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

Dr. 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: (I. J. Amat-Santos)

ABSTRACT

Introduction and objectives: A better positioning of left atrial appendage closure (LAAC) requires assessment of its clinical benefits to reduce thromboembolic and bleeding events in a real-word population.

Methods: Single-center retrospective study of our consecutive LAAC activity for 9 years. Both the device success and procedural success were registered as well as the reduction of the expected rates of thromboembolic and major bleeding events.

Results: A total of 260 LAAC procedures were performed in a population with nonvalvular atrial fibrillation with CHA2DS2-VASc and HAS-BLED scores of 4.3 ± 1.6 and 3.7 ± 1.2, respectively. Procedural success was 98.8%, and the rate of serious adverse events within the first 7 days was 2.3%. At a median follow-up of 2.5 ± 1.9 years and an estimated population of 637.9 patients-year, the thromboembolic event rate was 1.4 per 100 patients-year (75.5% risk reduction) and the rate of major bleeding was 3.0 per 100 patients-year (58.5% risk reduction), which was significantly lower than anticipated. The thromboembolic and major bleeding events per 100 patients-year showed a lower tendency for patients with very long follow-up (over 4 years) compared to the remaining of the population (0.7 vs 2.0 with P = .17, and 1.7 vs 4.0 with P = .09, respectively).

Conclusions: In our population, the LAAC showed high procedural success and a low rate of periprocedural adverse events. LAAC induced a significant reduction in the rate of predicted thromboembolic and hemorrhagic events, and this reduction was maintained even at very long follow-up.

Keywords: Percutaneous closure. Arterial embolism. Cerebral ischemia.

RESUMEN

Introducción y objetivos: Conocer el beneficio clínico del cierre percutáneo de la orejuela izquierda (OI) en nuestro medio; en concreto, la reducción de eventos tromboembólicos y hemorrágicos, que permitiría un mejor posicionamiento de esta intervención.

Métodos: Estudio retrospectivo que recoge la actividad del cierre de OI en un centro durante 9 años. Se registraron la tasa de éxito del dispositivo y del procedimiento, así como las tasas de eventos tromboembólicos y de hemorragia mayor.

Resultados: Se evaluaron 260 procedimientos de cierre de OI en una población con fibrilación auricular no valvular y puntuación en las escalas CHA2DS2-VASc de 4,3 ± 1,6 y HAS-BLED de 3,7 ± 1,2. El éxito del procedimiento fue del 98,8%, y la tasa de eventos adversos graves en los primeros 7 días fue del 2,3%. Con un seguimiento medio de 2,5 ± 1,9 años y una población de 637,9 pacientes-año, la tasa de eventos tromboembólicos fue de 1,4 por 100 pacientes-año (75,5% de reducción del riesgo) y la de hemorragia mayor fue de 3,0 por 100 pacientes-año (58,5% de reducción del riesgo), ambas significativamente menores que las predichas. Las tasas de eventos por 100 pacientes-año en los pacientes con seguimiento muy largo (más de 4 años) mostraron tendencia a ser menores que en el resto de la población (0,7 frente a 2,0, con p = 0,17, para evento tromboembólico, y 1,7 frente a 4,0, con p = 0,09, para hemorragia mayor).

Conclusiones: En nuestra población, el cierre de la OI mostró un elevado éxito del procedimiento y una baja tasa de eventos inmediatos. El cierre de la OI indujo una significativa reducción en la tasa prevista de eventos tromboembólicos y hemorrágicos, y dicha reducción se mantuvo a muy largo plazo.

Palabras clave: Cierre percutáneo. Embolia arterial. Isquemia cerebral.

INTRODUCTION

Percutaneous left atrial appendage closure (LAAC) has been extensively studied in clinical trials. Despite the excellent results of efficacy and safety regarding the LAAC from randomized clinical trials,1 these studies are limited by their design, which is still not applicable to our routine clinical practice. Maybe this is the reason why in our setting, the LAAC program is still far from reaching its full potential.2 Without detriment to the current level and grade of clinical recommendation for the LAAC,3 the medical community will only gain confidence in this procedure when further studies are presented assessing its performance in our routine clinical practice.

The LAAC is a solid structural procedure that in Spain is only second to transcatheter aortic valve implantation (TAVI).4 The experience gained with the LAAC has moved the focus of attention from the early aspects of success and safety towards other issues still not properly addressed such the performance of LAAC reducing long-term cardiovascular events or its lingering benefits over time.

To this day, there are very few papers gathering the long-term experience gained with the LAAC with a median follow-up of 2.5 years.1,5-9 It is only from this long-term perspective that we will understand the value of a procedure largely based on the prophylaxis of the thromboembolic complications occurred during the patient’s life.

The objective of this study was to present our own experience in the follow-up of the population treated with LAAC from the beginning of this program to assess its overall performance and, especially, the reduction of long and very long-term thromboembolic and bleeding events.

METHODS

Our study is a retrospective analysis of the LAAC activity developed consecutively in a teaching hospital from March 2011 through February 2020. This procedure was indicated by different large volume hospital units including the internal medicine, neurology, and cardiology units. Our unit has included the LAAC as a strategic program within our structural heart procedures.

Left atrial appendage closure: the procedure and the device implanted

All procedures were performed in an identical working setting (facilities and personnel). However, 3 different modalities were used: on the one hand, general anesthesia and conscious sedation, both with transesophageal ultrasound guidance, and a third modality with fluoroscopy guidance only while the patient remained awake.

Although at the beginning of our experience only general anesthesia was used, 2.5 years later the possibility of conscious sedation administered by our personnel started to become a reality; the criterion to choose between general anesthesia or conscious sedation was logistical due to the discretional participation of the anesthesiology unit in structural heart procedures. In both modalities, the type of probe used for the transesophageal ultrasound was the exact same one.

The protocol of conscious sedation consisted of sedoanalgesia through the IV administration of 50 mg of pethidine followed by a bolus of 0.5 mg/kg of propofol with slow infusion in 3 min. with continuous monitorization of saturation and hemodynamics. After the introduction of the transesophageal probe several boluses of 10 mg of IV propofol were administered on demand based on the patient’s discomfort or rejection.

The procedure guided by fluoroscopy only was spared for cases with absolute or relative contraindication for transesophageal ultrasound use (in our unit we do not have intracavitary ultrasound) and for patients considered very frail for anesthetic induction; however, it became a reality 4 years after we started our experience. In these patients, a coronary computed tomography angiography was recommended to assess the left atrial appendage and discard the presence of an inner thrombus; in any case, an angiography was performed via transseptal access through a pigtail catheter from the left atrial appendage ostium without selective cannulation to discard the presence of thrombus. After catheterizing the left atrial appendage, a 180º rotational acquisition was performed through the injection of contrast at a flow rate of 8 mL/s with a total of 48 mL; by doing this a 3D image of the left atrial appendage was obtained (software i-Pilot, Siemens, Germany) that fused with the real fluoroscopy.

The 2 most popular devices in the market today were used: the WATCHMAN device in its WATCHMAN 2.5 and WATCHMAN Flex versions; Boston Scientific, United States) and the AMPLATZER ACP/Amulet device (Abbott, United States); the LAmbre device (Lifetech Scientific, China) was implanted anecdotically. The selection of one or the other did not follow any clinical or anatomical criteria and the alternate use of both devices was well-balanced. Only in fluoroscopy-guided procedures the AMPLATZER Amulet device was preferential since its delivery criteria are basically fluoroscopic.

Performance of left atrial appendage closure and follow-up

The definitions were based on the Munich consensus document regarding the LAAC.10 Successful LAACs were defined as successful devices (successful implantation of the first device selected) and successful procedures (uneventful final successful implantation within the first 24 hours). The device was released after confirming the suitability of ultrasound and fluoroscopic parameters. In cases performed under fluoroscopy guidance, position and stability were assessed over the fusion imaging as well as the lack of uncovered lobes in the angiography.

Regarding treatment after the implant, there was no pre-specified criterion and the patient’s bleeding risk was adjusted. All patients were assessed using a thoracic ultrasound within the first 24 hours prior to hospital discharge. Adherence to the transesophageal ultrasound control 1.5 months after the procedure was very irregular.

Follow-up was conducted back in February 2020 by reviewing the Andalusian (Diraya) electronic health record system. The appearance and dates of the following events were registered: death and causes, ischemic stroke/systemic embolism, major bleeding (incapacitating and major hemorrhages), and medical therapy at the follow-up. The futility of the LAAC was defined as mortality rate due to non-cardiac causes reported within the first year.

The performance of the LAAC at the follow-up was assessed using the risk reduction rate of thromboembolic (ischemic stroke/systemic embolism) or bleeding events (major bleeding) while taking into account the risk estimates from the CHA2DS2-VASc11 and HASBLED scores,12 respectively.

A 4-year follow-up limit has been established to start taking about «very long evolution» since this was the follow-up period of the Protect AF clinical trial1 that confirmed the superiority regarding mortality of LAAC over anticoagulation.

Statistical analysis

The estimates were obtained using IBM SPSS v26.0 and Epidat 4.2 statistical software. Initially, a descriptive analysis of data was conducted by generating means and standard deviations of numerical variables, and frequency and percentage distributions of qualitative variables.

The comparison between the demographic and clinical quantitative variables was conducted using the ANOVA test after verifying the hypotheses of normality using the Shapiro-Wilks test; when significant differences were seen, multiple comparisons were conducted using the Bonferroni correction.

The comparison among the different qualitative variables was conducted using contingency tables and the chi-square test.

The comparison between event incidence rates was conducted using the Rothman index score and 95% confidence intervals (95%CI) were estimated using Rosner’s method.

Finally, Kaplan-Meier curves were generated and then compared using the log rank test.

RESULTS

Population

The population studied included 260 patients with nonvalvular atrial fibrillation aged between 42 and 92 years old. The clinical characteristics of the population are shown on table 1.

Table 1. Clinical characteristics of the population

Age (years) 74.8 ± 8.1
Males 160 (61.5%)
Risk factors
 Arterial hypertension 238 (91.5%)
 Diabetes (types 1 and 2) 118 (45.4%)
 Smoking 93 (35.8%)
 Dyslipidemia 130 (50%)
Kidney disease 64 (24.6%)
Ischemic heart disease 89 (34.2%)
Previous stroke
 Ischemic stroke 38 (14.6%)
 Hemorrhagic stroke 57 (21.9%)
CHA2DS2-VASc 4.3 ± 1.6
CHA2DS2-VASc ≥ 4 176 (67.7%)
HAS-BLED 3.7 ± 1.2
HAS-BLED ≥ 3 222 (85.4%)

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

The most common indication for LAAC was the absolute contraindication for anticoagulant therapy due to hemorrhagic events in 229 cases (88.1%) or high-risk (2 patients with brain tumors and 1 patient with an aortic dissection; 1.1%). In 28 patients (10.8%) indication was due to the inability to take oral anticoagulants due to different bleeding risks: in 13 due to rejection to anticoagulant therapy, in 6 due to previous psychiatric history that did not recommend it, in 3 due to higher risk of falling, in 3 due to poor control of the international normalized ratio, and in other 3 due to cardioembolic stroke yet despite the proper anticoagulant therapy.

When the LAAC was indicated, therapy was mostly anticoagulation (68.8% of the patients): vitamin K antagonists (83 cases, 31.9%), direct anticoagulants (71 cases, 27.3%) or dual therapy (anticoagulation and single antiplatelet therapy, 25 cases, 9.6%). Regarding patients who were not on anticoagulant therapy prior to the LAAC, 48 of them (18.5%) were on antiplatelet therapy and 33 (12.7%) did not use any antiplatelet/anticoagulant drugs.

While follow-up was being conducted (February 2020 or prior to the patient’s death), our population was being treated with absence of antiplatelet/anticoagulant therapy (51 patients, 19,9%), single antiplatelet therapy with acetylsalicylic acid (135 patients, 52.5%), single antiplatelet therapy with clopidogrel (51 patients, 19,9%), dual antiplatelet therapy (14 patients, 5.4%) or anticoagulation (6 patients, 3%) (figure 1).

Figure 1. Evolution of antithrombotic therapy prior to the left atrial appendage closure (LAAC) until the final follow-up (%).

Procedural characteristics

Procedures were performed mostly under general anesthesia and monitored under transesophageal ultrasound guidance (59.6%). Conscious sedation, also monitored under transesophageal ultrasound guidance, was performed in 27.3% of all procedures. Only 13.1% of all procedures were performed under fluoroscopy guidance only.

The most commonly used device was the WATCHMAN (142 patients, 54.6%) followed by the AMPLATZER ACP/Amulet (116 patients, 44.6%), and occasionally the LAmbre (2 patients, 0.8%). Given the extension of the follow-up period, 2 models of the WATCHMAN (generation 2.5 in 125 patients and WATCHMAN Flex in 17 patients) and 2 models of the AMPLATZER device (ACP in 16 patients and Amulet in 100 patients) were used.

