Author + information
- Received April 18, 2018
- Revision received June 18, 2018
- Accepted June 18, 2018
- Published online November 5, 2018.
- Laura M. Drudi, MD, MSca,b,
- Matthew Ades, MDa,c,
- Anita Asgar, MD, MScd,
- Louis Perrault, MDe,
- Sandra Lauck, RN, PhDf,
- John G. Webb, MDf,
- Andrew Rassi, MDg,
- Andre Lamy, MDh,
- Nicolas Noiseux, MD, PhDi,
- Mark D. Peterson, MDj,
- Marino Labinaz, MDk,
- Thierry Lefèvre, MDl,
- Jeffrey J. Popma, MDm,
- Dae H. Kim, MD, MScn,
- Giuseppe Martucci, MDo,
- Nicolo Piazza, MD, PhDo and
- Jonathan Afilalo, MD, MSca,p,∗ ()
- aDivisions of Cardiology & Clinical Epidemiology, Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, Quebec, Canada
- bDivision of Vascular Surgery, McGill University, Montreal, Quebec, Canada
- cDivision of Internal Medicine, McGill University, Montreal, Quebec, Canada
- dDivision of Cardiology, Institut de Cardiologie de Montréal, Université de Montréal, Montreal, Quebec, Canada
- eDivision of Cardiac Surgery, Institut de Cardiologie de Montréal, Université de Montréal, Montreal, Quebec, Canada
- fCentre for Heart Valve Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- gDepartment of Cardiology, Kaiser Permanente - San Francisco Medical Center, San Francisco, California
- hDivision of Cardiac Surgery, Hamilton Health Sciences, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- iDivision of Cardiac Surgery, Centre Hospitalier de l’Université de Montréal, Centre de Recherche du CHUM, Montreal, Quebec, Canada
- jDivision of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
- kDivision of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
- lDivision of Interventional Cardiology, Institut cardiovasculaire Paris Sud, Ramsay-générale de santé, Hôpital privé Jacques Cartier, Massy, France
- mDivision of Cardiology, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts
- nDivision of Gerontology, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts
- oDivision of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada
- pDivision of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- ↵∗Address for correspondence:
Dr. Jonathan Afilalo, Divisions of Cardiology & Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste Catherine Road, E-222, Montreal, Quebec H3T 1E2, Canada.
Objectives The authors sought to determine whether frail older adults undergoing nonfemoral transcatheter aortic valve replacement (TAVR) procedures had a higher risk of 30-day and 12-month mortality.
Background Frailty can help predict outcomes and guide therapy in older adults being considered for TAVR. Nonfemoral TAVR procedures are more invasive and impart a greater risk of adverse events, which may be less well tolerated in frail patients, compared with transfemoral TAVR procedures.
Methods This study was a post hoc analysis of the FRAILTY-AVR (Frailty Assessment Before Cardiac Surgery & Transcatheter Interventions) prospective multicenter cohort that consisted of older adults undergoing TAVR from 2012 to 2017. Frailty was assessed using the Essential Frailty Toolset (EFT). Endpoints of interest were 30-day and 12-month all-cause mortality. Interaction tables and multivariable logistic regression models were used to investigate statistical interaction on the additive and multiplicative scales.
Results The cohort consisted of 723 patients with a mean age of 84 ± 6 years, of which 556 (77%) had femoral access and 167 (23%) had nonfemoral access. In frail patients with EFT scores ≥3 (35%), nonfemoral access was associated with increased 30-day mortality (odds ratio [OR]: 3.91; 95% confidence interval [CI]: 1.48 to 10.31); whereas in nonfrail patients with EFT scores <3 (65%), nonfemoral access had no effect (OR: 1.29; 95% CI: 0.34 to 4.94). There was statistical evidence of interaction between frailty and access site on 30-day mortality on the additive scale (relative excess risk due to interaction = 5.95). Nonfemoral access was associated with increased 1-year mortality in frail patients (OR: 1.98; 95% CI: 1.00 to 3.93) but not in nonfrail patients (OR: 1.83; 95% CI: 0.90 to 3.74), although there was no statistical evidence of interaction.
