Expansion of the Indication of Transcatheter Aortic Valve Implantation – Feasibility and Outcome in "Off-Label" Patients Compared With "On-Label" Patients

Abstract: Background. We compare the feasibility and outcomes of “off-label” transcatheter aortic valve implantation (TAVI) patients with a standard “on-label” TAVI population. Methods. A total of 591 high-risk patients (pts) underwent a TAVI procedure at our institution. Of these, 435 pts [73.6%] were treated for an on-label indication (group A) and 156 pts [26.4%] were treated for an off-label indication (group B). Group B was further subdivided into patients with pure aortic regurgitation [n = 22; group B.1), anatomical considerations [n = 26; group B.2), very low ejection fraction ≤20% [n = 12; group B.3), concomitant severe mitral regurgitation >2+ (n = 44; group B.4), degenerated aortic bioprosthesis [n = 30; group B.5), and hemodynamic instability with the need for cardiopulmonary bypass (n = 22; group B.6). Outcome parameters were classified according to the Valve Academic Research Consortium-2 criteria. Results. The mean log EuroSCORE of the entire study group was 25 ± 16% (33 ± 21% in group B vs 22 ± 14% in group A; P<.001). Overall device success was 90% (91.3% in group A vs 86.5% in group B; P=.02). Overall 30-day mortality was 9.7%. Group B had a higher 30-day mortality compared with group A (14.7% vs 7.8%, respectively; P=.01). Group B.5 had the lowest 30-day mortality (3.3%). Conclusion. Corresponding to the higher surgical risk of group B, 30-day mortality was higher for off-label pts. Patients treated as valve-in-valve had the lowest 30-day mortality, emphasizing its great potential as opposed to redo open-heart surgery.  

J INVASIVE CARDIOL 2015;27(5):229-236

Key words: TAVI, aortic stenosis, off-label, mitral regurgitation, aortic regurgitation

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Besides mitral valve regurgitation (MR), the most common valvular heart disease in adults is degenerative calcified aortic valvular stenosis.¹ Despite clear indications for aortic valve replacement, more than 30% of patients did not undergo surgery in the past.¹ The prognosis for patients with severe aortic stenosis is fatal without surgery, due to a mortality risk of up to 50% within 12 months.² Since the introduction of transcatheter aortic valve implantation (TAVI) in 2002, global registry data of over 50,000 patients support a high efficiency rate, with a low 30-day mortality rate of 4%-10% despite high surgical risk.^3-7 The Partner A trial showed non-inferiority for TAVI compared with cardiac surgery in high-risk patients with a very low 30-day mortality of 3.4% in the transcatheter group vs 6.5% in the surgical group (P=.07). Even at 1-year follow-up, the mortality was comparable at 24.2% for TAVI vs 26.8% for the surgical group (P=.44).⁶ However, within the transfemoral TAVI group, mortality was less than half compared with surgical aortic valve replacement (SAVR) (30-day mortality rate, 3.7% vs 8.2%; P=.05).⁶

Until now, TAVI has been considered an off-label treatment option in patients with pure aortic regurgitation (AR), anatomical considerations (eg, bicuspid valve, annulus diameter out of the recommended range), very low ejection fraction (EF) <20%, concomitant severe MR, valve-in-valve (ViV) for degenerated bioprosthesis, and situations of hemodynamic instability. 

The current article describes the feasibility and outcomes of patients who are treated with off-label TAVI procedures vs a standard on-label TAVI population. 

Methods

Patient population and screening. Between August 2008 and November 2012, a total of 591 high-risk patients underwent a TAVI procedure at our institution. All patients were discussed within a heart team consisting of at least one interventional cardiologist and one cardiac surgeon. Of all patients, 435 (73.6%) were treated as on-label with a standard indication for TAVI (group A) and 156 patients (26.4%) as an off-label indication (group B). According to the current guidelines, on-label patients had a symptomatic severe aortic valve stenosis and an increased operative risk (logistic EuroSCORE >15% or an STS score >10% — or the presence of other risk factors contraindicating surgical valve replacement).⁸ Off-label treatment was classified in group B and further divided into patients with pure AR (n = 22; group B.1); anatomical considerations, eg, bicuspid valve, annulus diameter out of the range of current recommendations (n = 26; group B.2); a very low EF ≤20% (n = 12; group B.3); concomitant severe MR >2+ (n = 44; group B.4); degenerated aortic bioprosthesis (n = 30; group B.5), and situations of hemodynamic instability with the need for cardiopulmonary bypass (CPB) (n = 22; group B.6). All patients with an off-label indication had an increased operative risk. Patients were treated with either a Sapien/Sapien XT (Edwards Lifesciences) or CoreValve prosthesis (Medtronic). Prosthesis choice was mainly based on anatomical and vascular conditions (eg, the CoreValve prosthesis was preferred for smaller vessel sizes). Preinterventional screening included a transthoracic and transesophageal echocardiography as well as an angiogram of the aortic root and iliac and femoral arteries. Roughly one-fifth were additionally investigated by cardiac computer tomography. The access route for the procedure was chosen according to anatomical conditions as transfemoral (first choice), transaxillary (second choice), or transapically (third choice).

