Author + information
- Received May 6, 2016
- Revision received June 30, 2016
- Accepted July 12, 2016
- Published online October 11, 2016.
- S0735109716348045-98a01e784cf31e306de8014fa5d2d178Martine Gilard, MD, PhDa,∗ (, )
- S0735109716348045-7117d84583fa6dd515d159e1f618a898Hélène Eltchaninoff, MDb,
- S0735109716348045-03276ad60ce21de9162e2ef0a2920cf2Patrick Donzeau-Gouge, MD, PhDc,
- S0735109716348045-66971545f3eeefa69498d5a338c1aba6Karine Chevreul, MDd,
- S0735109716348045-a2fee2cfc950b9e0510483bda0fcdd64Jean Fajadet, MDe,
- S0735109716348045-4e4f35396f4318c2ee222fa73045f532Pascal Leprince, MDf,
- S0735109716348045-083a9bac681e2bf496e98f3ce5200d1fAlain Leguerrier, MDg,
- S0735109716348045-29704f0df8868224db3c3796a978ac4aMichel Lievre, PhDh,
- S0735109716348045-ff26991b9c8a117bda47ea7240661b60Alain Prat, MDi,
- S0735109716348045-ac6d485eddd7e99d50d900e70e08109aEmmanuel Teiger, MDd,
- S0735109716348045-1f139a1cd96b85850c55e4b57cb87673Thierry Lefevre, MDc,
- S0735109716348045-1d89a3a268baebf88bf7199a2278dc1fDidier Tchetche, MDe,
- S0735109716348045-b254c913fdc35020d7ddc3a399619997Didier Carrié, MDj,
- S0735109716348045-5b545bfc1c6b73795f7ce93fd6d8de6eDominique Himbert, MDk,
- S0735109716348045-6539df6fd391c7554dfe9f38bd4e74faBernard Albat, MDl,
- S0735109716348045-4b4d6b0ab57d7963ea1b7eae8afc0a62Alain Cribier, MDb,
- S0735109716348045-8de0ae2d6efdb9bda4c74e1f7be8c987Arnaud Sudre, MDi,
- S0735109716348045-50c6eb69913ca0ecadf31ca832d3a6a6Didier Blanchard, MDm,
- S0735109716348045-018e8de20eb7b56d94caa67864a29313Gilles Rioufol, MD, PhDh,
- S0735109716348045-85fa6587465d48b5a6f19fcf4f2a7198Frederic Collet, MDn,
- S0735109716348045-322d6f0cc8e1e11f02d02a15544f6fa1Remi Houel, MDo,
- S0735109716348045-253f27d8f1d172c6294f7b64a109ea8bPierre Dos Santos, MDp,
- S0735109716348045-dd17c6b5df6b43383ec19c0250602542Nicolas Meneveau, MD, PhDq,
- S0735109716348045-8253f294a5af5a5403d155591c420106Said Ghostine, MDr,
- S0735109716348045-513acba68c61544ec2e57a1a09ab7892Thibaut Manigold, MDs,
- S0735109716348045-f67b5953b1d41b612e610d27e34511a4Philippe Guyon, MDt,
- S0735109716348045-b9793beb9b19dd25a929f77006ae16aeDominique Grisoli, MDu,
- S0735109716348045-73dc4afcf02539fd9088140b9727f3f3Herve Le Breton, MDg,
- S0735109716348045-9c8c95a6d4ab5aba353416dc5307b9baStephane Delpine, MDv,
- S0735109716348045-04922536d0743a257a0e4850a20bd531Romain Didier, MDa,
- S0735109716348045-c9a2e7300dfddbcbb77d6a43117e7827Xavier Favereau, MDw,
- S0735109716348045-7c2a1d56705367af48980cc236f59f3dGeraud Souteyrand, MDx,
- S0735109716348045-13d19f4978c89c0fdbd8c720fe416a5bPatrick Ohlmann, MDy,
- S0735109716348045-80dc63fe1b3aac691a031a48ec22f5f7Vincent Doisy, MDz,
- S0735109716348045-44bf8a0d5197c121d36a5901e61ed7f6Gilles Grollier, MDaa,
- S0735109716348045-6ef246c706217a9fb8b655e435f2db96Antoine Gommeaux, MDbb,
- S0735109716348045-411d31908bb4f2ecfbbd6675ec0342a3Jean-Philippe Claudel, MDcc,
- S0735109716348045-6200a4c4a9534cc8d321411c039c1e4bFrancois Bourlon, MDdd,
- S0735109716348045-8368b8966e73f6495c9bd03a245875daBernard Bertrand, MDee,
- S0735109716348045-1113418fe61e29af37b66768c4bae74eMarc Laskar, MDff,
- S0735109716348045-ae6bd0a7b9e844a19025abd4cbfe1151Bernard Iung, MDk,
- FRANCE 2 Investigators
