Transcatheter aortic-valve replacement (TAVR) is expanding rapidly as an alternative to surgery in patients with severe symptomatic aortic stenosis (AS) that are high risk for surgical valve replacement. The TAVR procedure was first performed in a patient in 2002¹, and since then the valves as well as the delivery systems have undergone substantial modifications to improve their performance. In the United States, two TAVR systems are currently approved by the Food and Drug Administration for treatment of severe aortic stenosis: the balloon-expandable Sapien XT valve (Edwards Lifesciences), and the self-expanding CoreValve (Medtronic, Inc.). The balloon-expandable Sapien XT valve is comprised of three bovine pericardial leaflets mounted within a cobalt chromium frame. The valve is crimped on a balloon delivery catheter and deployed in the native aortic annulus by balloon inflation. The self-expanding CoreValve is made of a nitinol frame inside which three porcine pericardial leaflets are mounted. This valve is loaded in a catheter and deployed by unsheathing the nitinol stent within the native aortic valve.

Given their markedly different deployment mechanisms and device characteristics, theoretical arguments can be made for advantages of either valve system in specific clinical scenarios. The clinical efficacy and safety of each device has been studied independently in randomized clinical trials of high-risk surgical patients^2-5. Further, a growing body of evidence from registries provides insight into the performance of these devices in clinical practice^6,7. However, data from prospective direct comparisons of these devices has been lacking until recently. The Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis: Medtronic CoreValve vs Edwards Sapien XT (CHOICE) trial is the first randomized head-to-head comparison of the balloon-expandable Sapien XT valve and the self-expanding CoreValve.

The CHOICE investigators randomized 241 patients with symptomatic severe aortic stenosis to treatment with TAVR utilizing either the balloon-expandable or the self-expanding valve system, in five German centers⁸. The baseline characteristics were well matched between the two groups with the exception of a higher percentage of women that were treated with a self-expanding valve. Patients were deemed appropriate candidates for TAVR by a heart team. By STS score, the population was intermediate risk, with an average score of 5.6% in the balloon-expandable group and 6.2% in the self-expanding group. According to the authors, operators were highly experienced with both valve systems with 695 balloon-expandable and 790 self-expanding valve procedures performed cumulatively prior to initiation of the trial. However, individual operator numbers were not provided.

The primary end-point of the study was device success, as described by the first Valve Academic Research Consortium consensus paper⁹. This endpoint is a technical composite that consists of four components: (1) successful vascular access, delivery, and deployment of the device and successful retrieval of the delivery system; (2) correct position of the device in the proper anatomical location; (3) intended performance of the prosthetic heart valve; and (4) only one valve implanted in the proper anatomical location. In addtion, there were multiple pre-defined secondary endpoints that were evaluated.

The primary outcome of the CHOICE study, device success, was achieved with a significantly higher frequency in the balloon-expandable valve group (116 of 121 patients, 95.9%) compared with the self-expanding valve group (93 of 120 patients, 77.5%). This difference was mostly driven by a lower rate of residual more-than-mild aortic regurgitation as assessed by angiography (4.1% vs. 18.3% in the balloon-expandable and self-expanding groups, respectively), and the less frequent implantation of more than one valve (0.8% vs. 5.8% in the balloon-expandable and self-expanding groups, respectively).

No statistically significant differences between groups were found for cardiovascular mortality, strokes, bleeding, or vascular complications. However, patients treated with the self-expanding valve experienced more re-hospitalizations for heart failure (4% of patients compared with 0% with the balloon-expandable valve, p=0.02). In addition, the quality of life scores at 30 days were significantly higher in the balloon-expandable group. The incidence of new pacemaker implants was higher than that reported in previous studies for both groups^5,10. However, consistent with previous findings, implantation of self-expanding valves resulted in significantly more new permanent pacemakers (37.6% vs. 17.3% for balloon-expandable valves).

The CHOICE trial addresses an important question, because clinicians must choose the most appropriate device for their patients in daily practice. The findings from this study provide insight into some of the specific advantages and deficiencies of the two options currently available in the U.S. The main limitation of the study is that a surrogate endpoint of device success was used, which cannot substitute for long-term clinical outcomes including death, stroke, heart failure symptoms, and quality of life. However, these data expand the evidence from registries and prior studies and can guide our choices when we integrate the anatomical and functional patient characteristics into our device selection.

Some of the specific findings in this study deserve further discussion. First, this trial might not be generalizable to the population currently treated with these devices in the U.S. Five active centers in Germany screened only 405 patients over 22 months, of which 241 patients met inclusion criteria. It is possible that a greater number of patients was evaluated for TAVR in those centers over the study period, but were not included in the CHOICE trial. In addition, selection bias might also result from the requirement that patients had to qualify for both devices. Each device has certain limitations and clinicians might have not included patients in the screening process if they were better suited for one device (e.g., use of a self-expanding device for patients with severe LVOT calcium at risk for annular rupture).

