Coração dos Pacientes ? TAVI : the Game Changer for the Future ! Are We Ready to Implant Hope into Patient ’ s Heart ?

Amanda Rodrigues de Oliveira Siqueira1, Sara Rodrigues de Oliveira Siqueira1, Jose Armando Mangione2, Salvador André Bavaresco Cristóvão2, Maria Fernanda Zuliani Mauro2, Fernando Augusto Alves da Costa3  1Universidade Anhembi Morumbi – Curso de Graduação em Medicina – São Paulo, SP – Brasil 2Hospital Beneficência Portuguesa de São Paulo – Setor de Cardiologia Hemodinâmica – São Paulo, SP – Brasil 3Hospital Beneficência Portuguesa de São Paulo – Setor de Cardiologia – São Paulo, SP – Brasil


Introduction
Degenerative calcified aortic stenosis (AoS) affects mostly the elderly population, present in 29.0% of individuals aged >65.This rate increases with age and the disease occurs most frequently in males 1 .Symptoms of AoS are generally progressive, evolving into the classical triad of angina, heart failure and syncope.At this stage, if patients are not subjected to a final treatment, the mortality rate may reach 50.0% in the first two years after the onset of symptoms 1,2 .
It is known that surgical aortic valve replacement (SAVR) is the standard treatment of symptomatic AoS.However, elderly patients with severe symptomatic AoS have significant comorbidities and conventional SAVR with cardiopulmonary bypass may be associated with unacceptable risk of perioperative morbidity and mortality 3,4 .
The therapeutic options for these patients are limited and isolated clinical therapy offers no survival benefit.Minimally i n v a s i v e a l t e r n a t i v e s s u c h a s transcatheter aortic valve implantation (TAVI), have been developed for these patients 2,3 .
The current consensus is that TAVI be reserved for patients with indications for standard SAVR, but defined as of high operative risk, and when surgery is contraindicated 1 .Exceptionally, moderate-risk patients may be eligible.However, the definition of candidates f o r T A V I i s c o m p l e x a n d v e r y challenging 1,5 .
Although it is considered effective and safe, some aspects inherent in the procedure are not yet fully established.The multicenter study PARTNER I 2 (Edwards SAPIEN) and the CoreValve High-Risk Study 6 (Medtronic) compared SAVR with TAVI, demonstrating higher incidence of vascular complications and stroke associated with the percutaneous treatment 2,6 .However, in the Medtronic pilot test, the one-year mortality rate was lower in the TAVI group than in the surgery group 6,7 .
However, the adoption of TAVI should be justified and should ensure long-term performance.Therefore, it is critical to study the population with indication and the complications involved in the procedure.
The objective of this study was to analyze the characteristics of patients with severe AS undergoing TAVI and investigate the associated complications, describing the experience of a single center with its first procedures.

Methods
Retrospective non-randomized cross-sectional clinical trial was conducted on high-risk patients with severe AoS from November 2008 to November 2014 at Hospital Beneficência Portuguesa de São Paulo.
This study has been approved by the Research Ethics Committee of the institution under no.209.341.Since it consists in the analysis of medical records, the Informed Consent Form was not necessary.
To define severity, the following were considered: aortic valve area <1 cm² and/or mean aortic gradient > 40 mmHg and/or presence of symptoms related to the disease 1 .
Inoperable patients or those with significant risk factors for SAVR 1 were considered eligible for the percutaneous procedure.To determine surgical risk, the instruments of EuroSCORE I/II and STS score were used by setting as values greater than 20%, 5% and 10%, respectively, as high risk 5 .
Pre-procedure protocols including clinical history, laboratory and specific tests (electrocardiography, echocardiography, computed tomography and/or angiography) have been examined.Data analysis was conducted using the statistical software SPSS 2.0.The continuous variables were expressed as mean±standard deviation and categorical variables were expressed in percentage analyzed by the chi-square test and, as appropriate, Fisher's correction.
Associations between continuous variables were assessed by Student's t-test and when correlation between the two was assessed, linear regression analysis was conducted.A p value ≤0.05 was considered significant.
Potential predictors evaluated for the success of the procedure were the clinical variables and pre-procedural, periprocedural and post-procedural images.
The success of the in-hospital device/procedure and complications were studied according to the concepts of Valve Academic Research Consortium (VARC) 1 and 2 8 .Periprocedural and/or immediate complications (<7 days), early complications (within 30 days) and late complications, including mortality, have been evaluated, also considering the outpatient follow-up of patients.

