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      Renin-angiotensin system inhibitors in hospitalised patients with COVID-19

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      The Lancet. Respiratory Medicine
      Elsevier Ltd.

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          Abstract

          Following the onset of the COVID-19 pandemic, by February 2020, there was widespread speculation circulating on social media and in the medical press that treatment with medications that inhibit the renin-angiotensin system might increase susceptibility to COVID-19. 1 This concern was not insignificant because, globally, hundreds of millions of people are treated with renin-angiotensin system inhibitors, particularly angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) for hypertension, heart failure, or chronic kidney disease. Many wondered if they should discontinue these treatments, and inevitably some will have done. The concern was fuelled by recognition that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry into cells by binding to a component of the renin-angiotensin system notably ACE2, which is ubiquitously expressed on many cells, including the lung. 2 Previous studies in rodents had suggested that inhibition of the renin-angiotensin system could lead to increased cellular expression of ACE2, 3 driving speculation that this might facilitate more efficient viral entry into cells and thus increase the risk of COVID-19 infection and severity of infection. The situation was further complicated by a plausible counter hypothesis, that blockade of the renin-angiotensin system might actually protect against severe outcomes from COVID-19 by upregulating ACE2, resulting in protective, anti-inflammatory effects in the lung. 4 Indeed, rather than withdrawing ACEIs or ARBs, studies were being initiated to treat hospitalised patients with COVID-19 with these drugs (eg, ClinicalTrials.gov, NCT04312009). Amidst the confusion, specialist clinical organisations issued cautious but reassuring statements for their patients, urging them not to discontinue their medications, while emphasising the urgent need for more data. The scientific response to this dilemma, as for the pandemic in general, has been remarkable, characterised by global collaboration, scale, and speed. High-quality, large-scale, case-controlled observational cohort studies reported their results within weeks, importantly demonstrating that chronic treatment with ACEIs or ARBs was not associated with increased risk of becoming infected with SARS-CoV-2, or of becoming hospitalised or dying from COVID-19.5, 6, 7 This provided much-needed reassurance to clinicians and their patients. However, it is well recognised that observational studies have important limitations and despite best efforts, they can sometimes lead to the wrong conclusions due to unmeasured confounding. This limitation of observational studies was compounded by the fact that we soon became aware that many of the risk factors for severe COVID-19 disease and death are the same factors that co-segregate with likelihood of being treated with medications that inhibit the renin-angiotensin system (eg, advanced age, hypertension, diabetes, obesity, heart failure, and chronic kidney disease). 8 Thus, it was complex to address confounding by indication and its associated multimorbidity, not to mention unmeasured confounding. The optimal solution was to confirm the messages coming from the observational studies with randomised controlled trials (RCTs). Herein lay the next major challenge, could an RCT be rapidly designed, initiated, and completed to address whether renin-angiotensin system inhibition was safe to continue, or should be discontinued, in patients hospitalised with COVID-19? Moreover, this question is not mono-dimensional because renin-angiotensin system inhibition is usually prescribed for a reason. Inhibition of the renin-angiotensin system improves the outcomes of patients with the aforementioned comorbidities and thus a decision to withdraw these treatments may not be benign. In The Lancet Respiratory Medicine, Jordana B Cohen and colleagues 9 report the first results from an RCT (the REPLACE COVID trial) examining the impact of continuing or withdrawing chronic ACEIs or ARB treatment in 152 patients hospitalised with COVID-19 across 20 international centres. To compensate for the small size of the study and to increase power for the primary outcome, they used a hierarchical global rank score comprising time to the major outcomes of interest in patients with COVID-19 (ie, ventilation, multiorgan failure or support, or death). Their study showed that outcomes for patients previously treated with ACEIs or ARBs and hospitalised for COVID-19 were similar, irrespective of whether their renin-angiotensin system inhibitor treatment was continued or discontinued during their hospital admission. Alone, a small study like this one would not provide sufficient reassurance regarding the impact of renin-angiotensin system inhibition on the outcomes of patients hospitalised with COVID-19. Nor does it address the question about whether chronic treatment with renin-angiotensin system inhibition affects the risk of becoming infected in the first place. However, these new data, allied to the data from the aforementioned large observational case-controlled studies, does provide a consistent message: that there appears to be no justification to withdraw renin-angiotensin system inhibitor treatment in the context of COVID-19. Further reassurance comes from the fact that the conclusions of this REPLACE COVID trial are broadly consistent with the results from a previously presented, but as yet unpublished, RCT, the BRACE CORONA study (ClinicalTrials.gov, NCT04364893), which also tested continuation versus discontinuation of ACEIs or ARBs in 659 hospitalised patients with COVID-19 in Brazil. This study also found no difference in outcomes based on days alive or out of hospital 30 days after continuation or discontinuation of renin-angiotensin system inhibition. It should be noted that both the REPLACE COVID and BRACE CORONA trials are characterised by study populations with a younger mean age (62 years and 53 years, respectively) than we typically see in the most severely ill patients with COVID-19 in many hospitals. Indeed, the impact of age and comorbidity on outcomes in COVID-19 is clearly evident from the fact that many fewer people died or had intensive care dependency in the larger but younger study population of the BRACE CORONA trial than the smaller but older study population of the REPLACE COVID trial. An important caveat for both studies is that the data most reliably apply to patients previously receiving ACEIs or ARB treatment for hypertension and associated conditions, other than for heart failure, which was an important exclusion criteria for both studies because of the higher perceived risk of withdrawing the benefits of renin-angiotensin system inhibition in patients with heart failure. It is an extraordinary scientific achievement by the investigators, and a remarkably selfless contribution by the unwell and hospitalised patients who took part in these studies, that less than a year after we first became aware of this pandemic and the nature of the virus, we are discussing the results of RCTs that better inform our clinical practice. The irony is, that alongside these RCTs, we have also discovered that the COVID-19 RAS-inhibition controversy was most likely ill-founded in the first place, as recent data suggest that these drugs do not seem to increase ACE2 expression, especially in the lung, after all.10, 11 © 2021 Juan Gaertner/SPL 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Is Open Access

          OpenSAFELY: factors associated with COVID-19 death in 17 million patients

          COVID-19 has rapidly impacted on mortality worldwide. 1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths. COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively). We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.
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            Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19

            Abstract Background There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). Methods We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. Results Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. Conclusions We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
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              Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19

              Abstract Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
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                Author and article information

                Journal
                Lancet Respir Med
                Lancet Respir Med
                The Lancet. Respiratory Medicine
                Elsevier Ltd.
                2213-2600
                2213-2619
                7 January 2021
                7 January 2021
                Affiliations
                [a ]Institute of Cardiovascular Sciences, University College London, London W1T 7DN, UK
                [b ]National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK
                Article
                S2213-2600(21)00003-5
                10.1016/S2213-2600(21)00003-5
                7836517
                33422264
                7013f8ac-72e4-4574-80da-b51cec17368b
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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