Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT
Authors: Bohula Erin A. , Berg David D. , Lopes Mathew S. , Connors Jean M. , Babar Ijlal , Barnett Christopher F. , Chaudhry Sunit-Preet , Chopra Amit , Ginete Wilson , Ieong Michael H. , Katz Jason N. , Kim Edy Y. , Kuder Julia F. , Mazza Emilio , McLean Dalton , Mosier Jarrod M. , Moskowitz Ari , Murphy Sabina A. , O’Donoghue Michelle L. , Park Jeong-Gun , Prasad Rajnish , Ruff Christian T. , Shahrour Mohamad N. , Sinha Shashank S. , Wiviott Stephen D. , Van Diepen Sean , Zainea Mark , Baird-Zars Vivian , Sabatine Marc S. , Morrow David A. , Im Kyung Ah , Saxena Retu , Wiley Brandon , Benson Carina , Delamed Roman , Skeik Nedaa , Chopra Ami , Judson Marc , Beegle Scott , Shkolnik Boris , Tiwari Anupama , Wu Gregory , Raval Abhijit , Branch Emerald , Rischard Franz , Hypes Cameron , Bixby Billie , Bime Christian , Sundaram Madhan , Sweitzer Nancy , Sandoval Alfredo Vazquez , White Heath , Berg Katherine , Shaefi Shahzad , Donnino Michael , Carroll Brett , Ieong Michael , Ackerbauer Kimberly , Murphy Jaime , Bhatt Ankeet , Blood Alexander , Patel Siddharth , Luu Victor , Narechania Shraddha , Lorganger Austin , Plambeck Robert , Nayfeh Ali , Sanley Michael , Del Cor Michel , Hegg AJ , Nara Winston , Snyder Michael , Khan Faisal , Shawa Imad , Larned Joshua , Collado Elias , Al Faiyumi Mohammed , Mehta Rajeev , Komanapalli Sudarshan , Muppidi Vijayadershan , Desai Mehul , Flanagan Casey , Genovese Leonard , Haddad Tariq , King Christopher , Peterson Amber , Htun Thane , Pionk Elizabeth , Mouawad Nicolas , Kumar Chintalapudi , Nguyen Kevin , Mughal Majid , Malek Ryan , Parekh Akarsh , Provenzano Christopher , Ianitelli Melissa , Prentice-Gaytan Nicole , Bykowski Adam , Tait Don , Schendel Shelley , Yalamanchili Varun , Lala Vasim , Hunyadi Victor , Papolos Alexander , Kenigsberg Benjamin , Shenoy Aarthi , Stuckey Thomas , McQuaid Douglas , Mannam Praveen , McClung Jeffrey , Nilsson Kent , McKown Andrew , Wells Jason , Hotchkin David , Jacobs Marc , Strauss Wayne , Balestra Rick , Sahni Vikram , Snell R. Jeffrey , Suradi Hussam , Sungurlu Sarah , Kuppy Jessica , Gajo Eileen , Adams Foster , Shehadeh Abbas , Suleiman Addi , Nandigam Harish , Slim Jihad , Babar Sardar Ijlal , Baral Dipti , Nawaz Talha , Waheed Syed Abdullah , Roth Randy , Sitaula Subhas , Hayat Shahid , Babu Jooby , Caberto Jason , Hsu Victor , Chang Robert , Bochan Markian , Garcia-Cortes Rafael , Skopicki Hal , Chen On , Pilato Lauren , Richman Paul , Adler Alexander , Sudhindra Praveen , Beversdorf Jamie , Kashyap Ravindra , Mehta Parth , Mehrad Borna , Ataya Ali , Lascano Jorge , Brantly Mark , Austin Adam , Koman Eduard , Galski Thomas , Kumar Vijaya , Soubani Ayman , Harrison Nicolas , Reddy Vineet , Fonkam Audrey 
Published: August 2022

Background:

The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain.

Methods:

COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit–level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit–level COVID-19 rates.

Results:

At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08–3.55];
P
=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32–0.99];
P
=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (
P
=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%;
P
=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56–1.48];
P
=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy.

Conclusions:

In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04409834.