The device success rate was 98.5% (failed in 4 patients). Failed cases were due to the device not meeting the sealing criteria for the left atrial appendage so it had to be recaptured; after choosing a different device (different size, and in 1 case, also a different model), the procedure ended satisfactorily.

Procedural success was 98.8%; 1 oropharyngeal hemorrhage due to traumatic intubation and 2 tamponades were the reason for the lack of success. Tamponades (0.77%) were due, in the first case, to a perforation of the left atrial appendage in the recapture maneuver of the WATCHMAN device; the second case, after 24 hours, was due to the perforation of the left pulmonary artery possibly eroded by the LAmbre device. These 2 patients had a good clinical progression, the first one after pericardiocentesis and the second one after surgery with pericardial patch interposition between the pulmonary artery and the left atrial appendage. No deaths, strokes, or systemic embolisms were reported during the procedure or within the first 24 hours.

The number of serious adverse events reported within the first week was 6 (2.3%) as shown on table 2.

Table 2. Serious adverse events within the first 7 days after the implant

Day Event Description Death
Procedure Hemorrhage Traumatic intubation for general anesthesia No
Procedure Tamponade Pericardiocentesis No
1 day Tamponade Perforation of pulmonary artery Surgery No
4 days Bronchial aspiration Bronchial aspiration while eating Yes
4 days Hemorrhage Upper gastrointestinal bleeding Yes
6 days Hemorrhage Upper gastrointestinal bleeding No

The comparative analysis between the results of the first 50 LAACs and the remaining ones give us a glimpse of the existence of a learning curve that can be seen in the procedural variables that assess the operator’s technical skills (significant reduction of fluoroscopy time and radiation dose from the first 50 procedures): 13.6 ± 5.5 min vs 18.7 ± 18.2 min and 18 413 µGym ± 11 622 µGym vs 24 798 µGym ± 18 802 µGym,2 respectively with P values = .03). However, no differences were found in the procedural success rate (98% for the first 50 cases and 99% for the remaining ones).

The procedural characteristics of the left atrial appendage closure are shown on table 3.

Table 3. Procedural characteristics

Procedural modality
 General anesthesia 155 (59.6%)
 Conscious sedation 71 (27.3%)
 Fluoroscopy 34 (13.1%)
Device
 ACP-Amulet 116 (44.6%)
 WATCHMAN 142 (54.6%)
 LAmbre 2 (0.8%)
Device size (mm) 25.2 ± 3.4
Fluoroscopy time (min) 14.6 ± 9.7
Radiation (µGym2) 19 636 ± 13 488
Device success 98.5%
Procedural success 98.8%

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

Follow-up and events

With a median follow-up of 2.5 years ± 1.9 years (median, 1.4 years; 95%CI, 1.1 to 1.9 years) our series included 637.9 patients-year.

A total of 58 deaths were reported at the follow-up (22.3% of the sample, 9.1% patients-year). Half of them were due to cardiac causes (4.6% patients-year). A total of 6 deaths were due to noncardiac causes within the first year, which means that LAAC futility rate was 2.3%.

Events such as ischemic strokes/systemic embolisms were reported in 9 patients (1.4% patients-year, 95%CI. 0.6-2.7); compared to the estimated risk of 5.7% patients-year, the reduction of relative risk was 75.2% (P < .001). A total of 19 major hemorrhages were reported (3.0% patients-year. 95%CI. 1.8-4.7), which is a 58.5% reduction of relative risk compared to the estimated risk of 7.2% patients-year (P < .001)

The assessment of the protective capacity of LAAC to avoid long-term thromboembolic phenomena and major hemorrhages is very relevant. Events were compared in patients with follow-ups of up to 4 years (n = 206; 346.7 patients-year) and in patients beyond this 4-year follow-up mark (n = 54; 291.3 patients-year). It was confirmed that, over time, protection against thromboembolic and hemorrhagic events still remains, and there is even a decreasing tendency: annual rate per 100 patients-year for ischemic stroke/embolism of 2.0 vs 0.7 (P = 0.17) and for major hemorrhages of 4.0 vs 1.7 (P = .09) in patients with up to 4-year follow-ups and longer follow-ups, respectively. The comparison of event-free survival rates for thromboembolism and major bleeding between the different populations based on the duration of the follow-up did not show any significant results (log rank with P = .10 for thromboembolisms and P = .54 for hemorrhages) (figure 2).

Figure 2. Thromboembolic event-free (A) and major bleeding-free (B) survival curves of patients with < 4 year (green) and > 4-year follow-up (gray). The curve comparison does not show any significant differences for either one of the events.

Follow-up based on the type of device implanted

A comparative analysis of the event-free survival rate in patients treated with the WATCHMAN and AMPLATZER devices found no significant differences between the 2 regarding their protective capabilities against ischemic strokes/systemic embolisms (log rank P = .86); however, the WATCHMAN showed a major hemorrhage-free cumulative incidence rate superior to the AMPLATZER device (log rank P = .01) (figure 3).

Figure 3. Thromboembolic event-free (A) and major bleeding-free (B) survival curves of patients with the AMPLATZER (green) and the WATCHMAN device (gray). No differences were seen in the devices used for thromboembolic events, but there were differences regarding major bleeding with a higher event-free survival rate in patients treated with the WATCHMAN device.

DISCUSSION

This real-world single-center registry shows our experience performing left atrial appendage closure in 260 consecutive patients with nonvalvular atrial fibrillation over the last 9 years. Results have been exposed in an attempt to answer the following questions: what were the results of LAAC in our population? what is the actual performance of LAAC reducing thromboembolic or hemorrhagic events compared to the estimated risk rates? and finally, is this this event reduction maintained at the follow-up?

The clinical characteristics of our population are consistent with those of the LAAC target population in the routine clinical practice. Thus, our population showed clinical characteristics of thromboembolic risk that were similar to those published in large registries: the CHA2DS2-VASc score of 4.3 was intermediate between the AMPLATZER Amulet registry13 with a CHA2DS2-VASc score of 4.2 and the NCDR registry14 with a CHA2DS2-VASc score of 4.6. Regarding the risk of bleeding, in our population the mean HAS-BLED score was 3.8, slightly higher compared to the numbers already published, and situated between the EWOLUTION registry with a HAS-BLED score of 2.315,16 and the AMPLATZER Amulet registry with a HAS-BLED score of 3.3.13

This high risk of bleeding of our population may be explained by the fact that the indication for LAAC for almost 90% of the patients was a past medical history of bleeding (mostly gastrointestinal followed by cerebral); for the remaining 10%, the indication for LAAC was the «inability to take oral anticoagulants due to different risks of bleeding»,10 that is, by a number of reasons that forced the patient (5% of the population) or the doctor to make the decision of choosing mechanical local therapy over the anticoagulant therapy. Although in our case the volume of elective decisions regarding the LAAC is far from the volume reported in the German registry LAARGE,17 where patient selection was essential to propose the indication in a fourth of the population, a reflection can be made on to what extent information brought to the patient is decisive to generalize this therapy.

The LAAC is a procedure with high device and procedural success rates in most of the series already published. In our series the device success rate in the implant was 98.5%; 1.5% of failed procedures were due to an erroneous selection of the size of the device. However, the left atrial appendages of all the patients from the series were eventually sealed, which contrasts with up to 7% of the procedures cancelled due to inaccessible left atrial appendage anatomies;14 this may have to do with our capacity to approach this procedure using different modalities (general anesthesia, conscious sedation, and fluoroscopy without ultrasound guidance) and different types of occluder devices (yet the device had to be changed for a different one only in 1 patient in order to finish the procedure). Our procedural success rate was 98.8%, which is higher compared to the rate reported in other registries with similar populations regarding their baseline clinical characteristics.14 Regarding procedural safety, our adverse event rate within the first 7 days after the procedure was 2.3%, which is consistent with the rate reported by large registries.13-16 Overall, this speaks of the progressive decline seen in the rate of adverse events reported during the early stage after the procedure.

In the consecutive analysis of procedural results like the left atrial appendage closure, right from the beginning of our experience and until today, the presence of a learning curve may be anticipated. However, beyond procedural variables like the radiation duration and dose, no differences were reported regarding the procedural success rate between the early period and the rest of the experience. Standardizing procedures and training the operators may be the reasons of the high success rate reported in left atrial appendage closure despite the poor early experience reported.18

Our registry, with a median follow-up of 2.5 years and a fifth of the patients with follow-up periods > 4 years allows us to assess the efficacy of the LAAC with a certain perspective. In the first place, mortality rate is surprisingly high since 22.3% of the patients included died at the follow-up. This is an annual mortality rate of 9.1%, 3 times higher compared to the 4-year follow-up of the Protect AF,1 but it is nearly identical as other registries with a similar risk population compared to ours.9 The highest mortality risk seen at the follow-up has been associated with factors such as age, male sex, history of stroke or intracranial hemorrhage, low ejection fraction, and chronic kidney disease;8,9 in any case, this high mortality rate seen at the follow-up shows how frail this diseased population really is, which would justify an interesting debate on the futility of the LAAC in some patients19 (2.3% in our series).

The primary endpoint of LAAC is to reduce the risk of cardiac embolism in a population with nonanticoagulated atrial fibrillation. In our case, the annual rate of ischemic stroke and embolism was 1.4%, which was a significant reduction of the relative risk of 75%, which is consistent with the best data reported in the medical literature.20 Regarding major bleeding, in a population with an estimated rate of bleeding > 7%, our rate was 3.0%, that is, half the rate reported by other authors.9

To this day, very few studies have been conducted on the long-term efficacy profile of the left atrial appendag-e closure. In the Ibérico II registry,8 the rate of thromboembolic events remained low while the rate of major bleeding was lower compared to the early rates at the 2-year follow-up. In our population, the analysis of patients with very long clinical courses (implantation times > 4 years) revealed that the efficacy of the LAAC still remains. Also, that thromboembolic and bleeding events showed a tendency towards a lower incidence rate compared to the earliest stage.

Limitations

This study has some limitations. In the first place, no systematic antithrombotic pattern was followed after implantation. Instead, it was left to the operator’s discretion, which may have impacted the short-term bleeding rate. On the other hand, no systematic imaging follow-up was arranged 45 days to 3 months after implantation, which means that an important piece of information was lost: the rate of thrombosis associated with the device, lack of residual sealing…

CONCLUSIONS

In our setting, left atrial appendage closure is an effective therapy for patients with nonvalvular atrial fibrillation and coagulation issues. It significantly reduces the rates of thromboembolic and hemorrhagic events that remain consistent in the very long term.

CONFLICTS OF INTEREST

None reported.

WHAT IS KNOWN ABOUT THE TOPIC?

  • – It is estimated that only 5% of the patients with nonvalvular atrial fibrillation and inability to use oral anticoagulant therapy have benefited from the left atrial appendage closure. The evidence from randomized clinical trials is based on a population that is not similar to the one considered eligible for LAAC in the real world, which is a limitation. Relevant real-world registries do not have long-term follow-ups either.

WHAT DOES THIS STUDY ADD?

  • – Our study provides data on the performance of the left atrial appendage closure in our routine clinical practice on procedural success and performance reducing thromboembolic and major bleeding events, which, overall, is significant compared to the estimated rates and also remains consistent over the very long-term.

REFERENCES

1. Reddy VY, Sievert H, Halperin J, et al. Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation:A Randomized Clinical Trial. JAMA. 2014;312:1988-1998.

2. Fukutomi M, De Backer O, Søndergaard L. Indications, current adoption and future perspectives for percutaneous left atrial appendage closure. EuroIntervention. 2019;14:1707-1709.

3. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehaa612.

4. Ojeda S, Romaguera R, Cruz-González I, Moreno R. Registro Español de Hemodinámica y Cardiología Intervencionista. XXIX Informe Oficial de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2019). Rev Esp Cardiol. 2020;73:927-936.

5. Wiebe J, Franke J, Lehn K, et al. Percutaneous Left Atrial Appendage Closure With the Watchman Device:Long-Term Results Up to 5 Years. J Am Coll Cardiol Intv. 2015;8:1915-1921.

6. Betts TR, Leo M, Panikker S, et al. Percutaneous left atrial appendage occlusion using different technologies in the United Kingdom:A multicenter registry. Catheter Cardiovasc Interv. 2017;89:484-492.

7. Korsholm K, Nielsen KM, Jensen JM, Jensen HK, Andersen G, Nielsen-Kudsk JE. Transcatheter left atrial appendage occlusion in patients with atrial fibrillation and a high bleeding risk using aspirin alone for post-implant antithrombotic therapy. EuroIntervention. 2017;12:2075-2082.

8. López-Mínguez JR, Nogales-Asensio JM, Infante De Oliveira E, et al. Reducción de eventos a largo plazo tras el cierre de la orejuela izquierda. Resultados del Registro Ibérico II. Rev Esp Cardiol. 2019;72:449-551.