- aDepartment of Cardiology, Brest University Hospital, Brest, France
- bDepartment of Cardiology, Rouen University Hospital, Rouen, France
- cDepartment of Cardiology and Surgery, Institut Cardiovasculaire Paris Sud, Massy, France
- dDepartment of URC-ECO and Cardiology, Creteil University Hospital, Paris, France
- eDepartment of Cardiology, Clinique Pasteur, Toulouse, France
- fDepartment of Surgery, Pitié Salpetrière University Hospital, Paris, France
- gDepartment of Cardiology and Surgery, Rennes University Hospital, Rennes, France
- hUMR and Department of Cardiology, Lyon University Hospital, Lyon, France
- iDepartment of Cardiology and Surgery, Lille University Hospital, Lille, France
- jDepartment of Cardiology, Toulouse University Hospital, Toulouse, France
- kDepartment of Cardiology, Bichat University Hospital, Paris, France
- lDepartment of Surgery, Montpellier University Hospital, Montpellier, France
- mDepartment of Cardiology, Clinique St. Gatien, Tours, France
- nDepartment of Surgery, Hospital Clairval, Marseille, France
- oDepartment of Surgery, Hospital Saint Joseph, Marseille, France
- pDepartment of Cardiology, Bordeaux University Hospital, Bordeaux, France
- qDepartment of Cardiology, Besancon University Hospital, Besancon, France
- rDepartment of Cardiology, Centre Cardiologique Marie Lannelongue, Le Plessis Robinson, France
- sDepartment of Cardiology, Nantes University Hospital, Nantes, France
- tDepartment of Cardiology, Centre Cardiologique du Nord, Saint Denis, France
- uDepartment of Surgery, Marseille University Hospital, Marseille, France
- vDepartment of Cardiology, Angers University Hospital, Angers, France
- wDepartment of Cardiology, Parly 2 Hospital, Le Chesnay, France
- xDepartment of Cardiology, Clermont Ferrand University Hospital, Clermont Ferrand, France
- yDepartment of Cardiology, Strasbourg University Hospital, Strasbourg, France
- zDepartment of Surgery, Clinique du Tonkin, Lyon, France
- aaDepartment of Cardiology, Caen University Hospital, Caen, France
- bbDepartment of Cardiology, Hôpital Bois Bernard, Bois Bernard, France
- ccDepartment of Cardiology, Infirmerie Protestante, Lyon, France
- ddDepartment of Cardiology, Centre Cardio-Thoracique, Monaco
- eeDepartment of Cardiology, Grenoble University Hospital, Grenoble, France
- ffDepartment of Surgery, Limoges University Hospital, Limoges, France
- ↵∗Reprint requests and correspondence:
Dr. Martine Gilard, Département de cardiologie, CHU de la Cavale Blanche, Boulevard Tanguy Prigent, 29609 Brest cedex, France.
Background Transcatheter aortic valve replacement (TAVR) has revolutionized management of high-risk patients with severe aortic stenosis. However, survival and the incidence of severe complications have been assessed in relatively small populations and/or with limited follow-up.
Objectives This report details late clinical outcome and its determinants in the FRANCE-2 (FRench Aortic National CoreValve and Edwards) registry.
Methods The FRANCE-2 registry prospectively included all TAVRs performed in France. Follow-up was scheduled at 30 days, at 6 months, and annually from 1 to 5 years. Standardized VARC (Valve Academic Research Consortium) outcome definitions were used.
