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Impact of antihypertensive agents on clinical course and in-hospital mortality: analysis of 169 hypertensive patients hospitalized for COVID-19

SUMMARY

OBJECTIVE

Coronavirus disease 2019 (COVID-19) is an emerging health threat caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Previous studies have noted hypertension is associated with increased mortality due to COVID-19; however, it is not clear whether the increased risk is due to hypertension itself or antihypertensive agents. We aimed to evaluate the impact of antihypertensive agents on the clinical outcomes of hypertensive patients with COVID-19.

METHODS

Our study included 169 consecutive hypertensive patients hospitalized due to COVID-19 between March 20 and April 10, 2020. The demographic characteristics, clinical data, and type of antihypertensive agents being used were reviewed.

RESULTS

The mean age of patients was 65.8±11.7 years.30 patients(17.7%) died during hospitalization. A total of 142 patients(84%) were using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), 91 (53.8%) were using diuretics, 69 (40.8%) were using calcium channel blockers (CCBs), 66 (39.1%) were using beta-blockers, 12 (7.1%) were using alpha-blockers, and 5 (2.9%) were using mineralocorticoid receptor antagonists (MRAs). There was no significant difference between survivors and non-survivors based on the type of antihypertensive agents being used. Binary logistic regression analysis showed that the type of the antihypertensive agent being used had no effect on mortality [OR=0.527 (0.130-2.138), p=0.370 for ACEIs/ARBs; OR=0.731 (0.296-1.808), p=0.498 for CCBs; OR=0.673 (0.254-1.782), p=0.425 for diuretics; OR=1.846 (0.688-4.950), p=0.223 for beta-blockers; OR=0.389 (0.089-1.695), p=0.208 for alpha-blockers; and OR=1.372 (0.107-17.639), p=0.808 for MRAs].

CONCLUSION

The type of antihypertensive agent being used had no effect on the clinical course and mortality in hypertensive patients with COVID-19. The use of these agents should be maintained for the treatment of hypertension during hospitalization.

Coronavirus Infections; Antihypertensive Agents; Hypertension; Hospital Mortality

RESUMO

OBJETIVO

A doença de coronavírus 2019 (COVID-19) é uma ameaça emergente à saúde causada por um novo coronavírus denominado síndrome respiratória aguda grave coronavírus 2 (Sars-COV-2). Estudos anteriores observaram que a hipertensão está associada a um aumento da mortalidade devido ao COVID-19, no entanto, não está claro se o aumento do risco pertence à própria hipertensão ou a agentes anti-hipertensivos. Nosso objetivo foi avaliar o impacto de agentes anti-hipertensivos nos resultados clínicos em pacientes hipertensos com COVID-19.

MÉTODOS

Nosso estudo incluiu 169 hipertensos consecutivos internados por COVID-19 entre 20 de março e 10 de abril de 2020. As características demográficas, dados clínicos e o tipo de anti-hipertensivos em uso foram revistos.

RESULTADOS

A idade média dos pacientes foi de 65,8±11,7 anos. Trinta pacientes (17,7%) faleceram durante a internação. Cento e quarenta e dois pacientes (84%) usavam inibidores da enzima de conversão da angiotensina (ACEIs) ou bloqueadores dos receptores da angiotensina II (ARBs), 91 (53,8%) usavam diuréticos, 69 (40,8%) usavam bloqueadores dos canais de cálcio (CCBs), 66 (39,1%) usavam betabloqueadores, 12 (7,1%) usavam bloqueadores alpha e cinco (2,9%) usavam antagonistas dos receptores de mineralocorticoides (MRAs). Não houve diferença significativa entre sobreviventes e não sobreviventes com base no tipo de agentes anti-hipertensivos em uso. A análise de regressão logística binária mostrou que o tipo de agente anti-hipertensivo utilizado não teve efeito na mortalidade (OR=0,527 (0,130-2,138), p=0,370 para ACEIs/ARB; OR=0,731 (0,296-1,808), p=0,498 para CCBs; OR=0,673 (0,254-1,782), p=0,425 para diuréticos; OR=1,846 (0,688-4,950), p=0,223 para bloqueadores beta; OR=0,389 (0,089-1,695), p=0,208 para bloqueadores alpha e OR=1,372 (0,107-17,639), p=0,808 para MRAs).

