Cover Story

New Frontiers in Valvular Heart Disease

Transcatheter interventions for mitral and tricuspid valve disease show promise, but are still in early development.

During the past 15 years, transcatheter aortic valve replacement ushered in a new era of less invasive treatment for aortic stenosis. Now, the field of transcatheter interventions for mitral and tricuspid valve disease appears poised to undergo a similar revolution.

Currently, a multitude of devices designed to treat mitral or tricuspid valve regurgitation are in development. Although the initial data are promising, physicians and researchers have a long road ahead, Howard C. Herrmann, MD, director of the cardiac catheterization laboratories and health system director for interventional cardiology at the Hospital of the University of Pennsylvania and John Winthrop Bryfogle Professor of Cardiovascular Diseases at the Perelman School of Medicine at the University of Pennsylvania, told Cardiology Today’s Intervention.

Howard C. Herrmann

“We essentially have no recent pivotal randomized trial results,” he said, noting that much of the research in mitral valve regurgitation is limited to phase 1 studies or registry data. “It’s like it was 10 years ago with TAVR. We’re trying new things, but it’s still very early and no device or therapy has emerged as a clear winner yet.”

The unique challenges associated with these valves and disease pathways, however, will likely prevent the same relatively rapid development and progress that occurred with TAVR, according to Michael J. Mack, MD, chairman of the cardiovascular service line at Baylor Scott and White Health in Dallas and Cardiology Today’s Intervention Editorial Board Member.

“This will not be TAVR redux,” he said in an interview. “The complexities of mitral and tricuspid valve disease outstrip those of aortic stenosis and require different approaches and considerations.”

Considerable Complexity

As transcatheter solutions for mitral and tricuspid valve disease enter the spotlight, experts who spoke with Cardiology Today’s Intervention said it is important for physicians to temper their expectations and not expect development to follow in TAVR’s footsteps.

First the anatomies of the mitral valve and tricuspid valves differ from that of the aortic valve.

Source: © Lisa Clark

“The mitral and tricuspid valves are more complex in that not only do they have an annulus and leaflets like the aortic valve, but they also have chords and are attached to the ventricles, so ventricular diseases and chordal disease all have an input in how the valve structure functions,” Herrmann, also a Cardiology Today’s Intervention Editorial Board Member, said.

Mitral and tricuspid valves are also much more irregularly shaped than aortic valves and therefore make for a much more challenging landing zone for prosthetic valves, according to Paul Sorajja, MD, Roger L. and Lynn C. Headrick Family Chair for Valve Science Research at Minneapolis Heart Institute Foundation.

Additionally, patients with mitral regurgitation tend not to have the calcium buildup present in patients with aortic stenosis, Mathew Williams, MD, director of the Heart Valve Program at NYU Langone Medical Center, said in an interview.

Mathew Williams

“In TAVR, we rely on the calcium to anchor these valves, which makes it easier to get the valve in place,” he told Cardiology Today’s Intervention.

Moreover, he said, the mitral and tricuspid valves are larger and, consequently, require larger prostheses and catheters.

“With these large devices, we risk causing an obstruction of the left ventricular outflow tract in some patients, particularly with transcatheter mitral valve replacement,” Williams said.

Second, heterogeneity in this patient population is a significant challenge, according to Sorajja. For instance, the two etiologies of mitral regurgitation — primary, or degenerative, mitral regurgitation and secondary, or functional, mitral regurgitation — have a whole host of causes with multiple modes of treatment.

“This complicates transcatheter approaches because there are many different complex solutions,” Williams said. “Whereas we have dozens of surgical approaches that we use to fix mitral regurgitation depending on the location of the leak and number of leaflets involved, one transcatheter approach that works well in one patient’s given anatomy may be completely ineffective in another patient.”

Another major concern is uncertainty, Sorajja told Cardiology Today’s Intervention.

“In terms of disease pathways, if aortic stenosis goes untreated, the patient will die. With mitral regurgitation and tricuspid regurgitation, however, there is relatively greater uncertainty as to how the treatment impacts patients. It hasn’t yet been proven that these interventions actually save patients’ lives,” he said.

