BACKGROUND AND PURPOSE: 

• Thrombosis and inflammation may be a cause of poor COVID-19 outcomes, and therapeutic doses of anticoagulation may improve outcomes 
• Investigators (ATTACC, ACTIV-4a, and REMAP-CAP Investigators; NEJM, 2021) sought to determine whether unfractionated or low-molecular-weight heparin improves outcomes in hospitalized patients  

METHODS: 

• Open-label, adaptive, multiplatform, controlled trial 
  • Response-adaptive randomization allows for randomization probabilities to be modified as evidence about treatment effects are accrued  
• Participants 
  • Non-critically ill arm 
    • Hospitalized COVID-19 patients who did not require critical care–level organ support at enrollment 
  • Critically ill arm 
    • Hospitalized COVID-19 patients with ICU-level respiratory or cardiovascular organ support 

Note: Patients were further subcategorized based on D-dimer levels 

• Interventions 
  • Therapeutic dose anticoagulation with heparin 
  • Usual care pharmacologic thromboprophylaxis 
• Primary outcome 
  • Organ support–free days 
    • Evaluated on an ordinal scale that combined in-hospital death  
  • Number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge 
    • Evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level 

RESULTS: 

Non-Critically Ill Patients 

• 2219 patients  
• Probability that heparin increased organ support–free days compared with usual-care thromboprophylaxis was 98.6% 
  • aOR 1.27 (95% Credible Interval [CrI], 1.03 to 1.58) 
• The adjusted absolute between-group difference in survival until hospital discharge without organ support favored therapeutic-dose anticoagulation  
  • Usual-care group: 76.4% survived until hospital discharge  
  • Therapeutic-dose group: 80.2%  
  • 95% CrI, 0.5 to 7.2 
• Probability of the superiority of heparin over usual-care thromboprophylaxis based on D-dimer levels 
  • High D-dimer cohort: 97.3% 
  • Low D-dimer cohort: 92.9% 
  • Unknown D-dimer cohort: 97.3% 
• Major bleeding occurrences 
  • Therapeutic-dose group: 1.9% 
  • Usual care group: 0.9% 

Critically Ill Patients 

• 1098 patients: 534 in heparin cohort | 564 in usual care 
• Median organ support-free days 
  • Therapeutic-dose group: 1 day (IQR -1 to 16) 
  • Usual care group: 4 days (IQR -1 to 16) 
  • Adjusted proportional odds ratio 0.83 (95% CrI, 0.67 to 1.03) 
  • Posterior probability of futility (defined as an odds ratio <1.2), 99.9% 
• The percentage of patients who survived to hospital discharge was similar in the two groups 
  • Heparin group: 62.7% 
  • Usual care group: 64.5% 
  • aOR 0.84 (95% CrI, 0.64 to 1.11) 
• Major bleeding occurrences 
  • Heparin group: 3.8% 
  • Usual care group: 2.3% 

CONCLUSION: 

• For non-critically ill hospitalized COVID-19 patients, therapeutic doses of heparin increased the probability of survival to hospital discharge, and reduced the number of days requiring cardiovascular or respiratory organ support 
  • Limitation of study: lack of detailed screening data and therefore reasons for trial exclusion were not available (other than risk for bleeding or other clinical indication for anticoagulation)  
  • More major bleeding complications were associated with the therapeutic dosing group  
• For critically ill COVID-19 patients, heparin did not have an effect on survival to hospital discharge or number of days free of organ support 
• An accompanying editorial concludes

…available evidence does not support use of therapeutic-dose heparin or LMWH for thrombosis prevention in critically ill patients 

In spite of the signals of benefit of anticoagulation in noncritically ill patients with Covid-19, physicians must deal with the key issues regarding the lack of insight into the mechanisms by which heparin or LMWH does (or does not) provide protection and the question of whether the individual patient’s bleeding risk outweighs the benefit 

Learn More – Primary Sources: 

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19 

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 

Editorial: Surviving Covid-19 with Heparin? 

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