An international team led by researchers in the Perelman School of Medicine at the University of Pennsylvania (U-Penn) found that medications to treat high blood pressure did not affect outcomes among patients hospitalised with COVID-19. This study published online on 8 January 2021 in The Lancet Respiratory Medicine, is the first randomized controlled trial to show that there is no risk for patients continuing these medications while hospitalised for COVID-19. This confirms a few earlier observational studies.

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Researchers examined whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) could mitigate complications or lead to more severe symptoms. ACEIs and ARBs are two classes of medications to treat blood pressure. This trial was a part of The Randomized Elimination or ProLongation of Angiotensin Converting Enzyme inhibitors and angiotensin receptor blockers (REPLACE COVID 19 study).

“More than 49 million U.S. adults take medication to treat hypertension, and among those, about 83 percent (41 million) take an ACEI or ARB, according to the Centers for Disease Control and Prevention,” a press release from the university said.

Did the arrival of SARS-CoV-2 virus throw a spanner in the works?

During the early stages of the pandemic, there was legitimate concern on the use of ACEIs or ARBs in the setting of COVID-19, since some studies suggested that these medications could up-regulate cellular receptors for the SARS-CoV-2 virus potentially aiding viral replication. However, it was also considered that some effects of these medications could be protective against the virus.

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The need for further study

It is in this context that the American College of Cardiology (ACC), American Heart Association (AHA) and Heart Failure Society of America (HFSA) posted a joint statement on line on March 17, 2020. The statement clarified:

“Patients with underlying cardiovascular diseases appear to have an increased risk for adverse outcomes with coronavirus disease 2019 (COVID-19). Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients also may have severe cardiovascular damage. Angiotensin converting enzyme 2 (ACE2) receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to up-regulate ACE2 expression in the heart. Though these have not been shown in human studies, or in the setting of COVID-19, such potential up-regulation of ACE2 by ACE inhibitors or ARBs has resulted in a speculation of potential increased risk for COVID-19 infection in patients with background treatment of these medications.”

The ACC, AHA and HFSA published a joint statement recommending continued use of renin angiotensin aldosterone system (RAAS) antagonists, including ACEi and ARBs, during the COVID-19 outbreak. They based their recommendations on the lack of experimental or clinical data demonstrating beneficial or adverse outcomes with ACEi or ARBs use among COVID-19 patients using these agents.

They advised that any RAAS-related treatments of patients should not be added or removed beyond actions based on standard clinical practice.

The HFSA, ACC, and AHA recommended that in the event patients with cardiovascular disease are diagnosed with COVID-19, individualised treatment decisions should be made according to each patient's haemodynamic status and clinical presentation.

Richard J. Kovacs, President of American College of radiology said, "The continued highest standard of care for cardiovascular disease patients diagnosed with COVID-19 is top priority, but there are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACE-I or ARB medications."

He stressed the recommendations of ACC, AHA and HFSA- "We urge urgent, additional research that can guide us to optimal care for the millions of people worldwide with cardiovascular disease and who may contract COVID-19. These recommendations will be adjusted as needed to correspond with the latest research."

The authors opined in Lung India, 2020:

“The biological plausibility of ACE inhibitors/ARBs with COVID-19 is controversial and unproven. Sudden discontinuation of ACE inhibitors/ARBs in the population already on these drugs would precipitate heart failure and can cause rebound hypertension, thereby leading to increased morbidity and mortality. Thus, the key learning point is to continue these drugs till further evidence.”

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The WHO scientific brief

On 7 May 2020, after a rapid review using Ovid MEDLINE and the Cochrane Database of Systematic Reviews from 1 January 2003 to 24 April 2020 as well as the World Health Organization database of COVID-19 publications and other such relevant papers, the WHO in a scientific brief concluded that there is low-certainty evidence that patients on long-term therapy with ACE inhibitors or ARBs are not at higher risk of poor outcomes from COVID-19.

In this context, the latest study led by U-Penn is most important. The senior author of the present study, Julio A. Chirinos, an associate professor of cardiovascular medicine in the Perelman School of Medicine, U-Penn, stated that some researchers have carried out observational studies. However, randomised trials are important to establish a definitive answer regarding the potential impact of these commonly used blood pressure medications in the setting of COVID-19. "Our trial results importantly show that these medications can be safely continued for patients hospitalised with COVID-19." Professor Chirinos asserted in a U-Penn press release on the study.

