Mary Stewart

With any new medical treatment, there are two types of risks: those that are known and anticipated from precommercial clinical work, and those that are unknown, can’t be predicted and only emerge once a device or procedure is exposed to real-world clinical practice. New products and procedures start out by being vetted in the protected, false security of clinical trials, involving small numbers of hand-picked patients often treated by leading physicians under ideal circumstances. Only as real-world clinical experience accumulates in large numbers of patients with a multitude of unpredictable comorbidities and complications do the unanticipated problems begin to emerge.

That’s where TAVI (transcatheter aortic valve implantation) is today. Minimally invasive transcatheter treatments for the aortic valve as an alternative to surgical valve replacement have been available in Europe since 2007 (and in the U.S. since November 2011), and in recent years the number of procedures in Europe has more than tripled, according to a presentation made at this year’s EuroPCR interventional cardiology meeting in Paris in May. Dr. Nicolo Piazza of the German Heart Center (Munich, Germany) noted that for Europe as a whole, TAVI procedures numbered 4,498 in 2009, 14,599 in 2010 and 18,372 in 2011. To date, an estimated 50,000 patients have been treated in 46 countries. That’s enough time and experience for the cracks in the new procedures to start to show.

The most serious problems to emerge include vascular and bleeding complications, stroke and paravalvular leaks. Innovators in the field, like Edwards Lifesciences Corp., the first on the market in Europe and the US, Medtronic Inc.’s Medtronic CoreValve LLC, which has TAVI products on the market in Europe, and numerous emerging companies are devoting lots of energy to the improvement of prosthetic valves and their delivery systems. These companies are looking to optimize valve design with the goal of minimizing the trauma the devices cause in the vessels on the way to the heart, or are crafting ways to position them better in the native annulus of the aortic valve. JenaValve Technology GMBH and Symetis SA, for example, believe they’ve grabbed second-generation advantages with valves that self-position and can be repositioned. Clinicians believe that better valve positioning will reduce paravalvular leaks. Colibri Heart Valve LLC is developing a smaller device, an atraumatic low-profile foldable aortic valve that can be delivered through a 14 French (14F) procedural sheath. Today, sheath diameters for current transcatheter heart valves range from 18F to 24F. A smaller device is easier to navigate through vessels, and theoretically causes less damage in very sick patients with fragile, thin, tortuous, or calcified vessels. For the start-ups developing these next-generation technologies the real question may be: Will clinicians prefer that the heart valves be revised to provide better access, or will they prefer a new method of access?

More than a dozen companies developing devices for access site management answer the latter in the affirmative. Their thesis is that new access devices can improve outcomes and bring more patients to minimally invasive treatments for structural heart disease.

One group of companies is working on vascular closure devices for large-bore procedures, that is, the delivery of large-diameter devices in the range of 12-24F. (The conventional balloons and stents of interventional cardiology can be delivered through sheaths 5-8F in diameter.) Large-bore procedures result in sizable wounds and overstretched vessels that will not close by manual compression, which is still the gold standard means of closure for small-bore procedures. This group includes Abbott Laboratories Inc., AccessClosure Inc. (a leader in small-bore vascular closure now developing a large-bore closure product), Promed Ltd., VivaSure Medical Ltd. and VasoStitch Inc.

The other group is targeting a newer access method, the less developed transapical procedure where the chest and apex of the heart are punctured to allow access to the left ventricle. The first products of Apica Cardiovascular Ltd. and Entourage Medical Technologies Inc., profiled in this issue, fit into this category, as do those of NovoGateMedicalLtd. and Micro Interventional Devices Inc.

As the long list of start-ups suggests, any truly successful new therapy will bring with it more products than just a single type of therapeutic implant (in this case the transcatheter heart valve). Michael Whitman, president and CEO of Micro Interventional Devices, says, "Whenever there is a disruptive or transformative technology, there is often a need to create peripheral devices around it to support it." MID plans to take advantage of the short and straight path to the heart that is available through the apex to enable a range of treatments for structural heart disease. (See Micro Interventional Devices: Creating A Tool Box For Structural Heart Disease, IN VIVO, June 2012.)