CONCLUSÃO

O tipo de agente anti-hipertensivo utilizado não teve efeito no curso clínico e na mortalidade em pacientes hipertensos com COVID-19. O uso desses agentes deve ser mantido no tratamento da hipertensão durante a hospitalização.

Infecções por coronavírus; Anti-hipertensivos; Hipertensão; Mortalidade hospitalar

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is an emerging health threat caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Previous studies have noted that hypertension is associated with an increased risk of mortality due to COVID-19; however, it is not clear whether the increased risk is due to hypertension itself or the antihypertensive agents being used11. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. . Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are the most important and widely used antihypertensive agents, they act by inhibiting the renin-angiotensin-aldosteron system (RAAS). It is known that coronavirus binds to the angiotensin-converting enzyme-2 (ACE-2) receptor, and there are controversial results in terms of the effects of ACEIs on the course of the disease22. Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol. 2020;e201624.

3. Meng J, Xiao G, Zhang J, He X, Ou M, Bi j, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757-60.
- 44. Zhang P, Zhu L, Cai J, Lei F, Quin JJ, Xie J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671-81. . However, the effect of other types of antihypertensive agents on this disease has not been elucidated yet. In our study, we aimed to investigate the association of antihypertensive agents and clinical outcomes of patients with hypertension and COVID-19.

METHODS

Our present study included 169 consecutive patients with a history of hypertension whose laboratory results confirmed COVID-19 and who were hospitalized in the Sakarya Education and Research Hospital between March 20 and April 10, 2020. All patients were diagnosed with COVID-19 according to World Health Organization interim guidance55. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. Geneva: World Health Organization; 2020. [cited 2020 May 8]. Available from: https://apps.who.int/iris/handle/10665/330893
https://apps.who.int/iris/handle/10665/3...
. The demographic characteristics, clinical data, and type of antihypertensive agents used were recorded. We excluded patients under 18 years old and hypertensive patients without any medication. The ethics approval was obtained from the local ethics committee. Only cases confirmed by laboratory tests were considered positive based on a real-time reverse transcriptase-polymerase chain reaction assay of a specimen obtained from a naso- or oropharyngeal swab and were included in this study. To identify SARS-COV-2 infection, swab specimens were collected from all patients at admission and during hospitalization. The antihypertensive agents used by patients were continued during hospitalization unless contraindicated. Patients with respiratory distress (>30 breaths/min), oxygen saturation <90 at rest, under nasal oxygenation with 5-6 liters/min, arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) <300 mmHg were admitted to intensive care unit (ICU).

Statistical analysis

Descriptive analyses of the variables were expressed as mean±SD in normal distributions, and parameters with abnormal distribution were expressed as medians of the 25th–75th percentile. Categorical data were expressed as proportions. The chi-square and the Student’s t-test were used for categorical and continuous variables, respectively. Fisher’s exact test was applied to analyze small samples. For continuous variables, differences between the two groups were evaluated using the Student’s t-test when data were normally distributed and the Mann–Whitney U test when the assumption of normality was not met. Binary logistic regression analysis was performed to determine independent factors associated with mortality. A p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using statistical software (SPSS 20.0, Chicago, IL, USA).