Results A total of 4,201 patients were enrolled between January 2010 and January 2012 in 34 centers. Approaches were transarterial (transfemoral 73%, transapical 18%, subclavian 6%, and transaortic or transcarotid 3%) or, in 18% of patients, transapical. Median follow-up was 3.8 years. Vital status was available for 97.2% of patients at 3 years. The 3-year all-cause mortality was 42.0% and cardiovascular mortality was 17.5%. In a multivariate model, predictors of 3-year all-cause mortality were male sex (p < 0.001), low body mass index, (p < 0.001), atrial fibrillation (p < 0.001), dialysis (p < 0.001), New York Heart Association functional class III or IV (p < 0.001), higher logistic EuroSCORE (p < 0.001), transapical or subclavian approach (p < 0.001 for both vs. transfemoral approach), need for permanent pacemaker implantation (p = 0.02), and post-implant periprosthetic aortic regurgitation grade ≥2 of 4 (p < 0.001). Severe events according to VARC criteria occurred mainly during the first month and subsequently in <2% of patients/year. Mean gradient, valve area, and residual aortic regurgitation were stable during follow-up.
Conclusions The FRANCE-2 registry represents the largest database available on late results of TAVR. Late mortality is largely related to noncardiac causes. Incidence rates of severe events are low after the first month. Valve performance remains stable over time.
Transcatheter aortic valve replacement (TAVR) is a well-established alternative to surgical valve replacement in high-risk patients with aortic stenosis (AS) and is the treatment of choice in nonsurgical candidates (1–6). Evaluation of late survival and its determinants is of particular importance for assessing the TAVR technique, and contributes to decision making in interventions for AS. Survival after TAVR, its predictive factors, and the incidence of severe complications has been assessed so far in relatively small populations from clinical trials or in larger registries, but with limited follow-up (1,7–10).
The FRANCE-2 (FRench Aortic National CoreValve and Edwards) registry, including all patients from all centers in France, was set up to analyze patient characteristics and clinical outcome after TAVR. This report details late clinical outcome and its determinants in all high-risk patients who underwent TAVR in France during a 2-year period.
Details of the trial were previously published (11). Consecutive patients were enrolled in the FRANCE-2 registry between January 2010 and January 2012 in 33 centers. The center in Monaco subsequently volunteered to participate, for a total of 34 centers. Institutional review board approval was obtained from the French Ministry of Health. This prospective registry included all symptomatic adults (New York Heart Association [NYHA] functional class ≥II) requiring TAVR for severe AS, in whom surgical aortic valve replacement (AVR) was contraindicated or considered as high risk by a multidisciplinary team. Severe AS was defined as aortic valve area <0.8 cm2, mean aortic valve gradient ≥40 mm Hg, or peak aortic jet velocity ≥4.0 m/s.
All patients who had undergone implantation on the basis of these criteria in France and Monaco were prospectively included in the registry, without exclusion criteria. All patients provided written informed consent for anonymous processing of their data.
Study devices and procedures
The technical aspects of the TAVR procedure were previously reported in detail (11,12). In brief, 2 TAVR systems were used in the FRANCE-2 registry: a self-expandable prosthesis (Medtronic CoreValve ReValving System, Medtronic, Minneapolis, Minnesota) and a balloon-expandable prosthesis (Edwards SAPIEN valve, Edwards Lifesciences, Irvine, California). Both balloon- and self-expandable prostheses were used in most centers, and the choice of the prosthesis was left up to the individual teams. No pre-specified recommendations were made regarding use of a transfemoral, transapical, or subclavian approach. All patients received aspirin (≤160 mg daily) and clopidogrel (300-mg loading dose, then 75 mg daily) before the procedure, and aspirin alone after 1 month of dual therapy. The choice between general and local anesthesia for transfemoral implantation was left up to the individual team.
Follow-up was scheduled in the protocol at 30 days, 6 months, and 1, 2, 3, 4, and 5 years on the basis of consultations with recording of clinical status, events, and echocardiography.
The primary endpoint was death from any cause at 1 month, 6 months, or 1, 2, 3, 4, or 5 years. Secondary safety endpoints were major adverse cardiovascular or cerebrovascular events, cardiac events, cardiac or vascular surgery, bleeding or stroke during follow-up, and NYHA functional class. Secondary efficacy endpoints were success rate and complications on the VARC (Valve Academic Research Consortium) criteria (13). Periodic echocardiographic assessments of aortic valve function were performed during the first 3 years, including evaluation of mean gradient and valve area, as well as screening for the presence and severity of aortic or mitral regurgitation. Regurgitation severity was graded on a scale from 0 to 4, with higher grades indicating greater severity.