Results
The study population included 47 patients, including 22 (46.8%)males, whose characteristics are shown in Tables 1 and 2.
The average age of the population was 80.0±7.0.All patients presented the definition criteria for severe AoS.Only 1 patient had porcelain aorta.On average, the surgical risk was high, with postoperative mortality ranging from 20.1±18.8% and 16.07±13.71%(EuroSCORE I and STS score, respectively).Echocardiography showed left ventricular ejection fraction (LVEF) 66.0±10.6%(<50% in 4 patients).The aortic valve area was 0.6±0.2cm 2 and the average gradient ranged from 50.0±15.2mmHg.On angiography, in all patients, the femoral-iliac anatomy was favorable (Table 2).
The characteristics of the procedure and the clinical evolution of patients are shown in Table 3.In all cases, the access route was transfemoral.The most used bioprosthesis was CoreValve (55.3%) compared to SPXT (44.7%).
No death occurred during the procedure.Periprocedural complications were observed in 12 (25.53%)patients, especially those related to heart rhythm disorder (Table 4).Four complete atrioventricular blocks (CHB) were evidenced during the procedure.In three of them, permanent pacemaker (PPM) was implanted.
Likewise, the main post-procedural complication was the permanent pacemaker implantation.Complication with acute renal failure (ARF) was observed in 5 patients.For this reason, there was an attempt to correlate this outcome (assessing creatinine clearance estimated by the Cockroft & Gault formula) with the volume of contrast used; however, the data obtained from linear regression did not confirm this association (r=0.18)(Table 3).
Mortality rate related to TAVI was 17.0% (n=8).The causes of death associated with the procedure and the event period are shown in Table 4.During follow-up, 7 patients died from unrelated events, 5 of which died after more than two years and the other deaths occurred after one year of follow-up.The main cause of deaths was infection (pneumonia evolving to septic shock, septic shock due to intestinal obstruction, ARF post-sepsis), upper gastrointestinal bleeding and accidental fall with traumatic head injury.
Due to the small number of deaths and the small study population, the type of death was not considered; only death from all causes.
The deaths were associated with older patients: 83.47±7.425years (p=0.029)and the STS score for mortality was higher in patients who evolved to death (24.0±18.4%;p=0.047), unlike the EuroSCORE, which did not present this type of correlation.Binary logistic regression analysis was conducted to assess, altogether, potential predictors of mortality.Despite the association between prior carotid disease and death in this population, p=0.008 (odds ratio = 0.26 (CI95: 0.15-0.42), in the logistic regression, this variable did not influence the outcome.
Regarding the investigation of other comorbidities, due to the small number of deaths (events), it was not possible to find independent predictors of mortality.

