Impact of frailty on mortality after transcatheter aortic valve implantation

    Impact of frailty on mortality after transcatheter aortic valve implantation Pawel Kleczynski, Artur Dziewierz, Maciej Bagienski, Lukasz Rzeszutko, Danuta Sorysz, Jaroslaw Trebacz, Robert Sobczynski, Marek Tomala, Maciej Stapor, Dariusz Dudek PII: DOI: Reference:

S0002-8703(16)30285-X doi: 10.1016/j.ahj.2016.12.005 YMHJ 5338

To appear in:

American Heart Journal

Received date: Accepted date:

14 June 2016 9 December 2016

Please cite this article as: Kleczynski Pawel, Dziewierz Artur, Bagienski Maciej, Rzeszutko Lukasz, Sorysz Danuta, Trebacz Jaroslaw, Sobczynski Robert, Tomala Marek, Stapor Maciej, Dudek Dariusz, Impact of frailty on mortality after transcatheter aortic valve implantation, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.12.005

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ACCEPTED MANUSCRIPT Impact of frailty on mortality after transcatheter aortic valve implantation Pawel Kleczynski*, Artur Dziewierz, Maciej Bagienski, Lukasz Rzeszutko, Danuta Sorysz,

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Jaroslaw Trebacz, Robert Sobczynski, Marek Tomala, Maciej Stapor, Dariusz Dudek

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From Institute of Cardiology, Jagiellonian University, Krakow, Poland

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Short title: Frailty and mortality after TAVI

*Corresponding author:

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Pawel Kleczynski MD, PhD

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Institute of Cardiology, University Hospital, Kopernika 17 Street, 31-501 Krakow, Poland,

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Tel +48 12 424 71 81, Fax +48 12 424 71 84,

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e-mail: [email protected]

Conflict of interest: none

ACCEPTED MANUSCRIPT ABSTRACT Background: We sought to investigate the relation between frailty indices and 12-month

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mortality after transcatheter aortic valve implantation (TAVI).

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Methods: We included 101 consecutive patients with severe aortic stenosis who have

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undergone TAVI. Frailty indices according to VARC-2 recommendations [5-meter walk test (5MWT) and hand grip strength] as well as other available scales of frailty [Katz index,

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elderly mobility index (EMS), Canadian Study of Health and Aging (CSHA) scale, Identification of Seniors at Risk (ISAR) scale] were assessed at baseline. The primary

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endpoint was 12-month all-cause mortality.

Results: Twelve-month all-cause mortality was 17.8%. According to 5MWT 17.8% were

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frail, hand grip test - 6.9%, Katz index - 17.8%, EMS scale – 7.9%, CSHA scale - 16.9%, and

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ISAR scale – 52.5%. Associations between frailty indices and 12-month all-cause mortality after TAVI were significant in Cox regression analysis (frail vs. not frail, presented as HR

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(95%CI) adjusted for logistic EuroScore): for 5MWT 72.38 (15.95-328.44); for EMS 23.39 (6.89-79.34); for CSHA scale 53.97 (14.67-198.53); for Katz index 21.69 (6.89-68.25); for

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hand grip strength 51.54 (12.98-204.74); for ISAR scale 15.94 (2.10-120.74). Similarly, such relationship was confirmed when 5MWT, EMS, and CSHA were used as continuous variable [HR (95%CI) adjusted for logistic EuroScore: for 5MWT per 1 sec increase 2.55 (1.94-3.37); for EMS per 1 point decrease 2.90 (1.99-4.21); CSHA per 1 point increase 3.13 (2.17-4.53)]. Conclusions: Our study confirmed a strong predictive ability of most of the proposed frailty indices for 12-month mortality after TAVI. For patients scheduled for TAVI the use of frailty indices which are easy and quick to assess on clinical basis but with strong performance e.g. 5MWT, EMS scale or hand grip test may be advocated.