An independent clinical events committee adjudicated mortality (Online Table 1). All adverse events were adjudicated according to the VARC classification system (13). Data were recorded on a standardized electronic case report form and sent to a central database (Axonal) over the Internet. Database quality control was performed by checking data against source documents for 10% of patients in randomly selected centers. All fields were examined for missing data or outliers, and teams were asked to complete or correct data wherever possible. Outlying data were checked and excluded if they were erroneous; such exclusion applied to <1% of data.
Absolute numbers, percentages, and mean ± SD were computed to describe the population. Mortality was calculated using Kaplan-Meier survival analysis, taking into account the exact follow-up duration (i.e., scheduled 3-year visits could occur before 36 months). Rates of cardiovascular deaths were estimated using the Aalen competing risk analysis.
Nonfatal events were not analyzed using the Kaplan-Meier method because repeated events may occur in a given patient. All events were taken into account, and we calculated the corresponding percentages by dividing the total number of events by the estimated number of patients exposed during each time period. To take into account competing risks, we estimated the number of patients exposed for each time period, assuming a uniform distribution of withdrawals, as follows: n exposed patients = n exposed at the beginning − 0.5 · (n deaths + n lost to follow-up).
Comparison between groups and univariate analysis of associated variables used the Student t test, analysis of variance, or nonparametric tests for continuous variables and chi-square test or Fisher exact test for categorical variables. A search for predictive factors of 3-year survival was performed using a univariable Cox model with the following variables: age, sex, atrial fibrillation, dialysis, body mass index (BMI), logistic EuroSCORE, NYHA functional class, recent myocardial infarction, cerebrovascular disease, approach, type of valve, need for permanent pacemaker implantation within 30 days, and post-implant periprosthetic aortic regurgitation (AR). Variables with p < 0.20 were included in a multivariate Cox model, with a method for automatic selection of variables (stepwise) with p = 0.05. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from the final Cox multivariate model. All tests were 2-sided. A p value of 0.05 was considered to indicate statistical significance. All analyzes were performed using SAS software, version 9.2 (SAS Institute, Cary, North Carolina).
A total of 4,201 patients were treated by TAVR in France between January 2010 and January 2012 in 34 hospitals and were consequently included in the FRANCE-2 registry. Table 1 shows baseline characteristics. Procedural details are presented in Online Tables 2 and 3. Balloon- and self-expandable devices were implanted in 2,774 (66.0%) and 1,413 (33.7%) patients, respectively; the type of valve was not recorded for 14 (0.3%) patients. The implantation approach was transfemoral in 3,064 (72.9%), transapical in 735 (17.5%), subclavian in 242 (5.8%), other (mainly transaortic or transcarotid) in 134 (3.2%), and not recorded in 26 (0.6%) patients. Patients with coronary or peripheral arterial disease and those with an increased logistic EuroSCORE were more likely to undergo a transapical procedure (p < 0.001 for both comparisons) (Online Table 2). Procedures were performed under local anesthesia for 42.7% of femoral approaches, with surgical puncture site closure in 29.4%. Mean hospital stay was 11.5 ± 13.0 days. Procedural success rate (completion with lowered mean gradient) was 97.2%, without significant differences between approaches (p = 0.22).
The 30-day mortality was 9.2% (388 patients). Post-implant echocardiographic examination was available in 3,752 (90.4%) patients and showed a mean aortic valve area of 1.81 cm2 and a mean gradient of 10.6 mm Hg. Periprosthetic AR was quantified in 3,600 patients and was absent in 1,428 (39.7%), grade 1 in 1,643 (45.6%), grade 2 in 499 (13.9%), grade 3 in 29 (0.8%), and grade 4 in 1 (<0.1%) patient.
Median follow-up was 3.8 years. Vital status was available in 4,085 (97.2%) patients at 3 years and in 75.1% at 4 years. Clinical follow-up data were available in 3,781 (90.0%) patients at 3 years. We therefore focused on 3-year follow-up, which was available for almost all patients in the cohort. The scheduled 3-year visit was actually performed before 36 months in 282 patients, and between 35 and 36 months in 50% of patients.
