Setting the Bar

Recent trials have shaped standards for future treatments of secondary mitral regurgitation.

Results from two highly anticipated trials — COAPT and MITRA-FR — have painted fairly different pictures of transcatheter mitral valve repair for secondary mitral regurgitation in HF. However, experts agree that data from both studies provide standards against which other treatments will be measured and create markers to guide development of future clinical trials.

The trials examined transcatheter mitral valve repair in patients with HF and secondary mitral regurgitation; the severity of regurgitation and intensity of background medical therapy differed somewhat between the two trials. In COAPT, transcatheter mitral valve repair was linked to improvements in survival, HF hospitalization and other outcomes, but in MITRA-FR, it was not.

“COAPT has maybe redefined our expectations regarding what we should be able to provide our patients and many of the new devices in this particular space will have to be prepared to measure up to what was achieved in COAPT,” Mark Reisman, MD, section head of interventional cardiology and clinical professor of medicine at the University of Washington in Seattle, told Cardiology Today’s Intervention.

Similarly, MITRA-FR, especially as a real-world study, is just as important in that it fills gaps in knowledge about which patients may not benefit from transcatheter mitral valve repair with the MitraClip device (Abbott) and what factors may affect patient outcomes, according to Gregg W. Stone, MD, co-principal investigator of COAPT and director of cardiovascular research and education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian/Columbia University Irving Medical Center.

“The two trials have helped us determine which types of patients with heart failure and mitral regurgitation are likely to benefit or not benefit from transcatheter mitral valve repair with the MitraClip,” Stone, a Cardiology Today’s Intervention Editorial Board Member, said in an interview.

Most importantly, though, these trials shine a spotlight on secondary, or functional, mitral regurgitation and have energized this field of research, according to Jean-François Obadia, MD, PhD, primary investigator of the MITRA-FR study and chief of cardiothoracique surgery department at Hopital Cardiovasculaire Louis Pradel in Lyon, France.

“The good news is that the time of evidence-based medicine for the treatment of secondary mitral regurgitation is here and we have to encourage our community to go further to better understand this complex and severe disease,” Obadia wrote in an email to Cardiology Today’s Intervention.

Defining the Problem

Understanding the clinical dilemma presented by secondary mitral regurgitation is complicated by a number of factors.

“Nobody knows exactly what the scope of the problem is, but it is thought to be quite large, with up to 40% to 50% of patients with HF having some degree of secondary mitral regurgitation — that is, those patients who have left ventricular dysfunction in HF — and about 10% having severe mitral regurgitation,” Stone said.

The oft-quoted number of patients with significant mitral regurgitation — the majority of whom have secondary mitral regurgitation — is 4.5 million, according to Michael Mack, MD, co-primary investigator of the COAPT trial and chair of the cardiovascular service line at Baylor Scott and White Health in Dallas.

“That said, the number of patients undergoing surgery each year in the United States for mitral regurgitation is 45,000 and the overwhelming majority of those surgeries are for primary, or degenerative, mitral regurgitation,” Mack, a Cardiology Today’s Intervention Editorial Board Member, said in an interview. “It is also said that anywhere from one-quarter to one-third of patients with HF have secondary mitral regurgitation and most patients with secondary mitral regurgitation are in HF clinics. So, I am concerned that there may be somewhat less than 4.5 million patients with significant mitral regurgitation, and if there are that many patients out there, they are certainly not falling out of the trees to get treatment.”

Other issues also complicate the characterization of secondary mitral regurgitation, Reisman noted.

“Secondary mitral regurgitation has been one of the great conundrums for a long time in cardiology because it bridges valvular heart disease and congestive heart failure or LV dysfunction,” he said. “As a result, for many years now, we have been trying to discern what is really the focal point of therapy: the ventricle, the valve or a combination of the two? Are there opportunities to uniquely treat one vs. the other or are there opportunities to treat both at the same time? Is there an optimal window of opportunity during which to treat? And, is there a point where any therapy would be beyond the potential for the patient to recover?”

COAPT and MITRA-FR in Context

The COAPT trial, presented at TCT 2018 and published in The New England Journal of Medicine, showed positive results at 2 years with transcatheter mitral valve repair with MitraClip plus maximal doses of guideline-directed medical therapy vs. medical therapy alone in symptomatic patients with HF and moderate to severe or severe secondary mitral regurgitation (Table).

