Time Passages: More Follow-up, More Answers from ACC.15
Cover Story | After the winter that much of the nation suffered, timing could not have been better for the Scientific Sessions in San Diego, CA. At ACC.15, interventional cardiology headline-grabbers included TAVR, radial access, newer stents versus CABG, antithrombotic selection for PCI, as well as a number of creative approaches that simply did not work.
PARTNER 1 at 5 Years
Like one, two, and three year data, the final 5-year follow-up of the PARTNER study continues to demonstrate that the SAPIEN transcatheter heart valve is a feasible option for patients with severe aortic stenosis deemed to be at high risk for open-heart surgery. There were no signs of structural valve deterioration or loss of valve function with transcatheter aortic valve replacement (TAVR).
“The negative part of this trial is the ongoing issue of paravalvular leak with TAVR,” said Michael Mack, MD, Baylor Scott and White Health, Dallas, TX. Moderate or severe leaking was 14 percent with TAVR versus 2.1 percent with surgery. Mortality was 9 percent higher in patients with paravalvular leak, and even mild leaking was associated with increased mortality at 5 years compared to patients who had none or only a trace amount.
Since trial enrollment started, much has been learned about the predictors and causes of paravalvular leak and methods for proper sizing of the valve prosthesis relative to the aortic annulus. Use of three-dimensional (3D) multislice computed tomography scan reconstruction and 3D transesophageal echocardiography, which were not used in PARTNER, has refined valve sizing. Additionally, the availability of a wider range of valve sizes has helped to address this problem.
“At five year follow-up,” Dr. Mack said, “PARTNER 1 supports the fact that TAVR is an alternative to surgery in high-risk patients, both approaches having similar mortality and other major clinical outcomes as well as similar functional outcomes while improvements in valve function were maintained in both groups.” Overall, he added, “Any time you have two treatments and one’s more invasive than the other, the less invasive treatment always wins, so the fact that TAVR and surgery were a tie in PARTNER 1 means TAVR wins.”
Jeffrey Popma, MD, director of interventional cardiology clinical services, Beth Israel Deaconess Medical Center and a professor of medicine, Harvard Medical School, Boston, MA, said, “I think it’s just spectacular that we were able to follow these patients out to 5 years and that a third of them are alive. And they lived 3.5 more years after TAVR (median: 44.5 months). It’s just incredible.”
In their paper, published simultaneously in The Lancet, the authors noted that clinical outcomes and valve performance in this trial might not reflect that of subsequent generations of balloon-expandable transcatheter valves. Indeed, the SAPIEN device used in the trial is no longer being implanted, replaced by a second-generation device (SAPIEN XT; Edwards Lifesciences, Irvine, CA).
At ACC.15, investigators presented pivotal trial results for the newer SAPIEN 3 heart valve. They reported lower death, stroke, and paravalvular leak rates than earlier generation devices among patients at high risk for surgery (TABLE 1). Susheel Kodali, MD, Columbia University Medical Center/New York-Presbyterian Hospital, New York City, NY, said, “We now have intermediate-risk data where we’re getting to a 30-day 1 percent mortality risk and a 1 percent stroke risk; how much better data do we need?”
Dr. Kodali added that, for several years now, the concept has been to consider TAVR when surgery is not a good option, “But based on this data with a 1 percent stroke risk and 1 percent mortality, maybe the conversation shouldn’t be ‘TAVR when surgery’s not a good option’ but rather TAVR is the preferred option—at least in 80-year olds.” (Average age at baseline in this trial was 82.6 years.)
Mack MJ, Leon MB, Smith CR, et al. Lancet. 2014;doi: 10.1016/S0140-6736(15)60308-7.
Bivalirudin vs. Unfractionated Heparin
As just seen, part of the MATRIX Access trial was a randomized multicenter superiority trial comparing transradial versus transfemoral access in patients with ACS. Patients who went on to percutaneous coronary intervention (PCI) were then randomized to either bivalirudin or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor. The bivalirudin group did not show significant improvements in either of two co-primary endpoints—like above, a composite of death, MI, or stroke at 30 days or MACE plus major bleeding.
