SARS-CoV-2 is a member of a class of viruses: angiotensin converting enzyme 2 (ACE2)-binding viruses that study calls "ABVs". The World Health Organization (WHO) and others are performing randomized controlled trials (RCTs) of vaccines and novel antivirals to address SARS-CoV-2 directly. However, the critical illness complications of COVID-19 are caused in part by SARS-CoV-2's binding and inhibiting ACE2 and the consequent host response. ACE 2 is the receptor for H1N1, H5N1, and SARS-CoV-2. After binding ACE2, SARS-CoV-2 is endocytosed, and surface ACE2 is down-regulated, increasing angiotensin II (ATII a potent vasoconstrictor) in COVID-19. The original ARBs limits lung injury in murine influenza H7N9 and decreases viral titre and RNA. Study has a unique opportunity to complement vaccine and anti-viral RCTs with an RCT modulating the host response using an angiotensin II type 1 receptor blocker (ARBs) to decrease the mortality of hospitalized COVID-19 patient.
PURPOSE: There is clinical equipoise around the safety and efficacy of ARBs in COVID-19, but
there are few RCTs of ARBs in COVID-19. Guo and colleagues' meta-analysis showed that
ARBs/ACE inhibitor use was associated with decreased mortality. Our structured literature
review (Cheng et al., submitted) shows that SARS-CoV-2 and other viruses that bind ACE2 cause
acute cardiac injury in nearly 50% of cases. Safety concerns of ARBs in COVID-19 arise
because ARBs increase cardiac ACE2, potentially increasing SARS-CoV-2 cellular uptake and
worsening outcomes. On the other hand, ARBs block the effects of excess angiotensin II and
could be beneficial. Our proposed ARBs CORONA II Phase 3 RCT will establish whether ARBs can
decrease mortality in hospitalized COVID-19 patients.
HYPOTHESIS:
Primary - ARBs (losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan,
olmesartan, telmisartan) decreases mortality and are safe in hospitalized COVID-19 infected
adults compared to standard of care.
Secondary - ACE pathway proteins (ATI, AT1-7, ATII, ACE and ACE2 levels), cytokines and
metabolomics/proteomics predict mortality and efficacy of ARBs in hospitalized COVID19
adults.
RESEARCH DESIGN: Study will assess ARBs (losartan, valsartan, azilsartan, candesartan,
eprosartan, irbesartan, olmesartan, telmisartan) (see 6.3 Intervention for more) vs. usual
care for safety and efficacy in decreasing organ dysfunction and mortality of hospitalized
adults with COVID-19. Dr. Srinivas Murthy and Dr Rob Fowler, co-investigators herein and PIs
of the CATCO RCT in Canada, Dr. John Marshall, co-investigator herein and PI of REMAPCAP, and
Dr. Russell have coordinated alignment by allowing co-enrollment and harmonization of data
and sample collection and primary endpoints.
Drug: Losartan
Oral losartan 25 mg, stepped up to 50 mg and then up to 100 mg peak dose, as tolerated.
Other Name: Cozaar
Drug: Valsartan
Oral Valsartan 40 mg, stepped up to 80 mg and then up to 160 mg peak dose, as tolerated.
Other Name: Diovan
Drug: Azilsartan
Oral Azilsartan 40 mg, and stepped up to 80 mg.
Other Name: Edarbi
Drug: Candesartan
Oral Candesartan 8 mg, stepped up to 16 mg and then up to 32 mg peak dose, as tolerated.
Other Name: Atacand
Drug: Eprosartan
Oral Eprosartan 400 mg, stepped up to 600 mg and then up to 800 mg peak dose, as tolerated.
Other Name: Teventen
Drug: Irbesartan
Oral Irbesartan 75 mg, stepped up to 150 mg and then up to 300 mg peak dose, as tolerated.
Other Name: Avapro
Drug: Olmesartan
Oral Olmesartan 10 mg, stepped up to 20 mg and then up to 40 mg peak dose, as tolerated.
Other Name: Olmetec
Drug: Telmisartan
Oral Azilsartan 40 mg, and stepped up to 80 mg.
Other Name: Micardis
Inclusion Criteria:
- Hospitalized
- Must be first admission of COVID-19, not re-admission
- Primary reason for hospitalization or prolonged hospitalization is because of acute
COVID-19 diagnosis
- Adults 18 years of age or greater
- Laboratory-proven COVID-19 within 14 days prior to hospital admission
Exclusion Criteria:
- Hypotension (SAP < 100 mmHg or DAP < 50 mmHg or MAP < 65 mmHg)
- Hyperkalemia (> 5.5 mmol/l)
- Acute kidney injury (urine output < 0.5 ml/kg/hr and new creatinine > 200 mmol/l, or
increase > 100 mmol/l, or GFR < 30 ml/min)
- Use of aliskiren in patients with diabetes mellitus (type 1 or type 2) or
moderate-severe renal impairment (GFR less than 60mL/min)
- Use of ARB/ACEi within 7 days of presentation
- Pregnant or breastfeeding
- Have a known allergy to ARBs or any component of the drug product
- Have written legal document to withhold life-sustaining (patients not wishing to
receive Cardiopulmonary Resuscitation (CPR) can participate if other medical
treatments will be given)
- Have signed a Do No Resuscitate (DNR) Form
University of Calgary - Foothills
Calgary, Alberta, Canada
Royal Jubilee Hospital
Nanaimo, British Columbia, Canada
Surrey Memorial Hospital
Surrey, British Columbia, Canada
St Paul's Hospital
Vancouver, British Columbia, Canada
Vancouver General Hospital
Vancouver, British Columbia, Canada
The Ottawa Hospital
Ottawa, Ontario, Canada
Niagara Health
Saint Catharines, Ontario, Canada
St Michael's Hospital
Toronto, Ontario, Canada
Sunnybrook Hospital
Toronto, Ontario, Canada
CHU de Québec - Université Laval
Laval, Quebec, Canada
McGill University Health Center
Montréal, Quebec, Canada
Université de Sherbrooke
Sherbrooke, Quebec, Canada
Centre Hospitalier Universitaire d'Angers
Angers, France