Interventional cardiologist Dr. Martin Leon, of Columbia University and the Cardiovascular Research Foundation discussed the progress being made in transcatheter valves and related devices at the Innovations in Cardiovascular Interventions meeting in Tel Aviv in December 2011. In the past, he said, early TAVI prototypes relied heavily on operator creativity and off-the-shelf accessory devices. But as the field has evolved, each part of the procedure needs to be refined. Speaking at a session entitled "TAVR: Future Technology and Clinical Targets," Leon said, "Now, and especially in the future, all major and minor components of a TAVR system will be fully customized and designed for specific functional tasks. Moreover, adjunctive technology is being developed to enhance TAVR outcomes and reduce complications."

Transfemoral or Transapical: Which Is Better?

The start-ups profiled here are offering those adjunctive technologies to improve the management of the access sites, the two most common being transfemoral, generally the first-choice option, and transapical. (There are other methods, including the direct aortic, subclavian or axillary routes to the heart, but this article discusses only transfemoral and transapical approaches, which are the most widely used.)

Many considerations influence the choice of one route over the other. Probably most important is the skill set of the physician performing the procedure; interventional cardiologists generally prefer transfemoral access since it involves the catheter skills with which they are most experienced, and surgeons like the transapical approach because it requires their surgical skills. Transfemoral access provides access to the heart via a cut-down in the groin to gain entry to the femoral artery, through which the prosthetic valve is advanced on a guidewire over the aortic arch to the aortic valve. Transfemoral is the default option largely because it’s less invasive than transapical delivery, which requires an incision in the chest and the outer wall of the heart. There are other considerations; the quality of the patient’s vessels or his or her overall health status. The transfemoral approach is not feasible or is risky for patients with vessels that are too small, thin, fragile or tortuous for the large, stiff 18-24F delivery catheters or in patients with atherosclerotic or calcified vasculature. The transfemoral approach comes with certain risks of vascular complications: vessel perforations, the risk of dislodging embolic debris and complications of the vascular access site.

Because of those exclusions, in fact, 50% of TAVI procedures performed in Europe today employ the transapical route even though it is more invasive. Today’s transapical access methods require a mini-thoracotomy to access the chest space and a puncture in the apex of the left ventricle. The heart wall puncture is then dilated to allow the prosthetic valve to pass into the ventricular space. The transapical approach has demonstrated a reduced risk of stroke, generally attributed to the fact that the large diameter devices don’t travel through the vessels and over the aortic arch and thus don’t risk scraping off plaque, which can send embolic particles upstream to the brain.

The start-ups profiled here believe that improving access site management will go beyond procedural advantages to influence clinical outcomes. Better transapical access devices would provide a short and straight distance to the native annulus of the aortic and mitral valves, so it should be much easier to position the valves using this approach. The transapical route can also accommodate much larger heart valves because transfemoral access is limited by vessel size and quality. These are important features because improper valve positioning and insufficient valve size are two factors implicated in paravalvular leaks, a condition that increases mortality, and as noted, transapical access has the potential to improve upon both. But the transapical approach carries with it the increased risk resulting from its more invasive nature, along with the risk of access site bleeding. These disadvantages provide opportunities for device developers aiming to improve transapical procedures.

No matter which option is chosen, TAVI clinical practice is distinguished from other interventional or surgical procedures because of its emphasis on the need for the two groups of clinicians to operate as a team, since surgeons are sometimes required to do a cut-down in the femoral artery and manage it with sutures, and interventionalists sometimes need to lend their over-the-wire skills to surgeons advancing heart valves through the apex. (That’s why Edwards Lifesciences called its TAVI trial PARTNER.) The new access site management devices, by making access and closure safer, more reproducible and less dependent upon one specific skill set or the other, should help both groups of clinicians embrace this emerging hybrid practice area.

