Author + information
- Received June 8, 2016
- Revision received August 23, 2016
- Accepted August 25, 2016
- Published online February 6, 2017.
- Jeffrey J. Popma, MDa,∗ (, )
- Michael J. Reardon, MDb,
- Kamal Khabbaz, MDa,
- J. Kevin Harrison, MDc,
- G. Chad Hughes, MDc,
- Susheel Kodali, MDd,
- Isaac George, MDd,
- G. Michael Deeb, MDe,
- Stan Chetcuti, MDe,
- Robert Kipperman, MDf,
- John Brown, MDf,
- Hongyan Qiao, PhDg,
- James Slater, MDh and
- Mathew R. Williams, MDh
- aDepartments of Internal Medicine (Cardiovascular Division) and Surgery (Cardiovascular Surgery), Beth Israel Deaconess Medical Center, Boston, Massachusetts
- bDepartment of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Institute, Houston, Texas
- cCardiology Division in the Duke Department of Medicine, Duke University Medical Center, Durham, North Carolina
- dDepartment of Surgery, Columbia University Medical Center–New York Presbyterian Hospital, New York, New York
- eDepartment of Cardiac Surgery, University of Michigan Health Systems, Ann Arbor, Michigan
- fDepartment of Cardiology, Morristown Memorial Hospital, Morristown, New Jersey
- gStatistical Services, Medtronic, Minneapolis, Minnesota
- hDepartments of Medicine (Cardiology) and Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York
- ↵∗Address for correspondence:
Dr. Jeffrey J. Popma, Interventional Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Boston, Massachusetts 02215.
Objectives This study sought to evaluate this transcatheter aortic valve (TAV) bioprosthesis in patients who are poorly suitable for surgical aortic valve (AV) replacement.
Background A novel self-expandable TAV bioprosthesis was designed to provide a low-profile delivery system, conformable annular sealing, and the ability to resheath and reposition during deployment.
Methods The Evolut R U.S. study included 241 patients with severe aortic stenosis who were deemed to be at least high risk for surgery treated at 23 clinical sites in the United States. Clinical outcomes at 30 days were evaluated using Valve Academic Research Consortium-2 criteria. An independent echocardiography laboratory was used to evaluate hemodynamic outcomes.
Results Patients were elderly (83.3 ± 7.2 years of age) and had high surgical risk (Society of Thoracic Surgeons predicted risk of mortality of 7.4 ± 3.4%). The majority of patients (89.5%) were treated by iliofemoral access. Resheathing or recapturing was performed in 22.6% of patients; more than 1 valve was required in 3 patients (1.3%). The 30-day outcomes included all-cause mortality (2.5%), disabling stroke (3.3%), major vascular complications (7.5%), life-threatening or disabling bleeding (7.1%), and new permanent pacemaker (16.4%). AV hemodynamics were markedly improved at 30 days: the mean AV gradient was reduced from 48.2 ± 13.0 mm Hg to 7.8 ± 3.1 mm Hg (p < 0.001) and AV area increased from 0.6 ± 0.2 cm2 to 1.9 ± 0.5 cm2 (p < 0.001). Moderate residual paravalvular leak was identified in 5.3% of patients.
Conclusions We conclude that this novel self-expanding TAV bioprosthesis is safe and effective for the treatment of patients with severe aortic stenosis who are suboptimal for surgery. (Medtronic CoreValve Evolut R U.S. Clinical Study; NCT02207569).
Transcatheter aortic valve replacement (TAVR) has become the default therapy for patients with severe aortic stenosis who are at increased risk for surgical aortic valve replacement (1,2). Self-expanding transcatheter aortic valves have been shown to improve mortality or major stroke compared with a pre-specified performance goal in patients who are unsuitable for surgery (3), and have lower mortality compared with aortic valve surgery in patients with increased surgical risk (4); these benefits have been confirmed at 2 years after the procedure (5,6). These results have been attributed to the unique design of the supra-annular porcine valve that supplies superior hemodynamics compared with surgery (5), and to the self-expanding nitinol frame that provides continued outward force that may result in annular remodeling after the procedure (7).
