Author + information
- Received April 21, 2014
- Revision received July 23, 2014
- Accepted August 14, 2014
- Published online February 1, 2015.
- Ruben L. Osnabrugge, MSc∗,†,
- Suzanne V. Arnold, MD, MHA†,
- Matthew R. Reynolds, MD, MSc‡,§,
- Elizabeth A. Magnuson, ScD†,
- Kaijun Wang, PhD†,
- Vincent A. Gaudiani, MD‖,
- Robert C. Stoler, MD¶,
- Thomas A. Burdon, MD#,
- Neal Kleiman, MD∗∗,
- Michael J. Reardon, MD∗∗,
- David H. Adams, MD††,
- Jeffrey J. Popma, MD‡‡,
- David J. Cohen, MD, MSc†∗ (, )
- CoreValve U.S. Trial Investigators
- ∗Erasmus University Medical Center, Rotterdam, the Netherlands
- †Saint Luke’s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri
- ‡Lahey Hospital & Medical Center, Burlington, Massachusetts
- §Harvard Clinical Research Institute, Boston, Massachusetts
- ‖Pacific Coast Cardiac and Vascular Surgeons, Redwood City, California
- ¶Baylor Heart and Vascular Hospital, Dallas, Texas
- #Department of Cardiothoracic Surgery, Stanford University, Stanford, California
- ∗∗Methodist DeBakey Heart & Vascular Center, Houston, Texas
- ††Mount Sinai Medical Center, New York, New York
- ‡‡Beth Israel Deaconess Medical Center, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. David J. Cohen, Saint Luke’s Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, 4401 Wornall Road, Kansas City, Missouri 64111.
Objectives The purpose of this study was to characterize health status outcomes after transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis among patients at extreme surgical risk and to identify pre-procedural patient characteristics associated with a poor outcome.
Background For many patients considering TAVR, improvement in quality of life may be of even greater importance than prolonged survival.
Methods Patients with severe, symptomatic aortic stenosis who were considered to be at prohibitive risk for surgical aortic valve replacement were enrolled in the single-arm CoreValve U.S. Extreme Risk Study. Health status was assessed at baseline and at 1, 6, and 12 months after TAVR using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Short Form-12, and the EuroQol-5D. The overall summary scale of the KCCQ (range 0 to 100; higher scores = better health) was the primary health status outcome. A poor outcome after TAVR was defined as death, a KCCQ overall summary score (OS) <45, or a decline in KCCQ-OS of 10 points at 6-month follow-up.
Results A total of 471 patients underwent TAVR via the transfemoral approach, of whom 436 (93%) completed the baseline health status survey. All health status measures demonstrated considerable impairment at baseline. After TAVR, there was substantial improvement in both disease-specific and generic health status measures, with an increase in the KCCQ-OS of 23.9 points (95% confidence interval [CI]: 20.3 to 27.5 points) at 1 month, 27.4 points (95% CI: 24.2 to 30.6 points) at 6 months, 27.4 points (95% CI: 24.1 to 30.8 points) at 12 months, along with substantial increases in Short Form-12 scores and EuroQol-5D utilities (all p < 0.003 compared with baseline). Nonetheless, 39% of patients had a poor outcome after TAVR. Baseline factors independently associated with poor outcome included wheelchair dependency, lower mean aortic valve gradient, prior coronary artery bypass grafting, oxygen dependency, very high predicted mortality with surgical aortic valve replacement, and low serum albumin.
Conclusions Among patients with severe aortic stenosis, TAVR with a self-expanding bioprosthesis resulted in substantial improvements in both disease-specific and generic health-related quality of life, but there remained a large minority of patients who died or had very poor quality of life despite TAVR. Predictive models based on a combination of clinical factors as well as disability and frailty may provide insight into the optimal patient population for whom TAVR is beneficial. (Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902)
Aortic stenosis is the most common form of valvular heart disease in the elderly and is associated with high morbidity and mortality once cardiac symptoms develop (1). In patients who are at extreme risk for serious complications during or after surgery, transcatheter aortic valve replacement (TAVR) has been shown to result in substantial reductions in mortality and improvement in quality of life compared with standard therapy (2,3). Despite these health benefits, patients at extreme risk who undergo TAVR have high rates of both short- and long-term mortality, with mortality rates of 30% and 43% at 1 and 2 years, respectively (2,4). Moreover, given the advanced age and multiple comorbid conditions that are invariably present in the extreme risk population, improvements in quality of life may be of even greater importance than improved survival.
