Innovation in interventional cardiology

ABSTRACT

Introduction and objectives: Transcatheter aortic valve implantation (TAVI) has proven safe and effective in low-to-high risk patients, but emergency procedures have been excluded from the landmark trials. We aimed to assess the current outcomes and main factors conditioning the prognosis during emergency TAVI.

Methods: A systematic search in PubMed and Google Scholar was conducted for all studies comparing elective vs emergency TAVI. Searched terms were “emergency” and/or “urgent”, “elective”, and “transcatheter valve replacement” and/or “heart failure” and/or “cardiogenic shock”. Emergency TAVI was considered as any unscheduled TAVI performed to treat refractory heart failure or cardiogenic shock. A random-effects model was used.

Results: A total of 7 studies with 84 427 TAVI patients were included (14 241 emergency procedures; 70 186 elective TAVIs). Emergency cases presented higher risk scores (logistic EuroSCORE 65.9% ± 21% vs 29.4% ± 18%, P < .001; Society of Thoracic Surgeons Risk Score 29.4% ± 27.4% vs 13.7% ± 11.6%, P < .001). More advanced heart disease was observed with deterioration of left ventricular (LV) function (39.5% ± 17.8% vs 52.5% ± 12.8%; P < .001) and larger LV end-diastolic diameters (55 ± 9 mm vs 48 ± 7 mm; P < .001) despite similar aortic valve areas and gradients. Elective TAVIs presented a greater success rate (93.6% vs 92.5%; odds ratio [OR] = 0.84; 95%CI, 0.74-0.95; P = .005), less acute kidney injury, and a lower need for dialysis and mechanical circulatory support. Overall, non-emergency cases had lower in-hospital (3.3% vs 5.7%; P < .001), 30-day (4.4% vs 8.8%; P < .001) and 1-year mortality rates (19.7% vs 34.75%; P = .0001). The main determinants of mortality were need for new dialysis (OR = 2.26; 95%CI, 1.84-2.76; P < .001) or mechanical circulatory support (OR = 2.55; 95%CI, 1.14-5.67; P < .001).

Conclusions: Emergency TAVI recipients presented worse baseline risk and more advanced cardiac disease that determined greater in-hospital, 30-day, and 1-year mortality rates. The early identification of patients at risk for requiring mechanical circulatory support or dialysis may contribute to a better indication of TAVI in emergency scenarios.

Keywords: Cardiogenic shock. Heart failure. Transcatheter aortic valve replacement. Aortic stenosis.

RESUMEN

Introducción y objetivos: El implante percutáneo de válvula aórtica (TAVI) ha demostrado ser seguro y eficaz en pacientes tanto de bajo como de alto riesgo, pero los procedimientos emergentes se han excluido en los principales estudios. El objetivo fue determinar los resultados actuales y los condicionantes del pronóstico durante el TAVI emergente.

Métodos: Se realizó una búsqueda sistemática en PubMed y Google Scholar de cualquier estudio que comparara el TAVI electivo frente al emergente. Los términos empleados fueron «emergent» y/o «urgent», «elective», y «transcatheter valve replacement» y/o «heart failure» y/o «cardiogenic shock». Se consideró TAVI emergente todo procedimiento no programado realizado para tratar la insuficiencia cardiaca refractaria o el shock cardiogénico. Se utilizó un modelo de efectos aleatorios.

Resultados: Se incluyeron 7 estudios (84.427 pacientes) tratados con TAVI (14.241 emergentes y 70.186 electivos). Los casos electivos presentaron una mayor puntuación de riesgo (EuroSCORE logístico 65,9 ± 21 frente a 29,4 ± 18%, p < 0,001; Society of Thoracic Surgeons Risk Score 29,4 ± 27,4 frente a 13,7 ± 11,6%, p < 0,001). Presentaron una enfermedad cardiaca más avanzada, con peor función ventricular izquierda (39,5 ± 17,8 frente a 52,5 ± 12,8%; p < 0,001) y mayor diámetro telediastólico del ventrículo izquierdo (55 ± 9 frente a 48 ± 7 mm; p < 0,001), pese a tener similar área valvular aórtica y gradientes. El TAVI electivo tuvo mayor tasa de éxito (93,6 frente a 92,5%; odds ratio [OR] = 0,84; IC95%, 0,74-0,95; p = 0,005), con menor tasa de fallo renal agudo y menos necesidad de diálisis y de soporte circulatorio mecánico. En conjunto, los casos no emergentes tuvieron menor mortalidad intrahospitalaria (3,3 frente a 5,7%; p < 0,001), a 30 días (4,4 frente a 8,8%; p < 0,001) y a 1 año (19,7 frente a 34,75%; p = 0,0001). Los principales determinantes de mortalidad fueron la nueva necesidad de diálisis (OR = 2.26; IC95%, 1,84-2,76; p < 0,001) o requerir soporte circulatorio mecánico (OR = 2,55; IC95%, 1,14-5,67; p < 0,001).

Conclusiones: Los receptores de TAVI emergente presentaron peor riesgo basal y enfermedad cardiaca más avanzada, que determinaron una mayor mortalidad intrahospitalaria, a 30 días y a 1 año. La identificación precoz del riesgo de precisar soporte circulatorio mecánico o diálisis podría ayudar a una optimización de la indicación de TAVI emergente.

Palabras clave: Shock cardiogenico. Insuficiencia cardiaca. Implante percutaneo de valvula aortica. Estenosis aortica

Abbreviations AS: aortic stenosis. CKD: chronic kidney disease. CS: cardiogenic shock. HF: heart failure. SAVR: surgical aortic valve replacement. TAVI: transcatheter aortic valve implantation.

INTRODUCTION

Aortic stenosis (AS) is the most commonly treated valvular heart disease in Western countries.1 In a relatively small but growing proportion of patients (from 3.5% to 12%), AS may present as cardiogenic shock (CS) with an estimated short-term mortality as high as 70% if definitive surgical or percutaneous treatment is not provided.2 CS is characterized by an inadequate tissue perfusion as a result of a decompensated cardiac disease that translates into a low-output state. Early management is directed toward keeping a steady hemodynamic profile and ensuring tissue oxygenation through medication or advanced support.3 However, specific therapies are required to ensure a complete resolution, yet conventional surgical aortic valve replacement (SAVR) is often associated with a very high risk of mortality.2

Several trials have shown that transcatheter valve implantation (TAVI) is a safe alternative to SAVR in low-to-high risk patients in stable situations and it is currently considered the preferred alternative in those of high prohibitive surgical risk.4-7 Nevertheless, the risk scores for the main studies that settled the evidence for TAVI procedures were estimated after excluding patients with CS. As a consequence, the main outcomes in this challenging scenario have not been randomly compared to surgery. Actually, such a comparison is unlikely to be performed due to the highly variable baseline profile and differential availability of resources such as mechanic circulatory assist devices. In addition, the different outcomes in emergency TAVIs and planned interventions have been scarcely researched; still, they are key to improve results in what stands as the worst possible clinical scenario. We aimed to assess the current outcomes of emergency/urgent TAVI and the main factors conditioning its prognosis through a systematic review and meta-analysis.

METHODS

Literature search strategy

A systematic review of all published articles in PubMed and Google Scholar databases between January 2014 and January 2020 regarding emergency/urgent versus elective TAVI in severe AS was independently performed by 2 of the authors (A. Aparisi and M. Carrasco-Moraleja). Searched terms were “emergency” and/or “urgent”, “elective”, AND “transcatheter valve replacement” or “TAVR” (transcatheter aortic valve replacement) or “heart failure” and/or “cardiogenic shock”. Definition of emergency/urgent procedures was variable, but the consensus reached for this article was to include patients who required an unscheduled TAVI procedure to treat their refractory heart failure or CS to correct this condition within the next 72 hours after admission. A total of 7 studies8-14 were chosen, and the inclusion criteria established by our group were: a) the study population included patients with aortic stenosis who underwent TAVI; b) only cohort studies that compared emergency or urgent to elective TAVI were included; c) only full English peer-reviewed papers with enough data of outcomes were chosen. The selected exclusion criteria were: a) abstracts; b) case reports; c) editorials; d) experts’ opinions; and e) repetitive studies. Discrepancies between reviewers were resolved through discussion, and consensus was reached. Flowchart is shown on figure 1 and the main features of the studies included are shown on table 1 of the supplementary data.

Figure 1. Flowchart showing search results and selection of the studies included in the meta-analysis.

Table 1. Baseline clinical and echocardiographic characteristics of patients undergoing elective or emergency TAVIs

Variable No. of patients Overall TAVI population N = 84 427 Elective TAVI N = 70 186 (83.1%) Emergency/urgent TAVI N = 14 241 (16.9%) P
Clinical characteristics
 Sex (male) (%) 84 427 43 735/84 427 (51.8%) 36 576/70 186 (52.11%) 7 159/14 241 (50.27%) < .001
 Age (years) 44 385 81.12 ± 8.47 81.16 ± 8.27 80.96 ± 9.08 .041
 EuroSCORE (%) 1387 31.24 ± 18.15 29.42 ± 17.99 68.88 ± 20.97 < .001
 STS score (%) 985 14.76 ± 13.34 13.66 ± 11.61 29.39 ± 27.39 < .001
 Anemia (%) 42 524 11 415/42 524 (26.84%) 8004/32 382 (24.71%) 3411/10 142 (33.63%) < .001
 Atrial fibrillation (%) 41 185 17 373/41 885 (41.47%) 15 304/37 780 (40.51%) 2069/4105 (50.40%) < .001
 CAD (%) 41 329 25 723/41 329 (62.24%) 23 178/37 308 (62.13%) 2545/4021 (63.29%) .147
 CKD (%) 83 308 17 948 /83 308 (21.54%) 13 368/69 187 (19.32%) 4580/14 121 (32.43%) < .001
 COPD (%) 84 398 25 081/84 398 (29.72%) 20 315/70 157 (28.96%) 4766/14 241 (33.47%) < .001
 Diabetes (%) 84 040 29 670/84 040 (35.30%) 24 571/69 820 (35.19%) 5099/14 220 (35.86%) .130
 Hypertension (%) 83 308 70 608/83 308 (84.75%) 59 117/69 187 (85.44%) 11 491/14 121 (81.38%) < .001
 NYHA III-IV (%) 41 143 33 056/41 143 (80.34%) 29 297/37 065 (79.04%) 3759/4078 (92.17%) < .001
 PAD (%) 84 069 25 236/84 069 (30.02%) 20 933/69 849 (29.96%) 4303/14 220 (30.26%) .490
 Porcelain aorta (%) 40 669 2158/40 669 (5.3%) 1914/36 669 (5.22%) 244/4000 (6.1%) .018
 Previous AVR (%) 40 658 1599/40 658 (3.93%) 1292/36 664 (3.53%) 307/3994 (7.69%) < .001
 Previous CABG (%) 83 656 20 924/83 656 (25.01%) 18 000/69 442 (25.92%) 2924/14 214 (20.57%) < .001
 Previous MI (%) 83 040 15 173/83 040 (18.27%) 12 597/68 868 (18.29%) 2576/14 172 (18.18%) .747
 Previous PCI (%) 83 029 22 118/83 029 (26.64%) 18 979/68 863 (27.56%) 3139/14 166 (22.16%) < .001
 Previous PM/ICD 40 774 8304/40 774 (20.36%) 7401/36 723 (20.15%) 903/4051 (22.29%) .001
 Previous stroke/TIA (%) 42 244 8815/42 244 (20.87%) 7884/38 118 (20.68%) 931/4126 (22.57%) .005
Ecocardiographic characteristics
 Aortic valve area (cm²) 2 230 0.7 ± 0.23 0.7 ± 0.23 0.66 ± 0.21 .308
 LVEDD (mm) 616 48.98 ± 7.34 48.53 ± 7.20 55.05 ± 9.03 < .001
 LVEF (%) 1861 51.51 ± 13.24 52.23 ± 12.71 29.58 ± 14.89 < .001
 Mean gradient (mmHg) 1398 43.71 ± 16.42 43.91 ± 16.31 40.26 ± 18.29 .061
 AR III-IV (%) 41 032 8156/41 032 (19.88%) 7159/37 033 (19.33%) 997/3999 (24.93%) < .001
 PHT (%) 43 251 2003/43 251 (4.63%) 1536/33 088 (4.64%) 467/10 163 (4.6%) .843

AR, aortic regurgitation; AVR, aortic valve replacement; CABG, coronary artery bypass graft; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ICD, implantable cardioverter defibrillator; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA; New York Heart Association; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; PHT; pulmonary hypertension; PM, pacemaker; STS, Society of Thoracic Surgeons score; TIA, transient ischemic attack; TAVI, transcatheter aortic valve implantation.

Primary endpoints

Primary endpoints were short-term mortality and procedural success. Secondary outcomes were perioperative complications. Complications were mostly reported by using the definitions established by the Valve Academic Research Consortium-2.15

Statistical analysis

Qualitative variables were expressed as absolute frequency and percentage. Continuous variables were expressed as mean ± standard deviation unless specified otherwise. To compare the demographic variables and the risk factors between thew groups, the chi-square test or Fisher’s exact test were used for the categorical variables. The Student t test was used for the continuous variables, when applicable.

As a measure of the combined effect, the studies included the odds ratio (OR), a 95% confidence interval, and statistical significance. The homogeneity among the studies was compared using the QH statistic. With regard to the low sensitivity of this test, P values < .10 were considered significant. To somehow overcome this limitation, the I2 statistic was estimated as well, which measures the percentage of the overall variation of the studies explained by the heterogeneity and its 95%CI. A random effects model was used for cases in which the I2 statistic was > 50% and a fixed effects model was used for the opposite cases. The potential publication bias was assessed using a funnel plot, Egger’s test, and Begg and Mazumdar rank correlation test. In the presence of publication bias, the trim-and-fill method was used to reassess the pooled OR. Sensitivity analyses sequentially eliminating dissimilar studies were also conducted.

All P values were 2-tailed. Statistical analyses were conducted using the R software, version 3.6.1 (R Project for Statistical Computing) and Review Manager 5.3.

RESULTS

Patient distribution and baseline characteristics

Seven studies were selected including a total of 84 427 patients who underwent TAVIs, with 70 186 elective procedures (83.1%) and 14 241 emergency ones (16.9%). The main baseline characteristics according to the elective or emergency character of the intervention are shown on table 1 and sensitivity and asymmetry analyses are shown on table 2 of the supplementary data and figure 1 of the supplementary data. Asymmetry was detected for acute kidney injury and, therefore, the trim-and-fill method had to be used to reassess the odds ratio. The percentage of men who underwent elective procedures (52.1%) was higher compared to emergency interventions (50.27%, P < .001). Overall, patients treated urgently showed more comorbidities as summarized by the logistic EuroSCORE (65.9% ± 21% vs 29.4% ± 18%, P < .001) and the Society of Thoracic Surgeons Risk Score (STS) (29.4 ± 27.4 vs 13.7 ± 11.6, P < .001). However, the classical cardiovascular risk factors did not differ among groups (hypertension and diabetes mellitus) and the rates of myocardial infarction and percutaneous coronary intervention were similar. On the contrary, those treated urgently more often had undergone a previous aortic valve replacement. Regarding the main echocardiographic characteristics, emergency procedures were performed in patients with left ventricular (LV) function deterioration (39.5% ± 17.8% vs 52.5% ± 12.8%; P < .001), larger LV end-diastolic diameters (55 ± 9 vs 48 ± 7; P < .001), but similar aortic valve areas (0.66 ± 0.21 vs 0.70 ± 0.23; P = .308), and transaortic mean gradients (40.3 ± 18.3 vs 43.9 ± 16.3; P = .061).

Table 2. Procedural characteristics of patients undergoing elective or emergency/urgent TAVIs

Variable No. of patients Overall TAVI population Elective TAVI Emergency/urgent TAVI P
Success rate (%) 41 140 38 765/41 440 (93.54%) 35 038/37 413 (93.65%) 3727/4027 (92.55%) .007
Device migration (%) 40 042 105/40 042 (0.26%) 90/36 090 (0.25%) 15/3952 (0.38%) .129
General anesthesia (%) 40 669 34 419/40 669 (84.6%) 31 004/36 669 (84.55%) 3415/4000 (85.37%) .170
Transapical (%) 83 953 14 742/83 953 (17.56%) 12 194/69 790 (17.47%) 2548/14 163 (18%) .139
Transfemoral (%) 83 811 66 526/83 811 (79.38%) 55 196/69 612 (79.29%) 11 330/14 199 (79.79%) .177
Transsubclavian (%) 40 813 643/40 813 (1.57%) 573/36 834 (1.55%) 70/3979 (1.76%) .327
Mechanical circulatory support (%) 83 326 1858/83 326 (2.29%) 1355/69 211 (1.96%) 503/14 115 (3.56%) < .001

TAVI, transcatheter aortic valve implantation.

Perioperative characteristics

Procedural results from the studies included are shown on table 2. Transfemoral access (79.3% vs 76.8%; P = .177) and use of general anesthesia (84.5% vs 85.4%; P = .17) were the preferred approaches in both groups. Elective TAVIs showed a higher procedural success rate (93.6% vs 92.5%; P = .007) and a lower need for mechanical circulatory support (1.96% vs 3.56 %; P < .001). Other procedural outcomes were comparable between both cohorts.

Postoperative outcomes

The main postoperative outcomes are shown on table 3 and figure 2. The ORs for perioperative myocardial infarction, life-threatening bleedings, need for permanent pacemaker implantation, and stroke were similar regardless of the planned or emergency setting. On the contrary, the elective cohort showed a smaller rate of acute kidney injury (9.6% vs 22.4%; OR = 2.26; 95%CI, 1.84-2.76; P < .001), and need for dialysis (1.1% vs 2.8%; OR = 2.37; 95%CI, 2.09-2.68; P < .001). Overall, this translated into shorter hospital stays for elective cases, lower in-hospital (3.3% vs 5.75%; OR = 1.32; 95%CI, 1.32-2.83; P < .001), 30-day (4.43% vs 8.84%; OR = 3.13; 95%CI, 1.68-5.80; P < .001), and 1-year mortality rates (19.7% vs 34.47%; OR = 2.87; 95%CI, 1.67-4.94; P = .0001) for elective TAVI (figure 3).

Table 3. Main postoperative outcomes of patients undergoing elective or emergency/urgent TAVIs

Variable No. of patients Overall TAVI population Elective TAVI Emergency/urgent TAVI P
Clinical outcomes
 Life-threatening bleeding (%) 83 811 13 170/83 811 (15.71%) 9903/69 612 (14.22%) 3267/14 199 (23.01%) < .001
 Major bleeding (%) 43 400 14 725/43 400 (33.93%) 11 065/33 180 (33.35%) 3660/10 220 (35.81%) < .001
 Major vascular complications (%) 41 656 513/41 656 (1.23%) 460/37 572 (1.22%) 53/4084 (1.29%) .686
 Myocardial infarction (%) 82 671 1299/82 671 (1.57%) 557/68 526 (0.81%) 742/14 145 (5.24%) < .001
 Acute kidney injury (%) 83 811 9856/83 811 (11.75%) 6678/69 612 (9.59%) 3178/14 199 (22.38%) < .001
 Need for dialysis (%) 82 197 1178/82 197 (1.43%) 782/68 130 (1.15%) 396/14 067 (2.81%) < .001
 PPMI (%) 84 069 8786/84 069 (10.45%) 7188/69 849 (10.29%) 1598/14 220 (11.24%) < .001
 Stroke (%) 83 442 2242/83 442 (2.69%) 1824/69 270 (2.63%) 418/14 172 (2.94%) .034
 In-hospital mortality rate 83 427 3099/83 427 (3.71%) 2284/69 255 (3.3%) 815/14 172 (5.75%) < .001
 30-day mortality rate 46 228 2268/46 228 (4.9%) 1830/41 274 (4.43%) 430/4954 (8.84%) < .001
 1-year mortality rate 41 156 8706/41 156 (21 15%) 7327/37 156 (19.72%) 1379/4000 (34.75%) < .001
Echocardiographic outcomes
 Mean gradient (mmHg) 369 7.75 ± 4.15 7.82 ± 4.22 6.9 ± 3.2 .269
 AR III-IV (%) 17 977 1465/17 977 (8.15%) 1299/16 125 (8.05%) 166/1852 (8.96%) .176

AR, aortic regurgitation; PPMI, permanent pacemaker implantation; TAVI, transcatheter aortic valve implantation.

Figure 2. Forest plot showing the main postoperative complications of patients included in the meta-analysis.* * Vertical line represents “no difference” point between the emergency and the elective TAVI groups. Horizontal lines represent the 95%CI. Squares represent the OR for each study (the size of each square shows the amount of information given by each study). Diamonds represent pooled OR from all studies.

Figure 3. Forest plot showing the in-hospital to 1-year mortality rates of patients included in the meta-analysis.* * Vertical line represents “no difference” point between the emergency and the elective TAVI groups. Horizontal lines represent the 95%CI. Squares represent OR for each study (the size of each square shows the amount of information given by each study). Diamonds represent pooled OR from all studies.

DISCUSSION

When patients with AS present with severe acute heart failure (HF) or CS the 5-year all-cause mortality is above 60% despite the implementation of therapies to treat valvular heart disease, which poorly compares to this rate in patients free of HF (~20%) or with chronic HF symptoms (~30%) in this setting (16). Determining the factors that condition such a high mortality rate is the key to improve the management of this growing group of patients. The main findings of this study are: a) patients who required emergency TAVIs had a higher baseline risk compared to planned procedures, not only due to the emergency setting, but also to a high burden of comorbidities and deterioration of LV function; b) although procedural success rate was significantly higher in planned cases, this difference was small (93.6% vs 92.5%; P = .007) suggestive that the higher short- and mid-term mortality rates seen in emergency cases were mainly due to postoperative complications, not to the intervention per se; c) need for mechanical circulatory support and dialysis was higher after emergency cases. The early identification of patients at risk who may require these therapies might be useful for a better indication of TAVI in emergency settings.

Baseline characteristics and predicted mortality

In our study, emergency/urgent TAVI patients had a more significant number of comorbid conditions compared to those who underwent elective procedures. We should mention that the Society of Thoracic Surgeons (STS) score has been widely used to assess mortality risk in SAVR patients.17 Nevertheless, the score developed by the Transcatheter Valve Therapy (TVT) group to evaluate in-hospital and 30-day mortality rates18 may be more accurate. According to that score, the prognosis is strongly influenced by the presence of chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and need for emergency TAVI. Of note, AS with concomitant CKD has been linked to higher all-cause and cardiovascular mortality rates compared to patients with AS and without this condition; indeed, the increase of all-cause mortality exponentially correlates with a decline in the glomerular filtration rate.19 In addition, the higher rate of anemia20 and increased bleeding risk in CKD patients is well-known, which conditions a higher need for red blood cell transfusion21 parallel to a deterioration of renal function and survival rate.

The LV function is a well-known prognostic factor of valvular heart disease and its deterioration conditions surgical or transcatheter aortic valve treatment even in asymptomatic patients.22 We should mention that the similar transaortic gradient, despite a reduced LV function in the emerging baseline cases, suggests a more severe valve disease, probable more calcified and degenerated native valves, as also suggested by the higher rate of aortic regurgitation of this cohort. Therefore, the multidisciplinary and multi-imaging approach might be particularly useful for procedural planning and outcome improvement.23

Procedural complications and mortality

Most procedural complications were similar in elective and emergency TAVIs. Although this may be partially explained by the growing operators’ experience worldwide and the lack of differences in the rate of transfemoral approach,24 the greater use of mechanical circulatory support devices may have been particularly relevant in emergency/urgent cohorts. Indeed, the more limited LV contractile reserve of this group of patients can lead to rapid deterioration in the presence of complications like periannular shunts, severe aortic regurgitation or coronary obstruction. Therefore, the presence of risk factors for these complications may suggest the need for circulatory support devices in certain cases before valve implantation as a potential strategy to avoid dreadful prognoses if they occur in the emergency setting.25-27 Prior experience with the Impella device and extracorporeal membrane oxygenation is shown on table 3 of the supplementary data; however, whether there are mortality differences between those with and without mechanical support requires further research. Since procedural success was similar to that of the standard setting, the clinical translation of this is that, even if these cases can be performed successfully in all centers by implanting TAVI, this profile of patients should only be treated in centers with mechanical circulatory support devices available (particularly ECMO), which would exclude low volume or non-surgical centers.

In the present meta-analysis, the cases treated with isolated balloon aortic valvuloplasty were not included. This strategy bears a class IIb-C level of evidence in the last iteration of the guidelines, but it is often used as a bridging therapy to definitive TAVI in hemodynamically unstable patients.28,29 A single-center retrospective study found that TAVI may be superior to a stand-alone balloon aortic valvuloplasty and medical therapy in patients with severe AS and CS, since the isolated balloon aortic valvuloplasty is not free of complications (~25%) and has higher mortality rates.30 Despite of this, large randomized controlled trials exploring this scenario with TAVI are lacking.

Postoperative complications associated with a higher mortality rate

In this systematic review and meta-analysis, we found that emergency/urgent TAVIs had a significantly higher rate of AKI, hemodialysis, and mortality. This is consistent with previous reports that found that patients with post-TAVI AKI were more likely to die. Besides, AKI is a predictor of sepsis, which is also an independent predictor of mortality. The main factors increasing the risk of AKI include CKD, peripheral artery disease, diabetes mellitus, and deterioration of LV function.31,32 A prophylactic strategy may vary from simple hydration with a normal saline solution to forced diuresis with early supportive measures;33 indeed, the use of prophylactic dialysis has been explored in TAVI patients with a high risk of AKI and may be particularly useful in the emergency setting.

Study limitations

There are several limitations related to this systematic review and meta-analysis. First, the studies included were observational since no multicenter randomized studies specifically addressing this topic could be found. Secondly, the definition of emergency/urgent procedures was variable in the studies although an inclusive definition was reached by the study team. Finally, the results may not be generalizable and should be interpreted with caution due to the high heterogenicity reported, which may relate to variability in the study samples and designs.