Design improvements of transcatheter bioprostheses have focused on reducing procedural complications by decreasing delivery catheter profile, improving annular sealing, and providing the ability to reposition the transcatheter valve during deployment. The fourth-generation Evolut R self-expanding bioprothesis (Medtronic, Minneapolis, Minnesota) addresses these issues; it includes a 14-F equivalent EnVeo R Deliver Catheter System (Medtronic), a modified nitinol design at the annulus that optimizes radial expansive force, a longer porcine pericardial sealing skirt, and a nitinol delivery catheter capsule that allows resheathing and recapturing during deployment (Figure 1).
The objectives of this study were to assess the early safety and efficacy of the device in patients with severe aortic stenosis who are at suboptimal risk for surgery, and to define the hemodynamic performance of the Evolut R bioprothesis after implantation.
The CoreValve Evolut R U.S. Clinical Study was a prospective, multicenter, controlled, nonrandomized single-arm clinical study performed at 23 clinical sites in the United States. Each institutional review board approved the study protocol and written informed consent was obtained from all patients. The trial was conducted in accordance with the International Conference on Harmonization, Good Clinical Practice Guidelines, and the Declaration of Helsinki.
The sponsor, Medtronic, designed the study in collaboration with the principal investigators and funded the study. Clinical site selection, data collection and monitoring, and statistical analyses were also performed by the sponsor. Study oversight included an independent clinical events committee that adjudicated all major adverse clinical events, an independent data safety monitoring board responsible for study oversight, and an independent echocardiographic core laboratory (Mayo Clinic, Rochester, Minnesota) to analyze all hemodynamic data.
The study cohort comprised patients with severe, symptomatic (New York Heart Association functional class II or more) aortic stenosis who were deemed to be at high through extreme risk for surgery. Local heart teams determined patient suitability for the trial, after which all information was reviewed by the central National Screening Committee to confirm eligibility in the study. Information reviewed included demographics and comorbidities, medical history, and clinical assessment, including frailty measures of the 5-m gait speed and grip strength, transthoracic echocardiography, and multislice computed tomography. The protocol required that patients be implanted within 30 days of screening acceptance into the study. Severe aortic stenosis was defined as an aortic valve area ≤1.0 cm2 or aortic valve index ≤0.6 cm2/m2 and either a mean aortic valve gradient >40 mm Hg or a peak aortic valve velocity >4.0 m/s, at rest or with dobutamine. Principal exclusion criteria were a gastrointestinal hemorrhage precluding anticoagulation, end-stage renal disease, left ventricular ejection fraction <20%, recent percutaneous coronary or peripheral intervention, a major stroke within the prior 6 months, or a life expectancy <1 year due to comorbidities.
All patients considered for inclusion underwent computed tomographic imaging (64-slice minimum) with retrospective electrocardiographic gating. End-systolic images were used to estimate perimeter-based annular diameters, along with estimates of the proximal ascending aorta, aortic root, and left ventricular outflow tract. Evolut R valve sizing was based on clinical site readings. A 23-mm Evolut R valve was selected for diameters between 18 and 20 mm; a 26-mm Evolut R was selected for diameters between 20 and 23 mm; and a 29-mm Evolut R was selected for diameters between 23 and 26 mm. To assess the effectiveness of these sizing recommendations, post hoc analysis of the device-annular sizing ratio was performed. Device-annular sizing ratio = ([valve perimeter – annulus perimeter]/annular perimeter) · 100.
The details of the procedure, valve, and delivery system have been described elsewhere (8). Balloon pre-dilation was left to the discretion of the operator. The self-expanding Evolut R valve was ideally positioned such that the inflow portion of the frame was 3 to 5 mm inferior to the noncoronary basal annulus. After deployment, valve performance was evaluated using transthoracic or transesophageal echocardiography, aortography, and invasive measurements of transaortic valve gradients and left ventricular end-diastolic pressures. Resheathing was defined as an attempt to intentionally resheath only a portion of the Evolut R bioprosthesis into the capsule of the delivery catheter. Recapture was defined as an attempt to intentionally fully resheath the entire Evolut R bioprosthesis into the capsule of the delivery catheter until there was no gap between capsule and the tip. Post-dilation was recommended in the event of moderate or severe paravalvular leak (PVL) due to frame underexpansion.