As ACEIs and ARBs are among the most commonly prescribed medications in the world, a potential link between those medications and COVID-19 outcomes has large global health implications, the authors said.

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The present study

The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in the USA, Canada, Mexico, Sweden, Peru, Bolivia, and Argentina. A data coordinating centre at the University of Pennsylvania (Philadelphia, PA, USA) oversaw data management and statistical analyses. The ethics committee of each participating centre, or in the USA, via reliance agreements with a central institutional review board (University of Pennsylvania, Philadelphia, PA, USA) approved the trial design. An independent data safety monitoring board provided independent oversight of the trial.

The researchers enrolled 152 participants across the referral hospitals in the participating countries between March 31 and August 20, 2020, who were hospitalized with COVID-19 and who were already using one of the medications. The eligible patients were aged 18 years or older, who were admitted to a hospital with a clinical presentation consistent with COVID-19, and were prescribed ACEI or ARB therapy as an outpatient before the hospital admission.

The researchers randomly assigned the participants to either continue or discontinue renin–angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body mass index was 33 kg/m² (SD 8), and 79 (52%) had diabetes.

The researchers closely monitored them to evaluate the effect of temporarily stopping the therapy.

The most interesting part of the study was that the investigators developed an innovative global rank score to classify patient outcomes based on four factors:

• Time to death
• Length of time supported by mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
• Length of time on renal replacement therapy
• Modified sequential organ failure assessment score

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Conclusions

By analysing the patient outcome data, the team concluded that the discontinuation of ACEIs and ARBs compared with continuation of these medications had no effect on the global rank score.

“Continuation of ACEI or ARB therapy among patients admitted to hospital with COVID-19 had no overall effect on severity of COVID-19 disease course. We observed no significant difference in the primary hierarchical endpoint between participants who continued their ACEI or ARB therapy compared with those who discontinued therapy. Secondary and subgroup analyses were otherwise consistent with our primary endpoint, showing no difference in length of COVID-19 hospitalisation, need for intensive care, invasive mechanical ventilation, or death between treatment groups,” the authors found.

The researchers observed that multi-organ dysfunction was also similar across treatment groups. They observed no difference in blood pressure control, serum potassium, or serum creatinine over the course of follow-up among patients whose ACEI or ARB therapy was continued versus discontinued. The researchers listed the strengths of their study thus:

• To their knowledge, it is the only registered, multicentre, international trial aiming to evaluate continuation versus discontinuation of ACEI or ARB use in patients with COVID-19
• The recruited participants were across low-resource and high-resource settings and had clinical characteristics similar to those reported in most studies of hospitalised patients with COVID-19
• Thus the results are likely to be widely generalisable to patients on ACEIs or ARBs for the management of hypertension
• The trial was pragmatic, applying clinician implementation of the treatment strategy during routine inpatient care, further supporting the generalisability of the findings

According to the researchers, the novel hierarchical endpoint provides the trial sufficient statistical power to evaluate the study question with a smaller sample size than is required for typical binary endpoints and offers greater insight into the breadth of COVID-19-related adverse outcomes (ie, time to death; duration of mechanical ventilation, renal replacement therapy, vasopressor therapy, and hospitalisation; and severity of multi-organ dysfunction using information available in low-resource settings) than other commonly used endpoints.

One of the limitations of the study is the small sample size, which limits the ability to draw conclusions from the secondary outcomes.

The authors concluded that among patients admitted to hospital with COVID-19, continuation and discontinuation of renin–angiotensin system inhibitors have similar effects on acute hospitalisation outcomes. “Consistent with current international society recommendations, providers should continue to prescribe these medications in patients admitted to hospital with COVID-19 unless there is a distinct medical contraindication to ongoing therapy,” they suggested.

The researchers revealed that ongoing trials will determine whether de novo use of these medications is effective for the treatment of COVID-19. "At the start of the pandemic, patients were worried about perceived harm based on limited and incomplete information, and unfortunately, some insisted on stopping their medications. However, stopping these medications unnecessarily can increase the risk for severe complications, including heart attack and stroke," the first author Jordana B. Cohen, an assistant professor in the division of Renal-Electrolyte and Hypertension, and a co-principal investigator with Chirinos said in the U-Penn press release.

"Now we have high quality evidence to support our recommendation that patients continue to take these medications as prescribed," the researcher concluded. This study makes an important contribution to our war against the most unwelcome virus of 2020.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph.D from University of Leeds, UK, he is a medical physicist with specialization in radiation safety and regulatory matters. He was a Research Associate in the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.