The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

Angus, Derek C.; Berry, Scott M.; Lewis, Roger J.; Al-Beidh, Farah; Arabi, Yaseen M.; Bentum-Puijk, Wilma van; Bhimani, Zahra; Bonten, Marc J. M.; Broglio, Kristine; Brunkhorst, Frank M.; Cheng, Allen; Chiche, Jean‐Daniel; Jong, Menno D. de; Detry, Michelle A.; Goossens, Herman; Gordon, Anthony; Green, Cameron; Higgins, Alisa; Hullegie, Sebastiaan J.; Krüger, Peter; Lamontagne, François; Litton, Edward; Marshall, John C.; McGlothlin, Anna; McGuinness, Shay; Mouncey, Paul; Murthy, Srinivas; Nichol, Alistair; O'Neill, Genevieve K.; Parke, Rachael; Parker, Jane; Rohde, Gernot; Rowan, Kathy; Turner, Anne; Young, Paul; Derde, Lennie; McArthur, Colin; Webb, Steven A R

doi:10.1513/annalsats.202003-192sd

Cited by 270 publications

(303 citation statements)

References 142 publications

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“…A recent propensity score-matched study compared 913 patients receiving anticoagulation (antiplatelet or anticoagulation therapy) with 2859 patients receiving neither at the time of COVID-19 diagnosis and found no statistically significant difference in survival, mechanical ventilation and need for hospital admission between both groups [25]. The uncertainty highlighted in observational studies and disagreement between guidelines re-iterates the importance of ongoing randomised trials such as COVID-HEP (NCT04345848) and REMAP-CAP [26].…”

Section: Discussionmentioning

confidence: 99%

“…A higher proportion of patients with thrombotic complications died when compared with those without but this was not statistically significant (32 (39.5%) vs. 27 (25.5%), p = 0.059). Median (IQR) ICU length of stay was longer in patients who developed thrombotic complications 17 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) days vs. 12 (7-13) days, p = 0.003).…”

Section: Mortalitymentioning

confidence: 99%

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Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study

et al. 2020

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Background Optimal prophylactic and therapeutic management of thromboembolic disease in patients with COVID-19 remains a major challenge for clinicians. The aim of this study was to define the incidence of thrombotic and haemorrhagic complications in critically ill patients with COVID-19. In addition, we sought to characterise coagulation profiles using thromboelastography and explore possible biological differences between patients with and without thrombotic complications. Methods We conducted a multicentre retrospective observational study evaluating all the COVID-19 patients received in four intensive care units (ICUs) of four tertiary hospitals in the UK between March 15, 2020, and May 05, 2020. Clinical characteristics, laboratory data, thromboelastography profiles and clinical outcome data were evaluated between patients with and without thrombotic complications. Results A total of 187 patients were included. Their median (interquartile (IQR)) age was 57 (49–64) years and 124 (66.3%) patients were male. Eighty-one (43.3%) patients experienced one or more clinically relevant thrombotic complications, which were mainly pulmonary emboli (n = 42 (22.5%)). Arterial embolic complications were reported in 25 (13.3%) patients. ICU length of stay was longer in patients with thrombotic complications when compared with those without. Fifteen (8.0%) patients experienced haemorrhagic complications, of which nine (4.8%) were classified as major bleeding. Thromboelastography demonstrated a hypercoagulable profile in patients tested but lacked discriminatory value between those with and without thrombotic complications. Patients who experienced thrombotic complications had higher D-dimer, ferritin, troponin and white cell count levels at ICU admission compared with those that did not. Conclusion Critically ill patients with COVID-19 experience high rates of venous and arterial thrombotic complications. The rates of bleeding may be higher than previously reported and re-iterate the need for randomised trials to better understand the risk-benefit ratio of different anticoagulation strategies. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Mortalitymentioning

confidence: 99%

Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study

et al. 2020

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“…The most relevant synthetic compounds are Eritoran (E5564), TAK-242, and FP7, a drug with good bioavailability, high-water solubility, lack of toxicity, and selective TLR4 antagonist action [ [135] , [136] , [137] , [138] , [139] , [140] , [141] , [142] ]. In addition, Eritoran (Eisai co.) is soon to be introduced in the REMAP-COVID study, a sub-platform of the clinical trial REMAP-CAP, that evaluates specific treatments to COVID-19 [ 143 ]. Plant-based extracts are another source of natural immune modulators, several are used in Traditional Chinese and Ayurveda medicine for centuries and seem to interact with the TLR4 complex [ 144 , 145 ]…”

