CT Surgeons Rise to Challenge, Lead Way in COVID Clinical Trials

STS News, Spring 2021 — Since its establishment approximately 15 years ago through government funding, the Cardiothoracic Surgical Trials Network (CTSN) has been involved in important research that addresses evidence gaps and answers meaningful questions in cardiothoracic surgery.

With the onset of the pandemic and the related public health emergency in early 2020, its scope of work dramatically changed after CTSN received two calls.

Instead of focusing on research topics such as mitral regurgitation, atrial fibrillation, and coronary artery disease, CTSN pivoted toward critically ill COVID-19 patients. This would be the first time that the Network would become involved in studying areas related to infectious disease.

The first request was from an industry partner that was exploring the possibility of using stem cells for patients with acute respiratory distress syndrome (ARDS) as a result of COVID-19. At the time, the pandemic left large numbers of people suffering with ARDS and requiring ventilation in intensive care units, with dismal outcomes.

The company invited CTSN researchers to help evaluate its allogeneic mesenchymal stem cell product via a randomized, controlled trial. It was thought that this therapy could have immunomodulatory properties capable of counteracting the cytokine storm associated with the inflammatory conditions related to COVID-19.

While there was some initial resistance from CTSN leadership about becoming involved in this trial, Peter K. Smith, MD, from Duke University in Durham, North Carolina, and Michael J. Mack, MD, an STS Past President from Baylor Scott & White Health in Plano, Texas, decided that the trial was in line with CTSN’s mandate to rigorously evaluate novel therapies for public health imperatives; thus, they led the charge. Both Drs. Smith and Mack are principal investigators for their respective institutions, which are Core Clinical Centers in CTSN.

“The two of us said, ‘we’ll do this.’ So we designed and executed a trial for stem cell infusion in COVID-19 patients who were on ventilators,” explained Dr. Smith. “We created teams that were headed by surgeons but also included pulmonologists, critical care experts, hospitalists, and infectious disease specialists.”

Michael J. Mack, MD, is a principal investigator for Baylor Scott & White Research Institute, which is Core Clinical Center in the Cardiothoracic Surgical Trials Network.

The trial—designed in 2 weeks and sponsored by industry and the National Heart, Lung, and Blood Institute (NHLBI)—ran from April to September 2020. Results have not yet been published.

“It has been an immensely gratifying experience to be able to mobilize resources so quickly and address the scourge that has overtaken the world,” said Annetine C. Gelijns, PhD, a leader in the CTSN Data and Clinical Coordinating Center and also co-director of the International Center for Health Outcomes and Innovation Research at Mount Sinai in New York, New York. “We have been humbled by the generosity of all investigators and coordinators of the Network, who have come together in their selfless efforts to care for patients and advance science.”

Operation Warp Speed

Not long after that first call, Operation Warp Speed came along. This program was initiated by the US government to facilitate and accelerate the testing, supply, development, and distribution of safe and effective COVID-19 vaccines, therapeutics, and diagnostics.

Several Operation Warp Speed trials—all backed by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), and NHLBI—were planned to study a number of topics, including the safety and effectiveness of different therapies such as monoclonal antibodies for the treatment of COVID-19 in patients who had been hospitalized. Operation Warp Speed also coordinated with existing efforts such as the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.

“The NIH asked us to step up as good citizens and become involved in the Operation Warp Speed COVID research trials, even though that wasn't part of our core mission,” said Dr. Mack. “Not only did we step up, but we did so in an extremely short period of time. That bespoke the value of having a ready-made infrastructure of sites that was experienced with conducting research.”

According to CTSN Program Director Marissa A. Miller, who also is chief of the Advanced Technologies and Surgery Branch at NHLBI, the shift to these critical COVID-19 trials was transformative and elevated the Network “beyond a recognized trial platform within NHLBI to a national resource supporting the collective mission of the ACTIV enterprise.”

CTSN was involved in three Operation Warp Speed trials and, notably, of the five networks that participated in these studies, CTSN consistently was the highest enroller of patients, providing at least half of the total number of participants in each trial (50%, 59%, and 67%). In recognition of its substantial involvement, CTSN received a congratulatory letter from NIH Director Francis S. Collins, MD, PhD.

