Anticoagulation Therapy in Patients With Coronavirus Disease 2019

Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 (HOPE-COVID19))

Francesco Santoro, MD, PhD; Ivan J. Núñez-Gil, MD, PhD; María C. Viana-Llamas, MD; Charbel Maroun Eid, MD; Rodolfo Romero, MD; Inmaculada Fernández Rozas, MD; Alvaro Aparisi, MD; Victor Manuel Becerra-Muñoz, MD; Marcos García Aguado, MD; Jia Huang, MD; Ludovica Maltese, MD; Enrico Cerrato, MD; Emilio Alfonso-Rodriguez, MD; Alex Fernando Castro Mejía, MD; Francisco Marin, MD; Sergio Raposeiras Roubin, MD; Martino Pepe, MD; Victor H. Moreno Munguia, MD; Gisela Feltes, MD; Jesus Varas Navas, MD; Bernardo Cortese, MD; Luis Buzón, MD; Cristoph Liebetrau, MD; Raquel Ramos-Martinez, MD; Antonio Fernandez-Ortiz, MD; Vicente Estrada, MD; Natale Daniele Brunetti, MD, PhD

Disclosures

Crit Care Med. 2021;49(6):e624-e633. 

In This Article

Results

Baseline Features

Five thousand eight hundred thirty-eight patients were enrolled in the study. Mean age of patients admitted was 65 ± 16 years, 58% were male. Nine percent of patients were admitted in ICU. During hospitalization, 13% of patients required noninvasive ventilation and 7% invasive ventilation. All demographic features are reported in Table 1. Mean follow-up was 15 ± 11 days.

During hospitalization, 2,601 patients (44%) received anticoagulation therapy, among these patients, 327 (12%) had history of anticoagulation treatment. Anticoagulation therapy in subjects not anticoagulated before admission was given for prophylaxis in 83% of cases, while 15% received full dose of low-molecular-weight heparin, 1% oral anticoagulation with vitamin K antagonists, and 1% direct oral anticoagulants (Figure 1).

Figure 1.

Anticoagulation regimens in general population (A), respiratory failure (RF) (B), RF treated with noninvasive ventilation (NIV) and invasive ventilation (IV). DOAC = direct oral anticoagulant, LMWH = low-molecular-weight heparin, Pro = prophylactic dose, th = therapeutic dose, VKA = vitamin K antagonist.

Three-hundred twenty-seven patients (5.7%) were taking anticoagulation therapy before hospitalization. Most of them (n = 230) were taking oral anticoagulation due to history of atrial fibrillation and remaining patients due to previous DVT and PE. In an additional analysis comparing subjects anticoagulated before admission, after admission and not anticoagulated, those anticoagulated before admission showed worse mortality rates (Supplement Figure 1, http://links.lww.com/CCM/G283 [legend, http://links.lww.com/CCM/G285]; log-rank p < 0.001).

Anticoagulation in General Population

Patients who received anticoagulation therapy were older (66 ± 15 vs 63 ± 27 yr; p = 0.01), more frequently were male (60% vs 58%; p = 0.02), had diabetes (21% vs 17%; p = 0.01), obesity (24% vs 21%; p = 0.01), renal insufficiency (creatinine clearance < 30 mL/min) (7% vs 6%; p = 0.01), history of lung disease (21% vs 17%; p = 0.01), and heart disease (26% vs 21%; p = 0.01) (Table 1).

Among patients without previous anticoagulation therapy, anticoagulation was not associated with better survival rate (81% vs 81%; p = 0.94) but with higher risk of bleeding (2.7% vs 1.8%; p = 0.03) (Figure 2). In this setting, lower mortality rates were associated with prophylactic parenteral anticoagulation when compared with therapeutic anticoagulation therapy including oral or IV administration (Supplement Figure 2, http://links.lww.com/CCM/G284 [legend, http://links.lww.com/CCM/G285]; log-rank p < 0.001).

Figure 2.

Rates of occurrence of death and bleeding in general population (A), naive subjects with respiratory failure (B), invasive ventilation (IV) (C), and noninvasive ventilation (NIV) (D), according to anticoagulant therapy during hospitalization. *Differences that are statistically different (p < 0.05). AC = anticoagulation.

Respiratory Failure

Among patients admitted with respiratory failure (49%, 2,859 patients, including 391 and 583 patients requiring invasive and nonventilation, respectively), anticoagulation started during hospitalization was associated with lower mortality rates (32% vs 42%; p < 0.01) (Figure 3A; log-rank p < 0.001) and not significant higher risk of bleeding (3.4% vs 2.7%; p = 0.3). In this subset of patients, 40% received prophylactic dose and 11% therapeutic dose (Figure 1B).

Figure 3.

Cumulative death occurrence (A) in subjects not anticoagulated before admission and with respiratory failure according to anticoagulant therapy during hospitalization. Cumulative death occurrence (B) in subjects not anticoagulated before admission and with invasive ventilation according to anticoagulant therapy during hospitalization.

Three-hundred ninety-one patients (14%) underwent invasive ventilation; of these, 154 received (39%) prophylactic dose anticoagulation and 110 (28%) therapeutic dose. Additional anticoagulation therapy was associated with lower mortality rates (53% vs 64%; p = 0.05) without increased rates of bleeding (9% vs 8%; p = 0.88) (Figure 3B; log-rank p < 0.001). Fourteen patients (3.4%) were on anticoagulation before hospitalization and two patients interrupted anticoagulation.

Five-hundred eighty-three patients (20%) underwent noninvasive ventilation; of these, 186 (32%) received prophylactic dose anticoagulation and 127 (22%) therapeutic dose. Additional anticoagulation therapy was not associated with lower mortality rates (35% vs 38%; p = 0.40), without increased rates of bleeding (4.4% vs 3.3%; p = 0.55). Thirty-eight patients (5%) were on anticoagulation therapy before hospitalization.

Multivariate Analysis

When evaluating patients admitted with respiratory failure (not anticoagulated before admission) in a multivariable Cox' regression analysis model including age, gender, prior history of heart, pulmonary or cancer disease, atrial fibrillation, admission to ICU, hypertension, diabetes, obesity, drug therapy during hospitalization with β-blockers, or angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers, anticoagulation was associated with lower mortality (risk ratio [RR], 0.58; 95% CI, 0.49–0.67; p < 0.001) (Table 2). In patients undergoing invasive ventilation the RR with anticoagulation was 0.50 (95% CI, 0.37–0.70; p < 0.001), 0.72 (95% CI, 0.51–1.01; p = 0.0575) in noninvasive ventilation.

processing....