Potential protective effects of antihypertensive treatments during the Covid-19 pandemic: from inhibitors of the renin-angiotensin system to beta-adrenergic receptor blockers

From the beginning of the pandemic hypertension appeared as one of the most common comorbidities in patients hospitalised with a Covid-19 infection. Hypertension, diabetes, overweight, chronic pulmonary disease and heart failure, together with advanced age were the typical characteristics of patients who suffered a fatal outcome of severe Covid-19 disease. However, hypertension is highly prevalent in the adult population, particularly among the elderly, overweight people, and patients with diabetes. Therefore, it remains unclear, whether hypertension per se predisposes patients to develop Covid-19 disease, to make it more severe or to predict a poor outcome, or whether the other comorbidities or patient characteristics such as overweight or advanced age, confound the data.

A major consideration in the management of hypertensive patients in the time of the Covid-19 pandemic regards the choice of antihypertensive medications and their potential impact on the disease outcome. It started with the question of whether treatment with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are safe [1,2]. ACEIs and ARBs may up-regulate ACE2, the receptor used by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter host cells. Therefore, treatment with ACEIs and ARBs could potentially increase the risk of SARS-CoV-2 infection [1,2]. However, cardiopulmonary diseases are associated with decreased ACE2 activity. By limiting the effects of angiotensin II on the heart and vasculature, ACE2 could protect against the more severe complications of Covid-19 infection [3,4]. Experimentally elevated ACE2 expression might confer potential protective pulmonary and cardiovascular effects [5]. The potential use of drugs increasing ACE2 activity as a treatment target in COVID-19, despite its role to allow viral entry into host cells, has therefore been suggested [5]. Almost all recent retrospective studies have concluded that treatment with ACEIs or ARBs has either a neutral or a favourable impact on the outcome of patients with Covid-19 disease. Therefore, administration of blockers of the renin-angiotensin system for the treatment of hypertension or other cardiovascular diseases that either antedated the Covid-19 infection or appeared in the course of Covid-19 related vascular inflammation should be continued [4–6].

All of the studies that bear on the use of ACEIs or ARBs were observational until the first randomised study appeared at the virtual European Society of Cardiology meeting on September 1, 2020. The BRACE CORONA trial [7] was a randomised study testing two strategies: temporarily stopping the ACEIs/ARBs for 30 days vs. continuing ACEIs/ARBs in patients who were taking these medications chronically and hospitalised with COVID-19. The trial comprised 659 patients from 34 sites in Brazil [8]. The average number of days alive and out of hospital at 30 days was 21.9 days for patients who stopped ACEIs/ARBs and 22.9 days for patients who continued these medications. The average ratio of days alive and out of hospital between the suspending and continuing groups was 0.95 (95% confidence interval [CI] 0.90 to 1.01, p = 0.09). The average difference between groups was −1.1 days (95% CI −2.33 to 0.17). The proportion of patients alive and out of hospital by the end of 30 days in the suspending ACEIs/ARBs group was 91.8 vs. 95% in the continuing group. A similar 30-day mortality rate was seen for patients who continued and suspended the ACEs/ARBs (2.8 vs. 2.7%, respectively, with a hazard ratio of 0.97). Though statistically probably somewhat underpowered, the BRACE CORONA trial [7] provided ‘evidence’ concluding in line with the observational research [6]: during Covid-19 infection ACEIs and ARBs should not be withdrawn. A 1.4 million patient nation-wide Swedish registry analysis came to the same conclusion [9]: After adjustment for 45 potential confounders, use of ACEI or ARB was associated with a reduced risk of hospitalisation/death for Covid-19 (Odds Ratio [95% CIs]: 0.86 [0.81–0.91]) in the overall population, and with reduced mortality in Covid-19 cases (Hazard Ratio: 0.89 [0.82–0.96]).