The CoreValve transcatheter heart valve (Medtronic, Inc., Minneapolis, Minnesota) is a self-expanding bioprosthesis that is widely used outside of the United States. In a recently completed trial, the CoreValve heart valve was shown to be safe and effective for patients with symptomatic severe aortic stenosis at extreme risk for surgical valve replacement (5), but the quality of life benefits of this device are unknown. To address this gap in knowledge, we sought to characterize health status outcomes among patients at extreme surgical risk who were enrolled in the CoreValve U.S. Pivotal Trial. Our secondary objective was to identify pre-procedural patient characteristics (including comorbidities, surgical risk scores, and measures of frailty and disability) associated with a poor outcome after self-expanding TAVR.
Study design and patient population
The design and results of the CoreValve U.S. Extreme Risk Pivotal Trial have been reported previously (5). Briefly, the trial enrolled patients with severe aortic stenosis and New York Heart Association functional class II, III, or IV heart failure symptoms. Patients were classified as extreme risk if the 30-day risk of mortality or irreversible morbidity was estimated to be ≥50% by 2 cardiac surgeons and 1 interventional cardiologist (5). In the screening process, each patient was reviewed in detail by a national screening committee that included at least 2 cardiac surgeons and 1 interventional cardiologist, each of whom had to agree that the patient met eligibility, risk, and imaging criteria for the trial. After confirmation by the trial oversight committee, patients underwent TAVR via an iliofemoral approach, using the Medtronic self-expanding CoreValve system (Medtronic, Inc.). The study was approved by the institutional review board at each site, and all patients provided written informed consent prior to participation.
Health status assessment
Disease-specific and generic health status were assessed at baseline and at 1, 6 and 12 months after enrollment using written questionnaires. Questionnaires were administered either during in-person visits to the study sites or by mail. Disease-specific health status was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), a 23-item self-administered questionnaire that assesses specific health domains pertaining to heart failure: symptoms, physical limitation, social limitation, self-efficacy, and quality of life (6). The individual domains can be combined into an overall summary score (OS), which was the pre-specified primary endpoint for this study. Values for all KCCQ domains and the summary score range from 0 to 100, with higher scores indicating less symptom burden and better quality of life. Prior studies have shown that the KCCQ-OS generally correlates with New York Heart Association functional class as follows: class I: KCCQ-OS 75 to 100; class II: 60 to 74; class III: 45 to 59; and class IV: 0 to 44 (7,8). Changes in the KCCQ-OS of 5, 10, and 20 points correspond to small, moderate, or large clinical improvements, respectively (7). The KCCQ has been shown to be a reliable, responsive, and valid measure of symptoms, functional status, and quality of life among a variety of patients with heart failure symptoms, including those with severe, symptomatic aortic stenosis (8).
Generic health status was evaluated with the Medical Outcomes Study Short Form-12 (SF-12) questionnaire (9) and the EuroQol-5D (EQ-5D) (10). Derived from the Short Form-36, the SF-12 provides mental and physical summary scores that are scaled to overall U.S. norms of 50 with standard deviations of 10. Higher scores indicate better quality of life, and the minimum clinically-important difference for the SF-12 summary scores is 2 to 2.5 points (11). The EQ-5D is a generic health status measure consisting of 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), which can be converted to utilities using an algorithm developed for the U.S. population (12). Utilities are preference-weighted health status assessments with scores that range from 0 to 1, with 1 representing perfect health and 0 corresponding to the worst imaginable health state (13).
At each follow-up time-point, scores for each of the disease-specific and generic health status scores were compared with baseline values using paired t tests. At each time-point, the baseline value comparator consisted of only those patients that had a quality-of-life assessment performed at that time-point, thereby addressing survivor bias caused by attrition of sicker patients over time.