“COAPT unequivocally demonstrated the benefit of secondary mitral regurgitation reduction in HF patients. It met all prespecified primary and secondary safety and effectiveness endpoints, including those evaluating the effects of the MitraClip device on mortality, HF hospitalizations, exercise capacity, quality of life and functional status,” William T. Abraham, MD, FACP, FACC, FAHA, FESC, FRCPE, co-principal investigator of COAPT and professor of internal medicine and chief of the division of cardiovascular medicine at The Ohio State University Wexner Medical Center in Columbus, wrote in an email to Cardiology Today’s Intervention.

In contrast, MITRA-FR, which was presented at the European Society of Cardiology Congress and also published in NEJM, demonstrated no advantage of transcatheter mitral valve repair with MitraClip plus medical therapy vs. medical therapy alone in terms of HF hospitalization and mortality at 1 year in patients with HF with reduced LV ejection fraction and severe secondary mitral regurgitation (Table).

Three main factors likely account for the contrasting results between the two trials, according to Stone.

First, COAPT investigators used the more stringent American Society of Echocardiography criteria for the definition of severe mitral regurgitation, compared with the ESC and European Association for Cardio-Thoracic Surgery criteria used in MITRA-FR. Additionally, unlike MITRA-FR, COAPT had an upper limit of left ventricular size, and as a result MITRA-FR enrolled some patients with extremely dilated ventricles, whereas COAPT enrolled less dilated ventricles.

Second, MITRA-FR was a real-world study in which patients were treated with HF medications but were not required to be on maximally tolerated doses of guideline-directed medical therapy as they were in COAPT, according to Stone. This may have led to greater differences in medical therapy use between the MitraClip and control groups in MITRA-FR compared with COAPT.

Third, the U.S. and Canadian investigators in COAPT had been using the MitraClip for many years, whereas the device was not widely available in France due to lack of reimbursement and therefore the French investigators in MITRA-FR had less experience with the MitraClip, Stone added. This difference was reflected in somewhat lower success rates and more procedural complications in MITRA-FR than in COAPT.

Both trials, however, had high rates of technical success and low rates of device-related complications, confirming MitraClip’s safety and efficacy in reducing mitral regurgitation.

It is important to bear in mind, though, that transcatheter mitral valve repair may not be a cure for HF, Mack told Cardiology Today’s Intervention. Secondary mitral regurgitation is primarily caused by LV function, although the regurgitant mitral valve contributes to the vicious cycle of progressive LV dilatation and HF, according to Mack. What was not known until COAPT, he explained, was whether interrupting mitral regurgitation would change the course of the disease.

“On the basis of COAPT, we can say it probably does. However, if you look in detail at the trial, interruption of mitral regurgitation does not reverse the disease but rather stabilizes and prevents progression of the disease,” he said. “In the medical therapy arm vs. the medical therapy plus MitraClip arm, everything from the LV size to the 6-minute walk test indicates that the ventricles of the patients did not got better with the device; they just did not continue to get worse, as they did in the control arm.”

Lessons for Clinical Practice

In light of the new data, researchers have identified patients with symptomatic HF on optimally tolerated guideline-directed HF therapy who continue to demonstrate moderately severe or severe secondary mitral regurgitation as the most appropriate candidates for transcatheter mitral valve repair with MitraClip, Abraham told Cardiology Today’s Intervention.

Patients should also have left ventricles that are not too dilated and still have the potential to recover, Mack added.

“Indeed, if we look at COAPT, the one group that did not respond to the intervention were those with the most dilated ventricles and only moderate mitral regurgitation,” Mack said. “The bottom line is that a patient’s left ventricle cannot be too far gone and he or she must have severe mitral regurgitation in order to benefit.”

On the basis of COAPT, physicians will likely alter their approach to treating patients with HF and severe mitral regurgitation, but it will not happen immediately, according to Stone.

“First, the MitraClip indication for severe secondary mitral regurgitation in patients with HF needs to go through the FDA-approval process to receive a labeled indication. Second, it must be evaluated by guidelines committees of the professional societies to achieve appropriate recommendations for the appropriate patients. Finally, adequate reimbursement from insurers is necessary to make this therapy widely available for patients,” he said.