Procedure. All procedures were done in a hybrid operating room. Details of Sapien/Sapien XT and CoreValve implantation procedures were previously described.^6,9 For all but 1 transfemorally treated patient, TAVI was performed using a truly percutaneous technique with a preclosure device (10 Fr ProStar XL; Abbott Vascular) and without surgical exposure of the access vessel. With increasing experience of the transaxillary access route, a truly percutaneous technique was also used, as previously described.¹⁰ The transapical approach was performed through a small intercostal incision over the left ventricular apex. 

In cases of hemodynamic instability, a heart-lung machine was connected percutaneously via the femoral artery and vein for CPB before the procedure. Outcome parameters were classified according to the Valve Academic Research Consortium (VARC)-2 criteria.¹¹ 

Follow-up. After discharge from hospital, a follow-up with transthoracic echocardiogram, laboratory values, and clinical presentation was carried out after 30 days, 6 months, and 12 months. 

Ethics. All patients were fully informed about the procedure and were requested to sign a written informed consent form.

Statistical methods. Continuous data were described as means and standard deviations, if the variables were normally distributed, or as medians if they were not. Differences of metric variables between two groups were analyzed with t-tests if the data were approximately normally distributed, and with Wilcoxon-Mann-Whitney test in case of non-normally distributed data and very unequal group sizes. Categorical data were described with absolute and relative frequencies. Differences between categorical variables were evaluated with the Chi-square test or with Fisher’s exact test in cases of small expected cell frequencies. Survival curves were estimated by the Kaplan-Meier method and the log-rank test was used to examine survival differences. For overall tests, P≤.05 was considered significant. All calculations were performed with the statistical analysis software SAS v. 9.3 (SAS Institute, Inc).

Results

Baseline characteristics. A total of 591 high-risk patients (44.9% male; age, 80.4 ± 7.0 years) underwent a TAVI procedure. A total of 435 patients (73.6%) were treated as on-label procedures (group A) and 156 patients (26.4%) as off-label (group B) procedures. The mean log EuroSCORE for all 591 patients was 25 ± 17%. There was a significantly higher log EuroSCORE for group B (33 ± 21% vs 22 ± 14% for group A; P<.001). Within group A, implantation of a CoreValve prosthesis was performed in 244 patients (56.1%) and a Sapien/Sapien XT in 191 patients (43.9%; P=.01). Also, a CoreValve prosthesis was significantly more often implanted within group B (63.5% vs 36.5% in group A; P=.01). A significant difference according to the type of prosthesis (CoreValve vs Sapien/Sapien XT) was only seen in group B.1 (pure AR; 95.5% vs 4.5%; P=.01). According to the prosthesis, there was no significant difference within the rest of group B (B.2, B.3, B.4, and B.5; 58.2% vs 41.8%; P=.06). All patients in group B.5 had a degenerated aortic bioprosthesis (6x SAV 21; 2x SAV 23; 1x SAV 21; 5x Hancock 21; 3x Hancock 23; 1x Hancock 27; 2x Mosaic 25; 1x Mosaic 27; 1x Mosaic 23; 1x Biotronic 23; 1x Mitroflow 23; 1x St. Jude Medical 23; 1x St. Jude Medical 21; 1x Soren 27; 1x Sorin 23; 1x Sorin 21; and 1x Homograft 26). No statistically significant difference occurred regarding the type of TAVI prosthesis (CoreValve vs Sapien/Sapien XT, 63.3% vs 36.7%; P=.16). A total of 478 patients (80.9%) underwent transfemoral access, 47 patients (7.9%) underwent transaxillary access, and 66 patients (11.2%) underwent transapical access. 