Key words: aortic stenosis, elderly, frailty, transcatheter aortic valve implantation, mortality

ACCEPTED MANUSCRIPT INTRODUCTION

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Frailty assessment has been shown as an important factor of overall health status, which is

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combined with morbidity and mortality in various clinical settings. In patients with severe

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aortic stenosis (AS) frailty assessment has become crucial for decision-making. Until recently, surgical aortic valve replacement (AVR) was the standard treatment for patients with symptomatic severe AS [1]. Transcatheter aortic valve implantation (TAVI) has emerged as a

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less invasive treatment option for elderly high-risk patients with symptomatic severe AS than

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AVR. More importantly, TAVI improves survival [2,3] and quality of life [4,5] as compared to medical treatment in inoperable patients. However, a successful TAVI procedure requires complex selection of patients, including detailed imaging of the aortic valve anatomy and the

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peripheral arteries as well as critical clinical assessment by an interdisciplinary Heart Team [6]. Risk assessment should mostly rely on the Heart Team’s clinical judgement in addition to

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the risk estimation using surgical risk scores. The reported mid- and long-term mortality after TAVI varies from 24% to 43% in high-risk and inoperable patients [7-9]. However, surgical

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risk scores, which are commonly used to estimate perioperative morbidity as well as mortality and provide relatively good discrimination, do not provide a reliable estimate of the exact operative risk in valvular heart disease due to a significant lack of calibration [10,11]. Frailty is a common condition among elderly patients undergoing TAVI and has been associated with poor outcomes after AVR and TAVI [12-17]. So far, frailty has not been incorporated in the risk assessment despite a relevant impact on the outcome of TAVI. Frailty assessment is recommended while screening for TAVI according to the Valve Academic Research Consortium-2 consensus (VARC-2) [18]. More importantly, there is limited data on which of the frailty indices best predicts clinical outcomes. Therefore, we aimed to determine the long-

ACCEPTED MANUSCRIPT term predictive value of different frailty indices in a single-center cohort of patients

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undergoing TAVI.

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METHODS

Study protocol was approved by the institutional Ethical Board. All patients provided

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informed consent. A total of 101 consecutive high-risk elderly patients with severe symptomatic AS undergoing TAVI were enrolled. Patient screening and selection was

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performed by a multidisciplinary Heart Team supported by clinical and imaging resources. TAVI procedures were performed using Edwards Sapien, Edwards Sapien XT, Edwards

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Sapien 3 (Edwards Lifesciences, Irvine, USA), Medtronic Corevalve (Medtronic Inc.,

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Minneapolis, USA) and JenaValve (JenaValve Technology, Munich, Germany). Access routes were transfemoral and transapical. Procedures were performed under general

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anesthesia or analgosedation. Baseline characteristics, procedural and outcomes data were collected. Frailty index was assessed before TAVI with Katz index of Independence of

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Activities in Daily Living (KI of ADL): 6 points – not frail, <6 points – frail [19]; elderly mobility scale score (EMS): <10 points - high level of help with mobility and activities in daily living, 10-14 points - borderline in terms of safe mobility and independence in activities of daily living i.e. home with help, >14 points – independent mobility, home and no help needed [20]; Canadian Study of Health and Aging (CSHA) scale; 1 - very fit for one’s age, 2 well but less fit than people in category 1, 3 - well, with treated comorbid disease, 4apparently vulnerable although not frankly dependent, 5 - mildly frail with limited dependence, 6 - moderately frail, help is needed, 7 - severely frail, completely dependent from others, 8 - terminally ill [21]; 5-meter walking test (5MWT): ≥6 seconds – frail, <5 seconds not frail [12]; dominant hand grip strength, and Identification of Seniors at Risk (ISAR) scale:

ACCEPTED MANUSCRIPT -≥2 points - person at high risk of functional decline, 0 or 1 - person at low risk [22]. Both 5MWT and hand grip strength were variables without validated scientific thresholds with

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respect to age and gender. Hand grip strength assessment was performed by one physician and