Transthoracic echocardiograms obtained at baseline, hospital discharge, and 30 days were analysis by the independent echocardiography core laboratory. Post-procedural regurgitation was graded using multiple parameters including regurgitation color jet density and width, circumferential extent of turbulent regurgitation color jet around the aortic annulus for PVL, descending and abdominal aorta diastolic flow reversal on pulsed wave Doppler, and pressure one-half time of aortic regurgitation on the continuous wave Doppler signal. When there was discordance regarding the severity of PVL among these parameters, color flow imaging was the first priority in the hierarchy of determining its severity as follows: trace regurgitation when there is a trace of short lasting (less than the entire diastole) with or without a dot of regurgitation jet around the aortic annulus; mild regurgitation where the circumferential extent was <10% with turbulent aortic regurgitation jet; moderate regurgitation when the circumferential extent was 10% to 20%; and severe regurgitation when the circumferential extent was >20% (9).
The 2 primary safety endpoints were the occurrence of all-cause mortality at 30 days and the rate of disabling stroke at 30 days. The secondary safety endpoints included the Valve Academic Research Consortium-2 (VARC-2)–defined composite endpoint (10), comprising all-cause mortality, all stroke, life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction requiring intervention, major vascular complication and valve-related dysfunction requiring repeat intervention, and the individual components at 30 days. The rate of new permanent pacemaker implantation at 30 days was also a secondary safety endpoint.
The primary clinical efficacy endpoint included the occurrence of the VARC-2 device success rate at 1 to 7 days, and the percentage of patients with no more than mild aortic regurgitation at the early post-procedure echocardiogram (10). Secondary clinical efficacy endpoints included recapture success rate (when attempted), and mean prosthetic valve gradient, effective orifice area, and the degree of prosthetic valve regurgitation at 30 days.
Safety outcomes were analyzed for patients who underwent an attempted implant. Efficacy outcomes are analyzed for patients who were successfully implanted. Categorical variables were summarized as numbers and percentages. Continuous variables were presented as mean ± SD. Kaplan-Meier estimates were used for the time-to-event analysis. The 30-day echocardiographic measurements were compared with baseline values using paired Student t test. All testing used a 2-sided alpha level of 0.05. All statistical analyses were performed with the use of SAS software, version 9.2 (SAS Institute, Cary, North Carolina).
A total of 241 patients underwent attempted implant of the Evolut R transcatheter aortic valve from September 2014 to July 2015. Clinical demographics are found in Table 1. Patients were elderly (83.3 ± 7.2 years of age) and had high surgical risk (Society of Thoracic Surgeons predicted risk of mortality = 7.4 ± 3.4%). Additional comorbid conditions and indexes of frailty and disability confirm the high surgical risk of this patient population (Table 1).
Of the 241 patients who underwent attempted implant, 237 received the Evolut R system. Procedural outcomes are found in Table 2. The majority of cases (80.7%) were performed using general anesthesia. An iliofemoral access route was used in 89.5% of cases. There were no cases of myocardial infarction. Resheathing or recapturing was performed in 22.6% of patients. The use of more than 1 Evolut R was uncommon (1.3%). These 3 cases include 1 Evolut-R positioned high within the annulus resulting in paravalvular regurgitation despite balloon post-dilation, 1 due to incomplete expansion due to excessive calcium, and 1 ectopic placement in the sinus of Valsalva at the time of deployment. There were no cases of valve endocarditis, valve thrombosis, valve embolization or migration, valve dysfunction requiring reintervention, or structural damage to the mitral valve apparatus. One patient experienced a coronary occlusion that was successfully stented without sequelae. Figure 2 shows New York Heart Association functional class symptoms over time.
The 30-day clinical outcomes are found in Table 3. The all-cause mortality rate was 2.5%; all deaths were deemed cardiovascular in nature. Three deaths occurred within the first 24 h: 2 were due to aortic dissection and 1 related to left ventricular perforation. Additional deaths occurred at days 3 (cardiac arrest following procedural valve in valve and possible stroke), 5 (retroperitoneal hematoma and respiratory failure), and 13 (post-procedural left bundle branch block and sudden death while asleep). The frequency of disabling stroke was 3.3%. Vascular and bleeding complications were uncommon. A permanent pacemaker was placed in 16.4% of patients for conduction system abnormalities.