Significant differences for patients in group B.2 (anatomy) compared with group A were male sex (92.3% vs 40.5%; P<.001) and preexistent kidney failure (57.7% vs 35.9%; P=.02). Significant differences for patients within group B.3 (very low EF) were higher log EuroSCORE (50 ± 23% vs 22 ± 14%; P<.001), coronary artery disease (CAD; 91.7% vs 61.8%; P=.04), and a porcelain aorta (50.0% vs 22.3%; P=.02). Patients within group B.4 (MR >2+) also had a significantly higher log EuroSCORE (32 ± 18% vs 22 ± 14%; P<.001) and pulmonary hypertension more often (61.4% vs 35.2%; P<.001). Patients in group B.5 (ViV) were significantly younger (76.6 ± 6.9 years vs 80.8 ± 7.0 years; P=.01), were more often male (70% vs 40.5%; P=.01), and had a higher log EuroSCORE (32 ± 20% vs 22 ± 14%; P=.01) and a higher prevalence of pulmonary hypertension (53.3% vs 35.2%; P=.04). Within group B.6 (CPB), patients had significantly higher log EuroSCORE (44 ± 23% vs 22 ± 14; P<.001), atrial fibrillation (68.2% vs 44.6%; P=.03), peripheral artery disease (PAD; 40.9% vs 21.1%, P=.04), and pulmonary hypertension (63.6% vs 35.2%; P=.01) compared with group A. Detailed patient characteristics are listed in Tables 1 and 2. 

Outcomes. Overall device success rate according to the VARC-2 criteria was 90% (91.3% for group A vs 86.5% for group B; P=.02). The main reason for device failure was the presence of ≥ moderate aortic valve regurgitation (n = 36; 6.1%) and/or the need for a second valve (n = 10; 1.7%). Reasons for a second valve were valve embolization in 5 patients and significant paravalvular leakage in 5 patients. The lowest device success rate was seen in the off-label group B.2 (anatomy) compared with group A (73.1% vs 91.3%; P=.01). The need for pacemaker implantation was 0% in group B.5 (ViV) (0% vs 23% in group A; P=.01). There were no significant differences for the occurrence of major vascular complication, stroke, and acute kidney failure within the different groups (Table 4). 

Overall 30-day mortality was 9.7%, with a higher 30-day mortality in group B (all off-label patients) compared with group A (all on-label patients) (14.7% vs 7.8%, respectively; P=.01). The highest 30-day mortality was found for group B.1 (AR: 22.7%; P=.03) and group B.6 (CPB: 22.7%; P=.03). Group B.5 (ViV) also had a lower 30-day mortality compared with group A (3.3% vs 7.8%, respectively; P=.72). 

Overall 12-month survival was 75.7%, with a significantly higher survival rate for group A (79.5% vs 64.7% in group B, P<.001) (Figure 1). Comparing separate off-label groups, we found the lowest 12-month survival rate for group B.3 (low EF: 25.0% vs 79.5% in group A; P<.001), followed by group B.1 (AR: 63.6% vs 79.5% in group A; P=.048) and group B.6 (CPB: 63.6% vs 79.5%; P=.04). The highest 12-month survival rate was seen in off-label group B.5 (ViV). Detailed outcome rates are listed in Tables 3 and 4. 

Discussion

Nowadays, the guidelines for valvular heart disease recommend TAVI as a treatment option in patients with severe aortic stenosis and high surgical risk.⁸ In contrast, patients with pure AR, specific anatomical considerations, very low ejection fraction, concomitant severe MR, degenerated bioprosthesis, and situations of hemodynamic instability have been considered as off-label indications for TAVI. 

These data are the first description of the outcomes of various off-label indications, directly compared to an on-label treated patient collective. 

Pure AR (group B.1). Although the study showed no significant differences for baseline data between patients of group B.1 (n = 22) and group A (n = 435), the device success rate tended to be lower compared with group A (77.3% vs 91.3%; P=.05). Moreover, the survival rate was significantly lower after 12 months (63.6% vs 79.5%; P=.048). Clearly, this observation has to be judged in light of the small sample size. Current evaluation of a retrospective multicenter study comprising 43 patients with pure native AR, treated with a CoreValve prosthesis, showed a 30-day mortality rate of 9.3% and a 12-month mortality rate of 21.4%.¹² The presence of AR with no calcification is still considered to be a relative contraindication for TAVI. This assumption is related to the fear of insufficient anchoring of the bioprosthesis within the annulus. Accordingly, the overall rate of valve embolization in the registry by Roy and colleagues was 18.6%, affecting only those patients without calcification.¹² In this regard, the JenaValve prosthesis (JenaValve Technology) seems to be especially appealing due to its anchoring mechanism using a “clipping” technology to the native aortic leaflets. Currently, published results on a small number of patients with pure AR treated with the JenaValve prosthesis showed excellent procedural data, with a 3-month mortality rate of 0%.¹³ Therefore, the JenaValve received the CE mark in September 2013. 

