Author + information
- Received July 3, 2013
- Revision received October 1, 2013
- Accepted October 8, 2013
- Published online March 4, 2014.
- Joachim Schofer, MD∗∗ (, )
- Antonio Colombo, MD†,
- Silvio Klugmann, MD‡,
- Jean Fajadet, MD§,
- Federico DeMarco, MD‡,
- Didier Tchétché, MD§,
- Francesco Maisano, MD†,
- Giuseppe Bruschi, MD‡,
- Azeem Latib, MD†,
- Klaudija Bijuklic, MD∗,
- Neil Weissman, MD‖,
- Reginald Low, MD¶,#,
- Martyn Thomas, MD∗∗,
- Christopher Young, MD∗∗,
- Simon Redwood, MD∗∗,
- Michael Mullen, MD††,
- John Yap, MD††,
- Eberhard Grube, MD‡‡,
- Georg Nickenig, MD‡‡,
- Jan-Malte Sinning, MD‡‡,
- Karl Eugen Hauptmann, MD§§,
- Ivar Friedrich, MD§§,
- Michael Lauterbach, MD§§,
- Michael Schmoeckel, MD‖‖,
- Charles Davidson, MD¶¶ and
- Thierry Lefevre, MD∗∗∗
- ∗Medical Care Center Prof. Mathey, Prof. Schofer, Hamburg University Cardiovascular Center, Hamburg, Germany
- †San Raffaele Hospital, Milan, Italy
- ‡Azienda Ospedaliera Niguarda Ca Granda, Milan, Italy
- §Clinique Pasteur, Toulouse, France
- ‖MedStar Health Research Institute, Georgetown University, Washington, DC
- ¶University of California Davis, Davis, California
- #St. Thomas' Hospital, London, England
- ∗∗The Heart Hospital, London, England
- ††University Hospital Bonn, Bonn, Germany
- ‡‡Krankenhaus der Barmherzigen, Trier, Germany
- §§Asklepios Klinik St Georg, Hamburg, Germany
- ‖‖Northwestern Memorial Hospital, Chicago, Illinois
- ¶¶L'Institut Cardiovasculaire Paris Sud, L'Institut Hospitalier Jacques Cartier, Massy, France
- ∗∗∗Clinical Imaging Analytics, Guerneville, California
- ↵∗Reprint requests and correspondence:
Dr. Joachim Schofer, Medical Care Center Prof. Mathey, Prof. Schofer, Hamburg University Cardiovascular Center, Wördemanns Weg 25-27, Hamburg, Hamburg 22527, Germany.
Objectives The study sought a prospective multicenter nonrandomized evaluation of the Direct Flow Medical (DFM) system for the treatment of severe aortic stenosis.
Background The DFM transcatheter aortic valve system is a nonmetallic design with a pressurized support structure that allows precise positioning, retrieval, and assessment of valve performance prior to permanent implantation.
Methods One hundred high surgical risk patients with severe aortic stenosis were evaluated for the primary endpoint. There were 75 patients in the group evaluable for the secondary endpoints and 25 in the pre-specified roll-in training phase. Echocardiographic and angiographic data were evaluated by an independent core laboratory and adverse events adjudicated by clinical event committee and classified according to Valve Academic Research Consortium (VARC) criteria.
Results There was 99% freedom from all cause mortality at 30 days (primary endpoint). VARC criteria defined 30 day combined freedom from patient safety event rate was 91% and overall device success was 93%. The post-implantation echocardiography results demonstrated mild or no aortic regurgitation in 99% (73 of 74) with a mean gradient of 12.6 ± 7.1 mm Hg (n = 72) and effective orifice area of 1.50 ± 0.56 cm2 and New York Heart Association functional class was I or II in 92% of cases.
Conclusions The present study demonstrates the safety and efficacy of the DFM system in surgical high risk patients with severe aortic stenosis and complex anatomy aortic regurgitation was less than moderate in 99% of patients.
Transcatheter aortic valve replacement has been successfully applied to high risk patients with symptomatic aortic stenosis (1,2). Currently available devices include the inability to fully reposition or remove it after deployment. Misplacement of the valve can result in severe complications (3,4).