CONCLUSIONS

In conclusion, the association between emergency/urgent TAVIs and a higher short-to-mid-term mortality rate is mainly due to a high-risk baseline profile, advanced stage of the cardiac disease, and higher rate of acute renal failure. The early identification and referral of patients at high risk for circulatory collapse or AKI need to be properly identified to reduce the TAVI related mortality rate. Further research is needed to elucidate the role of TAVI in emergency or urgent scenarios.

FUNDING

No funding to declare.

CONFLICTS OF INTEREST

I. J. Amat-Santos is a proctor for Boston Scientific.

WHAT IS KNOWN ABOUT THE TOPIC?

  • TAVI is performed mainly in hemodynamically stable patients, otherwise aortic balloon valvuloplasty is empirically preferred as a bridging therapy to TAVI. However, few studies have addressed TAVI in life-threatening scenarios and multicenter randomized controlled trials are still lacking.

WHAT DOES THIS STUDY ADD?

  • In this large pooled meta-analysis (n = 84 427) emergency TAVI was not rare but associated with higher in-hospital, 30-day, and 1-year mortality rates compared to elective procedures. The need for dialysis or mechanical circulatory support conditioned the mortality rate following emergency TAVIs. The early identification of patients at risk of circulatory collapse or acute kidney injury may help to determine if TAVI is futile in this setting.

MATERIAL ADICIONAL

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12. Kolte D., Khera S., Vemulapalli S., et al. Outcomes Following Urgent/Emergency Transcatheter Aortic Valve Replacement:Insights from the STS/ACC TVT Registry. Jacc Cardiovasc Interventions 2018;11:1175-1185.

13. Elbadawi A., Elgendy IY., Mentias A., et al. Outcomes of urgent versus nonurgent transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2020 Jul;96:189-195.

14. Ichibori Y., Li J., Patel T., et al. Short-Term and Long-Term Outcomes of Patients Undergoing Urgent Transcatheter Aortic Valve Replacement Under a Minimalist Strategy. J Invasive Cardiol. 2019:E30-E36.

15. Kappetein AP., Head SJ., Généreux P., et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation:the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012;33:2403-2418.

16. Nagao K., Taniguchi T., Morimoto T., et al. Acute Heart Failure in Patients With Severe Aortic Stenosis- Insights From the CURRENT AS Registry. Circ J. 2018;82:874-885.

17. Yakubov SJ., Adams DH., Watson DR., et al. 2-Year Outcomes After Iliofemoral Self-Expanding Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis Deemed Extreme Risk for Surgery. J Am Coll Cardiol. 2015;66:1327-1334.

18. Arnold SV., O'Brien SM., Vemulapalli S., et al. Inclusion of Functional Status Measures in the Risk Adjustment of 30-Day Mortality After Transcatheter Aortic Valve Replacement A Report From the Society of Thoracic Surgeons/American College of Cardiology TVT Registry. JACC Cardiovasc Interv. 2018;11:581-589.

19. Patel KK., Shah SY., Arrigain S., et al. Characteristics and Outcomes of Patients With Aortic Stenosis and Chronic Kidney Disease. J Am Heart Assoc. 2019 Feb 5;8:e009980.

20. DeLarochellière H., Urena M., Amat-Santos IJ., et al. Effect on Outcomes and Exercise Performance of Anemia in Patients With Aortic Stenosis Who Underwent Transcatheter Aortic Valve Replacement. Am J Cardiol. 2015;115:472-479.

21. Kanjanahattakij N., Rattanawong P., Krishnamoorthy P., et al. Anaemia and mortality in patients with transcatheter aortic valve replacement:a systematic review and meta-analysis. Acta Cardiol. 2018;74:1-7.

22. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

23. Fassa A-A., Himbert D., Vahanian A. Mechanisms and management of TAVR-related complications. Nat Rev Cardiol. 2013;10:685-695.

24. TerréJA., George I., Smith CR. Pros and cons of transcatheter aortic valve implantation (TAVI). Ann Cardiothorac Surg. 2017;6:444-452.

25. Chieffo A., Ancona MB., Burzotta F., et al. Observational multicentre registry of patients treated with IMPella mechanical circulatory support device in ITaly:the IMP-IT registry. EuroIntervention. 2020 Feb 7;15:e1343-e1350.

26. Singh V., Damluji AA., Mendirichaga R., et al. Elective or Emergency Use of Mechanical Circulatory Support Devices During Transcatheter Aortic Valve Replacement. J Interv Cardiol. 2016;29:513-522.

27. Shreenivas SS., Lilly SM., Szeto WY., et al. Cardiopulmonary bypass and intra?aortic balloon pump use is associated with higher short and long term mortality after transcatheter aortic valve replacement:A PARTNER trial substudy. Catheter Cardiovasc Interv. 2015:316-322.

28. Singh V, Damluji AA, Mendirichaga R, et al. Elective or Emergency Use of Mechanical Circulatory Support Devices During Transcatheter Aortic Valve Replacement. J Interv Cardiol. 2016;29:513-522.

29. Baumgartner H., Falk V., Bax JJ., et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

30. Saia F., Marrozzini C., Ciuca C., et al. Emerging indications, in-hospital and long-term outcome of balloon aortic valvuloplasty in the transcatheter aortic valve implantation era. Eurointervention. 2013;8:1388-1397.

31. Ram P., Mezue K., Pressman G., Rangaswami J. Acute kidney injury post-transcatheter aortic valve replacement. Clin Cardiol. 2017;40:1357-1362.

32. Wang J., Yu W., Zhou Y., et al. Independent Risk Factors Contributing to Acute Kidney Injury According to Updated Valve Academic Research Consortium-2 Criteria After Transcatheter Aortic Valve Implantation:A Meta-analysis and Meta-regression of 13 Studies. J Cardiothor Vasc An. 2017;31:816-826.

33. Putzu A, Berto MB, Belletti A, et al. Prevention of contrast-induced acute kidney injury by furosemide with matched hydration in patients undergoing interventional procedures:a systematic review and meta-analysis of randomized trials. JACC Cardiovasc Interv. 2017;10:355-363.

* Corresponding author: Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario de Valladolid, Ramón y Cajal 3, 47005 Valladolid, Spain.

E-mail address: ijamat@gmail.com (I. J. Amat-Santos)

ABSTRACT

Introduction and objectives: To analyze if there is an association between certain structural variables of the treating centres (availability of cardiac surgery and an intensive care unit [CICU] led by cardiologists) and the volume of procedures performed that may be impacting the results of surgical (SAVR) or transcatheter (TAVI) aortic valve treatment.

Methods: Retrospective and observational study of all patients discharged from hospitals from the Spanish National Health System who underwent a SAVR or a TAVI procedure. The source of the data was the administrative minimum basic data set. The outcome variables analyzed were in-hospital mortality, length of stay (both of them risk-adjusted), and presence of complications. As structural variables for the centers studied we used the availability of cardiac surgeries and CICU.

Results: A total of 2055 TAVI and 15 146 SAVR episodes were identified. The adjustment models for in-hospital mortality showed good discrimination (AUC for the SAVR and TAVI model: 0.84; 95%CI, 0.82-0.85) and calibration (P < .001). The model median odds ratio was 1.73, indicative of a high inter-hospital variability. High-volume hospitals, with cardiac surgery services, and CICU-capable centers had the lowest risk-adjusted mortality rate in both procedures.

Conclusions: A consistent association is observed between the structural characteristics of the treating centers and the results of aortic valve management both surgical and transcatheter. Also, the availability of a CICU could be a relevant factor in the outcomes of these procedures.

Keywords: TAVI. Volume. Results. Aortic stenosis. Surgery.

RESUMEN

Introducción y objetivos: Analizar la asociación entre algunas variables estructurales de los centros tratantes (disponibilidad de cirugía cardiaca y de unidad de cuidados intensivos cardiológicos [UCIC]), así como su volumen de procedimientos, con los resultados del reemplazo quirúrgico de válvula aórtica (RQVA) o transcatéter (TAVI).

Métodos: Estudio observacional retrospectivo de todos los pacientes dados de alta en los hospitales del Sistema Nacional de Salud español a quienes se realizó un procedimiento RQVA o TAVI en los años 2014 y 2015. La fuente de los datos fue el Conjunto Mínimo Básico de Datos. Las variables de resultados analizadas fueron la mortalidad intrahospitalaria, la duración de la estancia (ambas ajustadas por el riesgo) y la presencia de complicaciones. La disponibilidad de cirugía cardiaca y la disponibilidad de UCIC se utilizaron como variables estructurales de los centros.

Resultados: Se analizaron 2.055 TAVI y 15.146 RQVA. Los modelos de ajuste para la mortalidad intrahospitalaria mostraron una buena discriminación (área bajo la curva ROC para el modelo conjunto de TAVI y RQVA: 0,84; IC95%, 0,82-0,85) y calibración (p < 0,001). La odds ratio mediana del modelo fue de 1,73, lo que señala una elevada variabilidad interhospitalaria. Los hospitales con mayor volumen de actividad, con servicio de cirugía cardiaca y dotados de UCIC muestran menor mortalidad ajustada al riesgo en ambos procedimientos.

Conclusiones: Se observa una asociación consistente entre las características estructurales de los centros tratantes y los resultados del reemplazo valvular aórtico, tanto quirúrgico como transcatéter. Además, la disponibilidad de UCIC podría ser un factor relevante en los resultados de dichos procedimientos.

Palabras clave: TAVI. Volumen. Resultados. Estenosis aórtica. Cirugía.

Abbreviations RA-SMR: risk-adjusted standardized mortality ratio. RA-LOSR: risk-adjusted length of stay ratio. MBD: minimum basic dataset. SAVR: surgical aortic valve replacement. TAVI: transcatheter aortic valve implantation.

INTRODUCTION

Severe aortic stenosis is a common disease in our setting and has high morbidity and mortality rate. Its basic treatment is valve replacement.1 Over the last 2 decades, transcatheter aortic valve implantation (TAVI) has joined the traditional surgical aortic valve replacement (SAVR).2

Data are clear on the association between results and certain characteristics of the centers. The fact that has been most described in the medical literature is that, regarding mortality and complications, better results are obtained in those centers that reach the activity threshold (per center and per operator) for certain processes and procedures,3-7 including coronary artery bypass graft (CABG)5,8 and primary angioplasty.9-11 Regarding TAVI, the association between volume and results has been reported in hospitals in the United States.12-14 In Germany, this association is less obvious.15 In Spain, the association between volume and results has also been reported for CABG.16

There are fewer studies that analyze the structural characteristics of the centers and their association with the characteristics of the healthcare systems of every country and the results obtained. In Spain, Bertomeu et al.17 found a lower mortality rate in patients with acute myocardial infarction (AMI) in high-volume centers with higher complexity. Worner et al.18 described a lower mortality rate in the management of AMI in hospitals with cardiac surgery and intensive care unit (CICU) capabilities. Rodríguez-Padial et al.19 found better results in the management of AMI in hospitals serving large communities. The association between CICU availability and better results has also been reported in our setting for the management of cardiogenic shock due to ST-segment elevation myocardial infarction.20

Our objective was to analyze the structural variables of the treating centers (availability of CICU), the volume of procedures performed and their association with results obtained after aortic valve replacement (whether through TAVI or SAVR).

METHODS

Population and sources of data

This is an observational and retrospective study of all the patients discharged from the hospitals of the Spanish National Healthcare System who underwent a SAVR o a TAVI procedure. The source of data was the minimum basic dataset (MBD) of the Spanish National Healthcare System of 2014 and 2015 (the only years available with a specific code for TAVI in the MBD). The clinical results of the patients transferred were assigned to the centers from which they were eventually discharged. Whenever the same episode was treated through TAVI and SAVR, it was considered as a TAVI treated episode and SAVR as a TAVI related complication. The main result variables were in-hospital mortality, length of the hospital stay, and in-hospital complications. The codes used for the complications seen are shown on table 1 of the supplementary data.

Table 1. Differences in the profile of patients and in the results of transcatheter aortic valve implantation based on the structural characteristics of each center (2014-2015)

Type 3 hospitals Type 4 hospitals
Non-CICU CICU Non-CICU CICU P
Number of episodes 85 25 865 1064
Age 81.3 ± 5.9 82.4 ± 2.5 80.6 ± 6.9 80.8 ± 6.8 .408
Sex 54.1 44 52.1 50.4 .705
Charlson index 7.6 ± 1.5 7.2 ± 1.8 7.1 ± 1.6 7.3 ± 1.7 .022
Cardiogenic shock 1.2 0.0 0.8 1.1 .854
Previous percutaneous transluminal coronary angioplasty 12.9 24.0 20.6 15.7 .02
Infectious endocarditis 0.0 0.0 0.1 0.2 .952
CABG in the episode 0.0 0.0 0.5 0.3 .836
Percutaneous transluminal coronary angioplasty in the episode 2.4 0.0 3.7 5.4 .155
Previous CABG in the episode 3.5 8.0 9.1 7.9 .311
Cancer, metastatic cancer, and acute leukemia (CC8_14) 3.5 4.0 3.2 5.0 .293
Protein-calorie malnutrition (CC21) 0.0 0.0 0.5 0.3 .836
Morbid obesity: other endocrine/metabolic/nutritional disorders (CC22_25_26) 50.6 64.0 55.1 48.1 .011
Vascular or circulatory disease (CC27_32) 5.9 0.0 3.1 5.1 .103
Other gastrointestinal disorders (CC38) 16.5 8.0 10.6 11.3 .404
Dementia or other specific cerebral disorders (CC51_53) 1.2 0.0 1.4 2.4 .307
Hemiparesis, paraplegia, paralysis, functional disability (CC70_74_103_104_189_190) 0.0 0.0 1.2 2.0 .27
Congestive heart failure (CC85) 43.5 44.0 28.8 32.0 .014
Acute myocardial infarction (CC86) 1.2 0.0 0.7 0.9 .878
Unstable angina and other acute ischemic heart diseases (CC87) 0.0 0.0 0.9 0.6 .634
Angina; acute myocardial infarction (CC88) 3.5 12.0 2.4 2.7 .036
Hypertension (CC95) 43.5 56.0 58.6 51.9 .005
Stroke (CC99_100) 2.4 0.0 1.3 0.8 .492
Vascular or circulatory disease (CC106_109) 17.6 28.0 18.6 21.6 .267
Chronic obstructive pulmonary disease (CC111) 9.4 24.0 13.4 12.7 .277
Pneumonia (CC114_116) 1.2 0.0 1.2 2.3 .259
Kidney dialysis (CC134) 2.4 0.0 0.3 0.8 .139
Kidney damage (CC135_140) 36.5 24.0 23.9 27.8 .04
Pressure ulcers or chronic skin ulcer (CC157_160) 1.2 4.0 0.5 0.3 .031
Chronic skin ulcer except for pressure ulcers (CC161) 0.0 0.0 0.6 0.0 .078
Diabetes mellitus or diabetic complications except for proliferative retinopathy (CC17_19_123) 34.1 32.0 34.7 32.9 .868

CABG, coronary artery bypass graft; CC, Condition Categories;25 CICU, cardiac surgery and intensive care unit.

Note: 16 episodes could not be identified into any of the 4 groups of hospitals.

Data are expressed as no. (%) or mean ± standard deviation.

Hospital structural variables

To analyze the possible correlation between the hospital structural variables and the results of aortic valve implantation both the volume of procedures performed and the cardiovascular resources available were studied. Hospitals were classified based on the availability of cardiology related resources and according to the RECALCAR criteria21 (table 2 of the supplementary data). Regarding this study, to analyze the inter-hospital differences, only those with cath lab capabilities without (type 3) and with cardiac surgery (type 4) were included. The availability of CICU based on a survey previously conducted by the Spanish Society of Cardiology was also included.22 The characteristics to consider the presence of a CICU were: a) a comprehensive capacity to manage patients in critical condition including invasive mechanical ventilation, and b) the administrative adhesion of the CICU to the cardiology unit.

Table 2. Differences in the profile of patients and in the results of surgical aortic valve replacement based on the structural characteristics of each center (2014-2015)

Hospitales tipo 4
Non-CICU CICU P
Number of episodes 6456 7523
Age 69.3 ± 11.2 69.6 ± 11.3 .053
Sex 41.7 41.8 .823
Charlson index 6.5 ± 1.8 6.5 ± 1.9 .885
Cardiogenic shock 2.0 1.3 .001
Previous percutaneous transluminal coronary angioplasty 4.9 3.9 .004
Infectious endocarditis 1.5 1.4 .507
CABG in the episode 18.9 18.9 .894
Percutaneous transluminal coronary angioplasty in the episode 0.5 0.8 .116
Previous CABG in the episode 2.4 3.5 < .001
Cancer, metastatic cancer, and acute leukemia (CC8_14) 2.0 2.6 .023
Protein-calorie malnutrition (CC21) 0.6 0.2 < .001
Morbid obesity: other endocrine/metabolic/nutritional disorders (CC22_25_26) 49.7 49.5 .789
Vascular or circulatory disease (CC27_32) 4.1 3.7 .209
Other gastrointestinal disorders (CC38) 7.0 8.2 .006
Dementia or other specific cerebral disorders (CC51_53) 0.8 0.8 .666
Hemiparesis, paraplegia, paralysis, functional disability (CC70_74_103_104_189_190) 1.7 1.7 .737
Congestive heart failure (CC85) 19.2 24.1 < .001
Acute myocardial infarction (CC86) 1.4 1.4 .670
Unstable angina and other acute ischemic heart diseases (CC87) 1.7 1.6 .528
Angina; acute myocardial infarction (CC88) 1.2 1.4 .242
Hypertension (CC95) 55.6 53.5 .015
Stroke (CC99_100) 1.7 2.0 .140
Vascular or circulatory disease (CC106_109) 19.7 21.1 .034
Chronic obstructive pulmonary disease (CC111) 7.7 7.7 .893
Pneumonia (CC114_116) 1.9 2.1 .309
Kidney dialysis (CC134) 0.3 0.4 .857
Kidney damage (CC135_140) 18.9 18.5 .576
Pressure ulcers or chronic skin ulcer (CC157_160) 0.8 0.5 .058
Chronic skin ulcer except for pressure ulcers (CC161) 0.2 0.2 .707
Diabetes mellitus or diabetic complications except for proliferative retinopathy (CC17_19_123) 25.3 23.3 .007

CABG, coronary artery bypass graft; CC, Condition Categories;25 CICU, cardiac surgery and intensive care unit.

Note: 1167 episodes could not be identified in any of the 2 groups of hospitals.

Data are expressed as no. (%) or mean ± standard deviation. Only statistically significant factors with OR > 1 are shown.

Statistical analysis

The risk adjustment models were specified based on the Centers for Medicare and Medicaid Services (CMS) methodology. Regarding CABG, the variables included in the 30-day mortality model were considered as independent variables.23 Also, certain variables anticipated by the Society of Thoracic Surgeons score for aortic valve replacement—and that can be identified in the MBD24—were included too. Finally, the CMS model was adjusted to the data structure of the MBD after gathering secondary diagnoses based on clinical categories.25 The multilevel logistics regression models were also adjusted.26,27 Only statistically significant comorbidities and odds ratio (OR) > 1.0 were considered for the adjustment model.

Based on specified models the risk-adjusted standardized mortality ratio (RA-SMR) was estimated.28 To adjust the length of the hospital stay, the Poisson regression model was used including the year of hospital discharge, the sex of the patient, and the degree of severity of groups related by refined diagnosis as risk factors. The expected length of the hospital stay was obtained from the individual predictions of the adjusted model. Also, the risk-adjusted length of stay ratio (RA-LOSR) was estimated as the coefficient between the length of the stay observed and the length of the stay expected.

To distinguish between high and low-volume hospitals (based on the number of episodes treated), a group clustering algorithm was used. To that end, the mathematical model used was developed with two thirds of the database and validated with the remaining third. The algorithm ranked as high-volume centers for TAVI those that performed ≥ 46 procedures, and as high-volume centers for SAVR those that performed ≥ 240 procedures during the study 2 year-period (2014-2015).

Quantitative variables were expressed as means ± standard deviations and the qualitative ones as frequencies and percentages. The correlation among the quantitative variables was analyzed using Pearson correlation coefficient. For comparison purposes, the Student t test for 2 samples and the analysis of variance (ANOVA) were used with correction of the level of significance using the Bonferroni method for ≥ 3 groups. Comparisons among the different categorical variables were conducted using the chi-square test or Fisher’s exact test.

All comparisons were bilateral, and differences were considered statistically significant with P values < .05. Statistical analyses were conducted using the STATA 13 and SPSS v21.0 software package.

RESULTS

A total of 2055 TAVIs and 15146 SAVRs were performed. Back in 2014 a total of 812 TAVIs were performed in 47 centers and in 2015 the number went up to 1243 in 53 centers.

The differences seen in the profile of the patients who underwent TAVI and SAVR are shown on table 1 and table 2, respectively, based on the type of hospital where procedures were performed. No statistically significant differences regarding age and sex were seen in patients who underwent TAVI in any of the 4 groups. Still, comorbidity was significantly higher (higher Charlson index and higher incidence of heart failure) in patients treated in type 3 non-CICU hospitals.

Regarding patients who underwent SAVR, by definition in type 4 hospitals, no statistically significant differences were seen regarding age, sex or presence of comorbidities among patients treated with and without CICU except for a higher prevalence of cardiogenic shock and previous percutaneous coronary interventions in non-CICU hospitals (2.0% vs 1.3%, P < .001; and 4.9% vs 3.9%, P = .004, respectively) (table 2).

The in-hospital mortality adjustment model for surgical aortic valve replacement showed good discrimination capabilities (area under the ROC curve, 0.84; 95% confidence interval [95%CI], 0.82-0.85) and calibration (P < .001). The model median odds ratio was 1.73, indicative of a high inter-hospital variability.

The SAVR specific in-hospital mortality adjustment model also showed excellent discrimination and calibration capabilities too (area under the ROC curve, 0.84; 95%CI, 0.83-0.84; calibration, P < .001) that were slightly lower for the TAVI specific adjustment model (area under the ROC curve, 0.79; 95%CI, 0.74-0.84; calibration, P < .001).

Characteristics of the treating center and TAVI results

Type 4 hospitals had a significantly lower RA-SMR compared to type 3 hospitals (4.04 ± 0.98 vs 4.47 ± 0.79). No statistically significant differences were seen on the RA-LOSR (0.99 ± 0.81 vs 1.07 ± 0.81; P = .278). The presence of a CICU was associated with a slightly lower, but sill statistically significant, RA-SMR (4.03 ± 0.87 vs 4.1 ± 1.07; P < .001). The correlation between CICU and a lower RA-SMR was also found in type 4 (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) and type 3 hospitals (4.09 ± 0.06 vs 4.59 ± 0.87; P < .001) (table 3).

Table 3. Differences in the results of transcatheter aortic valve implantation based on the characteristics each center (2014-2015)

Type 3 hospitals Type 4 hospitals P
Non-CICU CICU Non-CICU CICU
Acute myocardial infarction 1.2 0.0 0.7 0.9 .878
Implantation of permanent pacemaker 17.6 16.0 13.2 15.0 .536
Postoperative stroke 1.2 0.0 1.0 0.6 .624
Prosthetic heart valve complications 3.53 0.00 1.85 4.32 .002
Postoperative shock 0.00 0.00 0.58 1.79 .017
Postoperative kidney damage 1.2 0.0 2.5 2.4 .743
Hemorrhage or hematoma complicating the procedure 16.5 32.0 10.5 13.7 .003
Accidental puncture or laceration during the procedure 3.5 0.0 3.2 4.0 .600
Postoperative infection 1.2 0.0 0.6 1.7 .145
Sepsis 0.0 0.0 0.8 0.8 .819
Vascular surgery during admission 2.4 4.0 5.0 5.7 .542
RA-LOSR 1.10 ± 0.87 0.97 ± 0.47 0.98 ± 0.77 1.00 ± 0.85 .581
RA-SMR 4.59 ± 0.87 4.09 ± 0.06 4.05 ± 1.08 4.03 ± 0.88 < .001

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

CICU capable type 4 hospitals had a higher incidence of postoperative shock (1.8% vs 0.6%; P = .017), the same incidence of sepsis (0.8% vs 0.8%; P < .819), and a lower RA-SMR (4.03 ± 0.88 vs 4.05 ± 1.08; P < .001) compared to non-CICU hospitals.

Regarding the volume of procedures performed by the hospitals, the median of TAVI per year was 11 [2-36 for low-volume centers and 33 [9-67] for high-volume hospitals. The RA-SMR was lower in high-volume hospitals (3.95 ± 1.08 vs 4.26 ± 0.72; P < .001) (table 4 and figure 1). The mean adjusted stay did not show any differences between CICU capable and non-CICU hospitals (1.00 ± 0.85 vs 0.98 ± 0.77; P = .581). In general, regarding the crude complication rates, TAVI did not show any statistically significant differences between high and low-volume hospitals (table 4).

Table 4. Differences in the results of transcatheter aortic valve implantation based on the volume of cases of each center (2014-2015)

Low-volume centers High-volume centers P
Acute myocardial infarction 0.63 0.95 .311
Implantation of permanent pacemaker 14.21 14.36 .489
Postoperative stroke 0.91 0.71 .402
Prosthetic heart valve complications 2.92 4.86 .366
Postoperative shock 1.46 1.33 .172
Postoperative kidney damage 2.54 2.29 .412
Hemorrhage or hematoma complicating the procedure 13.60 12.15 .188
Accidental puncture or laceration during the procedure 2.72 4.18 .054
Postoperative infection 1.30 1.10 .424
Sepsis 1.17 0.55 .105
Vascular surgery during admission 4.15 5.92 .049
RA-LOSR 0.992 ± 0.655 1.008 ± 0.787 .237
RA-SMR 4.26 ± 0.72 3.95 ± 1.08 < .001

RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

Figure 1. In-hospital mortality adjusted comparison for transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Note that, regarding SAVR, in low-volume centers with CICU only 1 center was excluded. CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Characteristics of the treating center and SAVR results

The presence of a CICU turned out to be a protective factor for in-hospital mortality in these patients (OR, 0.79; 95%CI, 0.67-0.93; P = .005). However, the different RA-SMRs seen among various centers with and without CICU capabilities did not show statistically significant differences (5.91 ± 1.49 with CICU vs 5.94 ± 1.72 without it; P = .335) (figure 1). The same thing happened with the RA-LOSR. CICU capable type 4 hospitals had a higher incidence of postoperative shock (2.2% vs 1.3%; P = .024) but a lower incidence of sepsis (1.1% vs 2.3%; P < .001) (table 5).

