One of the most important unanswered questions in medicine today -- the best treatment for stable ischemic heart disease -- may never get a satisfactory answer because cardiologists are unwilling to enter their patients in a clinical trial.
One major reason why the question is urgent: About a third of the 1 million percutaneous coronary intervention (PCI) procedures performed each year in the U.S. are for patients with stable ischemic heart disease.
The ongoing NIH-funded was designed to test the two main competing approaches to treating stable ischemic heart disease. The conservative approach is to try optimal medical therapy before moving on to catheterization and possible revascularization only if necessary after medical therapy has failed. The more aggressive approach, favored by many interventional cardiologists, also uses optimal medical therapy but starts with a trip to the cath lab followed, if necessary, by revascularization.
This is the latest stage of a long-running battle. Almost a decade ago the tide turned away from the aggressive and towards the conservative approach with the appearance of the COURAGE trial.
But the interventionalists who favored the more aggressive approach never gave up the fight, partly animated by the conviction that COURAGE was not a fair test. In particular, they noted that it was easy for physicians to support medical therapy in the trial since all the patients had already undergone catheterization, thus eliminating high-risk patients from the trial population. Other objections include the use in the trial of now-outdated technologies, including bare-metal stents and the absence of fractional flow reserve or other methods to assess risk.
The NIH sought to settle the issue by funding the ISCHEMIA trial, which might be thoughts of as "Son of COURAGE." The trial is testing an invasive strategy that starts with optimal medical therapy and cardiac catheterization followed by optimal revascularization against a conservative strategy consisting of optimal medical therapy alone without catheterization unless medical therapy fails.
The "trial has been designed to overcome prior trial limitations by including randomization before the patient undergoes catheterization, enrollment of patients with higher ischemic burden, and use of contemporary revascularization and medical therapy," noted trial chair , of NYU Langone Medical Center in New York City, and , of NYU Langone, and , of Stanford University.
Until ISCHEMIA and other trials are performed, they concluded in a , "patients should be informed about the uncertainty of the benefits of PCI and CABG surgery so they can participate in shared decision making prior to deciding what treatment is best for them."
But it's by no means clear that most patients today with stable disease are fully informed of this "uncertainty." It's also becoming clear that it is at least possible that we may never get a satisfactory answer to the ISCHEMIA question.
Getting patients into the trial -- an absolute necessity to answer the trial question -- has been really difficult. The investigators want to enroll 8,000 patients. Since the start of the trial in 2012, they have only randomized 2,368 patients.
Unless the rate of patients entering the trial is raised dramatically, ISCHEMIA will probably have to modify its design, which would also almost certainly lead to criticism that it would not be able to deliver a robust answer to the question it was originally supposed to answer.
The major obstacle to enrollment is that cardiologists are not enrolling their patients. Despite a widespread consensus that the necessary equipoise for a clinical trial exists, many practicing cardiologists continue to believe that "more is more." They feel it is irresponsible or imprudent to let their patients go without visualizing their anatomy.
"There's no doubt it's tough," said Hochman in an interview. Although the American College of Cardiology and the American Heart Association have urged cardiologists to enroll patients in ISCHEMIA, the organizations have little leverage in this context.
One possibility is for CMS to drive enrollment by not paying for the procedure in certain clinical situations, but so far this has not happened. But, acknowledges Hochman, it's difficult to restrict reimbursement for an already-established technology. "Once the cat is out of the bag, it's really hard to get it back in," she said.
The seriousness of the problem may be no more evident than at Columbia's New York-Presbyterian Hospital, where, the New York Times reported in June, into the trial. This is despite the fact that Columbia is home to , a co-principal investigator of ISCHEMIA. But Stone is also a leader of the highly-aggressive interventional cardiology community, both nationwide and at Columbia. Interventional cardiologists are known for their persistent faith in procedures and devices.
Another ISCHEMIA investigator, , of California's Stanford University, also said he was deeply concerned about the future of the trial but conceded that some of the problems may be self inflicted.
In particular, he is disturbed by the failure of the NIH to allow the investigators to perform a really large and simple practical trial. "ISCHEMIA has become a much more complicated trial than it should have been," said Harrington. He referred specifically to the requirement that patients have a CT angiogram to rule out left main disease. "It went from a simple trial to a complicated trial." Harrington blames the NIH for insisting that trials be more complicated than they need to be.
But these problems don't let clinicians off the hook, said Harrington. "For major public health questions for which we don't know the answer there is an ethical and moral obligation to participate in those trials," he said. "I would even like to see policies aimed at tying reimbursement to participation" in clinical trials, he said, echoing Hochman's remarks.
, the president-elect of the ACC, pointed out that many physicians are not given the time and don't have the manpower to educate patients about clinical trials. "It demands a significant amount of time to explain," he said. Chazal also noted that although he feels comfortable offering optimal medical therapy to stable patients, "many of my colleagues are not comfortable without having clear anatomic data."
This raises the interesting question of whether an invasive strategy is adopted to increase the comfort level of physicians or their patients.
"Honestly, it takes me more time to explain to patients why I'm not doing" a catheterization, Chazal observed. "I can actually take less time to explain the risks of catheterization than to explain why I don't want" to perform the procedure.