Conclusions Frail patients undergoing TAVR via a more invasive nonfemoral access face a substantially higher risk of 30-day mortality, whereas nonfrail older adults tolerate the procedure with a low short-term risk irrespective of access route.
Transcatheter aortic valve replacement (TAVR) is increasingly used to treat aortic stenosis in frail older adults who are deemed to be high risk for surgical aortic valve replacement. The preferred approach to perform TAVR is via a percutaneous transfemoral arterial access; to determine whether this is feasible, patients undergo pre-procedural evaluation of their peripheral vasculature focused on common femoral artery diameter, arterial tortuosity, and iliofemoral calcification (1). Candidates who do not meet the anatomic requirements for transfemoral vascular access may have alternative nonfemoral vascular access via subclavian, axillary, transaortic, transapical, or transcaval approaches. Despite high rates of technical success with all approaches, nonfemoral TAVR procedures are more invasive and impart a greater risk of major bleeding, conversion to open surgery, and prolonged length of stay, as well as short- and mid-term mortality compared with transfemoral TAVR procedures (2,3).
Frailty is a multidimensional geriatric syndrome that reflects a state of decreased physiological reserves and vulnerability to iatrogenic or pathological stressors (4). Frail patients are less likely to tolerate invasive procedures, which is one of the reasons why the minimally invasive TAVR procedure has gained acceptance in this patient population (5–7). However, TAVR has a spectrum of access site options with nonfemoral TAVR procedures being inherently more invasive than transfemoral, hence exposing frail patients to additional operative stress and risk (8). Consideration of this interaction between patient frailty and procedural approach may modify risk and in turn influence decision making. Thus, the FRAILTY-AVR (Frailty Assessment Before Cardiac Surgery & Transcatheter Interventions) cohort was studied to test the hypothesis that frail patients experienced an incrementally higher risk of adverse outcomes when treated with nonfemoral TAVR procedures.
Study design and population
This study is an analysis of the FRAILTY-AVR (Frailty Assessment Before Cardiac Surgery &Transcatheter Interventions [NCT01845207]) prospective cohort, which was designed to compare the prognostic value of frailty scales in aortic valve replacement (9). A total of 14 centers participated in the United States, Canada, and France. For the purposes of this study, older adult patients who underwent TAVR between July 1, 2012, and June 21, 2017, were identified and stratified according to transfemoral and nonfemoral access. Exclusion criteria were emergency procedures, clinical instability, severe neuropsychiatric impairment, and prohibitive language barriers. This study was approved by the ethics committee at the participating centers, and patients were required to sign an informed consent before being enrolled.
Transfemoral access was defined as delivery of the TAVR device through percutaneous or open access of the left or right common femoral artery (10). Nonfemoral access was defined as delivery of the TAVR device through open access of the subclavian artery, carotid artery, ascending aorta (via a right mini-sternotomy), or left ventricular apex (via a left mini-thoracotomy). Peripheral arterial disease (PAD) status was ascertained by a combination of patient questionnaire and electronic health records.
Pre-procedural frailty was assessed using the Essential Frailty Toolset (EFT) (11), which reflects lower-extremity muscle weakness, cognitive impairment, anemia, and hypoalbuminemia. Secondarily, frailty was assessed using the Short Physical Performance Battery (SPPB), which encompasses lower-extremity muscle weakness, slowness, and balance (12). The EFT and SPPB score were represented in ordinal form, and also in dichotomous form using the accepted cutoff of ≥3/5 for EFT and ≤5/12 for SPPB.
The primary endpoint was 30-day all-cause mortality. The secondary endpoint was 12-month all-cause mortality. Vital status was ascertained by contacting the patients or their family members by telephone and verifying the hospital-level electronic health records and linked administrative databases. There were no patients lost to follow-up at these time points. Post-procedural major adverse cardiovascular complications were defined according to the VARC 2 (Valve Academic Research Consortium 2) consensus criteria (13).
