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Peripheral, Structural Developments Poised to Change Practice
Game-changing data have provided hope and given pause to interventional cardiologists.
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In recent months, there have been many impressive CV advancements as several trials have shed light on issues affecting our patients that are critical and noteworthy. However, some red flags have been raised from analyses that have shone a spotlight on potentially serious outcomes that need significant reviews before the field can move forward. These developments, which affect the peripheral and structural subspecialties of interventional cardiology, have the potential to significantly alter the landscape of clinical practice.
COAPT and MITRA-FR
From the structural front, the presentation at TCT and subsequent publication in The New England Journal of Medicine of the COAPT study by Cardiology Today’s Intervention Editorial Board Member Gregg W. Stone, MD, director of cardiovascular research and education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian/Columbia University Irving Medical Center, and colleagues represents a landmark. The trial of patients with functional (nondegenerative) mitral insufficiency was presented to a stunned audience.
The COAPT investigators enrolled patients with HF and functional mitral regurgitation grade 3 to 4 (moderate to severe, or severe) who were symptomatic despite guideline-directed medical therapy. These patients had left ventricular ejection fraction 20% to 50% from nonischemic or ischemic cardiomyopathy. In all, 302 patients were assigned to transcatheter mitral valve repair (MitraClip, Abbott) plus guideline-directed medical therapy and 312 were assigned guideline-directed medical therapy alone. The device group had significantly lower all-cause hospitalization within 24 months compared with medical therapy group (35.8% vs. 67.9%). The important result that has yet to be duplicated in this type of trial is that death from any cause within 24 months was 29.1% in the device group and 46.1% in the control group. This is a remarkable outcome.
In contradistinction to previous studies, this trial was the only one to show a mortality benefit in patients with functional mitral regurgitation using the MitraClip device. The mortality benefit was driven by all-cause mortality.
This trial was driven for significant mitral regurgitation, and both groups had approximately 43% with NYHA class II HF, 51% with class III HF and 6% with class IV HF. This is an important finding because the all-cause mortality difference was still seen in those who would have been considered to have “compensated” HF. The forest plot of this trial demonstrates that with little exception, in all comers, regardless of cause for HF, mortality or death from any CV cause was greatly limited with the device compared with medical therapy alone. Further, the benefit of HF rehospitalization was immediate, but the mortality benefit was noted at 3 months and the separation of the curves continued throughout, without a late catch-up.
In contradistinction, the MITRA-FR manuscript from Jean-Francois Obadia, MD, PhD, chief of the cardiothoracic surgery department at Hopital Cardiovasculaire Louis Pradel in Lyon, France, and colleagues in the same NEJM edition revealed that in patients with similar functional mitral regurgitation, LVEF 15% to 40% and NYHA class II to IV, there was no difference in outcomes with the MitraClip compared with guideline-directed medical therapy. At 12 months, there was no difference between the two groups in all-cause death or HF hospitalization (intervention, 54.6%; control, 51.3%). Mortality was similar at 24.3% vs. 22.4%, respectively, as were HF readmissions, 49% vs. 47%.
The differences in these trials may be due to the run-in phase in COAPT that mandated guideline-directed medical therapy optimization before enrollment to allow those that improved after medical therapy to be excluded. Further, the mitral regurgitation was more severe in the COAPT cohort compared with the MITRA-FR cohort. Lastly, the number of clips for COAPT was higher than in MITRA-FR, which may have led to less mitral regurgitation in each trial at their conclusions, leading to the different outcomes. Either way, it appears there will still be much to discuss here.
The interest in device-based therapy for functional mitral regurgitation has leapt above and beyond what many would have considered, aside from use of the MitraClip in degenerative mitral regurgitation based on the EVEREST trial. No doubt the COAPT trial and its implications for treating functional mitral regurgitation without surgery will be a primary interest for many structural heart specialists in the coming year.
Peripheral DES Go Head-to-Head
Another recent trial that I believe to be critical was the IMPERIAL study. This trial, presented at TCT and published in The Lancet, is the first head-to-head comparative trial in the peripheral vascular world. It tested the Eluvia peripheral drug-eluting stent (Boston Scientific), which has a polymer coating and a low drug dose, against the Zilver PTX DES (Cook Medical), which has a standard drug dose and no polymer coating.