Access Devices Foster Team Spirit

In the United State, the heart team approach that sees surgeons and interventional cardiologists working together is required by the Food and Drug Administration approval of the Edwards’ Sapien valve. The Centers for Medicare & Medicaid Services have also made the joint participation of the two clinical specialties a condition of reimbursement. But even in Europe, where many centers have a choice to use one specialty or the other, the two groups still opt to work together because it’s important, when treating patients with heart valve disease, to be able to adapt to a particular patient’s circumstances. Cardiovascular industry veteran Jim Greene, now CEO of Apica Cardiovascular, says, "These are very old patients with very high risk scores. They are absolutely the worst patients I have ever seen." In Greene’s experience, clinicians are truly working together in teams, not just paying lip service to the concept. They’re jointly making decisions based on peripheral problems, the pumping function of the heart, carotid access and how much potential there is for stroke. "When this becomes truly endoscopic and percutaneous, you will see cardiologists doing transapical procedures and surgeons doing transfemoral TAVI. They are cross-training even now," Mr. Greene says. Cardiac surgeon and serial medical device entrepreneur Dr. Frank Litvack, chairman of Entourage Medical, says, "Clearly, the better the transfemoral access method and adjunct closure devices get, the more pressure there will be on the transapical area to improve, and the better the transapical devices get, the more pressure there will be on the transfemoral side." Many companies in this space are thus working on both sides of the problem to make available different access options for different patients – a patient-centered, rather than clinician-centered approach.

Dr. Litvack has participated in the development of the field of interventional cardiology since the 1980s, and he says this time, there is great partnership from the surgeon community. "Back in the ’80s and ’90s, surgeons tried to fight coronary interventions," he recalls. "But now they recognize there is an important place for these structural interventions and that they should participate and assist in the process."

Indeed, TAVI is only the first major intervention for structural heart disease. Many others lie ahead. Transcatheter treatment of the mitral valve is next and it’s an enormous market. More than 50% of the 5.2 million people with heart failure in the US suffer from mitral regurgitation. After a decade of development, this market is finally emerging. In June 2012, CardiAQ Valve Technologies Inc. became the first company to begin clinical trials of a transcatheter prosthetic mitral valve. Mitral valves will require much larger delivery systems (29F) and will benefit from a straight shot to the mitral annulus through the apex.

Other up and coming indications include the endovascular repair of abdominal aortic and thoracic aortic aneurysms, a potential market for large-bore closure devices. This is a growing market where least-invasive technology has the opportunity to electively treat a larger proportion of the 1.1 million people in the US who have abdominal aortic aneurysms.

Better transapical access could enable miniature LVADs (left ventricular assist devices) to be delivered to the left ventricle through the apex without the need to put very sick patients on cardiopulmonary bypass, which would be a breakthrough therapy for end-stage heart failure patients, a strategy of Apica Cardiovascular.

Certain types of electrophysiology ablations will also be easier to do transapically. When the foci of ablation are located in the mitral valve annulus area, it is much easier to get to the pulmonary vein from the apex and up through the mitral valve.

Micro Interventional Devices sees the potential to use its transapical access platform to treat patent foramen ovale and other congenital heart defects. It’s becoming clear that if companies succeed with their new access and closure devices, they’ll be doing more than offering procedural refinements for TAVI. They’ll be creating the gateway to interventional therapies for structural heart disease.

Editor’s note: This story appears courtesy of Start-Up, a monthly Elsevier magazine covering trends in the biopharma, Medtech, and diagnostics industries and leading-edge companies. To learn more, contact customer service at 800-332-2181 or see http://www.elsevierbi.com/publications/start-up.

With any new medical treatment, there are two types of risks: those that are known and anticipated from precommercial clinical work, and those that are unknown, can’t be predicted and only emerge once a device or procedure is exposed to real-world clinical practice. New products and procedures start out by being vetted in the protected, false security of clinical trials, involving small numbers of hand-picked patients often treated by leading physicians under ideal circumstances. Only as real-world clinical experience accumulates in large numbers of patients with a multitude of unpredictable comorbidities and complications do the unanticipated problems begin to emerge.

That’s where TAVI (transcatheter aortic valve implantation) is today. Minimally invasive transcatheter treatments for the aortic valve as an alternative to surgical valve replacement have been available in Europe since 2007 (and in the U.S. since November 2011), and in recent years the number of procedures in Europe has more than tripled, according to a presentation made at this year’s EuroPCR interventional cardiology meeting in Paris in May. Dr. Nicolo Piazza of the German Heart Center (Munich, Germany) noted that for Europe as a whole, TAVI procedures numbered 4,498 in 2009, 14,599 in 2010 and 18,372 in 2011. To date, an estimated 50,000 patients have been treated in 46 countries. That’s enough time and experience for the cracks in the new procedures to start to show.

