Year in Review: Physicians Highlight the Most Important Interventional News of 2014

The past year featured presentations of much-anticipated results from several trials, headlined by SYMPLICITY HTN-3 and the DAPT Study. In this article, several prominent interventionalists queried by TCTMD share their views on these studies and other high-impact research of 2014.

SYMPLICITY HTN-3

The first sham-controlled trial of renal denervation proved disappointing to those who believe the procedure is an effective treatment for resistant hypertension, with 6-month data showing no reduction in blood pressure with denervation over the sham procedure.

SYMPLICITY HTN-3 randomized 535 patients with severe resistant hypertension to renal denervation with the Symplicity catheter (Medtronic) or a sham procedure at 88 US centers. By the time its findings were presented at the American College of Cardiology/i2 Scientific Session in March and simultaneously published in the New England Journal of Medicine, the main results were already known, having been announced in January by the manufacturer.

Commentary 

Robert S. Schwartz, MD
Minneapolis Heart Institute Foundation
Minneapolis, MN

This year saw harsh reality set in for renal denervation as a treatment of resistant hypertension. Irrational exuberance took a mighty fall into abject rejection by some. This interesting procedure fell out of favor as a result of SYMPLICITY HTN-3. Many have abandoned the procedure clinically, while others have ceased development completely and stopped clinical trials. Many start-up technologies are withering on the vine as funding has vanished. Both… perspectives are probably wrong.

Recent speculation, while cautioning against post hoc analyses, suggests the trial is a hypothesis-generating opportunity. Reasons the trial failed may relate to it being a first-generation technology, the inclusion of inexperienced operators, suboptimal and nonstandardized technique, nontreatment of accessory renal arteries, and medication changes within the trial. Now is the time for hard scientific scrutiny to better understand the mechanisms, physiology, and optimal ways to exploit the opportunity. Groups that are willing to stay involved for the long term and perform more detailed scientific discovery will likely prove this technique successful, in my opinion.

David E. Kandzari, MD
Piedmont Heart Institute
Atlanta, GA

SYMPLICITY HTN-3 was the largest randomized trial [looking at medical therapy with or without renal denervation] in individuals with treatment-resistant hypertension. Compared with previous studies describing substantial reductions in blood pressure with renal denervation, the HTN-3 trial surprised most in the medical community. As the first pivotal trial of this technology in many ways, the study also explored new territory regarding enrollment criteria, trial conduct, and a sham-controlled procedure.

Following HTN-3, the issue has not been whether enough evidence exists for this procedure to become routine therapy, but instead if there is enough evidence to support further study. Despite the failure of HTN-3 to demonstrate the efficacy of renal denervation, the therapy proved to be safe, and—equally important—insights from the study have since identified new areas for investigation that may still clarify its potential. Additional preclinical research has further advanced our understanding relative to neural anatomy and therapeutic targets.

Given the expectations from early trials in a patient population with limited therapeutic options, the enthusiasm for renal denervation in clinical practice exceeded the science. SYMPLICITY HTN-3 has been an unexpected opportunity to revisit the science. It reminds us that forthcoming evaluation of renal denervation for treatment of hypertension will require careful trial design that permits demonstration of biologic efficacy, differentiates potential confounders of observer and patient bias, and focuses on less variable and more independent endpoints.

Hitinder S. Gurm, MD
University of Michigan Cardiovascular Center
Ann Arbor, MI

Renal denervation once appeared to be the most exciting new technology in cardiovascular medicine. It made physiological sense, the early data were impressive, and we finally were going to have something to cure resistant hypertension. The results of this study reaffirmed 2 facts. First, when hypertension is managed with the appropriate pharmacotherapy and patients are compliant, it can be controlled. Second, it is important to evaluate new therapies using rigorous randomized controlled trials. I still think the therapy could be immensely beneficial in patients who are noncompliant or intolerant of antihypertensive medications, but the challenge will be to design a study that can enroll and follow these challenging patients.

DAPT Study

The optimal duration of dual antiplatelet therapy (DAPT) after DES implantation remains an area of debate, even after release of the DAPT Study results, which were presented at the American Heart Association Scientific Sessions in November and simultaneously published in the New England Journal of Medicine.

The trial, which enrolled nearly 26,000 patients at 452 sites in 11 countries, showed that continuing DAPT beyond 1 year was tied to lower risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events accompanied by a higher risk of bleeding from 12 to 30 months postimplantation. The risk of death appeared to be higher with prolonged therapy. 