At 3 years, 1,731 patients had died from any cause, including 727 from cardiovascular causes. Kaplan-Meier all-cause mortality was 23.2% (95% CI: 22.0% to 24.6%) at 1 year, 32.9% (95% CI: 31.5% to 34.3%) at 2 years, and 42.0% (95% CI: 40.5% to 43.5%) at 3 years. Mortality of cardiovascular cause was 12.2% (95% CI: 11.3% to 13.3%) at 1 year, 15.3% (95% CI: 14.2% to 16.4%) at 2 years, and 17.5% (95% CI: 16.4% to 18.7%) at 3 years (Central Illustration).
For patients suitable for a transfemoral approach, all-cause mortality at 3 years was 39.6% and cardiovascular mortality 15.9%; for those suitable for a transapical approach, all-cause mortality was 47.7% and cardiovascular mortality 21.2%. All-cause and cardiovascular mortality rates were significantly lower with the femoral approach at all assessment time points: 1, 2, 3, and 4 years (Online Table 3).
Multivariate predictive factors of 3-year all-cause mortality comprised male sex, low BMI, atrial fibrillation, dialysis, NYHA functional class III or IV, higher logistic EuroSCORE, transapical and subclavian approaches, need for permanent pacemaker implantation, and post-implant periprosthetic AR grade ≥2 of 4 (Table 2).
Events during follow-up are detailed in Figure 1 and Online Table 4. The majority of severe events according to VARC criteria occurred during the first month, and the incidence was subsequently below 2% per year. Hospital readmission for any reason occurred in 1,032 (28.1%) patients between 30 days and 1 year, 557 (21.5%) patients during the second year, and 515 (25.6%) patients during the third year. At 3 years, 90.0% of surviving patients were asymptomatic or only mildly symptomatic (NYHA functional class I or II) (Figure 2).
The evolution of mean aortic gradient and valve area are represented in Figure 3 according to the approach and type of prosthesis in patients who had echocardiographic measurements for all time points up to 3 years. Table 3 details paired analysis of mean aortic gradient and valve area at 1, 2, and 3 years in patients who had both measurements available at the beginning and end of each time point. Evolution of periprosthetic AR is shown in Figure 4A in the whole population and in Figure 4B for the 1,014 patients who had echocardiographic evaluation at 3 years. No patients required reoperation or reintervention due to structural valve failure. Four-year follow-up data was available in 795 patients and is shown in Online Figure 1.
The FRANCE-2 registry evaluated every TAVR performed in all 34 active centers in France and Monaco during a 2-year period. Because vital status was known in 97% of patients and events in more than 90% of a cohort of 4,201 patients without selection bias, this registry provides accurate estimations and represents the largest available database on late results of TAVR. Most severe events according to VARC criteria occurred during the first month and subsequently in <2% of patients/year. Mean gradient, valve area, and residual aortic regurgitation were stable during follow-up.
Late survival after TAVR and AVR
The all-cause mortality rate of 42% at 3 years is consistent with reported rates of between 36% and 49% in other multicenter registries or trials also including high-risk patients (1,3,7–9). The narrow 95% CIs attest to the accuracy of the present survival estimates, as more than 2,000 patients were exposed at 3 years. The number of patients exposed at 3 years was 1,032 in the U.K. registry (8) and <200 in the other series (1,7,9). In addition, the FRANCE-2 registry has the strength of including the 2 most widely used prostheses and all approaches. The inclusion of all patients during a 2-year period beginning in 2010 is also important, as late results of TAVR are worse when procedures performed at the beginning of the TAVR experience are included (8). Approximately one-half of deaths were from cardiovascular causes. This is in agreement with other series, and illustrates the effect of comorbidity in these high-risk patients (7,14).
The comparison with the results of surgery is more difficult because the FRANCE-2 registry included only patients with contraindications to or who were at high risk for surgery, who are frequently under-represented in surgical databases. In a large series from the Society of Thoracic Surgeons, 3-year mortality was 50% to 55% after isolated AVR in 1,139 high-risk patients, defined by a Society of Thoracic Surgeons score ≥10% (15). A smaller subgroup analysis reported a 3-year mortality survival around 45% in 185 high-risk patients who had a mean EuroSCORE of 26% (16). As expected, survival is higher in series analyzing surgical AVR in unselected octogenarians who have comparable ages, but much lower risk profiles, as attested by risk scores, than in TAVR series (15,17). The 2 randomized trials comparing TAVR to surgery in high-risk patients did not find significant differences in 3-year mortality rates, which were around 40% after surgical AVR (1,3).
