Therapeutic Anticoagulation
Unfractionated heparin (UFH) is a blood thinner (also called an anticoagulant). Low molecular weight heparins (LMWH) - such as drugs like dalteparin, enoxaparin and tinzaparin - are also anticoagulants, which come from unfractionated heparin that has been broken down into smaller pieces. Anticoagulants are often given to either prevent clots (known as a prophylactic dose) or to treat clots (therapeutic dose), as well as reduce inflammation.
Both LMWH and UFH are widely used in clinical practice - such as in acute coronary syndromes, VTE, stroke prevention and have been shown in many clinical studies to have highly acceptable safety profiles and low rates of major hemorrhage.(1) Clinicians have extensive experience and familiarity with dosing and management of patients in hospital on therapeutic anticoagulation.
Bleeding is the most frequently encountered complication from heparin. Patients with bleeding risk factors will be excluded from the trial. In non-critically ill patients hospitalized for COVID-19 pneumonia, the rate of major bleeding (hemorrhage) in those treated with therapeutic-dose heparin was low compared to usual care thromboprophylaxis (1.9% (n=22/1180) and 0.9% (n=9/1047), respectively).(2) Furthermore, the incidence of major hemorrhage associated with therapeutic-dose LMWH for symptomatic VTE is ~0.9% (n=6/694).(3)
Heparin Induced Thrombocytopenia (HIT) is a rare but potentially serious complication of heparin exposure.(1) The overall incidence of HIT is 0.2-0.5%, and is higher in patients receiving therapeutic doses (0.79%) compared to prophylactic doses (<0.1%).4 In our mpRCT (n=2231), no confirmed cases of HIT were reported in non-critically ill patients.
Therapeutic Anticoagulation in CAP
The clinical utility of therapeutic-dose heparin in CAP specifically, has never been studied in a randomized clinical trial (RCT). Nonetheless, a significant body of evidence including laboratory data,(5,6) animal models,(7) observational studies,(8) and RCTs in humans, support the potential for therapeutic-dose heparin to reduce mortality in sepsis (the body’s extreme response to an infection).(9-11)
In a review of six RCTs that evaluated therapeutic-dose heparin vs. placebo or usual care in patients with sepsis and septic shock (n=2,477 patients), therapeutic-dose heparin was associated with a 12% reduction in the risk of death.(4) Similarly, a second analysis of 17 RCTs enrolling patients with sepsis (n=1,167 patients) demonstrated decreased 28-day mortality associated with enhanced-dose heparin Importantly, heparin was not associated with increased risk of major hemorrhage.(4,12) In an analysis of RCTs that included patients with acute respiratory distress syndrome (ARDS), therapeutic-dose heparin was associated with improved oxygenation and reduced 28-day mortality compared with conventional treatment.(3) Given that CAP is the most common antecedent for sepsis and ARDS, we have hypothesized that use of therapeutic-dose heparin early in CAP will result in improved outcomes and reduced burden of critical illness.
References
1. Tiryaki F, Nutescu EA, Hennenfent JA, et al. Anticoagulation therapy for hospitalized patients: patterns of use, compliance with national guidelines, and performance on quality measures. Am J Health Syst Pharm 2011;68:1239-44.
2. Lawler PR, Goligher EC, Zarychanski R, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med 2021;385:790-802.
3. Jiang X, Feng R, Liu J, et al. Meta-analysis of the curative effect of low molecular weight heparin on acute respiratory distress syndrome. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020; 32:1472-8.
4. Zarychanski R, Abou-Setta AM, Kanji S, et al. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med 2015; 43:511-8.
5. Lever R, Hoult JR, Page CP. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro. Br J Pharmacol 2000;129:533-40.
6. Mummery RS, Rider CC. Characterization of the heparin-binding properties of IL-6. J Immunol 2000; 165:5671-9.
7. Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98:579-86.
8. Zarychanski R, Doucette S, Fergusson D, et al. Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med 2008; 36:2973-9.
9. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301-11.
10. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018; 378:797-808.
11. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301-8.
12. Liu Z, Zhu H, Ma X. Heparin for treatment of sepsis: a systemic review. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014;26:135-41.