Registry-based clinical trial puts heart treatment to the test

A study challenging the value of a device used when unclogging blocked arteries is raising the prospect that inexpensive registry trials, which use observational data to assess outcomes, may soon be widely used to challenge expensive add-ons to medical procedures that may not improve patient care.

Experts say the new model holds promise as a quick, low-cost way to conduct large-scale research from registries and patient records, whose results can be disseminated far more quickly than traditional clinical trials. The growing availability of electronic health records is spurring interest in such trials to determine if high-cost medical devices and drugs perform as well in actual medical settings as they did in the original randomized clinical trials that led to their regulatory approval.

In September, a team of Swedish researchers released trial results showing no difference in 30-day all-cause mortality rates for patients with ST-elevation myocardial infarction (STEMI), a severe form of heart attack, who underwent thrombus aspiration prior to percutaneous coronary intervention compared with patients who underwent PCI alone.

The aspiration procedure entails inserting a thin plastic tube into a coronary artery and sucking the thrombus, or clot, into a syringe. That's followed by PCI, where the plaque-clogged artery is pressed open with a balloon catheter and a stent is implanted to hold the expanded vessel walls in place.

The popularity of thrombus aspiration has grown significantly since 2008, when a randomized trial known by the acronym TAPAS—thrombus aspiration during primary percutaneous coronary intervention—suggested mortality rates could be improved by aspirating clots prior to PCI. The American Heart Association and the American College of Cardiology in 2009 recommended aspiration thrombectomy as “reasonable for patients undergoing primary PCI” based on the results of that trial.

But this latest trial, dubbed TASTE—thrombus aspiration during ST-segment elevation myocardial infarction—and published last month in the New England Journal of Medicine, is casting doubts on whether thrombus aspiration should be an automatic add-on for PCIs and whether the uncertain outcomes associated with the procedure justify the additional costs.

“Maybe aspiration is not as important as we thought,” said Dr. Ralph Brindis, clinical professor of medicine at the University of California at San Francisco, and past president of the American College of Cardiology.

The issue has financial implications for hospitals that must foot the bill for the thrombus aspiration catheters, which cost about $500 to $800 apiece. Since treatment for most patients undergoing catheterization is paid for under the DRG system, the cost of related devices, such as aspiration catheters, comes out of hospitals' set payment for PCI.

“The trial was pretty persuasive that (thrombus aspiration) does not provide a benefit,” said Dr. Harlan Krumholz, professor of cardiology at Yale University School of Medicine and director of Yale-New Haven (Conn.) Hospital's Center for Outcomes Research and Evaluation. “I don't think many people were convinced of its value anyway.”

But the procedure has gained widespread acceptance among interventional cardiologists. In some facilities, there is near-universal use prior to PCIs in STEMI patients. A 2009 report from Millennium Research Group estimated that the market for thrombus aspiration catheters—both manual and mechanical—would approach $300 million by this year.

Interventional cardiologists are already pushing back on the registry study's conclusions. They expressed concern that the 30-day window was not long enough to accurately gauge mortality. And they pointed to gains from thrombus aspiration in other endpoints, such as 30-day re-hospitalizations and stent thrombosis, although those reductions were not statistically significant.

“It's an important trial, but the bottom line is it won't affect my practice,” said Dr. Gary Schaer, director of cardiology research at 664-bed Rush University Medical Center, Chicago. Schaer said he and his colleagues nearly always aspirate blood clots prior to performing PCI in STEMI patients. “I was impressed by the data on re-hospitalizations.”

That view was echoed by Dr. Kirk Garatt, director of interventional cardiology and associate chair of quality and research at 539-bed Lenox Hill Hospital, New York.

“I would say it's very, very unlikely to result in any important change in clinical practice,” Garatt said, who added that he had spoken with other cardiologists who all planned to continue to perform thrombus aspiration. Garatt also predicted hospitals will remain willing to foot the bill because of data suggesting there might be a lowered risk of readmission after the procedure.

The growing controversy has raised the stakes for another traditional randomized clinical trial on thrombus aspiration prior to PCI that's currently underway. Dubbed TOTAL, its results are expected in about a year, said lead investigator Dr. Sanjit Jolly, an interventional cardiologist and associate professor of cardiology at McMaster University in Canada.

Even if practice doesn't change immediately because of the TASTE trial, there will no doubt be more efforts to use registry-based trials to judge the value of procedures and drugs that may be contributing to higher costs without improving outcomes.

The research model is a “new paradigm going forward,” said UCSF cardiologist Brindis, who also is senior medical officer for the ACC's National Cardiovascular Data Registry. “It's cheap, you can enroll patients more easily, and you can get a better, broader picture of what is going on.” Traditional clinical trials can cost

$50 million or more, while the TASTE trial costs only $50 per person, or well under $500,000.

Clinical data registries, such as the ACC's NCDR, are used to collect standardized demographic and quality information for use in tracking, benchmarking, identifying best practices and improving performance.

In an accompanying commentary in NEJM, Dr. Michael Lauer, director of cardiovascular sciences at the National Heart, Lung and Institute, Bethesda, Md., and Ralph D'Agostino, a professor at the Harvard Clinical Research Institute, Boston, called registry trials “a disruptive technology.” “Today we can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of millions of dollars,” they wrote. “But today we also have registries and other powerful digital platforms.”

Registry trials, which generate results far faster than traditional randomized trials, may be just the first step in using outcomes data to conduct retrospective outcomes trials. Registries currently require an added layer of data collection, according to Yale's Krumholz. “It works well, but I see it as an intermediary step,” he said. “We're moving toward exporting data directly from (electronic health records) without that additional burden.”

The TASTE trial enrolled patients using the Swedish Coronary Angiography and Angioplasty Registry, comprised of data from hospitals across Scandinavia. The researchers found the mortality rate 30 days following surgery was 3.0% in the PCI-only group and 2.8% in the aspiration group—not a statistically significant difference. The procedure's “general use in international guidelines should be downgraded,” said lead author Dr. Ole Frobert, a cardiologist at Orebro University Hospital in Sweden. He also pointed to recent research that suggested the procedure leads to a slightly higher rate of stroke.

The leading U.S. manufacturer of thrombus aspiration catheters, Minnesota-based Medtronic, which provided unrestricted grant funding for both the TAPAS and TASTE trials, said in a statement that it remained “confident in the procedural and clinical benefits of manual thrombus aspiration,” and looked forward to additional research that would clarify the appropriate role for the treatment.

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