The Direct Flow Medical (DFM) transcatheter aortic valve system is a nonmetallic design with an inflatable and deflatable support structure (Fig. 1) that allows precise positioning, retrieval and assessment of valve performance in its final position. An 18-F sheath is used for all valve sizes.
The aim of this prospective multicenter study was to determine the safety and performance of the DFM system.
Patients with symptomatic aortic stenosis who were >70 years of age were required to have a logistic EuroSCORE ≥20% or other high surgical risk features that lead the heart team including the cardiologist and cardiovascular surgeon at the clinical site recommend transcatheter aortic valve replacement (TAVR). Inclusion and exclusion criteria for all patients were reviewed by an independent patient review committee (Online Appendix).
Severe aortic valve stenosis was defined by echocardiographic criteria including a mean gradient >40 mm Hg or peak jet velocity >4.0 m/s and aortic valve area ≤0.8 cm2 or aortic valve area index ≤0.5 cm2/m2. There was core laboratory evaluation for gated cardiac computed tomography (Clinical Imaging Analytics, Guerneville, CA) and echocardiographic and angiographic studies (Medstar, Washington, DC). Aortic regurgitation was assessed according to Valve Academic Research Consortium (VARC) criteria.
Exclusion criteria included an annulus diameter by computed tomography scan <19 mm or >26 mm, prior to valve surgery, prosthetic heart valve in any position, greater than moderate mitral insufficiency, left ventricular ejection fraction <30%, myocardial infarction or coronary intervention within 30 days prior, stroke or transient ischemic attack within 6 months, or chronic kidney disease (creatinine >3.0 mg/dl).
The primary endpoint was freedom from all-cause mortality at 30 days. Secondary endpoints included VARC-defined patient safety and device success (5). Clinical events and safety of the study were adjudicated by independent committees (Online Appendix). All operators were trained on a simulated bench model and in an animal laboratory. To allow for the operator to gain technical expertise with this new technology, the study was designed with a preplanned roll-in cohort of 3 patients per site. These patients were not evaluated for secondary endpoints.
The DFM aortic valve (Fig. 1) is a nonmetallic percutaneous bovine pericardial valve with an expandable Dacron polyester double ring design containing noncompliant angioplasty balloon technology. The upper (aortic) and lower (ventricular) ring balloons, interconnected by a tubular bridging system, can be pressurized independently through position-fill lumens. The bioprosthesis is provided in 25 mm size for annular diameter of 19 to 24 mm and in 27 mm size for 22 to 26 mm. Valve size recommendations are based on computed tomography dimensions.
All procedures were performed transfemorally. Following balloon valvuloplasty, the DFM implant delivery catheter is positioned in the left ventricle (Fig. 2). Both ring balloons are pressurized by injecting a mixture of saline and contrast media through the position-fill lumens. Immediately, the valve is functional, without the need for rapid ventricular pacing. The aortic ring balloon is deflated. By retracting and/or pushing the 3 position wires, the ventricular ring is aligned to the aortic annulus. The aortic ring balloon is pressurized. The performance and correct position are assessed. If desired, the balloons can be depressurized and the prosthesis repositioned or completely retrieved. For retrieval both ring balloons are deflated and the valve is pulled into a Nitinol basket (Direct Flow Medical, Santa Rosa, California) in the abdominal aorta and retrieved through the introducer sheath. Once optimal position is obtained, a polymer is infused into the bioprosthesis replacing the contrast and saline by maintaining the pressure in the bioprosthesis at 12 atm. The polymer solidifies and the device is no longer retrievable.
For categorical data, the denominator included only subjects in whom the outcome could be assessed. The p values for categorical outcomes are based on the chi-square or Fisher's exact test, and p values for continuous variables were based on the 2-sample t test, unless the data showed evidence of a significant departure from normality in which case the Wilcoxon rank sum test was used. Results for effective orifice area, mean gradient, left ventricular ejection fraction, and aortic regurgitation were reported from post-procedure through 30 days by taking the first available data point.
