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HYPERTENSION AND COVID-19 Statement and Summary of Information from the Council on Hypertension 28 April 2020

Category: Statements

The Council on Hypertension of the Philippine Heart Association issues the following statements with regard to Hypertension and Covid-19:

 

  • Patients with hypertension and maintained on ACEI/ARB, who tested positive for COVID-19 should continue taking ACEI/ARB in the outpatient setting to maintain normal blood
  • Patients with hypertension and maintained on ACEI/ARB, presently hospitalized due to COVID-19, may continue taking ACEI/ARB to maintain normal blood pressure.
  • It is reasonable to give ACEI/ARB as add-on anti-hypertensive in patients with hypertension hospitalized for COVID-19 if blood pressure is not

 

 

Several clinical insights coming from Wuhan, the original epicenter of the novel coronavirus suggest a strong association between disease severity and comorbidities, particularly hypertension and diabetes. An underlying cardiovascular disease is also observed to increase risk of death 1. In a meta-analysis 2 of 10 studies with 76,993 patients, 16% were hypertensive. In another series3 of 140 patients, hypertension was as high as 30% . The pattern of increased proportion of hypertension among severe cases are consistently being observed. In a study4 where 173 of 1,099 patients had severe disease, 23.7% were hypertensive. A meta-analysis5 consisting of 6 studies with 1,527 patients showed a 17.1% proportion of hypertension in Covid-19 cases, the incidence of which is twice higher in ICU/severe cases than in non-ICU/severe counterparts. A similar meta-analysis 6 of 7 studies with 1,576 patients showed a 21.1% prevalence of hypertension, and based on pooled odds ratios, hypertension, among others, may be a risk factor for severe patients compared with non-severe patients. Thus it can be said that patients with hypertension, among other comorbidities, may be at greater risk for developing severe disease or poorer prognosis.

SARS-CoV and SARS-CoV2 (herein used to refer to the virus) are both mediated by binding to ACE2. Since ARBs,  ACEIs, and mineralocorticoid receptor antagonists (MRAs) increase ACE2 receptor expression, the idea of probable counter productivity of these medications have surfaced7. A further confusion arises from the fact that ACE2 is considered a potential therapeutic strategy for hypertension and cardiovascular disease being a homeostatic regulator of Angiotensin 2, and for lung injury and fibrotic diseases being anti-inflammatory.

ACE2: Basic Biology 8, 9

ACE2 is a transmembrane glycoprotein predominant in bronchi, lung parenchyma, heart endothelium, kidneys, duodenum, and small intestine. ACE acts on Angiotensin I (Ang I) to form a potent vasoconstrictor and proinflammatory substance Angiotensin II (Ang II). ACE2 acts on Ang II to generate Ang-(1-7), or in a lesser activity, it also acts on Ang I to generate Ang-(1-9). Simply put, both ACE and ACE2 provide the counterbalancing of Angiotensin metabolism: ACE forming Ang II and ACE2 removing it by conversion to Ang-(1-7). Ang-(1-7) has a range of anti- inflammatory, antioxidant, vasodilatory, and natriuretic effects via what is called Mas receptor. The protective effects of ACE2/Ang-(1-7)/Mas receptor axis are primarily mediated by reductions in Ang II and proinflammatory cytokine release and inhibition of signaling pathways involved in tissue fibrosis.

ACE2 and the Cardiovascular System

ACE2 has been established as an important regulator of cardiovascular function primarily by its counterbalancing of the RAAS. This is mainly achieved by the regulation of Ang II, the substrate that activates several signaling cascades promoting myocardial hypertrophy and fibrosis. The ACE2/Ang-(1-7)/Mas axis also has an important role in the modulation of proinflammatory cytokine expression responsible for cardiac fibrosis and vascular remodeling9. Because of this, research has focused on the potential of ACE2 as a cardiovascular drug.