Discrete categorical variables were summarized as counts and percentages. Differences between categorical variables across access site groups were expressed as 95% confidence interval (CI) proportional differences. Continuous variables were summarized as sample means and SDs. Differences between continuous variables across access site groups were expressed as a p value using the independent Student’s t-test. Univariate analysis was performed to assess the association of all relevant covariates with the study endpoints. Multivariable logistic regression was used to estimate the association between nonfemoral access and all-cause mortality adjusting for the covariates found to be significantly associated with access route in the univariate analysis: frailty, age, sex, PAD, coronary artery disease, chronic lung disease, atrial fibrillation, and prior cardiac surgery.
An interaction term for frailty and access site was added to this model. Survival curves were generated with the Kaplan-Meier method. The reporting of interaction followed the recommendations from the International Epidemiological Association (14). Additive interaction was reported with relative excess risk due to interaction (RERI), with a score of >0 as evidence of positive additive interaction. A type I error rate of 20% was used for the RERI test statistic to maximize power (15). Multiplicative interaction was reported as an adjusted odds ratio (OR) for the interaction term in the logistic regression model, as well as stratified interaction tables. Statistical analyses were performed with RStudio version 0.99.491 (RStudio, Boston, Massachusetts) and STATA version 14.1 (StataCorp, College Station, Texas).
Our cohort consisted of 723 patients who underwent TAVR with a mean age of 83.5 ± 5.6 years and 55% males. The access site was transfemoral in 556 patients (77%) and nonfemoral in 167 patients (23%), including 75 apical (10%), 66 direct aortic (9%), 14 axillary or subclavian (2%), and 12 carotid (2%) accesses. The prevalence of frailty was 35% when defined according to the EFT and 39% when defined according to the SPPB score. Patients that had nonfemoral access were more likely to have PAD (p < 0.001) and coronary artery disease (p = 0.001), and less likely to have atrial fibrillation (p = 0.005). Other comorbid conditions as well as frailty scores were balanced between the transfemoral and nonfemoral groups (Tables 1 and 2⇓⇓). Among patients without PAD, 489 (82%) underwent transfemoral access and 107 (18%) underwent nonfemoral access. Among patients with PAD, 67 (52%) underwent transfemoral access and 61 (48%) underwent nonfemoral access (Online Table 1).
At 30 days, 24 deaths (4%) were observed in the transfemoral group and 15 deaths (9%) were observed in the nonfemoral group (Online Table 2). On univariate analysis, nonfemoral access was associated with a 2-fold increase in 30-day mortality (unadjusted OR: 2.19; 95% CI: 1.12 to 4.27; p = 0.02). When adjusted for potential confounders (Table 3) and stratified according to frailty status (Table 4), nonfemoral access was associated with increased 30-day mortality in frail patients with EFT ≥3 (adjusted OR: 3.91; 95% CI: 1.48 to 10.31; p = 0.006), but not in nonfrail patients with EFT <3 (adjusted OR: 1.29; 95% CI: 0.34 to 4.94; p = 0.71) (Table 5). There was interaction between frailty and TAVR access site on 30-day mortality on the additive scale (RERI = 5.95; 95% CI: −1.91 to 13.81; p = 0.14), but not on the multiplicative scale (adjusted OR: 2.08; 95% CI: 0.47 to 9.28; p = 0.337). In a sensitivity analysis using the SPPB instead of the EFT to classify frailty, interaction was similarly present on the additive scale (RERI = 4.16; 95% CI: −0.90 to 9.21; p = 0.11) (Online Table 3).
At 12 months, 88 deaths (17%) were observed in the transfemoral group, and 38 deaths (24%) were observed in the nonfemoral group. On univariate analysis, nonfemoral access was associated with a borderline increase in 12-month mortality (unadjusted OR: 1.55; 95% CI: 1.01 to 2.38; p = 0.046). When adjusted for potential confounders (Table 3) and stratified according to frailty status (Table 4), nonfemoral access was similarly associated with trend toward increased 12-month mortality in frail patients with EFT ≥3 (adjusted OR: 1.98; 95% CI: 1.00 to 3.93; p = 0.05) and nonfrail patients with EFT <3 (adjusted OR: 1.83; 95% CI: 0.90 to 3.74; p = 0.10). Using survival curves and margins for predicted probabilities, the estimated 12-month mortality was greatest in patients who were frail and had TAVR via nonfemoral access (Figure 1). However, there was no statistically significant interaction between frailty and TAVR access site on 12-month mortality on the additive scale (RERI = 2.08; 95% CI: −1.85 to 6.01; p = 0.30) or the multiplicative scale (adjusted OR: 0.97; 95% CI: 0.39 to 2.41; p = 0.94).