To provide additional insight into the changes in health status over time, we also performed several categorical analyses. First, among the survivors at each time-point, we calculated the proportion of patients who had a moderate (≥10 points) or large (≥20 points) improvement in the KCCQ-OS compared with baseline. Second, we calculated the proportion of enrolled patients at each time-point with favorable and excellent outcomes, defined as being both alive and having a moderate or large improvement, respectively, in the KCCQ-OS compared with baseline. For these latter metrics, death was considered to be the same as failure to improve by the specified amount. The 95% confidence interval for proportion was based on the binomial distribution.
Finally, we calculated the proportion of patients with a poor outcome at 6 months after TAVR. For this analysis, a poor outcome was defined as any of the following at 6 months after TAVR: 1) death; 2) KCCQ-OS <45 points; or 3) decrease of ≥10 points on the KCCQ-OS from baseline (14). We then used multivariable logistic regression to identify pre-procedural factors associated with poor 6-month outcome. Candidate variables for this analysis are listed in Online Table 1. We used stepwise selection to identify variables associated with poor outcome at a significance level of p ≤ 0.10, and then refit the model with the identified variables. The baseline score on the KCCQ-OS was forced into the model.
All statistical analyses were performed using SAS software, version 9.2 (SAS Institute, Inc., Cary, North Carolina). A 2-sided p value <0.05 was considered statistically significant with no correction for multiple comparisons.
Between February 2011 and August 2012, 737 patients with severe symptomatic aortic stenosis and at extreme surgical risk from 41 U.S. sites were approved by the trial screening committee for inclusion in the CoreValve U.S. Extreme Risk Study. Of these, 18 were not enrolled (due to withdrawal by the patient or treating physician), 85 were roll-in patients or were treated in a separate registry with the 23-mm CoreValve, and 147 were planned for noniliofemoral access, leaving 487 patients in the intention-to-treat population. Sixteen patients subsequently did not undergo iliofemoral TAVR, and an additional 35 did not have baseline health status data. With the exception of being somewhat younger, patients with missing baseline health status assessments were generally similar to those patients with complete baseline data (Online Table 2). As such, the analytic population for our study included 436 patients who underwent iliofemoral TAVR and had baseline health status assessment (Figure 1).
The baseline characteristics of these patients are summarized in Table 1. The mean age was 84 years, and 49% were male. The mean aortic valve gradient was 48 mm Hg, and 92% were classified as New York Heart Association functional class III to IV. The patients had a high burden of chronic medical conditions, including 30% who were on home oxygen and 16% who were wheelchair bound. Both disease-specific and generic health status measures demonstrated substantial impairment at baseline. The mean KCCQ-OS score was 37.9 ± 22.2 (roughly comparable to New York Heart Association functional class IV); the mean SF-12 physical summary score was 28.5 ± 8.3 (∼2 SD below the standard for the general U.S. population); the mean SF-12 mental summary score was 45.8 ± 12.3; and the mean baseline EQ-5D score was 0.65 ± 0.24.
Follow-up health status
Follow-up health status data were available for 58% of surviving patients at 1 month, 74% at 6 months, and 77% at 12 months after TAVR. Mean scores and the mean changes from baseline at each follow-up time-point are summarized in Table 2 and Figure 2. On average, KCCQ-OS scores increased by 23.9 points at 1 month and 27.4 points at 6 and 12 months after TAVR compared with baseline (p < 0.001 for all comparisons). The individual KCCQ subscales showed similar patterns (Table 2, Figure 2). The SF-12 physical and mental summary scores improved by ∼5 points at 6 and 12 months compared with baseline, and EQ-5D utility values also increased substantially at all time-points as well (p < 0.003 for all comparisons) (Table 2, Figure 3).
The rates of moderate and large improvements in KCCQ-OS and favorable and excellent outcomes at each time-point are shown in Table 3. Among responders to the surveys, the proportion of patients with large KCCQ-OS improvements was 58% at 1 month and 59% at 12 months after TAVR. The proportion of treated patients with an excellent outcome (i.e., alive with a large improvement in KCCQ-OS) was 52% at 1 month and 41% at 12 months after TAVR.