Section: Therapeutic Perspectives Targeting Tlr4 Pathwaymentioning

confidence: 99%

Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

Brandão

Ramos

Dompieri

et al. 2021

Cytokine & Growth Factor Reviews

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Highlights Some inflammatory diseases are related to severe forms of COVID-19, characterized by an immune system overactivation. SARS-CoV-2 Spike protein binds with human innate immune receptors, mainly TLR4, increasing secretion of IL‐ 6 and TNF‐ α. The main inflammatory diseases seen as risk factors for COVID-19 are hypertension, diabetes, obesity, and atherosclerosis. The TLR4 signaling pathway is connected to inflammatory diseases seen as risk factors for COVID-19.

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“…Once a new intervention has become standard of care, it can be tested against alternatives or combinations of drugs. For sites that don't have the capacity to generate local trials, participation in platform trials like REMAP-CAP (The Randomised, Embedded, Multi-Factorial, Adaptive Platform Trial for Communityacquired Pneumonia) (14) should be encouraged.…”

mentioning

confidence: 99%

COVID-19: First Do No Harm

Waterer

Rello

Wunderink

2020

Am J Respir Crit Care Med

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In his book "Of the Epidemics" Hippocrates advises physicians that they must "have two special objects in view with regard to disease, namely, to do good or to do no harm" (1). Facing the challenge of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, this advice remains as pertinent now as it was over 2,400 years ago. In response to the 1919 Spanish flu pandemic, physicians in desperation turned to the antimalarial quinine (2). It is disappointing that 100 years later, despite the emphasis on evidence-based medicine, the same strategy was adopted, owing to the highly emotional need to treat patients with "something." Faced with a new disease, numbers of patients that have in many cases vastly overwhelmed healthcare resources, and no available effective treatment, an extraordinary array of experimental therapies have been given to critically ill patients, often in combination. Whether this approach has harmed more patients that it has helped remains to be seen. Desperate times are felt to justify desperate measures. However, in this issue of the Journal, the case series by Du and colleagues (pp. 1372-1379) (3) demonstrates that access to basic critical care support, not experimental therapies, is the most important determinant of the high mortality reported in some SARS-CoV-2 series. Despite acute respiratory distress syndrome in 74% and shock in 81%, only 21% of cases received invasive mechanical ventilation. Many physicians across the world are recommending treatments even while researchers and regulators claim that the evidence of benefit is limited, and therapies should be tested in a randomized controlled trial. These physicians believe that the chance of potential benefit outweighs the chance of harm. However, safety concerns may be significantly underestimated since most of these drugs have never been properly studied in critically ill patients. For example, many of the experimental therapies used are potentially cardiotoxic, including hydroxychloroquine, ritonavir, lopinavir, IFN a-2-b, azithromycin, and methylprednisolone. As myocarditis is reported as a potential complication of SARS-CoV-2, if all these agents are used in combination, is it a surprise that very high rates of cardiac complications occur, such as the 60% incidence of arrhythmia reported in the case series from Du and colleagues (3) in this issue and by others (4)? IFNs are generally proinflammatory and may be deleterious in patients with hyperinflammation with high plasma IL-6. Anti-IL-6 monoclonal antibodies have been associated with cytomegalovirus reactivation, episodes of bacterial septic shock, and bowel perforation, particularly when combined with high-dose corticosteroids (5, 6). Many of these experimental agents have pharmacologic interactions with a large list of drugs commonly This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.

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The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

Cited by 270 publications

References 142 publications

Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study

Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study

Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

COVID-19: First Do No Harm

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