Predictive factors of late mortality
Factors associated with late survival after TAVR have thus far been either analyzed in large cohorts and limited to 1- or 2-year survival (8,18) or analyzed in smaller populations (n < 500) with longer follow-up (1,7,14,19). The present study identified 8 predictive factors of 3-year all-cause mortality: 6 baseline patient characteristics, 1 procedural variable, and 1 post-procedural variable.
The relationship between high EuroSCORE and increased mortality is consistent with previous findings. Although surgical risk scores were originally developed to predict early post-operative mortality, they are also strongly associated with late mortality after surgery or TAVR (8,15,18). Survival was particularly poor in patients with a logistic EuroSCORE >30%.
Other baseline characteristics not included in the EuroSCORE that were associated with mortality were BMI, dialysis, NYHA functional class, and atrial fibrillation. Low BMI was associated with increased late mortality after surgical AVR and TAVR (1,16,20), and with increased 30-day mortality after TAVR in the FRANCE-2 registry (21), and weight loss is included in indexes of frailty.
Male sex was associated with reduced 1-year survival in the American registry (18). Renal failure (but not dialysis) is included in the EuroSCORE, and the incremental predictive value of dialysis highlights the particular high-risk profile of end-stage renal failure, which is consistent with outcome after AVR (15). NYHA functional class III to IV was associated with higher mortality, similar to surgical AVR (22). Atrial fibrillation was associated with higher mortality in other series of TAVR or surgical AVR (1,7,8,18,23,24). The strong predictive value of NYHA functional class III to IV and atrial fibrillation reflects the evolutionary stage of AS and shows that late referral for TAVR impairs late survival, even in high-risk patients.
Nontransfemoral approaches were associated with a marked increase in 3-year mortality. The transapical approach was been associated on multivariate analysis with increased early mortality in the FRANCE-2 registry and with midterm mortality in the U.K. registry and a propensity-matched analysis of the PARTNER trial (21,25,26). The present analysis is the first to show that the subclavian approach is also associated with increased late mortality. Unlike the transapical approach, the increased mortality with the transfemoral approach is not observed early after the procedure, but progressively increases over time. These findings confirm that the transfemoral route is the definite approach of choice for TAVR.
The type of prosthesis was not associated with 3-year survival in this registry, which is consistent with the other series including balloon- and self-expandable prostheses (8,27). This comparison should be interpreted with caution in observational series, given the number of confounding factors that may be involved in the choice of the prosthesis (e.g., the operator, the size of the annulus, the center’s habits and approach). An unbiased comparison of the type of prosthesis requires a randomized trial, and available data do not show different outcomes according to the type of prosthesis (28).
We found an association between the need for permanent pacemaker implantation within 30 days following TAVR and increased 3-year mortality. The 2 largest series published on this topic included 1,556 and 1,973 patients, with 173 and 239 pacemaker implantations, and a mean follow-up of 12 and 22 months, respectively (29,30). They led to conflicting results on the effect of pacemaker implantation on clinical events and left ventricular ejection fraction. Besides statistical power, these discrepancies can be related, in particular, to differences in baseline left ventricular function, indications for pacemaker implantation, and pacemaker dependency.
Periprosthetic AR is a recognized predictive factor of late mortality after TAVR, but concerns were raised regarding the level of AR severity that has a prognostic effect (31–33). The present findings strengthen the association between at least moderate AR (grade ≥2 of 4) and midterm mortality after TAVR, without supporting a negative effect of mild AR.
The fact that age was not associated with survival in this large cohort supports the attitude of not refusing surgery for AS on the sole grounds of age.
Severe cardiovascular events occurring during late follow-up after TAVR have not previously been detailed according to time points up to 3 years. The present analysis shows that the vast majority of events occurred during the first month. Major bleeding was observed in 1.7% of patients between 1 month and 1 year. A higher rate of major bleeding of 5.9% was reported in an analysis of the PARTNER cohort (34). The difference can be explained by a higher patient risk profile, as attested by older age and higher EuroSCORE in the PARTNER cohorts. In addition, one-half of the patients in the PARTNER cohorts had <1-year follow-up, leading to an over-representation of the first months of follow-up, when bleeding risk is higher, due, in particular, to dual antiplatelet therapy.