Baseline, post-procedural, and 30-day echocardiographic findings are found in Table 4. Marked improvements in aortic valve hemodynamics were demonstrated at 30 days; the mean aortic valve gradient was reduced from baseline, 48.2 ± 13.0 mm Hg to 7.8 ± 3.1 mm Hg (p < 0.001), and the aortic valve area increased from baseline, 0.6 ± 0.2 cm2 to 1.9 ± 0.5 cm2 (p < 0.001). At 30 days, no patients had severe PVL, and moderate residual PVL was identified in 5.3% of patients. The frequency of the residual PVL was inversely related to the device to annular ratio (Figure 3).
We report the early clinical outcomes of patients treated with the novel Evolut R transcatheter bioprosthesis, an iterative self-expanding transcatheter design with a lower 14-F equivalent delivery catheter profile, enhanced annular conformability, and the ability to resheath and recapture the bioprosthesis in the event of suboptimal position. The results of this study support the safety and efficacy of this device in patients with severe aortic stenosis with a low frequency of moderate or greater aortic regurgitation and lower requirement for permanent pacemaker due to conduction abnormalities.
We have previously shown that the device annular ratio, an estimate of the degree of TAV oversizing, is an important predictor of the occurrence of moderate or severe residual aortic regurgitation after self-expanding TAVR (7). The Evolut R was designed to provide optimal TAV sizing, with the nominal size of the Evolut R now targeted to the recommended implantation depth of 3 to 5 mm below the basal annular plane. The device annular ratio ranged from 15.0% to 27.8% for the 23-mm Evolut R, 13.0% to 30.0% for the 26-mm Evolut R, and 11.5% to 26.1% for the 29-mm Evolut R. We also found a trend between the device annular ratio and the occurrence of moderate or severe PVL, particularly for the 29-mm Evolut R (Figure 3). Appropriate sizing using computed tomography is 1 of the most important predictors of residual aortic regurgitation with the self-expanding bioprosthesis.
Aortic valve hemodynamics post-TAVR
Prior studies evaluating the predicate CoreValve self-expanding transcatheter aortic valve have demonstrated very low (<10 mm Hg) mean residual aortic valve gradients after placement of the self-expanding bioprosthesis, related, in part, to the supra-annular location of the porcine pericardial valve (3,4). Compared with surgical prostheses, the residual gradients were significantly lower following self-expanding TAVR 2 years after the procedure (5). We have shown the frequency of severe prosthesis-patient mismatch, an important predictor of outcome (11), was lower with a self-expanding bioprothesis than with surgical valves (12). The current study confirmed the low residual aortic valve gradient (7.8 ± 3.1 mm Hg) and large effective orifice area (1.9 ± 0.5 cm2) associated with the use of the self-expanding Evolut R bioprosthesis despite substantial modification of the nitinol frame. These low gradients may also have implications for low rates of late structural valve deterioration. We did not find a significant difference in the residual gradients for the 26-mm (7.5 ± 2.6 mm Hg) and 29-mm (7.9 ± 3.1 mm Hg) Evolut R valves (p = 0.44) at 30 days.
Residual aortic regurgitation
A number of studies have shown the importance of residual aortic regurgitation and long-term outcomes (13,14). Prior analyses with the CoreValve transcatheter aortic valve have demonstrated the importance of using multidetector computed tomography to estimate annular dimensions and that the upper range of sizing resulted in less residual PVL (15). With an emphasis on better sizing, optimal implantation methods, and the improved Evolut R bioprosthesis design, including a longer skirt (13 mm rather than 12 mm) and better conformability to the annulus, we have seen a reduction in the frequency of moderate or severe residual PVL at 30 days from the CoreValve U.S. Pivotal Extreme Risk Trial (11.4%) (3), to the U.S. Pivotal High Risk Trial (9.0%), and to the current CoreValve Evolut R U.S. Trial (5.3%). The ability to reposition the device, which was performed in 22.6% of cases, likely added to the ability to obtain optimal placement with this bioprosthesis.
