Early in the COVID-19 pandemic, Mount Sinai researchers were among the first to show that anti-coagulation therapy was associated with improved survival among hospitalised COVID-19 patients. But many questions remained – about the size of the potential benefit, and about what dosage of this therapy might be more effective. Now, the research team has suggested some possible answers.
In this observational study, the researchers found all regimens of anticoagulants – drugs that prevent blood clotting – were far superior to no anticoagulants in COVID-19 patients. More specifically, patients on both a “therapeutic” or full dose, and those on a “prophylactic” or lower dose, showed about a 50% higher chance of survival, and roughly a 30% lower chance of intubation, than those not on anticoagulants. The researchers looked at six different anticoagulant regimens, including both oral and intravenous dosing, within both therapeutic and prophylactic groups. They observed that therapeutic and prophylactic subcutaneous low-molecular weight heparin, and therapeutic oral apixaban may lead to better results.
“This work from the Mount Sinai COVID Informatics Centre provides additional insight on the role of anti-coagulation in the management of patients admitted to the hospital with COVID-19. Although this is an observational study, it helped in the design of a large-scale international clinical trial that we are coordinating. The randomised trial focuses on those three anti-thrombotic regimens— therapeutic and prophylactic subcutaneous low-molecular weight heparin, and therapeutic oral apixaban,” says senior corresponding author Dr Valentin Fuster, director of Mount Sinai Heart and physician-in-chief of The Mount Sinai Hospital.
This study is an extension of Mount Sinai research that showed that treatment with anticoagulants was associated with improved outcomes both in and out of the intensive care unit among hospitalized COVID-19 patients. The work was prompted by the discovery that many patients hospitalised with COVID-19 developed high levels of life-threatening blood clots.
The team of investigators evaluated electronic medical records of 4,389 confirmed COVID-19-positive patients admitted to five hospitals in the Mount Sinai Health System in New York City (The Mount Sinai Hospital, Mount Sinai West, Mount Sinai Morningside, Mount Sinai Queens, and Mount Sinai Brooklyn) between 1 March and 30 April, 2020. They specifically looked at survival and death rates for patients placed on therapeutic and prophylactic doses of blood thinners (oral anti-thrombotics, subcutaneous heparin, and intravenous heparin) versus those not placed on blood thinners. The researchers used a hazard score to estimate risk of death, which took relevant risk factors into account before evaluating the effectiveness of anti-coagulation, including age, ethnicity, pre-existing conditions, and whether the patient was already on blood thinners. The researchers also took into account and corrected for disease severity, including low oxygen saturation levels and intubation.
Of the patients analysed, 900 (20.5%) received a full-treatment dose of anticoagulants. Another 1,959 patients (44.6%) received a lower, prophylactic dose of anticoagulants, and 1,530 (34.5%) were not given blood thinners. There was a strong association between blood thinners and reduced likelihood of in-hospital deaths: both therapeutic and prophylactic doses of anticoagulants reduced mortality by roughly 50% compared to patients on no blood thinners.
Overall, 467 (10.6%) of the patients required intubation and mechanical ventilation during their hospitalisation. Those on therapeutic blood thinners had 31% fewer intubations than those not on blood thinners, while those on prophylactic blood thinners had 28% fewer.
Bleeding rates – a known complication of blood thinners – were surprisingly low overall among all patients (3% or less), but slightly higher in the therapeutic group compared to the prophylactic and no-blood-thinner groups, the researchers said. Their findings suggest that clinicians should evaluate patients on an individual basis given the benefit-risk trade-off.
Separately, the researchers looked at autopsy results of 26 COVID-19 patients and found that 11 of them (42%) had blood clots – pulmonary, brain, and/or heart – that were never suspected in the clinical setting. These findings suggest that treating patients with anticoagulants may be associated with improved survival.
“This report is much more in-depth than our previous brief report and includes many more patients, longer follow-up, and rigorous methodology. Clearly, anti-coagulation is associated with improved outcomes and bleeding rates appear to be low,” says corresponding author Dr Anu Lala, assistant professor of medicine (cardiology) and director of heart failure research at the Icahn School of Medicine at Mount Sinai. “As a clinician who has treated COVID-19 patients on the front lines, I recognise the importance of having answers as to what the best treatment for these patients entails, and these results will inform the design of clinical trials to ultimately give concrete information.”
"These observational analyses were done with the highest level of statistical rigor and provide exciting insights into the association of anti-coagulation with critical in-hospital outcomes of mortality and intubation," says first author Dr Girish Nadkarni, co-founder and co-director of the Mount Sinai COVID Informatics Centre and clinical director of the Hasso Plattner Institute for Digital Health at Mount Sinai. “We are excited that results from this observational study in one of the largest and most diverse hospitalised populations have led to an ongoing trial of type, duration, and doses of anti-coagulation. Ultimately we hope this work will lead to improved outcomes and treatment for COVID-19 patients."
“This work highlights the need to better understand the disease from a diagnostic and therapeutic point of view and the importance of conducting properly designed diagnostic and interventional studies,” explains co-author Dr Zahi Fayad, co-founder of the Mount Sinai COVID Informatics Centre and director of Mount Sinai’s Bio-Medical Engineering and Imaging Institute.
Abstract
Background: Thromboembolic disease is common in coronavirus disease-19 (COVID-19). There is limited evidence on association of in-hospital anticoagulation (AC) with outcomes and post-mortem findings.
Objective: To examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies.
Methods: A retrospective analysis examining association of AC with mortality, intubation and major bleeding. We also conducted sub-analyses on association of therapeutic vs prophylactic AC initiated ≤48 hours from admission. We describe thromboembolic disease contextualized by pre-mortem AC among consecutive autopsies.
Results: Among 4,389 patients, median age was 65 years with 44% female. Compared to no AC (n=1530, 34.9%), therapeutic (n=900, 20.5%) and prophylactic AC (n=1959, 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]=0.53; 95%CI: 0.45-0.62, and aHR=0.50; 95%CI: 0.45-0.57, respectively), and intubation (aHR 0.69; 95%CI: 0.51-0.94, and aHR 0.72; 95% CI: 0.58-0.89, respectively). When initiated ≤48 hours from admission, there was no statistically significant difference between therapeutic (n=766) vs. prophylactic AC (n=1860) (aHR 0.86, 95%CI: 0.73-1.02; p=0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27/900 (3.0%) on therapeutic, 33/1959 (1.7%) on prophylactic, and 29/1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3/11 (27%) were on therapeutic AC.
Conclusions: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared to prophylactic AC, therapeutic AC was associated with lower mortality, though not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.
Authors
Girish N Nadkarni, Anuradha Lala, Emilia Bagiella, Helena L Chang, Pedro Moreno, Elisabet Pujadas, Varun Arvind, Sonali Bose, Alexander W. Charney, Martin D Chen, Carlos Cordon-Cardo, Andrew S Dunn, Michael E. Farkouh, Benjamin Glicksberg, Arash Kia, Roopa Kohli-Seth, Matthew A Levin, Prem Timsina, Shan Zhao, Zahi A Fayad, Valentin Fuster
[link url="https://www.mountsinai.org/about/newsroom/2020/mount-sinai-team-offers-additional-data-on-efficacy-of-blood-thinners-for-covid19-and-insight-on-best-potential-regimens-pr"]Mount Sinai material[/link]
[link url="https://www.onlinejacc.org/content/early/2020/08/24/j.jacc.2020.08.041"]Journal of the American College of Cardiology abstract[/link]