The most serious problems to emerge include vascular and bleeding complications, stroke and paravalvular leaks. Innovators in the field, like Edwards Lifesciences Corp., the first on the market in Europe and the US, Medtronic Inc.’s Medtronic CoreValve LLC, which has TAVI products on the market in Europe, and numerous emerging companies are devoting lots of energy to the improvement of prosthetic valves and their delivery systems. These companies are looking to optimize valve design with the goal of minimizing the trauma the devices cause in the vessels on the way to the heart, or are crafting ways to position them better in the native annulus of the aortic valve. JenaValve Technology GMBH and Symetis SA, for example, believe they’ve grabbed second-generation advantages with valves that self-position and can be repositioned. Clinicians believe that better valve positioning will reduce paravalvular leaks. Colibri Heart Valve LLC is developing a smaller device, an atraumatic low-profile foldable aortic valve that can be delivered through a 14 French (14F) procedural sheath. Today, sheath diameters for current transcatheter heart valves range from 18F to 24F. A smaller device is easier to navigate through vessels, and theoretically causes less damage in very sick patients with fragile, thin, tortuous, or calcified vessels. For the start-ups developing these next-generation technologies the real question may be: Will clinicians prefer that the heart valves be revised to provide better access, or will they prefer a new method of access?

More than a dozen companies developing devices for access site management answer the latter in the affirmative. Their thesis is that new access devices can improve outcomes and bring more patients to minimally invasive treatments for structural heart disease.

One group of companies is working on vascular closure devices for large-bore procedures, that is, the delivery of large-diameter devices in the range of 12-24F. (The conventional balloons and stents of interventional cardiology can be delivered through sheaths 5-8F in diameter.) Large-bore procedures result in sizable wounds and overstretched vessels that will not close by manual compression, which is still the gold standard means of closure for small-bore procedures. This group includes Abbott Laboratories Inc., AccessClosure Inc. (a leader in small-bore vascular closure now developing a large-bore closure product), Promed Ltd., VivaSure Medical Ltd. and VasoStitch Inc.

The other group is targeting a newer access method, the less developed transapical procedure where the chest and apex of the heart are punctured to allow access to the left ventricle. The first products of Apica Cardiovascular Ltd. and Entourage Medical Technologies Inc., profiled in this issue, fit into this category, as do those of NovoGateMedicalLtd. and Micro Interventional Devices Inc.

As the long list of start-ups suggests, any truly successful new therapy will bring with it more products than just a single type of therapeutic implant (in this case the transcatheter heart valve). Michael Whitman, president and CEO of Micro Interventional Devices, says, "Whenever there is a disruptive or transformative technology, there is often a need to create peripheral devices around it to support it." MID plans to take advantage of the short and straight path to the heart that is available through the apex to enable a range of treatments for structural heart disease. (See Micro Interventional Devices: Creating A Tool Box For Structural Heart Disease, IN VIVO, June 2012.)

Interventional cardiologist Dr. Martin Leon, of Columbia University and the Cardiovascular Research Foundation discussed the progress being made in transcatheter valves and related devices at the Innovations in Cardiovascular Interventions meeting in Tel Aviv in December 2011. In the past, he said, early TAVI prototypes relied heavily on operator creativity and off-the-shelf accessory devices. But as the field has evolved, each part of the procedure needs to be refined. Speaking at a session entitled "TAVR: Future Technology and Clinical Targets," Leon said, "Now, and especially in the future, all major and minor components of a TAVR system will be fully customized and designed for specific functional tasks. Moreover, adjunctive technology is being developed to enhance TAVR outcomes and reduce complications."

Transfemoral or Transapical: Which Is Better?

The start-ups profiled here are offering those adjunctive technologies to improve the management of the access sites, the two most common being transfemoral, generally the first-choice option, and transapical. (There are other methods, including the direct aortic, subclavian or axillary routes to the heart, but this article discusses only transfemoral and transapical approaches, which are the most widely used.)

Many considerations influence the choice of one route over the other. Probably most important is the skill set of the physician performing the procedure; interventional cardiologists generally prefer transfemoral access since it involves the catheter skills with which they are most experienced, and surgeons like the transapical approach because it requires their surgical skills. Transfemoral access provides access to the heart via a cut-down in the groin to gain entry to the femoral artery, through which the prosthetic valve is advanced on a guidewire over the aortic arch to the aortic valve. Transfemoral is the default option largely because it’s less invasive than transapical delivery, which requires an incision in the chest and the outer wall of the heart. There are other considerations; the quality of the patient’s vessels or his or her overall health status. The transfemoral approach is not feasible or is risky for patients with vessels that are too small, thin, fragile or tortuous for the large, stiff 18-24F delivery catheters or in patients with atherosclerotic or calcified vasculature. The transfemoral approach comes with certain risks of vascular complications: vessel perforations, the risk of dislodging embolic debris and complications of the vascular access site.