One of the main differences in device success in this cohort was derived from aortic regurgitation after valve implantation. A design limitation of transcatheter aortic valves has been paravalvular regurgitation (PVL), which results from incomplete circumferential apposition of the prosthesis with the annulus. Several studies indicate an association between significant PVL and mortality for both valves^4,10. Studies suggest that there are three primary causes for PVL: sizing, calcium burden and positioning of the valve¹¹. Consequently, attempts have been made to reduce PVL with better valve sizing based on three-dimensional imaging and changes in valve design. In the CHOICE trial, sizing was based on three-dimensional imaging with multidetector CT in ~80% of the cases. In the U.S., however, it is currently standard practice to assess annulus sizing with three-dimensional imaging to optimize valve sizing in all patients^11,12. Also the CHOICE trial did not specify the positioning algorithm used by its investigators. Implantation depth has been found to be an important determinant for certain procedural complications (i.e. conduction abnormalities, PVL) and therefore, positioning recommendations, especially for the self-expanding valve, have changed over time. Finally, PVL was assessed acutely by angiography, which is acknowledged by the authors as a potential study limitation. Quantification of PVL remains problematic by angiography, echocardiography and CMR. The immediate angiographic quantification of PVL resulted in an incidence of more than mild PVL of 4.1% for the balloon-expandable and 18.3% for the self-expanding valve. Some have suggested that PVL decreases over time with self-expanding valves and therefore acute assessment with angiography may overestimate severity. However, in the CHOICE trial the acute angiographic assessment correlated well with the incidence of PVL by CMR at 30 days which demonstrated a higher incidence of more than mild PVL in the self-expanding group (18.2% vs. 1.8%). Unfortunately, the incidence of moderate/severe PVL by echocardiography did not correlate with either angiography or CMR for the self-expanding valve while correlating relatively well for the balloon-expandable valve. This highlights the difficultly in assessing PVL particularly for self-expanding valves and further studies will be needed to clarify the incidence and mechanisms.

Seven of the patients that received a self-expanding valve (5.8%) required implantation of a second device. This is in contrast to only one patient (0.8%) that required a second valve in the balloon-expandable group. Specifically, five patients received a second self-expanding valve to treat significant aortic regurgitation and two patients were treated for device embolization. It is unclear whether or not improper valve sizing contributed to these events. This finding might not be relevant in the long-term, as a new generation self-expanding device is already available in Europe and is currently under investigation in the U.S., which allows the operator to retrieve and reposition the valve prior to final deployment. The ultimate success of this strategy will become apparent over time.

Consistent with prior reports, the CHOICE investigators observed a higher incidence of new pacemaker implants in patients receiving a self-expanding valve compared with patients in the balloon-expandable group. Of note, the overall pacemaker rates post TAVR were higher in the CHOICE trial compared with the PARTNER trial and the CoreValve US Pivotal trial^5,10. This might be explained in part by a higher rate of pre-existing pacemakers of about 20% in the U.S. trials^3,5 compared with a rate of about 6-8% in CHOICE⁸. Regardless, the increased incidence of postprocedural pacemakers after implantation of self-expanding valves is consistent across studies, and is a potential drawback of these devices. The need for pacemakers requires patients to undergo additional procedures, it adds costs, and furthermore, permanent right ventricular pacing may not be well tolerated in patients with heart failure. As the TAVR field evolves towards lower-risk and younger patients, this problem only becomes more relevant.

The CHOICE trial raises further potential differences between the two different devices. The major stroke rates were nearly identical at 2.5% and 2.6%, for balloon-expandable and self-expanding valves, respectively. However, patients in the balloon-expandable group experienced an additional 3.3% of minor strokes compared with no minor strokes in the self-expanding group. Nevertheless, the overall stroke rate was not statistically different. Neurological deficits in these elderly patients are associated with significant impairment in quality of life. However, the quality of life scores were overall higher for the balloon-expandable valves. In any case, new devices are currently under investigation to protect patients against peri-procedural embolic neurological events.

The CHOICE trial also raises some other considerations. Two patients in the balloon-expandable group experienced coronary obstructions, but due to the low frequency of the event this was not statistically significant. In any event, this is a potentially life-threatening complication that must be scrutinized. A meta-analysis of studies reporting coronary obstruction also suggests that this complication may be more frequent with the balloon-expandable valve¹³. Importantly, the study found one of the risks for coronary obstruction is a small sinus of Valsalva. Currently, three-dimensional imaging allows us to identify patients at risk so this complication can be prevented or treated more effectively. Of note, the valve manufacturers' recommendations specifically define the sinus diameters appropriate for each valve to reduce the risk of coronary obstruction. Finally, there were no cases of annular rupture reported in the CHOICE trial, but previous studies demonstrated a higher risk of annular rupture with balloon-expandable valves.

