ABSTRACT
Background and Rationale: The benefits of awake prone positioning (APP) in patients with hypoxemic respiratory failure due to Coronavirus disease 2019 (COVID-19) remain uncertain. This systematic review and meta-analysis aimed to determine the efficacy and safety of APP versus usual care in non-intubated adults with COVID-19 hypoxemic respiratory failure. Method(s): We searched MEDLINE, Embase and CENTRAL for randomized trials on APP for hypoxemic respiratory failure. The primary outcome was endotracheal intubation. Secondary outcomes were mortality, ventilator-free days, intensive care unit and hospital length of stay, escalation of oxygen modality, change in oxygenation and respiratory rate, and adverse events. Random-effects meta-analysis was performed for the primary and secondary outcomes. Bayesian meta-analysis was performed for endotracheal intubation and mortality outcomes. Result(s): Seventeen trials (2931 patients) met eligibility criteria. APP, versus usual care, reduced the risk of intubation (24.2% vs 29.8%, relative risk [RR] 0.83, 95% Confidence Interval [CI] 0.73-0.94;I =0%, high certainty). APP did not significantly affect mortality or other secondary outcomes. Bayesian meta-analysis using non-informative priors found a high probability of benefit with APP for intubation (mean RR of 0.84, 95% Credible Interval [CrI] 0.72 to 0.97;posterior probability for RR <1 of 0.99) but not for mortality (mean RR of 0.94, 95% CrI 0.78 to 1.14: posterior probability for RR <1 of 0.75). Conclusion(s): APP reduces the risk of intubation versus usual care in patients with COVID-19 but did not improve mortality or other secondary outcomes.
ABSTRACT
Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd
ABSTRACT
Background: The efficacy and safety of awake prone positioning (APP) in hypoxemic patients with coronavirus disease 2019 (COVID-19) is unclear. Aim(s): To evaluate the efficacy and safety of APP in non-intubated adults with COVID-19. Method(s): We performed a pragmatic, international, randomized trial at 21 centers in Canada, Saudi Arabia, Kuwait, and the United States between May 19, 2020, and May 18, 2021. Eligible patients were hospitalized adults with COVID-19 requiring >40% oxygen. Patients were randomized to APP (n=205) or usual care (n=195). The primary outcome was intubation by day 30. Secondary outcomes included mortality at 60 days, ventilation-free days at 30 days, intensive care unit (ICU) and hospital-free days at 60 days, adverse events, and serious adverse events. Result(s): Patients in the APP group proned for a median of 4.8 hours per day (IQR 1.8 to 8.0) in the first 4 days. By day 30, 70/205 patients (34.1%) in the APP group and 79/195 (40.5%) in the control group were intubated (hazard ratio [HR] 0.81;95% confidence interval [CI] 0.59 to 1.12). APP did not reduce mortality at 60 days (HR 0.93;95% CI 0.62 to 1.40) and had no effect on days alive invasively or noninvasively ventilated at 30 days, or days out of ICU or hospital at 60 days. There were no serious adverse events in either group. A prespecified subgroup analysis suggested that APP reduced intubation among patients with SpO2:FiO2 >150 (HR of 0.44, 95% CI 0.23 to 0.87) but not among patients with SpO2:FiO2 <150 (HR 1.02;95% CI 0.70 to 1.48;P-interaction= 0.03). Conclusion(s): APP did not significantly reduce intubation at 30 days or mortality at 60 days overall, but may be effective in patients with SpO2:FiO2 >150.