Table 5. Differences in the results of surgical aortic valve replacement based on the characteristics of each center (2014-2015)

Type 4 hospitals P
Non-CICU CICU
Acute myocardial infarction 1.4 1.4 .67
Implantation of permanent pacemaker 4.0 4.5 .138
Postoperative stroke 1.1 1.3 .305
Prosthetic heart valve complications 2.5 1.1 .729
Postoperative shock 1.3 2.2 .024
Postoperative kidney damage 6.9 6.1 .038
Hemorrhage or hematoma complicating the procedure 6.2 6.3 .767
Accidental puncture or laceration during the procedure 1.0 0.8 .095
Postoperative infection 1.8 2.2 .132
Sepsis 2.3 1.1 < .001
Vascular surgery during admission 2.7 3.1 .166
RA-LOSR 1.00 ± 0.68 0.99 ± 0.67 .770
RA-SMR 5.91 ± 1.49 5.94 ± 1.72 .335

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

In relation to the volume of procedures performed, the RA-SMR was lower in high-volume hospitals (5.89 ± 1.54 vs 6.27 ± 2.02; P < .001) (table 6) without any statistically significant differences with respect to the RA-LOSR (0.99 ± 0.73 vs 1.06 ± 0.75; P = .463). No statistically significant differences were seen between high and low-volume hospitals in the crude complication rates (table 6).

Table 6. Differences in the results of surgical aortic valve replacement based on the volume of cases of each center (2014-2015)

Low-volume centers High-volume centers P
Acute myocardial infarction 1.81 1.37 .066
Implantation of permanent pacemaker 3.75 4.32 .117
Postoperative stroke 0.93 1.22 .117
Prosthetic heart valve complications 1.54 1.14 .072
Postoperative shock 2.26 2.44 .320
Postoperative kidney damage 6.63 6.67 .462
Hemorrhage or hematoma complicating the procedure 5.95 6.35 .279
Accidental puncture or laceration during the procedure 0.82 0.88 .445
Postoperative infection 1.57 2.04 .112
Sepsis 1.46 1.69 .269
Vascular surgery during admission 2.22 2.93 .055
RA-LOSR 1.06 ± 0.75 0.99 ± 0.73 .463
RA-SMR 6.27 ± 2.02 5.89 ± 1.54 < .001

CICU, cardiac surgery and intensive care unit; RA-LOSR, risk-adjusted length of stay ratio; RA-SMR, risk-adjusted standardized mortality ratio.

Data are expressed as no. (%) or mean ± standard deviation.

Association between TAVI and SAVR results

In type 4 hospitals, no statistically significant linear correlations were found between the RA-SMRs of TAVI and those of SAVR (r = 0.21; P = .14). Similarly, the SAVR high-volume variable had a non-statistically significant protective effect when it was introduced in the risk-adjustment model of TAVI related in-hospital mortality (OR, 0.73; 95%CI, 0.33-1.62). The 17 hospitals (1134 episodes identified) that shared the TAVI and SAVR high-volume feature had a TAVI related RA-SMR that was significantly lower compared to centers with the TAVI and SAVR low-volume feature (4 ± 1.1 vs 4.5 ± 0.7; P < .001). A single center (80 episodes) with a high-volume of TAVI and a low-volume of SAVR had the lowest TAVI related RA-SMR of all (2.8 ± 0.3; P < .001 with respect to a high-volume of TAVI and SAVR performed).

DISCUSSION

This study findings that included real-world data in our country, show a consistent correlation between the hospital structural characteristics and the results obtained in aortic valve replacement procedures, both surgical and transcatheter (figure 1). High-volume hospitals with cardiac surgery and intensive care units (CICU) have lower risk-adjusted mortality rates in both procedures.

In relation to the association between volume and results, our study also shows TAVI results that are consistent to those described by the medical literature,10-14 with mortality rates that are similar to those seen in other countries in the study period (2014-2015) and higher to those published for 2015-2017.14 In Spain, the mortality rate differences seen after adjusting for high and low-volume centers are lower to the ones reported, which may be explained because, actually in those years in Spain, low-volume centers were being compared to very low-volume centers. Therefore, 52 out of the 53 center that performed TAVIs in Spain from 2014 through 2015 were within the range of the 2 lower quartiles (5-54 procedures per year), per volume of procedures performed, in the study conducted by Vemulapalli et al.14. Only 7 of those centers were above the range of the lower tercile in the study conducted by Kaier et al.15.

These data should be interpreted in the context of the learning curve of this technique in our country.29

The correlation between a higher volume and a lower RA-SMR was also found for SAVR. Again in this case, low-volume centers were being compared since only 12 and 10 out of the 42 centers, in 2014 and 2015 respectively, performed > 200 SAVRs, and over 70% of the centers were within the 2 lower quartiles of SAVR volume according to the study conducted by Hirji et al.30.

In this study, TAVI and SAVR high-volume centers had a lower TAVI-adjusted mortality rate compared to low-volume centers for both procedures, which is consistent with the findings reported by Mao et al.31. However, the only hospital identified as a high-volume center for TAVI and a low-volume center for SAVR had excellent TAVI results; since it was a single center with limited number of cases (4% of all TAVIs performed), this finding, suggestive that specific experience is more relevant than global experience in aortic valve replacement procedures, should be studied in the future. However, this is reasonable because it shows that here experience accumulates per processes or specific dedicated teams rather than centers in general.

Since no references were found in the medical literature, the newest finding of this study was the association between the presence of a CICU and the lower mortality rate reported for both techniques. This correlation is even more solid and clinically significant for TAVI rather than SAVR, which seems somehow intuitive, since patients treated with SAVR are often referred to general intensive care units.

The association between CICU availability and optimal results in the management of cardiogenic shock in the AMI setting20 had been described by the Spanish National Healthcare System. However, this association had not been reported in surgical procedures. Medical literature describes a virtuous relation between the volume of SAVRs performed and TAVI results, which is probably associated with the greater experience of the heart team.29,31 The presence of a CICU can be a variable that includes both the cardiologists’ greater experience and higher participation in the management of patients in critical cardiac condition and the experience of the hospital, cardiology unit, and cardiac surgery unit. In both cases, the CICU contributes to a better management of patients treated with interventional procedures (TAVI and SAVR) across the entire healthcare process.

Therefore, the results described may me important to plan healthcare and allocate resources such as teaching and training in the 2 aforementioned procedures.

Limitations

This study is a retrospective analysis of administrative data. However, even with its inherent limitations, the validity of its design has been compared to clinical registries.26,32 Such reliability allows us to compare the results of multiple hospitals33 and has been used specifically to analyze TAVI results.11-13,29,30 However, we should mention that data from the MBD should be interpreted with caution because they were not audited. Finally, this study shows the early experience with TAVI, probably still within the learning curve of this technique in the centers studied, which is why findings should be compared to more recent and larger series.

CONCLUSIONS

There is a correlation between the structural characteristics of the treating centers and the results obtained in aortic valve replacement, both surgical and endovascular, with great heterogeneity among the various centers. Large volume hospitals with cardiac surgery units and CICU capabilities have a lower risk-adjusted mortality rate in both procedures.

FUNDING

This study has been funded by an unconditional grant from the Interhospital Foundation for Cardiovascular Research.

AUTHORS' CONTRIBUTIONS

I. J. Núñez-Gil: conceptualization, drafting of the manuscript and analysis; J. Elola and M. García-Márquez: conceptualization, data collection and analysis, drafting and critical review of the manuscript; J. L. Bernal and C. Fernández: data collection and analysis and critical review of the manuscript; A. Íñiguez, L. Nombela Franco, P. Jiménez-Quevedo, J. Escaned and C. Macaya: elaboration and critical review of the manuscript; and A. Fernández-Ortiz: conceptualization, data analysis, preparation and critical review of the manuscript.

CONFLICTS OF INTEREST

None reported.

ACKNOWLEDGEMENTS

We wish to thank the Health Information Institute of the Spanish National Healthcare System at the Spanish Ministry of Health, Consumer Affairs and Social Welfare for partially disclosing the MBD database.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Symptomatic severe aortic stenosis is a common cause of morbidity and mortality in our country. The treatment recommended here is aortic valve replacement.
  • In numerous medical and surgical procedures, the volume of procedures performed by the treating hospital has proven to play a significant role in the results obtained.
  • This correlation between volume and results has been specifically reported for TAVI. In Spain, it has been reported for AMI, cardiogenic shock, and coronary revascularization surgery, among others.

WHAT DOES THIS STUDY ADD?

  • This article analyses real-world data in our country from over 17000 patients who received a prosthetic aortic valve through SAVR or TAVI.
  • The findings show an important heterogeneity and a consistent correlation between the structural character-istics of the treating centers and the results obtained in aortic valve replacement both through SAVR and TAVI.
  • Large-volume centers with cardiac surgery units and CICU capabilities run by cardiologists have lower risk-adjusted mortality rates in both procedures.

SUPPLEMENTARY DATA


REFERENCES

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17. Bertomeu V, Cequier A, Bernal JL, et al. Mortalidad intrahospitalaria por infarto agudo de miocardio. Relevancia del tipo de hospital y la atención dispensada. Estudio RECALCAR. Rev Esp Cardiol. 2013;66:935-942.

18. Worner F, San Román A, Sánchez PL, Viana A, González-Juanatey JR. Atención a los pacientes con enfermedades cardiacas agudas y críticas. Posición de la Sociedad Española de Cardiología. Rev Esp Cardiol. 2015;69:239-242.

19. Rodriguez-Padial L, Elola FJ, Fernández-Pérez C, et al. Patterns of inpatient care for acute myocardial infarction and 30-day, 3-month and 1-year cardiac readmission rates in Spain. Int J Cardiol. 2017;230:14-20.

20. Sánchez-Salado JC, Burgos V, Ariza-SoléA, et al. Trends in cardiogenic shock management and prognostic impact of type of treating center. Rev Esp Cardiol. 2020;73:546-553.

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22. Worner F, San Román A, Sánchez PL, Viana Tejedor A, González-Juanatey JR. The healthcare of patients with acute and critical heart disease. Position of the Spanish Society of Cardiology. Rev Esp Cardiol. 2016;69:239-242.

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28. Shahian DM, Normand SL, Torchiana DF, et al. Cardiac surgery report cards:comprehensive review and statistical critique. Ann Thorac Surg. 2001;72:2155-2168.

29. Lunardi M, Pesarini G, Zivelonghi C, et al. Clinical outcomes of transcatheter aortic valve implantation:from learning curve to proficiency. Open Heart. 2016;3:e000420.

30. Hirji SA, McCarthy E, Kim D, et al. Relationship Between Hospital Surgical Aortic Valve Replacement Volume and Transcatheter Aortic Valve Replacement Outcomes. JACC Cardiovasc Interv. 2020;13:335-343.

31. Mao J, Redberg RF, Carroll JD, et al. Association Between Hospital Surgical Aortic Valve Replacement Volume and Transcatheter Aortic Valve Replacement Outcomes. JAMA Cardiol. 2018;3:1070-1078.

32. Bernal JL, Barrabés JA, Íñiguez A, et al. Clinical and administrative data on the research of acute coronary syndrome in Spain:minimum basic data set validity. Rev Esp Cardiol. 2018;72:56-62.

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* Corresponding author: Unidad de Cardiología Intervencionista, Hospital Clínico San Carlos, IdISSC, Prof. Martín Lagos s/n, 28040 Madrid, Spain.

E-mail address: ibnsky@yahoo.es (I.J. Núñez-Gil).

ABSTRACT

Introduction and objectives: There is great interest in the development of devices for the percutaneous management of mitral regurgitation (MR). For this reason, having an experimental model that reproduces the conditions of the disease is of great importance. Our objective was to validate an experimental model of MR in a porcine model.

Methods: For the model creation phase 3, 2-month-old 25 ± 3 kg large white pigs were used. An acute myocardial infarction was caused in the circumflex artery territory that hampered the perfusion of the posteromedial papillary muscle. Then, volume overload was induced in the animal by creating an arteriovenous shunt and connecting the aorta and the pulmonary artery using a Dacron tube. Echocardiography and magnetic resonance imaging were performed before the intervention and on week 8. Afterwards, the animal was euthanized to conduct the pathological study.

Results: One out of the 3 pigs died during the intervention due to ventricular fibrillation. The remaining 2 pigs survived the procedure and were euthanized as scheduled on week 8. In both cases a transmural infarction occurred, 1 at lateral level and the other one at posteroinferior level with moderate secondary mitral regurgitation. Ventricular dimensions and volumes increased and the overall contractility was maintained despite segmental alterations.

Conclusions: The experimental model of chronic MR based on the ischemic damage of the posteromedial papillary muscle associated with volume overload is feasible, safe and reproducible. Also, it can be very useful to test the safety and efficacy of future devices for the management of this condition.

Keywords: Mitral regurgitation. Experimental model. Porcine model.

RESUMEN

Introducción y objetivos: Existe un creciente interés en el desarrollo de dispositivos para el tratamiento de la insuficiencia mitral (IM) de forma mínimamente invasiva. Para este propósito, disponer de un modelo experimental que reproduzca las condiciones de la enfermedad sería de gran utilidad. Nuestro objetivo fue validar un modelo experimental de IM en cerdos.

Métodos: Para esta fase de creación del modelo se han utilizado 3 cerdos de raza large white, de 2 meses de edad y un peso de 25 ± 3 kg. Se provocó un infarto en el territorio de la arteria circunfleja que afectó la perfusión del músculo papilar posteromedial, y posteriormente se sometió al animal a una sobrecarga de volumen mediante creación de un shunt arteriovenoso, con la conexión de la aorta y la pulmonar mediante un tubo de dacrón. Se realizó análisis mediante ecocardiografía y resonancia magnética antes de la intervención y a las 8 semanas, y posteriormente el animal fue eutanasiado para realizar el estudio anatomopatológico.

Resultados: De los 3 cerdos, 1 falleció durante la intervención por fibrilación ventricular y los otros 2 sobrevivieron al procedimiento y fueron eutanasiados como estaba previsto a las 8 semanas. En ambos se produjo un infarto transmural, uno lateral y otro posteroinferior, con IM moderada secundaria. Las dimensiones y los volúmenes ventriculares aumentaron, y la contractilidad global se mantuvo a pesar de las alteraciones segmentarias.

Conclusiones: El modelo experimental de IM crónica basado en el daño isquémico del músculo papilar posteromedial asociado a una sobrecarga de volumen es factible, seguro y reproducible, y puede ser de gran utilidad para comprobar la seguridad y la eficacia de los futuros dispositivos para el tratamiento de esta afección.

Palabras clave: Insuficiencia mitral. Modelo experimental. Modelo porcino.

Abbreviations: MR: mitral regurgitation.

INTRODUCTION

Mitral valve repair surgery is the treatment of choice for the management of patients with severe mitral regurgitation (MR) who meet the criteria and indications proposed in the clinical practice guidelines.1 However, almost 50% of the patients referred to surgery are not operated on,2,3 mainly due to the presence of comorbidities, left ventricular dysfunction or age related issues.4 In these cases, the use of transcatheter techniques has become a valid alternative.

Given the complexity of the mitral valve, there are several devices in the pipeline to reduce the degree of regurgitation using transcatheter approaches.5,6 Of all the devices available, very few have been eventually used for the management of patients. Among these, only MitraClip—inspired in the Alfieri technique—has proven great clinical utility.7-9

That is why it is important to have an animal model of MR available to test the safety, efficacy, and tissue response of these new devices in a scenario that reproduces the future clinical situations we may encounter faithfully. Our objective was to assess the feasibility of creating an experimental model of MR capable of reproducing the actual conditions with an acceptable safety and efficacy profile.

METHODS

Animal model

Different experimental models have been described by the medical literature to induce MR by causing ischemic damage through the selective occlusion of the circumflex artery and rupture of a mitral chorda tendinae,10 the production of ischemia in both the circumflex and right coronary arteries11 or the production of selective ischemia in the marginal arteries that supply the papillary muscle.12 A Spanish group studied the role of atrial infarction in ischemic MR and atrial and ventricular remodeling through the occlusion of the circumflex artery before or after the origin of the atrial branch.13 The models based on the production of ischemic damage only caused moderate MR. Only the model designed by Cui et al.,10 that combined mitral chordae tendinae ruptures with the corresponding volume overload, induced severe regurgitation. Our group designed a new model to induce MR by combining ischemic damage and the creation of an aortopulmonary shunt as the mechanism of volume overload.

To create this experimental model, 3 Large White domestic pigs were used. They were 2 months old and weighted 25 ± 3 kg. All procedures were performed in full compliance with the national legislation in force (Royal Decree 53/2013 of February 1st on the basic standards for the protection of animals used for scientific purposes) and European Directive 2010/63/EU.

The echocardiographic studies were conducted using a Vivid I GE ultrasound system with 3S cardiac sector probe (1.5-4 MHz). Parasternal short-axis and long-axis slice planes and apical 4-chamber planes were acquired.

The magnetic resonance imaging study was conducted using a Signa HDx 3.0 T GE MR system through FIESTA balanced steady-state free precision multifarious sequences of specific cardiac planes (of 2, 3, and 4 chambers, and in the short axis) to assess both the anatomy and the cardiac function. All images were processed using the ReportCard 4.0 software package.

Conceiving the experimental model

Anesthetic procedure to perform the procedure destined to induce MR and magnetic resonance imaging study

On the day of the surgery, anesthetic premedication was administered based on a combination of midazolam (0.35 mg/kg, Midazolam Normon, Normon), ketamine (5 mg/kg, Imalgene 1000, Merial), and methadone (0.1 mg/kg, Semfortan, Dechra) via intramuscular access. After confirming the correct sedation of the animals, preoxygenation with oxygen mask at 100% concentration was administered. Then, venoclysis was performed in the marginal atrial vein using a 20-gauge endovenous catheter followed by maintenance fluid therapy with lactated Ringer’s solution at an infusion rate of 10 mL/kg per hour. Propofol (2-4 mg/kg, Propovet, Esteve) was used for the induction of anesthesia followed by conventional tracheal intubation. The maintenance anesthetic agent used was sevoflurane (Sevorane, Abbot) at a dose of 1-1.5 MAC. Fentanyl (Fentanest, Janssen) was the intraoperative analgesic used. It was administered through a slow IV bolus of 5 µg/kg and followed by the continuous infusion of a 6 µg/kg/hour dose during the entire procedure. Bail-out doses were administered if necessary.

Prior to the thoracotomy the neuromuscular blocking agent atracurium (Tracrium, Glaxo SmithKline) was administered intravenously at a dose of 0.25 mg/kg. This dose was repeated after 30 minutes if necessary.

As an additional analgesic measure and prior to performing the thoracotomy, intercostal nerve block was achieved using bupivacaine at 0.5% (Bupivacaine, Braun) at a dose of 2 mg/kg in 5 sites: the intercostal space of the surgical site, 2 cranial spaces, and 2 spaces immediately caudal to this one.

The anticoagulant therapy used was sodium heparin at a dose of 200 IU/kg via IV access. The antiarrhythmic therapy used was an infusion of amiodarone (Trangorex, Sanofi-Aventis) at a dose of 5 mg/kg every hour.

Volume controlled ventilation was used during the entire procedure. The ventilator parameters used were: inspired oxygen fraction (0.4), tidal volume (10 mL/kg) by controlling maximal inspiratory pressure and adjusting respiratory rate based on the volume per minute and partial pressure of carbon dioxide, inspiratory/expiratory ratio (1:2-1:3) (based on arterial oxygenation and arterial pressures), inspiratory pause time (10%), and positive end-expiratory pressure of 4 that gradually went up to 8 after the thoracotomy. Alveolar recruitment maneuvers were performed every 20 minutes to avoid alveolar collapse and atelectases.

Vital signs were monitored every 10 minutes and arterial blood-gas tests were performed by measuring the ventilator parameters during the procedure.

During the immediate postoperative 1.6 mg/kg of furosemide (Seguril, Aventis) and 4 mg/kg of carprofen (Rimadyl, Pfizer) were administered via IV access. The postoperative analgesic agent used was transdermal fentanyl (Durogesic, Janssen) at a dose of 50 µg/h within the first 72 hours followed by buprenorphine (Buprex, Life) at a dose of 0.01 mg/kg via subcutaneous access every 8 hours for 3 days. Also, oral carprofen (Rimadyl) was administered at a dose of 4 mg/kg every 24 hours as anti-inflammatory therapy for 5 days followed by a 9-day course of oral amoxicillin-clavulanic acid (Synulox, Pfizer) at a dose of 20 mg/kg every 12 hours as antibiotic therapy.

The protocol to perform the magnetic resonance imaging included the administration, on the day of the procedure, of anesthetic premedication: a combination of midazolam (0.35 mg/kg, Midazolam Normon) and ketamine (5 mg/kg, Imalgene 1000) via intramuscular access. Once the correct sedation of the animals was confirmed, they were transferred to the preparation area and preoxygenation with oxygen mask at 100% concentration was started. Then, venoclysis was performed in the marginal atrial vein using a 20-gauge endovenous catheter. Propofol (2-4 mg/kg, Propovet) was used for the induction of anesthesia followed by conventional tracheal intubation. Sevoflurane (Sevorane) at 1-1.5 CAM was used as maintenance anesthesia.

Mechanical ventilation followed the same parameters as during the entire procedure with periodic monitoring of the vital signs and arterial blood-gas tests.

Inducing the infarction in the circumflex artery territory

After anesthetizing the animal, its thorax was opened, and the pericardium dissected to access the circumflex coronary artery and induce the infarction in this artery through surgical ligation. Prior to this an injection of contrast and echocardiographic study were used to see what branches of this artery were supplying the posteromedial papillary muscle. Once identified, ligation was attempted to occlude the 2 and 3 obtuse marginal arteries to avoid inducing a massive MR.

Creation of an arteriovenous shunt

After the infarction volume overload was attempted through the creation of an arteriovenous shunt by connecting a branch of the pulmonary artery to the aorta using a Dacron tube graft. This procedure was performed with clamping and without extracorporeal circulation.

After performing both procedures the thorax was closed, and the pig was transferred to its storage facility the for control and maintenance.

Follow-up

The presence of MR and the effect of cardiac remodeling were assessed through echocardiographic and magnetic resonance imaging 8 weeks after the procedure and through ventriculography during euthanasia.

The degree of MR was assessed with an ultrasound scan using semi-quantitative methods (estimation of color area, vena contracta). In these ultrasound and MRI studies the volumes of the cardiac chambers (right and left ventricular diameters and volumes, left atrial diameters and volumes) and their function were measured.

Anatomopathological study

At the 8-week follow-up, the animals were euthanized following the directives established by Royal Decree 53/2013 on animal protection.

A complete, organized, and systematic necropsy of each animal corpse was conducted to identify and diagnose any possible conditions associated with the procedure. The samples obtained were fixed in formaldehyde at 10% for histopathological study. In the macroscopic study of the heart, its weight was recorded and its cavities, walls, papillary muscles, mitral chordae tendinae, annulus, and valve leaflets analyzed. All the possible anomalies seen in these structures were documented photographically. Afterwards, the leaflets were extracted from their insertion location and up to their free borders including their chordae tendinae and they were fixed in formaldehyde at 10% and included in paraffin for histopathological study. Three µm thick serial sections were stained with the usual hematoxylin and eosin technique; the Van Gieson elastin stain protocol was used to study elastic and collagen fibers; the Masson trichrome stain protocol was used to differentiate muscular from collagen fibers; finally, the alcian-blue PAS staining protocol was used for the detection of mucopolysaccharides. The histopathological changes identified were semi-quantitatively assessed by establishing the different degrees of damage.

After collecting the leaflets to characterize the infarction, another 4 cross-sectional cuts were performed from the vertex of the heart towards its base. They were weighted and stained with triphenyltetrazolium chloride histochemical staining to enhance the viable area (red color) of the necrotic region (white color). For that purposes, the levels established were submerged in a solution of triphenyltetrazolium chloride (Sigma-Aldrich) at 1% in a phosphate buffered saline solution (pH 7.4) for 5 to 10 minutes at 37 °C, and then they were submerged in formaldehyde at 10%. The sections were photographed, and the areas measured using the Image J system. Samples of the infarction region, limit, and non-infarcted region were collected from every level, submerged in paraffin, and stained using the hematoxylin and eosin technique and the Masson trichrome stain protocol to characterize ischemic damage.

RESULTS

The first animal died during the procedure due to an unresponsive ventricular fibrillation; the remaining 2 completed the 8-week follow-up without complications.

Echocardiographic study

Animal #1

Echocardiographic data at baseline and at the 8-week follow-up from the parasternal short-axis and apical 4-chamber planes are shown on table 1. In the baseline study, ventricular thickness at anteroseptal level was 10.6 mm and at posteroinferior level, 9 mm. The mitral valve was morphologically normal with thin normally moving leaflets and no regurgitation on the color Doppler ultrasound. At the 8-week follow-up there were segmental alterations of contractility that were seriously hypokinetic in the 3 segments of the lateral side with hypercontractility of the remaining segments. Also, a mitral valve with a thickened posterior leaflet and low motility, and moderate mitral regurgitation in the form of posteriorly directed eccentric regurgitation jet was seen too.

