My Takeaways From AHA 2016: Too Late, Too Soon—Time Waits for No Trial
Too little time, or too much—clinical trials in cardiology are beset with the same problems plaguing modern humans.
NEW ORLEANS, LA—Too little time, or too much—it’s starting to feel like clinical trials in cardiology are beset with the same problems plaguing modern humans. We’re impatient, always rushing. We never quite feel we’ve done things quite as well as we’d hoped in the time allowed.
Some version of that scenario could be applied to some of the top trials and analyses at this year’s American Heart Association (AHA) Scientific Sessions 2016. Take, for example, the FUTURE trial testing the utility of functional testing prior to coronary revascularization. As Gilles Rioufol, MD (Hospices Civils de Lyon, France), said when he presented its results at AHA, the study yields more questions than answers, mainly because the data and safety monitoring board halted the trial early after seeing an increased risk of death at 1 year in the fractional flow reserve arm.
“It’s a shame it was stopped prematurely,” Justin Davies, MD (Imperial College, London, England), told TCTMD. “I think looking at the reasons for [it] being stopped early—the increased death rate between the two arms [in FUTURE]—the numbers are small, so you wonder if it’s just a statistical chance. As time plays out, we may well find out the two [event] curves start to come back together.”
Good Things Come to Those Who Wait?
Then we had the ART trial comparing two internal-thoracic-artery, or mammary-artery, grafts instead of a single arterial graft (plus vein grafts) for CABG. At 5 years, echoing the 1-year results, a single arterial graft plus saphenous vein grafts was no better for the endpoint of mortality or the composite of death, MI, or stroke. There were also no differences in major bleeding or repeat revascularization, although patients randomized to bilateral grafting experienced more sternal wound complications and reconstruction.
Nevertheless, ART study author David Taggart, MD (University of Oxford, England), predicted the final 10-year results will show a benefit of the two-artery approach and said, if he himself needed CABG today, he would “insist” on receiving bilateral grafting “with an experienced operator” versus single.
Picking at PRECISION
And what about a problem of too much time? Physicians have waited more than 10 years for the PRECISION trial testing the cardiovascular safety of the COX-2 inhibitor celecoxib against two of the world’s most popular anti-inflammatory drugs, ibuprofen and naproxen.
According to results presented by Steven Nissen, MD (Cleveland Clinic, OH), at AHA 2016, the COX-2 inhibitor is just as safe in terms of cardiovascular events, but the risk of gastrointestinal events is significantly lower with this agent than with naproxen and ibuprofen. The problem? While the trial mandated a minimum follow-up of 18 months, a full 68.8% of patients dropped out of the trial during its decade-long struggle to enroll enough patients who would stay on their assigned drug. More than one in four patients discontinued their follow-up appointments, and others withdrew consent or vanished. Patients in the trial also ended up being at lower risk for cardiovascular disease than investigators had planned on at the outset.
“If we had also required you to have existing heart disease, the trial would still be going on,” Nissen said. “It took 10 years to find enough of these patients, so we had to make some compromises.”
Unfortunately, trial observers say that study flaws—related to drop-outs, patient risk profile, and duration of follow-up—“intersect to question the validity of the conclusions around noninferiority,” as Garret A FitzGerald put it. “There are so many problems with the interpretation of PRECISION that it fails to inform clinical practice.”
Time Will Tell
Happily, there were a number of early results aired at AHA 2016 that gave everyone plenty of time to look forward to good news, or at least more results, sometime down the road.
Interventionalists are excited about a new “outside the box” idea for a transcatheter intracardiac shunt device for patients with preserved or mildly reduced ejection fraction that was studied in the REDUCE-LAP pilot trial. A randomized study is now underway.
Lipid folks are keeping a sharp eye on a first-in-class agent called inclisiran (Medicines Company/Alnylam Pharmaceuticals), a PCSK9 synthesis inhibitor. In the 90-day interim analysis of the phase II dose-ranging study, investigators observed “significant and durable” reductions in LDL cholesterol after a single injection, with the 300-mg dose reducing LDL cholesterol 51% at day 90. Even greater reductions were seen among patients who received a second injection at day 90. Presented during the same session at AHA 2016, 18-month results from GLAGOV showed that PCSK9 inhibitor evolocumab (Repatha, Amgen) appears to lower LDL while also reducing percent atheroma volume on intravascular ultrasound. Data from the large cardiovascular outcomes trial with evolocumab, known as FOURIER, are due out in early 2017.
Finally, there’s the happy prospect of finding out just how durable—or not—transcatheter aortic valve replacement is in comparison to surgical valve replacement in intermediate- and low-risk patients. New data from the German Aortic Valve Registry presented at AHA 2016 showed that intermediate-risk patients with aortic stenosis face significantly higher 1-year mortality if they are treated with TAVR versus surgery. But according to multiple experts gathered in New Orleans, the results reflect the “real-world” realities of the patients currently being selected for each procedure and no amount of analyses can level the playing field in terms of the many factors that could contribute to the survival difference.
As such, it’s the long-term results from randomized clinical trials in intermediate- and low-risk patients that will be needed to answer the durability question, among others. Isn’t that always the case? We just need a little more time.
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