In the first phase of the SARS-CoV-2 epidemic, multiple information had spread regarding the class of anti-hypertensive drugs consisting of the inhibitors of the renin-angiotensin-aldosterone system (RAS or RAAS) or the angiotensin receptor blockers (ARB or sartans) and angiotensin converting enzyme inhibitors (ACE inhibitors).
Renin-angiotensin-aldosterone system - Image CC BY-SA 3.0
According to the first surveys, these drugs would have favored the risk of contracting the virus or, in any case, contributed to worsening the symptoms in already infected patients.
In this regard, the results of an observational study conducted in Lombardy have been published online in the New England Journal of Medicine.
A study signed by researchers from the University of Milan-Bicocca, in collaboration with the National Cancer Institute of Milan and the Regional Agency ARIA (Regional Company for Innovation and Purchasing).
Studies not conducted in humans have shown that angiotensin converting enzyme 2 (ACE2), a membrane-bound aminopeptidase that is abundantly expressed in the lungs, heart and other tissues, is used by the coronavirus spike protein as a functional receptor for their entry into cells.
Coronavirus replication cycle - Image CC BY 4.0
Sartans and ACE inhibitors, as they are capable of increasing the expression of the enzyme ACE2, are among the most used drugs in the world as a treatment for the control of hypertension, disorders such as heart failure, post-infarct states of the myocardium, diseases chronic kidney and other cardiovascular diseases.
In view of these facts and observations, the hypothesis that their use may change the susceptibility to infections with severe acute respiratory syndrome in humans has developed.
However, there is no consensus that the risk and severity of SARS-CoV-2 infection can be increased or reduced with the use of these agents.
The current published clinical data are largely limited to small, uncontrolled studies of the demographic and clinical characteristics of patients affected by COVID-19, with little information on the type of anti-hypertensive treatment they were taking at the time or close to the time of infection.
This lack of information was problematic, given the possibility that the blockers of the RAS system could influence the susceptibility and severity of COVID-19, a possibility that aroused a lot of echo in the mass media and that could influence the patient's behavior compared to the hiring or suspending these agents, despite the advice of a number of professional scientific societies not to interrupt them.
It should be noted that, to date, reports indicate that the suspension of RAS blockers in patients with conditions for which these drugs are commonly used, leads to a marked increase in the risk of complications and death.
The recent Covid-19 epidemic, which spread and increased exponentially in Italy before in any other western country, hit Lombardy particularly seriously and the Regional Health Authority promptly established a patient-based registry with a confirmed diagnosis of SARS-CoV-2 infection.
Leveraging the regional availability of a healthcare use database that records essential drugs and services provided, the researchers conducted a case-control survey to evaluate the association between RAS blocker use and COVID-19 risk.
The analysis has been extended to other antihypertensive agents and a large number of other drugs. The data were also analyzed based on the sex, age and severity of COVID-19.
The researchers compared a total of 6272 cases of patients with severe respiratory infection caused by the SARS-CoV-2 virus identified between February 21 and March 11, 2020, with 30759 healthy people as a control group, all registered in the health register of the Lombardy Region.
Between patients and controls, the mean age (+/- SD) was 68 +/- 13 years and 37% were women.
For every case of COVID-19 patient, 5 control units of the same age, gender and municipality of residence were randomly paired.
The information on the use of drugs and the patient's clinical profiles were obtained from the regional health care database, while for the whole sample a prognosis index was used, with a score from 0 to 4, where the highest value indicates a worse clinical state.
The probability ratios and 95% confidence intervals for drug-infection associations, with adjustment for confounders, were estimated by logistic regression.
- ARB and ACE inhibitors were both prescribed more frequently to Covid patients than to people in the control group.
- The percentage of those who received ARB was 22.2% among Covid patients and 19.2% in the control group (relative difference, 13.3%)
- The percentage of patients who received ACE inhibitors was 23.9% and 21.4% respectively (relative difference, 10.5%).
Other anti-hypertensive drugs have also been used more in patients than in the control group, with a generally greater difference compared to ACE inhibitors and ARBs.
In addition, sick patients used a combination of anti-hypertensive drugs more frequently than healthy patients, had a more frequent history of hospitalization for cardiovascular and non-cardiovascular diseases and, according to the CReSc index (Chronic Related Score) with an increasing score of 0 to 4 in line with the aggravation of the clinical situation, presented a substantially worse clinical profile.
The analysis showed that patients infected with the virus have a higher score, make more frequent use of anti-hypertensive drugs and are more affected by cardiovascular diseases.
This suggests that the clinical manifestations of the infection occur mainly in clinically fragile individuals and, among these, in patients suffering from cardiovascular and metabolic diseases.
However, drugs such as ACE inhibitors and sartans do not seem to have any direct role in promoting a greater risk of infection development or aggravation.
In particular, it emerged that, compared to the control group, patients with COVID-19 make greater use of 10-13% of ACE inhibitors and sartans, but also of other antihypertensives, such as beta-blockers and diuretics, and of other drugs such as antidiabetics.
This revealed that the patients who contracted the virus are those who preferentially have a somewhat compromised state of health, of which the increased consumption of drugs is a reflection.
The study included sub-analyzes in order to take into account any differences by gender or age (over 60 vs under 60), but in both cases the results were confirmed, without therefore highlighting significant differences between the different groups.
Furthermore, the hypothesis that the risk for patients receiving anti-hypertensive drugs was not only an increase in the probability of being infected with the virus, but of developing the symptoms in a more severe form due to exposure to the blockers of the RAS system, was also investigated.
The analysis of over 600 cases, including patients admitted to intensive care and the deceased, has also denied the latter hypothesis.
Overall, no statistical evidence has emerged of an independent association between the use of a combination of anti-hypertensive drugs (in which an ACE inhibitor or a sartan is by far the most common component) and the risk of COVID-19.
Therefore, the results of this study don't provide evidence of an independent relationship between RAAS blockers and susceptibility to Covid-19 in humans.
As said, Covid-19 patients had a higher baseline prevalence of cardiovascular conditions and diseases (hypertension, coronary heart disease, heart failure and chronic kidney disease) for which treatment with the drugs studied here is often used.
In addition, two other articles on the same topic were published on the "New England Journal of Medicine" based on similar data from other countries that showed the same results.
One of the strengths of the study is the large number of clinical cases and the inclusion of a large and well-coordinated control group, without which the interpretation of the collected data would have been difficult.
A strong point was also the fact that the Lombard database included previous hospitalizations and made it possible to accurately observe the drugs prescribed for outpatients.
In fact, the possibility of being able to use the data from the flows and databases of the Lombardy Region and the regional COVID register, has made it possible to trace the clinical and diagnostic-therapeutic history of patients up to 5 years prior to the study, including all episodes of hospitalization for various diseases, including tumor pathologies, and to be able to reasonably exclude that the dosing of these drugs increases the risk of incurring the infection and having an unfavorable prognosis.
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- Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020 May 1. [Epub ahead of print] doi: 10.1056 / NEJMoa2006923