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it was subjectively distinguished into 1-weak, 2-mild, 3-strong. It was performed using

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patient’s dominant hand and patients were asked to squeeze hand as tightly as possible (repeated twice). 5MWT was assessed by the same physician each time at cardiology ward, using a standard stopwatch and the distance of 5 meters was estimated with a retractable

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counter and precisely marked. The test was performed three times and we present the mean

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result of the three trials. Periprocedural complications and mortality rates were evaluated according to VARC-2 definitions [18]. All survivors were clinically followed-up during outpatient visits up to 12 months and the primary endpoint for this study was all-cause

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mortality at 12 months. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and

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editing of the paper and its final contents.

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Statistical analysis

Results are presented as numbers of patients (percentages) or the median (interquartile range [IQR]) where applicable. The difference in 12-month mortality between subgroups with and without frailty features were tested using chi-square test and the Fisher’s exact test as appropriate. In addition, the difference in mortality between groups during follow-up was assessed by the Kaplan-Meier method. Univariable associations between frailty indices and 12-month mortality were assessed by Cox regression analysis and presented as hazard ratios (HR) with 95% confidence intervals (CI). Results of univariable analysis were adjusted for age/gender (model 1) and logistic EuroScore (model 2). Logistic EuroScore was used as

ACCEPTED MANUSCRIPT continuous variable. Indices of frailty were analyzed as continuous measures as well as categories of frail vs. not frail (as defined for each frailty scale). Receiver-operating

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characteristic (ROC) curve analysis was used to assess the ability of frailty scales to predict

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death at 12 months. Data are presented as unadjusted and adjusted area under the ROC curve

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(AUC) with 95%CI. All tests were two-tailed, and a p value <0.05 was considered statistically significant. All statistical analysis was performed using SPSS 15.0 (SPSS, Inc., Chicago, IL,

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USA).

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RESULTS

A total of 101 patients underwent elective TAVI. The patients were symptomatic presenting

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with NYHA III/IV in 83.2% of cases. Median age was 81.0 (76.0-84.0) years, and 60.4% were female (Table 1). Median aortic valve area (AVA) was 0.6 (0.4-0.8) cm2 and the median

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value of maximal / mean transaortic gradient was 87.0 (71.5-108.0) / 51.0 (42.5-66.5) mmHg. All patients were considered high-risk according to logistic EuroSCORE I 16.5 (7.0–23.0)%

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and Society of Thoracic Surgeons (STS) score 15.4 (4.0–24.0)%. Procedures were mainly performed under general anesthesia (91.1%). Transfemoral approach was used in 77.2%, transapical in 20.8% and direct aortic 2% of patients. Balloon predilatation was done in all patients. Edwards Sapien was used in 49.5%, Edwards Sapien XT 23.7%, Edwards Sapien 3 in 2.9%, Medtronic Corevalve in 19.8%, Jena Valve in 4%. Aortic regurgitation after TAVI grade ≥2 according to VARC-2 criteria was observed in 7.9% of patients. Twelve-month mortality rate was 17.8%. According to 5MWT 17.8% were frail, EMS scale – 7.9%, CSHA scale - 16.9%, Katz index - 17.8% patients, hand grip test - 6.9%, and ISAR scale – 52.5%. As shown in Table 2 and Figure 1A-F, presence of frailty features according to

ACCEPTED MANUSCRIPT Katz score, EMS score, CSHA score, ISAR score, 5MWT, hand grip strength were good predictors of increased all-cause mortality at 12 months. More importantly, unadjusted and

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adjusted Cox regression analyses have confirmed the association between different frailty

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indices and 12-month all-cause mortality after TAVI (Table 3). Interestingly, even a small

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change in 5MWT (1 sec increase), EMS score (1 point decrease) and CSHA score (1 point increase) resulted in almost three times higher mortality at 12 months (Table 3). In the ROC analysis, all of the tested frailty indices were good predictors of 12-month all-cause mortality

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after TAVI with the highest AUC value for 5MWT and the hand grip strength (Table 4,

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Supplementary Figure 1).

