Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for COVID-19, a global pandemic with catastrophic consequences for healthcare systems and populations around the world. SARS-CoV-2 was initially described in December 2019 in Wuhan, China [1].
The virus rapidly escalated and on March 11, 2020; the World Health Organization declared it a pandemic. SARS-CoV-2 shares similarities with SARS-CoV, the virus responsible for the 2002–2003 SARS epidemic, and Middle Eastern respiratory syndrome coronavirus (MERS), the virus responsible for MERS [2].
Following the SARS epidemic, researchers extensively investigated the pathophysiologic mechanisms of SARS-CoV infection, including the interaction of the virus with the heart and lungs.
Based on these studies, researchers believe that the angiotensin-converting enzyme 2 (ACE2) receptor, located on alveolar epithelial cells, serves as a high affinity receptor and co-transporter for SARS-CoV-2 to enter the lungs [3].
Medications, such as angiotensin-converting enzyme inhibitors (ACEI), block ACE2 receptors, which may predispose or protect against COVID-19 infection. This editorial summarizes the current scientific evidence surrounding this subject in order to guide clinical practice.
Background
The renin-angiotensin-aldosterone system (RAAS) maintains plasma sodium concentration via feedback from blood pressure, baroreceptors, and sodium and potassium levels. First, the kidneys secrete renin, which metabolizes angiotensinogen into angiotensin I.
Next, the kidneys and lungs secrete ACE, which converts angiotensin I into angiotensin II. Finally, angiotensin II stimulates vasoconstriction, cardiovascular response, and aldosterone and ADH production; this ultimately increases blood pressure and body fluid volume through sodium, potassium, and free water resorption [3].
ACE2 receptor, a homolog of the angiotensin I-converting enzyme (ACE) receptor, is a type I transmembrane aminopeptidase with high expression in heart and lung tissue [4], but which is also expressed in the endothelium and kidney (see Fig. 1, illustrating the RAAS activation pathway).
Discovered in 2000, ACE2 receptor appears to counter-regulate RAAS activation by degrading angiotensin II [5]. The RAAS system is widely implicated in DM, hypertension, and heart failure.
ACEI and ARB drugs, based upon strong evidence of efficacy, are commonly used in the management of hypertension, heart failure, post myocardial infarction care, and to slow progression of renal disease associated with diabetes.
COVID-19 and Comorbidity
With the exponential rise of COVID-19 cases worldwide, observational studies have identified risk factors for infection and poor outcomes. Three separate studies identified hypertension and DM as highly prevalent among COVID-19 patients:
A. According to Yang et al., among 52 critically ill patients, DM was present in 17% of cases [6].
B. According to Guan et al., among 1099 patients, DM was present in 16.2% of cases and hypertension was present in 23.7% of cases [7].
C. According to Zhang et al., among 140 hospitalized patients, DM was present in 12% of cases and hypertension was present in 30% of cases [8].
While both hypertension and DM are treated with ACEI and ARB, medication use was not assessed in any of the three aforementioned studies, leading to an inconclusive hypothesis. However, one study to date has analyzed the effect of ACEI and ARB use on the COVID-19 population.
According to Peng et al., among 112 patients, cardiovascular comorbidities led to worse outcomes, with most deaths occurring secondary to fulminant inflammation, lactic acidosis, and thrombotic states [9]. ACEI and ARB use did not influence morbidity or mortality [9].
In addition to these observations, there is a well-known association between the viruses, SARS-CoV and MERS-CoV, and deleterious cardiac events, including cardiac injury in SARS-CoV as well as myocarditis and heart failure in MERS-CoV [10].
Furthermore, SARS-CoV-2 was recently associated with cardiac injury, defined by a troponin > 28 pg/ml or electrocardiogram/echocardiogram abnormalities, in 12% of patients from a COVID-19 cohort. These data demonstrate a cardiac affinity with all three viruses [11].
Pros and Cons of ACE Inhibition
The etiology of cardiac damage in patients with COVID-19 is unclear, but ACE2 receptors may play a role, given the high affinity of SARS-CoV for ACE2 receptors [12]. A recent commentary published in the Lancet Respiratory Medicine hypothesizes that the use of ACE2 receptor increasing drugs is at higher risk for severe COVID-19 infection.
ACEI initially inhibits ACE leading to decreased angiotensin I levels, causing a possible negative feedback loop that ultimately upregulates more ACE2 receptor to be able to interact with the decreased angiotensin I substrate available [13] (see Fig.1.).
This ACE2 receptor upregulation results in increased binding sites for SARS-CoV-2, leading to preferential COVID-19 infection. This is particularly observed in patients with diabetes and/or hypertension, since they are usually taking ACEI or ARB [12].
This comment was released before the findings published by Peng et al. [9]. An editorial response by Sommerstein et al. [14], based on the findings by Ferrario et al. showing a 5-fold increase in ACE2 levels with lisinopril and 3-fold increase in ACE2 levels with losartan [15], was published in the British Medical Journal.
Conversely, some investigators argue that ACEI or ARB use may be beneficial in COVID-19 infection prevention. Li et al., for example, proposed that ACEI inhibition of ACE may stimulate a negative feedback (given the lack of angiotensin II, upregulating ACE2 receptors and decreasing overall inflammation [16]).
