Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

Building on treatment protocols developed at the height of the COVID-19 pandemic, Mount Sinai Heart has launched the global FREEDOM COVID Anticoagulation Trial to determine the most effective dosage and regimen of anticoagulant therapy in improving the survival rate of hospitalized COVID-19 patients.

“While vaccines are being used and clinical trials are underway, there is an urgent need to determine how to best treat the next hundreds of thousands of COVID-19 patients around the world,” says Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, and principal investigator of the FREEDOM trial. “This is a coordinated international effort, launched as an investigator-led trial to speed up the process.”

In March 2020, during the early days of the pandemic, Dr. Fuster closely observed patients with blood clots in their legs who had been admitted with COVID-19. After hearing from colleagues in China of other cases of small, pervasive, and unusual clotting that had triggered myocardial infarctions, strokes, and pulmonary embolisms, he initiated decisive action. “We became one of the first medical centers in the world to treat all COVID-19 patients with anticoagulant medications,” says Dr. Fuster, a pioneer in the study of atherothrombotic disease. “It was a decision that we believe saved many lives.”

That early protocol—based largely on intuition, Dr. Fuster says—led to groundbreaking research and insights by Mount Sinai into the role of anticoagulation in the management of COVID-19-infected patients. That work includes a study published in August 2020 in Journal of the American College of Cardiology that showed a 50 percent higher chance of survival compared to patients given no anticoagulant. The analysis was conducted by the Mount Sinai COVID Informatics Center.

Dr. Fuster says, “While our study was observational, it helped us design the large-scale FREEDOM COVID Anticoagulation Trial in partnership with more than 100 sites in 14 countries in order to reach 3,600 patients.”  The prospective study will be randomized to investigate the effectiveness and safety of the anticoagulants enoxaparin and apixaban in patients age 18 and older who have been hospitalized with confirmed COVID-19, but are not in an ICU or intubated. The trial is currently enrolling and set for completion in June 2021.

Clotting in organs including the lungs, brain, and heart can be a complication of COVID-19, autopsies have shown. And anticoagulation therapies are associated with better outcomes in hospitalized patients with the virus. The FREEDOM clinical trial will evaluate different regimens.

The FREEDOM trial is based on months of clinical observation and pathology work conducted as deaths from the COVID-19 pandemic mounted globally in spring 2020 and thromboembolism emerged as an important disease manifestation. Autopsy studies at Mount Sinai demonstrated a high incidence of macrothrombi and microthrombi, prompting the suggestion that in-hospital use of blood thinners could be beneficial to COVID-19 patients. To help clarify the pivotal questions of anticoagulant choice, dosing, and treatment duration, Mount Sinai began an observational study in May 2020 of 4,389 COVID-19-positive patients who were admitted to five hospitals in the Mount Sinai Health System.

“In this observational study, anticoagulation was associated with improved outcomes, and bleeding rates appeared to be low,” says corresponding author Anu Lala, MD, 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, the importance of having answers as to what the best treatment for these patients entails is immeasurable. Ultimately, clinical trials are what will inform those answers.”

Researchers looked at six different anticoagulant regimens, including oral and intravenous dosing. They found that both therapeutic and prophylactic doses of anticoagulants were associated with significantly improved in-hospital survival, and with a 30 percent reduced risk of admission to an ICU or intubation. The researchers used a hazard score to estimate risk of death, which took relevant risk factors into account before evaluating the effectiveness of anticoagulation, including age, ethnicity, pre-existing conditions, and whether the patient was already on blood thinners.

Separately, the researchers looked at autopsy results of 26 COVID-19 patients and found that 11 of them (42 percent) had blood clots—pulmonary, brain, and/or heart—that were never suspected in the clinical setting. These findings suggest that treating COVID-19 patients with anticoagulants as a preventive measure may be associated with improved survival.

Researchers were further encouraged by the finding that overall rates of major bleeding were low (3 percent or less), though slightly higher in the therapeutic group compared to the prophylactic and no-blood-thinner groups. This suggested to the team that clinicians should evaluate COVID-19 patients on an individual basis, weighing the risks and benefits of anticoagulant therapy.

“These observational analyses were done with the highest level of statistical rigor and provide important insights into the association of anticoagulation with critical in-hospital outcomes of mortality and intubation,” says first author Girish Nadkarni, MD, Co-Founder and Co-Director of the Mount Sinai COVID Informatics Center, and Clinical Director of the Hasso Plattner Institute for Digital Health at Mount Sinai.

The study also provided a strong rationale for the FREEDOM Trial, says co-author Zahi Fayad, PhD, Professor of Medicine (Cardiology), and Diagnostic, Molecular and Interventional Radiology, and Director of Mount Sinai’s BioMedical Engineering and Imaging Institute. “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.”