A detailed presentation of patients with at least one positive frailty category is shown in

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Supplementary Table 1. ISAR scale identified the widest range of potentially frail subjects.

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Three patients were identified as frail according to six frailty indices (ISAR, Katz index, 5MWT, CSHA, EMS, grip strength), seven according to five indices, and four based on four

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indices. Twelve-month all-cause mortality for patients with five or six positive categories of frailty was 100%, with three or four - 75%, with one or two - 2.6%, and without any positive

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category of frailty - 2.2% (Figure 2). More importantly, death in a patient identified as a frail only according to ISAR scale was rather late (357 days after TAVI). Also, there was only one death which was clearly related to periprocedural complications among patients without frailty features. 5MWT, hand grip test and EMS may seem to be the most powerful tools to predict long-term mortality after TAVI. Moreover, subjects identified as frail by 5MWT or hand grip test were identified as frail by other tests.

ACCEPTED MANUSCRIPT DISCUSSION

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Stratification of the risk of patients is crucial for selecting appropriate candidates for

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TAVI. The EuroScore and the STS score are the most commonly used risk scores to predict operative mortality in cardiac surgery. However, these models were developed and validated in a standard surgical risk population. Therefore, the predictive power of both models may be

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suboptimal in high-risk patients with valvular heart disease. Thus, current models could be improved by the addition of specific clinical and anatomical variables that affect mortality.

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The presence of a porcelain aorta, liver cirrhosis, pulmonary insufficiency, osteoporosis, myopathy, cachexia are frequently considered by Heart Team during patient evaluation.. In

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addition, frailty evaluation plays a crucial role in final patient’s assessment [12], however it is

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frequently judged subjectively based on ‘eyeballing’.

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In our study, frailty scores recommended by VARC-2 as well as other not specifically TAVI-dedicated scores were tested. . All the tested scores were appropriate to predict 12-month all-cause mortality. However, 5MWT, EMS score and hand grip test were

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the most accurate ones. Thus, these seem to be the most powerful tools for predicting longterm mortality after TAVI. 5MWT or hand grip test identify frail patients very precisely. Moreover, if a subject is identified by 5MWT or a hand grip test as frail, he/she will also be identified as frail by other tests. ISAR score qualifies too many patients as frail and additional assessment would be required for better detection of frailty. Furthermore, we were able to identify frailty status as strongly predictive for 12-month all-cause mortality after TAVI using different frailty scales. During follow-up, survival was significantly reduced in patients performing 5MWT ≥6 seconds, with poor performance status (EMS scale <10 meaning high level of help with mobility and activities in daily living required; CSHA scale 6-7 meaning dependant and frail, or Katz index <6), whereas subjects presenting more independent, with

ACCEPTED MANUSCRIPT better performance status (5MWT <5 seconds, EMS >10, CSHA scale <5 or Katz index >6) had better long-term survival rates. More importantly no patient who had frailty defined by

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five or six scores survived 12 months. There is no gold standard for defining and assessing

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frailty. Physical performance assessments such as gait speed and hand grip strength are more

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objective performance measures that may capture an individual's overall functional status. Continuous measures, like 5MWT, may be less redundant and can be repeated. These limitations are more often found in patients with more comorbidities and may coexist with

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certain laboratory findings (low serum albumin, anemia etc.) that further reflect the health

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state and physiological reserve of the frail patient [17]. Baseline evaluation of the presence of cognitive dysfunction (mild cognitive impairment or dementia) has also emerged as an essential part of the initial risk stratification in elderly subjects. Preprocedural cognitive

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assessment may also help to avoid attributing postprocedural mental status changes to stroke categories. In the present study, however, a cognitive status of patients was not assessed.