One hundred patients were enrolled in 9 centers in Europe (Fig. 3). Each center was allowed 3 roll-in patients. Two centers enrolled only 2 patients, and therefore there was a total of 25 patients in the pre-specified training cohort (cohort A). The primary endpoint of all-cause mortality is reported for all 100 patients. All secondary endpoints are reported for the 75 evaluable patients (cohort B). Baseline characteristics for both cohort A and B are shown in Table 1. There were no statistically significant differences between the groups.
Freedom from all-cause mortality at 30 days was met in 99 of 100 patients (99%). One patient died at day 12 due to complications of pneumonia. All of the cohort B patients underwent balloon aortic valvuloplasty with an average of 1.5 balloon inflations. Balloon sizes were 23 mm for the 25 mm and 25 mm for the 27 mm valve. Seventy-four of 75 patients received the study device, 44 patients a 25 mm, and 30 a 27-mm valve. No patient required post-implant balloon dilation.
The average time from sheath insertion to vessel closure was 37.6 min including the time to position and assess valve function, which was on average 14 min. This included transesophageal echocardiography, invasive hemodynamics, and angiography. The recommended minimal arterial access size was >6.5 mm and the minimum diameter accessed was 5.2 mm. Based on investigator preference, 15 patients (20%) had surgical femoral cut-down and 60 (80%) percutaneous arterial closure. New York Heart Association functional class improved by at least 1 in 83%, at least 2 in 34%, and 3 in 1.5% of patients.
VARC-defined device success
VARC-defined device success was obtained in 93% (70 of 75 patients) (Table 2). Device failure was due to a post-implant transvalvular gradient ≥20 mm Hg or peak velocity ≥3 m/s in 2 patients. One patient (1.4%) had moderate aortic regurgitation. Eight patients required retrieval of the initially attempted valve implant that was successful in all cases. Six retrievals were done to place a different size valve and 2 were due to retraction of the valve into the aorta during attempted placement. In all patients, another DFM valve was successfully implanted.
VARC-defined patient safety at 30 days
The 30-day freedom from event rate was 91% (68 of 75 patients) (Table 3). Major strokes occurred in 3, at days 1, 2, and 19 after the procedure. The third had chronic atrial fibrillation without oral anticoagulation. The composite of stroke and death within 30 days occurred in 3 patients. Two patients had life-threatening or disabling bleeding due to femoral arterial access site bleeding and retroperitoneal hematoma. VARC-defined major vascular complications occurred in 2: retroperitoneal hematoma and closure device failure requiring surgical repair. Periprocedural myocardial infarction occurred in 1 patient. An acute conversion to surgical aortic valve replacement was performed in 1 patient due to improper initial placement of the valve. The patient had an uneventful postoperative recovery. The rate of pacemaker implantation for all 100 patients was 17%.
Echocardiographic transvalvular gradient
The mean gradient decreased from an average of 45.9 ± 9.6 mm Hg (n = 72) to an average of 12.6 ± 7.1 mm Hg (n = 72) post-procedure through 30 days (Table 4). The effective orifice area at baseline was 0.65 ± 0.18 cm2 (n = 60) and increased to 1.50 ± 0.56 cm2 (n = 64) at 30 days.
The post implantation VARC-defined aortic regurgitation was mild or less in 73 of 74 (98.6%) No patient had severe aortic regurgitation (Table 5). The severity of central aortic regurgitation was graded as none or mild in all 74 patients. Paravalvular regurgitation was none in 70.3%, mild in 28.4%, and moderate in 1 (1.4%) (Fig. 4). Aortic regurgitation could be evaluated by contrast aortography immediately post implant in 63 patients. According to American College of Cardiology/American Heart Association criteria (6), it was mild or less in 62 (97%) and moderate in 2 (3%).