Advances in Mitral Valve Repair and Replacement

For mitral valve disease, repair and replacement are the two methods of treatment.

Currently, the only FDA-approved transcatheter mitral valve repair device is the MitraClip system (Abbott Vascular), which involves mechanical edge-to-edge coaptation of the mitral leaflets. Although this device is approved only for high-risk surgical patients with severe primary mitral regurgitation, researchers are evaluating its use in secondary mitral regurgitation in the COAPT trial. The trial, which is comparing the device with medical therapy, has enrolled 610 patients and the results are expected to be presented at TCT 2018.

“COAPT will have a significant impact on the field,” Mack, who is a co-primary investigator for the trial, told Cardiology Today’s Intervention. “If the trial is positive, it will accelerate and catalyze the field. However, if the trial is not positive and doesn’t meet its primary endpoint, then it will significantly pause but not stop the whole field and all of its devices.”

Michael J. Mack

In addition to MitraClip, a number of other transcatheter mitral valve repair devices are on the horizon. For instance, early anecdotal experience with the Pascal system (Edwards Lifesciences) — a device that employs the same edge-to-edge repair principle with a design that facilitates its use in patients with more challenging anatomy — have been positive (See Table).

Other types of transcatheter mitral repair devices in development include a direct annuloplasty system (Cardioband, Valtech Cardio/Edwards Lifesciences), which has begun a pivotal trial in the United States called ACTIVE, and an indirect annuloplasty system (Carillon, Cardiac Dimensions), which will be evaluated in the CARILLION trial that is currently enrolling patients, Mack said.

Transapical surgical devices, according to Herrmann, are also being studied for mitral valve repair. For example, two devices that involve beating-heart chordae implantation — the NeoChord DS1000 system (NeoChord) and the Harpoon TSD-5 system (Harpoon Medical/Edwards Lifesciences) — have begun or are soon beginning U.S. trials.

The field of transcatheter mitral valve replacement has experienced significant growth as well, according to Mack, who noted that there are at least 14 devices in various stages of development, with seven currently in early feasibility trials in the United States.

In particular, data on early experiences with two transapically delivered, self-expanding nitinol valves — the Tendyne (Abbott Vascular) and Intrepid (Medtronic) systems — have recently been published in the Journal of the American College of Cardiology (See Table). The Intrepid system is now being evaluated in the pivotal APOLLO trial and the Tendyne system is slated to enter a pivotal trial soon.

Transcatheter mitral valve replacement, however, is far from perfect at this point, Herrmann said. He noted that these technologies are more invasive and are associated with higher mortality in early studies.

“We’re still trying to understand who would be good candidates for a transcatheter repair vs. a transcatheter replacement technology,” he told Cardiology Today’s Intervention. “As we move forward, this will require complex decision-making that takes into account patient characteristics, the goals of care, including patient preferences, and the specific safety and efficacy of each device for a patient’s individual anatomy.”

‘The Forgotten Valve’

Once referred to as “the forgotten valve,” the tricuspid valve has also become a target for transcatheter interventions, experts told Cardiology Today’s Intervention.

Several devices are in development, including the Forma system (Edwards Lifesciences), which includes a spacer and a rail that is anchored within the right ventricle. Early data presented at TCT 2017 show the device reduced tricuspid regurgitation at 30 days, but it was also associated with distal anchor dislodgements and right ventricle perforations (See Table).

“The Forma results were not great but not totally unexpected from an early feasibility study,” Mack said. “Many of the patients did have correction in tricuspid regurgitation, but it was not as great an improvement as one would hope to see. So, we’re still trying to figure out which patients would benefit, what the best delivery technique is and how the device needs to be modified.”

Several devices that are being investigated for mitral regurgitation are also being studied for use in the tricuspid valve, including MitraClip and Cardioband. The latter device was shown to be safe and effective in patients with severe secondary tricuspid regurgitation in the TRI-REPAIR trial, also presented at TCT 2017.

“MitraClip does not appear to work as well in the tricuspid valve both in terms of delivery and design of the device,” Mack said. “Cardioband, however, may be a great option for tricuspid regurgitation because it’s easier to deliver on the right side of the heart, where the tricuspid valve is, as opposed to the left side of the heart.”