The shift in perception of how to treat these patients, though, may already be underway, according to Mack. He said data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry showed that about 15% of patients who received a MitraClip device last year had secondary mitral regurgitation, despite it being an off-label indication.

However, concerns remain about replicating the results of COAPT in the real world. The trial, for instance, hammered home the importance of optimizing guideline-directed medical therapy before and after the procedure to achieve the best outcomes, according to Mack.

“Although the results of COAPT were superb, I am concerned that the real-world results will look more like MITRA-FR — meaning that in general practice, there will not be as much attention paid to optimizing guideline-directed medical therapy and therefore the results will be less positive,” he told Cardiology Today’s Intervention.

Should these concerns play out in the real world, the availability of a treatment that would help many patients may be hindered, Mack added.

“The majority of patients with secondary mitral regurgitation are seen in HF clinics and some, though not all, in the HF community have generally been skeptical that any device therapy works in HF and, unless COAPT-like results are delivered in the real world, HF specialists are not going to refer their patients for the treatment,” he said. “Therefore, it is critical that we do everything possible to reproduce COAPT conditions in the real world.”

Concerns about whether clinical trial results are generalizable are well founded, Reisman noted, but if interpreted correctly, the COAPT trial could perhaps be more of a call to arms.

“Most doctors would hope that patients could be treated medically before having an invasive procedure,” he said. “However, the percentage of doctors that really follow guideline-directed therapies in general is low. [COAPT] could serve as a reminder for cardiologists, interventionalists, HF specialists and surgeons that they should ensure that the patient has the opportunity to receive conceivably simpler treatment with medical therapy as opposed to an invasive procedure.”

Additionally, both the COAPT and MITRA-FR trials highlight the integral role of a heart team approach in treating severe secondary mitral regurgitation in HF, experts told Cardiology Today’s Intervention.

“Patient selection requires a strong multidisciplinary team approach that includes HF specialists, interventional cardiologists, cardiac imagers and possibly cardiac surgeons to optimize patient outcomes,” Abraham said.

Unanswered Questions

Although COAPT and MITRA-FR established benchmarks for study in this field, many unresolved issues were revealed, experts told Cardiology Today’s Intervention.

One major question again pertains to the contrasting outcomes between COAPT and MITRA-FR, according to Obadia, who noted that patient selection likely accounts for the difference in results but not the robustness of the difference.

“The mortality rate is similar in both groups of MITRA-FR and the control group of COAPT, so the populations of the two studies are probably not so different. However, there was not even a positive trend detected in any subgroup of MITRA-FR,” he said. “Further, after decades of publications on secondary mitral regurgitation, including surgical randomized clinical trials, COAPT is the first publication reporting a positive impact on rehospitalization and mortality, with an effect superior to any medical treatment recently published. Moreover, the durability of the mitral regurgitation correction is almost miraculous if we consider the previous surgical publications or percutaneous registries for MitraClip.”

Despite the positive results, the rates of mortality in both COAPT study arms — 29.1% in the intervention group and 46.1% in the control group — were high, according to Reisman.

“There are very few trials of other therapies that were able to achieve what COAPT was able to achieve, but those mortality rates suggest that we’re nowhere near where we need to be,” he said.

Stone also noted that only about three-quarters of patients with severe secondary mitral regurgitation may have the appropriate anatomy for the MitraClip.

Furthermore, the COAPT trial studied a relatively narrow cross-section of patients with HF and mitral regurgitation. Evaluation of the performance of the device in patients not included in the trial, such as asymptomatic patients with similar degrees of mitral regurgitation and LV dilatation or even sicker patients with the appropriate severity of mitral regurgitation, in future studies is essential, Stone said.

Future Directions

Looking ahead, greater understanding of the pathology of nonischemic and ischemic heart disease, identifying better predictors of when which patients will decompensate and how to use ambulatory monitoring are important areas of exploration for treatment of secondary mitral regurgitation, according to Reisman.

However, COAPT and MITRA-FR may have made the biggest impact on the whole host of other devices coming into play.

“COAPT will definitely help MitraClip, but I do think it will create a coattail effect in terms of other devices as well. Also, should MitraClip become standard of care, all other devices in the field will likely have to be compared to MitraClip in order to get FDA approval and reimbursement,” Mack said.