Delivery catheter size
Our protocol required a minimal lumen diameter of the iliofemoral artery >5.0 mm, which now allows patients with iliofemoral vessel diameter between 5.0 and 6.0 mm who were previously excluded from transfemoral access using an 18-F sheath. Our prior studies found that 21.1% of patients required alternative access (16). With the 14-F equivalent delivery system, we were now able to treat nearly 90% of patients with transfemoral access. Moving to smaller vessel diameters was achieved without an increase in major vascular complication or life-threatening or disabling bleeding compared with prior reports of self-expanding transcatheter valves using an 18-F sheath in the CoreValve U.S. Pivotal Extreme Risk (8.2% and 12.7%, respectively) (3) and U.S. Pivotal High Risk (5.9% and 13.6%, respectively) studies (4). Given the potentially higher complication rate and morbidity in patients requiring alternative access, the 14-F equivalent EnVeo R Catheter Delivery System with EnVeo Inline Sheath (Medtronic) may help patients with borderline iliofemoral anatomy.
The current study includes only patients with perimeter-based diameters between 18 and 26 mm and does not include an evaluation of this novel design in larger annular sizes. An Evolut R 34 XL will be studied in annular ranges of 26 to 30 mm. The EnVeo In-Line Sheath may require placement of an 18-F sheath in the setting of very tortuous anatomy. We did not study the effect of annular and left ventricular outflow tract calcification on the frequency of residual aortic regurgitation.
We conclude that this novel self-expanding transcatheter bioprothesis is safe and effective for the treatment of severe aortic stenosis in patients who are suboptimal for surgery. The reduced profile allows more patients to be treated with transfemoral access with low rates of vascular and bleeding complications. The ability to reposition the device during deployment allows more precision positioning, resulting in reduced rates of residual aortic regurgitation and conduction disturbances requiring permanent pacemaker placement.
WHAT IS KNOWN? TAVR is now established therapy for patients with aortic stenosis deemed suboptimal surgery.
WHAT IS NEW? A novel self-expanding transcatheter aortic valve design iteration that provides a lower catheter profile, enhanced annular sealing, and retrievability to optimize valve positioning was shown to be safe and effective in symptomatic patients with aortic stenosis at high risk or greater for surgery.
WHAT IS NEXT? Further iterations of self-expanding transcatheter heart valves will be designed to provide further reductions in residual aortic regurgitation and lower pacemaker requirements, critical features as TAVR is expanded into lower-risk populations.
Dr. Popma has received grant support to his institution from Medtronic, Boston Scientific, and Direct Flow Medical; has served on the medical advisory board for Boston Scientific; and has served as a consultant for Direct Flow Medical. Dr. Reardon has received fees from Medtronic for providing educational services. Dr. Harrison has received institutional research grants from Boston Scientific, Direct Flow Medical, Edwards Lifesciences, and Medtronic; has served on an Advisory Board for St. Jude Medical; and is on the Data Safety and Monitoring Board for CardiAQ. Dr. Kodali has received grant and research support from Boston Scientific, Claret Medical, Edwards Lifesciences, and Medtronic; has served on the steering committee for Claret Medical, Edwards Lifestyle, and Meril; has held equity in Thubrikar Aortic Valve; and has received honoraria from Claret Medical and St. Jude Medical. Dr. George is a consultant to Edwards Lifesciences and Medtronic; and is surgical national principal investigator of the Direct Flow Medical SALUS trial. Dr. Deeb has served on the advisory board and as a proctor for Medtronic; is a consultant and research investigator for Edwards Lifesciences; is a consultant and proctor for Terumo; and is a research investigator for Gore Medical. Dr. Chetcuti has received grants from Medtronic, Edwards Lifesciences, and Boston Scientific. Dr. Qiao is an employee and shareholder of Medtronic. Dr. Slater has received consulting fees and honoraria from Medtronic. Dr. Williams has served as a consultant for Edwards Lifesciences and Medtronic; is a speaker for Abbott Laboratories; and has received research grants from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- paravalvular leak
- transcatheter aortic valve replacement
- Valve Academic Research Consortium
- Received June 8, 2016.
- Revision received August 23, 2016.
- Accepted August 25, 2016.
- American College of Cardiology Foundation
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