9. Regueiro A, Cruz-Gonzalez I, Bethencourt A, et al. Long-term outcomes following percutaneous left atrial appendage closure in patients with atrial fibrillation and contraindications to anticoagulation. J Interv Card Electrophysiol. 2018;52:53-59.

10. Tzikas A, Holmes DR, Gafoor S, et al. Percutaneous left atrial appendage occlusion:the Munich consensus document on definitions, endpoints and data collection requirements for clinical studies. EuroIntervention. 2016;12:103-111.

11. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach:the euro heart survey on atrial fibrillation. Chest. 2010;137:263-272.

12. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients:The Euro Heart Survey. Chest. 2010;138:1093-1100.

13. Landmesser U, Schmidt B, Nielsen-Kudsk JE, et al. Left atrial appendage occlusion with the AMPLATZER Amulet device:periprocedural and early clinical/echocardiographic data from a global prospective observational study. EuroIntervention. 2017;13:867-876.

14. Freeman JV, Varosy P, Price MJ, et al. The NCDR left atrial appendage occlusion registry. J Am Coll Cardiol. 2020;75:1503-1518.

15. Boersma LV, Schmidt B, Betts TR, et al. EWOLUTION investigators. Implant success and safety of left atrial appendage closure with the WATCHMAN device:peri-procedural outcomes from the EWOLUTION registry. Eur Heart J. 2016;37:2465-2474.

16. Boersma LV, Ince H, Kische S, et al. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation:1-year follow-up outcome data of the EWOLUTION trial. Heart Rhythm. 2017;14:1302-1308.

17. Fastner C, Nienaber CA, Park JW, et al. Impact of left atrial appendage morphology on indication and procedural outcome after interventional occlusion:results from the prospective multicenter German LAARGE registry. EuroIntervention. 2018;14:151-157.

18. Sawant AC, Seibolt K, Sridhara S, et al. Operator experience and outcomes after transcatheter left atrial appendage occlusion with the Watchman device. Cardiovasc Revasc Med. 2020;21:467-472.

19. Asmarats L, Rodés-Cabau J. Resultados a largo plazo tras el cierre de la orejuela izquierda:ampliando la perspectiva en la prevención no farmacológica del ictus en pacientes con fibrilación auricular. Rev Esp Cardiol. 2019;72:440-442.

20. Glikson M, Wolff R, Hindricks G, et al. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion –an update. EuroIntervention. 2020;15:1133-1180.

Corresponding author: Servicio Endovascular, Hospital Virgen Macarena, Avda. Doctor Fedriani 3, 41009 Sevilla, Spain.


E-mail addres: (R.J. Ruiz-Salmerón).

Abstract

Introduction and objectives: Patients with a low post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) are at a higher risk for future adverse cardiac events. The objective of the current study was to assess specific patient and procedural predictors of post-PCI FFR.

Methods: The FFR-SEARCH study is a prospective single-center registry of 1000 consecutive all-comer patients who underwent FFR measurements after an angiographically successful PCI with a dedicated microcatheter. Mixed effects models were used to search for independent predictors of post-PCI FFR.

Results: The mean post-PCI distal coronary pressure divided by the aortic pressure (Pd/Pa) was 0.96 ± 0.04 and the mean post-PCI FFR, 0.91 ± 0.07. After adjusting for the independent predictors of post-PCI FFR, the left anterior descending coronary artery as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P < .0001) followed by the postprocedural minimum lumen diameter (adjusted β = 0.039; 95%CI, 0.015-0.065; P = .002). Additionally, male sex, in-stent restenosis, chronic total coronary occlusions, and pre- and post-dilatation were negatively associated with postprocedural FFR. Conversely, type A lesions, thrombus-containing lesions, postprocedural percent stenosis, and stent diameter were positively associated with postprocedural FFR. The R2 for the complete model was 53%.

Conclusions: Multiple independent patient and vessel related predictors of postprocedural FFR were identified, including sex, the left anterior descending coronary artery as the measured vessel, and postprocedural minimum lumen diameter.

keywords: Percutaneous coronary intervention. Post-PCI FFR. Predictors.

RESUMEN

Introducción y objetivos: Los pacientes con una reserva fraccional de flujo (FFR) posintervención coronaria percutánea (ICP) baja tienen mayor riesgo de futuros eventos cardiacos adversos. El objetivo del presente estudio fue evaluar predictores específicos de pacientes y procedimientos de FFR tras una ICP.

Métodos: El estudio FFR-SEARCH es un registro prospectivo de un solo centro que incluyó 1.000 pacientes consecutivos que se sometieron a una evaluación de la FFR tras una ICP con éxito angiográfico utilizando un microcatéter específico. Se utilizaron modelos de efectos mixtos para buscar predictores independientes de FFR tras la ICP.

Resultados: La media de presión distal dividida entre la presión aórtica tras la ICP fue de 0,96 ± 0,04, y la media de la FFR tras la ICP fue de 0,91 ± 0,07. Tras ajustar por predictores independientes de FFR tras la ICP, la arteria descendente anterior izquierda como vaso medido fue el predictor más fuerte (β ajustado = −0,063; IC95%, −0,070 a −0,056; p < 0,0001), seguida del diámetro luminal mínimo posprocedimiento (β ajustado = 0,039; IC95%, 0,015 a 0,065; p = 0,002). Además, el sexo masculino, la reestenosis del stent, las oclusiones totales crónicas y la pre- y posdilatación se correlacionaron negativamente con la FFR posprocedimiento. Por el contrario, las lesiones de tipo A, las lesiones con trombos, el porcentaje de estenosis posprocedimiento y el diámetro del stent se correlacionaron positivamente con la FFR posprocedimiento. El R2 para el modelo completo fue del 53%.

Conclusiones: Se identificaron diversos predictores independientes relacionados con los pacientes y con los vasos para la FFR posprocedimiento, incluyendo el sexo, la arteria descendente anterior izquierda como vaso medido y el diámetro luminal mínimo posprocedimiento.

Palabras clave: Intervención coronaria percutánea. FFR post-ICP. Predictores.

Abbreviations: FFR: fractional flow reserve. LAD: left anterior descending coronary artery. MLD: minimum luminal diameter. PCI: percutaneous coronary intervention.

INTRODUCTION

The limitations of an accurate assessment of the hemodynamic significance of coronary artery lesions through angiographic guidance alone are well-known.1 Instead, the fractional flow reserve (FFR) has proven to be a useful technique to address the coronary physiology and the hemodynamic significance of coronary segments before and after performing an intervention.2-4 Also, measuring FFR post-stenting has proven to be a strong and independent predictor of major adverse cardiovascular events at the 2-year follow-up.3-5

While FFR primarily takes into account the relative luminal narrowing and the amount of viable myocardium perfused by a specific vessel, several factors have been shown to impact the FFR values prior to performing a percutaneous coronary intervention (PCI). Therefore, longer lesion length, high syntax scores, calcifications, and tortuosity are associated with significantly lower FFR values. Conversely, the presence of microvascular dysfunction, chronic kidney disease and female gender have been associated with higher FFR values.6-11

At the present time, there is lack of data on independent predictors of post-PCI FFR. Therefore, the objective of the present study was to assess the patient and procedural characteristics associated with low post-PCI FFR in an all-comer patient population.

METHODS

The FFR-SEARCH study is a prospective single-center registry that assessed the routine distal pressure divided by the aortic pressure (Pd/Pa) and FFR values of all consecutive patients after an angiographically successful PCI. The primary endpoint was to study the impact of post-PCI FFR on the rate of major adverse cardiovascular event at the 2-year follow-up. Accordingly, no further actions were taken to improve post-PCI FFR. The study was performed in full compliance with the Declaration of Helsinki. The study protocol was approved by the local ethics committee. All patients gave their written informed consent to undergo the procedure. Also, anonymous datasets for research purposes were used in compliance with the Dutch Medical Research Act. A total of 1512 patients treated between March 2016 and May 2017 at the Erasmus Medical Center were eligible to enter our study. A total of 504 of these patients were excluded due to hemodynamic instability (156), a rather small distal outflow (129), the operator’s decision not to proceed with post-PCI hemodynamic assessment (148) or other reasons (79). A total of 1000 patients were included in the study. The microcatheter could not cross the treated lesion in 28 patients, technical issues with the catheter prevented post-PCI assessments in 11 patients, and in 2 patients the post-PCI FFR measurements had to be aborted prematurely due to adenosine intolerance. This left 959 patients whose post-PCI FFR values were measured in at least 1 angiographically successfully treated lesion.

Quantitative coronary angiography

The preprocedural lesion type was defined according to the ACC/AHA guidelines12 and divided into 4 categories: A, B1, B2, and C. Comprehensive quantitative coronary angiography analyses were performed pre- and post-stent implantation in all the treated lesions. An angiographic view with minimal foreshortening of the lesion and minimal overlapping with other vessels was selected. Similar angiographic views were used pre- and post-stent implantation. Measurements included pre- and postprocedural percent diameter stenosis, reference vessel diameter, lesion length, and minimum luminal diameter (MLD). In case of a total occlusion in patients presenting with ST-segment elevation myocardial infarction (STEMI) or chronic total coronary occlusion (CTO), the MLD was considered zero and the percent diameter stenosis, 100%. The reference vessel diameter and the lesion length were measured from the first angiographic view with restored flow. All measurements were taken using CAAS for Windows, version 2.11.2 (Pie Medical Imaging, The Netherlands).

Fractional flow reserve measurements

All FFR measurements were acquired using the Navvus RXi system (ACIST Medical Systems, United States), a dedicated FFR microcatheter with optical pressure sensor technology.13,14 Measurements were performed after an intracoronary bolus of nitrates (200 µg). The catheter was advanced while mounted over the previously used guidewire approximately 20 mm distal to the most distal border of the stent. The FFR was defined as the mean distal coronary artery pressure divided by the mean aortic pressure during maximum hyperemia achieved by the continuous IV infusion of adenosine at a rate of 140 µg/kg/min via the antecubital vein. In this study no vessels were assessed using intracoronary adenosine.

Statistical analysis

At baseline, the categorical variables were expressed as counts (percentage) and the continuous ones as mean ± standard deviation. To assess the independent predictors of post-PCI FFR, all the patient and vessel characteristics were primarily assessed through an univariate test using a mixed effects model (LME-model) with a random effect for the patients and a fixed effect for the post-PCI FFR. All variables were subsequently inserted in a multivariate LME-model using the enter method that resulted in all the significant independent predictors of post-PCI FFR values. A forest plot was developed to depict all variables with the corresponding 95% confidence intervals (95%CI). Beta (β) values show the average increase or decrease of the FFR values in the case of dichotomous variables or the increment per unit increase in the case of continuous variables. Statistical analyses were performed using the statistical software package R (version 3.5.1, packages: Hmisc, lme4 and nlme, RStudio Team, United States).

RESULTS

Demographic characteristics

The mean age was 64.6 ± 11.8 years and 72.5% were males. In 959 patients, at least, 1 lesion was measured with an overall 1165 successfully treated and measured lesions. The patient demographics and baseline characteristics are shown on table 1. Up to 70% of the patients presented with an acute coronary syndrome, and 18% had confirmed thrombus as seen on the angiography. Intravascular imaging modalities were used in 9.6% of the patients to guide the procedure. Overall, 1.4 ± 0.6 lesions were treated per patient and in 1.2 ± 0.5 lesions per patient the post-PCI FFR was successfully assessed. The average overall stent length per vessel was 29 mm ± 17 mm with an average stent diameter of 3.2 mm ± 0.5 mm.

Table 1. Baseline patient and vessel characteristics

Variable Total FFR-SEARCH registry
Patient characteristics (n = 1000)
Age 64.6 ± 11.8
Sex, male 725 (73)
Hypertension 515 (52)
Hypercholesterolemia 451 (45)
Diabetes 191 (19)
Smoking history 499 (50)
Previous stroke 77 (8)
Peripheral arterial disease 76 (8)
Previous myocardial infarction 203 (20)
Previous PCI 264 (26)
Previous CABG 57 (6)
Indication for PCI
 Stable angina 304 (30)
 NSTEMI 367 (37)
 STEMI 329 (33)
Vessel characteristics (n = 1165)
Lesion type
 A 125 (11)
 B1 233 (20)
 B2 379 (33)
 C 428 (37)
LAD 593 (51)
Bifurcation 138 (12)
Calcified 402 (35)
In-stent restenosis 39 (3)
Thrombus 214 (18)
Stent thrombosis 14 (1)
Ostial 97 (8)
CTO 42 (4)
Stenosis pre procedural 69 ± 22
Reference diameter pre procedural (mm) 2.6 ± 0.6
Length pre procedural (cm) 21 ± 11
MLD pre (mm) 0.9 ± 0.6
Predilatation 769 (66)
Postdilatation 691 (59)
Stenosis post procedural 44 ± 13
Reference diameter post procedural (mm) 2.7 ± 0.5
Length post procedural (cm) 24 ± 13
MLD post procedural (mm) 2.6 ± 0.5
Number of stents 1.4 ± 0.6
Stent length (cm) 29 ± 17
Stent diameter (mm) 3.2 ± 0.5
Mean post-PCI Pd/Pa 0.96 ± 0.04
Mean post-PCI FFR 0.91 ± 0.07

CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; FFR, fractional flow reserve; LAD, left anterior descending artery; MLD, minimum luminal diameter; NSTEMI, non-ST segment elevation acute myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; Pd/Pa, ratio of mean distal coronary artery pressure to mean aortic pressure; Values are expressed as mean ± standard deviation or no. (%).