Marco Valgimigli, MD, said, “We saw an impressive reduction in bleeding with bivalirudin compared to the control, which likely contributed to the reduced mortality in this group.” Commenting on the significant 70 percent reduction in fatal bleeding with bivalirudin, David Kandzari, MD, added, “So the translation of the reduction in bleeding into significant improvement in survival is much clearer here than in previous trials.”
Importantly, Dr. Valgimigli said, “One of the major findings of MATRIX is that the two elements—access site selection and antithrombotic selection—are completely independent; we saw no interaction whatsoever.”
Said Sanjit Jolly, MD, McMaster University, Hamilton, Ontario: “MATRIX showed that not only did bivalirudin reduce bleeding in a very high-risk population but it reduced mortality. So, I think this study is going to be the one that is going to change guidelines and make radial access our default approach.”
Valgimigli M, Gagnor A, Calabró P, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)60292-6.
Transradial vs. Transfemoral
Technically more demanding? Of course. But authors of a new study evaluating radial versus femoral access in patients with acute coronary syndrome (ACS) believe their results should prompt a re-evaluation of clinical guidelines, and that transradial should be the preferred approach for most catheter-based heart procedures.
According to Marco Valgimigli, MD, PhD, Erasmus University Medical Center, the Netherlands: “The radial artery is 2 mm in size, the femoral artery is probably 20 times greater than that; so the difficulties from a technical standpoint that you can face when you do complex procedures are much, much bigger with the transradial approach.”
Having said that, he thinks the results of a new randomized study “should compel a switch to the radial approach” as the preferred method. The study, dubbed MATRIX Access (Minimizing Adverse haemorrhagic events by TRansradial access site and systemic Implementation of angioX), randomly assigned more than 8,400 patients at 78 hospitals in four European countries to undergo angiography via the arm or the groin. All study participants had ACS.
There was a 15 percent relative risk reduction for major adverse cardiac events (MACE 9.8 percent vs. 11.7 percent), which would have been significant at a nominal 5% alpha, but it was not significant at the pre-specificed alpha of 2.5 percent. Significance was achieved for the co-primary endpoint (MACE plus bleeding). So differences between groups were driven by reductions in 30-day Bleeding Academic Research Consortium (BARC) major bleeding (any BARC 3 or 5 bleeding: rate ratio [RR] 0.67; p = 0.013; access site bleeding: RR 0.37; p = 0.0004) and all-cause mortality (RR 0.72; p = 0.045) (FIGURE 1). There was no difference with respect to rates of myocardial infarction (MI) or stroke, which should still be reassuring given early concerns that radial access might increase cerebrovascular embolization.
As part of their paper (simultaneously published in The Lancet), Valgimigli and colleagues updated their meta-analysis of all ACS trials that randomly assigned patients to radial or femoral access after the landmark RadIal Vs femorAL access for coronary intervention (RIVAL) study. They demonstrated a “statistically robust” (RR = 0.72; p = 0.0011) and “clinically relevant” reduction in all-cause mortality by radial compared with femoral access.
“Interventional cardiologists who are experienced with the radial approach have nothing to lose and everything to gain by using the arm as the access point for these procedure,” said Dr. Valgimigli.
Commenting on the study, David Kandzari, MD, director of interventional cardiology and chief scientific officer at Piedmont Heart Institute, Atlanta, GA, said, “We know that the performance of radial intervention is variable across different geographies and one end of the spectrum is the United States where it still represents less than 20 percent of all PCI procedures. I think this trial further motivates radial access to be the default strategy for PCI.”
Modest Benefit of DAPT, But Not Practice-Changing
The dual duel continues: Investigators randomized 21,162 patients with an MI one to three years earlier to ticagrelor plus low-dose aspirin and then followed them for a median of 33 months. Marc Sabatine, MD, MPH, Brigham and Women’s Hospital, Boston, MA, reported: “Adding ticagrelor to low-dose aspirin in stable patients with a history of myocardial infarction reduced the incidence of cardiovascular death, myocardial infarction, and stroke, and the benefit of ticagrelor was consistent over the duration of treatment.”
The question: Is dual platelet therapy (DAPT) with high-potency agents approaching the point of diminishing returns? Yes, compared with placebo, ticagrelor was associated with an absolute benefit of 1.19 percentage points (90 mg dose) and 1.27 percentage points (60 mg dose) in the primary endpoint, as well as with absolute increases of 1.54 and 1.24 percentage points, respectively, for clinically significant bleeding and 1.71 and 1.37 percentage points for transfusion.