Another device — the NaviGate catheter-guided tricuspid atrioventricular valved stent (NaviGate Cardiac Structures) — is being evaluated as a transcatheter tricuspid valve replacement technology.

Although the field of transcatheter interventions for tricuspid regurgitation is expanding, the success of various devices will likely go hand-in-hand with developments in the mitral valve space, according to Sorajja.

Paul Sorajja

“For any transcatheter mitral therapy to become viable as a main option for these patients, it will have to be delivered with a tricuspid therapy as well, meaning that the mitral valve can’t be treated while leaving the tricuspid valve alone,” he told Cardiology Today’s Intervention.

He noted that several of these technologies in development already take advantage of being able to treat both mitral and tricuspid valve disease.

“A good example is MitraClip. We can leverage the experience in the mitral valve into the tricuspid valve,” he said. “Companies will struggle a bit more developing singular technologies for tricuspid regurgitation unless they can demonstrate more efficacy in comparison with these other technologies.”

The Future of the Field

Although the current data demonstrate safety and feasibility of these transcatheter devices for mitral and tricuspid regurgitation, there is a question of how they fit into the treatment landscape in light of the available surgical options.

Judging from the data thus far, these transcatheter treatment options are likely to work best in higher-risk populations, according to Williams. Younger, healthier patients with primary mitral valve disease, for instance, do well with surgery, whereas older, higher-risk patients may have improved quality of life with surgery, but will not have a survival benefit and will spend considerable time recovering from the procedure itself.

Less is known, however, about the devices’ use in secondary mitral regurgitation, he noted.

“Surgically, we know that treating secondary mitral regurgitation does not tend to make patients live longer, which is not a problem with the valve but a problem with the ventricle,” Williams said. “Therefore, COAPT is going to be important. In addition to showing whether MitraClip is effective for treating secondary mitral regurgitation, it’s going to tell us if there is even a benefit to treating these patients because they still have the ventricular problem. If there’s a quality-of-life benefit, there is some advantage, but if there’s a survival benefit, that’s a huge deal. In many ways, this will dictate how the rest of these technologies can progress.”

Moving forward, the devices and techniques will also have to evolve, according to Sorajja.

“Many of the devices in this area are currently delivered transapically, but transfemoral versions are being developed for all of them. The sooner we can get away from the apex of the heart so we can prevent bleeding deaths related to apical access, the better,” he said.

Patient selection, however, will be the most vital element as these devices become more widely available. Physicians will have to consider anatomical issues to ensure that a patient can accommodate a certain device, gain a greater understanding of who needs to be treated and weigh the risks and benefits of the transcatheter procedures for individual patients, Herrmann noted.

As these transcatheter treatments move into practice, collaboration will also be essential. A heart team approach will be necessary to balance the complex issues involved in the decision-making, he said, and imaging experts, who guide these procedures, and cardiac surgeons will also be integral to their success.

Despite the considerable development in transcatheter treatments for mitral and tricuspid valve regurgitation, the field is still in the early stages and the data are somewhat lacking, experts told Cardiology Today’s Intervention.

The forward momentum, though, is encouraging, according to Sorajja.

“The feasibility of these transcatheter technologies has been established. There is no doubt about the fact that what we once thought to be difficult or impossible is now very possible,” he said. – by Melissa Foster

Disclosures: Herrmann reports he is a consultant for Edwards Lifesciences, has equity in Micro Interventional Devices and has received research funding to his institution from Abbott Vascular, Bayer, Boston Scientific, Edwards Lifesciences, Medtronic and St. Jude Medical. Mack reports he is co-principal investigator for the PARTNER 3 trial funded by Edwards Lifesciences, co-principal investigator for the COAPT trial funded by Abbott Vascular and chairman of the executive committee of the APOLLO trial funded by Medtronic. Sorajja reports he receives consultant fees and honoraria from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Integer and Medtronic, as well as grants from Abbott Vascular, Boston Scientific, Edwards Lifesciences and Medtronic. Williams reports he has received research funding from Caisson and Medtronic and is a consultant for Abbott.