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A specific phenotype of frailty has been described, which includes five components: unintentional weight loss, weakness (measured by grip strength), self-reported fatigue

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(measured by questionnaire), slowness (measured by 5MWT), and diminished physical activity (measured by questionnaire) [23]. On the other hand, a frailty assessment tool should be characterized by simplicity, reproducibility, objectivity and applicability to the busy clinical setting. The so-called "eyeballing" is very simple to perform but clearly lacks objectivity and reproducibility. The available frailty scores are objective but relatively timeconsuming. Physical performance assessments (such as hand grip strength) as surrogate markers are objective and reproducible, but sometimes do not point out clear areas for modification of frailty to the clinician. Importantly, functional status (commonly evaluated by the ability to complete activities of daily living (ADL) and instrumental activities of daily living) is a strong predictor of morbidity and mortality in the geriatric population,

ACCEPTED MANUSCRIPT independently from the patient’s age [25] . Inouye et al. [26] found that any ADL impairment was associated with a 1.9-fold increased risk of all-cause mortality at two years in a

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population of patients aged 70 years or older admitted to general medicine departments.

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Furthermore, it has been demonstrated that frailty and the onset of dependence in ADL are

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trongly associated [27]. Afilalo et al. [11] established 5MWT as an incremental predictor of in-hospital mortality and major morbidity in 131 elderly patients undergoing cardiac surgery, associated with a two-fold to three-fold increase in risk. A subsequent study [8] established

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cardiac surgery risk scores with different scales of frailty and disability to improve

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identification of elderly patients at increased risk of postoperative mortality or major morbidity. Rodes-Cabau et al. [7] identified frailty (among other risk factors) as an independent predictor of two-year mortality in 339 patients treated with TAVI. However,

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frailty status was assessed by “eyeballing” and without objective measures in this study. There is also a growing evidence that measures of frailty and disability are able to improve

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risk stratification in the setting of AS and TAVI. The prevalence of frailty measured by 5MWT in patients with severe AS was recently defined in a series of 102 subjects who were

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screened for TAVI [28]. Slow gait speed was present in 63% of patients and was independently associated with disability (as measured by dependence in ADL). Stortecky et al. [29] evaluated multidimensional geriatric assessment for risk stratification in 100 consecutive patients undergoing TAVI. All geriatric parameters were significantly associated with mortality and major adverse cardiovascular events at 30 days and 12 months after TAVI. Green et al. [30] prospectively measured gait speed, grip strength, serum albumin, and ADL status in 159 subjects who underwent TAVI in order to derive a frailty score. Frailty was not associated with increased periprocedural complications, but was associated with increased one-year mortality after TAVI.

ACCEPTED MANUSCRIPT In addition, the presence of baseline heart failure symptoms may raise questions about its impact on frailty assessment. Heart failure is associated with the derangement of

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muscle structure and metabolism, contributing to exercise intolerance, frailty, and mortality.

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Among patients with frailty, loss of mean muscle mass despite preserved overall body mass

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may contribute to decreased functional reserve and increased needs for rehabilitation after TAVI [31]. However, in our study we have not found any clear relationship between NYHA class and frailty indices. Also, associations between frailty indices were significant in Cox

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regression analysis even after adjustment for NYHA class (data not shown).

Study limitations

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Our study represents a single-centre experience with a relatively small sample size which

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could be regarded as a limitation of the study. However, the complete analysis of consecutive patients without any exclusion criteria and with follow-up data available for all patients was

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performed. Hand grip strength assessment was not performed with a hydraulic dynamometer in kilograms/force but only subjectively evaluated as mentioned in the methods section. In our

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study we have not performed an evaluation of the presence of cognitive dysfunction (mild cognitive impairment or dementia).