The mean post-PCI FFR was 0.91 ± 0.07 and 7.7% of vessels had a post-PCI FFR ≤ 0.80. In the LME-model and after adjusting for independent predictors of post-PCI FFR, the left anterior descending coronary artery (LAD) as the measured vessel was the strongest predictor of post-PCI FFR (adjusted β = -0.063; 95%CI, -0.070 to -0.056; P < .0001) followed by the postprocedural MLD (adjusted β = 0.039; 95%CI, 0.015-0.065]; P = .002). Additionally, male sex, in-stent restenosis, CTO, and pre- and post-dilatation were negatively correlated with postprocedural FFR. Conversely, type A lesions, thrombus-containing lesions, postprocedural percent diameter stenosis, and stent diameter were positively correlated with postprocedural FFR. The R2 for the entire model was 53%. Figure 1 shows all significant and non-significant adjusted predictors included in the LME-model. Table 2 shows all adjusted and unadjusted predictors with corresponding β values and 95%CI. The most important predictors are shown on figure 2.

Figure 1. Forest plot of independent predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. Triangles indicate significant predictors while circles are indicative of non-significant predictors in the multivariate generalized mixed model to predict post-PCI FFR. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

Table 2. Predictors for post-PCI FFR

Variable Unadjusted Adjusted
P β(95%CI) P β(95%CI)
Patient characteristics
Male sex .214 -0.006 (-0.015 – 0.003) .001 -0.013 (-0.021 – -0.005)
Age (per 10 years) .976 0.000 (-0.03 – 0.03) .724 0.001 (-0.002 – 0.003)
Hypertension .013 -0.010 (-0.018 – -0.002) .610 0.002 (-0.006 – 0.010)
Hypercholesterolemia < .001 -0.019 (-0.027 – -0.011) .287 -0.004 (-0.012 – 0.004)
Diabetes < .001 0.018 (0.008 – 0.042) .081 -0.008 (-0.017 – 0.001)
Smoking history .007 0.020 (0.010 – 0.019) .054 0.007 (-0.0001 – 0.014)
Previous stroke .831 -0.002 (-0.017 – 0.013) .342 0.006 (-0.0007 – 0.019)
Peripheral arterial disease .022 -0.017 (-0.032 – -0.003) .460 -0.005 (-0.018 – 0.008)
Previous myocardial infarction .002 -0.016 (-0.026 – -0.006) .137 -0.008 (-0.019 – 0.003)
Previous PCI < .001 -0.016 (-0.025 – -0.007) .569 -0.032 (-0.014 – 0.008)
Previous CABG .896 -0.001 (-0.019 – 0.017) .166 -0.011 (-0.014 – 0.004)
Indication for PCI
 Stable angina < .001 -0.025 (-0.034 – -0.016) .563 -0.002 (-0.011 – 0.005)
 STEMI < .001 0.032 (0.025 – 0.041) .171 0.006 (-0.003 – 0.015)
Vessel characteristics
Lesion type
 A <.001 0.022 (0.009 – 0.035) .040 0.012 (0.0005 – 0.023)
 C .045 -0.008 (-0.016 – -0.0002) .172 -0.006 (-0.014 – 0.002)
LAD <.001 -0.070 ( -0.077 – -0.064) <.001 -0.063 (-0.070 – -0.056)
Bifurcation < .001 -0.024 (-0.036 – - 0.012) .883 0.001 (-0.010 – 0.011)
Calcified < .001 -0.025 (-0.033 – -0.017) .409 -0.003 (-0.011 – 0.005)
In-stent restenosis .006 -0.031 (-0.053 – -0.009) .007 -0.029 (-0.051 – -0.008)
Thrombus < .001 0.031 (0.021 – 0.042) .026 0.012 (-0.001 – 0.023)
Stent thrombosis .920 0.002 (-0.034 – 0.038) .362 0.019 (-0.022 – 0.060)
Ostial .181 -0.010 (-0.024 – 0.005) .165 -0.010 (-0.024 – 0.004)
CTO .002 -0.034 (-0.056 – -0.013) .036 -0.027 (-0.053 – -0.002)
Stenosis pre procedural (per 10%) <.001 0.007 (0.005 – 0.009) .105 0.004 (-0.0009 – 0.009)
Reference diameter pre procedural (mm) <.001 0.030 (0.023 – 0.037) .704 0.002 (-0.008 – 0.011)
Length pre procedural (cm) .900 -0.00002 (-0.004 – 0.003) .101 0.004 (0.0008 – 0.009)
MLD pre procedural (mm) <.001 -0.015 (-0.022 – -0.008) .638 0.004 (-0.014 – 0.023)
Predilatation <.001 -0.019 (-.027 – -0.011) .002 -0.012 (-0.020 – -0.005)
Postdilatation <.001 0.027 (-0.035 – -0.019) .015 -0.009 (-0.016 – -0.002)
Stenosis post procedural (per 10%) .077 0.003 (-0.0003 – 0.006) .029 0.01 (0.0007 – 0.01)
Reference diameter post procedural (mm) <.001 0.035 (0.027 – 0.042) .067 -0.022 (-0.045 – 0.002)
Length post procedural (cm) .312 -0.002 (-0.005 – 0.001) .086 0.001 (-0.0007 – 0.001)
MLD post procedural (mm) <.001 0.032 (0.024 – 0.040) .002 0.039 (0.015 – 0.063)
Number of stents <.001 -0.012 (-0.018 – -0.006) .620 -0.002 (-0.012 – 0.007)
Stent length (cm) <.001 0.019 (0.009 – 0.041) .286 -0.003 (-0.009 – 0.002)
Stent diameter (mm) <.001 0.033 (0.025 – 0.042) .026 0.012 (0.001 – 0.022)

Beta (β) values are indicative of the average increase or decrease of the FFR values in cases of dichotomous variables or the increment per unit increase in cases of continuous variables. 95%CI, 95% confidence interval; CABG, coronary artery bypass graft; CTO, chronic total coronary occlusion; FFR, fractional flow reserve; LAD, left anterior descending coronary artery; MLD, minimum lumen diameter; STEMI, ST-segment elevation myocardial infarction.

Figure 2. Forest plot of most important predictors of post-PCI FFR. Adjusted beta values with 95% confidence intervals. The figure includes all significant predictors from the multivariate generalized mixed model predicting post-PCI FFR except for categorical variables with beta values < 0.02. LAD, left anterior descending coronary artery; CTO, chronic total coronary occlusion; MLD, minimum lumen diameter.

DISCUSSION

This study is the largest report to this day of predictors of post-PCI FFR. Based on data derived from the FFR-SEARCH registry, we could identify several patient and procedural predictors of post-PCI FFR. These predictors will bring more in-depth interpretations of post-PCI FFR values to be able to identify correctly which vessels are prone to future events. At first, male gender appeared to be negatively correlated with postprocedural FFR. This finding is consistent with the findings of former studies that focused on the impact of gender on pre-PCI FFR measurements.6,11,15,16 Compared to females, males are known to have a lower prevalence of microvascular dysfunction.8,17 The concept of FFR is based on drug-induced maximal hyperemia to minimize microvascular resistance. Microvascular dysfunction may hamper this vasodilator response and consequently result in a dampened flow response and high FFR.15 Subsequently, on average, males have larger myocardial masses and myocardial perfusion territories compared to females.18,19 The importance of the latter is illustrated by the second and strongest predictor of post-PCI FFR in this study, the FFR measurements in the LAD. FFR values are associated with the myocardial mass and the outflow territory of the measured vessel. As such, the LAD—the vessel with the largest perfusion area—has previously been associated with lower pre- and postprocedural FFR values.20-22

The diameters of the stents implanted in the RCA are larger, on average, but the outflow territory of the LAD is even larger.23 This discrepancy between luminal dimensions and myocardial mass may explain why the optimal improvement of the FFR measurements in the LAD is difficult to achieve.23

Thirdly, larger stent diameters and larger post-PCI MLDs were associated with higher post-PCI FFR values. However, higher postprocedural percent stenosis was also associated with higher post-PCI FFR values. While these findings may seem contradictory, post procedural percent stenosis was not associated with post-PCI physiology in the DEFINE PCI study either.24

In the intravascular ultrasound substudy of the FFR-SEARCH registry, van Zandvoort et al. showed that evident signs of residual luminal narrowing including focal lesions, underexpansion, and malapposition were present in a significant amount of vessels with post-PCI FFR values ≤ 0.85. These findings were not readily apparent on the comprehensive quantitative coronary angiography.25 Percent diameter stenosis was 20% in the cohort of patients with post-PCI FFR values ≤ 0.85 and > 0.85.26

Together with the latter predictors of post-PCI FFR we identified several others. A dedicated analysis of 26 CTOs recently showed that postprocedural FFR values are typically low initially; however they seem to increase at the 4-month follow-up. The initially low post-PCI FFR values is thought to be due to the microvascular dysfunction of the recently opened vessel, a phenomenon that improves after several months.27 In-stent restenosis and pre- and postdilatation were associated with lower post-PCI FFR values. A finding that is consistent with former studies that showed that, in general, complex lesions are associated with lower post-PCI FFR values.20,21,26,28

Also, it was interesting to see the impact of clinical presentation on post-PCI FFR values in the study population in which most patients presented with acute coronary syndrome. Contrary to former studies that questioned the validity of invasive hyperemic physiological indices in patients with acute coronary syndrome, we could not confirm the impact of clinical presentation on post-PCI FFR values. However, the identification of a thrombus, that often occurs after a ruptured plaque in patients with acute coronary syndrome, was associated with significantly higher FFR values. Despite the restoration of epicardial flow by the PCI, a relatively large number of patients with STEMI have abnormal myocardial perfusion at the end of the procedure.29 This phenomenon is thought to be related to microvascular obstruction due to distal embolization (reperfusion injury) and tissue inflammation due to myocyte necrosis.30,31 The latter may explain the significantly higher post-PCI FFR values reported in patients presenting with thrombus-containing lesions compared to those without such lesions. Conversely, our findings also show that in patients without thrombus-containing lesions the post-PCI FFR may be a valuable diagnostic tool for the identification of patients at a high risk of future adverse cardiac events.

Limitations

This study was conducted with the Navvus microcatheter, a dedicated rapid exchange microcatheter with a mean diameter of 0.022 in that proved its utility in a slight but significant underestimation of the FFR compared to conventional 0.014 in pressure guidewires.32 That is why we cannot directly extrapolate the current findings to wire-based FFR devices.14 Based on the study protocol, no further action was taken in the presence of low post-PCI FFR values. The Target FFR and FFR REACT studies (NCT03259815 and NTR6711) will provide further information on post-PCI FFR and the potential of further actions to improve post-PCI FFR and clinical outcomes.33,34 These studies should also focus on the trade-off of potential benefits and harm when performing additional interventions in order to improve the final FFR values.

CONCLUSIONS

In this substudy of the FFR-SEARCH registry, the largest real-world post-PCI FFR registry conducted to this day, we identified sex, LAD vessels, postprocedural MLD, and several other independent predictors of postprocedural FFR.

CONFLICTS OF INTEREST

L.J.C. van Zandvoort received institutional research support from Acist medical Inc. J. Daemen received institutional research support from Pie Medical, ACIST Medical Inc., PulseCath, Medtronic, Boston Scientific, Abbott Vascular, Pie Medical and speaker and consultancy fees from PulseCath, Medtronic, ReCor Medical, ACIST Medical Inc. and Pie Medical. The remaining authors declared no conflicts of interest.

WHAT IS KNOWN ABOUT THE TOPIC?

  • – FFR has proven to be a useful technique to address coronary physiology and the hemodynamic significance of coronary segments pre- and post-intervention.
  • – Also, the FFR post-stenting has proven to be a strong and independent predictor of major adverse cardiovascular events at the 2-year follow-up.
  • – Unfortunately, at present, there is lack of data on independent predictors of post PCI FFR.

WHAT DOES THIS STUDY ADD?

  • – This study is the largest report to this day on predictors of post-PCI FFR.
  • – Based on data from the FFR-SEARCH registry, we could identify several patient and procedural predictors of post-PCI FFR.
  • – The main predictors included sex, LAD vessels, and postprocedural lumen dimensions. These predictors will help us interpret post-PCI FFR values and identify correctly the vessels that are prone to future events.