Because of those exclusions, in fact, 50% of TAVI procedures performed in Europe today employ the transapical route even though it is more invasive. Today’s transapical access methods require a mini-thoracotomy to access the chest space and a puncture in the apex of the left ventricle. The heart wall puncture is then dilated to allow the prosthetic valve to pass into the ventricular space. The transapical approach has demonstrated a reduced risk of stroke, generally attributed to the fact that the large diameter devices don’t travel through the vessels and over the aortic arch and thus don’t risk scraping off plaque, which can send embolic particles upstream to the brain.

The start-ups profiled here believe that improving access site management will go beyond procedural advantages to influence clinical outcomes. Better transapical access devices would provide a short and straight distance to the native annulus of the aortic and mitral valves, so it should be much easier to position the valves using this approach. The transapical route can also accommodate much larger heart valves because transfemoral access is limited by vessel size and quality. These are important features because improper valve positioning and insufficient valve size are two factors implicated in paravalvular leaks, a condition that increases mortality, and as noted, transapical access has the potential to improve upon both. But the transapical approach carries with it the increased risk resulting from its more invasive nature, along with the risk of access site bleeding. These disadvantages provide opportunities for device developers aiming to improve transapical procedures.

No matter which option is chosen, TAVI clinical practice is distinguished from other interventional or surgical procedures because of its emphasis on the need for the two groups of clinicians to operate as a team, since surgeons are sometimes required to do a cut-down in the femoral artery and manage it with sutures, and interventionalists sometimes need to lend their over-the-wire skills to surgeons advancing heart valves through the apex. (That’s why Edwards Lifesciences called its TAVI trial PARTNER.) The new access site management devices, by making access and closure safer, more reproducible and less dependent upon one specific skill set or the other, should help both groups of clinicians embrace this emerging hybrid practice area.

Access Devices Foster Team Spirit

In the United State, the heart team approach that sees surgeons and interventional cardiologists working together is required by the Food and Drug Administration approval of the Edwards’ Sapien valve. The Centers for Medicare & Medicaid Services have also made the joint participation of the two clinical specialties a condition of reimbursement. But even in Europe, where many centers have a choice to use one specialty or the other, the two groups still opt to work together because it’s important, when treating patients with heart valve disease, to be able to adapt to a particular patient’s circumstances. Cardiovascular industry veteran Jim Greene, now CEO of Apica Cardiovascular, says, "These are very old patients with very high risk scores. They are absolutely the worst patients I have ever seen." In Greene’s experience, clinicians are truly working together in teams, not just paying lip service to the concept. They’re jointly making decisions based on peripheral problems, the pumping function of the heart, carotid access and how much potential there is for stroke. "When this becomes truly endoscopic and percutaneous, you will see cardiologists doing transapical procedures and surgeons doing transfemoral TAVI. They are cross-training even now," Mr. Greene says. Cardiac surgeon and serial medical device entrepreneur Dr. Frank Litvack, chairman of Entourage Medical, says, "Clearly, the better the transfemoral access method and adjunct closure devices get, the more pressure there will be on the transapical area to improve, and the better the transapical devices get, the more pressure there will be on the transfemoral side." Many companies in this space are thus working on both sides of the problem to make available different access options for different patients – a patient-centered, rather than clinician-centered approach.

Dr. Litvack has participated in the development of the field of interventional cardiology since the 1980s, and he says this time, there is great partnership from the surgeon community. "Back in the ’80s and ’90s, surgeons tried to fight coronary interventions," he recalls. "But now they recognize there is an important place for these structural interventions and that they should participate and assist in the process."

Indeed, TAVI is only the first major intervention for structural heart disease. Many others lie ahead. Transcatheter treatment of the mitral valve is next and it’s an enormous market. More than 50% of the 5.2 million people with heart failure in the US suffer from mitral regurgitation. After a decade of development, this market is finally emerging. In June 2012, CardiAQ Valve Technologies Inc. became the first company to begin clinical trials of a transcatheter prosthetic mitral valve. Mitral valves will require much larger delivery systems (29F) and will benefit from a straight shot to the mitral annulus through the apex.