Factors associated with poor outcome
The proportion of patients with a poor outcome was 39% at 6 months (22% death, 16% very poor quality of life, and 1.4% quality of life decline). Pre-procedural factors that were independently associated with a poor outcome are shown in Table 4. Patients who were wheelchair-bound were 2.6 times more likely to have a poor outcome after TAVR, compared with patients who were able to ambulate (95% confidence interval: 1.3 to 5.2). In addition, having a lower aortic valve gradient, having previous coronary artery bypass grafting, and requiring home oxygen were strongly associated with a poor outcome. The association between the Society of Thoracic Surgeons risk score (i.e., the predicted risk of operative mortality with surgical aortic valve replacement) and a poor outcome of TAVR was only significant for an STS mortality risk >15%.
When patients were compared according to whether they met VARC criteria for procedural success (15), those patients who achieved procedural success had greater improvements in health status (mainly at the 1-month time-point) and were more likely to experience favorable or excellent outcomes at all time-points (Online Tables 3 and 4). After adjusting for those pre-procedure factors summarized in Table 4, procedural success was inversely associated with a poor outcome after TAVR (adjusted odds ratio: 0.40, p < 0.001).
The CoreValve U.S. Extreme Risk Study has demonstrated that TAVR using a self-expanding bioprosthesis is safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical replacement (5). In this pre-specified quality-of-life substudy, we found that among patients at prohibitive risk of surgical complications, treatment with the CoreValve device via a transfemoral approach leads to substantial improvement in disease-specific and general health status. These benefits were evident by 1 month after TAVR and were followed by modest additional improvement through 12 months. In addition, we identified several factors, including comorbid conditions, disability/frailty, and valve physiology, that were independently associated with poor outcomes after TAVR—a finding that, if replicated in future studies, may help to inform clinical decision-making in patients considering TAVR.
We observed substantial improvements in both disease-specific and generic health status measures after TAVR. Among surviving patients, the mean improvements in the KCCQ-OS scale were >20 points at all follow-up time-points; in previous studies, a 5-point change in this scale has been found to be clinically meaningful and also correlates with important differences in survival and health care costs (16,17). Furthermore, we observed increases in SF-12 physical and mental component scores of ∼5 points. This increment represents twice the minimum clinically-important difference for an individual patient (11) and is roughly comparable to reversing 10 years of normal decline in health in the general population (18).
Previous studies have also reported substantial improvements in health status after surgical aortic valve replacement (19,20) and TAVR (3,21–23). However, most of these studies have only examined changes in generic health status. To date, only 1 other multicenter trial, the PARTNER (Placement of AoRTic TraNscathetER Valve) trial, has rigorously evaluated disease-specific health status after TAVR (3,23). In PARTNER Cohort B, which included patients who were considered surgically inoperable (i.e., similar to the CoreValve Extreme Risk U.S. trial), TAVR resulted in substantial improvement in both disease-specific and generic health status. Although cross-trial extrapolation should be considered purely exploratory, the health status outcomes observed in the CoreValve Extreme Risk and PARTNER B trials were roughly comparable with respect to both disease-specific and generic health status measures through the first year of follow-up (Online Table 5). The current study thus confirms that the health status benefits of TAVR are not restricted solely to balloon-expandable transcatheter valves, but also apply to the CoreValve self-expanding transcatheter valve.
Although many patients have excellent outcomes after TAVR, we also found that nearly 40% of patients did not experience meaningful improvements in survival or functional status at 6 months after TAVR. We identified pre-operative factors that are associated with poor outcomes, which included measures of disability and frailty (e.g., wheelchair dependency and low serum albumin), comorbidity (prior coronary artery bypass grafting, extremely high predicted surgical mortality, and oxygen dependency) and valve physiology (mean aortic valve gradient). Compared with prior work investigating predictors of poor outcome after TAVR in the PARTNER population (both inoperable and high-risk patients) we found some similar predictors (e.g., poor functional status, oxygen dependence, and low aortic valve gradient) and some novel predictors (e.g., low albumin and prior bypass surgery) in the CoreValve population (14). Further work is needed to establish a model that can be applied across all TAVR patients, regardless of valve type and surgical risk, such that patients at high risk for poor outcomes may be identified prospectively. In the future, this information could be invaluable to help both patients and physicians decide whether or not to undergo TAVR and also to set realistic expectations for recovery.