After 1 year, most types of events occurred in <1% of patients, except for pacemaker implantation, and there was no trend for any increase over time. Although most pacemakers are implanted during the first month following TAVR, subsequent implantations may be needed because of late conduction disturbances (35). However, annual rates of pacemaker implantation have not been previously reported in large series. These event rates should be interpreted in the light of their frequency in the general population. For example, the annual rate of stroke is estimated to be 1.4% between 75 and 84 years of age, and 3.2% in men and 2.0% in women after 85 years of age (36).
Several studies have shown a significant improvement in functional status after TAVR (1,7,9,14,19,23). The present study confirmed these findings as a consequence of the number of patients followed for 3 years.
The improvement in mean aortic gradient and valve area was sustained up to 3 years, irrespective of the approach or type of prosthesis. Serial echocardiographic examinations have been reported in a limited number of series, and included a maximum of 180 patients at 3 years (1,3,7,19). This highlights the relevance of the present findings obtained in more than 1,000 patients of the FRANCE-2 cohort undergoing echocardiographic follow-up for up to 3 years. In addition, the analysis of patients who had echocardiographic measurements for all time points avoids survivor bias. Similarly, the frequency of moderate or severe periprosthetic AR was stable over time after the first month.
The present findings were obtained from a large number of patients representing all-comers candidates to TAVR, without the potential selection bias that may be observed in randomized trials. The sustained clinical improvement and low rate of clinical events after the first month contribute to strengthening the current indication for TAVR in high-risk patients. The absence of deterioration of valve function is also relevant with regard to the perspective of potentially extending the indications to patients at lower risk. The association between pacemaker implantation and late survival deserves further specific studies with long-term follow-up.
The accuracy of event rates may be questioned because events were declared by participating centers and were not independently adjudicated. Because of this, we analyzed only major events according to VARC classification, as they are less likely to be under-reported during long-term follow-up than minor events and are the most clinically relevant. In contrast, mortality estimation is highly reliable because vital status was available and centrally validated after 3 years in more than 97% of included patients.
The lack of a centralized core laboratory for serial echocardiographic evaluations is another limitation. This is of particular concern for the quantification of periprosthetic AR, which remains subject to debate.
Pacemaker implantation may be needed during the course of follow-up. Modeling pacemaker implantation using a time-updated Cox proportional hazards model would allow all pacemaker implantations occurring during follow-up to be taken into account. In our analysis, we considered pacemaker implantations only during the first month, during which time they are more likely to be attributable to the TAVR procedure; these corresponded to 85% of all implantations.
Late outcomes after TAVR are characterized by progressive mortality largely related to noncardiac causes in this high-risk population. The effect of comorbidity is also attested by the weight of comorbidities in the analysis of predictive factors of survival. This analysis also highlights the need to avoid intervention at an advanced stage of the disease. The influence of the approach shows that the transfemoral route should be favored whenever possible. The low rate of adverse events and good valve performance after the first month are further proof of the sustained efficacy of TAVR.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In high-risk patients with AS undergoing TAVR, later mortality is due mainly to noncardiac causes. Beyond the first month after the procedure, prosthetic valve function remains stable, the incidence of clinical events is low, and functional improvement is usually sustained.
TRANSLATIONAL OUTLOOK: Longer-term follow-up studies, including both registries and clinical trials, are needed to develop predictors of abbreviated survival after TAVR in defined subgroups, such as patients undergoing periprocedural pacemaker implantation.
The authors thank Mr. Nicolas Lemaire from Axonal for performing the statistical analysis.
For supplemental tables and a figure, please see the online version of this article.