Valentin Fuster, MD, PhD, editor-in-chief of the JACC, said, “This study adds to the evolving trend in coronary artery disease of using long-term dual antiplatelet agents, but I think we should be cautious and not try to imply that this trial is some sort of breakthrough that will have a significant impact on practice.”
AF + HF = Big Problem
Patients with atrial fibrillation (AF) and heart failure (HF) are at especially high risk of serious complications and death. In a little more than 200 patients with both conditions, those who underwent catheter ablation were less likely to die, be hospitalized, or have recurrent AF than patients taking amiodarone. Specifically, 71 percent of patients treated with ablation were free of AF (the study’s primary endpoint) after two years versus only 34 percent of patients on antiarrhythmic drug therapy.
Luigi Di Biase, MD, PhD, Albert Einstein College of Medicine at Montefiore Hospital, New York City, NY, said, “It’s very important to control persistent atrial fibrillation in patients with heart failure because these patients need every bit of blood that the heart can pump and it becomes particularly dangerous when an arrhythmia happens. [However,] if you limit your ablation to pulmonary vein isolation in patients with heart failure, the outcome will not be as good than if you do more.”
One caveat: Marc Gillinov, MD, Cleveland Clinic, Cleveland, OH, noted, “Having the ablation gave far superior control of the heart rhythm. On the other hand, if you do the ablation, there is a higher need for a permanent pacemaker in the first year after surgery.”
Remote Ischemic Preconditioning: Safe, Simple – Ineffective
It’s a simple conditioning procedure involving the inflation and deflation of a blood pressure cuff on the upper arm before coronary artery bypass graft surgery (CABG). However, in the first large randomized controlled trial to investigate the effectiveness of remote ischemic preconditioning, it had no effect on long-term clinical outcomes.
Derek Hausenloy, MD, PhD, University College London, United Kingdom, noted, “Remote ischemic preconditioning is a simple, noninvasive, low-cost intervention that has no obvious downsides. Unfortunately, we showed no benefit on long-term clinical outcomes in our patients undergoing CABG. I think the concept of ischemic preconditioning is still valid, but we haven’t found the right intervention yet.”
Commenting on the study, John Jarcho, MD, deputy editor, New England Journal of Medicine, said, “The premise for this study was based on an old observation that patients who have recurring bouts of angina and then go on to have an MI tend to have smaller MIs than patients who never had any angina, just an MI. So if you induce ischemia, the hypothesis was that the tissue produces some factor that confers protection later when the MI happens.”
CABG? PCI? Medical Therapy Alone?
Three papers shed light on the comparative value of bypass, stenting, and medical therapy. A pair of studies shed light on the shared decision-making process when determining the best therapy. The third looks at managing elderly patients.
The Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease (BEST) trial is one of only two randomized controlled trials to compare CABG to PCI since the introduction of everolimus-eluting stents. Like the SYNTAX trial before it, BEST found CABG was better.
The study included 880 patients treated at 27 hospitals in four countries. All patients had multivessel disease and were determined to be equally appropriate candidates for either PCI or bypass. Patients were followed for an average of more than 4.5 years. Seung-Jung Park, MD, of the Asan Medical Center, Seoul, South Korea, and the study’s lead author, said, “During this relatively long-term follow-up, angioplasty was associated with a significant increase in the incidence of death, myocardial infarction, and target vessel revascularization.”
John Jarcho, MD noted in a press conference, “Despite steady progress in the development of better catheter-based techniques, it seems we probably still have further to go to meet up to the standard of CABG.”
Bangalore and colleagues used observational data from the New York State cardiac registries to compare a contemporary cohort of patients with multivessel CAD who underwent CABG with those who underwent PCI with second-generation everolimus-eluting stenting. CABG was associated with lower short-term risks of death and stroke and a similar long-term risk of death. PCI was associated with a higher risk of MI—at least among patients who had incomplete revascularization—and a higher risk of repeat revascularization. Overall, CABG was associated with a higher risk of stroke. In their paper, simultaneously published in The New England Journal of Medicine, they emphasized the decision-making process by patients and their providers regarding revascularization.