The panel on the left shows the host cell with an ACE2 receptor, which is the binding target for the SARS-CoV-2 virus spike protein that mediates entry into the cell. An antibody competes for binding with the ACE2 receptor and blocks (or neutralizes) this interaction. The panel on the right shows that even when an individual mutation (highlighted in red) disrupts or reduces the binding affinity of antibodies to one area of the spike protein, the body’s immune response to infection or vaccination typically generates a spectrum of antibodies that target different areas of the virus.

A new variant of SARS-CoV-2, the virus that causes COVID-19, appeared in Great Britain in greater frequency in December and has been reported in New York State. The new variant appears to spread more rapidly than older ones and has a distinct set of genetic changes, or mutations. This prompted renewed vigilance among scientists throughout the world who carefully monitor mutations of the virus within their own countries and share their data on public repositories. The genetic codes of 250,000 virus samples from all over the world have already been shared, according to the World Health Organization. Moreover, another new SARS-CoV-2 variant that appears to spread more quickly, but that is different from the English one, has been found in patients with COVID-19 in South Africa.

The Mount Sinai Health System’s Pathogen Surveillance Program continually studies the evolution of SARS-CoV-2 variants through genetic sequencing, a technique that allows them to examine the genetic composition of the virus and identify changes in its genetic code. The team’s work has yielded a series of firsts. Last spring, they reported that the first wave of SARS-CoV-2 in New York City started with several independent introductions of viruses that could be traced back to Europe. These studies also provided evidence for untracked community transmissions of the virus in February and March of 2020.

Mount Sinai Today recently discussed the latest SARS-CoV-2 variants with two leaders of Mount Sinai’s Pathogen Surveillance Program: Viviana Simon, MD, PhD, Professor of Microbiology, and Medicine (Infectious Diseases); and Harm van Bakel, PhD, Assistant Professor of Genetics and Genomic Sciences.

Has Mount Sinai’s Pathogen Surveillance team found this new UK variant in New York City?

Harm van Bakel, PhD

Dr. van Bakel: Although the UK variant has now been detected in New York State, in Saratoga Springs, we have not yet encountered it in our ongoing surveillance of patients cared for by the Mount Sinai Health System. Considering that New York City is a major hub for international travel we fully expect this to change as we continue to generate more data.

This new variant of SARS-CoV-2 from the United Kingdom has a set of distinct mutations—23 to be precise. Does that make it particularly noteworthy?

Dr. van Bakel: SARS-CoV-2 is a virus that tends to mutate slowly and the multiple mutations in this UK variant do make it different. Usually about one to two mutations occur each month. Mutations occur randomly and most of them do not change anything for the virus. But sometimes an occasional mutation makes it more transmissible or potentially less susceptible to existing immunity.

Viviana Simon, MD, PhD

Dr. Simon: There is some emerging evidence that the UK variant, termed B.1.1.7, is more transmissible, although that data is still being worked on. Importantly, there is no evidence that this variant is more deadly. One of the mutations in the UK variant is located within the receptor binding domain (RBD) of the virus’s spike protein, so that has created some concern. The RBD is an area of the virus that attracts a strong immune response from the human body. It is the area where the spike meets the cell receptor and where many neutralizing antibodies bind to prevent the virus from entering the cell.

Dr. van Bakel: A few months ago another variant arose in Danish mink farms that carried a different mutation in the RBD. We have also occasionally seen other RBD mutations as part of our surveillance efforts in New York City during the past few months. When this happens, the worry is that these variants can reduce the effectiveness of existing immunity, but we have not seen any evidence of that yet. There is also always a concern that the viruses become more infectious when they jump from humans to animals such as mink and back into humans. But thus far, we have not seen anything that points to this.

What can we say about this variant so far?

Dr. Simon: It is really important to note that there is no data suggesting that the UK variant is more dangerous or lethal. We are actively doing surveillance on this British variant. We are also looking at other variants that we know are in our city and in Mount Sinai’s patient populations. Starting in September, we began to notice a slow increase in diversity of SARS-CoV-2 detected in the patients seeking care at the Mount Sinai Health System. This is not surprising because SARS-CoV-2 is an RNA virus, and like other RNA viruses, such as influenza and HIV, the more people are infected, the more viral diversity is observed. SARS-CoV-2 does mutate more slowly than influenza viruses or HIV and the majority of these mutations are meaningless insofar as the properties of the virus remain unchanged.

Dr. van Bakel: We are waiting for functional data on the UK variant to tell us if there are differences with regard to how antibodies neutralize it. These data will come from already ongoing controlled experiments using sera from COVID-19 survivors as well as from vaccine recipients. Some genetic changes can render the virus more transmissible. For example, most of the SARS-CoV-2 variants circulating globally over the past 10 months carry a D614G mutation in the spike protein. Studies in animal models have shown that this mutation allows improved transmission compared to the original viral variant first reported in China. Similar studies are needed to determine if this is also the case for the distinct mutations seen in the UK variant.