ACE2 and Anti-Hypertension Drugs related to RAAS

MRAs: Brojakowska9 cited a particular study of heart failure patients treated with  Spironolactone at 25 mg once  daily. After a month, human monocyte-derived macrophages showed 43% reduction in ACE activity, 53% reduction in ACE mRNA expression, and ACE2 activity increased by 300% and ACE2 mRNA expression increased by 654%. Together with some animal studies, MRAs appear to reduce oxidative stress, decrease ACE activity, increase ACE2 activity and expression, suggesting their protective role by increased generation of Ang-(1-7) and decreased formation of Ang II.

 

ARBS: The same treatise9 showed that although animal experiments showed slight variability in results, the general trend was an upregulation of ACE2 using Olmesartan , Telmisartan, and Losartan in separate studies. The Olmesartan study was compared with the use of Hydralazine and Atenolol and the Olmesartan arm showed a 5-fold increase in ACE2 mRNA and increased Ang-(1-7) in thoracic aorta. The studies imply that cardiac remodeling benefits seen with the use of ARB is accompanied with AT1 receptor blockade and increased ACE2 expression/activity. Conflicts in this area arise from the difference in ACE2 cell surface expression and plasma levels.

ACE Inhibitors: ACE2 is not antagonized by ACEI. ACEI blocks the conversion of Ang I to Ang II, promotes the vasodilating effect of Bradykinin by inhibiting its hydrolysis, helps endothelium-dependent vasodilatation by increasing prostaglandin and NO production, and down regulation of AT1 receptor. Since the action of ACEIs  are more complex, the results of studies9 are more varied. ACE2 mRNA and ACE2 activity showed varying result with ACE inhibition. ACEI alone or with losartan was shown to increase plasma Ang-(1-7) and decrease plasma Ang II. Compared to the upregulation of ACE2 seen with Losartan, there was blunting of this upregulation when combined with Lisinopril. As mentioned before, to a lesser extent, ACE2 can convert Ang I to Ang-(1-9) which may in turn be converted to Ang-(1-7).

ACE2 and Covid-19

Aside from being a counter-regulator of the RAAS, ACE2 was discovered as a cellular receptor for SARS-CoV and SARS- CoV 2. SARS-CoV2 enters the cell by attaching to its receptor ACE2 which serves as binding site for the anchoring spike of the virus . With endocytosis leading to several complex reactions, surface ACE2 is downregulated and the unopposed Ang II accumulates. This initial event is perpetuated via several mechanisms (upregulation of ADAM 17), and Ang II further accumulates, also causing the release of proinflammatory cytokines, and the viral insults of inflammation and fibrosis occurs, together with vasoconstriction, cell proliferation and hypertrophy10. This ACE2 downregulation may also contribute to the CV events seen in COVID-19 patients.

ACE2 hence, can either act favorably as a counterbalance to the RAS system, or unfavorably as SARS-CoV 2 receptor11. Clinical studies on the implications of RAS blockers on COVID-19

Generally with ARDS and sepsis, ACE and Ang II are increased. A study cited by Brojakowska9 showed increase in

plasma renin and Ang II is correlated with the degree of organ failure and microvascular dysfunction. In a recent study12 of 12 cases of pneumonia where 6 patients developed SARS, the plasma Ang II levels were markedly elevated and directly associated to viral load and extent of lung injury. These levels were significantly higher compared to that of healthy subjects. The Ang II levels are also inversely related to the PaO2/FiO2, the measure of ARDS severity.

Since ACE2 acts as a modulator of Ang II by converting it to Ang-(1-7), there were studies using recombinant ACE2 (rhACE2) in ARDS. One such study in 2017 by Khan et al9 showed attenuation of RAS mediators but no clinical improvement was observed.