REFERENCES

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3. Wolfrum M, Fahrni G, de Maria GL, et al. Impact of impaired fractional flow reserve after coronary interventions on outcomes:a systematic review and meta-analysis. BMC Cardiovasc Disord. 2016;16:177.

4. Rimac G, Fearon WF, De Bruyne B, et al. Clinical value of post-percutaneous coronary intervention fractional flow reserve value:A systematic review and meta-analysis. Am Heart J. 2017;183:1-9.

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6. Sareen N, Baber U, Kezbor S, et al. Clinical and angiographic predictors of haemodynamically significant angiographic lesions:development and validation of a risk score to predict positive fractional flow reserve. EuroIntervention. 2017;12:e2228-e2235.

7. Baranauskas A, Peace A, Kibarskis A, et al. FFR result post PCI is suboptimal in long diffuse coronary artery disease. EuroIntervention. 2016;12:1473-1480.

8. Crystal GJ, Klein LW. Fractional flow reserve:physiological basis, advantages and limitations, and potential gender differences. Curr Cardiol Rev. 2015;11:209-219.

9. Ahmadi A, Leipsic J, Ovrehus KA, et al. Lesion-Specific and Vessel-Related Determinants of Fractional Flow Reserve Beyond Coronary Artery Stenosis. JACC Cardiovasc Imaging. 2018;11:521-530.

10. Tebaldi M, Biscaglia S, Fineschi M, et al. Fractional Flow Reserve Evaluation and Chronic Kidney Disease:Analysis From a Multicenter Italian Registry (the FREAK Study). Catheter Cardiovasc Interv. 2016;88:555-562.

11. Fineschi M, Guerrieri G, Orphal D, et al. The impact of gender on fractional flow reserve measurements. EuroIntervention. 2013;9:360-366.

12. Ryan TJ, Faxon DP, Gunnar RM, et al. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation. 1988;78:486-502.

13. Diletti R, Van Mieghem NM, Valgimigli M, et al. Rapid exchange ultra-thin microcatheter using fibre-optic sensing technology for measurement of intracoronary fractional flow reserve. EuroIntervention. 2015;11:428-432.

14. Menon M, Jaffe W, Watson T, Webster M. Assessment of coronary fractional flow reserve using a monorail pressure catheter:the first-in-human ACCESS-NZ trial. EuroIntervention. 2015;11:257-263.

15. van de Hoef TP, Meuwissen M, Escaned J, et al. Fractional flow reserve as a surrogate for inducible myocardial ischaemia. Nat Rev Cardiol. 2013;10:439-452.

16. Kim HS, Tonino PA, De Bruyne B, et al. The impact of sex differences on fractional flow reserve-guided percutaneous coronary intervention:a FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) substudy. JACC Cardiovasc Interv. 2012;5:1037-1042.

17. Reis SE, Holubkov R, Lee JS, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 1999;33:1469-1475.

18. Iqbal MB, Shah N, Khan M, Wallis W. Reduction in myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. Circ Cardiovasc Interv. 2010;3:89-90.

19. Lin FY, Devereux RB, Roman MJ, et al. Cardiac chamber volumes, function, and mass as determined by 64-multidetector row computed tomography:mean values among healthy adults free of hypertension and obesity. JACC Cardiovasc Imaging. 2008;1:782-786.

20. Nam CW, Hur SH, Cho YK, et al. Relation of fractional flow reserve after drug-eluting stent implantation to one-year outcomes. Am J Cardiol. 2011;107:1763-1767.

21. Doh JH, Nam CW, Koo BK, et al. Clinical Relevance of Poststent Fractional Flow Reserve After Drug-Eluting Stent Implantation. J Invasive Cardiol. 2015;27:346-351.

22. Agarwal SK, Kasula S, Hacioglu Y, Ahmed Z, Uretsky BF, Hakeem A. Utilizing Post-Intervention Fractional Flow Reserve to Optimize Acute Results and the Relationship to Long-Term Outcomes. JACC Cardiovasc Interv. 2016;9:1022-1031.

23. Kimura Y, Tanaka N, Okura H, et al. Characterization of real-world patients with low fractional flow reserve immediately after drug-eluting stents implantation. Cardiovasc Interv Ther. 2016;31:29-37.

24. Jeremias A, Davies JE, Maehara A, et al. Blinded Physiological Assessment of Residual Ischemia After Successful Angiographic Percutaneous Coronary Intervention:The DEFINE PCI Study. JACC:Cardiovasc Interv. 2019;12:1991-2001.

25. van Zandvoort LJC, Masdjedi K, Witberg K, et al. Explanation of Postprocedural Fractional Flow Reserve Below 0.85. Circ Cardiovasc Interv. 2019;12:e007030.

26. van Zandvoort LJC, Witberg K, Ligthart J, et al. Explanation of post procedural fractional flow reserve below 0.85:a comprehensive ultrasound analysis of the FFR Search registry. In Cardiovascular Research Technologies (CRT) Conference 2018 March 3-6;Washingtong DC, United States. 2018.

27. Karamasis GV, Kalogeropoulos AS, Mohdnazri SR, et al. Serial Fractional Flow Reserve Measurements Post Coronary Chronic Total Occlusion Percutaneous Coronary Intervention. Circ Cardiovasc Interv. 2018;11:e006941.

28. Pijls NH, Klauss V, Siebert U, et al. Coronary pressure measurement after stenting predicts adverse events at follow-up:a multicenter registry. Circulation. 2002;105:2950-2954.

29. Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction:a randomized controlled trial. JAMA. 2005;293:1063-1072.

30. Shah NR, Al-Lamee R, Davies J. Fractional flow reserve in acute coronary syndromes:A review. Int J Cardiol Heart Vasc. 2014;5:20-25.

31. Cuculi F, De Maria GL, Meier P, et al. Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2014;64:1894-904.

32. Pouillot C, Fournier S, Glasenapp J, et al. Pressure wire versus microcatheter for FFR measurement:a head-to-head comparison. EuroIntervention. 2018;13:e1850-e1856.

33. van Zandvoort LJC, Masdjedi K, Tovar Forero MN, et al. Fractional flow reserve guided percutaneous coronary intervention optimization directed by high-definition intravascular ultrasound versus standard of care:Rationale and study design of the prospective randomized FFR-REACT trial. Am Heart J. 2019;213:66-72.

34. Collison D, McClure JD, Berry C, Oldroyd KG. A randomized controlled trial of a physiology-guided percutaneous coronary intervention optimization strategy:Rationale and design of the TARGET FFR study. Clin Cardiol. 2020;43:414-422.

Corresponding author: Department of Cardiology, Room Rg-628, Erasmus University Medical Center, P.O. Box 2040. 3000 CA Rotterdam, The Netherlands.


E-mail address: (J. Daemen).

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.

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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2. 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.

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5. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128-1137.

6. Gandjour A, Bannenberg A, Lauterbach KW. Threshold volumes associated with higher survival in health care:a systematic review. Med Care. 2003;41:1129-1141.

7. Ross JS, Normand ST, Wang Y, et al. Hospital Volume and 30-Day Mortality for Three Common Medical Conditions. N Engl J Med. 2010;362:1110-1118.

8. Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized?The empirical relation between surgical volume and mortality. N Engl J Med. 1979;301:1364-1369.

9. Canto JG, Every NR, Magid DJ, et al. The volume of primary angioplasty procedures and survival after acute myocardial infarction. N Engl J Med. 2000;342:1573-1580.

10. Vakili BA, Kaplan R, Brown DL. Volume-Outcome Relation for Physicians and Hospitals Performing Angioplasty for Acute Myocardial Infarction in New York State. Circulation. 2001;104:2171-2176.

11. Srinivas VS, Hailpern SM, Koss E, Monrad ES, Alderman MH. Effect of Physician Volume on the Relationship Between Hospital Volume and Mortality During Primary Angioplasty. J Am Coll Cardiol. 2009;53:574-579.

12. Kim LK, Minutello RM, Feldman DN, et al. Association between transcath eter aortic valve implantation volume and outcomes in the United States. Am J Cardiol. 2015;116:1910-1915.

13. Badheka AO, Patel NJ, Panaich SS, et al. Effect of hospital volume on outcomes of transcatheter aortic valve implantation. Am J Cardiol. 2015;116:587-594.

14. Vemulapalli S, Carroll JD, Mack MJ, et al. Procedural Volume and Outcomes for Transcatheter Aortic-Valve Replacement. N Engl J Med. 2019;380:2541-2550.

15. Kaier K, Oettinger V, Reinecke H, et al. Volume–outcome relationship in transcatheter aortic valve implantations in Germany 2008–2014:a secondary data analysis of electronic health records. BMJ Open. 2018;8:e020204.

16. Goicolea Ruigómez FJ, Elola J, Durante-López A, Fernández-Pérez C, Bernal JL, Macaya C. Cirugía de revascularización aortocoronaria en España. Influencia del volumen de procedimientos en los resultados. Rev Esp Cardiol. 2020;73:488-494.

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. 2019. https://doi.org/10.1016/j.rec.2019.10.004.

21. Íñiguez Romo A, Bertomeu Martínez V, Rodríguez Padial L, et al. The RECALCAR project. Healthcare in the cardiology units of the Spanish National Health System, 2011 to 2014. Rev Esp Cardiol. 2017;70:567-575.

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.

23. Procedure-Specific Measure Updates and Specifications Report Hospital-Level 30-Day Risk-Standardized Mortality Measure Isolated Coronary Artery Bypass Graft (CABG) Surgery –Version 4.0. Yale New Haven Health Services Corporation/Center for Outcomes Research & Evaluation (YNHHSC/CORE). Centers for Medicare & Medicaid Services (CMS). 2017.

24. Society of Thoracic Surgeons'. Online STS Adult Cardiac Surgery Risk Calculator. Available online:http://riskcalc.sts.org/stswebriskcalc/#/. Consultado 20 Dic 2019.

25. Pope GC, Ellis RP, Ash AS, et al. Principal inpatient diagnostic cost group model for Medicare risk adjustment. Health Care Financ Rev. 2000;21:93-118.

26. Sharon-Lise T, Normand SLT, Glickman ME, Gatsonis CA. Statistical methods for profiling providers of medical care:issues and applications. J Am Stat Assoc. 1997;92:803-814.

27. Goldstein H, Spiegelhalter DJ. League tables and their limitations:statistical aspects of institutional performance. J Royal Stat Soc. 1996;159:385-443.

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.

33. Krumholz HM, Wang Y, Mattera JA, et al. An administrative claims model suitable for profiling hospital performance based on 30 day mortality rates among patients with an acute myocardial infarction. Circulation. 2006;113:1683-1692.

Corresponding author: Unidad de Cardiología Intervencionista, Hospital Clínico San Carlos, IdISSC, Prof. Martín Lagos s/n, 28040 Madrid, Spain.
E-mail address: (I.J. Núñez-Gil).

ABSTRACT

Introduction and objectives: The STENTYS Xposition S stent (STENTYS S.A, Paris, France) is the only self-apposing sirolimus- eluting stent available in the market. The stent features make it useful to treat challenging lesions with proximal-distal different vessel diameter, ectasia, high thrombus burden, bifurcation lesions including the left main coronary artery or vein grafts. We describe our own experience with the use of this stent and evaluate its efficacy and safety profile.

Methods: We included all consecutive patients treated with the STENTYS Xposition S from January 2018 to October 2019. All coronary lesions were quantified using QCA (quantitative coronary angiography).

Results: A total of 62 lesions in 50 patients were treated with the STENTYS Xposition S. The median age of the patients was 66 years (49-92). The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%). Ectasia and significant vessel diameter variance were the most common scenario in 72.6% of cases and bifurcation in the remaining 27.4% (2 of them in the left main coronary artery). Pre-dilatation was performed in 32 lesions (51.6%) and post-dilatation in 37 (59.7%). Angiographic success was achieved in all patients except for 1. At the median 373-day follow-up (256-439), 1 patient had an acute myocardial infarction 3 months after the percutaneous intervention and 1 patient died due to cardiac failure during admission. There were no cases of definitive stent thrombosis or target lesion revascularization.

Conclusions: The STENTYS Xposition S self-apposing stent showed good angiographic and clinical outcomes in our real-world experience.

Keywords: Self-apposing stent. Coronary lesion. Major adverse cardiovascular events.

RESUMEN

Introducción y objetivos: El stent STENTYS Xposition S (STENTYS S.A., París, Francia) es el único stent autoexpandible liberador de sirolimus disponible en el mercado. Sus características hacen que resulte útil en lesiones que presentan gran diferencia del diámetro del vaso proximal-distal, ectasia, alta carga de trombo o que se encuentren en bifurcaciones e injertos venosos. Describimos nuestra experiencia con el uso de este tipo de stent, evaluando su seguridad y eficacia.