CONCLUSIONS

This study confirmed a strong association between most of the proposed indices of frailty and 12-month mortality after TAVI. In spite of limited data on their calibration and discrimination in the TAVI population, the multiple indices assessed had ability to discriminate patients at risk for 12-month mortality. No patient who had frailty defined by five or six scores survived

ACCEPTED MANUSCRIPT 12 months. The selection of any specific test may be less important than the use of one of the common frailty tests in this population. More work on the complimentary nature of these

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tools, because of limited data, is needed to further optimize their use as screening tests for

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TAVI. For patients scheduled for TAVI the use of frailty indices which are easy and quick to

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assess on clinical basis but with strong performance e.g. 5MWT, EMS scale or hand grip test may be advocated.

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Acknowledgements

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None Disclosures

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None

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15. Cockburn J, Singh MS, Rafi NH, et al. Poor mobility predicts adverse outcome better than other frailty indices in patients undergoing transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2015;86:1271-7. 16. Puls M, Sobisiak B, Bleckmann A, et al. Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living. EuroIntervention 2014;10:609-19. 17. Kamga M, Boland B, Cornette P, et al. Impact of frailty scores on outcome of octogenarian patients undergoing transcatheter aortic valve implantation. Acta Cardiol 2013;68:599-606.

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ACCEPTED MANUSCRIPT 28. Green P, Woglom AE, Genereux P, et al. Gait speed and dependence in activities of daily living in older adults with severe aortic stenosis. Clin Cardiol 2012;35:307-14.

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29. Stortecky S, Schoenenberger AW, Moser A, et al. Evaluation of multidimensional geriat-

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ric assessment as a predictor of mortality and cardiovascular events after transcatheter

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aortic valve implantation. JACC Cardiovasc Interv 2012;5:489-96.

30. Green P, Woglom AE, Genereux P, et al. The impact of frailty status on survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-

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center experience. JACC Cardiovasc Interv 2012;5:974-81.

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31. Huded CP, Huded JM, Friedman JL, et al. Frailty Status and Outcomes After

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Transcatheter Aortic Valve Implantation. Am J Cardio. 2016;117:1966-71.

ACCEPTED MANUSCRIPT FIGURES LEGEND

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Figure 1

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Kaplan-Meier curves for survival stratified by Katz index (A), 5-meter walking test (B), grip

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strength (C), elderly mobility score (D), Canadian Study of Health and Aging scale (E), Identification of Seniors at Risk scale (F)

5MWT - 5-meter walking test; CSHA - Canadian Study of Health and Aging; EMS - elderly

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mobility score; GS – grip strength; ISAR - Identification of Seniors at Risk' Katz – Katz index

Figure 2

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All-cause 12-month mortality stratified by the number of positive frail categories.

ACCEPTED MANUSCRIPT Table 1. Baseline characteristics N=101

Age [years], median (IQR)

81.0 (76.0-84.0)

Age ≥80 years, n (%)

59 (58.4)

Female, n (%)

61 (60.4)

Body mass index [kg/m2], median (IQR)

28.0 (25.2-31.1)

Arterial hypertension, n(%)

94 (93.1)

Diabetes mellitus, n(%)

35 (34.7)

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101 (100.0)

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Hyperlipidemia, n(%) Previous MI, n(%)

31 (30.7) 29 (28.7)

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Previous PCI , n(%)

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Previous pacemaker, n(%) Previous CABG, n(%)

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Variable

11 (10.9) 17 (16.8) 61.0 (39.0-81.0)

Atrial fibrillation, n(%)

35 (34.7)

Previous stroke, n(%)

10 (9.9)

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eGFR [mL/min/1.73 m2], median (IQR)

Chronic obstructive pulmonary disease, n(%)

12 (11.9)

Symptoms:

Canadian Cardiovascular Society I, n(%)

12 (11.7)

II, n(%)

24 (23.5)

III+IV, n(%)

66 (64.7)

New York Heart Association I, n(%)

0 (0.0)

II, n(%)

17 (16.8)

ACCEPTED MANUSCRIPT III+IV, n(%)

84 (83.2)

87.0 (71.5-108.0)

TG mean [mmHg], median (IQR)

51.0 (42.5-66.5)

Aortic valve area [cm2], median (IQR)

0.6 (0.4-0.8)