Many of these devices are already being studied. At TCT 2018, researchers presented results from REDUCE-FMR showing that a transcatheter device for indirect mitral annuloplasty (Carillon Mitral Contour System, Cardiac Dimensions) in a double-blind, sham-controlled study reduced regurgitant volume in patients with HF and secondary mitral regurgitation at 1 year. Other annuloplasty devices such as Cardioband (Edwards Lifesciences) and Millipede (Boston Scientific) as well as artificial cords including Harpoon (Edwards Lifesciences), Neochord (Neochord), and Pipeline (W.L. Gore and Associates) and at least five replacement devices are also in early feasibility or pivotal trials, Mack noted.

These investigations are important for a variety of reasons, according to Stone. He noted that next-generation MitraClip devices and different investigational edge-to-edge leaflet approximation technologies promise to make the procedure easier, even safer, more durable and perhaps applicable to more patients. There may also be room for transcatheter mitral valve repair techniques using annuloplasty approaches or other novel approaches to either complement or be used instead of MitraClip, he added.

“Transcatheter mitral valve replacement is also very exciting because it will likely eliminate mitral regurgitation in more than 90% of patients, which rarely occurs with mitral valve repair, and its effects should be more durable. However, these technologies are complex and large-profile, and relatively few patients have had the appropriate anatomy and clinical conditions to be enrolled in these early clinical trials. Ultimately, randomized studies are required to determine if they are more effective than MitraClip,” Stone said.

Importantly, though, COAPT and MITRA-FR may help researchers view novel treatments for secondary mitral regurgitation in HF in a different light, Reisman noted.

“Developers of some devices may look at these trials and determine that one identified more of a ventricular problem than a mitral regurgitation problem and decide to target the ventricle because they have a more ventricular-oriented device. On the other hand, others may decide to target the valve and include patients in whom valvular disease is a significant contributor because their device is more valve-oriented,” he said.

“In general, COAPT was a reset button for the whole field of secondary mitral regurgitation. All of the device makers and entrepreneurs are stopping to consider how their device compares to the MitraClip and how it works,” Reisman told Cardiology Today’s Intervention. “The trial did not halt or deter the mitral space, but it has caused everyone to pause to create a better clarity as to what the target of a therapy is and how best to achieve positive outcomes for the variety of devices that are out there.” – by Melissa Foster

• References:
• Obadia J-F, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1805374.
• Sievert H, et al. Late-Breaking Trials 3. Presented at: TCT Scientific Symposium; Sept. 21-25, 2018; San Diego.
• Stone GW, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1806640.

• For more information:
• William T. Abraham, MD, FACP, FACC, FAHA, FESC, FRCPE, can be reached at william.abraham@osumc.edu.
• Michael Mack, MD, can be reached at michael.mack@bswhealth.org.
• Jean-Francois Obadia, MD, PhD, can be reached at jean-francois.obadia@chu-lyon.fr.
• Mark Reisman, MD, can be reached at resimanm@uw.edu; Twitter: @MReisman09.
• Gregg W. Stone, MD, can be reached at gstone@crf.org; Twitter: @GreggWStone.

Disclosures: Abraham reports he has received fees for service from Abbott Vascular for his role as co-principal investigator of the COAPT trial and a member of the COAPT Patient Eligibility Committee. Mack reports he is co-principal investigator of the COAPT trial funded by Abbott, co-principal investigator of the PARTNER 3 trial funded by Edwards Lifesciences and study chair of the APOLLO trial funded by Medtronic. Obadia reports he received a grant from Abbott and he is a consultant for Abbott, Delacroix-Chevalier, Edwards, Landanger and Medtronic. Reisman reports he is the executive chair of the Cardioband mitral trials. Stone reports he has received consultant fees from Ablative Solutions, BackBeat, Claret, HeartFlow Matrizyme, Medical Development Technologies, Miracor, Neovasc, Reva, Robocath, Shockwave, Sirtex, TherOx, Valfix, Vascular Dynamics, V-Wave, and W.L. Gore and Associates; he has received lecture fees from Amaranth and Terumo; he has stock equity and options from Ancora, BioStar Fund, Cagent, Caliber and MedFocus Fund; he has received fees for serving as director and stock options from SpectraWave; he has received honoraria and stock equity and options from Qool Therapeutics; and royalties are paid to Columbia University, his employer, from Abbott.