Table 1. Echocardiographic data at baseline and at the 8-week follow-up (animal #1)

LVEDD (mm) LVESD (mm) FS (%) EF (%) Color area (cm2) Vena contracta (mm)
Baseline 46 30 34 62 0 0
8-week follow-up 49 32 34 60 4 4

EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Animal #2

Echocardiographic data at baseline and at the 8-week follow-up are shown on table 2. In the baseline study, ventricular thickness at anteroseptal level was 9 mm and at posteroinferior level, 6 mm. The mitral valve was morphologically normal with thin normally moving leaflets and no sign of regurgitation on the color Doppler ultrasound. At the 8-week follow-up, segmental alterations of contractility were seen in the medium and basal segments of the posterior side, a mitral valve with thickening of both leaflets, and moderate mitral regurgitation in the form of a mitral regurgitation central jet.

Table 2. Echocardiographic data at baseline and at the 8-week follow- (animal #2)

LVEDD (mm) LVESD (mm) FS (%) EF (%) Color area (cm2) Vena contracta (mm)
Baseline 44 28 36 65 0 0
8-week follow-up 47 30 36 63 6 5

EF, ejection fraction; FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Magnetic resonance imaging

The baseline study showed ventricles of normal dimensions, thickness, and also normal overall and segmental contractility for our cath lab in similar populations.

The 8-week follow-up revealed segmental alterations of contractility, lateral wall thinning, and fat transformation at posterior level in pig #1 and at posteroinferior level in pig #2 (figure 1). Ventricular volumes grew 10% and 7%, respectively.

Figure 1. Magnetic resonance imaging of animal #2. Short axis of the left ventricle. Presence of fat transformation at posterior level.

The values found in this study are shown on table 3 and table 4.

Table 3. MRI study at baseline and at the 8-week follow-up (animal #1)

LVEDD (mm) LVESD (mm) LVEDV (ml) LVESV (ml) EF (%) Left atrium (cm2)
Baseline 46 31 68 29 57 12
8-week follow-up 49 32 75 30 60 14

EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume.

Table 4. MRI study at baseline and at the 8-week follow-up (animal #2)

LVEDD (mm) LVESD (mm) LVEDV (ml) LVESV (ml) EF (%) Left atrium (cm2)
Baseline 42 29 58 29 50 10
8-week follow-up 44 31 62 30 52 11

EF, ejection fraction; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume.

Anatomopathological study

Animal #1

The macroscopic examination revealed an infarction region in the lateral side from apical to basal level. The use of triphenyltetrazolium chloride stain confirmed the occurrence of a transparietal infarction (figure 2) whose size is shown on table 1 of the supplementary data together with the weight of each level.

Figure 2. Animal #1. Presence of transparietal infarction areas from basal (A) to apical level (D). Triphenyltetrazolium chloride stain.

The mitral valve showed a thickened posterior leaflet without damage to the anterior one. Microscopically, the posterior leaflet showed focal thickening with increased deposition of mucopolysaccharides and vascularization of the proximal part with distal reduction in the number of vessels. The infarction regions were histologically characterized by the presence of mature connective tissue including islets of cardiac muscle fibers and inflammatory cells.

Animal #2

The macroscopic evaluation revealed the presence of a transparietal infarction region in the posterior side damaging the medium and basal segments (figure 3) and papillary muscle (figure 4). The spread of this lesion into the different levels is shown on table 2 of the supplementary data.

Figure 3. Animal #2. Presence of transparietal infarction areas from medium (B) to basal level (D). Triphenyltetrazolium chloride stain.

Figure 4. Papillary muscle lesion. Lower part of level C. Triphenyltetrazolium chloride stain.

In the macroscopic examination, the mitral valve showed thickened leaflets with hemorrhages in their atrial surface (figure 1A of the supplementary data). Histologically and added to the already mentioned hemorrhages, both leaflets appeared thickened due to the deposition of mucopolysaccharides, especially in the middle layer (figure 1B,C of the supplementary data). Small caliber vessels were seen together with a mild inflammatory response figure 2 of the supplementary data. The infarction regions were characterized by the presence of mature connective tissue including islets of cardiac muscle fibers with similar characteristics compared to animal #1.

DISCUSSION

Our group developed a safe and feasible experimental porcine model to induce ischemic MR after causing an infarction associated with volume overload by creating an aortopulmonary shunt.

Currently, several studies on experimental models (sheep and pigs, basically) have been conducted to induce and maintain MR. All of them have pros and cons and imitate different etiologies of MR such as dilated cardiomyopathy, ischemic MR, and even rupture of a mitral chorda tendinae.

In the model of ischemic MR, Llaneras et al.14 were able to induce MR in sheep through obtuse marginal artery ligation. The authors said that for this event to appear 2 prerequisites are required: a) the papillary muscle needs to be infarcted; b) the ventricle needs to be dilated. With just 1 of the 2 requirements no MR would be induced. In their results, the ligation of marginal arteries 2 and 3 induced a gradually developing MR. On the other hand, the ligation of marginal arteries 2, 3 plus the posterolateral artery led to the development of a massive MR with high lethality.

This model has been modified later on by inducing MR through the rupture of a mitral chordae tendinae and the association of an ischemic event in the territory of the circumflex artery by implanting an aneroid.10 This would induce an ischemic lesion with a dysfunctional papillary muscle and volume overload. However, the uncontrolled rupture of a mitral chorda tendinae may lead to a high mortality rate in animals when inducing massive MR, which is often poorly tolerated. The adverse events of the animals or if some of them died during the procedure was not reported in this study.

Considering the pros and cons of the models described, our objective was to create a sustainable model of ischemic MR that, according to the medical literature, seems to be reproducible. To that end, taking into consideration what has already been described in former studies, the model of ischemic damage to the posteromedial papillary muscle associated with volume overload seems to be the safest and most effective one. Since volume overload following the rupture of a chorda or the production of a major myocardial infarction can induce massive MR and severe deterioration of the animal, our objective was to create an arteriovenous shunt as a safe way to induce volume overload since former studies have proven that the creation of a systemic-to-pulmonary shunt induces biventricular remodeling.15

In our study we induced a small size acute myocardial infarction probably due to the isolated occlusion of the obtuse marginal arteries. Other authors occluded the marginal and posterolateral arteries too, which induced bigger acute myocardial infarctions, but at a price of a significantly higher mortality rate, which is why in our study we decided to occlude obtuse marginal arteries only.

Maybe the small size of the acute myocardial infarction was the cause for the moderate MR and discrete ventricular remodeling induced (10% and 7% increase in pigs #1 and #2) yet despite the segmental alterations of contractility seen. However, the possibility that an arteriovenous shunt of inadequate magnitude contributed to this cannot be discarded.

Finally, the possibility that in this model there is a mixed etiology for mitral regurgitation cannot be discarded either: the anatomopathological analyses revealed morphological anomalies in mitral leaflets, meaning that regurgitation would not be strictly functional only. This brings about new hypotheses on the repercussions of hemodynamic overload on mitral leaflets that may go beyond annular dilatation or the ischemic restriction of its movement.

Limitations

The limitations of our study are associated with its small sample size, which is a problem when trying to draw definitive conclusions. However, we think it is very useful to disclose this new experimental model to induce ischemic MR through coronary ligation and volume overload by the creation of an aortopulmonary shunt. However, the results should be confirmed in future studies.

Whether ventricular remodeling impacts the creation of the aortopulmonary shunt is still unknow. In light of this study results, future phases of this model should analyze whether the magnitude of the shunt truly impacts ventricular remodeling.

Infarcts created through surgical ligation of the circumflex artery were small. Maybe the implantation of a coil or other occlusion devices into the proximal circumflex artery would have induced bigger infarctions. In any case, the study design anticipated the surgical approach since a thoracotomy would be needed to create the arteriovenous shunt.

Another possible limitation may be the short period of time animals were followed (8 weeks). This may explain why the remodeling process after the acute myocardial infarction was not completed, which is the reason why ventricular volumes did not reach greater dimensions.

CONCLUSIONS

In our own early experience, the experimental model of chronic MR based on ischemic damage to the posteromedial papillary muscle and associated with volume overload is feasible, safe, and reproducible. It may be useful to assess the safety and efficacy profile of future devices for the management of this heart disease.

FUNDING

This study was partially funded through a grant from the Regional Healthcare Management of Castille and León, Spain (GRS1396_A_16).

CONFLICTS OF INTEREST

R. Estévez-Loureiro is a proctor for MitraClip and received a research grant from Abbott Vascular. A. Pérez de Prado participated and received funding for his consultancy job done for Boston Scientific and iVascular SL, and lectures given for Abbott, Braun Surgical, Terumo Medical Corporation, and Philips Volcano. The remaining authors declared no conflicts of interest whatsoever.

WHAT IS KNOWN ABOUT THE TOPIC?

  • MR is the second most common valve disease. Mitral valve repair surgery is the standard treatment, but over 50% of the patients are not operated on due to their comorbidities.
  • There are several devices available today to reduce the degree of regurgitation through transcatheter approaches. Also, there are several studies on experimental models to induce and maintain MR in order to test these devices. All of them have pros and cons and imitate different etiologies of MR such as dilated cardiomyopathy, ischemic MR, and even rupture of a mitral chorda tendinae.
  • After studying the models already published, 2 are the prerequisites to induce a sustainable model of MR: ischemic lesion with damage to the papillary muscle, and ventricular dilatation.

WHAT DOES THIS STUDY ADD?

  • A new experimental model to induce ischemic MR by combining the production of ischemic damage through the coronary occlusion of the branches supplying the papillary muscle and left ventricular volume overload with aortopulmonary sunt following the implantation of a Dacron tube graft between the aorta and a pulmonary branch.
  • We should mention that none of the animals survived surgery and died at the follow-up, which is indicative of a feasible and safe model of ischemic MR.

SUPPLEMENTARY DATA


REFERENCES

1. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

2. Mirabel M, Iung B, Baron G, et al. What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery?Eur Heart J. 2007;28:1358-1365.

3. Borger MA, Alam A, Murphy PM, Doenst T, David TE. Chronic ischemic mitral regurgitation:repair, replace or rethink?Ann Thorac Surg. 2006;81:1153-1161.

4. Jamieson WR, Edwards FH, Schwartz M, Bero JW, Clark RE, Grover FL. Risk stratification for cardiac valve replacement. National Cardiac Surgery. Ann Thorac Surg. 1999;67:943-951.

5. Herrmann HC, Maisano F. Transcatheter therapy of mitral regurgitation. Circulation. 2014;130:1712-1722.

6. Maisano F, Alfieri O, Banai S, et al. The future of transcatheter mitral valve interventions:competitive or complementary role of repair vs. replacement?Eur Heart J. 2015;36:1651-1659.

7. Mauri L, Foster E, Glower DD, et al. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol. 2013;62:317-328.

8. Nickenig G, Estevez-Loureiro R, Franzen O, et al. Percutaneous Mitral Valve Edge-to-Edge Repair:In-Hospital Results and 1-Year Follow-Up of 628 Patients of the 2011-2012 Pilot European Sentinel Registry. J Am Coll Cardiol. 2014;64:875-84.

9. Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve interventions in the real world:early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol. 2013;62:1052-1061.

10. Cui YC, Li K, Tian Y, et al. A pig model of ischemic mitral regurgitation induced by mitral chordae tendinae rupture and implantation of an ameroid constrictor. PloS One. 2014;9:e111689.

11. Minakawa M, Robb JD, Morital M, et al. A model of ischemic mitral regurgitation in pigs with three-dimensional echocardiographic assessment. J Heart Valve Dis. 2014;23:713-720.

12. Hamza O, Kiss A, Kramer AM, Tillmann KE, Podesser BK. Characterization of a novel percutaneous closed chest swine model of ischemic mitral regurgitation guided by contrast echocardiography. Eurointervention. 2019. pii:EIJ-D-19-00095.

13. Aguero J, Galan-Arriola C, Fernandez-Jimenez R, et al. Atrial Infarction and Ischemic Mitral Regurgitation Contribute to post-MI Remodeling of the Left Atrium. J Am Coll Cardiol. 2017;70:2878-2889.

14. Llaneras MR, Nance ML, Streicher JT, et al. Large animal model of ischemic mitral regurgitation. Ann Thorac Surg. 1994;57:432-439.

15. Pereda D, García-Lunar I, Sierra F, et al. Magnetic Resonance Characterization of Cardiac Adaptation and Myocardial Fibrosis in Pulmonary Hypertension Secondary to Systemic-To-Pulmonary Shunt. Circ Cardiovasc Imaging. 2016;9:e004566.

Corresponding author: Unidad de Cardiología Intervencionista, Hospital Álvaro Cunqueiro, Estrada de Clara Campoamor 341, 36213 Vigo, Pontevedra, Spain.
E-mail address: roiestevez@hotmail.com (R. Estévez-Loureiro).

Abstract

Introduction and objectives: A significant amount of patients undergoing transcatheter aortic valve implantation (TAVI) have an indication for oral anticoagulation due to atrial fibrillation. In these patients the bleeding risk is often high. The purpose of this study was to compare the clinical outcomes of patients treated with low doses of apixaban or the vitamin K antagonist (VKA) acenocumarol in this setting.

Methods: Multicenter observational registry including patients treated after TAVI with low doses of apixaban (2.5 mg/12 hours) or VKA both without associated antiplatelet therapy. Propensity score matching was conducted to select 2 comparable cohorts. Data were gathered for 12 months following the procedure. Coprimary endpoints of efficacy (death, myocardial infarction, and stroke) and safety (bleeding BARC ≥ 2) were considered.

Results: A total of 236 patients were included. They were divided into 2 comparable groups of 64 patients each. Only 19 patients (30%) strictly met the dose adjustment criteria for apixaban. The rate of death, myocardial infarction, and stroke was similar at the 12-month follow-up (12.5% with VKA vs 9.3% with apixaban, P = .5), but the rate of bleeding BARC ≥ 2 was significantly higher in the VKA group (7.8% vs 0%; P = .02). Most of the events seen in the apixaban group occurred in patients with incorrect dose titration.

Conclusions: In this registry of patients treated with TAVI and atrial fibrillation the use of low-dose apixaban compared to VKA—both without antiplatelet agents—was associated to a lower rate of actionable bleeding and a similar rate of thrombotic events.

Keywords: TAVI. Anticoagulation. Apixaban. Vitamin K antagonist.

RESUMEN

Introducción y objetivos: Una proporción significativa de pacientes sometidos a implante percutáneo de válvula aórtica (TAVI) presenta indicación de anticoagulación oral por fibrilación auricular. En estos pacientes, con frecuencia el riesgo hemorrágico es alto. El objetivo del estudio fue comparar los resultados clínicos en pacientes tratados con dosis baja de apixabán o con acenocumarol, un antagonista de la vitamina K (AVK).

Métodos: Registro observacional multicéntrico que incluyó pacientes sometidos a TAVI tratados con dosis baja de apixabán (2,5 mg/12 h) o AVK, en ambos casos sin tratamiento antiplaquetario asociado. Se llevó a cabo un emparejamiento por puntuación de propensión para seleccionar dos cohortes comparables. Se recabó la información de los 12 meses posteriores al procedimiento. Se consideraron objetivos coprimarios de eficacia (muerte, infarto de miocardio e ictus) y de seguridad (hemorragias BARC ≥ 2).

Resultados: Se incluyeron 236 pacientes y se obtuvieron 2 grupos de 64 pacientes comparables en cuanto a características basales. Solo 19 (30%) cumplieron estrictamente los criterios de ajuste a la baja de la dosis de apixabán. A los 12 meses, la incidencia de muerte, infarto de miocardio e ictus fue comparable (12,5% con AVK frente a 9,3% con apixabán; p = 0,5), pero la incidencia de hemorragia BARC ≥ 2 fue significativamente mayor en el grupo de AVK (7,8 frente a 0%; p = 0,02). La mayoría de los eventos trombóticos en el grupo de apixabán se observaron en pacientes con reducción de dosis no ajustada a criterios.

Conclusiones: En este registro de pacientes con TAVI y fibrilación auricular, el uso de la dosis baja de apixabán en comparación con el uso de AVK, sin antiagregantes concomitantes, se asoció a una menor incidencia de hemorragias mayores con una incidencia similar de eventos tromboembólicos.

Palabras clave: TAVI. Anticoagulación. Apixabán. Antagonistas vitamina K.

Abbreviations: AF: atrial fibrillation. BARC: Bleeding Academic Research Consortium. DOAC: direct oral anticoagulants. MACE: major adverse cardiovascular events. TAVI: transaortic valve implantation. VKA: vitamin K antagonist.

INTRODUCTION

The growing number of transaortic valve implantation (TAVI) procedures over the last few years is the consequence of the large and solid scientific evidence available that has broadened its indications.1-3

Atrial fibrillation (AF) is a common finding in these patients.4 Its presence prior to the implant and its new appearance at the follow-up are associated with a higher mortality rate and a higher incidence of stroke,5 but also with more hemorrhages mainly due to the need for anticoagulation.6,7 The risk of hemorrhage is particularly high in patients who undergo TAVI since they are often old patients.

Direct oral anticoagulants (DOAC) have proven a better safety and efficacy profile compared to vitamin K antagonists (VKA) in the nonvalvular AF setting. However, few studies have analyzed their role in patients with valvular AF and, today, only the guidelines on the management of valvular heart disease established by the European Society of Cardiology de 2017 recommend them with a class IIa level of evidence C 3 months after the implant of a surgical bioprosthesis.8 No obstante, to this day dabigatran is the only DOAC that has proven non-inferior to VKA in patients with surgical bioprosthesis.9

Regarding patients with AF treated with TAVI there is not much evidence available for DOAC. In one of the very few cases published, the use of apixaban was associated with a significantly lower rate of adverse events at 30 days compared to the use of VKA.10 However, there were significant differences between the groups, no statistical matching was conducted, and patients with associated antiplatelet therapy were included.

The population treated with TAVI is often old (> 80 years), shows different stages of chronic kidney disease, and at times low body weight. These conditions may justify the relatively high prevalence of low-dose apixaban (2.5 mg/12 h).

This study assessed the use of low-dose apixaban in patients with TAVI and compared its long-term clinical outcomes to patients treated with VKA. A multicenter registry was designed including patients with an indication for oral anticoagulation (without associated antiplatelet therapy) post-TAVI on VKA or apixaban at doses of 2.5 mg/12 h. The registry included propensity score matching of these patients to estimate the effect of treatment.

METHODS

Study population

A multicenter, retrospective and observational registry was designed from a review of individual TAVI registries from 4 hospitals nationwide.

The study population included all consecutive patients treated with TAVI from 2008 with a diagnosis of AF at hospital discharge and an indication for chronic oral anticoagulation only whether VKA or apixaban at a dose of 2.5 mg/12 h, and with a 1-year follow-up. Patients dead at admission were, therefore, excluded and there were no additional exclusion criteria.

The decision on the dose of apixaban was the responsibility of the patient’s treating physician. European Medicines Agency recommends low-dose apixaban in patients with non-valvular AF and glomerular filtration rate of 15-29 mL/min and in patients with, at least, 2 of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg or serum creatinine levels ≥ 1.5 mg/dL (133 µmol/L).11

Study endpoints and definition of events

All clinical variables, demographic data, and cardiovascular risk factors were recorded from each case. Also, previous TAVI procedures, the presence of cardiovascular disease or previous heart surgeries, chronic lung or kidney disease, liver cirrhosis or neoplasms was also recorded in all of the patients. Variables associated with cardiovascular status such as ventricular function, aortic stenosis and coronary artery disease were included as well. Surgical risks were assessed using the following risk scores: EuroSCORE log, EuroSCORE II, and the Society of Thoracic Surgery (STS) score. Given the presence of AF at hospital discharge (whether known or de novo), the annual risks of thromboembolic events were assessed using the CHA2DS2-VASc score while bleeding risk was assessed using the HAS-BLED score in all of the patients. Other data on the procedure and complications derived from it were also recorded as defined by the updated criteria established by the Valve Academic Research Consortium-2 (VARC-2).12

The rate of major adverse cardiovascular events (MACE) at the 1-year follow-up was studied in all of the patients after TAVI implantation in each center. MACE was defined as all-cause mortality, stroke (whether ischemic or hemorrhagic), and acute myocardial infarction, all of them defined according to the criteria established by VARC-2.11 Also, the rate of hemorrhages categorized according to the classification established by the Bleeding Academic Research Consortium (BARC)12 and considered relevant if BARC ≥ 2 was also studied. The net composite endpoint of efficacy-safety including all MACE and BARC type ≥ 2 bleeding was studied as well.

Two coprimary endpoints were studied: efficacy (through MACE) and safety (BARC type ≥ 2 bleeding). Secondary endpoints were a net composite endpoint of efficacy-safety, overall mortality, cardiac death, myocardial infarction, stroke, and hemorrhagic stroke.

The adjudication of events was left at the discretion of the researchers from each center according to the definitions previously indicated. The database did not include any events that allowed the identification of patients and anonymity was guaranteed at all time. The study was approved by the coordinating center ethics committee.

Statistical analysis

Continuous variables were expressed as mean and standard deviation or median and interquartile range according to their distribution. Categorical variables were expressed as percentages. The Kolmogorov-Smirnov test was used to determine whether the distribution of continuous variables was normal. If so both groups were compared using the independent-samples t-test was used. In cases of non-normal distribution Wilcoxon test was used. Qualitative or categorical variables were compared using the chi-square test or Fisher’s exact test when appropriate. Cox proportional hazards regression model was used in the entire sample before the matching to identify predictor variables of net composite event. Variables with P values < .1 in the univariate analysis were included.

Given the limitations and interpretation biases of the possible associations in the comparison of unadjusted variables of an observational study like this propensity score adjustment was made using the logistics regression model. The type of high anticoagulation was established (apixaban 2.5 mg vs VKA) as a dependent variable and the baseline characteristics shown on table 1 were included in the analysis as independent variables. Since the number of patients was clearly lower in the apixaban group, the goal of the propensity score matching to estimate the effect of treatment was to match each patient from the apixaban group with a patient from the VKA group. This procedure included 2 stages: 1) Propensity scores were estimated using the logistics regression model and treatment with apixaban was used as the outcome variable. All the covariables analyzed were used as predictors; and 2) patients were matched on a 1:1 ratio using the nearest neighbor matching based on a correlation algorithm that categorizes observations in the apixaban group based on the estimated propensity score. Then each unit was sequentially combined with a unit from the VKA group with the nearest propensity score. All the differences seen in the standardized means after matching were < 10%. Calibration was estimated using the Hosmer-Lemeshow test while precision was assessed using the area under the ROC (Receiver Operating Characteristic) curve. The PS Matching software and SPSS statistical package version 22.0 (IBM, United States) were used. The PS Matching software performs all R analyses using the SPSS R-Plugin. Event-free survival was studied using the Kaplan-Meier method. The log-rank test was used for group comparison. All analyses were 2-tailed and P values < .05 were considered statistically significant. Statistical analyses were conducted using the SPSS statistical package version 22.0.

Table 1. Baseline characteristics before and after propensity score adjustment

Overall cohort Matched cohort
Apixaban (n = 64) VKA (n = 172) P Apixaban (n = 64) VKA (n = 64) P
Male sex 41 (64) 60 (35) < .001 41 (64) 38 (59) .6
Age (years) 82 ± 6 83 ± 6 .3 82 ± 6 81 ± 7.5 .7
Weight (kg) 72 ± 12 71 ± 17 .6 72 ± 12 74 ± 14 .5
Height (cm) 161 ± 10 158 ± 14 .1 161 ± 10 160 ± 9 .32
HBP 55 (86) 140 (81) .4 55 (86) 48 (75) .11
Diabetes mellitus 27 (42) 51 (30) .07 27 (42) 19 (30) .14
Baseline glomerular filtration rate (mL/min) 58 ± 20 61 ± 23 .3 58 ± 20 60 ± 25 .6
Previous ACS 4 (6) 10 (6) .9 4 (6) 4 (6) 1
Previous PTA 9 (14) 10 (6) .04 9 (14) 8 (13) .8
Previous CABG 3 (5) 12 (7) .52 3 (5) 4 (6) .7
Previous AVR 7 (11) 6 (4) .03 7 (11) 4 (6) .3
Previous stroke 3 (5) 26 (15) .03 3 (5) 3 (5) 1
COPD 19 (30) 39 (23) .27 19 (30) 15 (23) .4
Cirrhosis 0 4 (2) .6 0 1 (1.6) 1
Neoplasm 11 (17) 16 (9) .09 11 (17) 6 (9) .2
Peripheral vascular disease 7 (11) 4 (5) .15 7 (11) 2 (6) .4
NYHA III-IV 30 (51) 111 (65) .06 30 (51) 37 (58) .4
Baseline LVEF (%) 53 ± 12 56 ± 13 .1 53 ± 12 56 ± 12 .3
EuroSCORE log 13.3 ± 9 18.5 ± 13 .002 13.3 ± 9 14 ± 8 .7
EuroSCORE II 4.2 ± 5 6.4 ± 6 .013 4.2 ± 5 4.7 ± 4 .55
STS mortality 6 [2-10] 7 [5-15] .4 6 [2-10] 11 [3-11] .5
CHA2DS2-VASc 4.5 ± 1.1 4.6 ± 1.4 .55 4.5 ± 1.1 4 ± 1.3 .07
HAS-BLED 2.8 ± 1 2.74 ± 1 .8 2.8 ± 1 2.5 ± 1.1 .3

ACS, acute coronary syndrome; AVR, aortic valve replacement; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; HBP, high blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PTA, percutaneous transluminal angioplasty; STS, Surgeon Thoracic Score; VKA, vitamin K antagonists.

Data are expressed as no. (%) or mean ± (standard deviation) or median [interquartile range].

RESULTS

Of a total of 1791 patients a final cohort of 236 patients who met the inclusion criteria was obtained. Of these 64 (27%) were treated with low-dose apixaban at discharge after TAVI, and 172 (73%) were treated with VKA. Using propensity score matching to estimate the effect of treatment 2 groups of 64 patients each were made. The flow chart of patients is shown on figure 1. The center-based distribution of cases with apixaban was 60%, 20%, 14%, and 3%.