Other up and coming indications include the endovascular repair of abdominal aortic and thoracic aortic aneurysms, a potential market for large-bore closure devices. This is a growing market where least-invasive technology has the opportunity to electively treat a larger proportion of the 1.1 million people in the US who have abdominal aortic aneurysms.

Better transapical access could enable miniature LVADs (left ventricular assist devices) to be delivered to the left ventricle through the apex without the need to put very sick patients on cardiopulmonary bypass, which would be a breakthrough therapy for end-stage heart failure patients, a strategy of Apica Cardiovascular.

Certain types of electrophysiology ablations will also be easier to do transapically. When the foci of ablation are located in the mitral valve annulus area, it is much easier to get to the pulmonary vein from the apex and up through the mitral valve.

Micro Interventional Devices sees the potential to use its transapical access platform to treat patent foramen ovale and other congenital heart defects. It’s becoming clear that if companies succeed with their new access and closure devices, they’ll be doing more than offering procedural refinements for TAVI. They’ll be creating the gateway to interventional therapies for structural heart disease.

Editor’s note: This story appears courtesy of Start-Up, a monthly Elsevier magazine covering trends in the biopharma, Medtech, and diagnostics industries and leading-edge companies. To learn more, contact customer service at 800-332-2181 or see http://www.elsevierbi.com/publications/start-up.

With any new medical treatment, there are two types of risks: those that are known and anticipated from precommercial clinical work, and those that are unknown, can’t be predicted and only emerge once a device or procedure is exposed to real-world clinical practice. New products and procedures start out by being vetted in the protected, false security of clinical trials, involving small numbers of hand-picked patients often treated by leading physicians under ideal circumstances. Only as real-world clinical experience accumulates in large numbers of patients with a multitude of unpredictable comorbidities and complications do the unanticipated problems begin to emerge.

That’s where TAVI (transcatheter aortic valve implantation) is today. Minimally invasive transcatheter treatments for the aortic valve as an alternative to surgical valve replacement have been available in Europe since 2007 (and in the U.S. since November 2011), and in recent years the number of procedures in Europe has more than tripled, according to a presentation made at this year’s EuroPCR interventional cardiology meeting in Paris in May. Dr. Nicolo Piazza of the German Heart Center (Munich, Germany) noted that for Europe as a whole, TAVI procedures numbered 4,498 in 2009, 14,599 in 2010 and 18,372 in 2011. To date, an estimated 50,000 patients have been treated in 46 countries. That’s enough time and experience for the cracks in the new procedures to start to show.

The most serious problems to emerge include vascular and bleeding complications, stroke and paravalvular leaks. Innovators in the field, like Edwards Lifesciences Corp., the first on the market in Europe and the US, Medtronic Inc.’s Medtronic CoreValve LLC, which has TAVI products on the market in Europe, and numerous emerging companies are devoting lots of energy to the improvement of prosthetic valves and their delivery systems. These companies are looking to optimize valve design with the goal of minimizing the trauma the devices cause in the vessels on the way to the heart, or are crafting ways to position them better in the native annulus of the aortic valve. JenaValve Technology GMBH and Symetis SA, for example, believe they’ve grabbed second-generation advantages with valves that self-position and can be repositioned. Clinicians believe that better valve positioning will reduce paravalvular leaks. Colibri Heart Valve LLC is developing a smaller device, an atraumatic low-profile foldable aortic valve that can be delivered through a 14 French (14F) procedural sheath. Today, sheath diameters for current transcatheter heart valves range from 18F to 24F. A smaller device is easier to navigate through vessels, and theoretically causes less damage in very sick patients with fragile, thin, tortuous, or calcified vessels. For the start-ups developing these next-generation technologies the real question may be: Will clinicians prefer that the heart valves be revised to provide better access, or will they prefer a new method of access?

More than a dozen companies developing devices for access site management answer the latter in the affirmative. Their thesis is that new access devices can improve outcomes and bring more patients to minimally invasive treatments for structural heart disease.

