Author + information
- aKlinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany
- bDeutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK) e.V. (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- ↵∗Address for correspondence:
Dr. Christian Hengstenberg, Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany.
Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of severe, symptomatic aortic stenosis in patients who are at intermediate or high risk for conventional surgery (1,2). With increasing operator experience and improved patient selection, along with continuous evolution of transcatheter heart valves (THVs) and refinement of delivery systems, a considerable improvement in outcome has been achieved. This is reflected by a reduction in 1-year mortality from 24% using older-generation THVs (3) to 12% with newer-generation devices (2). Considerable effort has been invested in both balloon-expandable and self-expanding THVs to address the limitations of earlier-generation devices. These include a reduction in paravalvular leakage (PVL), requirement for new permanent pacemaker implantations (PPIs), and vascular complications. Among these novel devices, the Evolut R (Medtronic, Minneapolis, Minnesota) is the latest-generation THV of the CoreValve family. It features a self-expanding nitinol frame with a supra-annular porcine pericardial valve, and may be implanted through a 14-F compatible delivery system. Additionally, this novel THV offers the possibility of being resheathed, repositioned, and if necessary, fully recaptured. The accuracy of deployment is enhanced by an improvement in torque response of the delivery system. Finally, the radial force of the frame has been enhanced by improvements in cell geometry.
In this issue of the Journal, the FORWARD study reports clinical short-term results with the Evolut R THV (Medtronic), in routine clinical practice (4). In this prospective, observational, single-arm, multicenter study, 1,038 patients were treated for severe, symptomatic aortic stenosis or degenerated bioprostheses. The all-cause mortality and disabling stroke rates were 1.9% and 1.8%, respectively. The rate of moderate or severe PVL was 2.0%.
This study significantly adds to the present experience with this THV, gathered since the first smaller series was published in 2015 (5). Since then, this novel THV has been mainly studied in smaller, high-risk populations, namely in the UK & Ireland Evolut R Implanters’ Registry (6) and the Evolut R U.S. Clinical Study (7). In the former, conducted in 264 high-risk patients, 30-day mortality was 2.3%, the stroke rate was 3.8%, and moderate to severe PVL was observed in 7.7% (6). In the latter, examining 241 patients at high risk, results were comparable, with a 30-day mortality of 2.5%, stroke rate of 3.3%, and moderate or severe PVL in 5.3% of cases (7). The FORWARD study includes a considerably larger population who are at intermediate risk, reflected by a mean Society of Thoracic Surgeons score of 5.5%. The FORWARD study demonstrates considerable improvement in valvular performance, with a core laboratory–adjudicated moderate or severe PVL rate in only 2.0% of cases. This figure compares very favorably to earlier experiences with the Evolut R, and especially with earlier studies of its predecessor, CoreValve (Medtronic), in which higher rates of PVL were consistently reported, such as 13% in the ADVANCE study (8) (Figure 1 [4,6–10]).
Although the study of novel THVs in large contemporary cohorts is important and the multicenter effort of the FORWARD study should be acknowledged, there are several issues that potentially limit the value of this trial and need to be addressed in more in detail.
In the absence of direct randomized comparisons between different THVs, the harmonization of endpoints is of special importance to compare registry data. Updated criteria were published by the Valve Academic Research Consortium-2 (VARC-2) (11). However, although the current FORWARD study adjudicated in-hospital and 30-day events according to the VARC-2 criteria, the investigators do not present the key composite endpoints, such as device success and early safety at 30 days. This is unfortunate because decisions to use one TAVR device or another must be made in daily practice. This decision is influenced by several factors, including anatomic considerations, the degree of leaflet calcification, calcification of the left ventricular outflow tract, and access site limitations. Successful implantation of TAVR valves can be measured using the VARC-2 criteria. In this context, the VARC-2 criteria not only help to make a patient-oriented choice for a valve according to their specific characteristics, but also demonstrate clinical benefits of device iterations over time. Among others, they include evaluation of mortality, PPI, stroke, moderate or severe PVL, and major vascular complications.
