Sildenafil for the Treatment of Patients With COVID-19 and Perfusion Mismatch on Subtraction Computed Tomography Angiography: A Pilot, Placebo-Controlled Randomised Trial

BACKGROUND: Severe gas exchange impairment can develop even in initial stages of COVID-19 pneumonia. SARS-CoV-2 seems to affect the regulation of pulmonary perfusion, through a renin-angiotensin system imbalance that occurs as a result of the virus binding to ACE2. Hypoperfusion to areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). We aimed to investigate the potential efficacy and safety of oral sildenafil in the treatment of inpatients with COVID-19 that showed perfusion abnormalities in sCTA. METHODS: This triple-blind, single-centre, placebo-controlled trial, was done at Hospital Naval Almirante Nef, Chile. We enrolled adult patients (>18 years of age) with clinically diagnosed, highly probable or confirmed COVID-19 infection, that were admitted for inpatient treatment, and with a sCTA carried out within 24 hours of admission that showed perfusion abnormalities in areas of well-aerated lung parenchyma. Patients were randomly assigned (1:1) to receive sildenafil (25 mg orally three times a day for seven days) or placebo. The primary endpoint was the change in the ratio between arterial oxygen partial pressure and fractional inspired oxygen (PaO 2 /FiO 2 ratio), and a co-primary endpoint was the change in alveolar-arterial oxygen gradient (A-a gradient), both of which were calculated 1 hour after administration of the intervention on the first day, and on a daily basis during follow-up, using samples from an arterial line in all patients, and analysed using a two-way repeated-measures analysis of variance (ANOVA). Secondary endpoints including intensive care unit admission, the requirement of non-invasive mechanical ventilation or requirement of high-flow nasal cannula, initiation of mechanical ventilation and mortality rates were evaluated using survival analysis with the Kaplan-Meier method and log-rank statistic. The trial is now done. This trial is registered with ClinicalTrials.gov, NCT04489446. FINDINGS: Between August 20, 2020 and March 31, 2021, we recruited 20 patients per group. No statistically significant differences in mean PaO 2 /FiO 2 ratios (repeated measures ANOVA p=0·67) and A-a gradients (repeated measures ANOVA p=0·69) were found between study groups. Invasive mechanical ventilation had to be initiated in four patients, all in the placebo arm, showing a statistically significant difference with the sildenafil arm (logrank p=0·04). Patients allocated to the sildenafil arm also showed a significantly shorter median length of stay in the hospital when compared with the placebo group (9 IQR 7-12 days vs 12 IQR 9-21 days, p=0·04). INTERPRETATION: Sildenafil treatment decreased the need for initiation of invasive mechanical ventilation and reduced the length of stay in the hospital. However, there were no statistically significant differences in the oxygenation parameter (PaO 2 /FiO 2 ratio and A-a gradient). The improvement in clinically relevant outcomes, without significant differences in specific laboratory outcomes, warrants the conduction of larger trials using sildenafil for the treatment of COVID-19 patients with specific perfusion patterns in sCTA. Clinical Trial Registration details: This trial is registered with ClinicalTrials.gov, NCT04489446.