Figure 1. Study flow chart. AF, atrial fibrillation; TAVI, transaortic valve implantation; VKA, vitamin K antagonist.

Regarding the adequacy of low-dose apixaban with respect to the degree of compliance of the characteristics recommended by the European Medicines Agency,11 it was confirmed that only 19 patients (30%) strictly met the criteria (figure 2). Sixty-eight per cent of the patients ≥ 80 years had chronic kidney disease stage IIIA (glomerular filtration rate 30-59 mL/min) and that factor was considered enough to indicate a dose of 2.5 mg.

Figure 2. Group of patients treated with low-dose apixaban according to the variables contemplated for the reduction of doses. The number of patients who met each and every criterion and the possible combination of these is shown too. The European Medicines Agency recommends low-dose apixaban in patients with non-valvular atrial fibrillation and glomerular filtration rates (GFR) of 15-29 mL/min, as well as in patients with, at least, 2 of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg or serum creatinine levels ≥ 1.5 mg/dL (133 µmol/L).11

Table 1 shows the baseline characteristics of the overall cohort and those adjusted by propensity score. In the overall cohort the group on apixaban included more males, more patients with previous coronary and valve interventions and less patients with a past medical history of strokes. The values of EuroSCORE were lower compared to the VKA group, but bleeding risk scores were similar. No significant differences were seen between the matched groups.

The procedural characteristics and complications seen in the groups already matched are shown on table 2. No significant differences were found for any of the aspects studied. It should be mentioned here that patients from the apixaban group showed higher hemoglobin levels at hospital discharge. Also, in this group, 10 patients had made it to TAVI on anticoagulant and antiplatelet therapy (suspended after TAVI) compared to only 1 patient from the VKA group. Regarding the timeline of AF, all the patients from the VKA group already showed it before TAVI, while only 5 patients from the apixaban group developed it after TAVI.

Table 2. Procedural characteristics, complications, and characteristics at hospital discharge of the matched cohort

Apixaban (n = 64) VKA (n = 64) P
Balloon-expandable aortic valve 51 (80) 50 (78) .8
Femoral access 64 (100) 62 (97) .5
Successful implant 64 (100) 64 (100) 1
Transfusions 7 (11) 5 (8) .5
Coronary occlusion 0 0
Valve embolization 0 0
Annular rupture 0 0
Periprocedural stroke 1 (1.6) 1 (1.6) 1
Vascular complication 7 (11) 10 (16) .4
BARC type ≥ 2 bleeding 4 (6.3) 4 (6.3) 1
Periprocedural ACS 0 0
Need for pacemaker 8 (13) 10 (16) .6
De novo atrial fibrillation 5 (8) 0 .06
Hemoglobin levels (g/dL) at hospital discharge 12 ± 1.6 11 ± 1.4 .05
Platelet levels at hospital discharge (109/L) 133 ± 92 160 ± 60 .2
Glomerular filtration rate (mL/min) at hospital discharge 68 [53-82] 66 [40-82] .5

ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; VKA, vitamin K antagonists.

Data are expressed as no. (%) or mean ± (standard deviation) or median [interquartile range].

No patients were lost to the follow-up. Table 3 shows the cardiovascular events seen from hospital discharge until 1 year later without significant differences between both groups regarding MACE. Four deaths occurred in the VKA group (6%) of which 2 were cardiac deaths (heart failure and sudden death) and the remaining 2 were due to major hemorrhages (hemorrhagic stroke and hypovolemic shock after a fall with hip fracture). The 3 deaths from the apixaban group were caused by pulmonary disease. It is interesting to see the events that occurred in the apixaban group based on the use of adjusted low doses and not on criteria since MACE occurred in the group with unadjusted doses.

Table 3. Major cardiovascular adverse events and hemorrhages at the 12-month follow-up

Apixaban VKA (n = 64) P *
LD (n = 64) ALD (n = 19) NALD (n = 45)
MACE 6 (9.3) 1 (5.3) 5 (11) 8 (12.5) .5
Death 3 (4.7) 0 3 (4.7) 4 (6.2) .7
Cardiac death 0 0 0 2 (3.1) .3
Myocardial infarction 1 (1.6) 0 1 (2.2) 1 (1.6) 1
Stroke 2 (3.1) 1 (5.3) 1 (2.2) 3 (4.7) .9
Hemorrhagic stroke 0 0 0 2 (3.1) .5
BARC type > 2 bleeding 0 0 0 5 (7.8) .02
Safety-efficacy target** 4 (6.2) 0 4 (8.8) 8 (12.5) .23

ALD, adjusted low dose; LD, low dose; MACE, major cardiovascular adverse events; NALD, non-adjusted low dose; VKA, vitamin K antagonists.

Data are expressed as no. (%).

* P values for the comparison between apixaban LD vs VKA.

** Composite of death, myocardial infarction, stroke, and BARC ≥ type 2 bleeding.

Only relevant hemorrhages were reported (BARC ≥ 2) in the VKA group with a significant difference compared to the apixaban group. Events occurred during months 1, 3, 5, 6, 11 after TAVI. Three of these major hemorrhages were due to digestive problems, 1 due to subarachnoid hemorrhage, and the other due to a spontaneous hematoma in the anterior rectus abdominis muscle. All of these patients required admission, surgery, and received 4 blood transfusions. In the apixaban group the rate of BARC type ≥ 2 bleeding seen (0%) was lower than anticipated by the HAS-BLED score (3.4%), but in the VKA group it was exactly the other way around: the rate seen (7.8%) was higher than expected (2.8%).

The cumulative MACE-free survival at 1 year showed no significant differences between the groups as shown on figure 3. Figure 4 shows the hemorrhage-free survival curves (BARC ≥ 2) with significant differences that favor the apixaban group. Mortality-free survival, infarction, stroke, and BARC type ≥ 2 bleeding curves did not show significant differences, but they did favor apixaban (figure 5). The Cox multivariate analysis conducted on the overall sample prior to case matching identified the use of apixaban as an independent predictor for the net composite endpoint of efficacy and safety (hazard ratio, 0.56; 95% confidence interval, 0.23-0.98; P = .04).

Figure 3. Major cardiovascular events (MACE)-free Kaplan-Meier survival curves at the 1-year follow-up. VKA, vitamin K antagonist.

Figure 4. BARC type ≥ 2 bleeding-free Kaplan-Meier survival curves. VKA, vitamin K antagonist.

Figure 5. Mortality-free Kaplan-Meier survival curves, infarction, stroke, and BARC type ≥ 2 bleeding.

DISCUSSION

The main study findings are: a) the use of apixaban is still not widespread compared to VKA in the population with TAVI and AF; b) the use of low-dose apixaban is very common in this context, but on many occasions it does not strictly adjust to the instructions for use and underdosing is a common thing; c) compared to VKA treatment with low-dose apixaban was associated with very similar rates of thrombotic-ischemic events and a significantly lower risk of major bleeding.

These findings together with the reservations derived from the study limitations would be consistent with the results of the ARISTOTLE trial subanalysis13 in patients with bioprosthesis. These results would confirm the safety and efficacy profile of apixaban in valvular patients, although only 31% of these were > 75 years old. A substudy of the ENGAGE AF-TIMI 48 trial14 of 191 patients with previous implant of a surgical or transcatheter bioprosthesis and AF showed a significant reduction of major bleeding with low-dose edoxaban (30 mg) compared to warfarin. The low and high doses (60 mg) of edoxaban were associated with a reduced composite of stroke, systemic embolism, major bleeding or death.

The population treated with TAVI includes elderly patients with multiple comorbidities who are not very well represented in the clinical studies of other contexts such as non-valvular AF.

The presence of previous or de novo AF after TAVI is not an uncommon finding in this population, and embolic and hemorrhagic risk is higher compared to other populations, which poses a significant challenge when having to decide what the best antithrombotic treatment should be.

There are still few studies that compare DOAC to VKA in the TAVI setting, and they are often registries. In the aforementioned Seeger et al.,10 141 patients treated with apixaban (most of them with doses of 5 mg) and 131 with VKA, the safety profile was better with apixaban and efficacy was similar. However, in this registry the low-dose apixaban and statistical matching were not studied and cases with concomitant antiplatelet therapy were included. In our study we thought it was very important to exclude patients with associated antiplatelet therapy and perform propensity score matching to estimate the effect of treatment. That is so because both aspects reduce significantly the load of biases associated with registry-based comparative studies. On the other hand, the low-dose study was very pertinent given its frequency of use in this population.

A different study compared the clinical progression of 154 patients treated with several DOAC and 172 treated with VKA always without antiplatelet therapy15 without statistical matching but with significant differences between the groups. The authors found very similar efficacy and safety profiles, although the DOAC group had a more adverse hemorrhagic and thrombotic baseline risk profile.

Finally, in the RESOLVE (The assessment of transcatheter and surgical aortic bioprosthetic valve thrombosis and its treatment with anticoagulation) and SAVORY (Subclinical aortic valve bioprosthesis thrombosis assessed with four-dimensional computed tomography) registries no significant differences were found regarding the move of the valve leaflets between DOAC and warfarin (3% vs 4%, respectively; P = .72), although both seemed better than non-anticoagulation.16

The high prevalence of underdosing of apixaban in this population is worth mentioning. We believe that it can be conditioned by the perception of a very high bleeding risk in these patients (most of them 80-year-old patients with a high prevalence of chronic kidney disease and other conditions) and a variable degree of frailty. Although it is not an established criterion per se to change the type and dose of anticoagulation it can certainly influence the decision-making process.

The fact that we found differences that favored apixaban at doses of 2.5 mg compared to VKA may lead us to think that underdosing does not penalize as much as in the general context of patients with non-valvular AF;13 as a matter of fact, it is associated with a better safety profile without affecting efficacy. However, the use of low doses cannot be recommended openly and we believe in the rigor of dose adjustment. Although the size of subgroups based on correct dose adjustment was not small and we cannot draw conclusive results, more thrombotic-ischemic events were seen within the apixaban group in the incorrect adjustment group. However, we should mention that dosing needs to be dynamic since dose adjustment conditions vary across follow-up and that is how the treatment of these patients is optimized at all time.

Having said this, the indications for treatment with these drugs are changing due to recent real-world data available. Until a year ago, apixaban was contraindicated in patients with acute kidney injury in whom VKA were still the treatment of choice. The studies most recently published show a clear benefit regarding hemorrhages with doses of apixaban of 2.5 mg, and thromboembolic events and mortality with doses of 5 mg in patients with acute kidney injury and dialysis.17

The difficulty of this was seen in the results reported by the GALILEO trial18 (Global study comparing a rivaroxaban-based antithrombotic strategy to an antiplatelet-based strategy after transcatheter aortic valve replacement to optimize clinical outcomes). This study showed that in patients without indication for oral anticoagulation after TAVI, a treatment strategy including rivaroxaban at doses of 10 mg/day plus antiplatelet therapy within the first 90 days was associated with a higher risk of death or thromboembolic complications and hemorrhages compared to a 90-day course of dual antiplatelet therapy and then single antiplatelet therapy.

The ongoing studies that are being conducted now will provide more solid evidence on what the best antithrombotic strategies are in patients after TAVI with and without AF.19

Limitations

The main limitation of this study is that it was not randomized. As any other observational registry, it is subject to more and less evident confounding factors. Although the use of propensity score matching to estimate the effect of treatment produced 2 groups with very similar baseline characteristics, the chances of bias were still present.

The size of the sample is the second most important limitation. The volume of patients with TAVI plus an indication for oral anticoagulation only is not high in any centers in our setting, especially if we wish to include those specifically treated with low-dose apixaban. Therefore, a multicenter study with high-volume centers was designed (compared to the average of the country), but still the size of the sample could not be higher. This creates an underpowered study that should be considered exploratory and hypothesis-generating only. This limitation is even more evident for subgroup comparisons based on dose adjustment. However, until statistically powered studies become available, the results from registries like this contribute to expand our knowledge base. Event adjudication was not centralized although the previously established standardized definitions were adjusted.11

CONCLUSIONS

The use of low-dose apixaban (2.5 mg/12 h) in patients treated with TAVI often did not strictly match the official recommendations. In this registry, the use of low-dose apixaban was associated with very similar figures of thrombotic-ischemic events compared to the use of acenocoumarol, but a significantly lower risk of major hemorrhages. This study suggests that, in patients treated with TAVI who have AF, the use of low-dose apixaban (if adequately prescribed) is safer and equally efficient compared to acenocoumarol.

CONFLICTS OF INTEREST

J.M. de la Torre Hernández has received unconditional institutional research grants and fees for as a counselor for Bristol-Myers Squibb. Also, he is the editor-in-chief of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed.

WHAT IS KNOWN ABOUT THE TOPIC?

  • The performance of TAVI has experienced significant growth. The prevalence of AF among patients with TAVI is high. DOAC have proven better safety and efficacy profile compared to VKA in the non-valvular AF setting. There are few studies analyzing the role of patients with TAVI and AF, and in particular none assessing low-dose apixaban.

WHAT DOES THIS STUDY ADD?

  • This multicenter registry shows that the use of apixaban is not widespread compared to the use of VKA in the population with TAVI and AF. In patients treated with apixaban the use of low doses is very common, but many times, it does not strictly follow the instructions for used. In this sense compared to VKA, treatment with low-dose apixaban was associated with very similar rates of thrombotic-ischemic events and a significant lower risk of major hemorrhages.

REFERENCES

1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198.

2. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609-1620.

3. Waksman R, Rogers T, Torguson R, et al. Transcatheter Aortic Valve Replacement in Low-Risk Patients With Symptomatic Severe Aortic Stenosis. J Am Coll Cardiol. 2018;72:2095-2105.

4. Koniari I, Tsigkas G, Kounis N, et al. Incidence, pathophysiology, predictive factors and prognostic implications of new onset atrial fibrillation following transcatheter aortic valve implantation. J Geriatr Cardiol. 2018;15:50-54.

5. Biviano AB, Nazif T, Dizon J, et al. Atrial Fibrillation Is Associated With Increased Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement:Insights From the Placement of Aortic Transcatheter Valve (PARTNER) Trial. Circ Cardiovasc Interv. 2016 ;9:e002766.

6. Kapadia S, Agarwal S, Miller DC, et al. Insights Into Timing, Risk Factors, and Outcomes of Stroke and Transient Ischemic Attack After Transcatheter Aortic Valve Replacement in the PARTNER Trial (Placement of Aortic Transcatheter Valves). Circ Cardiovasc Interv. 2016;9. pii:e002981.

7. Tarantini G, Mojoli M, Urena M, Vahanian A. Atrial fibrillation in patients undergoing transcatheter aortic valve implantation:epidemiology, timing, predictors, and outcome. Eur Heart J. 2017;38:1285-1293.

8. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791.

9. Durães AR, de Souza Roriz P, de Almeida Nunes B, et al. Dabigatran Versus Warfarin After Bioprosthesis Valve Replacement for the Management of Atrial Fibrillation Postoperatively:DAWA Pilot Study. Drugs R D. 2016;16:149-154.

10. Seeger J, Gonska B, Rodewald C, et al. Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement. JACC Cardiovasc Interv. 2017;10:66-74.

11. Agencia Europea de Medicamentos. Anexo I. Ficha técnica o resumen de las características del producto. Disponible en:https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_es.pdf. Consultado 12 Mar 2020.

12. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation:the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg. 2013;145:6-23.

13. Guimarães PO, Pokorney SD, Lopes RD, et al. Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair:Insights from the ARISTOTLE trial. Clin Cardiol. 2019;42:568-571.

14. Carnicelli AP, De Caterina R, Halperin JL, et al. ENGAGE AF-TIMI 48. Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves. Circulation. 2017;135:1273-1275.

15. Geis NA, Kiriakou C, Chorianopoulos E, Uhlmann L, Katus HA, Bekeredjian R. NOAC monotherapy in patients with concomitant indications for oral anticoagulation undergoing transcatheter aortic valve implantation. Clin Res Cardiol. 2018;107:799-806.

16. Chakravarty T, Søndergaard L, Friedman J, et al. RESOLVE and SAVORY In-vestigators. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves:an observational study. Lancet. 2017;389:2383-2392.

17. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation. 2018;138:1519-1529.

18. Dangas GD, Tijssen JGP, Wöhrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med. 2020;382:120-129.

19. Guedeney P, Mehran R, Collet JP, Claessen BE, Ten Berg J, Dangas GD. Antithrombotic Therapy After Transcatheter Aortic Valve Replacement. Circ Cardiovasc Interv. 2019;12:e007411.

Corresponding author: Unidad de Hemodinámica y Cardiología Intervencionista, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla 25, 1.ª Planta, 39008 Santander, Cantabria, Spain.
E-mail address: josemariadela.torre@scsalud.es (J.M. de la Torre Hernández).

ABSTRACT

Introduction and objectives: This study primary endpoint was to present the in-hospital all-cause mortality of the Spanish TAVI registry from its inception until 2018. Secondary endpoints included other in-hospital clinical events, 30-day all-cause mortality, and an assessment of the time trend of this registry.

Methods: All consecutive patients included in the Spanish TAVI registry were analyzed. In this time-based analysis, the population was been divided into patients treated before 2014 (cohort A: 2009-2013) and patients treated between 2014 and 2018 (cohort B).

Results: From August 2007 to June 2018, 7180 patients were included. The mean age was 81.2 ± 6.5 years and 53% were women. The logistic EuroSCORE was 12% (8-20). Transfemoral access was used in 89%. In-hospital and 30-day all-cause mortality was 4.7% and 5.7%, respectively. On the time-based analyses during the hospital stay, the rate of myocardial infarction, stroke, need for pacemakers, tamponade, coronary obstruction, and vascular complications was similar between both groups. However, cohort B showed less need for conversion to surgery and malapposition of the valve. Also, the implant success rate increased from 93% to 96% (P< .001). In-hospital and 30-day all-cause mortality was significantly lower in cohort B, ([OR, 0.65; IC95%, 0.48-0.86; P= .003] and [OR, 0.71; IC95%, 0.54-0.92; P= .002], respectively).

Conclusions: The time trend analysis of the Spanish TAVI registry showed a change in the patients’ clinical profile and an improvement in the in-hospital clinical outcomes and 30-day all-cause mortality in patients treated more recently.

Keywords: Transcatheter Treatment of the Aortic Valve. Records. Severe Aortic Stenosis.

RESUMEN

Introducción y objetivos: El objetivo primario de este estudio fue presentar la mortalidad total intrahospitalaria del registro español de implante percutáneo de válvula aórtica (TAVI) desde su inicio hasta el año 2018, y como objetivos secundarios otros eventos clínicos intrahospitalarios, la mortalidad total a los 30 días y la evaluación de cuál ha sido la evolución temporal de este registro.

Métodos: Fueron analizados todos los pacientes consecutivos incluidos en el registro español de TAVI. En este análisis temporal se dividió la población en pacientes tratados antes de 2014 (cohorte A: 2009-2013) y pacientes tratados entre los años 2014 y 2018 (cohorte B).

Resultados: Desde agosto de 2007 hasta junio de 2018 se incluyeron 7.180 pacientes. La edad media fue de 81,2 ± 6,5 años y el 53% eran mujeres. El EuroSCORE logístico fue del 12% (8-20). Se utilizó un acceso transfemoral en el 89%. La mortalidad total intrahospitalaria fue del 4,7% y a los 30 días fue del 5,7%. En el análisis temporal durante la fase hospitalaria, las tasas de infarto, accidente cerebrovascular, necesidad de marcapasos, taponamiento, obstrucción coronaria y complicaciones vasculares fueron similares en ambos grupos. Sin embargo, en la cohorte B se observó una reducción de la necesidad de conversión a cirugía y de malaposición de la válvula, y además la tasa de éxito del implante fue mayor (93 frente a 96%; p < 0,001). La mortalidad por cualquier causa ajustada tanto intrahospitalaria como a los 30 días, fue significativamente menor en la cohorte B (odds ratio [OR] = 0,65; intervalo de confianza del 95% [IC95%], 0,48-0,86; p = 0,003; y OR = 0,71; IC95%, 0,54-0,92; p = 0,002, respectivamente).

Conclusiones: En el análisis temporal del registro español de TAVI se observan un cambio en el perfil clínico de los pacientes y una mejora en la evolución clínica tanto intrahospitalaria como a los 30 días en los pacientes tratados en los últimos años.

Palabras clave: Tratamiento transcatéter de la válvula aórtica. Registros. Estenosis aórtica grave.

Abbreviations: TAVI: transcatheter aortic valve implantation.

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is the best therapeutic option today for most elderly patients with severe, degenerative aortic stenosis.1-4The evidence that supports this indication comes from rigorous randomized clinical trials conducted with balloon expandable valves5-7like self-expandable valves.8-10In this sense, this technique has recently consolidated after the publication of the initial results of new studies conducted in low-risk patients.11,12

Over the years, the implantation technique and the type of patients have changed.13,14These factors together with the new generations of valves including technical improvements have reduced the occurrence of major cardiovascular and cerebral events both in-hospital and in the long-term follow-up.15,16In the French TAVI registry (n = 16 969 patients) surgical risk was lower in the patients treated, a greater simplification of the technique via transfemoral access, and a lower short-term mortality rate over the last few years (2013-2015) compared to the first period studied (2010-2012). However, these differences were not found in the time trend analysis of the English registry (n = 3980).

The study primary endpoint was to present the in-hospital all-cause mortality rate of the Spanish TAVI registry from its inception until 2018. Secondary endpoints included other in-hospital clinical events, 30-day overall mortality, and a time trend analysis in 2 well-defined time periods: from August 2007 through December 2013 (cohort A), and from January 2014 through June 2018 (cohort B) by assessing the differences seen in the baseline clinical characteristics and the appearance of clinical events between both groups.

METHODS

The Spanish TAVI registry has been promoted by the board of directors of the Section of Hemodynamics and Interventional Cardiology of the Spanish Society of Cardiology. Since 2010, all Spanish TAVI-capable centers are invited every year to participate in this registry and enter data from all the patients with severe, aortic stenosis treated with TAVI. These data come from the units of cardiology and cardiac surgery and are entered into a periodically reviewed online dedicated database. Although there is not such a thing as a formal audit, the data entered in the registry are systematically reviewed to look for inconsistencies or lack of data; the review is conducted by a database expert who contacts the centers to solve any incidents found. Over the years 46 Spanish centers have participated in the registry (annex 1 of the supplementary data) and although it started back in 2010, 232 patients treated between 2007 and 2009 have been entered retrospectively and included in the analysis.

In this study all consecutive patients included in the Spanish TAVI registry were analyzed. In the time trend analysis, the population was divided into patients treated before 2014 (cohort A: 2009-2013) and those treated between 2014 and 2018 (cohort B) since 2014 was the year when the new generation of the 2 most popular valves in our country were implanted for the first time: the Edwards and the CoreValve.

Study variables

Events were defined according to the recommendations established by the Valve Academic Research Consortium17in cohort A, and according to the recommendations designed by the Valve Academic Research Consortium II18in cohort B. High surgical risk was defined as a logistic EuroSCORE value > 20% and as a Society of Thoracic Surgeons’ risk model value > 8%.

Statistical analysis

After confirming the variables normal distribution (Kolmogorov-Smirnov normality test), quantitative data were expressed as mean ± standard deviation or median and interquartile range, as appropriate. Qualitative data were expressed as absolute value and percentage. To assess the predictors of in-hospital mortality, the multivariable logistics regression model was used. Variables with probability values < 0.1 in the univariable analysis or clinically relevant were included in the analyses. To assess the predictors of 30-day mortality the Cox backward stepwise regression model was used. Survival curve was obtained using the Kaplan-Meier method. Two-tailed P-values < .05 were considered statistically significant. The statistical analysis was performed using the statistical software SPSS.19

RESULTS

Total results

Baseline and procedural characteristics

From August 2007 through June 2018, 180 patients were included in the Spanish TAVI registry.7Mean age was 81.2 ± 6.5 years and 53% were women. Logistics EuroSCORE was 12% (8-20). Transfemoral access was used in 89% of the cases in 78% of which percutaneous puncture was used and surgical dissection in the remaining cases. The most commonly used valve was the Core­Valve self-expandable system (49%) very closely followed by the balloon-expandable Edwards valve (46%). The most common valve size was number 26. The rate of successful device implantation was 94% (table 1and table 2).