Is there any evidence that the newly authorized COVID-19 vaccines will not work against this variant?

Dr. Simon:  We believe all of the new vaccines will be effective against this B.1.1.7 variant, as well as other variants, because the vaccines entice the immune system to make antibodies against different regions of the spike protein, and not only the sections of the RBD that are mutated. The immune responses developed upon vaccination will offer protection, even if we find out the RBD of the viral variants has been slightly changed.

Dr. van Bakel: Wearing face masks, maintaining social distancing, and observing all of the measures that have been put in place to protect oneself, as well as others, are still the most effective ways in controlling the spread of the virus until vaccines are more broadly available. Adhering to these guidelines will be effective regardless of the variant that is circulating.

Dr. Simon: Hope is on the horizon. We have highly protective vaccines, which will be delivered to as many people as possible in the coming weeks and months. Since the case numbers in our area remain worrisome, we really need to be careful and follow the guidelines that work for all SARS-CoV-2 variants.

Subtle changes in an individual’s heartbeat, which can be measured on an Apple Watch, are able to signal the onset of COVID-19 up to seven days before individuals are diagnosed with the infection. That preliminary observation was made by researchers at the Icahn School of Medicine at Mount Sinai in a new preprint from the Warrior Watch Study, which was recently uploaded to the medRxiv server.

The investigators followed 297 health care workers at the Mount Sinai Health System between April 29 and September 29. The participants downloaded a customized app onto their iPhones and wore Apple Watches. Changes in their heart rate variability (HRV)—a measure of nervous system function detected by the Apple Watch—were used to identify and predict whether the workers were infected with COVID-19.

“The watch showed significant changes in HRV metrics up to seven days before individuals had a positive nasal swab confirming COVID-19 infection and demonstrated significant changes at the time of symptom development,” says the study’s corresponding author Robert P. Hirten, MD, Assistant Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai. Daily symptoms that were collected included fever or chills, tiredness or weakness, body aches, dry cough, sneezing, runny nose, diarrhea, sore throat, headache, shortness of breath, loss of smell or taste, itchy eyes, or none.

Interestingly, the researchers also found that seven to fourteen days after diagnosis with COVID-19, the HRV pattern began to normalize and was no longer statistically different from the patterns of those who were not infected.

Robert P. Hirten, MD

“Developing a way to identify people who might be sick even before they know they are infected would really be a breakthrough in the management of COVID-19,” Dr. Hirten says. “One of the challenging things about COVID-19 is that many people are asymptomatic, meaning they have no symptoms but are still contagious. This makes it difficult to contain this infection by using the traditional method of identifying someone who is sick and quarantining them.”

As a gastroenterologist, Dr. Hirten has been an early proponent of using the Apple Watch and other wearable devices to better understand and manage chronic conditions such as Crohn’s disease and ulcerative colitis. He found that measuring HRV in patients with inflammatory bowel disease helps identify and predict periodic flare-ups. “When the COVID-19 pandemic hit,” he says, “we figured, ‘Let’s try to use the advances we’ve made in studying wearable devices to address the crisis.’”

The Warrior Watch Study, which is ongoing and includes a wide range of Mount Sinai employees—from doctors and nurses to security guards—was designed with two goals in mind, says Dr. Hirten. The first goal was to see whether infection prediction was possible by assessing the data that was collected through the end of September. The other goal was to gauge the effects of the pandemic on the mental health of Mount Sinai’s health care workers. This will be addressed in a separate paper.

“This technology allows us not only to track and predict health outcomes, but also to intervene in a timely and remote manner, which is essential during a pandemic that requires people to stay apart,” says the study’s co-author Zahi Fayad, PhD, Director of the BioMedical Engineering and Imaging Institute and the Lucy G. Moses Professor of Medical Imaging and Bioengineering at the Icahn School of Medicine at Mount Sinai.

Digital health is a relatively new field that holds enormous promise. It provides doctors with patient data that would not otherwise be readily available and requires little input from patients themselves. Mount Sinai’s study asks participants to wear the watch for at least eight hours a day and respond to daily questions that inquire about how they are feeling and whether they have been tested for COVID-19.

Apple Inc. and other wearable device manufacturers are very interested in how their products contribute to health care outcomes, as well. In September, Apple’s Chief Executive Officer, Tim Cook, mentioned Mount Sinai’s Warrior Watch Study during the company’s virtual product launch event.

“This study really highlights where digital health is moving,” Dr. Hirten says. “It shows that we can use these technologies to better address evolving health needs, which will hopefully help us better manage disease in the future. While we aren’t there yet, our goal is to operationalize these platforms to improve the health of our patients. The Warrior Watch Study is a significant step in that direction.”