Anatomical off-label considerations (group B.2). Anatomical factors such as the presence of a bicuspid aortic valve or large annulus diameters beyond the recommended extent are considered to be clear contraindications for TAVI. Recently, a prevalence of 22% with bicuspid aortic valves demonstrated a rather high occurrence in octogenarians undergoing SAVR.¹⁴ Current data suggest the feasibility of TAVI in bicuspid aortic valves with an acceptable outcome.^15,16 In our study, only a minority of patients (n = 4) with true bicuspid valves were treated with TAVI. With regard to the recommended annular diameters, current literature clearly emphasizes the use of three-dimensional imaging modalities.^17,18 Thus, a more comprehensive anatomical understanding, such as the extent and distribution of calcification (valvular and subvalvular) and the amount of eccentricity, clearly adds to higher device success rates. Sometimes, adding higher or lower volumes (eg, ±2 cc) to the nominal balloon fillings can be used to overexpand or underexpand a balloon-expandable valve, leading to improved sealing within the annulus. However, it has to be acknowledged that compromising on the final result may ultimately lead to unfavorable outcomes, including early mortalities (eg, annular rupture) and late mortalities (eg, paravalvular leaks). In particular, paravalvular leaks (≥2+) are currently considered to be a major determinant of early and late mortality.^19,20 In our study, no significant difference was found in terms of major vascular complications, new pacemakers, strokes, and ankle-knee index for group B.2. However, as mentioned above, a lower device success rate was found in group B.2 compared with group A (73.1% vs 91.3%; P=.01). The main reason was attributable to the presence of ≥ moderate AR post TAVI, most likely due to the fact that the prosthesis did not totally seal within the annulus. The 12-month survival rate tended to be lower, but this value was not statistically significant (65.4% vs 79.5%; P=.08). In retrospect, compromising on AR seems to be problematic and should only be considered for patients with no surgical option.

Low EF (group B.3). Recent data suggest that TAVI seems to be a better alternative to SAVR in patients with severe aortic stenosis and reduced EF (<45%), since a faster recovery of LV function can be observed after TAVI.^21,22 Nevertheless, Colombo et al showed in an analysis of 384 patients that those with a considerably reduced EF (mean EF, 27.7 ± 6.0%) had a poorer outcome, with a 30-day mortality of 10% compared with 3% in patients with an EF >35% (mean EF, 56.5 ± 8.7%; P=.01).²³ Another study showed a much worse outcome in patients with EF ≤50% compared with patients who had an EF >50% before TAVI.²⁴ In this study, survival at 1 year in the low EF group (average EF, 42 ± 8%) was also dependent on the preprocedural gradient, showing a mortality rate of 27% in patients with a high preprocedural gradient compared with a mortality of 39% for patients with a low gradient before TAVI.²⁴ Thus far, there are no systematic data about patients with very low EF (<20%) in the literature. Similarly, as with Gotzmann et al, we found a much higher mortality rate in our study group (12-year survival rate: 25.0% in group B.3 vs 79.5% in group A; P<.001). It should be noted that this excess mortality seems to be also attributable to an average log EuroSCORE of 50 ± 23%. Thus, further research on a larger group of patients must question at which point a TAVI should no longer be offered to these mostly irreversibly sick patients. 

