Samir R. Kapadia, MD

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital & Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital &amp; Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital &amp; Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.