A full list of the FRANCE 2 Investigators can be found in Online Table 1. Edwards Lifesciences and Medtronic have provided funding for the FRANCE-2 registry. Edwards Lifesciences and Medtronic had no role in data management, data analysis, or writing of the manuscript. Data are the property of the French Society of Cardiology. Dr. Eltchaninoff serves as a proctor for and receives lecture fees from Edwards Lifesciences. Dr. Pascal has served as a consultant to Medtronic. Drs. Carrié and Teiger serve as proctors for Medtronic. Dr. Lefevre has served as a proctor for Edwards Lifesciences. Dr. Himbert has served as a proctor and consultant for Edwards Lifesciences; and has served as a proctor for Medtronic. Dr. Cribier has served as a consultant for Edwards Lifesciences. Dr. Meneveau has served as a consultant for Edwards Lifesciences and St. Jude Medical. Dr. Souteyrand has served as a consultant to Medtronic, St. Jude Medical, Abbott, and Terumo. Dr. Doisy has served as a consultant for Edwards Lifesciences and St. Jude Medical. Dr. Iung has received consulting fees from Boehringer Ingelheim; and has received a speakers fee from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic regurgitation
- aortic stenosis
- aortic valve replacement
- body mass index
- confidence interval
- New York Heart Association
- transcatheter aortic valve replacement
- Valve Academic Research Consortium
- Received May 6, 2016.
- Revision received June 30, 2016.
- Accepted July 12, 2016.
- American College of Cardiology Foundation
- Mack M.J.,
- Leon M.B.,
- Smith C.R.,
- et al.,
- for the PARTNER 1 Trial Investigators
- Kapadia S.R.,
- Leon M.B.,
- Makkar R.R.,
- et al.,
- for the PARTNER Trial Investigators
- Deeb G.M.,
- Reardon M.J.,
- Chetcuti S.,
- et al.,
- for the CoreValve US Clinical Investigators
- Vahanian A.,
- Alfieri O.,
- Andreotti F.,
- et al.
- Nishimura R.A.,
- Otto C.M.,
- Bonow R.O.,
- et al.
- Rodés-Cabau J.,
- Webb J.G.,
- Cheung A.,
- et al.
- Ludman P.F.,
- Moat N.,
- de Belder M.A.,
- et al.,
- for the UK TAVI Steering Committee and the National Institute for Cardiovascular Outcomes Research
- Barbanti M.,
- Petronio A.S.,
- Ettori F.,
- et al.
- Yakubov S.J.,
- Adams D.H.,
- Watson D.R.,
- et al.,
- for the CoreValve United States Clinical Investigators
- Eltchaninoff H.,
- Prat A.,
- Gilard M.,
- et al.,
- for the FRANCE Registry Investigators
- Leon M.B.,
- Piazza N.,
- Nikolsky E.,
- et al.
- Bouleti C.,
- Himbert D.,
- Iung B.,
- et al.
- Brennan J.M.,
- Edwards F.H.,
- Zhao Y.,
- et al.,
- for the Developing Evidence to Inform Decisions About Effectiveness–Aortic Valve Replacement (DEcIDE AVR) Research Team
- Florath I.,
- Albert A.,
- Boening A.,
- et al.
- Toggweiler S.,
- Humphries K.H.,
- Lee M.,
- et al.
- Iung B.,
- Laouénan C.,
- Himbert D.,
- et al.,
- for the FRANCE 2 Investigators
- Duncan A.,
- Ludman P.,
- Banya W.,
- et al.
- Moat N.E.,
- Ludman P.,
- de Belder M.A.,
- et al.
- Blackstone E.H.,
- Suri R.M.,
- Rajeswaran J.,
- et al.
- Chieffo A.,
- Buchanan G.L.,
- Van Mieghem N.M.,
- et al.
- Abdel-Wahab M.,
- Neumann F.J.,
- Mehilli J.,
- et al.,
- for the CHOICE Investigators
- Urena M.,
- Webb J.G.,
- Tamburino C.,
- et al.
- Nazif T.M.,
- Dizon J.M.,
- Hahn R.T.,
- et al.,
- for the PARTNER Publications Office
- Athappan G.,
- Patvardhan E.,
- Tuzcu E.M.,
- et al.
- Van Belle E.,
- Juthier F.,
- Susen S.,
- et al.,
- for the FRANCE2 Investigators
- Généreux P.,
- Cohen D.J.,
- Mack M.,
- et al.
- Urena M.,
- Webb J.G.,
- Cheema A.,
- et al.
- Mozaffarian D.,
- Benjamin E.J.,
- Go A.S.,
- et al.