By BARRY MEIER
Published: December 9, 2013 The New York Times
A new report showing an increase in blood clots associated with a popular heart device is dividing experts over whether a clinical trial of the implant is potentially too risky for patients.
The debate, which involves a heart pump called the HeartMate II, sheds light on how researchers calculate whether to expose patients to a trial’s risks.
Medical researchers say such decisions are based on objective evidence. But a look at their decisions about HeartMate II trial shows how subjective those choices can be.
The trial, which has already faced delays, is set to start soon, if it receives a final go-ahead. But at least two hospitals that originally agreed to recruit patients for the trial have now withdrawn because of the new findings, while others have decided to stay in.
Some experts contend other factors might also be in play in those decisions, including an investment of years by some researchers to set up the study. In addition, more than $13 million has been earmarked for the trial by the HeartMate II’s maker, Thoratec, and the federal National Heart Lung and Blood Institute.
“You could argue it both ways,” said Dr. Carmelo A. Milano, a cardiologist at Duke University, which has decided not to participate, as has the Cleveland Clinic. “It certainly would be better if we didn’t have this problem.
The HeartMate II is a small pump that continuously pushes blood through the heart. Patients who get the device now are those facing imminent death from heart failure. Even the researchers who put together the new report said they would continue to use the pump in those cases.
The trial, called Revive-It, is intended to determine whether a HeartMate II can also benefit patients who have not quite reached that stage of heart failure. Such patients, who take drugs for their condition, typically struggle to perform physical activities, like walking short distances.
Because heart failure is a progressive condition, the new blood clot study has complicated the question of how to weigh the device’s risks and benefits to less sick patients.
“I would not embark on a clinical study until this problem is understood and mitigated,” said Dr. Robert G. Hauser of the Minneapolis Heart Institute Foundation, who is not involved in the trial.
In the new study, three big hospitals, the Cleveland Clinic, Duke and Washington University in St. Louis, jointly reported that the rate of HeartMate II-related blood clots had increased by nearly fourfold in devices implanted after early 2011.
Some patients died and others underwent emergency operations to get new pumps or transplanted hearts, according to a report in The New England Journal of Medicine.
Experts have yet to find a reason for the increase. But they say it most likely involves factors like changes in the device and changes in how doctors use anti-clotting drugs with such patients.
Long before the new report, however, word of a growing problem with the HeartMate II had been circulating among device experts. And researchers involved with Revive-It had already begun scrambling to understand its potential impact on the trial.
The issue began to take shape in March, when the Cleveland Clinic reported to the Food and Drug Administration and Thoratec that it was seeing a rise in pump-related clots. Physicians at other hospitals were also seeing an increase and were discussing the problem with colleagues at medical meetings or privately.
“There is an incestuous nature to our field,” said Dr. Scott Silvestry, a cardiologist at Washington University
In May, the principal investigators leading the trial — Dr. Keith Aaronson and Dr. Frank D. Pagani of the University of Michigan and Dr. Robert Kormos of the University of Pittsburgh — decided to delay the start of patient recruitment to examine the problem.
At that time, doctors at the Cleveland Clinic were keeping their findings confidential because they hoped to publish them in a medical journal.
But another source of data was available. In recent years, a federally funded registry at the University of Alabama at Birmingham has been tracking the safety of heart pumps like the HeartMate II. Known as Intermacs, the registry was showing that pump-related blood clots associated with the HeartMate II had risen to about 5 percent since early 2011, compared with about 2 percent in previous years.
But the registry also showed a variation in clot rates at differing hospitals, raising the possibility that facilities such as the Cleveland Clinic were outliers.
The trial’s lead investigators, Dr. Aronson, Dr. Pagani and Dr. Kormos, declined to be interviewed. But in a statement, they said the added risk detected by Intermacs was “small” and did not alter the trial’s balance of benefits and risks.
Based on the Intermacs data, officials at the F.D.A. and the National Heart Lung and Blood Institute and a panel of experts appointed by the institute to monitor the study’s safety came to the same conclusion.
“F.D.A. reviewed the Intermacs data and supported the Revive-It team’s decision to move forward,” the three researchers said a statement.
As a result, about 18 major hospitals nationwide again prepared to enroll patients. But now, the recent New England Journal of Medicine study published late last month has raised questions about which blood clot data is more reliable.
In their study, the Cleveland Clinic, Duke and Washington University reported a pump-related clot rate of 8.4 percent, compared with 2.2 percent in earlier years. The increase was significantly higher than the 5 percent rate reported by Intermacs.
Dr. Randall Starling of the Cleveland Clinic said he thought that Intermacs’ data was understating the problem’s scope.
“We believe our data is more accurate,” Dr. Starling said.
However, the import of new report was quickly disputed by the three investigators heading Revive-It. In a statement, they described the hospitals as outliers and said the Intermacs data was more reliable.
Dr. Milano, the cardiologist at Duke, said he thought that the reaction of researchers, who have spent years setting up the Revive-It study, was understandable.
“They are more apt to look at the data that suggests there is less of a problem,” Dr. Milano said. Still, at this point, he cannot see asking less-sick patients to get a device. “Knowing what I know, I probably won’t sign up,” he said. The three researchers leading the trial said it was imperative, given the shortage of donor hearts to know whether the device worked in earlier stage patients.
Whatever the case, the National Heart Lung and Blood Institute said in a statement that the study’s safety panel would soon review the new journal report and its implication, if any, for the trial.
In the meantime, specialists are going their separate ways. For example, while Dr. Hauser, the device expert in Minneapolis, says he thinks that the trial should be delayed, cardiologists at the hospital where he works are going forward. And unlike Duke and the Cleveland Clinic, Dr. Silvestry said Washington University hospital was also staying in the trial because it thought that the device’s potential benefits still outweighed its risks.
“We feel our patients will be served by a possibility of enrollment,” Dr. Silvestry said.