Commentary



Gregg W. Stone, MD
Columbia University Medical Center
New York, NY

The large-scale DAPT trial results were fascinating. Was this a positive, neutral, or negative trial? You can make the case for all 3 positions!

On the positive side, I was impressed that there was clear efficacy in reducing very late stent thrombosis with prolonged DAPT, even with best-in-class [everolimus-eluting stents (EES)]. There was also a substantial reduction in MI, approximately half of which arose from outside of the stent, presumably due to less thrombosis from plaque ruptures. On the flip side, however, was a substantial increase in major bleeding. And most concerning (and confusing!) was the increased mortality rate in the prolonged DAPT arm, which may have in part been due to chance. However, there were more deaths related to bleeding, trauma, and cancer in the prolonged DAPT arm, which is mechanistically plausible. And the efficacy results were clearly blunted with fluoropolymer-coated EES compared to other first-generation DES, lathering the risk/benefit ratio. Finally, there was an increase in the frequency of events within the first several months of stopping DAPT, even after 30 months, suggesting loss of protection.

So what should the clinician do? Clearly this calls for an individualized approach to DAPT duration. For the patients with a high risk of future thrombosis, either within the stent (eg, multiple stents placed in complex lesions or after ACS) or elsewhere (eg, diffuse atherosclerosis, recent ACS, or ongoing inflammation), serious consideration should be given to long-term DAPT. For the patient at high risk of bleeding complications (eg, frailty, [older age], anemia, or prior stroke or TIA), however, 6 months of DAPT might be appropriate. Based on the relative risks of ischemia or bleeding, I can envision prescribing anywhere between 3 months and life-long DAPT after metallic stents, on the basis of this and other trials.

David E. Kandzari, MD
Piedmont Heart Institute
Atlanta, GA

Following an FDA panel meeting in 2006 to address the safety of DES, a consensus opinion emerged that longer duration of DAPT could mitigate the risk of stent thrombosis. Although observational studies associated early DAPT discontinuation with stent thrombosis and evidence supporting a long-term duration for this indication was absent, guidelines endorsed at least 6 to 12 months of DAPT following DES revascularization.

The DAPT Study intended to address this clinical issue, and to date it is the largest randomized trial adequately designed to study the safety and efficacy of extended (> 12 months) DAPT duration. Against the background of numerous recent trials supporting shorter DAPT durations (£ 6 months) with newer-generation DES, the DAPT Study instead supports the benefit of 30 vs 12 months therapy, with a moderate but nonfatal bleeding risk. In addition, the trial showed the safety of DES relative to BMS, also highlighting the benefit of long-term DAPT with BMS.

Along with other recent data, the trial raises important questions; for example, whether there remains a role for BMS. [Moreover, a]cknowledging that patients in the trial were event-free for at least 12 months on DAPT, the study importantly did not address the issue of DAPT duration for patients commonly encountered in clinical practice in whom at least 12 months adherence is challenging.

The DAPT Study will definitely change practice and guidelines, especially for clinically stable patients on DAPT and distant from their procedure. How the results influence practice for the many patients in whom even 12 months of DAPT is uncertain will remain a dilemma.

PARTNER and CoreValve

Presented at the American College of Cardiology/i2 Scientific Session in March and simultaneously published in the New England Journal of Medicine, results from the high-risk cohort of the CoreValve US Pivotal Trial showed that TAVR with CoreValve (Medtronic) reduced mortality at 1 year relative to surgery in patients symptomatic severe aortic stenosis.

Also, at TCT 2014 researchers presented 5-year results from the PARTNER Cohort B Trial comparing TAVR with the Sapien valve (Edwards Lifesciences) and standard medical therapy in 358 inoperable patients with symptomatic severe aortic stenosis.

Over 5 years, TAVR reduced mortality by 21.8%, yielding a median survival time that was nearly 2.5 years longer than with standard therapy. TAVR also reduced the percentages of patients who were rehospitalized and who remained categorized as NYHA class III or IV. 

Commentary

Martin B. Leon, MD
Columbia University Medical Center
New York, NY

This was another landmark year for TAVR from the standpoint of clinical research and global procedural growth. The CoreValve high-risk randomized trial demonstrated that in patients with aortic stenosis at high risk for surgery (mean STS score approximately 7%), the 1-year all-cause mortality was lower after self-expanding TAVR than surgery.