The Eluvia stent only had early data to suggest benefit, but went head-to-head against the Zilver stent for 12 months in 465 patients. At 12 months, the rate of primary vessel patency was higher in the Eluvia group vs. the Zilver PTX group (86.8% vs. 77.5%).
This trial is the first, and we all hope not the last, to compare any device head-to-head against another. This is important because in the past, we have had to infer any head-to-head outcomes with the patients studied, but now we have a direct comparison between devices. It would be helpful to have all devices compared with each other in a direct way. This may never happen, but the prospect of knowing where and when to use the myriad of devices may become clearer when these types of trials occur.
Concerns About Paclitaxel
Successful studies of new technologies or new uses of existing technologies can substantially change clinical practice, but so can studies that signal harm.
On that front, a summary-level meta-analysis by Konstantinos Katsanos, MD, PhD, MSc, EBIR, assistant professor of interventional radiology at Patras University Hospital in Rion, Greece, and colleagues published in the Journal of the American Heart Association has put a huge spotlight on the use of drug-coated balloon and DES technologies in the treatment of lower limb revascularization.
There are many devices to treat arterial obstructive disease with patients with claudication that use paclitaxel. This drug, used in treatment of various cancers, binds to microtubule spindles and, thereby, inhibits mitosis, the principal process in any restenosis. The data have been largely clearly in favor of the medicated therapy compared with percutaneous transluminal angioplasty. From the earliest trial (THUNDER) to the more recent ILLUMENATE trials, investigators have employed a “leave nothing behind” approach in the SFA for patients with claudication. These trials have suggested — with only one negative study — that the use of these devices is safe and efficacious at the primary endpoint of 1 year, and the safety and efficacy continues through 3 or 4 years.
In their meta-analysis of 23 randomized trials, Katsanos and colleagues described an increase in all-cause mortality at 2 and 5 years in patients enrolled in these trials. The findings appear to suggest that the use of DCB and DES in these patients may have a secondary unwanted effect in mortality that no one has demonstrated or defined before. The authors suggested that an urgent review of the data is absolutely warranted, and the regulatory agencies have agreed.
In the meta-analysis, at 1 year there was little mortality difference in the patient groups. However, in 12 randomized trials with available 2-year data and in three randomized trials with available 5-year data, all paclitaxel-containing devices were associated with a higher-than-expected mortality compared with PTA (number needed to harm at 2 years = 29; number needed to harm at 5 years = 14). Also of note, Circulation recently published a correction to its publication of the 5-year data of the ZILVER PTX study, showing mortality was higher in the paclitaxel-eluting stent arm than the percutaneous transluminal angioplasty arm, not lower as previously reported.
The basis of the outcomes appears to be inferred from non-patient-level data in the subsequent years of study. Therefore, this meta-analysis, although critical and timely, suggests we need to have a further and open review of the data sets for all the trials tested and registries adjudicated. Basic review of the patient-level data may be the best way to impugn or refute these findings. In addition, the FDA and European regulators are eagerly and aggressively reviewing these findings. All we can do is just stay tuned.
Thought-provoking Research
The past few months have produced some of the most thought-provoking data that we have seen in recent memory, with the potential to change the practice of interventional cardiologists in a variety of ways. Clearly, we need to review all the data we have and find the best therapies for our patients. The goal should be to provide patients with the best lives we as their physicians can give them, using the best scientific evidence in doing so.
- References:
- Gray WA, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32262-1.
- Katsanos K, et al. J Am Heart Assoc. 2018;doi:10.1161/JAHA.118.011245.
- Obadia JF, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1805374.
- Stone GW, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1806640.
- For more information:
- Lawrence Garcia, MD, is an interventional cardiologist at Steward St. Elizabeth’s Medical Center in Boston. He can be reached at 736 Cambridge St., Boston, MA 02135; email: lawrence.garcia@steward.org.
Disclosure: Garcia reports he is a consultant for Abbott, Boston Scientific, Medtronic and Syntervention; he holds equity in CV Ingenuity, Essential Medical/Teledex, Scion CV, Syntervention and Tissue Genesis; and he receives research grants from Abbott, Boston Scientific and Medtronic.