In the wake of a call for retractions of dozens of papers from a high-profile Harvard University heart stem cell research lab, federal officials today announced they are pausing a clinical trial based on research in this field. The National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland, explained in a statement today that the pending retractions “have raised concerns about the scientific foundations of this trial.”
The treatment has seemed safe in the 90 patients studied so far, said David Goff, director of NHLBI’s Division of Cardiovascular Sciences. Many labs contributed to the basic research supporting the study, called CONCERT-HF, he said, not just the Harvard group. However, NHLBI is pausing the trial to review it because “it’s the prudent thing to do,” he said.
Lab studies by cardiologist Piero Anversa of Harvard Medical School and Brigham and Women’s Hospital in Boston have suggested a certain type of stem cell in the heart called a c-kit+ cell could regenerate heart muscle in mice. If true, the cells could form the basis of a treatment for patients with heart failure. But several labs have reported they could not replicate some of Anversa’s studies. In 2014, Harvard and Brigham and Women’s revealed they had begun a scientific misconduct investigation of Anversa’s work. (Anversa, who lost a lawsuit claiming the investigation was mishandled, no longer works at Harvard.)
The CONCERT-HF trial for patients with chronic heart failure began to enroll 144 patients 3 years ago and was to end about a year from now. The patients are receiving one of four possible treatments: c-kit+ cells derived from a patients’ own heart tissue, a combination of c-kit+ cells and mesenchymal stem cells from the patient’s bone marrow, mesenchymal stem cells alone, or a placebo. The trial has recruited 125 of a planned 144 participants, Goff said. Of them, 117 have had blood stem cells and heart tissue collected and 90 have received treatment. No safety issues related to the treatment have arisen, although one patient died after a heart biopsy, The Washington Post reported.
Goff said when the CONCERT-HF trial was approved, reviewers were aware of concerns about Anversa’s work. But eight other labs had published 11 studies supporting the c-kit+ cell treatment. “The scientific basis really relies on this independent body of work,” he said. But further concerns arose this month, when Harvard and Brigham and Women’s recommended that 31 papers from the Anversa lab be retracted because they included falsified or fabricated data. (At least one journal has already begun to retract papers.) That prompted NHLBI to convene the Data and Safety Monitoring Board that oversees the CONCERT-HF trial. It recommended last Thursday that the trial pause for a review.
NHLBI has now paused the trial and asked for Harvard’s list of 31 papers to ensure that the trial is scientifically sound “out of an abundance of caution,” Goff said.
He could not say how long review will take, but assured it will be done “in an expeditious manner,” particularly because patients have donated tissue and are awaiting treatment. About half of patients with chronic heart failure die within 5 years, he noted.
One longtime critic of Anversa’s work suggested that questions about how c-kit+ cells might repair heart tissue in mice suggest the CONCERT-HF trial never should have started. “The problem is that if you don’t know how something works, then you don’t really have a road map of what to address to make it better,” says Deepak Srivastava, a pediatric cardiologist and president of the Gladstone Institutes in San Francisco, California.
But other researchers think the trial should be completed because other basic work supports the approach. “There’s plenty of reason to believe that there’s still promise,” says cardiologist Christopher Granger of Duke University in Durham, North Carolina, who is experienced in clinical trials.
And cardiologist Roberto Bolli of the University of Louisville in Kentucky, a longtime Anversa collaborator and co–principal investigator of the CONCERT-HF trial, says that although Anversa’s contention that c-kit+ cells engraft in the heart and differentiate into cardiac cells has “been debunked,” other work supports the idea that these cells help by secreting so-called paracrine factors that promote heart tissue growth. “The controversy [over Anversa’s work] does not really change the validity of using c-kit cells,” Bolli says.
Another trial, based in Florida, planned to begin to treat infants born with a certain heart defect with c-kit+ cells this month; the status of the trial was unclear at press time.
Goff said NHLBI continues to support basic research on c-kit+ cells and heart disease—it now funds 14 preclinical grants, he said.
With reporting by Jennifer Couzin-Frankel.
*Update, 30 October, 2:30 p.m.: The number of preclinical grants supported by NHLBI has been updated.