Concomitant severe MR (group B.4). A combined aortic and mitral valve intervention in elderly and high-risk patients for existing severe aortic stenosis and concomitant MR is linked to an increased mortality.²⁵ In this regard, it is apparent that concomitant MR is an independent predictor of increased mortality after SAVR.²⁶ Various studies have shown that a preexisting MR might demonstrate a distinct improvement after TAVI, while conversely, the mortality rate for patients with concomitant MR is increased after TAVI.^27,28 These observations were also taken in our study, showing that patients with concomitant severe MR had a lower 12-month survival rate (68.2% in group B.4 vs 79.5% in group B; P=.06). Recently, data from the German TAVI registry confirmed these results, showing that concomitant MR ≥2+ is an independent predictor for mortality.²⁹ At this time, it remains unclear which patients suffering from aortic stenosis and MR will demonstrate an improvement in MR as opposed to those who might die. Hence, the need for additional investigations including percutaneous double valve interventions might be of some interest in the future. Ince et al have already successfully shown a few cases of double valve intervention. Accordingly, a TAVI was performed first, followed by subsequent MitraClip (Abbott Vascular) implantation if there was persistent severe MR.³⁰ 

Valve-in-valve intervention (group B.5). Elderly patients with degenerated aortic bioprosthesis have an increased mortality risk for redo surgery.³¹ In this regard, TAVI seems to be a valuable therapy option since another open-heart surgery can be avoided. Meanwhile, numerous studies have shown that ViV implantation can yield very promising results.^32-34 Thanks to these excellent results, the CoreValve (in May 2013) and Sapien XT prostheses (in February 2014) were granted expanded CE certification as new options to treat degenerated bioprostheses. In our study, which was performed before the specific CE mark approval, we found the highest 12-month survival rate in patients with ViV within all off-label groups (group B.5; 76.7%) compared with group A (79.5%; P=.82). This is a remarkable observation in light of a much higher log EuroSCORE (32 ± 20% vs 22 ± 14%; P=.01). In addition, the rate of new pacemakers in patients treated by ViV was 0% compared with 23% in group A (P=.01). Thus, according to our findings (and supported by findings in the current literature), the great potential of ViV should be emphasized in the future.

CPB (group B.6). In general, patients with hemodynamic instability and in need of CPB can be considered to have a life-threatening condition, which is usually not represented within any risk calculator. Nevertheless, as judged by the log EuroSCORE, the patients in this particular group (B.6) were clearly at higher risk compared with the on-label group A in this study (44 ± 23% vs 22 ± 14%; P<.001). Correspondingly, the 12-month survival rate was lower (63.6% vs 79.5%; P=.04), but still higher than we expected for these acute life-threatening situations. Despite additional insertion of several large-bore access-site sheaths (18 Fr arterial cannula, 23 Fr venous cannula) required for the use of CPB, the major vascular complication rate was not higher compared with the control (4.5% in group B.6 vs 6.6% in group A; P>.99). A similar survival rate in conjunction with a similar major vascular complication rate was described by another group, using CPB as a prophylactic tool in high-risk conditions.³⁵ These data demonstrate that TAVI combined with CPB can be used in life-threatening situations as a safe alternative to SAVR with low vascular complication rates that are similar to standard TAVI procedures. 

Study limitations. This is an observational study including 591 consecutive patients from a single center. In addition, the data represent a retrospective analysis without randomization. 

Conclusion

TAVI is a treatment option for surgically high-risk patients. The present study describes the feasibility and outcomes in patients treated in an off-label setting compared with a standard on-label TAVI population. Patients within the off-label group had higher surgical risk (log EuroSCORE: 33 ± 21% in group B vs 22 ± 14% in group A; P<.001). Corresponding to the higher surgical risk, 30-day mortality was higher for off-label treated patients (14.7% in group B vs 7.8% in group A; P=.01). 

Nevertheless, the higher mortality and lower device success rates warrant further investigation in a larger number of patients, especially in those with very low EF, severe AR, or anatomical observations considered to be contraindications. However, patients treated as ViV had the lowest 30-day mortality rate (3.3%), emphasizing its great potential as opposed to redo open-heart surgery. Last but not least, the data suggest that TAVI can be used in patients with cardiogenic shock as a safe alternative to SAVR. 

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_____________________________________________

From the ¹Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany; ²Asklepios Proresearch, Hamburg, Germany; and ³Department of Cardiac Surgery, Asklepios Klinik St. Georg, Hamburg, Germany.

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Schäfer and Dr Kuck report grants from Edwards Lifesciences and Medtronic, Inc. The remaining authors report no conflict of interest regarding the content herein.

Manuscript submitted February 26, 2014, provisional acceptance given July 14, 2014, final version accepted October 20, 2014.

Address for correspondence: Christian Frerker, MD, Asklepios Klinik St. Georg, Division of Cardiology, Lohmühlenstr. 5, 20099 Hamburg, Germany. Email: c.frerker@asklepios.com