Métodos: Se incluyeron todos los pacientes consecutivos tratados con STENTYS desde enero de 2018 hasta octubre de 2019. Todas las lesiones coronarias fueron cuantificadas por angiografía coronaria cuantitativa.

Resultados: Se trataron con STENTYS Xposition S 62 lesiones en 50 pacientes. La mediana de edad de los pacientes fue de 66 años (49-92). La clínica de presentación más frecuente fue el síndrome coronario agudo con elevación del segmento ST en 23 pacientes (46%). La ectasia coronaria y la gran diferencia en los diámetros proximal y distal a la lesión fue la indicación más frecuente para el uso de este tipo de stent, en el 72,6% de los casos, seguida del intervencionismo sobre bifurcación en el 27,4% de los pacientes (2 de ellos en el tronco coronario izquierdo). Se realizó predilatación en 32 lesiones (51,6%) y posdilatación en 37 (59,7%). Se logró el éxito angiográfico en todos los pacientes excepto en 1. Tras una mediana de seguimiento de 373 días (256-439), 1 paciente presentó infarto agudo de miocardio a los 3 meses y 1 paciente falleció durante el ingreso por insuficiencia cardiaca. No hubo ningún caso de trombosis definitiva del stent ni de revascularización de la lesión tratada.

Conclusiones: En nuestra experiencia de la vida real, el stent STENTYS Xposition S demostró un buen resultado angiográfico y clínico.

Palabras clave: Stent autoexpandible. Lesión coronaria. Eventos cardiovasculares adversos mayores.

Abbreviations LMCA: left main coronary artery. MACE: major adverse cardiovascular events.

INTRODUCTION

The STENTYS Xposition S (STENTYS S.A., Paris, France) is a sirolimus-eluting self-expanding nitinol stent designed to adapt its size to the vessel diameter and facilitate its complete apposition when exerting chronic strength towards the outside. It has long been confirmed that one of the most important factors of stent thrombosis is the incorrect apposition of the stent.1 The characteristics of this stent make it especially useful to revascularize acute coronary syndromes (ACS), especially ST-segment elevation acute coronary syndromes with lesions with high thrombotic load. Also, a potential benefit in ectatic coronary vessels and lesions with great proximal and the distal diameter mismatch has been confirmed, bifurcations (left main coronary artery [LMCA] included), and venous grafts.

The objective of this study was to assess the benefit of this stent in the routine clinical practice by analyzing the type of lesions this stent is used with and the immediate angiographic results and at the clinical follow-up.

METHODS

A cohort of consecutive patients treated with the STENTYS Xposition S stent was analyzed from January 2018 through October 2019 in a tertiary hospital where over 1000 percutaneous coronary interventions are performed each year. All coronary lesions were quantified using a quantitative coronary angiography. Lesions in vessels with changes in size (ectasia or proximal-distal diameter mismatch of the lesion), in a bifurcation, in the presence of a high thrombotic load or in a venous graft were analyzed. The interventional strategy to be followed, imaging modalities included, was left to the operator’s criterion. The clinical and follow-up data were obtained from the electronical clinical records of the healthcare system of our autonomous community. All events were defined in a standard way according to the Academic Research Consortium-2 (ARC-2) consensus document.2

The data analysis was conducted using the IBM SPSS 20.0 statistical software package. Continuous variables were expressed as mean ± standard deviation or median with interquartile range depending on whether they followed a normal distribution or not, respectively. Qualitative variables were expressed as relative percentage. The cumulative incidence of events at the follow-up was estimated.

RESULTS

From January 2018 through September 2019, 1692 percutaneous coronary interventions with stent implantation were performed. The STENTYS Xposition S stent was used in 50 patients (62 lesions). The patients’ median age was 66 years [49-92]. Eighty-eight per cent of the patients were males. Table 1 shows the clinical characteristic of patients and coronary lesions. The most common clinical presentation was ST-segment elevation acute coronary syndrome in 23 patients (46%) followed by non-ST-segment elevation acute coronary syndrome in 22 patients (44%), and stable angina in 5 patients (10%). According to the classification established by the American College of Cardiology/American Heart Association the most common type of lesion was B1 lesion (38.7%). The right coronary artery was the most frequently treated vessel in 33 patients (53.2%).

Table 1 Clinical characteristics of patients and angiographic characteristics of the lesions

Patients (n) 50
Age (years) 66.6 (49-92)
Males 44 (88%)
Arterial hypertension 33 (66%)
Body mass index (kg/m2) 27.9 ± 4.9
Dyslipidemia 32 (64%)
Diabetes mellitus 12 (24%)
Smoking 27 (54%)
Family history of ischemic heart disease 3 (6%)
Peripheral vasculopathy 3 (6%)
Atrial fibrillation 6 (12%)
Chronic pulmonary disease 6 (12%)
Kidney disease 6 (12%)
Stable angina pectoris 5 (10%)
NSTEACS 22 (44%)
STEACS 23 (46%)
Lesions (n) 62
Lesion length (mm) 14.56 ± 3.64
Reference diameter (mm) 4.1 ± 0.8
Percent stenosis. QCA (%) 70.08 ± 17
Location of the lesion
 Left main coronary artery 3 (4.8)
 Left anterior descending coronary artery 11 (17.7)
 Left circumflex artery 15 (24.2)
 Right coronary artery 33 (53.2)
Classification of the lesion
 A 0
 B1 24 (38.8)
 B2 19 (30.6)
 C 19 (30.6)
Indication for STENTYS
 Ectasia. Proximal-distal diameter mismatch 45 (72.6)
 Bifurcation 17 (27.4)
 Provisional stenting technique 15 (88.2)
 Double stent technique 2 (11.8)

NSTEACS, non-ST-segment elevation acute coronary syndrome; QCA, quantitative coronary angiography; STEACS, ST-segment elevation acute coronary syndrome.

Kidney damage: glomerular filtration rate < 60 mL/min/1.73 m2.

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

Ectasia and great proximal-distal diameter mistmatch at the lesion were the main indication for the use of this stent, in 72.6% of the lesions, with a mean vessel reference diameter of 4.1 mm ± 0.8 mm. A certain size was required to use this type of stent. The percutaneous coronary interventional on a bifurcation was the second most common indication, in 27.4% of the patients (2 of them on the LMCA). The most common type of bifurcation according to the Medina classification was 1-1-0, in 9 cases (52.9%). The secondary branch was damaged in 17% of the patients. The provisional stenting technique was the most widely used in 15 cases (88.2% of bifurcations) re-crossing to the secondary branch in 9 of them (60%). The dilatation of the secondary branch only occurred in 7 patients and only in the other 2 stents were implanted: one in a 0-1-1 bifurcation according to the Medina classification (minicrash technique) and the other in a 1-1-1 bifurcation according to this classification (TAP technique [T-and protrusion technique]). In both cases the STENTYS Xposition S stent was implanted in the main vessel and a non-self-apposing stent in the secondary branch (figure 1).

Figure 1. A: lesion with significant thrombotic load in the mid right coronary artery, which remains after thrombus aspiration. B: 3.5-4.5 mm × 27 mm Xposition S direct stent implantation. C: final angiographic result. D: significant stenosis in distal left main coronary artery. E: 3-3.5 mm × 27 mm Xposition S stent implantation from the proximal left main coronary artery to the left anterior descending coronary artery. F: angiographic result after postdilatation.

A high thrombotic load (Thrombolysis in Myocardial Infarction flow grade 4-5) was seen in 8 lesions. All of them in ectatic coronary vessels or with proximal-distal caliber mismatch. No case of venous graft treated with STENTYS was reported.

Predilatation occurred in 32 lesions (51.6%) and postdilatation in 37 (59.7%). The criterion used for postdilatation was angiography guided visual underexpansion. Intravascular ultrasound was performed in 15 patients (30%) before the implant. It was also used in 2 patients to optimize the percutaneous coronary intervention given the persistent stent underexpansion seen on the angiography. In both cases the minimum lumen area was > 5.5 mm2 with stent expansion > 80% and lack of incomplete apposition (defined as a strut separation of > 0.4 mm axial and 1 mm longitudinal) (figure 2). The optical coherence tomography was performed in a patient with ST-segment elevation acute coronary syndrome before and after the implant. It revealed a high thrombotic load with lack of immediate stent malapposition.

Figure 2. A: acute thrombotic occlusion in left circumflex artery with Thrombolysis in Myocardial Infarction flow grade 0. B: the intravascular ultrasound shows a great deal of thrombus in the lesions despite thrombus aspiration. C: implantation of 2 3.5-4.5 mm × 27 mm Xposition S overlapping stents. D: the intravascular ultrasound performed after stent implantation confirms the good angiographic results and lack of stent malapposition.

Angiographic success was achieved (with the stent properly implanted, a residual lesion ≤ 10%, and Thrombolysis in Myocardial Infarction flow grade 3) in all patients but 1, in whom stent implantation failed in a severely calcified LMCA lesion. In this case, predilatation was first attempted using a conventional balloon and then a cutting balloon on the LMCA severe distal lesion. A 3.3-4.5 mm × 22 mm STENTYS Xposition S stent was implanted with stent loss during retrieval, which remained braced to the guide catheter. Afterwards, a balloon-expandable drug-eluting stent was successfully implanted. The un-crimped stent was retrieved by crossing a guidewire from the femoral access through the stent distal struts. It was finally captured with a snare.

The median score obtained in the PRECISE-DAPT risk calculator (Predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) was 16.5 (7-25), and the median score obtained in the DAPT index (Dual antiplatelet therapy) was 1.15 (−2-4). Ticagrelor was the most commonly used P2Y12 inhibitor (58.1%). A 12-month course of dual antiplatelet therapy was prescribed in 48 patients (96%).

After a median follow-up of 373 days (256-439), 1 patient had an acute myocardial infarction 3 months after the intervention. However, the coronary angiography did not reveal coronary artery disease progression but confirmed the good results of the previous intervention. An 84-year-old woman died at admission due to heart failure. Three patients died of non-cardiac causes: 1 due to septic shock at admission, the other patient died 6 months after the percutaneous coronary intervention due to high-grade lymphoma, and the third one 4 months after the percutaneous coronary intervention due to lung cancer. No cases of definitive stent thrombosis or revascularization of the treated lesion were reported. No bleeding was seen either at the follow-up.

DISCUSSION

This type of stent is not widely used in our setting and we believe 2 are the reasons why. The first one is the need for a learning curve to know how to handle this implant. In former iterations of the device, the delivery system had some technical limitations like the jumping phenomenon that could occur right when the sheath was being released due to the elastic properties of nitinol. Unlike its predecessor (STENTYS sirolimus DES), the stent of the new STENTYS Xposition S system, is mounted over a semicompliant balloon and covered by a 0.0032 in-thick sheath. The reason for balloon inflation is not to dilate the stent, but to rupture the external sheath from the distal to the proximal border to allow a proper vessel-wall stent apposition. This has reduced the complexity of the release mechanism.3 However, we should remember that after the implant, the retrieval of both the balloon and the device sheath should be conducted with care by separating the guide catheter from the ostium to avoid deep intubation. The other reason that may explain why this stent is still not widely used can the augmented profile of the device and its rigidity, which both reduce its navigational and crossing capabilities compared to balloon-expandable stents.

Due to the characteristics of the stent and the experienced gained using it, the clinical settings where it can be useful are: ectatic vessel, since the stent reaches 6.5 mm of diameter with the device L size; proximal and distal diameter mismatch due to its adaptative capabilities to the vessel caliber; lesions with high thrombotic load, since this stent self-expanding capabilities facilitate its expansion until it reaches the vessel wall if thrombus reabsorption occurs, which avoids late stent malapposition; and bifurcations with ostial damage and 30º to 70° angles. The stent z-shaped mesh and the presence of small interconnectors facilitate re-crossing the lateral branch and disconnecting the struts without having to use the final kissing balloon technique. Thanks to its self-expanding capabilities, the unconnected struts cover the lateral branch ostium making the double stent technique unnecessary on many occasions.