While trials on the potential of rhACE2 are on the way (NCT04287686), RAS blockers, ARB in particular, are being eyed for the treatment of Covid-19, in its capacity to upregulate ACE2 and decrease Ang II levels. We take note of the following ongoing studies, among many others:

  • Effects of RAS inhibition and ACE2 regulation- Impact of ACEI and ARB treatment on severity and prognosis of Patients with Covid-19 (NCTO 4318301, NCTO 4318418)
  • Effect of Losartan on hospitalized patients (NCTO 4312009)
  • Effect of Losartan on ambulatory patients (NCTO 4311177)
  • Continuation vs replacement or withdrawal of RAS

We cite 2 particular studies that form part of evidence for the council’s statement:

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-1913

P: 1128 participants with hypertension and COVID-19, 188 were classified as ACEI/ARB group (median age 64 [IQR 55-68] years; 53.2% men) and the remaining 940 were classified as non-ACEI/ARB group (median age 64 [IQR 57-69]; 53.5% men)

Inclusion criteria - patients with COVID19, aged from 18 to 74 years, who were admitted to the hospitals in Hubei, China from December 31st, 2019 to February 20th, 2020.

 

Exclusion criteria - included incomplete medical records (e.g., transfer to any other hospital), pregnancy, acute lethal organ injury (e.g., acute myocardial infarction, acute coronary syndrome, acute pulmonary embolism, or acute stroke), decompensated or end stage of chronic organ dysfunction (e.g., decompensated cirrhosis, decompensated chronic renal insufficiency, or severe congestive heart failure), acquired immune deficiency syndrome (AIDS), or leukemia or malignancy.

Patients with hypertension were classified based upon clearly documented medical history with systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg.

  • E: ACEI/ARB users, non-ACEI/ARB users

O: Primary endpoint - Risk of 28-day all-cause mortality; Secondary endpoints - incidence of septic shock, and DIC M: Retrospective, multi-center study

Summary:

  • This study cohort included 3611 patients with COVID-19 who were admitted to the nine hospitals in Hubei, China as mentioned in the
  • After excluding 181 participants following the exclusion criteria, 3430 participants comprising 1128 hypertensive and 2302 normotensive cases were included in subsequent analysis
  • Among the 1128 participants with hypertension and COVID-19, 188 were classified as ACEI/ARB group (median age 64 [IQR 55-68] years; 53.2% men) and the remaining 940 were classified as non-ACEI/ARB group (median age 64 [IQR 57-69]; 53.5% men).
  • The risk of 28-day all-cause mortality was significantly lower in ACEI/ARB group versus nonACEI/ARB group (3.7% [7/188] vs. 9.8% [92/940]; P = 0.01). In the mixed-effect Cox model using site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications (antiviral and lipid lowering drugs), use of ACEI/ARB was associated with lower all-cause mortality (adjusted HR, 0.42; 95% CI, 0.19-0.92; P = 0.03) versus use of non-ACEI/ARB.
  • A propensity score-matched analysis was conducted to account for confounding that may have resulted in a protective association between ACEI/ARB use and all-cause mortality. The results remained consistent and statistically significant, demonstrating lower risk of all-cause mortality in patients who received ACEI/ARB (adjusted HR, 0.37; 95%CI, 0.15-0.89; P = 0.03) versus those who did not receive ACEI/ARB using this propensity score-matched analysis.
  • To further assess the robustness of the association between ACEI/ARB use and mortality, an additional sensitivity analyses by using different matching variables were performed. The results remained consistent and statistically significant in these sensitivity analyses with HRs of 0.34 (95%CI, 0.14-0.82; P = 0.02) in the first sensitivity analysis and of 0.33 (95% CI, 0.13-0.80; P = 0.01) in the second
  • Since there were 34.0% patients with hypertension who did not receive antihypertensive drugs during hospitalization, authors performed subgroup propensity score-matching analysis on the remaining 745 patients who received at least one anti-hypertensive medication during hospitalization to further minimize the potential bias from non-users. One hundred eighty-one patients using ACEI/ARB versus those using other anti-hypertensive drugs were paired at1:1. The results demonstrated that the in-hospital use of ACEI/ARB was associated with lower risk of all- cause mortality (adjusted HR, 0.29; 95%CI, 0.12-0.69; P = 0.005) due to COVID-19. This association was further supported by sensitivity analyses with adjusted HR of 0.29 (95% CI, 0.12-0.70; P = 0.01) in the first sensitivity analysis not including diabetes as a matching variable and of 0.30(95%CI, 0.13-0.71; P = 0.01) in the second sensitivity analysis adding cerebrovascular disease as a matching