First and foremost, the CoreValve U.S. Extreme Risk Study was a single-arm trial, and as such, there was no control arm to which the results of TAVR could be compared. Originally, the study design intended to randomize patients to CoreValve implantation versus medical therapy. However, after publication of the results from Cohort B of the PARTNER trial (2), the investigators and the U.S. Food and Drug Administration felt that it was no longer ethical to randomize these patients to standard therapy. Consequently, we were limited to comparing health status after TAVR with each patient’s individual baseline. Of note, the control arm of the PARTNER B trial, which enrolled a similar patient population, demonstrated modest short-term improvements in health status (most likely attributable to the high rate of balloon aortic valvuloplasty) that were not sustained at 1 year (3). Second, the proportion of patients with missing quality-of-life data increased modestly over time due to both mortality and nonresponse among surviving patients. To address this issue, we also reported categorical outcome variables that included all treated patients (as opposed to responding patients; i.e., excellent outcome), thereby treating patients with missing data (including death) as “treatment failures.” If sicker patients were less likely to respond, we may have overestimated the extent of clinical benefit. Third, our study was restricted to the iliofemoral cohort of the CoreValve extreme risk trial and included only 12 months of follow-up. Thus, the durability of the observed health status improvements, as well as the health status improvement after noniliofemoral procedures, remains unknown.
In patients with severe symptomatic aortic stenosis who are at extreme risk of surgical complications, TAVR using the CoreValve self-expanding aortic bioprosthesis via a transfemoral approach resulted in large improvements in both disease-specific and generic health status measures in the majority of surviving patients. Nonetheless, similar to prior studies with a balloon expandable transcatheter valve, there remains a substantial minority of patients who do not derive a meaningful survival or quality-of-life benefit from TAVR. A combination of pre-procedural clinical, frailty, disability. and physiological factors may provide further insight into identifying patients who are at high risk for poor outcomes.
The authors thank Holly Vitense and Jane Moore for their administrative assistance.
This study is funded by Medtronic. The industry sponsors reviewed the study design and were involved in data management for the CoreValve U.S. Pivotal trial. The sponsor had no role in the analysis and interpretation of the data or in the preparation of the manuscript.
Dr. Reynolds has received consulting fees from Medtronic. Dr. Magnuson has received grant support from Abbott Vascular, AstraZeneca, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Eli Lilly, and Medtronic. Dr. Stoler serves on medical advisory boards for Medtronic and Boston Scientific; and has served on the Speakers Bureau of Volcano. Dr. Kleiman has received fees through his institution from Medtronic for didactic training sessions. Dr. Reardon has received honoraria from Medtronic for participation on a surgical advisory board. Dr. Adams has received royalties through his institution from Medtronic for a patent related to a tricuspid-valve annuloplasty ring and from Edwards Lifesciences for a patent related to degenerative valvular disease–specific annuloplasty rings; and is national co-principal investigator on the Medtronic CoreValve Trial. Dr. Popma has received honoraria from Boston Scientific, Abbott Vascular, and St. Jude Medical for participation on medical advisory boards. Dr. Cohen has received grant support from Abbott Vascular, AstraZeneca, Biomet, Boston Scientific, Edwards Lifesciences, Eli Lilly, Janssen Pharmaceuticals, and Medtronic; and has received consulting fees from Abbott Vascular, AstraZeneca, Eli Lilly, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Osnabrugge and Arnold contributed equally to this work.
- Abbreviations and Acronyms
- Kansas City Cardiomyopathy Questionnaire
- Medical Outcomes Study Short Form-12
- transcatheter aortic valve replacement
- Received April 21, 2014.
- Revision received July 23, 2014.
- Accepted August 14, 2014.
- American College of Cardiology Foundation
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