Table 1. Baseline clinical and echocardiographic characteristics of the study patients

Baseline characteristics All patients (n = 7180) Cohort A (years 2009-2013) (n = 3075) Cohort B (years 2014-2018) (n = 4105) P
Clinical characteristics
 Age 81.2 ± 6.5 7171 81.0 ± 6.4 3075 81.2 ± 6.7 4096 .19
 Women 3796 / 7166 (53.0) 1636 / 3075 (53.2) 2160 / 4091 (52.8) .79
 Weight, kg 72.6 ± 14 7087 70.9 ± 13 3069 72.1 ± 14 4018 < .001
 Height, cm 160 ± 9 6714 159 ± 9 2879 160 ± 9 3835 < .001
 Body mass index 28.01 ± 4.9 6838 27.99 ± 4.9 2879 28.16 ± 4.9 3959 .143
 Hypertension 5728 / 7081 (80.9) 2437 / 3073 (79.3) 3291 / 4008 (82.1) .003
 Dyslipidemia 3903 / 6698 (58.3) 1586 / 2875 (55.1) 2317 / 3823 (60.6) < .001
 Diabetes mellitus 2447 / 6752 (36.2) 998 / 2875 (34.7) 1449 / 3877 (37.4) .02
Past medical history
 Previous stroke 764 / 6797 (11.3) 342 / 2879 (11.9) 422 / 3918 (10.7) .15
 Peripheral vascular disease 1009 / 6903 (14.6) 484 / 3071 (15.7) 525 / 3832 (13.7) .02
 Coronary artery disease 2090 / 7105 (29.4) 1231 / 3075 (40.0) 1576 / 4030 (39.1) .43
 Previous AMI 919 / 6565 (13.9) 396 / 2878 (13.7) 523 / 3687 (14.2) .62
 Previous PCI 1476 / 6879 (21.4) 651 / 3065 (21.2) 825 / 3814 (21.6) .70
 Previous revascularization surgery 645 / 6689 (9.6) 336 / 3059 (10.9) 309 / 3630 (8.5) .001
 Previous aortic valve replacement 210 / 4245 (4.9) 44 / 931 (4.7) 166 / 3314 (5.0) .73
 Previous mitral valve replacement 81 / 4245 (1.1) 6 / 931 (0.6) 75 / 3314 (2.3) .001
 Atrial fibrillation 1905 / 7037 (27.1) 855 / 3067 (27.9) 1050 / 3970 (26.4) .18
 Pacemaker 520 / 7037 (7.3) 216 / 3067 (7.0) 304 / 3970 (7.6) .33
 Creatinine clearance (mL/min/1.73 m2) 55 ± 25 6638 50 ± 47 2874 58 ± 27 3764 < .001
 Class III-IV dyspnea 4726 / 6810 (69.4) 2136 / 2877 (74.2) 2590 / 3933 (66.8) < .001
 Class III-IV angina 567 / 7062 (8.0) 303 / 3073 (9.8) 264 / 3989 (7) < .001
 Logistic EuroSCORE 12 (8-20) 6738 14 (9-22) 3027 11 (7-18) 3711 < .001
 STS score 5 (3-9) 3190 7 (4-18) 1024 5 (3-7) 2166 < .001
 High surgical risk 2010 (28.0%) 1139 (37%) 871 (22%) < .001
 Surgical contraindication 1854 / 7180 (25.8) 971 / 3075 (31.6) 883 / 4105 (21.5) < .001
Preprocedural echocardiographic data
 LVEF (%) 56.9 ± 13 6927 56.9 ± 14 3056 56.8 ± 13 3871 .66
 Mean aortic transvalvular gradient, mmHg 48 ± 15 6599 49 ± 15 3026 47 ± 15 3573 < .001
 Peak aortic transvalvular gradient, mmHg 79 ± 23 6606 81 ± 23 3033 77 ± 23 3573 < .001
 Indexed valve area, cm2 0.65 ± 0.2 4267 0.62 ± 0.2 1679 0.68 ± 0.2 2588 < .001
 Pulmonary artery pressure, mmHg 47 ± 18 3046 48 ± 16 1188 47 ± 20 1858 .17
 Diameter of aortic annulus, mm 23.2 ± 3 3935 22.9 ± 2 1224 23.2 ± 3 2711 .001
 Grade III-IV mitral regurgitation 410 / 5857 (7.0) 159 / 2368 (6.7) 251 / 3489 (7.2) .48
 Grade III-IV aortic regurgitation 121 / 3172 (3.8) 56 / 691 (8.1) 65 / 2481 (2.6) < .001

AMI, acute myocardial infarction; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons’ risk model.

Table 2. Procedural characteristics

All patients (n = 7180) Cohort A (years 2009-2013) (n = 3075) Cohort B (years 2014-2018) (n = 4105) P
Access < .001
 Transaortic 56 / 7180 (0.8) 28 / 3075 (0.9) 28 / 4105 (0.7)
 Subclavian axillary 144 / 7180 (2.0) 58 / 3075 (1.8) 86 / 4105 (2.0)
 Transapical 568 / 7180 (7.9) 431 / 3075 (14.0) 137 / 4105 (3.3)
 Transfemoral 6412 / 7180 (89.3) 2558 / 3075 (83.2) 3804 / 4105 (92.6)
Access route .57
 Dissection 1378 / 6225 (22.1) 526 / 2417 (21.7) 852 / 3808 (22.4)
 Puncture 4847 / 6225 (77.8) 1891 / 2417 (78.2) 2956 / 3808 (77.6)
Type of valve < .0001
 Engager 5 / 7180 (0.1) 0 / 3075 (0) 5 / 4105 (0.1)
 Direct Flow 8 / 7180 (0.1) 3 / 3075 (0.1) 5 / 4105 (0.1)
 Allegra 5 / 7180 (0.1) 0 / 3075 (0.1) 16 / 4105 (0.4)
 Lotus 60 / 7180 (0.8) 1 / 3075 (0.03) 59 / 4105 (1.4)
 Symetis 105 / 7180 (1.5) 0 / 3075 (0) 105 / 4105 (2.6)
 Portico 172 / 7180 (2.4) 0 / 3075 (0) 172 / 4105 (4.1)
 Edwards 3309 / 7180 (46.1) 1468 / 3075 (47.7) 1841 / 4105 (44.8)
 CoreValve 3516 / 7180 (48.9) 1603 / 3075 (52.1) 1913 / 4105 (46.6)
Valve size < .001
 23 1746 / 6712 (26.0) 742 / 2865 (25.9) 1004 / 3847 (26.1)
 26 2742 / 6712 (40.9) 1402 / 2865 (48.9) 1340 / 3847 (34.8)
 29 1791 / 6712 (26.7) 681 / 2865 (23.8) 1110 / 3847 (28.8)
 > 29 247 / 6712 (3.6) 37 / 2865 (1.2) 210 / 3847 (5.4)
 Other sizes 186 / 6712 (2.7) 3 / 865 (0.04) 183 / 3847 (4.7)
Predilatation 2072 / 3748 (55.3) 707 / 809 (87.4) 1365 / 2939 (46.4) < .0001
Posdilatation 1457 / 6767 (21.5) 561 / 3071 (18.3) 897 / 3696 (24.3) < .0001
Room < .0001
 Operating room 288 / 7180 (4.0) 223 / 3075 (7.2) 65 / 4105 (1.5)
 Catheterization laboratory 6575 / 7180 (91.6) 2759 / 3075 (89.7) 3816 / 4105 (92.5)
 Hybrid room 317 / 7180 (4.4) 93 / 3075 (3.0) 224 / 4105 (5.4)
Duration, minutes (mean ± standard deviation) 105 ± 45 106 ± 47 105 ± 43 .48
Median 95 (72-121) 5514 95 (72-122) 2834 95 (72-120) 2680 .94
Length of hospital admission, days (mean ± standard deviation) 8.3 ± 8 8.6 ± 8 8.0 ± 7 .002
Median 6 (5-9) 6459 6 (5-9) 2751 6 (4-8) 3708 .15
Successful implantation 6778 / 7153 (94.8) 2848 / 3062 (93.0) 3930 / 4091 (96.1) < .001

In-hospital and follow-up complications

The rates of in-hospital acute myocardial infarction, stroke, vascular complications, and hemorrhages were 0.9%, 1.9%, 10.7%, and 7.6%, respectively. Pacemaker implantation was required in 14% of the cases. The rates of overall in-hospital mortality and 30-day mortality were 4.7% and 5.7%, respectively (table 3).

Table 3. In-hospital events

All Cohort A (years 2009-2013) (n = 3075) Cohort B (years 2014-2018) (n = 4105) P Non-adjusted OR Adjusted OR P
Conversion to surgery 58 / 7076 (0.8) 34 / 3005 (1.1) 24 / 4062 (0.6) .013 0.52 (0.31-0.88) 0.49 (0.24-0.98) .04
Tamponade 57 / 6899 (0.8) 19 / 2900 (0.7) 38 / 3999 (1.0) .18 1.45 (0.83-2.56) 2.17 (1.08-3.85) .03
Coronary obstruction 23 / 6889 (0.3) 12 / 2897 (0.4) 11 / 3992 (0.3) .33 0.66 (0.29-1.52) 0.69 (0.28-1.69) .42
Malapposition 153 / 6884 (2.2) 92 / 2897 (3.2) 61 / 3987 (1.5) < .001 0.47 (0.34-0.66) 0.46 (0.32-0.66) .001
 Migration 119 / 6884 (1.7) 76 / 2897 (2.5) 43 / 3987 (1)
 Embolization 12 / 6884 (0.2) 2 / 2897 (0.1) 10 / 3987 (0.2)
 Unknown 22 / 6884 (0.3) 14 / 2897 (0.2) 8 / 3987 (0.1)
AMI 64 / 7055 (0.9) 28 / 3053 (0.9) 36 / 4001 (0.9) .94 0.98 (0.60-1.61) 0.97 (0.53-1.79) .93
Vascular complications 769 / 7055 (10.7) 268 / 3053 (8.8) 501 / 4001 (12.5) < .001 1.49 (1.27-1.72) 1.18 (0.98-1.41) .09
Hemorrhages 544 / 7054 (7.6) 169 / 3053 (5.5) 375 / 4001 (9.4) < .001 1.75 (1.47-2.13) 1.79 (1.43-2.22) < .001
Renal complications 377 / 7054 (5.3) 140 / 3053 (4.6) 237 / 4001 (5.9) .01 1.32 (1.05-1.61) 1.32 (1.03-1.69) .028
Stroke 133 / 7055 (1.9) 55 / 3053 (1.8) 78 / 4001 (1.9) .65 1.09 (0.76-1.54) 0.84 (0.55-1.28) .43
Pacemaker 1016 / 7092 (14.3) 416 / 3053 (13.6) 600 / 4001 (15.0) .14 1.11 (0.96-1.27) 0.99 (0.84-1.16) .91
In-hospital mortality 340 / 7054 (4.7) 200 / 3053 (6.6) 140 / 4001 (3.5) < .001 0.52 (0.41-0.65) 0.65 (0.48-0.86) .003

AMI, acute myocardial infarction; OR, odds ratio.

Results of the time trend analysis

Baseline and procedural characteristics

No differences were found between the groups regarding the patients’ mean age and sex. However, cohort B had more cardiovascular risk factors and surgeries performed prior to mitral valve implantation, but less peripheral vascular disease. Although the rate of coronary artery disease was similar in both groups, previous surgical coronary revascularizations were less common in cohort B. Creatinine clearance values were higher in cohort B. Regarding the clinical situation, the presence of severe symptoms (functional class III-IV) both for dyspnea (New York Heart Association) and angina (Canadian classification) was significantly lower in cohort B. Surgical risk was significantly lower in cohort B according to the logistics EuroSCORE and the Society of Thoracic Surgeons’ risk model. There were fewer inoperable patients or high surgical risk patients in cohort B as well. In this group, the severity of stenosis was lower (larger indexed valve area, lower transvalvular mean gradient) and annular diameter was larger. Regarding the route of access, the use of transfemoral approach started to grow back in 2014 (from 83% to 94%) mainly because the use of transapical access dropped from 14% to 3%. The type of valve used was almost exclusively the Edwards SAPIEN XT while the CoreValve was used in cohort A. In cohort B the new generations of these valves were used (Edwards SAPIEN 3 and Evolut R) as well as other types of self-expandable valves like the Portico (4.1%), the ACURATE neo (2.6%). and the Lotus valve (1.4%). The most common size of the valves was 26 mm in both groups. The rate of predilatation decreased in cohort B, but the rate of postdilatation grew. The rate of successful implantation increased significantly over the last period from 93% (cohort A) to 96% (cohort B). The working space where the TAVI was performed changed as well; although the cardiac catheterization laboratory was the most common working space in both cohorts fewer valves were implanted in the operating room and more valve were implanted in hybrid operating rooms in cohort B.

In-hospital and 30-day follow-up events

The length of hospital admission was reduced significantly in cohort B. In the hospital stage, the rates of acute myocardial infarction, stroke, need for pacemaker, and coronary obstruction were similar in both groups. However, the conversion rate to surgery (figure 1) and valve malapposition dropped significantly in patients treated from 2014. No inter-group differences were found regarding vascular complications. However, the overall rate of hemorrhages and renal complications were higher in cohort B. In-hospital all-cause mortality was significantly lower in cohort B with a 47% reduction (odds ratio [OR], 0.65; 95% confidence interval [95%CI], 0.48-0.86; P= .003).

Figure 1. Conversion rate to urgent surgery through the years.

Mortality rate dropped 32% at the 30-day clinical follow-up in cohort B (6.9 vs 4.7%) (OR, 0,71; 95%CI, 0.54-0.92; P= .002) (figure 2and figure 3). The 30-day mortality predictors are shown on table 4.

Figure 2. Survival rate at the 1-year follow-up of patients included in the Spanish TAVI registry treated in 2009-2013 and 2014-2018.

Figure 3. Survival rate at the 1-year follow-up of high surgical risk patients only treated in 2009-2013 and 2014-2018.

Table 4. Independent predictors of mortality at the 30-day follow-up

Variables predictors of death at the 30-day follow-up Univariate OR (95%CI) P Adjusted multivariate OR (95%CI) before the procedure P Adjusted multivariate OR (95%CI) before and after the procedure P
Preoperative
 Years 2014-2018 0.52 (0.41-0.65) < .001 0.59 (0.46-0.76) < .001 0.71 (0.54-0.92) .01
 Body mass index 0.97 (0.95-0.99) .007
 Dyslipidemia 0.93 (0.74-0.93) .54 0.94 (0.74-1.21) .64 0.89 (0.69-1.14) .35
 Creatinine clearance 0.99 (0.98-0.99) < .001 * *
 Peripheral vascular disease 1.49 (1.13-1.97) .005 * *
 Mean aortic gradient, mmHg 1.003 (0.99-1.01) .47 1.002 (0.99-1.01) .57 1.003 (0.99-1.01) .54
 Grade III-IV mitral regurgitation 1.98 (1.34-2.92) .001 * *
 Grade III-IV aortic regurgitation 2.06 (1.01-4.19) .05 * *
 Grade III-IV angina 1.08 (0.73-1.61) .69 1.16 (0.76-1.78) .50 1.16 (0.74-1.81) .52
 Grade III-IV dyspnea 1.48 (1.13-1.96) .005 * *
 Surgical risk 1.38 (1.09-1.74) .007 1.33 (1.03-1.71) .029 1.26 (0.96-1.64) .09
Postoperative
 Transfemoral access 0.50 (0.38-0.66) < .001 0.49 (0.36-0.67) < .001
 Successful implantation 0.10 (0.08-0.13) < .001 0.11 (0.09-0.15) < .001

95%CI, 95% confidence interval; OR, odds ratio.

*These variables were not part the model because they are used to estimate surgical risk.

DISCUSSION

The main findings of this study were: a)in Spain there is a time trend in the type of patients treated with TAVI through the years; b)there have been changes, transfemoral access has become widely used, postdilatation has increased, and the rates of valve malapposition and conversion to surgery have dropped. And the most important thing of all, there has been a significant increase in the rate of successful implantation since 2014; and c)there is a significant reduction of in-hospital and 30-day all-cause mortality in patients treated from 2014.

Differences in baseline characteristics

This study saw a time change in the risk profile of patients treated with TAVI in Spain. The percentage of high-risk patients over the first period was 37% vs 22% from 2014 onwards. These findings are consistent with those reported in the time analysis of the French registry15where the logistics EuroSCORE dropped from 21.7 ± 14.2% to 17.9 ± 12.3%. In this sense, the facts that may explain these findings are the appearance of randomized clinical trials that use TAVI in lower-risk patients.2,7From 2015 to 2016 the results from the NOTION (The Nordic Aortic Valve Intervention) and PARTNER II (Placement of Aortic Transcatheter Valves) clinical trials—on low-and-intermediate risk patients—were published. The NOTION trial did not find any significant differences between patients treated with TAVI or surgical aortic valve replacement regarding the composite endpoint of death, stroke or acute myocardial infarction at the 1 and 5-year follow-up. The PARTNER II clinical trial7randomized 2032 intermediate risk patients to be treated with TAVI or surgery. No significant differences were found in the primary endpoint of all-cause mortality or disabling stroke at the 2-year follow-up. However, when only the cohort treated with transfemoral access was studied, TAVI showed significantly lower rates of death and disabling stroke.

Procedural differences

This study describes the time changes that seem to impact the higher rate of successful implantation, a factor closely related to mortality. The difference found would be fewere cases of malapposition. Also, an increase of transfemoral access has been reported. All these changes are explained by the greater experience gained with the implantation technique that is focused on simplification and the improvements made in valve design. All through 2014, a new generation of valves (Edwards SAPIEN 3 and Evolut R) were implanted for the first time with technical breakthroughs like the smaller release system and greater use of transfemoral access seen in cohort B. The introduction of the outer skirt was associated with a lower rate of perivalvular leak, higher procedural success, and less need for valve overexpansion. This reduces potentially the rate of annular tear and need for conversion to surgery (a high mortality procedure). Also, in the case of the Evolut R valve the introduction of a fully retrievable platform may have lowered the rate of valve malapposition and increased the rate of successful implantation seen from 2014.

Reduced mortality

Back in 2013 the data of 1416 patients included in the years 2010 and 2011 in the Spanish TAVI registry were published.19In this analysis the rate of successful implantation was 94% and the in-hospital mortality rate 8%. In this study the overall mortality rate was 4.7%. A remarkable aspect of the Spanish registry time analysis is that it shows a clear mortality reduction over the second period studied (cohort B) regardless of the patients’ baseline characteristics. These results are consistent with the French registry time analysis that showed reduced in-hospital and 30-day mortality in the patients included in the 2013-2015 period.15On the contrary, in the English registry time analysis16from 2007 through 2012, no differences were found in the patients’ baseline characteristics or surgical risk studied through those years. However, there was a higher percentage of patients with ventricular dysfunction. In this registry, mortality reduction and shorter hospital stays were only seen over the first 2 years of follow-up in the patients treated back in 2012. The authors explain these results by the greater experience gained in the better selection of patients who may benefit the most from TAVI, something that may have also affected the results of this study.

In this registry, as it occurred in the French one, there was a higher rate of tamponade over the last period studied. However, the conversion rate to surgery was lower, suggestive that the consolidation of the procedure and the early diagnosis of complications may have influenced the results.

A remarkable aspect is the higher overall rate of hemorrhages and renal dysfunction seen in cohort B. These results should be interpreted with caution because there are no data on the severity and cause for these events. However, given the reduced mortality seen in this period, it can be concluded that there is no significant increase of major hemorrhages, although this is just speculation due to the lack of data on this regard.

Limitations

The main limitation of this study is that it is a registry whose data have not been audited externally. Also, it is a voluntary registry that does not include all Spanish centers with TAVI-capabilities. Certain variables appear in 50% of the patients, which is something exceptional if we consider that most variables are present in 90% of the cases. The degree and causes for vascular complications (hemorrhage and renal failure) are not available and data should be interpreted with caution. On the other hand, the change in the adjudication of events derived from the different definition used over the first and second periods (Valve Academic Research Consortium and Valve Academic Research Consortium II, respectively) may vary in some patients although this would be an exception.

CONCLUSIONS

This study shows the better risk profile and more successful implantation rate of patients treated over the last few years. This has reduced in-hospital and 30-day all-cause mortality.

ACKNOWLEDGEMENTS

The authors wish to thank Dr. María José Pérez-Vizcayno for her contribution during the entire process of database review and statistical analysis. The authors also wish to thank all the people and participant centers involved in the national Spanish TAVI registry.

FUNDING

The Section of Hemodynamics and Interventional Cardiology of the Spanish Society of Cardiology sponsors the maintenance and exploitation of the database.

CONFLICTS OF INTEREST

R. Trillo-Nouche is a proctor of TAVI valves for Medtronic and Boston Scientific. M. Pan has participated and received funds for the lectures given on behalf of Abbott, Terumo Medical Corporation, and Philips Volcano. R. Moreno is an associate editor of REC: Interventional Cardiology; the editorial protocol of the journal was observed to guarantee an impartial manuscript handling. R. Moreno has participated and received funds for lectures, counsel, and congress attendance on behalf of Edwards Lifesciences, and is a proctor of the Lotus and ACURATE neo valves (both from Boston Scientific). Also, R. Moreno has participated and received funds for the lectures, counsel, and congress attendance on behalf of Boston Scientific, and is a proctor of the Allegra valve from New Vascular Therapy. I. Amat-Santos is a proctor of Boston Scientific. R. Romaguera has participated and received funds from Medtronic and Palex Medical. A. Pérez de Prado has participated and received funds for counseling provided to Boston Scientifice iVascular, and for the lectures given on behalf of Abbott, B Braun Surgical, Terumo Medical Corporation, and Philips Volcano. L. Nombela-Franco is a proctor for Abbott and has participated and received funds for lectures given on behalf of Edwards Lifesciences. F. Alfonso is an associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. J.M. de la Torre Hernández is the editor-in-chief of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The remaining authors declared no conflicts of interest whatsoever.

WHAT IS KNOWN ABOUT THE TOPIC?

  • In national registries like the French one, a time change in the clinical profile and progression of patients treated with TAVI has been confirmed. However, these findings have not been made in the time analysis of the English registry.

WHAT DOES THIS STUDY ADD?

  • The main contribution of this study is the publication of all data from our national database. Also, that results will be included in the medical literature and that the time change seen in the profile of patients and clinical results is indicative of a growing experience with the implantation technique and improvements in valve design

SUPPLEMENTARY DATA


REFERENCES

1.  Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198.

2.  Thyregod HG, Steinbrüchel DA, I hlemann N, et al. Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis:1-Year Results From the All-Comers NOTION Randomized Clinical Trial. J Am Coll Cardiol. 2015;65:2184-2194.

3.  Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med. 2012;366: 1696-1704.

4.  Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients:a propensity score analysis. Lancet. 2016;387:2218-2225.

5.  Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med. 2012;366:1686-1695.

6.  Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607.

7.  Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2016;374:1609-1620.

8.  Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370:1790-1798.

9.  Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-1981.

10.  Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or Transcatheter Aortic- Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2017;376:1321-1331.

11.  Mack MJ, Leon MB, Thourani VH, et al. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients. N Engl J Med. 2019;380:1695-1705.

12.  Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med. 2019;380:1706-1715.

13.  Islas F, Almería C, García-Fernández E, et al. Usefulness of echocardiographic criteria for transcatheter aortic valve implantation without balloon predilation:a single-center experience. J Am Soc Echocardiogr. 2015;28:423-429.

14.  García E, Almería C, UnzuéL, Jiménez-Quevedo P, Cuadrado A, Macaya C. Transfemoral implantation of Edwards Sapien XT aortic valve without previous valvuloplasty:role of 2D/3D transesophageal echocardiography. Catheter Cardiovasc Interv. 2014;84:868-876.

15.  Auffret V, Lefevre T, Van Belle E, et al. Temporal Trends in Transcatheter Aortic Valve Replacement in France:FRANCE 2 to FRANCE TAVI. J Am Coll Cardiol. 2017;70:42-55.

16.  Ludman PF, Moat N, de Belder MA, et al. Transcatheter aortic valve implantation in the United Kingdom:temporal trends, predictors of outcome, and 6-year follow-up:a report from the UK Transcatheter Aortic Valve Implantation (TAVI) Registry, 2007 to 2012. Circulation. 2015;131:1181-1190.

17.  Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials:a consensus report from the Valve Academic Research Consortium. Eur Heart J. 2011;32:205-217.

18.  Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation:the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012;33:2403-2418.

19.  SabatéM, Cánovas S, García E, et al. In-hospital and mid-term predictors of mortality after transcatheter aortic valve implantation:data from the TAVI National Registry 2010-2011. Rev Esp Cardiol. 2013;66:949-958.

Corresponding author: Unidad de Hemodinámica, Hospital Clínico San Carlos, IdISSC, Martín Lagos s/n, 28040 Madrid, Spain.
E-mail address: patropjq@gmail.com (P. Jiménez-Quevedo).

ABSTRACT

Introduction and objectives: The Lotus Valve device (Boston Scientific) is a second-generation fully-retrievable and repositionable transcatheter aortic valve. We report the initial multicenter experience with the Lotus valve in the management of patients with severe aortic stenosis.

Methods: Observational study that described the short and long-term results of implanting the Lotus valve in 8 Spanish and Portuguese centers from March 2014 through April 2016.

Results: The study included 102 patients (mean age 80.4 ± 6.1 years; STS score 5.2% ± 3.3%) with severe symptomatic aortic stenosis (mean aortic valve area 0.66 ± 0.17 cm2, aortic gradients 74.3 / 45.6 mmHg). The valve was successfully implanted in 100 patients (98%), with significant improvement in both the peak and mean aortic valve gradients and with only one patient showing moderate paravalvular regurgitation. Upon hospital discharge, mortality rate was 3.9% while the stroke rate was 2.9%. No cases of valve embolization, ectopic valve deployment or additional valve implantation (valve-in-valve) were seen. Thirty-three patients (32.3%) received a permanent pacemaker.

Conclusions: The Lotus Valve System is effective and safe for the management of patients with severe symptomatic aortic stenosis. In particular, considering the low rate of periprosthetic regurgitation and lack of complications like embolization or ectopic valve deployment; however at the expense of a high pacemaker implantation rate.

Keywords: Transcatheter Aortic Valve. Aortic Stenosis.

RESUMEN

Introducción y objetivos: El dispositivo Lotus (Boston Scientific, Estados Unidos) es una prótesis valvular aórtica transcatéter de segunda generación, completamente recuperable y reposicionable. Se presenta la experiencia inicial con la prótesis Lotus en un registro multicéntrico.

Métodos: Estudio observacional que reporta los resultados a corto y largo plazo del implante transfemoral de prótesis Lotus entre marzo de 2014 y abril de 2016 en 8 centros de España y Portugal.

Resultados: Se incluyeron 102 pacientes (edad media 80,4 ± 6,1 años, índice STS medio 5,2% ± 3,3%) con estenosis aórtica grave sintomática (área valvular media 0,66 ± 0,17 cm2, gradientes 74,3/45,6 mmHg). Se implantó con éxito el dispositivo en 100 pacientes (98%), con mejoría significativa de los gradientes máximo y medio valvular, y un solo caso de regurgitación periprotésica moderada. No hubo ninguna embolización ni necesidad de implante de una nueva prótesis intravalvular. Hasta el alta hospitalaria, la mortalidad fue del 3,9% y la tasa de ictus fue del 2,9%. En 33 pacientes (32,3%) fue necesario el implante de marcapasos definitivo.