RESULTS

535 adult patients were hospitalized in the Sakarya University Education and Research Hospital with COVID-19 between March 20 and April 10, 2020. From these, we included 169 patients with a history of hypertension. The mean age of the patients was 65.8±11.7 years (range 37-96), and 90 of the patients were female (53.3%). 30 patients (17.7%) died during hospitalization and 45 (26.6%) required ICU intervention. 139 patients were discharged from hospital uneventfully. 59 of the patients (34.9%) had coexisting diabetes mellitus, 28 (16.6%) had hyperlipidemia, 25 (14.8%) had coronary artery disease, 18 (10.7%) had chronic obstructive pulmonary disease, 9 (5.3%) had cerebrovascular disease, 8 (4.7%) had chronic renal disease, 6 (3.6%) had congestive heart failure, 5 (2.9%) had malignities and 2 (1.2%) had peripheral artery disease. 142 of the patients (84%) were using ACEIs or ARBs, 91 (53.8%) were using diuretics, 69 (40.8%) were using calcium channel blockers (CCBs), 66 (39.1%) were using beta-blockers, 12 (7.1%) were using alpha-blockers and 5 (2.9%) were using mineralocorticoid receptor antagonists (MRAs) for the treatment of hypertension. The majority of the patients (131 [77.5%]) were using a combination of two or more antihypertensive agents ( table 1 ). When we compared the type of antihypertensive agents being used between surviving and non-surviving patients, there was no difference between the groups ( Table 1 ). We also compared the type of antihypertensive agents between the patients with or without ICU requirement, there was no significant difference between the groups ( Table 2 ). Binary logistic regression analysis was performed to identify independent factors associated with mortality due to COVID-19 in hypertensive patients. Age, gender, diabetes mellitus, coronary artery disease, chronic pulmonary disease, hyperlipidemia, and the type of antihypertensive agents being used were included in the equation. Age was found to be the only predictor for mortality (odds ratio=1.089, 95% confidence interval=1.038-1.142, p<0.001). The type of antihypertensive agent used had no effect on mortality [OR=0.527 (0.130-2.138), p=0.370 for ACEIs/ARBs; OR=0.731 (0.296-1.808), p=0.498 for CCBs; OR=0.673 (0.254-1.782), p=0.425 for diuretics; OR=1.846 (0.688-4.950), p=0.223 for beta-blockers; OR=0.389 (0.089-1.695), p=0.208 for alpha-blockers; and OR=1.372 (0.107-17.639), p=0.808 for MRAs] ( Table 3 ).

TABLE 1
DEMOGRAPHIC AND CLINICAL FEATURES OF HYPERTENSIVE PATIENTS WITH COVID-19.
TABLE 2
TYPE OF ANTIHYPERTENSIVE AGENTS USED IN PATIENTS WITH OR WITHOUT INTENSIVE CARE INTERVENTION.
TABLE 3
INDEPENDENT FACTORS ASSOCIATED WITH IN-HOSPITAL MORTALITY USING BINARY LOGISTIC REGRESSION ANALYSIS.

DISCUSSION

Hypertension is one of the most frequent comorbidities among patients hospitalized for COVID-1966. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. , 77. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20. . Several vascular abnormalities including widespread microthrombotic and macrothrombotic events were frequently observed in critically ill patients with COVID-19. Potential microvascular complications caused by chronic hypertension may predispose these vascular events and worsen the prognosis and outcomes of the disease. Recent studies have claimed that hypertension is a clinically important risk factor for severe illness and mortality in COVID-19, but it is difficult to state that11. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. , 66. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. . It is not clear whether the increased risk is due to hypertension itself or antihypertensive agents used. Although there are conflicting results with ACEIs and ARBs, other antihypertensive agents have not been fully evaluated for the treatment of hypertensive patients with COVID-1988. Hanff TC, Harhay MO, Brown TS, Cohen JB, Mohareb AM. Is there an association between COVID-19 mortality and the renin-angiotensin system: a call for epidemiologic investigations. Clin Infect Dis. 2020;ciaa329.

9. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020. doi: 10.1001/jama.2020.4812
- 1010. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020;382(17):1653-9. .