LVEF [%], median (IQR)

60.0 (47.5-65.0)

SC R

Risk of surgery

14.0 (10.0-22.5)

NU

Logistic EuroScore I [%], median (IQR)

IP

TG max [mmHg], median (IQR)

T

Aortic valve parameters:

MA

Society of Thoracic Surgeons Score [%], 12.0 (5.0-24.0)

D

median (IQR)

TE

CABG - coronary aortic bypass graft; eGFR - estimated glomerular filtration rate; IQR -

CE P

interquartile range; LVEF - left ventricle ejection fraction; MI - myocardial infarction; PCI -

AC

percutaneous coronary intervention; TG - transaortic gradient

ACCEPTED MANUSCRIPT Table 2

5.0 (4.0-5.0)

N (%)

0-5

SC R

5MWT

Categories

83 (82.2%)

(sec)

MA

≥6, frail EMS

2.4%

88.9%

8 (7.9%)

87.5%

10-13

66 (65.3%)

15.2%

>13

27 (26.7%)

3.7%

1-3

56 (55.4%)

1.8%

4

28 (27.7%)

7.1%

5, frail

3 (3.0%)

100.0%

6-7, frail

14 (13.9%)

85.7%

<6, frail

18 (17.8%)

72.2%

6, not frail

83 (82.2%)

6.0%

<0.001

<0.001

D TE CE P

3.0 (3.0-4.0)

AC

CSHA scale

Katz index

P value

mortality

18 (17.8%)

13.0 (12.0-14.0) <10, frail

(points)

(points)

12-month

NU

Median (IQR)

IP

T

Frailty indices and 12-month mortality in patient with and without frailty features

6.0 (6.0-6.0)

(points)

<0.001

<0.001

ACCEPTED MANUSCRIPT Grip

3.0 (3.0-3.0)

1 weak, frail

7 (6.9%)

100.0%

2 mild

14 (13.9%)

64.3%

3 strong

80 (79.2%)

<0.001

strength

2.0 (1.0-2.0)

0-1, low risk ≥2,

48 (47.5%)

functional 53 (52.5%)

2.5% 2.1%

<0.001

32.1%

NU

(points)

SC R

ISAR scale

IP

T

(grade)

D

MA

decline, frail

TE

5-meter walking test (5MWT): ≥6 seconds – frail, <5 seconds not frail; elderly mobility scale

CE P

(EMS): <10 - high level of help with mobility and activities in daily living, 10-14 - borderline in terms of safe mobility and independence in activities of daily living (ADL) i.e. home with help, >14 – independent mobility, home and no help needed; Canadian Study of Health and

AC

Aging (CSHA) scale: 1 - very fit for one’s age, 2 - well but less fit than people in category 1, 3 - well, with treated comorbid disease, 4- apparently vulnerable although not frankly dependent, 5 - mildly frail with limited dependence, 6 - moderately frail, help is needed, 7 severely frail, completely dependent from others, 8 - terminally ill; Katz index: 6 – not frail, <6 – frail; Identification of Seniors at Risk (ISAR) scale: ≥2 indicates person at high risk of functional decline, 0 or 1 indicates person at low risk;

ACCEPTED MANUSCRIPT Table 3 Unadjusted and adjusted associations between frailty indices and 12-month all-cause

HR

95%

P value

HR 95% CI

2.51 (1.94-

increase)

3.24)

5MWT (frail vs

82.92

not frail)*

(18.56-

EMS (<10 points,

age/gender

log

2.83

(2.01-

MA

D TE

2.81 (2.03-

p<0.001

15.96

p<0.001

(5.91-

AC

frail vs ≥10 points, not frail)*

p<0.001

3.89)

decrease)

Adjusted for

p<0.001

3.98)

CE P

EMS (per 1 point

p<0.001

HR 95% CI

Adjusted for

NU

5MWT (per 1 sec

370.39)