Conclusiones: La válvula Lotus es eficaz y segura para el tratamiento de pacientes con estenosis aórtica grave sintomática. Destacan la escasa tasa de insuficiencia periprotésica y la ausencia de complicaciones derivadas del mal posicionamiento o la embolización de la prótesis, a costa de un alta incidencia de implante de marcapasos.

Palabras clave: Prótesis aórtica transcatéter. Estenosis aórtica.

Abbreviations AR: aortic regurgitation. AS: aortic stenosis. TAVI: transcatheter aortic valve implantation.

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is a therapeutic option in patients with severe symptomatic aortic stenosis (AS) that has proven to be non-inferior to surgical aortic valve replacement even in low-risk patients.1-8

However, TAVI-related persistent complications can have a negative impact on the short and medium-long-term results including periprosthetic aortic regurgitation (AR)—associated with more in-hospital and medium and long-term mortality after TAVI.9-12 Several factors have been associated with the development of periprosthetic regurgitation like valve underexpansion following the severe calcification of the aortic annulus or valve malapposition. The latter is a factor associated with other complications like valve embolization. In order to minimize these setbacks, innovative, second-generation, fully or partially repositionable devices have been developed.

The Lotus device (Boston Scientific, United States) is a fully retrievable and repositionable second-generation transcatheter aortic valve. It has been designed to minimize the risk of complications related to valve malapposition, in particular periprosthetic AR and valve embolization.13

The objective of this study is to present the initial experience in Spain and Portugal in the management of AS with the Lotus valve.

METHODS

Patient selection

This observational study included all consecutive patients with severe AS treated with transfemoral Lotus valve implantation between March 2014 and April 2016 in Spanish and Portuguese centers that disclosed their databases voluntarily. All patients had symptomatic, severe AS (aortic valve area < 1 cm2) or with left ventricular dysfunction according to the recommendations from the European Society of Cardiology guidelines on the management of valvular heart disease;14 in any case, the indication was established according to the local protocols of each center after each particular case was individually assessed by the heart team. Surgical risk was assessed using the STS risk score.15 However, its value was not considered an inclusion or exclusion criterion in the registry because in the selection of patients, clinical and anatomical aspects not found in the surgical risk scores were also considered (porcelain aorta, patency of mammary artery bypass graft, hostile chest, etc.).

Study variables

The patients’ main baseline clinical and echocardiographic variables, procedural details, and clinical and echocardiographic results until hospital discharge were gathered. Special attention was paid to peri- and postoperative complications. Data mining was prospective in every center, although there was no common protocol for it or for the allocation of clinical and echocardiographic results. Each center disclosed its own database and they were all compiled in a single database.

The clinical assessment and diagnostic tests prior to the implant were similar to those of common recommendations.14 A few variables were not systematically collected in all the centers and, therefore, not included in the study final analysis.

Regarding procedural data, the main variables studied were the performance or not of a prior valvuloplasty, the device total or partial recapture, the need for post-dilation, the degree of valvular regurgitation, and postoperative transvalvular gradients. Finally, a comparison was drawn between mean and peak gradients and the prevalence of moderate AR before and after device implantation.

Procedural complications were gathered according to the recommendations established in the Valve Academic Research Consortium 2 consensus document.16 The following complications were analyzed: mortality, strokes, hemorrhagic complications, major and minor vascular complications, definitive pacemaker implantation, renal failure, echocardiographic data suggestive of prosthetic valve dysfunction (mean valve gradient > 20 mmHg, effective valvular area < 0.9-1.1 cm2, Doppler velocity index < 0.35, and moderate or severe AR). The combined efficacy parameter used this definition established according to the criteria of the Valve Academic Research Consortium 2: proper single valve implantation + lack of in-hospital mortality + lack of mean gradient > 20 mmHg, aortic valve area ≥ 1.2 cm2, Doppler velocity index < 0.35 or moderate or severe AR. The combined initial safety parameter (until hospital discharge) was defined as: lack of all-cause mortality, stroke, life-threatening bleeding, stage 2-3 renal failure, coronary obstruction requiring intervention, major vascular complication or valve dysfunction requiring reintervention.

Finally, patients were followed retrospectively 3 years after finishing the registry recruitment phase, and clinical (mortality and cardiovascular events) and echocardiographic parameters were collected.

Boston Scientific has not been involved in the design or development of this study whatsoever.

Description of the device

The Lotus device used in the registry is a bovine pericardial heart valve (3 cusps) mounted on a nitinol frame, preloaded, and deployed through a controlled mechanical expansion system. It measures 72 mm before expansion and 19 mm after implantation. There are 3 diameters available: 23 mm, 25 mm, and 27 mm. The Lotus Edge valve available today has a more flexible deployment catheter, an easier implantation system, and can be implanted through a 14-Fr expandable introducer.

The delivery system and the introducer sheath have been designed to facilitate a precise and predictable delivery to guarantee the valve early functionality, and the possibility of non-traumatic repositioning and retrieval at any time prior to the definitive delivery of the valve. The device has a sealing system (urethane membrane) designed to minimize the rate of paravalvular regurgitation.

Procedure

Implantation was performed according to the method described in the medical literature.13 It was performed in the cardiac catheterization laboratory under general anesthesia or deep sedation, in a sterile environment, following the operator’s preferences, and with or without transesophageal echocardiography guidance.

Transfemoral access was used in all cases using a fully percutaneous technique or surgical exposure. An 18-Fr introducer was advanced for the 23 mm-valve (minimum diameter required: 6 mm) and a 20-Fr introducer for the 25 mm and 27 mm-valves (minimum diameter required: 6.5 mm) towards the descending aorta. The native aortic valve was crossed using the routine technique. Before using the guidewire to cross to the left ventricle, a temporary transvenous pacemaker was implanted.

The Safari high-support guidewire was used (0.035 in guidewire, 260 cm) (Boston Scientific). The decision to perform a prior balloon valvuloplasty was left to the operator’s discretion.

To implant the device, the delivery system is steered, and the radiopaque marker is positioned towards the aorta external region to facilitate the advancement of the catheter thanks to its adapted morphology. After crossing the native aortic valve and without the need for cardiac pacing, the valve is expanded. The proper anchoring of the valve support systems and positioning of the valve are confirmed. Finally, it is delivered and the system removed (figure 1).

Figure 1. Lotus valve implantation procedure.

In the absence of significant atrioventricular conduction disturbances, the temporary pacemaker was removed 24-48 hours after the procedure. The indications for the definitive pacemaker were established by the local protocols of each center. Antithrombotic treatment at discharge was dual antiplatelet therapy with acetylsalicylic acid and clopidogrel during the first 3-6 months, except for cases with indications for chronic oral anticoagulation.

Statistical analysis

Statistical analysis was performed using the SPSS 22 statistical software package (SPSS Inc., United States). Categorical variables were expressed as percentages, and quantitative variables as mean ± standard deviation or median (interquartile range). Continuous variables were compared using the Student t test for paired data, and categorical variables were compared using the chi-square test.

RESULTS

Baseline characteristics of the patients

A total of 102 patients were included from 5 Spanish centers and 3 Portuguese centers (table 1). Baseline characteristics are shown on table 2. Mean age was 80.4 ± 6.1 years, 52.9% were women, and the STS score was 5.4% (3.7-7.7).

Table 1. Participant hospitals in the study and number of patients per hospital

Hospital Universitario La Paz, Madrid, Spain 33 (32.4%)
Policlínica Gipuzkoa, San Sebastián, Spain 19 (18.6%)
Hospital Universitari Vall d’Hebron, Barcelona, Spain 7 (6.9%)
Hospital Virgen de las Nieves, Granada, Spain 8 (7.8%)
Hospital Puerta del Mar, Cádiz, Spain 6 (5.9%)
Centro Hospitalar de Vila Nova de Gaia, Oporto, Portugal 8 (7.8%)
Centro Hospitalar de Lisboa Central, Lisbon, Portugal 10 (9.8%)
Hospital Santa Cruz, Lisbon, Portugal 11 (10.8%)

Table 2. Baseline characteristics of patients (N = 102)

Age (years) 80.4 ± 6.1
Feminine sex 54 (52.9%)
Coronary artery disease 44 (43.1%)
 Percutaneous revascularization 24 (54.5%)
 Surgical revascularization 11 (25%)
 No revascularization 9 (20.5%)
Cerebrovascular disease prior to TAVI 8 (7.8%)
Chronic kidney disease (CrCl < 60 mL/min) 37 (36.3%)
 Without dialysis 33 (32.4%)
 With dialysis 4 (3.9%)
Atrial fibrillation prior to TAVI 42 (41.2%)
 Paroxysmal 13 (12.7%)
 Permanent 29 (28.5%)
Ventricular function prior to TAVI (N = 82)
 > 50% 65 (79.3%)
 30%-50% 9 (11%)
 < 30% 8 (9.8%)
STS score 5.4% (3.7-7.735)
Pacemaker prior to TAVI 11 (10.8%)
CrCl, creatinine clearance; TAVI, transcatheter aortic valve implantation.

Most patients had preserved systolic function and they were all diagnosed with severe AS with a mean indexed valve area of 0.66 ± 0.17 cm2/m2 and peak and mean aortic gradients of 74.3 ± 23.7 and 45.6 ± 15.7 mmHg, respectively; 22% of the patients had moderate AR too (≥ 2).

Procedural characteristics

Procedural characteristics are shown on table 3. General anesthesia was used, and the procedure was transesophageal echocardiogram-­guided in most patients. Implantation was performed using transfemoral access; in 91.2% of the cases x-ray-guided percutaneous punctures and closures were performed.

Table 3. Procedural characteristics

Procedural characteristics (N = 102)
General anesthesia 94 (92.1%)
Perioperative transesophageal echocardiogram 94 (92.1%)
Transfemoral access 102 (100%)
Surgical exposure 8 (7.8%)
Percutaneous 94 (92.1%)
 ProGlide closure system 38 (37.2%)
 Prostar closure system 56 (54.9%)
Pre-dilation 20 (19.6%)
Repositioning
Partial 12 (11.8%)
Complete 1 (1%)
Post-dilation 0
Valve size
23 mm 43 (42.1%)
25 mm 27 (26.5%)
27 mm 32 (31.4%)

The size of the valve was decided based on the dimensions of the annular area and perimeter based on the computed tomography scan performed in each center. Valve pre-dilation was performed in 19.6% of the patients, and no patient was post-dilated.

Before the definite implantation the device had to be repositioned in 12 procedures (11.8%) and the valve fully recaptured in 1 occasion because the patient showed severe periprosthetic regurgitation due to valve malapposition; the same device was successfully re-implanted in this patient.

Procedural results

The valve was successfully implanted in 100 patients (98%), except for 2 patients due to major vascular complications: one case of a ruptured iliac artery that required surgical intervention (with good progression) and another case of aortic rupture prior to device implantation (the patient eventually died). In all the cases where the native aortic valve was accessed, the device was successfully implanted.

After the implant there was a significant reduction of transvalvular mean and peak gradients and the percentage of significant AR (P < .001) (figure 2). There was paravalvular leak grade 2 in 1 case, but no serious leaks whatsoever. In this case, a large annulus is described (a 27 mm diameter measured through CAT scan exceeding the upper limits recommended by the manufacturer). The main cause for the moderate paravalvular leak reported may have been a moderate oversized valve with respect to the annular size.

Figure 2. Gradients before and after valve implantation.

There were no complications associated with the valve malapposition and there was only 1 case of perioperative thromboembolic coronary occlusion. It soon resolved rusing coronary thromboaspiration and balloon angioplasty without any major adverse events (with intraoperative infarction but no death or worsening of the left ventricular ejection fraction after the procedure).

Complications are shown on table 4. In-hospital mortality was 3.9% (4 patients). As reported, 1 patient died of a ruptured aorta prior to device implantation. This patient had a porcelain aorta and the perioperative transesophageal echocardiogram performed showed plaque ulceration in the aortic wall. The second patient died of cardiogenic shock 4 days after admission; he showed ventricular dysfunction and left bundle branch block prior to device implantation. However, there were no complications during the procedure. The third patient suffered a perioperative ischemic stroke, and had a long hospital stay. He eventually died 74 days after admission of nosocomial infection. Finally, the fourth patient had a past medical history of hepatic failure and presented with liver failure and hemodynamic instability. He died within the first 30 days following the intervention.

Table 4. Procedural results

Procedural results (VARCS2 criteria) (N = 102)
Successful implantation 100 (98%)
Hospital stay (days)
 Mean 12.8 ± 16.5
 Median 8.5 ± 4.5
Device malapposition 0
 Migration 0
 Embolization 0
 Valve-in-valve 0
Coronary occlusion 1 (1%)
Periprosthetic aortic regurgitation (grade)
 0 81 (79.4%)
 1 20 (19.6%)
 2 1 (1%)
 3 0
In-hospital mortality 4 (3.9%)
Stroke 3 (2.9%)
 Disabling 2 (1.9%)
 Non-disabling 1 (1%)
Bleeding 5 (4.9%)
 Life-threatening 3 (2.9%)
 Major 1 (1%)
 Minor 1 (1%)
Renal failure
 Stage 2 5 (4.9%)
 Stage 3 2 (2%)
Vascular complications 11 (10.8%)
 Major 4 (3.9%)
 Minor 7 (6.9%)
Conversion to open surgery 1 (1%)
Definitive pacemaker implantation 33 (36.3%)
Combined efficacy parameter 95 (93.1%)
Combined safety parameter 92 (90.2%)

VARC2, Valve Academic Research Consortium 2.

The rate of perioperative stroke was 2.9%, and the rate of major vascular complications was 3.9%. There were 2 ruptured aortas with cardiac tamponade. In 1 case the patient died and in the other, the patient required conversion to sternotomy and surgery with good disease progression. The other 2 major complications were a ruptured iliac artery and a retroperitoneal hematoma that required intervention with good disease progression.

The rate of successful implantation defined according to the Valve Academic Research Consortium 2 criteria, was 93.1% (95 out of the 102 patients included), since 4 patients died. In 1 patient the device was not implanted due to a major vascular complication, another patient had a mean gradient > 20 mmHg after implantation, and another showed moderate AR. The combined initial safety parameter (until hospital discharge) reached 90.2% of the cases (92 out of the 102 patients included).

A definitive pacemaker was implanted prior to hospital discharge in 33 out of the 91 patients who did not carry a pacemaker prior to device implantation (36.3%).

Follow-up

Out of the 92 patients who reached the combined initial safety parameter, it was possible to analyze the 3-year follow-up results in 57 of them (62%) with a mean age of 80 ± 6 years and a median follow-up of 37 months (22-47).

The 1-year mortality was 10.5% (6 patients). Two patients died of endocarditis: 1 case of mitral valve endocarditis (a patient with severe mitral regurgitation prior to TAVI) 10 months after the procedure, and another case of aortic valve endocarditis 3 months after the implant. The 4 remaining patients died of non-cardiac causes (1 patient died of metabolic encephalopathy and 3 of sepsis of a different origin). The 3-year mortality rate was 35.1% (20 patients): 6 patients (10.5% of the total) died of cardiac causes, 10 of non-cardiac causes, and 4 for unknown reasons.

Regarding the echocardiographic parameters, the persistence of good long-terms results was seen without significant variations of the valvular gradients post-TAVI (mean gradient of 12 ± 9.3 mmHg at discharge vs 12.4 ± 6.8 mmHg at the 3-year follow-up; peak gradient of 22 ± 19.5 mmHg at discharge vs 24.5 ± 13.2 mmHg at the 3-year follow-up). However, valve thrombosis was seen in 2 patients (3.5%), both diagnosed in a routine echocardiographic examination without any associated clinical events. One case was an early thrombosis that occurred 2 months after device implantation in an 87-year-old patient with severe ventricular dysfunction and implantation of a 27-mm Lotus valve on dual antiplatelet therapy at hospital discharge. The other was a case of very late thrombosis —46 months after device implantation— in a 71-year-old patient with moderate ventricular dysfunction and implantation of a 23-mm Lotus valve. Both patients improved with anticoagulant medication. No cases of periprosthetic aortic regurgitation grade > 1 were reported at the follow-up, and no patient required reintervention.

DISCUSSION

This is the first study to report on real-life results of the Lotus valve (Boston Scientific) in the Iberian Peninsula. They are similar to the results published in former studies and registries (table 5),17-23 in particular the results of the RESPOND study.23 It should be mentioned the low rate of periprosthetic regurgitation (1% moderate and 0% severe), the lack of complications related to the valve malapposition, and no need for post-dilation despite a low rate of pre-dilation. Three factors are responsible for these results:

Table 5. Studies published on the Lotus valve

Series Number of patients Successful implantation Mortality Periprosthetic aortic regurgitation ≥ 2 Pacemaker
Reprise II17,18 120 100% 4.2% 1% 28.6%
Rampat et al.19 228 99.1% 1.8% 0.8% 31.8%
De Backer et al.20 154 100% 1.9% 0.6% 27.9%
Wöhrle et al.21 26 100% 0 0 26.9%
RESPOND23 1014 98.1% 2.9% 0.3% 34.6%
Current series 102 98% 3.9% 1% 36.3%

  • - The possibility of fully or partially repositioning and recapturing the device, thus facilitating a more accurate positioning of the valve.

  • - The presence of great valvular radial strength. It has a controlled mechanical expansion mechanism, not a self-expanding one (while the device is released from the delivery system, the nitinol frame shortens and expands always in a totally reversible way).

  • - The presence of a new sealing system (urethane membrane) adapted to the annulus irregular surface to minimize perivalvular regurgitation and also in heavily calcified and irregular annuli.

In our population in-hospital mortality (3.9%) is similar to that of the Reprise II trial15 and a little higher compared to that of the landmark registry published to this day of 1014 patients: the RESPOND clinical trial.23 However, results are hardly comparable due to the different populations included, especially the high-risk population of the Reprise II like that of recruitment centers. This is so because in the RESPOND trial the participant centers had a huge experience in Lotus valve implantation. Our registry included an intermediate-risk population (STS score of 4%-8%), similar to that of the PARTNER 2,6 and in our study all-cause mortality was consistent with the one reported in such trial (3.9% at 30 days). If we take into account the importance of the learning curve when analyzing the results of new devices and the fact that our registry included centers with < 10 years of experience, in-hospital mortality was relatively low. In our series, cardiovascular mortality was 3%.

One of the advantages of this device is that it guarantees the patient’s hemodynamic stability during the entire procedure. First, no cardiac pacing is required during implantation. Second, the leaflets start to function very early on and before the valve shortens because they are attached to the device most distal portion, thus avoiding hypotension periods. Third, it can be implanted directly without pre-dilation with certain frequency because it has tremendous radial strength. In our registry, only 19.6% of the patients were pre-dilated, fewer patients compared to the RESPOND trial (53.9%).

The rate of significant periprosthetic AR (grade ≥ 2) was fairly low with similar results to those of former studies published on the Lotus valve (table 5). Moderate periprosthetic regurgitation was seen in one patient only, but it was not serious. Moderate-severe periprosthetic AR (grade ≥ 2) has been associated with worst post-TAVI results and higher short and long-term mortality rate.9-12 The PARTNER 2 clinical trial revealed a 30-day rate of moderate-severe periprosthetic AR of 3.7%. The 2-year mortality rate in these patients was higher compared to those with grade 0-1 periprosthetic regurgitation (P < .001).6 Our registry and the Reprise II trial 1-year follow-up confirmed that the results seen during the first 30 days are kept in time including the low 1-year rate of significant periprosthetic regurgitation.18 The possibility of valve repositioning and retrieval prior to the device implantation reduces other valve malapposition-related complications. No cases of device embolization were seen in our population, and no patient required valve-in-valve implantation, which increases the device safety profile.

In our registry the rate of strokes was 2.9% (3 patients, of these 2 suffered disabling strokes) similar to that of the RESPOND trial23 (overall strokes: 3%; disabling strokes: 2.2%). However, due to the lack of a systematic neurological exam before and after the pro- cedure and an event adjudication committee we cannot draw definitive conclusions or compare the rate of this complication between our registry and other studies.

The rate of major vascular complications is not different from the one published in other series and with other devices.

The issue that still needs to be addressed with the Lotus valve is the rate of definitive pacemaker implantation. As previous studies report, around 30% of the cases require a definitive pacemaker, yet the reason for it is still not clear. Several factors have been proposed in association with this complication. The Reprise II trial suggested overstretching—defined as a ≥ 10% ratio between the valve theoretical area and the annular area or left ventricular outflow tract measured through CAT scan21—as the main independent predictive factor of pacemaker implantation. This, added to the higher rate of pacemaker implantation of some self-expandable valves24 and cases of valve deeper implants25 leads us to think that the occurrence of conduction disturbances may be associated with excessive mechanical stress in areas where the conduction system passes through like the aortomitral junction.26 Also, better valve size selection based on data from the CAT scan, technique modifications for higher valve implantation depths, and the arrival of the LOTUS Edge device may reduce the rate of this complication. Compared to the former Lotus valve system generation, the LOTUS Edge valve is easier to deliver, has a more flexible catheter, and is easier to follow-up. The Depth Guard delivery technology and the radiopaque markers added contribute to simplify the release. Depth Guard technology has been designed to minimize valve implantation depths, thus reducing its interaction with the left ventricular infundibulum. By reducing contact with the left ventricular infundibulum, the rates of definitive pacemaker implantation go down.

In conclusion, the results already published of the REPRISE III trial on a randomized comparison between the Lotus valve and the CoreValve self-expandable aortic valve (Medtronic, United States) are very interesting.27 The results available validate those from our registry regarding the safety and efficacy profile of the Lotus valve. No significant differences were seen at the 2-year follow-up either regarding the mortality and stroke rates compared to the CoreValve. Also consistent with our results, a lower rate of moderate-severe periprosthetic AR with the Lotus valve at the 2-year follow-up (0.3% with Lotus vs 3.8% with CoreValve; P < .01) and device embolization (0.0% with Lotus vs 2.0% with CoreValve; P < .01) was seen. However, there was a higher need for pacemaker implantation (41.7% with Lotus vs 26.1% with CoreValve; P < .01) and a higher rate (3%) of valve thrombosis at the long-term follow-up in our registry and in the REPRISE III trial.

CONCLUSIONS

This is the first study to describe the safety and functioning data of the Lotus valve in Spain and Portugal. Our results confirm those obtained by former studies and indicate that the Lotus valve is a safe and effective alternative for patients with symptomatic and severe AS. In particular, a low rate of periprosthetic AR after device implantation at the expense of a high rate of pacemaker implantation was reported.

Limitations

The study main limitations are probably the lack of a comparison group, and the non-negligible percentage of patients lost to follow-up since the study main initial objective was to assess the in-hospital results of device implantation. Second, the device available today is the LOTUS Edge valve that still has the advantages of the original Lotus valve plus an improved catheter and delivery system. Lastly, another limitation is the lack of a common predefined protocol for patient inclusion and result collection although it was prospective in each center.

CONFLICTS OF INTEREST

R. Moreno is associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. R. Moreno is also a proctor for Boston Scientific.

WHAT DOES THIS STUDY ADD?

  • The experience with this kind of device in our setting is still limited. The relevance of this study is that this is the first description of the safety and functioning data of the Lotus valve in Spain and Portugal. Our results confirm those of former studies: high successful implantation rate, low mortality, and low rate of periprosthetic aortic regurgitation at the expense of a high rate of pacemaker implantation. Also, our registry reported on the long-term follow-up results (3 years), making it even more relevant because there are very few data in the medical literature on the durability of this valve.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Despite the always growing experience in the percutaneous management of severe aortic stenosis, we still face TAVI-related complications. They can have a negative impact on the short and mid-long-term results, in particular periprosthetic aortic regurgitation. The Lotus is a fully retrievable and repositionable second-generation, transcatheter, aortic valve with good initial efficacy and safety results in former studies and registries. Also, it showed fewer major complications like periprosthetic aortic regurgitation or device malapposition.

REFERENCES

1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607.

2. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-1981.

3. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198.

4. Adams DH, Popma JJ, Reardon MJ, et al. Core Valve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370:1790-1798.

5. Salinas P, Moreno R, Calvo L, et al. Long term follow-up after Transcatheter Aortic Valve Implantation for severe aortic stenosis. Rev Esp Cardiol. 2016;69:37-44.

6. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2016;374: 1609-1620.

7. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients. N Engl J Med. 2019;380:1695-1705.

8. Popma JJ, Deeb GM, Yakubov SJ, et al.;Evolut Low Risk Trial Investigators. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med. 2019;380:1706-1715.

9. Moreno R, Calvo L, Salinas P, et al. Causes of peri-operative mortality after transcatheter aortic valve implantation:a pooled analysis of 12 studies and 1223 patients. J Invasive Cardiol. 2011;23:180-4.

10. Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation. 2011;123:299-308.

11. SabatéM, Cánovas S, García E, et al. Predictores de mortalidad hospitalaria y a medio plazo tras el reemplazo valvular aórtico transcatéter:datos del registro nacional TAVI 2010-2011. Rev Esp Cardiol. 2013;66:949-958.

12. Sinning JM, Vasa-Nicotera M, Chin D, et al. Evaluation and management of paravalvular aortic regurgitation after transcatheter aortic valve replacement. J Am Coll Cardiol. 2013;62:11-20.

13. Meredith I, Kristin L, Haratani N, Allocco D, Dawkins K. Boston Scientific Lotus Valve. EuroIntervention. 2012;8(Suppl Q):Q70-74.

14. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33:2451-2496.

15. O'Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models:part-2 –isolated valve surgery. Ann Thorac Surg. 2009;88(1 Suppl):S23-42.

16. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized end point definitions for transcatheter aortic valve implantation:the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012;33:2403-2418.

17. Meredith IT, Walters DL, Dumonteil N, et al. Transcatheter aortic valve replacement for severe symptomatic aortic stenosis using a repositionable valve system:30-day primary end point results from the REPRISE II study. J Am Coll Cardiol. 2014;64:1339-1348.