Sun et al. argued that ACEI use im pairs the ACE/angiotensin II/angiotensin-1 receptor pathway, therefore, impairing the integrity of the ACE2/angiotensin 1–7/MAS (MAS-related G protein-coupled receptor).
A disruption of the ACE2/angiotensin 1–7/MAS pathway could lead to decreased production of ACE2, decreasing chances of SARS-CoV-2 entering the cell [17]. Some RAAS inactivated animal models demonstrate symptom relief in acute severe pneumonia and respiratory failure, through vasoconstriction mechanisms [17].
Recent findings also demonstrate that patients on the ARB olmesartan had increased secretion of urinary ACE2, likely from an upregulation mechanism, although unclear [18]. Despite this hypothesis of ACE2 upregulation, a causal relationship decreasing mortality has not been demonstrated.
Finally, given the contradictory hypotheses, rapidly evolving nature of the disease, and social media-related hysteria, several cardiology associations (HFSA/ACC/AHA and ESC Hypertension Council) released an official statement regarding the continuation of ACEI and ARB for COVID-19 patients [19]. The associations strongly recommend continuing treatment with ACEI/ARB in patients who were previously taking either class of medication.
Conclusions
There is a lack of scientific evidence and clinical data to support discontinuing ACE/ARB use in patients with COVID-19 and co-existing heart failure, hypertension, or ischemic heart disease.
The well-studied reduction in mortality conferred by ACE/ARB use and the beneficial effects for patients with diabetes, chronic kidney disease, and proteinuria or albuminuria currently outweigh the theoretical risks.
As the COVID-19 pandemic continues to rapidly evolve and affect more patients with cardiovascular comorbidities, further research is needed to clarify the accuracy of existing hypotheses.
Effect of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on outcomes in patients with coronavirus disease 2019 (COVID-19) is uncertain.
Available evidence is limited to a few retrospective observational studies with small number of patients.
We did a meta-analysis to assess the effect of ACEi/ARB in patients with COVID-19 on severity of disease, risk for hospitalisation, and death compared to those not on ACEi/ARB.
We searched the Cochrane library, PubMed, Embase, ClinicalTrial.gov and medRxiv for studies published until 25.04.2020. Inclusion criteria included all studies with patients with confirmed COVID-19 either taking, or not taking, ACEi/ARB.
Depending on degree of heterogeneity, fixed or random effect model was selected to calculate effect size (Odds ratio).
Results: Six studies were eligible for this meta-analysis. These included 423 patients on ACEi/ARB, and 1419 not on ACEi/ARB.
Compared to patients with COVID-19 not on ACEi/ARB, there was a statistically significant 43% reduction (OR 0.57, CI: 0.37-0.88, I2 : 0.000) in the odds of death in those on ACEi/ARB.
There was a statistically non-significant 38% reduction (OR: 0.62, 95% CI: 0.31-1.23, I2 =70.36) in the odds of developing severe disease and 19% reduction (OR 0.81; 95% CI: 0.42-1.55, I2 : 0.000) in the odds of hospitalisation among those on ACEi/ARB.
Discussion: It is safe to use ACEi/ARB in patients with COVID-19 requiring these medications for associated comorbidities. Although limited by confounding factors typical of a meta- analysis of retrospective observational studies, our data suggests that use of these medications may reduce the odds of death.
Conclusion: Our meta-analysis of the updated studies on SARS-CoV-2 reassures the medical fraternity on the use of and continuation of ACEi/ARB, supporting all recent recommendations .
Evidence before this study
- The postulated dual role of angiotensin-converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with coronavirus disease 2019 (COVID-19) has created a dilemma for clinicians.
- On the one hand, there is speculation that by upregulating ACE2, ACEi/ARBs might increase the risk and severity of COVID-19.
- On the other hand, there is evidence that downregulation of ACE2 can mediate acute lung injury. Further evidence is urgently needed to guide clinicians in the use of ACEi/ARB in patients with COVID-19 with co-morbidities.
What does this article add
- Our meta-analysis, which is the first to assess the effect of use of ACEi/ARB in patients with COVID-19, reports that use of ACEi/ARB statistically significantly reduced the risk of death, with a trend towards reduction in risk of severe disease and hospitalisation compared to those who were not on ACEi/ARB.
- Further information from on-going RCTs shall take time to fruition; in the interim, based on these findings, clinicians can safely continue to use ACEi/ARB in patients with COVID-19 with comorbidities.
Review Criteria:
- A web-based search was conducted using the Cochrane library, PubMed, Embase, ClinicalTrial.gov and medRxiv using specific keywords.
- Narrowing down of the citations was done based on full text availability and a set of pre-determined inclusion criteria.
- Meta-analysis was conducted on the pooled data comparing ACEi/ARB group versus the non-ACEi/ARB group on death, severity of disease and hospitalization using the CMA software version 3, Biostat Inc., Englewood, NJ, USA.
- Effect size was reported as odds ratio with a 95% confidence interval and the degree of heterogeneity of the pooled data.
Message for the clinic:
- There is no indication from present evidence to withhold or withdraw ACEi/ARB in patients with SARS-CoV-2.
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