During the past 15 years, transcatheter aortic valve replacement ushered in a new era of less invasive treatment for aortic stenosis. Now, the field of transcatheter interventions for mitral and tricuspid valve disease appears poised to undergo a similar revolution.

Currently, a multitude of devices designed to treat mitral or tricuspid valve regurgitation are in development. Although the initial data are promising, physicians and researchers have a long road ahead, Howard C. Herrmann, MD, director of the cardiac catheterization laboratories and health system director for interventional cardiology at the Hospital of the University of Pennsylvania and John Winthrop Bryfogle Professor of Cardiovascular Diseases at the Perelman School of Medicine at the University of Pennsylvania, told Cardiology Today’s Intervention.

Howard C. Herrmann

“We essentially have no recent pivotal randomized trial results,” he said, noting that much of the research in mitral valve regurgitation is limited to phase 1 studies or registry data. “It’s like it was 10 years ago with TAVR. We’re trying new things, but it’s still very early and no device or therapy has emerged as a clear winner yet.”

The unique challenges associated with these valves and disease pathways, however, will likely prevent the same relatively rapid development and progress that occurred with TAVR, according to Michael J. Mack, MD, chairman of the cardiovascular service line at Baylor Scott and White Health in Dallas and Cardiology Today’s Intervention Editorial Board Member.

“This will not be TAVR redux,” he said in an interview. “The complexities of mitral and tricuspid valve disease outstrip those of aortic stenosis and require different approaches and considerations.”

Considerable Complexity

As transcatheter solutions for mitral and tricuspid valve disease enter the spotlight, experts who spoke with Cardiology Today’s Intervention said it is important for physicians to temper their expectations and not expect development to follow in TAVR’s footsteps.

First the anatomies of the mitral valve and tricuspid valves differ from that of the aortic valve.

Source: © Lisa Clark

“The mitral and tricuspid valves are more complex in that not only do they have an annulus and leaflets like the aortic valve, but they also have chords and are attached to the ventricles, so ventricular diseases and chordal disease all have an input in how the valve structure functions,” Herrmann, also a Cardiology Today’s Intervention Editorial Board Member, said.

Mitral and tricuspid valves are also much more irregularly shaped than aortic valves and therefore make for a much more challenging landing zone for prosthetic valves, according to Paul Sorajja, MD, Roger L. and Lynn C. Headrick Family Chair for Valve Science Research at Minneapolis Heart Institute Foundation.

PAGE BREAK

Additionally, patients with mitral regurgitation tend not to have the calcium buildup present in patients with aortic stenosis, Mathew Williams, MD, director of the Heart Valve Program at NYU Langone Medical Center, said in an interview.

Mathew Williams

“In TAVR, we rely on the calcium to anchor these valves, which makes it easier to get the valve in place,” he told Cardiology Today’s Intervention.

Moreover, he said, the mitral and tricuspid valves are larger and, consequently, require larger prostheses and catheters.

“With these large devices, we risk causing an obstruction of the left ventricular outflow tract in some patients, particularly with transcatheter mitral valve replacement,” Williams said.

Second, heterogeneity in this patient population is a significant challenge, according to Sorajja. For instance, the two etiologies of mitral regurgitation — primary, or degenerative, mitral regurgitation and secondary, or functional, mitral regurgitation — have a whole host of causes with multiple modes of treatment.

“This complicates transcatheter approaches because there are many different complex solutions,” Williams said. “Whereas we have dozens of surgical approaches that we use to fix mitral regurgitation depending on the location of the leak and number of leaflets involved, one transcatheter approach that works well in one patient’s given anatomy may be completely ineffective in another patient.”

Another major concern is uncertainty, Sorajja told Cardiology Today’s Intervention.

“In terms of disease pathways, if aortic stenosis goes untreated, the patient will die. With mitral regurgitation and tricuspid regurgitation, however, there is relatively greater uncertainty as to how the treatment impacts patients. It hasn’t yet been proven that these interventions actually save patients’ lives,” he said.

Advances in Mitral Valve Repair and Replacement

For mitral valve disease, repair and replacement are the two methods of treatment.