18. Meredith IT, Walters DL, Dumonteil N, et al. 1-Year Outcomes With the Fully Repositionable and Retrievable Lotus Transcatheter Aortic Replacement Valve in 120 High-Risk Surgical Patients With Severe Aortic Stenosis:Results of the REPRISE II Study. JACC Cardiovasc Interv. 2016;9:376-384.

19. Rampat R, Khawaja MZ, Byrne J, et al. Transcatheter Aortic Valve Replacement Using the Repositionable LOTUS Valve:United Kingdom Experience. JACC Cardiovasc Interv. 2016;9:367-372.

20. De Backer O, Götberg M, Ihlberg L, et al. Efficacy and safety of the Lotus Valve System for treatment of patients with severe aortic valve stenosis and intermediate surgical risk:Results from the Nordic Lotus-TAVR registry. Int J Cardiol. 2016;219:92-97.

21. Wöhrle J, Gonska B, Rodewald C, et al. Transfemoral aortic valve implantation with the repositionable Lotus valve compared with the balloon- expandable Edwards Sapien 3 valve. Int J Cardiol. 2015;195:171-175.

22. Larman Tellechea M, Telleria Arrieta M, Lasa Larraya G, Sanmartin Pena JC, Gaviria Molinero K. Transcatheter aortic valve replacement with Lotus valve:initial experience. Rev Esp Cardiol. 2014;67:956-958.

23. Falk V, Wöhrle J, Hildick-Smith D, et al. Safety and efficacy of a repositionable and fully retrievable aortic valve used in routine clinical practice:the RESPOND Study. Eur Heart J. 2017;38:3359-3366.

24. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement:the CHOICE randomized clinical trial. JAMA. 2014;311:1503-1514.

25. De Torres-Alba F, Kaleschke G, Diller GP, et al. Changes in the Pacemaker Rate After Transition From Edwards SAPIEN XT to SAPIEN 3 Transca­theter Aortic Valve Implantation:The Critical Role of Valve Implantation Height. JACC Cardiovasc Interv. 2016;9:805-813.

26. Moreno R, Dobarro D, López de Sá E, et al. Cause of complete atrioventricular block after percutaneous aortic valve implantation:insights from a necropsy study. Circulation. 2009;120:e29-30.

27. Reardon MJ, Feldman TE, Meduri CU, et al. Two-Year Outcomes After Transcatheter Aortic Valve Replacement With Mechanical vs Self-expanding Valves:The REPRISE III Randomized Clinical Trial. JAMA Cardiol. 2019;4:223-229.

Corresponding author: Playa de Sitges 39, 28290 Las Rozas de Madrid, Madrid, Spain.
E-mail address: daniele.gemma@hotmail.com (D. Gemma).

Abstract

Introduction and objectives: Mitral regurgitation is one society’s most prevalent valvular diseases. Transcatheter mitral valve repair with the MitraClip system has become more widely used for the management of this condition. The endpoints of the study were the changes in the mitral annular morphology, the recurrent grade III-IV mitral valve regurgitation, and a composite endpoing of heart failure readmission and all-cause mortality.

Methods: Single-centre, prospective and observational study. We included patients admitted due to transcatheter mitral valve repair between October 2015 and October 2018. The three-dimensional analysis of the mitral valve annulus was performed using the MVQ QLAB mitral valve quantification software (Philips; Amsterdam, The Netherlands).

Results: Fifty procedures were performed on 48 patients. A significant decrease of both annular diameters, perimeter and area was observed after the procedure. The antero-posterior diameter reduction was more significant in patients with functional mitral regurgitation compared to patients with organic mitral regurgitation (13.2 ± 8.8 vs 8.6 ± 7.5; P = .05). The posterior leaflet grasping was the only parameter associated with less chances of significant recurrent mitral regurgitation (OR = 0.89; 95CI%, 0.79-0.98).

Conclusions: Mitral annular morphological changes occur after MitraClip implantation. The magnitude of these changes varies depending on the etiology of mitral regurgitation. Posterior leaflet grasping is the main factor associated with these changes and prevents the recurrence of significant mitral regurgitation.

Keywords: Transcatheter mitral valve repair. MitraClip. Severe mitral regurgitation. Mitral annulus.

Resumen

Introducción y objetivos: La insuficiencia mitral es una de las enfermedades valvulares más prevalentes en nuestro medio. La reparación mitral transcatéter con el sistema MitraClip es un procedimiento cada vez más utilizado en este contexto. Los objetivos del estudio fueron evaluar los cambios morfológicos anulares, la recurrencia de la insuficiencia mitral significativa y un objetivo combinado de reingreso por insuficiencia cardiaca y mortalidad global.

Métodos: Estudio prospectivo, observacional y unicéntrico. Se incluyeron pacientes tratados con reparación mitral transcatéter entre octubre de 2015 y octubre de 2018. Se realizó un análisis tridimensional del anillo con el software de cuantificación mitral MVQ QLAB 10.0 (Philips; Amsterdam, Países Bajos).

Resultados: Se realizaron 50 procedimientos en 48 pacientes. Tras el procedimiento se observó una disminución significativa de ambos diámetros anulares, así como del perímetro y del área, y una mayor reducción del diámetro anteroposterior en los pacientes con insuficiencia mitral funcional con respecto a aquellos con insuficiencia mitral orgánica (13,2 ± 8,8 frente a 8,6 ± 7,5; p = 0,05). El porcentaje de grasping sobre el velo posterior fue el único parámetro que se asoció estadísticamente a una menor probabilidad de desarrollar insuficiencia mitral significativa (OR = 0,89; IC95%, 0,79-0,98).

Conclusiones: Tras el implante de MitraClip se producen cambios morfológicos en el anillo mitral. La magnitud de estos cambios es diferente según la etiología de la insuficiencia mitral. El grasping del velo posterior es el principal factor asociado a dichos cambios y previene la recurrencia de la insuficiencia mitral significativa.

Palabras clave: Anillo mitral. Insuficiencia mitral grave. MitraClip. Reparación mitral transcatéter.

Abbreviations: MR: mitral regurgitation. TVMR: transcatheter mitral valve repair.

Introduction

Mitral regurgitation (MR) is the most prevalent valvular disease in the United States and the second most prevalent in Europe1,2. The transcatheter mitral valve repair (TMVR) treated with the MitraClip system (Abbott Vascular, Menlo Park, California, United States) imitates the edge-to-edge approach surgical technique proposed by Alferi to achieve an effective reduction of the degree of MR3,4. This technique is more widely used, particularly in patients of high or prohibitive surgical risk because it is less invasive and has shown good efficacy and safety results in the mid-term5-7.

This procedure is thought to be able to operate changes in the anatomy of the mitral annulus beyond the edge-to-edge approach of the valvular leaflets, but there is very little information on this regard. Some studies speak about a significant change of anteroposterior diameters in RM of functional etiology8, while others describe changes of diameter, in non-constant areas and in etiologydependent areas9.

The goal of this study is to analyze the morphological changes occurring in the mitral valve after the TMVR and its relation to the degree of reduction of MR in the short and mid-terms, and its association with the clinical goals.

Methods

This is an observational, prospective study conducted at Hospital Universitario Central de Asturias de Oviedo, Spain.

Inclusion de patients

Patients were included between October 2015 and October 2018. These were the inclusion criteria: patients with grade III-IV symptomatic mitral failure despite the optimal medical therapy considered of high surgical risk by the multidisciplinary team and who would adequately meet the anatomical criteria needed for the implant4,7. These patients were excluded: patients with prior mitral surgical annuloplasty due to the impossibility of measuring annular anatomic changes. A prior transesophageal ecochardiography was conducted in all patients. The etiology of MR was categorized into organic or degenerative, and functional. Patients with a mixed etiological profile in their MR were recategorized into one of the aforementioned groups based on their predominant component after 2 expert cardiologists studied the transesophageal echocardiography and achieved consensus. All patients received oral written information on the risks and benefits of the procedure, and they all signed a written informed consent according to the Declaration of Helsinki.

Description of the procedure

The TMVR was performed using the MitraClip system, which received the European certificate of conformity (CE mark) in March 2018. The implantation procedure has already been described in prior studies7. In sum, the intervention is conducted under general anesthesia and guided by a 3D transesophageal echocardiography and under the supervision of a MitraClip technical expert. More than one clip was implanted in cases where the reduction of the degree of MR was not of, at least, one grade, and as far as there was no significant residual mitral stenosis estimated through the average diastolic transmitral valve pressure gradient10.

Echocardiographic study

All patients underwent transesophageal echocardiographic studies in 2 and 3 dimensions before and right after the completion of the procedure that was conducted by an expert echocardiography expert using a state-of-the-art echocardiography machine model EPIQ 7 (Philips; Amsterdam, The Netherlands). The patient’s afterload hemodynamic condition was taken into consideration before and after the procedure.

In order to conduct the 3D study of the mitral annulus, 3D images were acquired (Zoom 3D, Philips; Amsterdam, The Netherlands) during the procedure that were later analyzed using the MVQ QLAB 10.0 mitral quantification software (Philips; Amsterdam, The Netherlands). Figure 1 shows an example of 3D reconstruction before and after the procedure.

The analysis of the leaflet grasping was estimated using the lengths of both leaflets before and after the procedure in the same plane of the implant of the device. The length before the clip was measured between the anchor site of the leaflet to the annulus and the leaflet free-edge and, the length after the clip was estimated between the anchor site of the leaflet to the annulus and the leaflet site immediately proximal to the part of the leaflet inside the device:

– Total grasping (mm): pre mitral leaflet length − post mitral leaflet length.

– Per cent grasping (%): ([pre mitral leaflet length − post mitral leaflet length]/pre mitral leaflet length) × 100.

Figure 1. 3D analysis before the clip (A) and after the clip (B) of mitral annulus in frontal view from the left ventricle. A, anterior; AL, anterolateral; Ao, aorta; P, posterior; PM, posteromedial.

Study variables

Echocardiographic variables

The technical success, the device success, and the procedure success were all defined according to the consensus document put together by the Mitral Valve Academic Research Consortium11. Both the etiology and severity of the MR were classified and assessed according to the clinical practice guidelines designed by the European Society of Cardiology12-14, being severity subdivided into four degrees in a similar way to what the EVEREST clinical trial did4,7.

Clinical variables

The patient’ functional capacity was assessed following the New York Heart Association classification. Admission to due heart failure was defined as patients coming back to their hospital floor or being assisted in the ER and having to stay and sleep over. The EuroSCORE II and the Surgeon Thoracic Score were estimated too. Follow-up event was defined as a hospitalization due to heart failure or all-cause mortality.

Study goals

The study goals were the assessment of the annular morphological changes, the recurrence of MR (at least grade III/IV) and a composite endpoint of rehospitalization due to heart failure and global mortality.

Statistical analysis

Qualitative variables were expressed as absolute number and percentage and quantitative variables as mean ± standard deviation. The Student t test for paired data was used to assess morphological changes before and after the procedure. The chi-square and Student t tests were used for different groups as methods to compare categorical and quantitative variables. Linear regression analyses were conducted to assess the predictors of annular quantitative modification, the binary logistics regression analysis was used for the study of MR recurrence, together with the survival analysis using the Kaplan-Meier method. A peak alpha error of 0.05 was assumed. All analyses were conducted using the Stata 14 software (Stata Statistical Software: Release 14. College Station, Texas: Stata- Corp LP).

Results

Fifty TMVR procedures were conducted between October 2015 and October 2018 in 48 patients: 48 MitraClip primary implants and two reinterventions due to the partial detachment of the posterior leaflet. The average age was 74.8 ± 7.2 years and 31.3% of the patients were females. Ten procedures (20.8%) were conducted in patients with organic MR and 38 (79.2%) in patients with functional MR. The baseline characteristics of the population based on the etiology of the MR and the echocardiographic data are shown on table 1 and table 2. An average 1.5 ± 0.5 clips per procedure were implanted. In 43 (86%) cases, the first-generation clip was used, while in 7 (14%) cases, the XTr clip was used. Technical success was 100% and the procedural success was close to 92% (46/50). The four unsuccessful cases were due to partial detachments, one failed reintervention, and persistent grade III/IV MR after the implant.

Table 1. Baseline characteristics of the population

Global N = 48 (100%) Organic n = 10 (2.8%) Functional n = 38 (79.2%) P
Age, years 74.8 ± 7.2 76.6 ± 2.2 74.3 ± 1.2 .70
Women 15 (31.3) 5 (50) 10 (26.3) .15
Weight, kg 74.8 ± 14.2 75.3 ± 5.2 74.8 ± 2.2 .90
Height, cm 164.1 ± 9.1 158.6 ± 2.4 165.6 ± 2.5 .03
Hypertension 36 (75) 9 (90) 27 (71.1) .22
Diabetes mellitus 16 (33.3) 5 (50) 11 (29) .21
Dyslipidemia 22 (45.8) 6 (60) 14 (36.8) .24
Renal disease 20 (41.6) 3 (30) 17 (44.7) .19
Prior stroke 10 (20.8) 2 (20) 8 (21) .94
 Ischemic heart disease 23 (47.9) 4 (40) 19 (50) .48
 PCI 16 (33.3) 3 (30) 13 (24.4) .34
 CABG 7 (14.6) 1 (10) 6 (15.8) .36
Atrial fibrillation 30 (62.5) 6 (60) 24 (63.2) .84
Degree of MR
 III/IV 8 (16.7) 2 (20) 6 (15.8) .79
 IV/IV 40 (83.3) 8 (80) 32 (84.2) .80
SPAP, mmHg 43.5 ± 12.4 49.5 ± 4.4 41.8 ± 2.2 .06
COPD 11 (22.9) 3 (30) 8 (21) .55
Functional class
 NYHA III 35 (72.9) 7 (70) 28 (73.7) .83
 NYHA IV 13 (27.1) 3 (30) 10 (26.3) .79
EuroSCORE II 5.4 ± 4 4.7 ± 1.6 5.6 ± 2.2 .62
STS mortality 5.2 ± 3.2 7.2 ± 5.4 4.7 ± 2.1 .02

Data are expressed as n (%) or mean ± standard deviation.

CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; MR, mitral regurgitation; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SPAP, systolic pulmonary artery pressure; STS, Society of Surgeon Thoracic score.

Table 2. Echocardiographic characteristics

Global Organic MR Functional MR P
Left ventricular ejection fraction 41.5 ± 12.8 50.46 ± 4.1 39.15 ± 1.9 .01
LVESVi, mL/m2 85 ± 32.2 61.1 ± 19.9 91.4 ± 32 .01
LVESDi, mm/m2 60.5 ± 9.5 29.9 ± 4.1 33.9 ± 5 .02
ERO, cm2 0.38 ± 0.12 0.43 ± 0.12 0.36 ± 0.13 .09
Intercomissural diameter, mm 39.2 ± 4.7 37.8 ± 2.5 39.4 ± 5.1 .17
Anteroposterior diameter, mm 38.1 ± 5.3 35.8 ± 3.2 39.2 ± 5.6 .01
Bidimensional perimeter, mm 124.6 ± 14.6 114.9 ± 10.4 126.7 ± 14.6 .02
3D perimeter, mm 130.6 ± 16 117.7 ± 10 133.8 ± 15.7 .01
2D area, cm2 12.04 ± 3.1 10.1 ± 2.1 12.5 ± 3.1 .02
3D area, cm2 12.45 ± 3.2 10.2 ± 1.9 12.9 ± 3.2 .01
Anterior leaflet length, mm 24.7 ± 3.2 25.1 ± 2.8 26.2 ± 3.1 .11
Posterior leaflet length, mm 13.7 ± 2.4 12.6 ± 2.4 13.8 ± 2.4 .12
Anterior annulus-leaflet length, degrees 27.9 ± 6.3 25.8 ± 2.7 28.5 ± 6.5 .12
Posterior annulus-leaflet length, degrees 43.3 ± 10.8 39.7 ± 8.5 44.2 ± 11.2 .13

Data are expressed as n (%) or mean ± standard deviation.

ERO, effective regurgitant orifice; LVESVd, left ventricular end-diastolic volume diameter; LVESVi, left ventricular end-diastolic volume index; MR, mitral regurgitation.

After the procedure, in the 3D analysis of the mitral annulus, there was a significant reduction of both annular diameters, the perimeter and both 2D and 3D areas(table 3). The comparative analysis based on etiology (table 4) found a greater reduction in the anteroposterior diameter in patients with functional MR compared to those with organic MR (13.2 ± 8.8 versus 8.6 ± 7.5 of per cent reduction, respectively; P = .05) and a greater tendency to a reduced area in the same sense (13.3 ± 12.4 versus a 7.2 ± 11.1 of per cent reduction, respectively; P = .01).

Table 3. Global annular changes

Absolute reduction Relative reduction (%) P
Intercomissural diameter, mm 2.4 ± 2.2 5.99 ± 5.6 < .01
Anteroposterior diameter, mm 4.7 ± 3.8 12.1 ± 8.7 < .01
2D annular perimeter, mm 7.6 ± 7.1 6.1 ± 5.6 < .01
3D annular perimeter, mm 8.5 ± 6.2 6.4 ± 6.1 < .01
2D annular area, cm2 1.43 ± 1.3 11.8 ± 11.4 < .01
3D annular area, cm2 1.52 ± 1.3 11.9 ± 12.2 < .01

Data are expressed as n (%) or mean ± standard deviation.

2D, 2 dimensions; 3D, 3 dimensions.

Table 4. Annular changes and mitral leaflet grasping based on the etiology of mitral regurgitation

Organic MR Functional MR P
Intercomissural diameter reduction, % 6.1 ± 5.1 5.9 ± 6.3 .48
Anteroposterior diameter reduction, % 8.6 ± 7.5 13.2 ± 8.8 .05
2D annular perimeter reduction, % 5.4 ± 6.1 6.2 ± 5.5 .35
3D annular perimeter reduction, % 5.6 ± 5.5 6.7 ± 6.2 .35
2D annular area reduction, % 6.8 ± 11.3 13.1 ± 12.4 .09
3D annular area reduction, % 7.2 ± 11.1 13.3 ± 12.4 .10
Anterior leaflet grasping, mm 9.1 ± 3.8 7.3 ± 3.2 .07
Anterior leaflet grasping, % 36.6 ± 11.5 27.8 ± 11.4 .02
Posterior leaflet grasping, mm 4.3 ± 1.4 4.8 ± 1.8 .19
Posterior leaflet grasping, % 34 ± 8.1 34.4 ± 10.6 .44

Data are expressed as n (%) or mean ± standard deviation.

2D, 2 dimensions; 3D, 3 dimensions; MR, mitral regurgitation.

When it comes to both leaflet-grasping it was observed that in patients with organic MR, a greater percentage of anterior leaflet tissue inside the device is approached (36.6 ± 11.5% in the organic MR versus 27.8 ± 11.4% in the functional MR; P = .02), while posterior leaflet grasping is similar in both subtypes (34 ± 8.1% in the organic MR versus 34.4 ± 10.6% in the functional MR; P = .04).

In the simple linear regression analysis conducted of predictor factors of reduction of the annular anteroposterior diameter we observed that the percentage of posterior leaflet grasping and the anteroposterior diameter before the implant were the only factors associated with a greater reduction. After adjusting for the etiology of the MR, the indexed ventricular volumes, the annular diameters before the implant, and the anterior leaflet grasping, this association between the posterior leaflet grasping and the reduction of anteroposterior annular diameter was still statistically significant (ß coefficient = 0.27; 95%CI, 0.05-0.48; P = .02).

After an average 454 days of follow-up (interquartile range, 195- 699), 7 out of the 48 patients (14.6%) and 8 out of the 50 procedures conducted (16%) showed grade III/IV MR. In the binary logistics regression analysis conducted for grade III-IV/IV MR predictors at the echocardiographic follow-up (table 5) it was observed that the percentage of grasping over the posterior leaflet was the only parameter statistically associated with a lower probability to develop significant MR (OR, 0.89; IC95%, 0.79-0.98).

Table 5. Binary logistics regression analysis. Predictors of grade III-IV/IV mitral regurgitation after transcatheter mitral valve repair

OR (95%CI) P
Left ventricular ejection fraction 1.03 (0.97-1.1) .29
LVESVi 1.01 (0.98-1.03) .31
Intercomissural diameter relative reduction 1.02 (0.9-1.16) .65
Anteroposterior diameter relative reduction 0.95 (0.86-1.05) .50
3D annular perimeter reduction 0.94 (0.8-1.1) .47
3D annular area reduction 0.99 (0.92-1.06) .41
Anterior leaflet grasping 0.99 (0.93-1.06) .96
Posterior leaflet grasping 0.89 (0.79-0.98) .04

95%CI, 95% confidence interval; LVESVi, left ventricular end-diastolic volume index; OR, odds ratio.

There was a 16% rate of rehospitalizations due to heart failure and a global mortality rate of 12.5% (table 6). The composite endpoint of all-cause mortality or rehospitalization due to hear failure occurred in 10 (20.8%) patients. In the regression analysis for the composite endpoint of mortality or rehospitalization due to heart failure we did not observe an association between the parameters of annular reduction or the leaflet grasping and the endpoint under study. The heart failure-free or all-cause mortality-free survival curve is shown on figure 2.

Table 6. Mortality causes

Global mortality n (%)
Cardiovascular mortality 4 (8.33)
 Sudden death 1 (2.08)
Acute coronary syndrome 1 (2.08)
Non-cardiovascular mortality 2 (4.17)
 Sepsis 1 (2.08)
Neoplasm 1 (2.08)
Total 6 (12.5%)

Figure 2. Mortality-free or readmission due to heart failure-free survival estimated using the Kaplan-Meier method.

Discussion

The main finding of our study is that after TMVR with MitraClip there are important anatomical changes when it comes to the reduction of anteroposterior and intercomissural diameters, the annular diameters and areas, measured both in 2D and 3D. It was observed that, except for the intercomissural diameter, the remaining annular measurements (anteroposterior diameter, perimeter, and area) were significantly enlarged in patients with functional MR compared to patients with organic MR.

Similar to other studies published8,9, sit has been observed a significant reduction of the anteroposterior diameter after the implant. However, unlike Remy et al.9, describe in patients with functional MR, there was a greater relative reduction of the anteroposterior diameter and a non-significant tendency to a greater reduction of these patients’ area Also, in our series, we saw a reduction of the intercomissural diameter, which may have to do with a significant and sudden reduction of the regurgitation volume and with left intra-articular pressure, rather than with a direct mechanical effect coming from the clip.

With respect to the repercussion of these anatomical changes in the significant clinical results during follow-up, we did not observe any statistically significant correlation between these changes and rehospitalizations due to heart failure or global mortality. There was, however, an inversely proportional correlation between the reduced anteroposterior diameter and the possibility of III/IV MR recurrence (OR, 0.95; 95%CI, 0.89- 1.05). This data has been published in former statistically significant studies15. It is believed that the lack of signification in our study when it comes to these goals, and the non-association between the magnitude of diameters before the implant and MR recurrence may be associated with the number of patients of the overall cohort and the low number of events during follow-up.

There was a greater per cent anterior leaflet grasping in patients with organic MR compared to those with functional MR. This data may be explained by the greater anteroposterior annular diameters of patients with MR of functional etiology and by their association with the tenting phenomenon or apical displacement from the coaptation site, thus making an angle of greater magnitude between the annulus and the leaflet and, therefore, more difficulties to encompass the anterior leaflet during the procedure. On the other hand, it was observed that the posterior leaflet grasping was similar in both groups, which is a particularly important aspect because larger grasping percentages are associated with a greater relative reduction of the anteroposterior diameter with coefficients close to 0.3, which implies that by achieving just a 10% more grasping of the posterior leaflet we would be achieving a 3% reduction in the anteroposterior annular diameter. The posterior grasping was also a protective element against the possibility of significant MR recurrence at follow-up. In this sense, it is believed that patients whose mitral annulus will not allow minimum leaflet coaptation at baseline or will cause excessive tension in the leaflets while grasping with the corresponding risk of tear and break are those patients that may benefit the most from an associated annuloplasty system.

The role that the new generation MitraClip XTr may play in the mitral annular changes of our cohort has not been studied due to the low number of implants of this last device. It would be interesting to publish in the future whether this new device causes changes of different magnitude compared to the previous device, and whether these changes have to do with significant clinical changes at follow-up.

Limitations

This is a single-center study with a modest number of patients (48) and procedures (50). The analysis of predictors of mortality and rehospitalizations due to heart failure may be affected by the small size of the sample and small number of events reported. Also, this is a relatively new technique at our center, meaning that the representation of patients who were followed in the long-term is scarce. Also, no long-term 3D analysis of the mitral annulus after the implant was conducted.

Conclusions

After TMVR with MitraClip there are morphological changes in the mitral annulus. The magnitude of these changes is different based on the MR etiology. The posterior leaflet grasping is the main factor that influences the appearance of changes and is also associated with a lower probability of significant MR recurrence at follow-up.

Funding

This study received no funding whatsoever.

What is known about the topic?

  • After a TMVR procedure, there are morphological changes in the mitral annulus.
  • Significant reduction of the patients’ anteroposterior diameters with functional MR were confirmed, as well as an inverse relation between the reduction of the anteroposterior diameter and the probability of significant MR recurrence.

What does this study add?

  • Morphological changes do not happen in isolation in the mitral anteroposterior diameter, but they also affect other diameters, the area, and the perimeter.
  • We hereby state that the TMVR with the MitraClip system may induce the reconfiguration of the 3D structure of the mitral valve, due not only to its direct mechanical effect, but also to the modifications of the intracavitary volumes and pressures. How big these changes are is different based on the etiology of MR.
  • Posterior leaflet grasping turned out to be a crucial parameter in the morphological changes observed, and a protective factor of significant MR recurrence.

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Corresponding author: Área del Corazón, Hospital Universitario Central de Asturias, Avda. de Roma s/n, Oviedo, Asturias, España.
E-mail address: ipascua@live.com (I. Pascual Calleja).