Discussion
Patients with severe AoS, regardless of comorbidities, present high risk of death if they do not undergo definitive treatment 9,10 .It is known that advanced age and/or comorbidities are recurring factors of surgical intractability because they are considered important predictors of operative risk and survival in cardiac surgery.Age alone was a case of surgery refusal by physicians in approximately 32.0% of patients with AS in a European study and in about 62.0% in an American study 11,12 .
Surgical correction is a very aggressive procedure, with low application under these conditions, due to the unfavorable and even unacceptable outcomes 13 .TAVI, has emerged as alternative treatment for these patients 1,3 .
The EuroSCORE and STS score algorithms are also used to select patients to percutaneous treatment.No specific score is well established as a predictor of mortality, but the EuroSCORE II has been more used to assess the risk of mortality both in relation to surgical treatment and percutaneous risk 5,14 .
In this study, the EuroSCORE II stratified patients with score ≥5 as high surgical risk.The mean found was 8.95±6.53%.
General anesthesia was the most used technique (n=31; 81.57%), but this data was obtained from only 38 patients.
There are no reports of significant differences in results during and after the procedure between the local/ regional and general anesthesia groups in this type of treatment 15 .
The prostheses used were CoreValve (55.3%) and Edward SAPIEN-XT (44.7%).One of the important aspects for a successful TAVI involves the ability to ensure an access route for deployment of the valve.There are several access routes described, but the transfemoral access route has been the most used one and it is the access of choice for interventional cardiologists, except for cases of unfavorable anatomy of the femoral and iliac artery 16 .In all patients in this study, the transfemoral access route was chosen, with 95.7% success rate.There were no deaths during the procedure.
A recent meta-analysis released the three leading complications associated with the percutaneous procedure: CHB with PPM deployment (13.1%), vascular complications (10.4%) and ARF (4.9%) 17 .However, the demographic characteristics of patients, comorbidities, type of prosthesis and the access route should be considered, as well as the experience of the interventional cardiologist in the analysis of these results.
The need to deploy PPM through CHB may still vary from 10.0-50.0% in patients under post-TAVI follow-up.This is due to the proximity of the aortic annulus to the conduction system of the His bundle and atrioventricular node.According to literature data, the incidence of CHB is higher in the CoreValve implant (30.0%) compared to SPXT (5.0%) 18 .
Similarly to the global experience, PPM implant was the main complication (periprocedural and post-procedural) observed in this study, with indication in 9 (19.14%)patients during hospitalization, just like the CoreValve implant accounted for 57.15% of CHB requiring PPM during hospitalization.
Similarly, post-TAVI bleeding is a common vascular complication and is associated with increased mortality in one year, with an increased risk of stroke and ARF.Specific scores are still required to identify patients who are at increased risk of vascular complications associated with TAVI, as well as to guide the choice of the most appropriate route of access each patient 19,20 .
In the population studied, two cases had higher bleeding with cardiac tamponade, later evolving to early death.Although the femoral artery dissection is a frequent vascular complication (12.0-30.0%) 20, no patient presented this event, but 1 patient had iliac artery obstruction evolving to aortic dissection type B and immediate death.
Double-anti platelet aggregation is recommended before the procedure and continued with the medications for three to six months 21 .The patients in this study received loading dose (300 mg each) and maintenance dose (100 and 75 mg/day, respectively) of aspirin and clopidogrel for six to 12 months.Unfractionated heparin was administered as per protocol to achieve activated partial thromboplastin time >250 seconds before the procedure.
Development of stroke is still of deep concern, frequently occurring during the procedure or immediately after 22 .
In the population studied, only 1 patient developed transient ischemic attack during immediate post-TAVI outcome.It should be noted that the patient was nonagenarian with DM and atrial fibrillation.There is a downward trend in the risk of stroke after TAVI due to technological advances of the valves, the better selection of patients and the surgeon's experience 23 .Perhaps the adequate anticoagulation and the absence of other risk factors have also positively affected the absence of major cerebrovascular events in this study.
According to world records, the percutaneous procedure is strongly associated with increased risk of ARF.The incidence rate ranges from 8.3-29.0% in several studies and is related to mortality, especially in follow-up at day 30 and at year 1 24 .In this study, 5 (10.6%) patients had this acute complication, but there was no correlation between volume of contrast and development of post-TAVI ARF and in only one patient the event was associated with immediate death.
The irregular surfaces of a calcified aortic valve can greatly hinder a seal between the prosthesis and the tubular ring, increasing the chances of periprosthetic regurgitation.Choosing the prosthesis size, the aortic ring size, assessing the leaflets calcification degree and post-dilatation are feasible strategies to prevent leakage.New valves are being developed to seal the aortic annulus more appropriately 25 .
The authors have described an incidence of 15.0-20.0% of moderate/severe aortic regurgitation (AR) in the follow-up of patients undergoing TAVI.The medical community is aware that AR after the procedure is a predictor of long-term mortality, especially in degrees ≥2 25 .This study found that 1 patient developed severe AR requiring surgery and subsequent death in the followup at day 30.
As for the death rate, of 47 patients evaluated, 15 patients progressed to death, 8 (17.0%) of which were directly associated with the procedure.This rate is similar to what the literature shows, around 5.0-18.0%at day 30 4,26 .
During hospitalization and follow-up, the mortality rate directly associated with the procedure was 50.0%(n=4) in the first seven days; 3 (37.5%)from one week to 30 days; and 1 (12.5%) from 30 days to 1 year.The deaths were mainly related to vascular and cardiac complications according to other studies 4,6 .Most late deaths is due to comorbidities rather than complications with the prosthesis 2,6,26 .In this study, this has also been confirmed.
Mortality related to this type of treatment is arguably lower than the morbidity and mortality associated with the natural history of the disease.It should be noted that, in these patients, the mortality rate associated with TAVI is lower than that estimated by the EuroSCORE for surgical treatment.
The presence of carotid disease is associated with the risk of periprocedural stroke in patients undergoing cardiac surgery.However, little has been described on the prevalence and clinical significance of this condition in TAVI 27 .In this study, no significance between this disease and mortality has been found.
Regarding the comorbidities studied, due to the small number of deaths, it was not possible to affirm the existence of an independent association with the large number of variables presented, but only infer an association with death from all causes.
It should be noted that all patients undergoing TAVI receive rigorous outpatient treatment.Some publications reported late follow-up with survival results ranging from 70%-80% and important findings of clinical improvement 25,26 .In the follow-up of the patients studied, overall event-free survival at day 30 and year 1 was 85.1% and 78.1% (Figure 78,7).This survival rate was highly promising compared to the expected outcomes for these patients who, for being at high surgical risk, would be kept only under clinical treatment.
Overall hemodynamic performance after treatment was significant with a mean aortic gradient of 10.85±7.38 mmHg, similar to the reference standard of surgical valves 28 .
Early hemodynamic improvement is reflected in the rapid improvement of symptoms of heart failure, with benefits for the quality of life 25,26 .This procedure was associated with significant improvement in symptoms and functional class (FC-NYHA) in more than 96.0% of the patients during follow-up.
As a result, current evidence show that TAVI is a form of practical, reliable and promising treatment for patients with severe AoS and high surgical risk or even inoperable severe AoS.
As a new treatment option, it is expected that, in the near future, TAVI indication be extended to all patients at intermediate and possibly lower risk.Further studies are required to better understand the potential complications, guiding strategies to individualize and to better indicate this type of treatment.

Study limitations
This study has some limitations: small sample, which may have influenced the detection of statistical significance in several variables; and the retrospective analysis, for the loss of data related to clinical follow-up.

Table 2 Pre-procedure tests in the population studied
ECG -electrocardiogram; HB -heart block; ECHO -Doppler echocardiogram; L -left; R -right; SD -standard deviation

Table 3 Data of procedures and clinical evolution of the patients studied Procedures and clinical evolution Values
CrCl (C&G) -creatinine clearance (Cockcroft&Gault); SD -standard deviation