In the studies published on former iterations of the device, the self-expanding stent proved superior to the balloon-expandable stent regarding better apposition. The randomized APOSSITION II clinical trial,4 conducted among patients with acute myocardial infarction, showed a lower rate of stent malapposition (defined as > 5% of struts per patient as seen on the optical coherence tomography) 3 days after the primary percutaneous coronary intervention. The APOSSITION IV clinical trial,5 also conducted among patients with acute myocardial infarction, showed a significantly lower percentage of stent malapposition at the 4-month follow-up in patients treated with self-expanding stents compared to patients treated with balloon-expandable stents (0.07% vs 1.16%; P = .002). However, no inter-group differences were found at the 9-month follow-up (0.43% vs 0.28%; P = .55) or in the rate of major adverse cardiovascular events (MACE). The clinical repercussions of this improvement in the early apposition of the stent has not been studied thoroughly. The APOSSITTION III trial6 showed that the use of STENTYS BMS in the percutaneous coronary intervention setting was associated with acceptable cardiovascular results at the 2-year follow-up, an overall rate of MACE of 11.2%, and a rate of stent thrombosis of 3.3%. We should mention that this study revealed a significant reduction of adverse events after the systematic implementation of a standard protocol (predilatation, implantation, postdilatation). The data available support the hypothesis of the need for mild postdilatation to avoid early complications probably because the stent does not have enough radial strength to achieve a proper expansion in rigid often calcified lesions, especially when predilatation is not fully effective. Therefore, postdilatation would avoid the incomplete expansion of the stent, which may increase the risk of stent thrombosis.7

Our study with the STENTYS Xposition S stent reached angiographic success in 98.4% of the cases, although we should remember that, from the anatomical point of view, they were not complex lesions (only 30% were type C lesion). Stent implantation failed in 1 severely calcified LMCA lesion; it is precisely in this type of lesions where its use is ill-advised, especially if predilatation is not effective.8

Regarding its use in bifurcations the studies published to this day have also discussed a former iteration of this device with good results. In the observational, multicenter, and prospective OPEN II trial,9 the rate of MACE at the 12-month follow-up was 13% (10.1% at 6 months). This rate of events was basically due to the need for revascularization of the treated lesion, while the rate of stent thrombosis at the 12-month follow-up was 1%. We should also mention that the kissing balloon technique was only used in 21.7% of the patients. Also, there were no significant differences in the rate of MACE between patients in whom the kissing balloon technique was used and those in whom it was not used.9

To this day, the only study published on the new STENTYS Xposition S model is the TRUNC, a prospective and multicenter study that assessed the efficacy and safety profile of this type of stent in the LMCA. Angiographic success was achieved in 96.6% of the patients and the overall rate of MACE was 8.3% at the 12-month follow-up, basically due to revascularization of the lesion treated in 5.4%.10 Here we should mention the preliminary results reported by the SIZING (Worldwide every-day practice registry assessing the Xposition S self-apposing stent in challenging lesions with vessel diameter variance) and WIN (World-wide registry to assess the STENTYS Xposition S for revascularization of coronary arteries in routine clinical practice) registries. Both registries confirm the safety and efficacy profile of the current iteration of the stent in the routine clinical practice.

Limitations

Our study has several limitations. Because of its retrospective, single-center nature and the limited number of cases involved, we cannot draw definitive conclusions on the device safety and efficacy profile. No intracoronary imaging modality was performed systematically to guide the implant, which may have been useful, especially the optical coherence tomography. However, we believe that this study is relevant due to the scarce evidence available on the last iteration of this stent.

CONCLUSIONS

In our series of lesions located in ectatic vessels or with proximal-distal diameter mismatch and in bifurcations, the STENTYS Xposition S stent is a good therapeutic alternative that achieves good immediate angiographic results and good mid-term clinical results.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Balloon expandable stents can have limitation in certain scenarios like in the revascularization of lesions with significant proximal-distal diameter mismatch, high thrombotic loads, and situations of bifurcations or in venous grafts. In these situations, the STENTYS Xposition S self-expanding stent can be especially useful.

WHAT DOES THIS STUDY ADD?

  • This type of stent is not widely used in our specialty. We described the experience of our own center with the STENTYS Xposition S stent. Despite the greater difficulty when trying to advance it and the complexity involved in its delivery, the rate of successful implantation was high. We should not forget that this type of stent is recommended in non-complex or non-calcified anatomical lesions. In general, predilatation is recommended to prepare the lesion and postdilatation to secure the proper expansion of the stent since the stent lacks the necessary radial strength. In our series of patients, the STENTYS Xposition S stent was safe and with a low rate of adverse cardiovascular adverse events at the 1-year follow-up.

REFERENCES

1. Cook S, Eshtehardi P, Kalesan B, et al. Impact of incomplete stent apposition on long-term clinical outcome after drug-eluting stent implantation. Eur Heart J. 2012;33:1334-1343.

2. Garcia-Garcia HM, McFadden EP, Farb A, et al. Standardized End Point Definitions for Coronary Intervention Trials:The Academic Research Consortium-2 Consensus Document. Circulation. 2018;137:2635-2650.

3. Lu H, IJsselmuiden AJ, Grundeken MJ, et al. First-in-man evaluation of the novel balloon delivery system STENTYS Xposition S for the self-apposing coronary artery stent:impact on longitudinal geographic miss during stenting. EuroIntervention. 2016;11:1341-1345.

4. Van Geuns R-J, Tamburino C, Fajadet J, et al. Self-expanding versus balloon-expandable stents in acute myocardial infarction:Results from the APPOSITION II study. Self-expanding stents in ST-segment elevation myocardial infarction. J Am Coll Cardiol Intv. 2012;5:1209-1219.

5. Van Geuns RJ, Yetgin T, La Manna A, et al. STENTYS self-apposing sirolimus-eluting stent in ST-segment elevation myocardial infarction:results from the randomised APPOSITION IV trial. EuroIntervention. 2016;11:1267-1274.

6. Koch KT, Grundeken MJ, Vos NS, et al. One-year clinical outcomes of the STENTYS Self-Apposing(R) coronary stent in patients presenting with ST-segment elevation myocardial infarction:results from the APPOSITION III registry. EuroIntervention. 2015;11:264-271.

7. Sato T, Kameyama T, Noto T, Nozawa T, Inoue H. Impact of preinterventional plaque composition and eccentricity on late-acquired incomplete stent apposition after sirolimus- eluting stent implantation:an intravascular ultrasound radiofrequency analysis. Coron Artery Dis. 2012;23:432-437.

8. Verheye S, Ramcharitar S, Grube E, et al. Six-month clinical and angiographic results of the STENTYS R self-apposing stent in bifurcation lesions. EuroIntervention. 2011;7:580-587.

9. Naber CK, Pyxaras SA, Nef H, et al. Final results of a self-apposing paclitaxel-eluting stent for the percutaneous treatment of de novo lesions in native bifurcated coronary arteries study. EuroIntervention. 2016;12:356-358.

10. Tamburino C, Briguori C, Jessurun GA, et al. TCT-329 prospective evaluation of drug eluting selfapposing stent for the treatment of unprotected left main coronary artery disease:1-year results of the TRUNC study. J Am Coll Cardiol. 2018;72:134-135.

Corresponding author: Servicio de Cardiología, Hospital Universitario Miguel Servet, Paseo Isabel la Católica 1-3, 50009 Zaragoza, Spain.
E-mail address: (A. Pérez Guerrero).

ABSTRACT

Introduction and objectives: patients with long, sequential and diffuse coronary lesions who undergo a percutaneous coronary intervention remain at a high risk of suffering cardiovascular events despite the improved safety and efficacy of the new drug-eluting stents. The objective of this study was to analyze the utility of SyncVision/iFR-guided revascularization (SyncVision version 4.1.0.5, Philips Volcano, Belgium) in this type of lesions.

Methods: Randomized, multicenter, controlled, and open-label trial designed to compare SyncVision/iFR-guided and angiography-guided revascularizations in patients with long, sequential or diffuse significant angiographic coronary stenosis (ClinicalTrials.gov identifier: NCT04283734). A total of 100 patients will be randomized (1:1, no stratification). The primary endpoint is the average length of the stent implanted. The secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure; and the presence of residual ischemia as seen on single-photon emission computed tomography at the 6-month follow-up. Patients will be followed for 12 months after the procedure.

Results: The trial is currently in the recruitment phase, and it has already recruited the first 7 patients. We expect to complete the recruitment phase by February 2021 and the follow-up by February 2022.

Conclusions: The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

Keywords: Diffuse coronary artery disease. Long coronary artery disease. Instantaneous wave-free ratio. SyncVision software.

RESUMEN

Introducción y objetivos: Los pacientes con lesiones coronarias largas, secuenciales o difusas tratadas percutáneamente continúan presentando un riesgo alto de eventos cardiovasculares a pesar de la mejoría de la seguridad y de la eficacia de los nuevos stents liberadores de fármacos. El objetivo de este estudio es analizar la utilidad del software Syncvision/iFR (Syncvision versión 4.1.0.5, Philips Volcano, Belgium) para guiar la revascularización en este tipo de lesiones.

Métodos: Estudio aleatorizado, multicéntrico, controlado y abierto para comparar la revascularización guiada por Syncvision/iFR respecto a la revascularización guiada por angiografía en pacientes con lesiones coronarias largas, secuenciales o difusas (identificador de ClinicalTrials.gov: NCT04283734). Serán incluidos 100 pacientes (aleatorización 1:1 no estratificada). El objetivo primario es la longitud total del stent implantado. Como objetivo secundario se ha establecido un combinado de muerte cardiaca, infarto de miocardio, trombosis definitiva o probable del stent, nueva revascularización de la lesión tratada en el procedimiento basal o nueva revascularización de la lesión analizada en el procedimiento basal, y la presencia de isquemia residual evaluada por tomografía computarizada por emisión de fotón simple a los 6 meses de seguimiento. El tiempo de seguimiento será de 12 meses tras el procedimiento índice.

Resultados: El estudio se encuentra actualmente en fase de reclutamiento, con los primeros 7 pacientes ya incluidos. Esperamos completar el reclutamiento en febrero de 2021 y el seguimiento en febrero de 2022.

Conclusiones: El estudio iLARDI es el primer estudio aleatorizado para la evaluación de la potencial utilidad de la revascularización guiada por Syncvision en lesiones coronarias largas, secuenciales y difusas.

Palabras clave: Lesiones coronarias difusas. Lesiones coronarias largas. Relación en el periodo instantáneo libre de ondas. Software Syncvision.

Abbreviations: PCI: percutaneous coronary intervention. iFR: instantaneous wave-free ratio. MACE: major adverse cardiovascular events.

INTRODUCTION

The physiological assessment of coronary lesions is a routine practice in contemporary cath labs and is strongly recommended by the European guidelines to guide the percutaneous coronary intervention (PCI) decision-making process.1 Unlike fractional flow reserve, the new instantaneous wave-free ratio (iFR) index allows us to analyze the physiological significance of each lesion and each coronary segment.2-5 This has led to the creation of the new and specific SyncVision software package (SyncVision version 4.1.0.5, Philips Volcano, Belgium), that shows the functional compromise of each lesion and predicts the expected iFR improvement after percutaneous treatment.3,4

Few observational studies published have analyzed the reduction in the length of the stent implanted compared to angiography-guided revascularization in long and diffuse coronary lesions.4,5 However, this reduction could be detrimental to the complete coverage of the plaque in this type of lesions, which has proven to be a predictor of major adverse cardiovascular events at the follow-up.6

The objective of our study is to analyze the utility of the iFR and SyncVision software to guide the PCI decision-making process in long, sequential, and diffuse coronary lesions.

METHODS

We have designed a multicenter, randomized, controlled, and open-label trial to compare SyncVision/iFR-guided revascularization to angiography-guided revascularization in patients with long, sequential or diffuse significant angiographic coronary lesions (ClinicalTrials.gov identifier: NCT04283734). All the variables that will be analyzed during the study are shown on table 1.