1. Concerning all-cause mortality, there is a clear trend toward better survival over time for both CoreValve/Evolut R THVs and Edwards Sapien/Sapien XT/Sapien 3 (Edwards Lifesciences, Irvine, California). All-cause mortality rates after 30 days decreased from around 10% to approximately 2% to 3% (12,13). This is probably caused by several factors, including the selection of lower-risk patients, better sizing algorithms using multislice computed tomography, and better trained teams.
2. Although PPI rates in earlier studies with the first-generation CoreValve were almost 40% (14), the current rate in the FORWARD study reflects a considerable improvement. However, the rate of new PPI after TAVR with the Evolut R needs to be considered carefully, because the PPI rate is sometimes calculated using the entire study cohort as the denominator (i.e., including patients with a pacemaker or defibrillator at baseline). When calculating the “real” new PPI rate from current and previous CoreValve and Evolut R studies, a certain improvement in PPI rate over time can be seen (Figure 1). However, there is only a relatively small improvement of −6.6% from ADVANCE to FORWARD. Even when using the feature to reposition in one-quarter of cases, the actual PPI rate with Evolut R is maintained at almost 20%, which is comparable to the predecessor CoreValve in the High Risk Study (10). It needs to be mentioned, however, that other self-expanding THVs are reaching single-digit PPI rates and include advantageous features over others (15).
3. Moderate to severe aortic regurgitation (PVL) has been shown to be associated with poor prognosis. After identification of this risk factor, much effort has been put into developing THVs with properties that prevent PVL. Although in a series of early studies, PVL rates were around 15%, more recent studies with Evolut R showed great achievements, with rates as low as 2.0% in FORWARD. This technological advancement will be continued with the introduction of a “skirt” at the bottom of the valve frame to enhance sealing and reduce the rate of PVL. This sealing technology is available on the next generation of the CoreValve family, the Evolut Pro (Medtronic), the Sapien 3 (Edwards Lifesciences), the Lotus valve (Boston Scientific, Marlborough, Massachusetts), and the Acurate neo AS (Symetis, Ecublens, Switzerland). However, additional sealing material requires a larger sheath size. For the Edwards Sapien 3 valve, rates of moderate or severe PVL have been low as 2.6% (12) and 2.0% (13).
4. Major vascular complications were a serious concern in early studies and ranged around 20%. With the development of newer devices requiring smaller sheath sizes, these complications could be reduced to rates of around 5% for both CoreValve and Edwards devices. This positive development can also be demonstrated in the FORWARD study, where the rate of major vascular complication was 6.6% using a 14-F sheath with a true outer diameter of 18-F for all THV sizes.
So, is the FORWARD study taking us forward in our daily clinical practice? Yes and no. Yes, because it offers large-scale clinical data on a promising THV with very good valve performance. No, because the opportunity to provide important VARC-2–defined endpoints has been missed. The way forward requires randomized comparisons to determine the true comparative effectiveness of each THV in our armamentarium. This will enable us to better customize THV therapy, and ultimately, to offer better care to our patients.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Hengstenberg has served as a proctor for and received travel grants and speaker's honoraria from Edwards and Symetis. Dr. Husser has received proctor fees, Congress fees, and travel grants from Symetis.
- 2017 American College of Cardiology Foundation
- Grube E.,
- Van Mieghem N.M.,
- Bleiziffer S.,
- et al.,
- for the FORWARD Study Investigators
- Manoharan G.,
- Walton A.S.,
- Brecker S.J.,
- et al.
- Kalra S.S.,
- Firoozi S.,
- Yeh J.,
- et al.
- Popma J.J.,
- Reardon M.J.,
- Khabbaz K.,
- et al.
- Popma J.J.,
- Adams D.H.,
- Reardon M.J.,
- et al.,
- for the CoreValve United States Clinical Investigators
- Kappetein A.P.,
- Head S.J.,
- Généreux P.,
- et al.
- Herrmann H.C.,
- Thourani V.H.,
- Kodali S.K.,
- et al.,
- for the PARTNER Investigators
- Husser O.,
- Kim W.-K.,
- Pellegrini C.