Later in the year, the 5-year follow-up from the first inoperable cohort of the PARTNER trial indicated that the 20% absolute mortality benefit of balloon-expandable TAVR compared with standard therapy was maintained over 5 years. Bioprosthetic valve durability was also sustained during longitudinal echo analyses.

Thus, the clinical outcomes of TAVR appear robust in multiple clinical trials and the new transcatheter bioprosthetic valves also appear to be similar in performance to surgical valves during midterm follow-up. Clearly, TAVR is alive and well as an important therapeutic contribution to the management of patients with aortic stenosis.

ABSORB II

Presented at TCT 2014, results from the ABSORB II trial, which involved 501 patients with evidence of myocardial ischemia randomized at 46 sites in Europe and New Zealand, showed similar clinical outcomes and safety through 1 year when comparing the Absorb everolimus-eluting bioresorbable vascular scaffold (Abbott Vascular) with the metallic Xience DES (Abbott Vascular).

Commentary

Gregg W. Stone, MD
Columbia University Medical Center
New York, NY

This was the highly anticipated first randomized trial comparing the Absorb bioresorbable vascular scaffold to the Xience metallic DES in CAD. The 1-year results were quite favorable, with similar rates of MACE and less angina. These results were notable because the acute implant results were not as good in the Absorb arm as the Xience arm given the early experience with the device. The real hope for Absorb is that it will reduce the ongoing risk of ischemic events evident with all metallic stents beyond 1 year. Of course we will need long-term follow-up to see if that is the case, as well as the results of larger studies in more complex patients, which are ongoing (ABSORB III and IV).

HEAT-PPCI

The HEAT-PPCI trial, reported at American College of Cardiology/i2 Scientific Session in March and published in the Lancet in July, showed that STEMI patients slated for primary PCI had lower rates of MACE and stent thrombosis when randomized to unfractionated heparin vs bivalirudin. Bleeding risk was similar between the 2 groups. The study took ethical heat for gaining consent from participants only after treatment and during recovery.

Commentary

Hitinder S. Gurm, MD
University of Michigan Cardiovascular Center
Ann Arbor, MI

The paradigm shift in pharmacotherapy for primary PCI has been enlightening with a greater focus on reducing bleeding in addition to ischemic complications. HORIZONS-AMI taught us that we do not need [a glycoprotein IIb/IIIa inhibitor (GPI)] in all patients and that bivalirudin and provisional GPI use is at least as good, if not considerably better. HEAT-PPCI demonstrated that we do not really need bivalirudin in all and that the cheaper approach of heparin and provisional GPI is as good if not better. This was predominantly a radial trial, and it is not clear that the results would be similar in a predominantly femoral population. Nevertheless, this study made us question some of our strong beliefs and is already impacting practice.

BRIGHT

Following the HEAT-PPCI results, the BRIGHT trial, presented at TCT 2014, showed that bivalirudin reduces bleeding but does not affect ischemic events compared with heparin alone or with a GPI in patients undergoing PCI for acute MI.

Researchers credited a prolonged infusion of bivalirudin after the procedure with eliminating the increased risk of stent thrombosis seen with the drug in prior trials, including HEAT-PPCI.

Commentary

Gregg W. Stone, MD
Columbia University Medical Center

New York, NY

The major controversy over the use of bivalirudin during primary PCI in STEMI raised by the single-center HEAT-PPCI trial was addressed head on by BRIGHT, a large-scale multicenter trial. In BRIGHT, treatment of STEMI patients with bivalirudin compared to heparin monotherapy during PCI led to reduced rates of major bleeding with similar rates of MACE at 30 days and 1 year. Moreover, there was no excess stent thrombosis in the bivalirudin-treated patients in BRIGHT, likely due to the use of a 4-hour routine infusion after PCI (high dose transitioning to low dose). These data are consistent with those from EUROMAX, in which the PCI dose of bivalirudin, continued for 4 hours post-PCI, eliminated the acute stent thrombosis risk without increasing bleeding. So bivalirudin is superior to both heparin alone and with a GPI during primary PCI if you use it correctly, ensuring reasonable antithrombin coverage for several hours. Then you can have the benefits of reduced bleeding and thrombocytopenia (and possible lower cardiac mortality) that we’ve observed with this agent in our prior studies, without a concern of increased stent thrombosis within hours of stopping the drug.