Table 1. Variables that will be analyzed during the study

Variable Expressed as
Personal medical history
1 Sex (men/women) no. (%)
2 Age (years) no. ± SD
3 Hypertension no. (%)
4 Diabetes mellitus no. (%)
5 Dyslipidemia no. (%)
6 Former smoker no. (%)
7 Previous ischemic cardiomyopathy no. (%)
8 Previous revascularization no. (%)
9 Atrial fibrillation no. (%)
10 Heart failure no. (%)
11 Previous stroke no. (%)
12 Peripheral artery disease no. (%)
13 Previous significant bleeding no. (%)
14 Basal hemoglobin levels (mg/dL) no. ± SD
15 Basal creatinine levels (mg/dL) no. ± SD
16 Left ventricular ejection fraction (%) no. ± SD
17 Clinical presentation (stable angina/NSTEMI/STEMI) no. (%)
18 Baseline ultra-sensitive troponin levels (ng/L) no. ± SD
Procedural data
19 Arterial access (radial/femoral/other) no. (%)
20 P2Y12 inhibitor preload no. (%)
21 IIb/IIIa inhibitor use during the procedure no. (%)
22 Multivessel disease no. (%)
23 Syntax score no. ± SD
24 Randomized vessel (LAD/LCx/RCA/other) no. (%)
25 Vessel lesion length (mm) no. ± SD
26 Vessel reference diameter (mm) no. ± SD
27 Vessel stenosis (%) no. ± SD
28 Total stent length as seen on the angiography (mm) no. ± SD
29 Total length of the stent implanted (mm) no. ± SD
30 Differences between stent length estimated and implanted (mm) no. ± SD
31 Stent diameter (mm) no. ± SD
32 Optimal angiographic result (final TIMI III flow, absence of dissections and residual stenosis < 20%) no. (%)
33 Contrast (milliliters) no. ± SD
34 Use of intracoronary imaging no. (%)
35 Use of rotablation no. (%)
36 Procedural complications (no reflow/ dissection/acute vessel closure/perforation/other) no. (%)
37 Baseline iFR in the intervention group no. ± SD
38 Diffuse improvement of iFR by SyncVision no. (%)
39 Estimated stent length to achieve an iFR > 0.89 (mm) no. ± SD
40 Final iFR in the intervention group no. ± SD
41 Need to implant an additional stent no. (%)
Hospitalization data
42 Bleeding complications no. (%)
43 Ultra-sensitive troponin peak levels (ng/L) no. ± SD
44 Periprocedural myocardial infarction no. (%)
45 In-hospital death no. (%)
46 In-hospital stroke no. (%)
47 In-hospital stent thrombosis no. (%)
Pharmacological treatment at discharge
48 Aspirin no. (%)
49 P2Y12 Inhibitor (no/clopidogrel/ticagrelor/prasugrel) no. (%)
50 Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban) no. (%)
51 Beta-blockers no. (%)
52 ACEI/ARB/ARNI no. (%)
53 Calcium antagonists no. (%)
54 Other anti-ischemic drugs no. (%)
Follow-up visits (after 3, 6, and 12 months)
55 Bleeding complications no. (%)
56 Dual antiplatelet therapy no. (%)
57 Anticoagulation (no/acenocumarol/rivaroxaban/ dabigatran/apixaban/edoxaban) no. (%)
58 Probable or definitive stent thrombosis no. (%)
59 Spontaneous myocardial infarction no. (%)
60 New target lesion revascularization no. (%)
61 New target vessel revascularization no. (%)
62 Revascularization of other vessel no. (%)
63 Death no. (%)
64 Cause of death (cardiac/non cardiac) no. (%)
65 Stroke no. (%)
66 Beta-blockers no. (%)
67 ACEI/ARB/ARNI no. (%)
68 Calcium antagonists no. (%)
69 Other anti-ischemic drugs no. (%)
70 Residual angina (I/II/III/IV) no. (%)
71 Withdrawal from the study no. (%)
72 Lost to follow-up no. (%)

ACEI, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor blocker and neprilysin inhibitor; LAD, left anterior descending coronary artery; LCx, left circunflex artery; RCA, right coronary artery; SD, standard deviation; TIMI, Thrombolysis in Myocardial Infarction. NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Inclusion and exclusion criteria

Patients with the following criteria are being included: a) patients > 18 years old who require percutaneous coronary treatment due to ischemia (silent, stable angina or acute coronary syndrome); b) presence of a vessel with sequential lesions separated by < 10 mm from each other with a total lesion length > 25 mm and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 segment; or a coronary segment > 30 mm with diffuse disease, and a percent diameter stenosis > 60% (as seen on the quantitative coronary angiography assessment) in, at least, 1 region; c) baseline iFR ≤ 0.89 distal to a potentially randomizable lesion.

We have stablished the following exclusion criteria: a) patients with acute coronary syndrome with non-optimal results in the culprit vessel (final Thrombolysis in Myocardial Infarction (TIMI) flow grade < III, non-reflow phenomenon during treatment, residual coronary dissection, lost or compromise of a major side branch); b) patients with acute coronary syndrome and left ventricular ejection fraction < 45%; c) life expectancy < 12 months; d) patients with severe aortic stenosis; e) contraindication for dual antiplatelet therapy for at least 12 months; f) presence of significant thrombocytopenia (< 10 x 109/L); g) patients with an indication for bypass surgery according to the heart team; h) pregnancy; i) inability to understand the informed consent.

Endpoints

The study primary endpoint is the reduction of the average length of the stent implanted in the SyncVision-guided group measured in millimeters (mm) compared to the angiography-guided group. The study secondary endpoint is a composite of cardiac death, myocardial infarction, definitive or probable stent thrombosis, new target lesion revascularization or new target lesion failure (major adverse cardiovascular events [MACE]); and the assessment of residual ischemia through single-photon emission computed tomography at the 6-month follow-up.

Procedure

After the diagnostic phase, the use of intracoronary vasodilators is mandatory to exclude possible coronary spasms. Lesions will be assessed by 2 expert operators (prior to randomization) to determine the coronary segment to treat when the revascularization is angiography-guided based on current routine clinical practice. Afterwards, the iFR will be determined at baseline. If the obtained iFR is ≤ 0.89, patients will be randomized to the angiography-guided revascularization group (the control group) or to the iFR pullback-guided revascularization group using the SyncVision software (figure 1). Intracoronary imaging can be used in both groups based on the operator’s criteria to optimize the angiographic result.

Figure 1. Summary of randomization, treatment targets, and follow-up of the iLARDI study. iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.

In the intervention group, a pressure wire (Verrata pressure guidewire, Philips Volcano, Belgium) will be inserted trough a guide catheter towards the vessel ostium to normalize the pressure between the aortic and the vessel ostium. Secondly, the pressure wire will be advanced distally to the lesion. Under stable hemodynamic conditions (without the administration of vasodilators), we will determine the baseline iFR. Afterwards, the wire will be removed under continuous fluoroscopy, and in the same projection. If the iFR at the vessel ostium is 1 ± 0.02, the absence of drift will be confirmed and an angiogram in the same angiographic position will be performed. The SyncVision software can recognize the vessel analyzed and identify the physiological contribution of every lesion and every segment, predicting the improvement of the iFR after treatment. The iFR improvement is depicted as yellow dots. Each yellow dot represents an iFR improvement of 0.01 if that zone was percutaneously treated. The accumulation of many yellow dots suggests that the contribution of that lesion to physiological compromise is high. After performing the physiological assessment of each lesion, the operator would have to treat the minimum segment needed to achieve an iFR of 0.90. Cases without an accumulation of dots have been considered as physiological diffuse disease (defined as the presence of < 20% of the total number of dots) in the coronary segment physiologically assessed. Those cases will be medically treated due to the theoretical absence of benefit of the percutaneous treatment (figure 2 and figure 3).

Figure 2. Flowchart of technical treatment details of patients randomized to the intervention group.

* We consider as optimization the postdilatation of the previous stented area if an in-stent accumulation of yellow dots is seen; or the percutaneous treatment of a new segment with physiological compromise not seen in the baseline iFR-pullback study. iFR, instantaneous wave-free ratio.

Figure 3. Image of iFR co-registration using the SyncVision software in a patient included in the study and randomized to the intervention group with a diffuse lesion in the left anterior descending coronary artery, and the physiological contribution of every segment. The estimated length of the stent to achieve an iFR > 0.89 is 50.6 mm.

Follow-up

Patients will be followed either through phone calls or physical examination at the 3, 6 and 12-month follow-up. At the 6-month follow-up a stress single-photon emission computed tomography (physiological or pharmacological) will be performed in all patients. The composite of cardiovascular death, definitive or probably stent thrombosis, new target lesion failure or new target lesion revascularization will be considered as MACE.

Quantitative coronary measurements

Quantitative coronary measurements will be performed using a validated system (CAAS system, Pie Medica Imaging, Netherlands). The measurements analyzed will be the vessel reference diameter, the vessel minimal lumen diameter, and the percentage of stenosis. All measurements will be taken at baseline and after the PCI.

Statistical analysis

Regarding the statistical analysis, quantitative variables will be expressed as mean ± standard deviation and qualitative variables as absolute numbers and percentages. To determine the relationship among quantitative variables, we will be using the paired Student t test for paired data. To determine the relationship among the qualitative ones, we will use the chi-squared test. In all cases, differences will be considered significant with P values < .05. We will be using the IBM SPSS Statistics software package (version 24.0 for Macintosh, SPSS Corp., United States). To calculate the sample size, we have performed a retrospective analysis of the last 20 patients who were treated at our centre and showed a sequential or diffuse lesion in the coronary vessel analyzed from the iFR-pullback study. The mean length of the stent implanted was 43 ± 9 mm and the reduction of stent length was 12 ± 8 mm on the angiographic analysis. With these data, we have stablished an expected length reduction of 15 mm. The calculated sample size to achieve the primary endpoint with an 80% confidence level and a 5% margin of error was 100 patients.

RESULTS

The recruitment of patients started back in February 2020. After 1 month, we have included the first 7 patients. We expect to complete the recruitment by February 2021 and the follow-up by February 2022.

DISCUSSION

To our knowledge, this randomized study is, the first one to assess the potential benefits of using the SyncVision software in long, sequential or diffuse coronary lesions. Currently, the study is in the recruitment phase and the first patients have already been recruited.

The iFR has proven to be useful in the PCI guide decision-making process.7,8 However, the evidence supporting the use of SyncVision is scarce and controversial in long, sequential or diffuse lesions. On the one hand, the software allows us to know the coronary segments with the highest physiological compromise. This allows us to revascularize only those segments that immediately improve the physiological result with a potential reduction of the length of the stent implanted, which happens to be a predictor of MACE at the follow-up.9 On the other hand, it’s possible that even if we obtain a good immediate physiological result and a reduction of the stent length implanted we won’t be fully covering the plaque in some lesions or coronary segments, which has also proven to be a predictor of MACE.6

A limitation of the study is the sample size, enough to achieve the primary endpoint, but probably inadequate to see differences in MACE. However, we think that it can provide an early insight on the utility of iFR pullback study to guide the PCI decision-making process in this type of lesion. Also, it can be a hypothesis-generator study for future larger-scale studies to show benefits in terms of clinical events reduction.

For these reasons, we believe that the iLARDI is an interesting study that will shows us the potential benefit of SyncVision to guide the PCI decision-making process in long, sequential or diffuse coronary lesions. We intend to complete the results by February 2022.

CONCLUSIONS

The iLARDI study is the first randomized trial to assess the potential utility of SyncVision-guided revascularization in long, sequential and diffuse coronary lesions.

FUNDING

Funds from the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI) have been used to pay for the liability insurance associated with clinical research.

CONFLICTS OF INTEREST

F. Hidalgo, S. Ojeda, and J. Segura received personal fees from Philips Volcano. M. Pan received minor fees from Abbott, Philips Volcano, and Terumo. The remaining authors declared no conflicts of interest whatsoever.

WHAT IS KNOWN ABOUT THE TOPIC?

  • The physiological assessment of coronary lesions is a routine practice in the cath lab. The iFR and the SyncVision software allow us to know what is the individual contribution of every coronary lesion and contribute in the PCI decision-making process. However, to our knowledge, no randomized studies have been published on the utility of their use in long, sequential and diffuse coronary lesions.

WHAT DOES THIS STUDY ADD?

  • The iLARDI study will show the potential utility of SyncVision/iFR-guided revascularizations in this type of lesions (long, sequential and diffuse coronary lesions) regarding the reduction of the stent length and the potential reduction of major adverse cardiovascular events at the follow-up.

REFERENCES

1. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87-165.

2. Kim H-L, Koo B-K, Nam C-W, et al. Clinical and physiological outcomes of fractional flow reserve guided percutaneous coronary intervention in patients with serial stenosis within one coronary artery. JACC Cardiovasc Interv. 2012;5:1013?1018.

3. Nijjer SS, Sen S, Petraco R et al. The Instantaneous Wave-Free Ratio (iFR) pullback:a novel innovation using baseline physiology to optimise coronary angioplasty in tandem lesions. Cardiovasc Revasc Med. 2015;16:167-171.

4. Nijjer SS, Sen S, Petraco R et al. Pre-Angioplasty Instantaneous Wave-Free Ratio Pullback Provides Virtual Intervention and Predicts Hemodynamic Outcome for Serial Lesions and Diffuse Coronary Artery Disease. JACC Cardiovasc Interv. 2014;7:1386-1396.

5. Kikuta Y, Cook CM, Sharp ASP et al. Pre-Angioplasty Instantaneous Wave-Free Ratio Pullback Predicts Hemodynamic Outcome In Humans With Coronary Artery Disease. Primary Results of the International Mul-ticenter iFR GRADIENT Registry. JACC Cardiovasc Interv. 2018;11:757-767.

6. Costa MA, Angiolillo DJ, Tannenbaum M et al. Impact of Stent Deployment Procedural Factors on Long-Term Effectiveness and Safety of Sirolimus-Eluting Stents (Final Results of the Multicenter Prospective STLLR Trial). Am J Cardiol. 2008;101:1704-1711.

7. Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS et al. Use of instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med. 2017;376:1824-1834.

8. Gotberg M, Crhistiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med. 2017;376:1813?1823.

9. Coner A, Cicek D, Akinci S, et al. Mid-term clinical outcomes of new generation drug-eluting stents for treatment of diffuse coronary artery ||aadisease. Turk Kardiyol Dern Ars. 2018;46:659-666.

Corresponding author: Servicio de Cardiología, Hospital Universitario Reina Sofía, Avenida Menéndez Pidal 1, 14004 Cordoba, Spain.
E-mail address: (F. Hidalgo Lesmes).

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