P value

SC R

CI

IP

T

mortality after transcatheter aortic valve implantation

124.12

EuroScore

2.55

(1.94-

p<0.001

72.38

p<0.001

(15.95-

702.72)

328.44)

(2.13-

p<0.001

3.37)

(21.92-

3.14

P value

p<0.001

4.64)

2.90

(1.99-

p<0.001

23.39 (6.89-

p<0.001

4.21)

17.56 (5.95-

p<0.001

51.85)

79.34)

43.05)

CSHA scale (per 1

4.48 (2.77-

p<0.001

3.82

(2.46-

p<0.001

point increase)

7.22)

CSHA (5-7 points,

62.20

frail vs 1-4 points,

(17.19-

(17.35-

(14.67-

not frail)*

225.07)

240.94)

198.53)

Katz index (per 1

5.00 (2.88-

point decrease)

8.70)

5.94) p<0.001

p<0.001

11.64)

(2.17-

p<0.001

4.53)

64.65

6.06

3.13

p<0.001

(3.15-

p<0.001

53.97

5.22 9.39)

p<0.001

(2.90-

p<0.001

ACCEPTED MANUSCRIPT Katz index (frail

19.54

vs not frail)*

(6.88-

p<0.001

20.06 (6.93-

p<0.001

21.69 (6.89-

58.02)

p<0.001

68.25)

55.50)

(6.77-

15.18 (6.7234.28)

strength

42.40

p<0.001

37.93

p<0.001

(13.31-

(10.63-

grade 2 and 3, not

135.10)

135.35)

NU

(grade 1, frail vs

ISAR scale (per 1

2.88 (2.08-

point increase)

4.00)

(2.37-

points, not frail)*

133.81)

D

points, frail vs 0-1

(2.79-

p=0.005

17.71 (2.35-

51.54

p<0.001

(12.98204.74)

p<0.001

8.48)

TE

17.80

scale

4.86

p<0.001

2.97

(2.02-

p<0.001

15.94 (2.10-

p=0.007

4.39) p=0.005

133.49)

120.74)

CE P

(≥2

ISAR

p<0.001

MA

frail)*

16.39 (6.7939.56)

30.48) Grip

p<0.001

T

1 grade decrease)

p<0.001

IP

14.36

SC R

Grip strength (per

AC

Data derived from Cox regression analysis and presented as hazard ratios (HR) with 95% confidence intervals (95%CI). 5MWT - 5-meter walking test; CSHA - Canadian Study of Health and Aging scale; EMS elderly mobility scale; ISAR - Identification of Seniors at Risk scale * as defined in Table 2

ACCEPTED MANUSCRIPT Table 4 Receiver-operating characteristic curve analysis for the prediction of 12-month all-cause

Adjusted

AUC

for

0.91

(0.79- 0.91

(0.79- p<0.001

NU

D

TE

0.93 (0.84-1.00)

AC

Grip strength

0.83 (0.70-0.96)

CE P

Katz index

0.91 (0.80-1.00)

ISAR scale

0.89 (0.79-0.98)

log EuroScore

(0.85- 0.91

1.00)

CSHA scale

P value

1.00)

MA

0.91 (0.79-1.00)

EMS

for

(0.81- p<0.001

0.94

0.93 (0.84-1.00)

5MWT

Adjusted

SC R

age/gender

IP

T

mortality after transcatheter aortic valve implantation

0.92

1.00) (0.81- 0.91

1.00) 0.86

(0.73- 0.80

(0.64- p<0.001

0.96) (0.84- 0.93

1.00) 0.88

(0.79- p<0.001

1.00)

0.98) 0.94

1.00)

(0.85- p<0.001

1.00) (0.77- 0.88

0.98)

(0.79- p<0.001

0.98)

5MWT - 5-meter walking test; CSHA - Canadian Study of Health and Aging; EMS - elderly mobility scale; ISAR - Identification of Seniors at Risk scale

AC

CE P

TE

D

MA

NU

SC R

IP

T

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