FAME 2

The FAME 2 trial randomized 888 patients who had at least 1 flow-limiting lesion according to FFR to optimal medical therapy with or without FFR-guided PCI. The trial was stopped early because of a lower risk of the primary composite endpoint (all-cause death, MI, or urgent revascularization) in the FFR-guided arm, driven by a lower rate of urgent revascularization.

This past year, results presented at the European Society of Cardiology Congress and simultaneously published online in the New England Journal of Medicine showed similar outcomes over 2-year follow-up.

Commentary

Morton J. Kern, MD
University of California, Irvine
Irvine, CA

The FAME 2 study addressed the best treatment for patients with stable CAD by comparing optimal medical therapy with or without PCI for lesions with at least 1 stenosis. The outcome differences were striking.

This paper was among the most important not only in the last year but also the last decade with regard to the best approach for stable CAD patients who may require stenting implantation in addition to medical therapy. That appropriate stent placement based on ischemia is superior to stenting based on angiography alone was demonstrated in FAME 1. In patients with stable CAD, the FAME 2 study showed that ischemia-guided PCI, as compared with medical therapy alone, reduced the MACE rate and, moreover, when excluding periprocedural myocardial enzyme elevations, PCI with medical therapy reduced death and MI compared to medical therapy alone. FAME 2 showed that revascularization of ischemic lesions had a 10-fold reduction in need for urgent revascularization over 2-year follow-up.

Previous studies, like COURAGE, suggested that revascularization by either PCI or CABG did not improve survival or MI rates except in patients with severe or unstable CAD presentations (eg, 3-vessel/left main CAD or STEMI). The FAME 2 trial supports PCI for stable ischemic CAD patients and medical therapy for nonischemic patients, and the results both challenge and support the findings of COURAGE in that those patients with moderate-to-significant ischemia benefit by revascularization. While PCI for most stable patients is not generally a life-saving procedure, the FAME studies guide us on who will benefit most from revascularization over continued medical therapy.

HeartFlow NXT

Results of the HeartFlow NXT trial, originally presented at TCT 2013, were published online in January in the Journal of the American College of Cardiology. The study showed that a noninvasive method of measuring FFR by cardiac CT had high diagnostic accuracy for identifying functionally significant lesions in patients with CAD compared with invasive FFR.

Commentary
Robert S. Schwartz, MD
Minneapolis Heart Institute Foundation
Minneapolis, MN

This study is the largest published yet on the utility of noninvasive FFR derived by computational analysis of coronary CTA. It included 254 patients with moderate stenosis severity, building on earlier encouraging data from the DeFACTO study. The HeartFlow NXT trial showed FFR_CT was more accurate than CT alone, with about a 2-fold increase in specificity (79% vs 32%).

This nascent technology continued to improve in 2014 and has the clear potential to revolutionize interventional cardiology. It will do so in the context of noninvasively understanding stenosis severity and ischemic potential. It also will predict results of intervention. Implications are far-reaching, stretching not only from physiology to interventional and medical practice but also to reimbursement and procedure appropriateness. Moreover, the technology has massive potential for 3-D coronary CT imaging related to assessing image quality and assisting CT angiography for markedly increasing accuracy.

Advances in Transcatheter Valves

This past year saw the development of transcatheter mitral valve replacement (TMVR), growing use of MitraClip (Abbott Vascular) for percutaneous mitral valve repair, and initiation of the first head-to-head trial comparing TAVR devices.

Commentary

Ted Feldman, MD
Evanston Hospital
Evanston, IL

The last year marks the first successful TMVR procedures. While some procedures were done in the prior year or 2, clinical success was achieved just this year, with several different devices undergoing first-in-human use with some good clinical outcomes.

For percutaneous mitral repair, MitraClip remains the overwhelmingly most frequent approach. After FDA approval for a high-risk degenerative MR indication in 2013, MitraClip surpassed 1,000 implants in the United States and 17,000 worldwide implants overall, with any other percutaneous mitral repair technology having no more than 300 total implants.

Also, the prospective, randomized REPRISE III TAVR trial began, comparing the Lotus valve (Boston Scientific) with CoreValve (Medtronic). This is the first large head-to-head TAVR device approval trial. Over 1,000 patients will be enrolled. The Lotus valve is repositionable, completely retrievable, and has an adaptive seal to minimize paravalvular leak. Results from the CE approval trial in 120 patients validated the ability to position, reposition, or retrieve the device in a controlled manner and showed moderate leak in only 1% of patients at 6 months after implant.

 

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