The prevalence of hypertension in Turkey is approximately 27.5%1111. Kılıçkap M, Barçın C, Göksülük H, Karaaslan D, Özer N, Kayıkçıoğu M, et al. Data on prevalence of hypertension and blood pressure in Turkey: systematic review, meta-analysis and meta-regression of epidemiological studies on cardiovascular risk factors. Turk Kardiyol Dern Ars. 2018;46(7):525-45. . In our study, the incidence of hypertension was 29.9% in hospitalized patients due to COVID-19. Recent reports showed that hypertension is associated with poor outcomes in patients with COVID-19; however, it was also reported that hypertension was not more common in those than in the general population77. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20. , 1212. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-5. . These reports do not reveal the mechanism of this increased risk, i.e., whether it is due to hypertension itself or the antihypertensive agent used. SARS-COV-2 binds to their target cells through ACE-2, which is expressed by epithelial cells of the lung, kidney, intestine, and vessels1313. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7):e00127-20. . The expression of ACE-2 is substantially increased in patients treated with ACEIs and ARBs. The increased expression of ACE-2 may facilitate infection by COVID-19, therefore, it is hypothesized that hypertension treatment with ACE-2-stimulating drugs increases the risk of developing severe and fatal COVID-191414. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21. . On the contrary, Zhang et al.44. Zhang P, Zhu L, Cai J, Lei F, Quin JJ, Xie J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671-81. showed that inpatient use of ACEIs orARBs was associated with a lower risk of all-cause mortality compared with ACEI or ARBs non-users among hospitalized COVID-19 patients with hypertension. It has been hypothesized that excessive activation of RAAS might contribute to the progression of acute respiratory distress syndrome (ARDS) in patients with COVID-19 by promoting increased inflammatory response and cytokine storm1515. Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the immune system in hypertension. Physiol Rev. 2017;97(3):1127-64. . RAAS inhibition could mitigate this effect by interfering with the negative effects of angiotensin II on ACE-2 downregulation in infected patients. RAAS inhibitors such as ACEIs or ARBs could have a favourable impact on clinical outcomes.

Solaimanzadeh1616. Solaimanzadeh I. Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19. Cureus. 2020;12(5):e8069. reported that dihydropyridine CCBs such as nifedipine and amlodipine is associated with significantly improved mortality in elderly patients hospitalized for COVID-19. They also revealed that CCBs are associated with a significantly decreased risk for intubation and mechanical ventilation1616. Solaimanzadeh I. Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19. Cureus. 2020;12(5):e8069. . Previous studies revealed that nifedipine and amlodipine were found to increase pulmonary vasodilatation without decreasing arterial oxygenation in the treatment of pulmonary hypertension1717. Muramoto A, Caldwell J, Albert RK, Lakschminarayan S, Butler J. Nifedipine dilates the pulmonary vasculature without producing symptomatic systemic hypotension in upright resting and exercising patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. Am Rev Respir Dis. 1986;132(5):963-6. , 1818. Woodmansey PA, O’Toole L, Channer KS, Morice AH. Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension. Heart. 1996;75(2):171-3. . Amlodipine was also found to be an effective pulmonary vasodilator agent in pulmonary hypertension secondary to chronic obstructive pulmonary disease1919. Sajkov D, Wang T, Frith PA, Bune AJ, Alpers JA, McEvoy RD, et al. A comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to COPD. Chest. 1997;111(6):1622-30. . Nifedipine was shown to reduce pulmonary vascular resistance and increase oxygen delivery both at rest and during exercise even in patients with normal pulmonary artery pressures2020. Kennedy TP, Michael JR, Huang CK, Kallman CH, Zahka K, Schlott W, et al. Nifedipine inhibits hypoxic pulmonary vasoconstriction during rest and exercise in patients with chronic obstructive pulmonary disease: a controlled double-blind study. Am Rev Respir Dis. 1984;129(4):544-51. . Based on these results, they suggested that CCBs may be used as a first-line treatment in hospitalized patients with COVID-19.

Since all research on COVID-19 and antihypertensive treatment is especially focused on ACEIs and ARBs, there are not enough publications in the literature about other widely used antihypertensive agents such as beta-blockers, alpha-blockers, MRAs, and diuretics. In our study, we did not observe any effect of these antihypertensive agents on the clinical outcomes and in-hospital mortality.

Several reports revealed that ARDS in COVID-19 was associated with a strong interaction between SARS-CoV-2 and the ACE-2 receptor2121. Hoffmann M, Kleine-Wever H, Kruger N, Müller M, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry in target cells. BioRxiv. 2020; 01.31.929042. doi.org/10.1101/2020.01.31.929042. , 2222. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-74. . Therefore, an increase in expression of ACE-2 receptors attached to the lung endothelium could facilitate the entrance of SARS-CoV-2 into pulmonary cells and the progression of ARDS. Although attached ACE-2 may allow SARS-CoV-2 to enter cells, its free circulating forms may inactivate SARS-CoV-2 by stopping coupling to membrane ACE-2 receptors. Spironolactone, which is the main representative of mineralocorticoid receptor antagonists, has been reported to increase ACE-2 expression in plasma2323. Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97(9):946-53. . In contrast, it has been shown that ACEIs or ARBs have no effect on the plasma ACE-2 activity2424. Wysocki J, Ye M, Rodriguez E, Gonzalez-Pacheco FR, Barrios C, Evora K, et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010;55(1):90-8. . Additionally, spironolactone does not act in pulmonary RAAS, so it could reduce ACE-2 expression on lung-cell surfaces.