To our knowledge, this is the first study evaluating the interaction between frailty and access site on mortality in older patients undergoing TAVR. Although nonfrail patients achieved similar results regardless of procedural access, frail patients undergoing TAVR via nonfemoral access experienced a considerably higher risk of 30-day mortality. Although most TAVR procedures were performed via transfemoral access, 1 of 2 patients with comorbid PAD underwent TAVR via a nonfemoral access.
This study builds on the existing published reports that have shown nonfemoral access to be consistently associated with less favorable post-procedural outcomes (16). The FRANCE-2 (FRench Aortic National CoreValve and Edwards) registry of 3,195 patients demonstrated that those with PAD were more likely to undergo a transapical approach (p < 0.001), and that a transapical approach was associated with an increased risk of 30-day mortality (hazard ratio [HR]: 2.02; 95% CI: 1.47 to 2.78) and less so 1-year mortality (HR: 1.45; 95% CI: 1.09 to 1.92) (17,18). The SOURCE XT (Edwards SAPIEN XT Aortic Bioprosthesis Multi-Region Outcome) registry of 2,688 patients demonstrated that nonfemoral access was associated with an increased risk of 1-year mortality (HR: 1.84; 95% CI: 1.51 to 2.25) (19). Edwards et al. (20) developed predictive models using data from 13,718 patients undergoing TAVR in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy Registry, and identified nonfemoral access site as an independent predictor of in-hospital mortality (HR: 1.98; 95% CI: 1.65 to 2.33). Finally, a meta-analysis of 28 TAVR studies concluded that nonfemoral access was associated with an increased risk of 30-day (OR: 1.79; 95% CI: 1.56 to 2.04) and 1-year (OR: 1.47; 95% CI: 1.33 to 1.67) mortality compared with transfemoral access, but cautioned that further research was needed to evaluate whether this increased risk was similarly observed across intermediate-risk, high-risk, and prohibitive-risk subgroups (21).
Our results have addressed this knowledge gap, showing that the increased risk associated with nonfemoral TAVR procedures was mostly observed in patients with evidence of frailty. There are at least 2 hypothesized reasons to explain the interaction of frailty. The first reason pertains to the more invasive nature of the nonfemoral TAVR procedure, which imparts a greater iatrogenic stress to the patient with decreased physiological reserves and consequently places them at greater risk for morbidity and mortality. This risk can manifest in the short term owing to procedural complications or in the mid-term owing to progressive deconditioning. Nonfemoral TAVR procedures necessitate larger incisions and general anesthesia, resulting in longer hospitalizations and slower resumption of physical activities, hence predisposing to deconditioning. The second reason pertains to the higher prevalence and more extensive burden of PAD in patients undergoing nonfemoral procedures. PAD represents a state of systemic vascular inflammation (22) associated with an elevated risk of cardiovascular events and mortality (23,24). Taken together, pre-operative frailty, operative stress, and PAD may synergistically contribute to the inflammatory milieu that promotes sarcopenia, deconditioning, and adverse outcomes (25).
There is limited and debatable evidence concerning the prognostic effect of PAD in patients undergoing TAVR. PAD is included in the SURTAVI (SURgical replacement and Transcatheter Aortic Valve Implantation) trial risk score (26,27), and was shown to be predictive of 30-day mortality (HR: 1.8; 95% CI: 1.2 to 2.7) in another cohort study (28). Given this, some investigators recommended objective evaluation of PAD as a component of the pre-procedural assessment before TAVR regardless of access site (28). Alternatively, the effect of PAD on adverse outcomes may be confounded by the known associations between PAD and nonfemoral access (29), as well as between PAD and prevalent frailty (30,31). This bias may explain why the prognostic effect of PAD was attenuated and no longer statistical significant after adjusting for access site and frailty.
