Systemic Anticoagulation Linked to Lower Mortality in Hospitalized COVID-19

Both therapeutic and prophylactic anticoagulation in patients hospitalized with COVID-19 significantly reduce the risk of in-hospital mortality, as well as the need for intubation, when compared with no systemic anticoagulation, according to an observational analysis of patients treated at five New York City hospitals.

Overall, the rates of major bleeding were low, although the risk was slightly higher in patients treated with therapeutic anticoagulation.

“It’s an observational study,” said lead investigator Girish Nadkarni, MD (Icahn School of Medicine at Mount Sinai, New York, NY), discussing the clinical significance of the mortality signal, “but it has led to insights that have led to our ongoing clinical trial.”

That recently launched study, FREEDOM COVID-19, is headed up by Valentin Fuster, MD (Icahn School of Medicine at Mount Sinai). It’s testing prophylactic and full-dose enoxaparin, as well as apixaban (Eliquis; Bristol-Myers Squibb), in hospitalized COVID-19 patients. The optimal type, dose, and duration of anticoagulation also is being tested in other randomized clinical trials, including IMPROVE. Led by Sahil Parikh, MD (Columbia University Irving Medical Center, New York, NY), that trial is testing prophylactic anticoagulation against therapeutic dosing in patients with severe COVID-19.

Nadkarni, who led the observational study along with Anuradha Lala, MD (Icahn School of Medicine at Mount Sinai), said that when New York City was hit hard by COVID-19, there were already emerging reports from China suggesting an increased risk of thromboembolic events in hospitalized patients. Since then, there have been a number of reports showing that COVID-19 predisposes patients to venous and arterial thrombotic disease. COVID-19 is marked by a severe inflammatory response and critical illness, including traditional risk factors such as older age and immobility, which may lead to a heightened risk of thrombotic events, say experts.

“At that time, hospital leadership got together to develop a protocol in which patients were given aggressive prophylaxis at the very minimum,” said Nadkarni. “In patients who were sicker, or who had high D-dimer levels, therapeutic anticoagulation was recommended, although it was left to the discretion of the treating physician as well as the clinical team taking care of the patient, given the lack of randomized trial evidence.”

50% Lower Risk of Death

Back in May, the researchers published their initial experience with systemic anticoagulation in COVID-19, with that observational study similarly suggesting its use was associated with a lower risk of mortality, particularly for patients who required ventilation. The new analysis, which was published online August 26, 2020, ahead of print in the Journal of the American College of Cardiology, includes a more rigorous analysis with nearly twice as many patients as that earlier study.

The study included 4,389 patients (median age 65 years; 44% women) admitted with COVID-19 to the Mount Sinai Health System in March and April. Therapeutic anticoagulation was administered to 900 patients, 1,959 were given a prophylactic dose, and 1,530 were not prescribed any anticoagulation. At hospital presentation, patients prescribed therapeutic anticoagulation had higher blood pressures, higher heart and respiratory rates, and lower oxygen saturation. D-dimer concentrations were highest in those who received therapeutic anticoagulation. 

It has led to insights that have led to our ongoing clinical trial. Girish Nadkarni

Overall, 24.4% of patients died during the study period, 65.9% were discharged alive, and 9.7% were still hospitalized at the time the data set was frozen for analysis. Among patients who received prophylactic anticoagulation, 21.6% died in the hospital, 75.1% were discharged alive, and 3.2% were still hospitalized. With therapeutic anticoagulation, the respective rates were 28.6%, 54.3%, and 17.1%. For those who received no anticoagulation, the rates were 25.6%, 60.8%, and 13.5%, respectively.

Compared with no anticoagulation, and when adjusted for potential confounders, prophylactic anticoagulation was associated with a 50% lower risk of in-hospital mortality (HR 0.50; 95% CI 0.45-0.57) and a 28% lower risk of intubation (HR 0.72; 95% CI 0.58-0.89). Therapeutic anticoagulation was associated with a similar reduction in the hazard of in-hospital mortality (HR 0.53; 95% CI 0.45-0.62) and intubation (HR 0.69; 95% CI 0.51-0.94).

In a subanalysis restricted to patients who received either therapeutic or prophylactic anticoagulation within 48 hours of admission—done due to variations in when anticoagulation was started across patients—there was a trend toward a lower risk of in-hospital mortality with therapeutic anticoagulation, but the difference was not statistically significant. There also was no difference in the risk of intubation with the two doses.

“It’s tough to make anything of this finding because of the nature of the study,” said Nadkarni. “The difference in mortality wasn’t statistically significant [between the two doses], but there was—and I hesitate to use the word ‘trend’ because it can be misconstrued—some suggestion of more benefit with therapeutic anticoagulation when compared with prophylactic anticoagulation. It was in a subset of patients so it’s a hypothesis-generating finding that needs to be tested in large clinical trials.”

Bleeding Risks 

Major bleeding events occurred in 1.9% of patients not treated with anticoagulation, 1.7% of those who received prophylactic dosing, and 3.0% of patients treated with therapeutic anticoagulation. With a single therapeutic agent, bleeding rates were higher among those who received low-molecular-weight heparin (LMWH) compared with those who received a direct oral anticoagulant. For those who received a single prophylactic agent, there was more bleeding in those who received unfractionated heparin compared with LMWH.

Although he finds the bleeding rates reassuring, Nadkarni stressed that “anticoagulation is not a benign treatment” and advised that bleeding risks need to be evaluated so that treatment can be individualized. Although Mount Sinai initiated a system-wide protocol that strongly encouraged the use of systemic anticoagulation, a number of factors determine whether patients should be treated. These include the patient’s clinical condition, oxygen saturation levels, D-dimer concentrations, and bleeding risk, among others. “Patient function is also a big factor,” he said.

In the Mount Sinai Health System, autopsies have been performed on COVID-19 patients since late March. Of this series, 26 were completed and analyzed by a team of subspecialists across multiple organ systems. Just four patients were on anticoagulation prior to admission, but autopsy showed that 11 of the 26 people had evidence of thromboembolic disease, including four with pulmonary emboli, two with cerebral infarctions, and five with microthrombi in multiple organs, including the heart, liver, kidneys, and lymph nodes. There was no prior suspicion of thromboembolism in 25 of the 26 patients.

“It’s one of the largest autopsy series focused on thromboembolism,” said Nadkarni. “We found a much higher proportion of thromboembolism than what would be clinically suspected when the patient was alive. Thromboembolism not just in the lungs, but in various organs. The true incidence of thromboembolism in COVID-19 may be underestimated, because of lot of this wasn’t suspected premortem.”