Although abnormal blood clotting has been identified as one of the primary causes of death from COVID-19, early treatment in an intensive care unit (ICU) with therapeutic anticoagulation (anti-clotting) for adults who are critically ill with COVID-19 does not appear to improve chances of survival, and could do more harm than good by increasing the risk for major bleeding, a multicenter research group cautions.
"In patients critically ill with COVID-19, therapeutic dose anticoagulation started early in the ICU stay was not associated with improved survival,"says Hanny Al-Samkari, MD, an investigator in the Division of Hematology/Oncology at Massachusetts General Hospital (MGH) and lead author of a study reporting the findings in the journal Annals of Internal Medicine. (Whereas such patients almost always receive low, "prophylactic-dose" anticoagulation, therapeutic doses are much higher.)
Al-Samkari and colleagues at MGH, Brigham and Women's Hospital, and Harvard Medical School (HMS) analyzed health records from STOP-COVID (Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19), a multicenter study that included adults 18 and older who had laboratory-confirmed COVID-19 and were admitted to participating ICUs at 67 geographically diverse hospitals in the United States.
The researchers evaluated the incidence of venous thromboembolism (VTE), a serious and potentially fatal blood clotting event, as well as the occurrence of major, life-threatening bleeding. They also examined the effects of early therapeutic anticoagulation on survival.
To do this, they used data from the study to simulate a randomized clinical trial in which patients are randomly assigned to receive or not receive therapeutic anticoagulation within two days of being admitted to an ICU. The model took into account detailed data on demographics, comorbidities, medications and severity of illness that might otherwise influence the results.
They found that 6.3% of the 3,239 patients had VTE confirmed on imaging studies and 2.8% had major bleeding events. The incidence of VTE was considerably less frequent than in previous, mostly smaller studies of patients with COVID-19, which reported VTE rates as high as 42%.
The only factors that accurately predicted higher risk for VTE were male sex and higher circulating levels of D-dimer, a protein fragment produced when a blood clot breaks up.
Importantly, the results showed that there was no survival benefit for patients who received therapeutic anticoagulation in the first two days of an ICU stay compared with patients who did not receive early therapeutic anticoagulation.
"We looked at multiple subgroups of patients, including by age, sex and severity of illness, and we did not find any subgroup that benefited from early therapeutic anticoagulation," says senior author and principal investigator of STOP-COVID, David E. Leaf, MD, MMSc, director of clinical and translational research in acute kidney injury in the Division of Renal Medicine at the Brigham.
The study results also reinforce that "bleeding matters. Bleeding is not trivial in these patients," Al-Samkari says. Of the 90 patients who had a major bleeding event in the study, 60 were receiving therapeutic anticoagulation at the time of the event, and 56 of the 90 patients (62%) with a major bleed died within 28 days. The most common sites of bleeding were in the gastrointestinal tract and within the skull.
In addition to the clinical findings, the study results support the use of target trial emulation, the type of simulation the researchers used, to quickly acquire information that can be used to improve clinical care in a rapidly changing environment, says co-first author Shruti Gupta, MD, MPH, from the Division of Renal Medicine at the Brigham.
This is another example of how target trial emulation, which we've used in other important studies from our STOP-COVID consortium, can be applied to observational data and allow us to estimate the effects of different treatments on clinical outcomes. This is particularly important because randomized clinical trials often take time and require large numbers of patients to see meaningful differences in outcomes."
Hanny Al-Samkari, MD, Investigator, Division of Hematology/Oncology, Massachusetts General Hospital
Clinical staff at member institutions of the STOP-COVID consortium contributed data to the study. There was no outside funding source.
Al-Samkari, H., et al. (2021) Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19. Annals of Internal Medicine. doi.org/10.7326/M20-6739.