Other commonly used antihypertensive medications have received much less attention in the setting of Covid-19. A combined Dutch/German study [10] investigated 1134 patients recently hospitalised because of Covid-19 infection and extracted information from their electronic medical records. N = 415 patients suffered major outcomes such as death or requiring treatment in intensive care units. N = 245 patients were excluded because of unclear outcomes, and the remaining 468 suffered mild outcomes without stay in intensive care unit. Prior to hospitalisation 47% of patients had been treated with at least one antihypertensive drug. Treatment with ACEIs or ARBs did not influence the major outcome, while beta-blocker treatment significantly reduced the risk of major outcome. In contrast, calcium channel blocker (CCB) treatment worsened the major outcomes. There was also a statistically non-significant trend for diuretic treatment to worsen the major outcomes. Hypertension was the most important comorbidity in the German part of the study. The authors [10] concluded there was an urgent need for larger prospective studies of this issue.

A previous study [11] suggested a modestly lower likelihood of a positive test for Covid-19 among patients taking beta-blockers. Another recent paper suggested that non-selective beta-blockers blunt the excessive inflammatory burst commonly reported in severe Covid-19 infected patients [12]. Moreover, the authors of a multicenter retrospective study identified 2190 patients admitted for Covid-19 disease. They used multivariate logistic regression in patients with comorbid hypertension to examine the potential association between clinical outcomes, disease severity, and clinical characteristics with the use of ACEI, ARB, CCB, beta-blockers, and thiazide diuretics. Their data indicate that the hypertension drugs ACEI, ARB, CCB, and beta-blockers might be beneficial for Covid-19 patients [13].

The findings that pre-treatment with beta-blockers might be protective against Covid-19 infection, major hospital complications and death [10–13] are potentially important and deserve further investigations. Severe Covid-19 disease comes with oxygen deficit, which causes sympathetic nervous system activation similar to that seen during obstructive sleep apnoea [14] or heart failure [15]. It is reasonable to assume that beta-blocker treatment maybe protective against the deleterious effects of activation of the sympathetic nervous system. Hypotheses generating papers have in fact suggested multiple mechanism for how beta-blockers may be protective in Covid-19 infections [16–18]. Table 1 provides an overview of these potential protective mechanisms of beta-blocker treatment in Covid-19 disease.

Table 1. Potential protective mechanisms of beta-adrenergic receptor blocker treatment in Covid-19 disease (summarized from ref. [16]).

1. Beta-adrenergic blockers reduce the SARS-COV-2 host cell entry

2. Beta adrenergic blockers reduce interleukin-6 (IL-6)

3. Beta adrenergic blockers decrease pro-inflammatory cytokines and inhibit cytokine storm

4. Beta-adrenergic blockers might be beneficial in acute respiratory distress syndrome (ARDS) and respiratory failure condition

5. Beta-adrenergic blockers are beneficial in septic shock

6. Beta-adrenergic blockers may reduce the pulmonary edoema

7. Beta adrenergic blockers may reduce the hyper-coagulation state and prevent pulmonary embolism in Covid-19 patients

8. Beta-adrenergic blockers may improve oxygenation level

9. Beta-adrenergic blockers may reduce the mucus hypersecretion in Covid-19

10. Computational studies suggest the potential use of beta-adrenergic blocker in Covid-19

11. Beta-adrenergic blockers inhibit NOD-like receptor protein 3 (NLRP3) inflammasome

12. Use of beta-adrenergic blockers are safe in respiratory illness condition

NOD: nucleotide-binding oligomerization domain-like receptors.

We concur with the opinion of the many authors quoted above that more data are needed regarding the benefits and potential risks of beta-blocker, CCB and diuretic treatment in Covid-19 patients. We think that the global data on antihypertensive drugs in Covid-19 infected patients emphasise the need to have comorbidities (hypertension, diabetes, heart failure and so on) well controlled in order to save patients with severe Covid-19 infections. The treatment should not only focus on the viral disease but on other concomitant diseases as well.

Disclosure statement

SEK, KN, MB and SO are editors of Blood Pressure and report no conflict of interest to disclose related to this editorial.