One group of companies is working on vascular closure devices for large-bore procedures, that is, the delivery of large-diameter devices in the range of 12-24F. (The conventional balloons and stents of interventional cardiology can be delivered through sheaths 5-8F in diameter.) Large-bore procedures result in sizable wounds and overstretched vessels that will not close by manual compression, which is still the gold standard means of closure for small-bore procedures. This group includes Abbott Laboratories Inc., AccessClosure Inc. (a leader in small-bore vascular closure now developing a large-bore closure product), Promed Ltd., VivaSure Medical Ltd. and VasoStitch Inc.

The other group is targeting a newer access method, the less developed transapical procedure where the chest and apex of the heart are punctured to allow access to the left ventricle. The first products of Apica Cardiovascular Ltd. and Entourage Medical Technologies Inc., profiled in this issue, fit into this category, as do those of NovoGateMedicalLtd. and Micro Interventional Devices Inc.

As the long list of start-ups suggests, any truly successful new therapy will bring with it more products than just a single type of therapeutic implant (in this case the transcatheter heart valve). Michael Whitman, president and CEO of Micro Interventional Devices, says, "Whenever there is a disruptive or transformative technology, there is often a need to create peripheral devices around it to support it." MID plans to take advantage of the short and straight path to the heart that is available through the apex to enable a range of treatments for structural heart disease. (See Micro Interventional Devices: Creating A Tool Box For Structural Heart Disease, IN VIVO, June 2012.)

Interventional cardiologist Dr. Martin Leon, of Columbia University and the Cardiovascular Research Foundation discussed the progress being made in transcatheter valves and related devices at the Innovations in Cardiovascular Interventions meeting in Tel Aviv in December 2011. In the past, he said, early TAVI prototypes relied heavily on operator creativity and off-the-shelf accessory devices. But as the field has evolved, each part of the procedure needs to be refined. Speaking at a session entitled "TAVR: Future Technology and Clinical Targets," Leon said, "Now, and especially in the future, all major and minor components of a TAVR system will be fully customized and designed for specific functional tasks. Moreover, adjunctive technology is being developed to enhance TAVR outcomes and reduce complications."

Transfemoral or Transapical: Which Is Better?

The start-ups profiled here are offering those adjunctive technologies to improve the management of the access sites, the two most common being transfemoral, generally the first-choice option, and transapical. (There are other methods, including the direct aortic, subclavian or axillary routes to the heart, but this article discusses only transfemoral and transapical approaches, which are the most widely used.)

Many considerations influence the choice of one route over the other. Probably most important is the skill set of the physician performing the procedure; interventional cardiologists generally prefer transfemoral access since it involves the catheter skills with which they are most experienced, and surgeons like the transapical approach because it requires their surgical skills. Transfemoral access provides access to the heart via a cut-down in the groin to gain entry to the femoral artery, through which the prosthetic valve is advanced on a guidewire over the aortic arch to the aortic valve. Transfemoral is the default option largely because it’s less invasive than transapical delivery, which requires an incision in the chest and the outer wall of the heart. There are other considerations; the quality of the patient’s vessels or his or her overall health status. The transfemoral approach is not feasible or is risky for patients with vessels that are too small, thin, fragile or tortuous for the large, stiff 18-24F delivery catheters or in patients with atherosclerotic or calcified vasculature. The transfemoral approach comes with certain risks of vascular complications: vessel perforations, the risk of dislodging embolic debris and complications of the vascular access site.

Because of those exclusions, in fact, 50% of TAVI procedures performed in Europe today employ the transapical route even though it is more invasive. Today’s transapical access methods require a mini-thoracotomy to access the chest space and a puncture in the apex of the left ventricle. The heart wall puncture is then dilated to allow the prosthetic valve to pass into the ventricular space. The transapical approach has demonstrated a reduced risk of stroke, generally attributed to the fact that the large diameter devices don’t travel through the vessels and over the aortic arch and thus don’t risk scraping off plaque, which can send embolic particles upstream to the brain.

The start-ups profiled here believe that improving access site management will go beyond procedural advantages to influence clinical outcomes. Better transapical access devices would provide a short and straight distance to the native annulus of the aortic and mitral valves, so it should be much easier to position the valves using this approach. The transapical route can also accommodate much larger heart valves because transfemoral access is limited by vessel size and quality. These are important features because improper valve positioning and insufficient valve size are two factors implicated in paravalvular leaks, a condition that increases mortality, and as noted, transapical access has the potential to improve upon both. But the transapical approach carries with it the increased risk resulting from its more invasive nature, along with the risk of access site bleeding. These disadvantages provide opportunities for device developers aiming to improve transapical procedures.