“The performance of the network has been spectacular and has been recognized as the gold standard for performance across all the NIH-sponsored networks,” said Dr. Smith. “We've shown that we can make a major contribution to a national effort that's much larger than just cardiothoracic surgery.”

Results from one of the trials—on the monoclonal antibody therapy bamlanivimab—were published in The New England Journal of Medicine in December 2020.

“We've shown that we can make a major contribution to a national effort that's much larger than just cardiothoracic surgery.”

Peter K. Smith, MD

Origin of CTSN

The idea to form CTSN originally was conceived in 2004 after NHLBI challenged a working group of cardiac surgeons to assess the state of cardiac surgery research, identify critical gaps in current knowledge, and determine areas of opportunity.

Based on the group’s primary recommendation to form a cardiovascular surgery clinical network, NHLBI, in collaboration with the National Institute of Neurologic Disorders and Stroke and the Canadian Institutes for Health Research, created CTSN in 2007, with the mission to design, conduct, and analyze multiple, collaborative clinical trials that evaluate surgical interventions and related management approaches for the treatment of cardiovascular disease in adult patients.

During that time, Timothy J. Gardner, MD, from ChristianaCare Center for Heart & Vascular Health in Philadelphia, Pennsylvania, was a medical officer in the NHLBI Division of Cardiovascular Diseases and helped drive the program through NIH. Dr. Gardner was the first surgical chair of the CTSN steering committee, which is now led by A. Marc Gillinov, MD, from the Cleveland Clinic in Ohio.

Importantly, CTSN trials reflect the multidisciplinary partnership of many leading cardiothoracic surgeons, cardiologists, and neurologists; the infrastructure increases the efficiency of clinical research by providing a “clinical laboratory” in which multiple clinical questions can be asked without having to create a new infrastructure for each one.

“The most exciting part of the growth of the Cardiothoracic Surgical Trials Network and the ensuing work was helping a disparate group of investigators and site teams come together as a cohesive whole and answer the most important questions in cardiac surgical practice,” said Miller. “In this process, which was slow and challenging, the Network became a powerful clinical trial platform.”

Since its inception, CTSN has grown to 95 sites (60 in the US and 35 in Europe and South America) and been involved in approximately 20 trials—which is significant, considering the length of each trial from start to finish averages 3 to 7 years. With the enrollment of more than 2,000 patients in randomized trials and more than 14,000 patients in observational studies, CTSN is among the top performers of NHLBI- and NIH-sponsored networks.

“We want to be bigger, better, faster, stronger.”

Michael J. Mack, MD

Pre-Pandemic Work 

While COVID-19 has consumed much of CTSN’s time this past year, the group also has been working on other impactful research.

Some of the more prominent topics in the CTSN portfolio include rate control versus rhythm control for postoperative atrial fibrillation, surgical treatment of ischemic mitral regurgitation, surgical ablation of atrial fibrillation during mitral valve surgery, the management of postoperative atrial fibrillation after coronary artery bypass grafting, and neuroprotection in patients undergoing aortic valve replacement. Many of these trials have resulted not only in peer-reviewed articles in high-profile publications, but also in changes to clinical practice recommendations.

For example, trial results focusing on surgical treatment of ischemic mitral regurgitation altered clinical guidelines in the US, Canada, and Europe and, as a result, transformed clinical practice, explained Dr. Gelijns.     

Future Plans for CTSN

Described by Dr. Mack as an “inclusive, not exclusive” network, CTSN always is looking to expand and welcome additional sites (US and international) that serve underrepresented patient populations and young investigators who have special interests in diversity, inclusion, and health care disparities. It’s important to note that a major secondary purpose of CTSN is to develop qualified clinical investigators from the specialty who are able to design, develop, and execute clinical trials.

“In the early years, there were only a handful of investigators who were cardiothoracic surgeons and able to design and conduct clinical trials,” said Dr. Smith. “This was a major deficit and was specifically addressed with CTSN funding. The Network since has served as a training ground for principal investigators, so now there is an abundance of seasoned senior investigators and a large pipeline of formally trained young surgeon scientists.”

In addition to expanding the network, Dr. Mack would like to see CTSN enroll more patients, more quickly, in larger trials with longer-term follow up, which ultimately will bode well for cardiothoracic surgery.

“We want to be bigger, better, faster, stronger,” he said.

For more information about CTSN or to learn how to become involved, visit ctsurgerynet.org.

Read the STS press release