In conclusion, based on the results of this current study, the type of antihypertensive agent used had no effect on the clinical course and mortality of hypertensive patients with COVID-19. The use of these agents should be maintained for the treatment of hypertension during hospitalization. Further larger studies are needed to examine the role of these agents and their influence on the course of COVID-19.

Our study has some limitations. Firstly, this study was conducted in a single center, the study sample-size was modest and included 169 hypertensive patients. Secondly, due to the retrospective nature of this study, some parameters were not available in all patients, such as smoking habits.

REFERENCES

  • 1
    Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
  • 2
    Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol. 2020;e201624.
  • 3
    Meng J, Xiao G, Zhang J, He X, Ou M, Bi j, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757-60.
  • 4
    Zhang P, Zhu L, Cai J, Lei F, Quin JJ, Xie J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671-81.
  • 5
    World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. Geneva: World Health Organization; 2020. [cited 2020 May 8]. Available from: https://apps.who.int/iris/handle/10665/330893
    » https://apps.who.int/iris/handle/10665/330893
  • 6
    Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81.
  • 7
    Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
  • 8
    Hanff TC, Harhay MO, Brown TS, Cohen JB, Mohareb AM. Is there an association between COVID-19 mortality and the renin-angiotensin system: a call for epidemiologic investigations. Clin Infect Dis. 2020;ciaa329.
  • 9
    Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020. doi: 10.1001/jama.2020.4812
  • 10
    Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020;382(17):1653-9.
  • 11
    Kılıçkap M, Barçın C, Göksülük H, Karaaslan D, Özer N, Kayıkçıoğu M, et al. Data on prevalence of hypertension and blood pressure in Turkey: systematic review, meta-analysis and meta-regression of epidemiological studies on cardiovascular risk factors. Turk Kardiyol Dern Ars. 2018;46(7):525-45.
  • 12
    Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-5.
  • 13
    Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7):e00127-20.
  • 14
    Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21.
  • 15
    Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the immune system in hypertension. Physiol Rev. 2017;97(3):1127-64.
  • 16
    Solaimanzadeh I. Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19. Cureus. 2020;12(5):e8069.
  • 17
    Muramoto A, Caldwell J, Albert RK, Lakschminarayan S, Butler J. Nifedipine dilates the pulmonary vasculature without producing symptomatic systemic hypotension in upright resting and exercising patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. Am Rev Respir Dis. 1986;132(5):963-6.
  • 18
    Woodmansey PA, O’Toole L, Channer KS, Morice AH. Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension. Heart. 1996;75(2):171-3.
  • 19
    Sajkov D, Wang T, Frith PA, Bune AJ, Alpers JA, McEvoy RD, et al. A comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to COPD. Chest. 1997;111(6):1622-30.
  • 20
    Kennedy TP, Michael JR, Huang CK, Kallman CH, Zahka K, Schlott W, et al. Nifedipine inhibits hypoxic pulmonary vasoconstriction during rest and exercise in patients with chronic obstructive pulmonary disease: a controlled double-blind study. Am Rev Respir Dis. 1984;129(4):544-51.
  • 21
    Hoffmann M, Kleine-Wever H, Kruger N, Müller M, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry in target cells. BioRxiv. 2020; 01.31.929042. doi.org/10.1101/2020.01.31.929042.
  • 22
    Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-74.
  • 23
    Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97(9):946-53.
  • 24
    Wysocki J, Ye M, Rodriguez E, Gonzalez-Pacheco FR, Barrios C, Evora K, et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010;55(1):90-8.

Publication Dates

  • Publication in this collection
    21 Sept 2020
  • Date of issue
    2020

History

  • Received
    02 June 2020
  • Accepted
    12 June 2020
Associação Médica Brasileira R. São Carlos do Pinhal, 324, 01333-903 São Paulo SP - Brazil, Tel: +55 11 3178-6800, Fax: +55 11 3178-6816 - São Paulo - SP - Brazil
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