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The Take Home: TCT
This year, Transcatheter Cardiovascular Therapeutics was held in September in Washington, D.C. Cardiology Today’s Intervention spoke with several experts on impactful trials presented during the meeting. These included Editorial Board member Dominick J. Angiolillo, MD, PhD, of University of Florida, Jacksonville; Chandan Devireddy, MD, FACC, FSCAI, of Emory University, Atlanta; Timothy D. Henry, MD, of Cedars Sinai Heart Institute, Los Angeles; James B. Hermiller, MD, with St. Vincent’s Hospital, Indianapolis; and David G. Rizik, MD, with Scottsdale Lincoln Health Network, Scottsdale, Ariz.
BRIGHT
Henry: The BRIGHT trial was a very well-designed study; I am impressed with the fact that it had three different arms that studied bivalirudin alone (Angiomax, The Medicines Company; n=735), heparin alone (n=729) or heparin plus tirofiban (n=730). At 30 days, incidence of net adverse clinical events — the study’s primary endpoint — was lower in the bivalirudin group (8.8%) than in the heparin group (13.2%) or the heparin plus tirofiban group (17%; P<.001).
Timothy D. Henry
In the past, a lot of data have compared bivalirudin with heparin plus a glycoprotein IIb/IIIa inhibitor, and there has been so much controversy on which is better. This trial adds to the evidence that bivalirudin decreases bleeding in patients with STEMI. The BRIGHT trial is consistent with HORIZONS-AMI and EUROMAX, and the three-arm comparison really added to the evidence. In addition to showing that there is less bleeding with bivalirudin, the BRIGHT trial showed that there was no difference in ischemic events. So, we now have American, European and Chinese trials that show this; it’s encouraging when you get consistent results.
Hermiller: I think the bottom line with BRIGHT is twofold: First, there was no downside in terms of ischemic events in the bivalirudin group; in particular, there was no increased risk for stent thrombosis with bivalirudin, which had been seen in previous studies. This was probably due to the bivalirudin group getting a longer infusion after the treatment was done. The second important finding, which drove the primary endpoint, was that there was less bleeding with bivalirudin vs. heparin monotherapy or heparin plus tirofiban — this includes both minor and major bleeding. This is clinically relevant, and it gives me confidence that we can use bivalirudin and have less bleeding, without the trade-off of an increased risk for stent thrombosis or recurrent ischemic events.
Symplicity Flex
Devireddy: The Symplicity Flex trial was a very small (n=71), investigator-initiated study that, despite its size, included a blinded design with a sham procedure, which is to the credit of the investigators. They studied a population of patients with mild manifestations of resistant hypertension (baseline mean ambulatory BP, 135 mm Hg to 149 mm Hg systolic and/or 90 mm Hg to 94 mm Hg diastolic), which is probably more clinically relevant to physicians who treat hypertension in their day-to-day clinic. Of note, this target population was very different than the one studied in SYMPLICITY HTN-3.
Photo courtesy of the Cardiovascular Research Foundation
Although technically on paper the headline for the Symplicity Flex study reads as denervation missing the primary endpoint — mean change in 24 hour systolic BP from baseline to 6 months (renal denervation, −7 mm Hg vs. sham, −3.5 mm Hg; P=.15) — when you dissect the details it becomes much more interesting because there were a few patients in this treatment arm who did not receive adequate denervation, or any denervation at all. The debate that ensued at TCT was that the per-protocol analysis leads to statistically significant outcomes as compared with the intention-to-treat (ITT) analysis, because the ITT analysis mandated inclusion of all patients, regardless of whether proper denervation was performed. In the per-protocol analysis, the investigators found that there was a significant BP reduction in patients who received renal denervation (–8.3 mm Hg vs. –3.5 mm Hg; P=.042). This is impressive for a population with mild resistant hypertension and for using 24-hour ambulatory BP monitoring. Because of this, I think the debate over whether there is still benefit to renal denervation in the right patients and done the right way is still alive. For me, this trial provided optimism that there may be some answers for these types of patients. We have to potentially design our trials differently and refine the technology so that we can tease out who benefits or how we can do this procedure in a way that benefits patients. On the other hand, I sympathize with physicians who say that a per-protocol analysis does not maintain the spirit of proper trial design, as this is not how the study was designed and one has to report the primary prespecified outcomes. But my question from this study is that given this signal, can we ignore the possibility that there may be something more to offer patients with resistant hypertension? My hope is that industry and the FDA will say, “OK, let’s give this a second chance.”
ABSORB II
Rizik: The ABSORB II trial is the birthplace of high-level science for bioresorbable stents and goes a long way toward reassuring us that our enthusiasm, from a safety perspective, is warranted. There have recently been retrospective analyses — with lower levels of evidence — that have suggested concerns over safety. ABSORB II is another step toward putting these safety concerns to rest. There was no significant increase in stent thrombosis, according to the protocol, or periprocedural MI. In particular, I found the reduction in angina at 1 year with the bioresorbable stent to be most compelling (21.8% vs. 30.5%; P=.04). Earlier, we saw the ABSORB EXTEND trial, in which the Absorb scaffold was compared in 250 patients with a similar cohort treated with the best-in-class DES. What was noted was a very similar reduction in angina compared to the best-in-class DES. This is very important, because this is the gold standard; there is not a safer, more efficacious stent [than Xience]. While a reduction in chest pain is important on its own, I think these findings will have even more far-reaching implications. This could mean better performance on noninvasive testing, and a possible reduction in anginal medications, which is certainly going to mean cost savings for insurers. It may also mean a reduction in hospitalizations and repeat procedures.
ISAR TRIPLE
Dominick J. Angiolillo
Angiolillo: ISAR TRIPLE was a very important study, because it was the largest to assess antithrombotic treatment regimens in patients undergoing PCI who also require oral anticoagulation, which mostly consists of atrial fibrillation patients. It was designed to show superiority of 6 weeks vs. 6 months of clopidogrel therapy on a background of aspirin and oral anticoagulation, and its primary endpoint was not met. The study found that there were no differences in ischemic events and bleeding complications. Although the primary endpoint was not met, this is going to be a very important study because it shows that stopping clopidogrel early is not going to make a difference in terms of clinical outcomes. This adds to another important trial, WOEST, which looked at a different strategy — dropping aspirin in patients on oral anticoagulation who are undergoing PCI. So it’s a different approach between these two studies, but, nevertheless, they both represent what we have thus far come to understand from randomized trials. Although they are relatively small studies, they provide some information on how to manage this high-risk group of patients.
PARTNER I
Chandan Devireddy
Devireddy:tudy investigators of the PARTNER I trial found that at 5 years, all-cause mortality in inoperable aortic stenosis patients was 93.6% in the standard therapy cohort and 71.8% in the transcatheter aortic valve replacement group (P<.0001), and the standard therapy group had a median survival of less than 1 year vs. more than 2 years in the TAVR group (11.1 months vs. 29.7 months; P<.001). As a TAVR operator, it’s encouraging to see that we now have long-term data that support the use of this therapy. I think there are still physicians and patients in the community who may have lingering doubts about the transcatheter approach. With that in mind, mortality is as solid an outcome as you can get for a clinical study, and to have a continued, clear separation and a pretty low number of patients needed to treat to achieve a mortality benefit with TAVR is wonderful. On the other hand, the sobering reality of the study is that at least in these truly inoperable patients who were recruited, they are going to have other comorbidities, be elderly and their survival is going to be far less than what we’re used to seeing in randomized controlled trials in the coronary world. So it’s a matter of defining expectations.