In an NEJM accompanying editorial to the Park and Bangalore papers, Robert A. Harrington, MD, FACC, chair of the Department of Medicine at Stanford University School of Medicine, wrote that there are clearly trade-offs between the two revascularization strategies that need to be discussed with patients. The early hazard of CABG (the risk of stroke) may be unacceptable to some patients, whereas others might want to avoid the later hazards of PCI (the risk of needing a repeat PCI procedure or having a MI). Dr. Harrington added, “The decision should also take into account the results of coronary angiography, with particular focus on whether complete revascularization with PCI appears to be feasible — a factor that would make PCI more attractive than CABG.”
Finally, the After 80 Study evaluated elderly patients with non-ST-elevation myocardial infarction (NSTEMI) or unstable angina who were treated with PCI versus medical therapy alone. “Our study directly targeted a population over 80 (and) is the first to demonstrate that a more invasive strategy results in better outcomes in NSTEMI patients than medical therapy alone,” according to Nicolai Tegn, MD, Rikshospitalet Oslo University Hospital, Oslo, Norway.
PCI was associated with a 47 percent reduction in the study’s primary endpoint, a combined measure of subsequent MI, urgent revascularization procedures, stroke, and death compared to similar patients who were treated using a more conservative approach (TABLE 2). Importantly, there were no differences seen in complication rates (i.e., bleeding) between the two strategies.
Park S-J, Ahn J-M, Kim Y-H, et al. N Engl J Med. 2015;372:1204-12.
CoreValve Effects Also Sustained, Durable
Michael Reardon, MD, professor and Allison Family Chair of Cardiovascular Research at Houston Methodist Hospital, TX, presented the results of the CoreValve U.S. Pivotal High Risk Trial, declaring, “We have now followed these patients out to 2 years and we found that the survival advantage we saw for TAVR over surgery at one year was durable and sustainable, so it’s a very interesting start.”
Concerns regarding increased stroke risk with TAVR have eased with longer follow-up. In counting all stroke, the number was originally higher with TAVR but, Dr. Reardon said, “At two years, ‘all stroke’ was more common with surgery than with TAVR, so the issue of stroke—which was one of our early worries—really seems to have been put to bed (FIGURE 3).”
However, despite the drop in stroke reported with subsequent generations of the SAPIEN valve and the clearer picture emerging with longer-term follow-up of patients receiving a CoreValve, there is still an issue: “We are seeing that stroke rates are going down with these new devices, which is fantastic, but what’s not going down are silent ischemic brain lesions,” according to Alexandra Lansky, MD, Yale School of Medicine, New Haven, CT.
There have been eight studies using diffusion-weighted magnetic resonance imaging (DW-MRI) showing new lesions in the brains of between 58 percent and 93 percent of patients after TAVR. Dr. Lansky presented data on a first-in-field brain shield to be used during TAVR to protect the brain from embolic lesions. It was a small study (n = 83) with only preliminary results, but the prevalence of DW-MRI lesions was numerically lower in patients treated with the TriGuard device. “What I think is most striking in this study,” said Dr. Lansky, “and this is a new finding: we’re showing an increased proportion of patients who have complete freedom from these embolic lesions. So we are able to protect these brains completely in up to almost a third of patients.”
A Trio of Updates
As this issue of CSWN: Interventions was going to press, cangrelor (The Medicines Company) was endorsed by a US Food and Drug Administration (FDA) advisory committee for use in PCI. Specifically, the committee recommended approval for patients in whom an oral P2Y12 inhibitor was not used pre-procedure and was not feasible or desirable during PCI. The April 15, 2015, decision came after the drug was rejected by the same panel in February 2014 and subsequently failed to gain the agency’s approval.
In late March, the FDA approved a new administration option for ACS patients who are unable to swallow ticagrelor 90 mg tablets whole. Unlike other P2Y12 inhibitors, ticagrelor gets the green light from the FDA to be crushed and administered in water by swallowing or via nasogastric tube. In the general population, survey data show that about 40 percent of adults experience problems swallowing pills, which could be compounded with age and the setting of ACS. This new administration option for ticagrelor gives healthcare professionals a little more flexibility in treating ACS patients.
In April, the FDA approved Amgen’s ivabradine as the first new medicine for chronic heart failure approved in nearly a decade. Ivabradine is indicated to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35 percent, in sinus rhythm with resting heart rate ≥70 beats per minute (bpm), and either on maximally-tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
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