Currently, the only FDA-approved transcatheter mitral valve repair device is the MitraClip system (Abbott Vascular), which involves mechanical edge-to-edge coaptation of the mitral leaflets. Although this device is approved only for high-risk surgical patients with severe primary mitral regurgitation, researchers are evaluating its use in secondary mitral regurgitation in the COAPT trial. The trial, which is comparing the device with medical therapy, has enrolled 610 patients and the results are expected to be presented at TCT 2018.

“COAPT will have a significant impact on the field,” Mack, who is a co-primary investigator for the trial, told Cardiology Today’s Intervention. “If the trial is positive, it will accelerate and catalyze the field. However, if the trial is not positive and doesn’t meet its primary endpoint, then it will significantly pause but not stop the whole field and all of its devices.”

PAGE BREAK
Michael J. Mack

In addition to MitraClip, a number of other transcatheter mitral valve repair devices are on the horizon. For instance, early anecdotal experience with the Pascal system (Edwards Lifesciences) — a device that employs the same edge-to-edge repair principle with a design that facilitates its use in patients with more challenging anatomy — have been positive (See Table).

Other types of transcatheter mitral repair devices in development include a direct annuloplasty system (Cardioband, Valtech Cardio/Edwards Lifesciences), which has begun a pivotal trial in the United States called ACTIVE, and an indirect annuloplasty system (Carillon, Cardiac Dimensions), which will be evaluated in the CARILLION trial that is currently enrolling patients, Mack said.

Transapical surgical devices, according to Herrmann, are also being studied for mitral valve repair. For example, two devices that involve beating-heart chordae implantation — the NeoChord DS1000 system (NeoChord) and the Harpoon TSD-5 system (Harpoon Medical/Edwards Lifesciences) — have begun or are soon beginning U.S. trials.

The field of transcatheter mitral valve replacement has experienced significant growth as well, according to Mack, who noted that there are at least 14 devices in various stages of development, with seven currently in early feasibility trials in the United States.

In particular, data on early experiences with two transapically delivered, self-expanding nitinol valves — the Tendyne (Abbott Vascular) and Intrepid (Medtronic) systems — have recently been published in the Journal of the American College of Cardiology (See Table). The Intrepid system is now being evaluated in the pivotal APOLLO trial and the Tendyne system is slated to enter a pivotal trial soon.

Transcatheter mitral valve replacement, however, is far from perfect at this point, Herrmann said. He noted that these technologies are more invasive and are associated with higher mortality in early studies.

“We’re still trying to understand who would be good candidates for a transcatheter repair vs. a transcatheter replacement technology,” he told Cardiology Today’s Intervention. “As we move forward, this will require complex decision-making that takes into account patient characteristics, the goals of care, including patient preferences, and the specific safety and efficacy of each device for a patient’s individual anatomy.”

‘The Forgotten Valve’

Once referred to as “the forgotten valve,” the tricuspid valve has also become a target for transcatheter interventions, experts told Cardiology Today’s Intervention.

Several devices are in development, including the Forma system (Edwards Lifesciences), which includes a spacer and a rail that is anchored within the right ventricle. Early data presented at TCT 2017 show the device reduced tricuspid regurgitation at 30 days, but it was also associated with distal anchor dislodgements and right ventricle perforations (See Table).

PAGE BREAK

“The Forma results were not great but not totally unexpected from an early feasibility study,” Mack said. “Many of the patients did have correction in tricuspid regurgitation, but it was not as great an improvement as one would hope to see. So, we’re still trying to figure out which patients would benefit, what the best delivery technique is and how the device needs to be modified.”

Several devices that are being investigated for mitral regurgitation are also being studied for use in the tricuspid valve, including MitraClip and Cardioband. The latter device was shown to be safe and effective in patients with severe secondary tricuspid regurgitation in the TRI-REPAIR trial, also presented at TCT 2017.

“MitraClip does not appear to work as well in the tricuspid valve both in terms of delivery and design of the device,” Mack said. “Cardioband, however, may be a great option for tricuspid regurgitation because it’s easier to deliver on the right side of the heart, where the tricuspid valve is, as opposed to the left side of the heart.”