In summary, the CHOICE trial contributes important data for our device selection for patients undergoing TAVR. However, trials with longer follow-up and larger patient groups that focus on clinical endpoints are needed to further inform our selection. Unfortunately, by the time we have the answers to some of the questions raised by this trial we will likely no longer be implanting the devices tested in the CHOICE study. Given the fast pace of this technology, new generation valves and refined delivery systems with adjunct devices may already be in place to address the current shortcomings.

References

1. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, Derumeaux G, Anselme F, Laborde F, Leon MB. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106(24):3006-8.
2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S, Investigators PT. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. The New England journal of medicine 2010;363(17):1597-607.
3. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ, Investigators PT. Transcatheter versus surgical aortic-valve replacement in high-risk patients. The New England journal of medicine 2011;364(23):2187-98.
4. Popma JJ, Adams DH, Reardon MJ, Yakubov SJ, Kleiman NS, Heimansohn D, Hermiller J, Jr., Hughes GC, Harrison JK, Coselli J, Diez J, Kafi A, Schreiber T, Gleason TG, Conte J, Buchbinder M, Deeb GM, Carabello B, Serruys PW, Chenoweth S, Oh JK, CoreValve United States Clinical I. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. Journal of the American College of Cardiology 2014;63(19):1972-81.
5. Adams DH, Popma JJ, Reardon MJ. Transcatheter aortic-valve replacement with a self-expanding prosthesis. The New England journal of medicine 2014;371(10):967-8.
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7. Blackman DJ, Baxter PD, Gale CP, Moat NE, Maccarthy PA, Hildick-Smith D, Trivedi U, Cunningham D, MA DEB, Ludman PF, National Institute for Cardiovascular Outcomes R. Do outcomes from transcatheter aortic valve implantation vary according to access route and valve type? The UK TAVI Registry. Journal of interventional cardiology 2014;27(1):86-95.
8. Abdel-Wahab M, Mehilli J, Frerker C, Neumann FJ, Kurz T, Tolg R, Zachow D, Guerra E, Massberg S, Schafer U, El-Mawardy M, Richardt G, investigators C. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. Jama 2014;311(15):1503-14.
9. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Journal of the American College of Cardiology 2011;57(3):253-69.
10. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB, Investigators PT. Two-year outcomes after transcatheter or surgical aortic-valve replacement. The New England journal of medicine 2012;366(18):1686-95.
11. Athappan G, Patvardhan E, Tuzcu EM, Svensson LG, Lemos PA, Fraccaro C, Tarantini G, Sinning JM, Nickenig G, Capodanno D, Tamburino C, Latib A, Colombo A, Kapadia SR. Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature. Journal of the American College of Cardiology 2013;61(15):1585-95.
12. Willson AB, Webb JG, Labounty TM, Achenbach S, Moss R, Wheeler M, Thompson C, Min JK, Gurvitch R, Norgaard BL, Hague CJ, Toggweiler S, Binder R, Freeman M, Poulter R, Poulsen S, Wood DA, Leipsic J. 3-dimensional aortic annular assessment by multidetector computed tomography predicts moderate or severe paravalvular regurgitation after transcatheter aortic valve replacement: a multicenter retrospective analysis. Journal of the American College of Cardiology 2012;59(14):1287-94.
13. Ribeiro HB, Webb JG, Makkar RR, Cohen MG, Kapadia SR, Kodali S, Tamburino C, Barbanti M, Chakravarty T, Jilaihawi H, Paradis JM, de Brito FS, Jr., Canovas SJ, Cheema AN, de Jaegere PP, del Valle R, Chiam PT, Moreno R, Pradas G, Ruel M, Salgado-Fernandez J, Sarmento-Leite R, Toeg HD, Velianou JL, Zajarias A, Babaliaros V, Cura F, Dager AE, Manoharan G, Lerakis S, Pichard AD, Radhakrishnan S, Perin MA, Dumont E, Larose E, Pasian SG, Nombela-Franco L, Urena M, Tuzcu EM, Leon MB, Amat-Santos IJ, Leipsic J, Rodes-Cabau J. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. Journal of the American College of Cardiology 2013;62(17):1552-62.

Keywords: Aged, Algorithms, Angiography, Aortic Valve, Aortic Valve Stenosis, Aortic Valve Insufficiency, Biomarkers, Calcium, Chromium, Cobalt, Cost of Illness, Echocardiography, Heart Failure, Heart Valve Prosthesis, Imaging, Three-Dimensional, Prospective Studies, Sinus of Valsalva, Heart Valve Diseases, Stents, Stroke, Treatment Outcome, United States Food and Drug Administration

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