), hypertension (p = 0.0120) and diabetes (p = 0.0129), whereas ACE inhibitors or ARBs had no effect on mortality. There was no significant difference between the patients treated with ACE inhibitors and those treated with ARBs. CONCLUSION: The apparently increased mortality of patients with COVID-19 receiving long-term treatment with ACE inhibitors or ARBs is not due to the drugs themselves, but to the conditions associated with their use.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Humans , Hypertension/drug therapy , Italy/epidemiology , Renin-Angiotensin System , SARS-CoV-2
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