otherpublications

In this international RCT of critically ill patients with COVID-19, intermediate-dose heparin did not improve OSFDs or survival compared with standard thromboprophylaxis. The posterior distribution suggests clinically meaningful benefit is unlikely. Consistent with prior randomized trials and meta-analyses, these findings do not support routine escalation to intermediate dosing. Major bleeding rates were low and similar between groups.

REMAP-CAP contributed to important work on improving how clinical trials are conducted across borders. Conducting clinical research, especially during a public health emergency such as a pandemic, requires navigating a complex web of ethical, administrative, regulatory, and logistical (EARL) requirements. In this publication, we aimed to provide insights into where improvements could be made and analyzed EARL timelines in different countries, such as time to first patient enrollment. The results show the extraordinary amount of work of all teams across Europe. It was found that some countries, such as the UK and also France, were able to accelerate timelines substantially during the COVID-19 pandemic. In other settings, there were still challenges, particularly in long contracting timelines. We hope that these findings spark further conversation about how we can collectively streamline EARL processes to ensure that patients across Europe can keep benefitting from innovative research.

In the REMAP-CAP trial, adults admitted to the intensive care unit (ICU) with severe CAP were randomized to a 7-day course of intravenous hydrocortisone (50 mg every 6 h) or control (no corticosteroid). The primary end point was 90-day all-cause mortality, analyzed iteratively by a Bayesian hierarchical model estimating distinct treatment effects for patients presenting with influenza and shock. Among patients with severe CAP, treatment with a 7-day course of hydrocortisone, compared with no hydrocortisone, appears unlikely to yield a large reduction in mortality. Smaller benefits and possible harm are not excluded.

Simvastatin, a widely available and inexpensive drug that is included on the WHO list of essential medicines, was shown to have a high probability (96%) of improving outcomes (a combination of survival and length of time patients need support in an intensive care unit) when started as a treatment for critically ill patients with COVID-19, and a 92% chance of improving survival at 3 months. This equates to one life saved for every 33 patients treated with simvastatin. 2,684 critically ill patients were included at 141 hospitals across 13 countries.

Vitamin C is widely available around the world and was used in some settings for the treatment of COVID-19. Through harmonising two clinical trials – REMAP-CAP and LOVIT-COVID – over 2,500 patients in 20 countries took part, including both critically ill and non-critically ill patients with COVID-19 in hospital. It was shown that high-dose vitamin C did not improve outcomes for patients. This is the largest trial examining high-dose vitamin C in COVID-19 and provides evidence that high-dose vitamin C is not beneficial and suggests a high probability that it may be harmful.

In this letter we show that in patients who became critically ill while receiving therapeutic-dose heparin initiated when non-critically ill, continuation of therapeutic-dose compared with the lower doses confers no clinical benefit and appears harmful.

In this randomized clinical trial that included 779 patients, initiation of an ACE inhibitor or ARB did not improve organ support–free days. Among critically ill patients, there was a 95% probability that treatments worsened this outcome.

Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

Among critically ill adults with confirmed COVID-19, treatment with convalescent plasma had a low likelihood of providing improvement in organ support–free days.

In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.