No matter which option is chosen, TAVI clinical practice is distinguished from other interventional or surgical procedures because of its emphasis on the need for the two groups of clinicians to operate as a team, since surgeons are sometimes required to do a cut-down in the femoral artery and manage it with sutures, and interventionalists sometimes need to lend their over-the-wire skills to surgeons advancing heart valves through the apex. (That’s why Edwards Lifesciences called its TAVI trial PARTNER.) The new access site management devices, by making access and closure safer, more reproducible and less dependent upon one specific skill set or the other, should help both groups of clinicians embrace this emerging hybrid practice area.

Access Devices Foster Team Spirit

In the United State, the heart team approach that sees surgeons and interventional cardiologists working together is required by the Food and Drug Administration approval of the Edwards’ Sapien valve. The Centers for Medicare & Medicaid Services have also made the joint participation of the two clinical specialties a condition of reimbursement. But even in Europe, where many centers have a choice to use one specialty or the other, the two groups still opt to work together because it’s important, when treating patients with heart valve disease, to be able to adapt to a particular patient’s circumstances. Cardiovascular industry veteran Jim Greene, now CEO of Apica Cardiovascular, says, "These are very old patients with very high risk scores. They are absolutely the worst patients I have ever seen." In Greene’s experience, clinicians are truly working together in teams, not just paying lip service to the concept. They’re jointly making decisions based on peripheral problems, the pumping function of the heart, carotid access and how much potential there is for stroke. "When this becomes truly endoscopic and percutaneous, you will see cardiologists doing transapical procedures and surgeons doing transfemoral TAVI. They are cross-training even now," Mr. Greene says. Cardiac surgeon and serial medical device entrepreneur Dr. Frank Litvack, chairman of Entourage Medical, says, "Clearly, the better the transfemoral access method and adjunct closure devices get, the more pressure there will be on the transapical area to improve, and the better the transapical devices get, the more pressure there will be on the transfemoral side." Many companies in this space are thus working on both sides of the problem to make available different access options for different patients – a patient-centered, rather than clinician-centered approach.

Dr. Litvack has participated in the development of the field of interventional cardiology since the 1980s, and he says this time, there is great partnership from the surgeon community. "Back in the ’80s and ’90s, surgeons tried to fight coronary interventions," he recalls. "But now they recognize there is an important place for these structural interventions and that they should participate and assist in the process."

Indeed, TAVI is only the first major intervention for structural heart disease. Many others lie ahead. Transcatheter treatment of the mitral valve is next and it’s an enormous market. More than 50% of the 5.2 million people with heart failure in the US suffer from mitral regurgitation. After a decade of development, this market is finally emerging. In June 2012, CardiAQ Valve Technologies Inc. became the first company to begin clinical trials of a transcatheter prosthetic mitral valve. Mitral valves will require much larger delivery systems (29F) and will benefit from a straight shot to the mitral annulus through the apex.

Other up and coming indications include the endovascular repair of abdominal aortic and thoracic aortic aneurysms, a potential market for large-bore closure devices. This is a growing market where least-invasive technology has the opportunity to electively treat a larger proportion of the 1.1 million people in the US who have abdominal aortic aneurysms.

Better transapical access could enable miniature LVADs (left ventricular assist devices) to be delivered to the left ventricle through the apex without the need to put very sick patients on cardiopulmonary bypass, which would be a breakthrough therapy for end-stage heart failure patients, a strategy of Apica Cardiovascular.

Certain types of electrophysiology ablations will also be easier to do transapically. When the foci of ablation are located in the mitral valve annulus area, it is much easier to get to the pulmonary vein from the apex and up through the mitral valve.

Micro Interventional Devices sees the potential to use its transapical access platform to treat patent foramen ovale and other congenital heart defects. It’s becoming clear that if companies succeed with their new access and closure devices, they’ll be doing more than offering procedural refinements for TAVI. They’ll be creating the gateway to interventional therapies for structural heart disease.

Editor’s note: This story appears courtesy of Start-Up, a monthly Elsevier magazine covering trends in the biopharma, Medtech, and diagnostics industries and leading-edge companies. To learn more, contact customer service at 800-332-2181 or see http://www.elsevierbi.com/publications/start-up.