 

  • For the secondary outcomes, the incidence of septic shock (3.2% in ACEI/ARB vs. 8.0% in non-ACEI/ARB [P = 0.03]; IRD, - 0.19 [95%CI, -0.36 – -0.01]) and DIC (0.0% vs. 2.3%, P = 0.04; IRD, -0.23 [95%CI, -0.52 – 0.07]) were lower in the ACEI/ARB group than the non-ACEI/ARB
  • In propensity score-matched cohort analysis, the risk of septic shock was lower in ACEI/ARB group (adjusted HR, 0.32 [95%CI, 0.13-0.80; P = 0.01]; IRD, - 0.20[95%CI, -0.39 – -0.01]) than non-ACEI/ARB group among all individuals with hypertension. In a sub-group of patients, who received at least one anti-hypertensive medication during hospitalization, the findings remained consistent (adjusted HR, 0.24 [95%CI, 0.10-0.63; P = 0.003]; IRD, - 0.31 [95%CI, -0.54 – -0.09])
  • Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of

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, China14

P: Patients with COVID-19 admitted to the Central Hospital of Wuhan (Hubei Province, China) from January 15, 2020, to March 15, 2020

E: ACEI/ARB users, non-ACEI/ARB users

O: The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors.

M: Retrospective, single-center case series Summary:

  • The 362 patients with hypertension were further analyzed and form the basis of this article. There were 189 men (52.2%), 259 (71.5%) were older than 60 years, and 115 (31.8%) were taking ACEIs/ARBs.
  • The frequency of severity of illness, acute respiratory distress syndrome, and mortality did not differ with respect to ACEI/ARB
  • With respect to ACEI/ARB use, there was no difference between those with severe vs nonsevere illness in use of ACEIs (9.2% vs 10.1%; P = .80), ARBs (24.9% vs 21.2%; P = .40), or the composite of ACEIs/ARBs (32.9% vs 30.7%; P = .65). Similarly, there were no differences between nonsurvivors and survivors in use of ACEIs (9.1% vs 9.8%; P = .85), ARBs (19.5% vs 23.9%; P = .42), or the composite of ACEIs/ARBs (27.3% vs 33.0%; P = .34).
  • Because comorbidities may affect treatment options for hypertension, the authors analyzed the use of ACEIs/ARBs among patients with hypertension and various comorbid conditions, including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease, with respect to disease progression and mortality. In patients with each of these chronic conditions, the frequency of severe illness and death did not differ between those treated with and without ACEIs/ARBs.

Highlights

  1. Patients with hypertension, among other comorbidities, have a higher risk for Covid-19
  2. SARS-CoV2 enters the cell by attaching to ACE2 receptors.
  3. ACE2 is a modulator of the pro-inflammatory and potent vasoconstrictor Ang II by converting it to ANG 1-7 which has an anti-inflammatory, antioxidant, vasodilating and natriuretic
  4. ACE2 can either act favorably as a counterbalance of the RAAS, or unfavorably as SARS CoV2 receptor thus promoting

 

  1. RAS blockers increase the ACE2 expression/activity
  2. Available clinical studies, although limited, did not show association of the use of RAS blockers with harm towards severe and non-severe cases of Covid-19.
  3. More clinical studies about harm or benefit of RAS blockers on Covid-19 patients are under

These statement and summary of information regarding hypertension and Covid-19 are in no way final and complete. Knowledge about this disease is expected to widen, whether by research or serendipity. Some preprint studies have been included, with the caveat that this may have not passed a complete peer review.

 
   

 

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Acknowledgements:

Dr. Roberta Cawed-Mende for the appraisal of evidences

Dr. Federick Cheng for sharing contents of his webinar on Hypertension and Covid-19