Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Percutaneous coronary intervention in calcified stenoses: a protocol for a systematic review with meta-analysis, trial sequential analysis and network meta-analysis.

INTRODUCTION: Severely calcified coronary stenoses are difficult to treat with percutaneous coronary interventions. The presence of severe calcifications complicates lesion preparation, advancement of stents and achievement of full stent expansion. Intervention in these lesions is associated with an increased risk of complications and procedural failure compared with treatment of less calcified lesions. Due to the high burden of comorbidity, patients with severely calcified lesions are often excluded from interventional trials, and there is little evidence on how to treat these patients. METHODS AND ANALYSIS: We will conduct a systematic review of randomised trials enrolling patients with calcified coronary artery disease undergoing percutaneous coronary intervention. We will investigate any percutaneous treatment option including any lesion preparation, stenting or postdilatation technique. We will search The Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, and Excerpta Medica database for studies from inception to 31 October 2022. The coprimary outcome is all-cause mortality and serious adverse events. If appropriate, we will conduct meta-analysis, trial sequential analysis and network meta-analysis. ETHICS AND DISSEMINATION: No ethics approval is required for this study. The results will be published in a peer-reviewed journal in this field. PROSPERO REGISTRATION NUMBER: CRD42021226034.