Limitations of our study include that it is a post hoc analysis of the FRAILTY-AVR study, and as such, was not designed to capture the multifactorial reasoning for access site decisions made by treating clinicians. PAD ascertainment was largely performed through patient self-reports and electronic health records, which may be subject to inaccuracies and does not capture severity of atherosclerotic burden. It is unclear whether physical performance scores such as the SPPB are purely reflective of frailty in patients with concomitant PAD, as they may reflect underlying PAD rather than frailty status. However, sensitivity analyses using other frailty indicators such as the Fried scale yielded similar results. With the growing use of transfemoral access and declining use of nonfemoral access (especially apical), our reported findings are likely to affect a smaller subset of patients in the future. Lastly, although interaction terms were statistically significant for 30-day mortality on the additive scale, they were not conclusive on the multiplicative scale, for which larger sample sizes are typically required.
Nonfemoral access is associated with a greater risk of 30-day and 12-month mortality after TAVR, particularly in frail patients. Risk factors such as frailty and PAD should be carefully considered in identifying older adults likely to tolerate a nonfemoral procedure. Although access site is largely dictated by vascular anatomy, and cannot necessarily be altered on the basis of frailty status, clinicians should be alerted to the incremental short-term risk of nonfemoral access in highly frail patients. This may influence the clinician’s or patient’s decision to pursue the procedure or encourage them to optimize frailty status before the procedure. Supervised exercise training has been shown to be beneficial in ameliorating both frailty (32,33) and PAD symptoms (34,35), and thus, appears to be well suited to this group of patients. Frailty should not be equated with nonoperability, but rather integrated alongside clinical and anatomic factors to tailor the procedural approach and periprocedural care of these vulnerable patients.
WHAT IS KNOWN? Frail patients are less likely to tolerate invasive procedures, which is one of the reasons why the minimally invasive TAVR procedure has been advocated in this patient population.
WHAT IS NEW? Frail patients undergoing TAVR via a more invasive nonfemoral access face a substantially higher risk of 30-day mortality, whereas nonfrail older adults tolerate the procedure with a low short-term risk irrespective of access route.
WHAT IS NEXT? The interaction between frailty and nonfemoral access amplifies the patient's risk and may prompt the clinician to modify the treatment plan or optimize the frailty deficits prior to the procedure to improve outcomes.
Dr. Drudi was supported by grants from the Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarships, and Fonds de recherche du Québec- Santé (FRQS) Master’s Grant. Dr. Afilalo was supported by grants for the FRAILTY-AVR Study through an Operating Grant from the Canadian Institutes for Health Research (CIHR), a Clinical Research Scholars Award from the Fonds de Recherche du Québec en Santé (FRQ-S), and a Research Fellowship Award from the Heart and Stroke Foundation of Canada. Dr. Asgar has been a consultant for Edwards Lifesciences and Medtronic. Dr. Perrault has been a consultant for Somahlution; and served on an advisory board for Clearflow. Dr. Lauck has been a consultant for Edwards Lifesciences. Dr. Webb has been a consultant for Edwards Lifesciences and Abbott Vascular. Dr. Peterson has been a proctor for Edwards Lifesciences; and a consultant for LivaNova. Dr. Lefèvre has been a proctor for Edwards Lifesciences and Abbott Vascular. Dr. Popma has received institutional grants from Medtronic, Boston Scientific, Abbott Vascular, and Edwards Lifesciences; and has served on advisory boards for Boston Scientific and Edwards Lifesciences. Dr. Kim has been a consultant for Alosa Health (a nonprofit organization). Dr. Martucci has been a proctor and consultant for Boston Scientific and Medtronic. Dr. Piazza has been a consultant for Highlife, Microport, Boston Scientific, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- Essential Frailty Toolset
- hazard ratio
- odds ratio
- peripheral arterial disease
- relative excess risk due to interaction
- Short Physical Performance Battery
- transcatheter aortic valve replacement
- Received April 18, 2018.
- Revision received June 18, 2018.
- Accepted June 18, 2018.
- 2018 American College of Cardiology Foundation
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