Another device — the NaviGate catheter-guided tricuspid atrioventricular valved stent (NaviGate Cardiac Structures) — is being evaluated as a transcatheter tricuspid valve replacement technology.

Although the field of transcatheter interventions for tricuspid regurgitation is expanding, the success of various devices will likely go hand-in-hand with developments in the mitral valve space, according to Sorajja.

Paul Sorajja

“For any transcatheter mitral therapy to become viable as a main option for these patients, it will have to be delivered with a tricuspid therapy as well, meaning that the mitral valve can’t be treated while leaving the tricuspid valve alone,” he told Cardiology Today’s Intervention.

He noted that several of these technologies in development already take advantage of being able to treat both mitral and tricuspid valve disease.

“A good example is MitraClip. We can leverage the experience in the mitral valve into the tricuspid valve,” he said. “Companies will struggle a bit more developing singular technologies for tricuspid regurgitation unless they can demonstrate more efficacy in comparison with these other technologies.”

The Future of the Field

Although the current data demonstrate safety and feasibility of these transcatheter devices for mitral and tricuspid regurgitation, there is a question of how they fit into the treatment landscape in light of the available surgical options.

Judging from the data thus far, these transcatheter treatment options are likely to work best in higher-risk populations, according to Williams. Younger, healthier patients with primary mitral valve disease, for instance, do well with surgery, whereas older, higher-risk patients may have improved quality of life with surgery, but will not have a survival benefit and will spend considerable time recovering from the procedure itself.

PAGE BREAK

Less is known, however, about the devices’ use in secondary mitral regurgitation, he noted.

“Surgically, we know that treating secondary mitral regurgitation does not tend to make patients live longer, which is not a problem with the valve but a problem with the ventricle,” Williams said. “Therefore, COAPT is going to be important. In addition to showing whether MitraClip is effective for treating secondary mitral regurgitation, it’s going to tell us if there is even a benefit to treating these patients because they still have the ventricular problem. If there’s a quality-of-life benefit, there is some advantage, but if there’s a survival benefit, that’s a huge deal. In many ways, this will dictate how the rest of these technologies can progress.”

Moving forward, the devices and techniques will also have to evolve, according to Sorajja.

“Many of the devices in this area are currently delivered transapically, but transfemoral versions are being developed for all of them. The sooner we can get away from the apex of the heart so we can prevent bleeding deaths related to apical access, the better,” he said.

Patient selection, however, will be the most vital element as these devices become more widely available. Physicians will have to consider anatomical issues to ensure that a patient can accommodate a certain device, gain a greater understanding of who needs to be treated and weigh the risks and benefits of the transcatheter procedures for individual patients, Herrmann noted.

As these transcatheter treatments move into practice, collaboration will also be essential. A heart team approach will be necessary to balance the complex issues involved in the decision-making, he said, and imaging experts, who guide these procedures, and cardiac surgeons will also be integral to their success.

Despite the considerable development in transcatheter treatments for mitral and tricuspid valve regurgitation, the field is still in the early stages and the data are somewhat lacking, experts told Cardiology Today’s Intervention.

The forward momentum, though, is encouraging, according to Sorajja.

“The feasibility of these transcatheter technologies has been established. There is no doubt about the fact that what we once thought to be difficult or impossible is now very possible,” he said. – by Melissa Foster

Disclosures: Herrmann reports he is a consultant for Edwards Lifesciences, has equity in Micro Interventional Devices and has received research funding to his institution from Abbott Vascular, Bayer, Boston Scientific, Edwards Lifesciences, Medtronic and St. Jude Medical. Mack reports he is co-principal investigator for the PARTNER 3 trial funded by Edwards Lifesciences, co-principal investigator for the COAPT trial funded by Abbott Vascular and chairman of the executive committee of the APOLLO trial funded by Medtronic. Sorajja reports he receives consultant fees and honoraria from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Integer and Medtronic, as well as grants from Abbott Vascular, Boston Scientific, Edwards Lifesciences and Medtronic. Williams reports he has received research funding from Caisson and Medtronic and is a consultant for Abbott.