The major findings of this multicenter nonrandomized study of the DFM 18-F system for high surgical risk patients with severe aortic stenosis were a VARC-defined device success rate of 93% and 30-day freedom from VARC-defined safety event rate of 91% with an all-cause mortality rate of 1.0% (1 of 100) at 30 days. These results compare favorably to a recent meta-analysis of 16 studies including 3,519 patients using both Edwards (Edwards Lifesciences, Irvine, California) and CoreValve (CoreValve Medtronic, Minneapolis, Minnesota) prosthesis (7–9). In this analysis, combined device success was 92%, 30-day event rate was 22.1%, and 30-day mortality was 7.8%, stroke was 5.7%, vascular complications was 18.8%, new pacemaker was 13.9%, and the combined incidence of valve embolization or need for open surgery was 3.0%. Similar rates were reported in other studies (1–3,8).
Post implantation aortic regurgitation, using VARC criteria, was none in 62.2%, mild in 36.5%, and moderate in 1.4% of patients. No patients had severe aortic regurgitation. The device has conformable rings and is retrievable if the size of the prosthesis is incorrect, which is a frequent reason for significant paravalvular regurgitation. In contrast to the DFM valve, results obtained with the SAPIEN and CoreValve show incidences of moderate to severe AR ranging from 12% to 21%, respectively (7,8). The importance of this finding is reflected in the higher incidence of death in those with residual moderate or greater AR compared to those without.
The PARTNER trial demonstrated that neurologic events occurred more frequently after TAVR than surgical aortic valve replacement at 30 days and 1 year (10). In the present study, the incidence of stroke was 4% (n = 3). One of the 3 patients with stroke after 3 weeks had atrial fibrillation without oral anticoagulation at the time of the event. Nuis et al evaluated the frequency and causes of stroke with TAVR in 214 patients (11). Stroke occurred in 19 patients (9%). Independent determinants of stroke were new-onset atrial fibrillation and baseline aortic regurgitation grade ≥3.
Vascular and bleeding complications
The low profile and high degree of flexibility and trackability of the delivery catheter lead to low major vascular and life threatening or disabling bleeding complications. They were both 2.7%. In the PARTNER (Placement of AoRTic TraNscathetER Valve Trial) trial (12), major vascular complications and major bleeding after transfemoral TAVR were seen in 15.3% and 60.9%, respectively. Major vascular complications were associated with a more than 4-fold increase in 30-day mortality and a high rate of major bleeding (60.9%) at 30 days, and were an independent predictor of 1-year mortality.
New pacemaker implantations
The incidence of a new permanent pacemaker range from 24% to 29% in those receiving CoreValve and 5% to 11% with SAPIEN (8,9,13). The overall permanent pacing rate for all patients in this study was 17%.
The main limitations of this study are the small cohort and the limited follow-up duration. Core laboratory analyzable images were not available for all patients.
The present study demonstrates the safety and efficacy of the repositionable, retrievable DFM System in high and extreme risk patients with severe aortic stenosis. Less than moderate aortic regurgitation occurred in 99% of patients.
For a full list of members of the study management sections, please see the online version of this article.
Dr. Schoer is a consultant for Direct Flow Medical. Drs. Colombo and Davidson are consultants and minor share holders for Direct Flow Medical. Dr. DeMarco is a consultant for and has received proctoring fees from Direct Flow Medical. Dr. Maisano is a consultant for Abbott Vascular, Medtronic, St. Jude Medical, Valtech Cardio; has received royalties from Edwards Lifesciences; and is cofounder of 4Tech. Dr. Bruschi is a consultant for Medtronic and a proctor of CoreValve (Medtronic). Dr. Latib serves on the advisory board for Medtronic; and is a consultant and proctor for Direct Flow Medical. Dr. Weismann has received grant support from Direct Flow Medical, Abbott Vascular, Medtronic, St. Jude Medical, Sorin, and Edwards Lifesciences. Dr. Mullen is a consultant for Edwards Lifesciences. Dr. Lefevre is a proctor for Edwards Lifesciences; and has received minor fees from Direct Flow Medical and Symetis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Direct Flow Medical
- transcatheter aortic valve replacement
- Valve Academic Research Consortium
- Received July 3, 2013.
- Revision received October 1, 2013.
- Accepted October 8, 2013.
- American College of Cardiology Foundation
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