THE REMAP-CAP COVID-19 ANTICOAGULATION DOMAIN CLINICAL TRIAL

This domain within the REMAP-CAP platform is designed to test the effectiveness of different anticoagulation strategies for patients with acute illness due to suspected or proven Covid-19. In this domain of the REMAP-CAP trial, participants meeting the platform entry criteria with suspected or microbiological testing-confirmed COVID-19 infection were randomised to one of up to three interventions: Conventional low dose thromboprophylaxis, Intermediate dose thromboprophylaxis, and Continuation of therapeutic dose anticoagulation (only in the Prior Therapeutic Anticoagulation Stratum).

BACKGROUND

The clinical course of Covid-19 is characterised by an initial period of mild to moderate symptoms, followed by progressive respiratory failure and requirement for intensive care unit (ICU)-level organ support or death in some patients. The majority of patients requiring hospitalisation are moderately ill, not initially requiring ICU-level organ support. Limited therapies are available to prevent clinical progression to ICU-level organ support and death among moderately ill hospitalised patients.

Patients with Covid-19 have a notable incidence of macro and microvascular thrombosis and inflammation in association with poor clinical outcomes. Given the anti-thrombotic, anti-inflammatory, and possible anti-viral properties of heparins, it has been hypothesised that anticoagulation with heparin administered at doses higher than conventionally used for venous thromboprophylaxis may improve outcomes. Further, elevated D-dimer is associated with vascular thrombosis and poor clinical outcomes, and thus some have advocated using D-dimer to guide anticoagulant dosing in patients with Covid-19. In the absence of data from randomised trials, clinical guideline recommendations and practice vary widely.

To determine whether an initial strategy of therapeutic-dose anticoagulation with heparin improves survival to hospital discharge with reduced use of ICU-level organ support in hospitalized, non-critically ill patients with Covid-19, an international, adaptive, multi-platform randomised controlled trial (mpRCT) was conducted.

DOMAIN OBJECTIVES

The objective of this domain is to determine the effectiveness of different anticoagulation strategies for patients with acute illness due to suspected or proven pandemic infection. It was hypothesised that the probability of the occurrence of the primary endpoint specified in the relevant core protocol documents will differ based on allocation to different anticoagulation strategies. The following interventions were available:

• Conventional low dose thromboprophylaxis

• Intermediate dose thromboprophylaxis

• Continuation of therapeutic dose anticoagulation (only in the Prior Therapeutic Anticoagulation Stratum)

It was hypothesised that the treatment effect of different anticoagulation strategies would be different depending on whether SARS-CoV-2 infection was confirmed to be present or absent.

It was hypothesised that the treatment effect of different anticoagulation strategies would be different depending on whether prior therapeutic anticoagulation was present or absent.

It was hypothesised that the treatment effect of different anticoagulation strategies would be different depending on allocation status in the Antiplatelet Domain.

This is a treatment-by-treatment interaction between interventions in the Anticoagulation Domain and the Antiplatelet Domain.

TRIAL DESIGN

This domain is conducted as part of the REMAP-CAP trial. Treatment allocation is based on response adaptive randomisation. To accelerate evidence generation, three adaptive randomised controlled trial protocols evaluating therapeutic-dose anticoagulation with heparin in patients hospitalised for Covid-19 were integrated into a single mpRCT

Patients are eligible for this domain if they meet all of the platform-level inclusion and none of the platform-level exclusion criteria as specified in either the REMAP-CAP Core Protocol + Pandemic Appendix or the REMAP-COVID Core Protocol. Patients eligible for the REMAP may have conditions that exclude them from this specific COVID-19 Anticoagulation Domain.

Patients are eligible for this domain if:

• COVID-19 infection is suspected by the treating clinician or has been confirmed by microbiological testing (i.e. PISOP stratum)

• Microbiological testing for SARS-CoV-2 of upper or lower respiratory tract secretions or both has occurred or is intended to occur

Patients were excluded from this domain if they had any of the following:

• More than 48 hours has elapsed since ICU admission, unless the patient has already been assigned a treatment in another domain in the Moderate State in which case exclusion will occur if more than 48 hours has elapsed since commencement of sustained organ failure support in an ICU

• A clinical indication to commence or continue therapeutic dose anticoagulation

• Intention to continue or commence dual antiplatelet therapy

• Enrolment in a trial evaluating anticoagulation for proven or suspected COVID-19 infection, where the protocol of that trial requires continuation of the treatment assignment specified in that trial

• Known or suspected previous adverse reaction to UFH or LMWH including heparin induced thrombocytopenia (HIT).

• The treating clinician believes that participation in the domain would not be in the best interests of the patient

RESULTS

The first participant was randomised on April 21, 2020. On January 22, 2021, enrolment was discontinued on advice from the DSMBs after planned adaptive analyses of 1398 moderate severity participants demonstrated that the pre-specified stopping criteria for superiority of therapeutic-dose anticoagulation had been reached in both the high and low D-dimer groups. By that time, 2245 moderate severity participants had been randomised. The primary analysis population consisted of 2219 participants with SARS-CoV-2 confirmation for whom the primary outcome was known.

Among 2219 participants in the overall moderate severity cohort, the posterior probability that therapeutic-dose anticoagulation increased organ support-free days compared to usual care thromboprophylaxis was 99.0%. The proportion of participants in the thromboprophylaxis arm surviving to hospital discharge without receipt of organ support during the first 21 days (control event frequency) was 76.4%. The median adjusted absolute improvement in this proportion with therapeutic-dose anticoagulation was 4.6%. In the primary adaptive analysis groups, the final posterior probability for superiority of therapeutic-dose anticoagulation compared with usual care thromboprophylaxis was 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. The posterior probability of superiority of therapeutic-dose anticoagulation in the unknown D-dimer group was 97.3% The results were consistent in sensitivity analyses.

Therapeutic doses of heparin as compared with usual-care venous thromboprophylaxis, increased the probability of surviving to hospital discharge with fewer days of cardiovascular or respiratory support in patients with moderate Covid-19 but not in those with severe Covid-19.

KEY CONNECTIONS