For nearly 15 years, the Cardiothoracic Surgical Trials Network (CTSN) has played a key role in designing and conducting collaborative clinical trials aimed at improving surgical treatments for cardiovascular disease, the nation’s leading cause of death. CTSN’s efforts to learn more about these treatments – valve replacements, bypass procedures, therapies for heart arrhythmias, and others – have led to new discoveries and made the network highly influential in the field.
But last year, as COVID-19 began to tighten its deadly grip, doctors began cancelling or postponing elective cardiac surgeries in many parts of the world. As a result, CTSN, whose 95 worldwide clinical sites enroll thousands of patients each year, was also forced to curtail its ongoing cardiothoracic clinical trials.
Its work did not slow down for long, however.
As the government mobilized to address the growing pandemic, the NHLBI, which supports many of the network trials, asked it to play a brand-new role in fighting COVID. That’s because CTSN already had an existing infrastructure of dozens of sites already in place that could mobilize immediately.
“We had to move quickly; people were dying,” said Marissa Miller, D.V.M., M.P.H, a former CTSN program director who now serves as a senior advisor in the Advanced Technologies and Surgery branch in the NHLBI Division of Cardiovascular Sciences. “CTSN jumped in and rose to the challenge,” Miller added.
CTSN eventually partnered with the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership launched last year to speed development of the most promising treatments and vaccine candidates. It represents the first time that the Network has been involved in the study of infectious disease.
According to Miller, who has been with CTSN since its inception, the shift to COVID-related studies elevated it “beyond a recognized trial platform within NHLBI to a national resource supporting the collective mission of the ACTIV enterprise.”
To date, CTSN has been involved in four COVID-directed clinical trials, with a special focus on improving the treatment of hospitalized patients. Three of the trials are NIH-funded and focus on the development and testing of monoclonal antibodies, synthetic versions of disease-fighting proteins produced naturally by the immune system, through the ACTIV program.
The fourth COVID trial, conducted by a subgroup of CTSN investigators but separately funded by industry, is an example of CTSN’s independent work that builds on its collaborative experience. This trial involved the use of blood stem cells to combat the so-called cytokine storm, a deadly immunological reaction that can occur in the lungs of patients with COVID. Results from a pilot study suggested that the stem cell treatments may hold promise in reducing deaths in some ventilator-dependent patients with COVID, but larger studies are needed.
Most recently, CTSN began enrollment for another NIH-funded COVID-related clinical trial. This one involves the use of two novel drugs in hospitalized patients with COVID who experience Acute Respiratory Distress Syndrome, or ARDS, a life-threatening condition in which the lungs are severely inflamed and unable to provide sufficient oxygen to the blood. The drugs include Zyesami (an antiviral/anti-inflammatory agent) and remdesivir (an antiviral agent), both alone and in combination.
“At one time, the cardiothoracic surgery community had a reputation of completing few randomized clinical trials,” said Wendy Taddei-Peters, Ph.D., a program director in the Advanced Technologies and Surgery branch at the NHLBI. The prevailing practice was to incorporate new surgical procedures and devices without objective evaluation of their benefits compared to established therapies. “That is no longer the case,” said Taddei-Peters, noting that cardiothoracic surgeons have proven that objective clinical trials evaluating the safety and efficacy of surgical interventions can be conducted.
“Since the establishment of the CTSN, its dedicated cardiac surgeons, research coordinators, and experts in trial design and analysis are successfully conducting long-needed randomized trials that have the potential to close existing knowledge gaps, improve racial and gender diversity, extend lives and improve quality of life,” Taddei-Peters said. “It is both a privilege and a pleasure to work with the CTSN investigators.”
Peter K. Smith, M.D., a CTSN principal investigator from Duke University, said he was proud of the program’s work. “We've shown that we can make a major contribution to a national effort that’s much larger than just cardiothoracic surgery,” he said in a press release.
CTSN’s clinical trial sites include 60 in the United States and Canada and 35 in Europe and South America. It has been involved in about 20 trials over the years.
Today, as more people become vaccinated against COVID and restrictions are lifted, the CTSN is beginning once again to resume its original mission of conducting clinical trials in cardiac surgery and using the findings to improve patient outcomes.
But CTSN remains committed to helping the NIH fight COVID.
“There are still not enough treatments for COVID,” NHLBI’s Miller cautioned. “We haven’t stopped looking for answers.”