Effectiveness of rosuvastatin plus colchicine, emtricitabine/tenofovir and combinations thereof in hospitalized patients with COVID-19: a pragmatic, open-label randomized trial

Abstract

Background The use of rosuvastatin plus colchicine and emtricitabine/tenofovir in hospitalized patients with SARS-CoV-2 disease (COVID-19) has not been assessed. The objective of this study was to assess the effectiveness and safety of rosuvastatin plus colchicine, emtricitabine/tenofovir, and their combined use in these patients. Methods This was a randomized, controlled, open-label, multicentre, parallel, pragmatic study conducted in six referral hospitals in Bogotá, Colombia. The study enrolled hospitalized patients over 18 years of age with a confirmed diagnosis of COVID-19 complicated with pneumonia, not on chronic treatment with the study medications, and with no contraindications for their use. Patients were assigned 1:1:1:1. 1) emtricitabine with tenofovir disoproxil fumarate (FTC/TDF, 200/300 mg given orally for 10 days); 2) colchicine plus rosuvastatin (COLCH+ROSU, 0.5 mg and 40 mg given orally for 14 days); 3) emtricitabine with tenofovir disoproxil plus colchicine and rosuvastatin at the same doses and for the same period of time (FTC/TDF+COLCH+ROSU); or 4) the Colombian consensus standard of care, including a corticosteroid (SOC). The primary endpoint was 28-day all-cause mortality. A modified intention-to-treat analysis was used together with a usefulness analysis to determine which could be the best treatment. The trial was registered at ClinicalTrials.gov: NCT04359095 Findings Out of 994 candidates considered between August 2020 and March 2021, 649 (65.3%) patients agreed to participate and were enrolled in this study; among them, 633 (97.5%) were included in the analysis. The mean age was 55.4 years (SD ± 12.8 years), and 428 (68%) were men; 28-day mortality was significantly lower in the FTC/TDF+COLCH+ROSUV group than in the SOC group, 10.7% (17/159) vs. 17.4% (28/161) (hazard ratio [HR] 0.53; 95% CI 0.29 to 0.96). Mortality in the FTC/TDF group was 13.8% (22/160, HR 0.68, 95% CI 0.39 to 1.20) and 14.4% in the COLCH+ROSU group (22/153) (HR 0.78, 95% CI 0.44 to 1.36). A lower need for invasive mechanical ventilation was observed in the FTC/TDF+COLCH+ROSUV group than in the SOC group (risk difference [RD] - 0.08, 95% CI 0.11 to 0.04). Three patients presented severe adverse events, one severe diarrhoea in the COLCH+ROSU and one in the FTC/TDF+COLCH+ROSU group and one general exanthema in the FTC/TDF group. Interpretation The combined use of FTC/TDF+COLCH+ROSU reduces the risk of 28-day mortality and the need for invasive mechanical ventilation in hospitalized patients with pulmonary compromise from COVID-19. More randomized controlled trials are needed to compare the effectiveness and cost of treatment with this combination versus other drugs that have been shown to reduce mortality from SARS-CoV-2 infection and its usefulness in patients with chronic statin use.

Biological Actions, Implications, and Cautions of Statins Therapy in COVID-19

“…The combined use of emtricitabine with tenofovir disoproxil plus colchicine and rosuvastatin reduces the risk of 28-day mortality and the need for IMV in hospitalized patients with COVID-19 (47).…”

“…In INSPIRATION/INSPIRATION-S study (NCT04486508) conducted in Iran ICU admitted COVID-19 patients, atorvastatin (20 mg/day) was not associated with a significant reduction in the composite of thrombosis, ECMO treatment, or all-cause mortality; however, atorvastatin treatment was safe, and may have clinical importance with lower overall event rates ( 46 ). Another study (NCT04359095) was conducted in Colombia ( 47 ), emtricitabine with tenofovir disoproxil (200/300 mg/day for 10 days) plus colchicine and rosuvastatin (0.5 mg and 40 mg/day for 14 days) combination reduced the risk of 28-day all-cause mortality by 22%, and lowered the need for IMV ( 47 ). These findings indicated safety and potential benefits of statins for COVID-19 treatment, yet the therapeutic effect varies from cohort and medications.…”

Effects of statins on clinical outcomes in hospitalized patients with COVID-19

“…Search strategy yielded 496 potentially relevant records and six fulltext articles were assessed for eligibility. Five RCTs [2][3][4][5][6] were selected for the meta-analysis (Supplementary file) and a total of 1132 patients were included, 556 in the intervention group and 576 in the control group (placebo or standard protocol). Of the included trials, four used atorvastatin (20 mg/day [2,3] or 40 mg/day [4,5]) and one used rosuvastatin (40 mg/day) [6] as treatment for hospitalized patients with COVID-19 (Supplementary file).…”

“…Five RCTs [2][3][4][5][6] were selected for the meta-analysis (Supplementary file) and a total of 1132 patients were included, 556 in the intervention group and 576 in the control group (placebo or standard protocol). Of the included trials, four used atorvastatin (20 mg/day [2,3] or 40 mg/day [4,5]) and one used rosuvastatin (40 mg/day) [6] as treatment for hospitalized patients with COVID-19 (Supplementary file). Overall, the RCTs had a low risk of selection and attrition bias, but 40% presented a potential risk for performance, detection, and reporting bias.…”

Response to ‘The use of tenofovir in patients with COVID‐19’

“…Participants randomized to TDF/emtricitabine following a recent diagnosis (<7 days) of non‐severe COVID‐19 showed a mean real‐time polymerase chain reaction cycle threshold difference of 2.9 (95% confidence interval [CI] 0.1–5.2, p = 0.044) but no difference in time to symptom recovery, and the study was not powered to collect other clinical outcomes [ 4 ]. Although a larger pragmatic randomized trial of TDF/emtricitabine, rosuvastatin plus colchicine, or a combination of the four medications showed lower mortality in participants receiving all four medications (hazard ratio [HR] 0.53; 95% CI 0.29–0.96; p = 0.038), TDF/emtricitabine alone was not associated with a reduction in 28‐day mortality in the TDF/emtricitabine arm compared with standard of care (HR 0.69; 95% CI 0.39–1.20; p = 0.187) [ 5 ]. Two ongoing randomized controlled trials investigating TDF/emtricitabine as treatment for COVID‐19 are registered in the clinicaltrials.gov database at the time of writing (NCT04712357, NCT04890626).…”