Author + information
- Received March 11, 2011
- Revision received May 6, 2011
- Accepted May 24, 2011
- Published online October 4, 2011.
- David J. Cohen, MD, MSc⁎,⁎ (, )
- Joshua M. Stolker, MD†,
- Kaijun Wang, PhD⁎,
- Elizabeth A. Magnuson, ScD⁎,
- Wayne M. Clark, MD‡,
- Bart M. Demaerschalk, MD, MSc§,
- Albert D. Sam Jr, MD∥,
- James R. Elmore, MD¶,
- Fred A. Weaver, MD, MMM#,
- Herbert D. Aronow, MD, MPH⁎⁎,
- Larry B. Goldstein, MD††,
- Gary S. Roubin, MD, PhD‡‡,
- George Howard, DrPH§§,
- Thomas G. Brott, MD∥∥,
- CREST Investigators
- ↵⁎Reprint requests and correspondence:
Dr. David J. Cohen, Saint Luke's Mid America Heart Institute, 4401 Wornall Road, Kansas City, Missouri 64111
Objectives The purpose of this study was to compare health-related quality of life (HRQOL) outcomes in patients treated with carotid artery stenting (CAS) versus carotid endarterectomy (CEA).
Background In CREST (Carotid Revascularization Endarterectomy versus Stenting Trial), the largest randomized trial of carotid revascularization to date, there was no significant difference in the primary composite endpoint, but rates of stroke and myocardial infarction (MI) differed between CAS and CEA. To help guide individualized clinical decision making, we compared HRQOL among patients enrolled in the CREST study. We also performed exploratory analyses to evaluate the association between periprocedural complications and HRQOL.
Methods We measured HRQOL at baseline, and after 2 weeks, 1 month, and 1 year among 2,502 patients randomly assigned to either CAS or CEA in the CREST study. The HRQOL was assessed using the Medical Outcomes Study Short-Form 36 (SF-36) and 6 disease-specific scales designed to study HRQOL in patients undergoing carotid revascularization.
Results At both 2 weeks and 1 month, CAS patients had better outcomes for multiple components of the SF-36, with large differences for role physical function, pain, and the physical component summary scale (all p < 0.01). On the disease-specific scales, CAS patients reported less difficulty with driving, eating/swallowing, neck pain, and headaches but more difficulty with walking and leg pain (all p < 0.05). However, by 1 year, there were no differences in any HRQOL measure between CAS and CEA. In the exploratory analyses, periprocedural stroke was associated with poorer 1-year HRQOL across all SF-36 domains, but periprocedural MI or cranial nerve palsy were not.
Conclusions Among patients undergoing carotid revascularization, CAS is associated with better HRQOL during the early recovery period as compared with CEA—particularly with regard to physical limitations and pain—but these differences diminish over time and are not evident after 1 year. Although CAS and CEA are associated with similar overall HRQOL at 1 year, event-specific analyses confirm that stroke has a greater and more sustained impact on HRQOL than MI. (Carotid Revascularization Endarterectomy versus Stenting Trial [CREST]; NCT00004732)
Carotid endarterectomy (CEA) plus medical management of modifiable risk factors is an established approach for primary and secondary stroke prevention for patients with significant carotid atherosclerosis (1–4). Some patients, however, are considered poor candidates for surgical revascularization because of anatomic complexity or medical comorbidities, and adverse outcomes occur more frequently in these patients (5). Carotid artery stenting (CAS) was developed as a less invasive option for carotid revascularization. The results of clinical trials of CAS have varied, with several finding acceptable rates of safety and efficacy (6–11), but others reporting higher rates of adverse events as compared with CEA (12–14).
The CREST (Carotid Revascularization Endarterectomy versus Stenting Trial) recently compared CAS and CEA in patients at low risk of surgical complications and found no difference in the primary composite endpoint of stroke, myocardial infarction (MI), or death during the periprocedural period, or ipsilateral stroke within 4 years (15). Individual endpoints, however, varied between treatment groups, with patients assigned to CAS having higher rates of stroke and patients assigned to CEA having higher rates of MI. These differences in risk of periprocedural stroke and MI between the 2 treatment groups in the CREST study have led to considerable debate regarding the optimal treatment strategy for patients undergoing carotid revascularization (16–19).
In light of this ongoing controversy, evaluation of health-related quality of life (HRQOL) may help further inform individualized clinical decision making for patients undergoing carotid revascularization. Prior studies have suggested less impairment during the early recovery period after CAS as compared with CEA, but these differences were brief and limited to highly sensitive, disease-specific outcomes and physical role limitations (20,21). Moreover, these findings were based on nonrandomized studies or small randomized trials that enrolled highly selected patients. To address these gaps in knowledge, we performed a prospectively planned analysis of HRQOL among patients randomly assigned to CAS or CEA in the CREST study. In addition, we performed exploratory analyses to evaluate the association between periprocedural complications and HRQOL during 1 year of follow-up.
Details of the CREST study design and primary outcomes have been described previously (15,22). In brief, the CREST study was a randomized trial of CAS versus CEA in both symptomatic and asymptomatic adult patients with significant carotid stenosis by ultrasonography, computed tomography, magnetic resonance imaging, or conventional angiography. Exclusion criteria were prior severe stroke, atrial fibrillation, unstable angina, or acute MI within the past 30 days. Clinical and anatomical suitability for either revascularization approach was required, after which patients were enrolled and treated by certified operators (based on adequate procedural volume and low complication rates) at 117 centers in the United States and Canada (23).
Risk factor modification and aspirin were recommended for all patients, and CEA was performed according to published guidelines. Patients undergoing CAS received the Rx Acculink stent and Rx Accunet embolic protection device (Abbott Vascular Solutions, Santa Clara, California) whenever feasible. Anticoagulation therapy was administered according to local practice, and thienopyridine therapy was recommended for a minimum of 4 weeks after the procedure. Neurologic evaluation at scheduled intervals, including the use of standardized stroke assessment measures, was performed in all patients. Cardiac biomarkers and electrocardiograms were obtained in all patients before and after the index procedure and after signs or symptoms of cardiac ischemia. Approval was obtained from the Human Studies Committee at each enrolling site, and all patients provided written informed consent before participation.
The periprocedural period was defined as the time from randomization through 30 days after revascularization (or 36 days after randomization when the procedure was not performed within 30 days of randomization). Stroke was defined as an acute neurologic event with focal findings consistent with cerebral ischemia that lasted for 24 h or more. MI was defined as the presence of elevated cardiac biomarkers at least twice the upper limit of normal at the site's hospital laboratory, plus either: 1) electrocardiographic changes consistent with coronary ischemia; or 2) symptoms of a coronary event. Cranial nerve palsy was defined as evidence of new cranial nerve injury on either the post-procedure or 1-month neurologic assessment.
Health status assessment
The HRQOL was assessed using standardized questionnaires at baseline, and at 2 weeks and 1 month after the procedure and 1 year after randomization in all patients. The baseline and 1-year questionnaires were administered in written fashion, whereas the 2-week and 1-month assessments were performed by telephone by a single, trained interviewer using the same questionnaires. Overall health status was assessed using the Medical Outcomes Study Short-Form 36 (SF-36) (24). The SF-36 is a commonly used health survey that assesses 8 dimensions of health status (physical functioning, physical role limitations, bodily pain index, vitality, general health, social functioning, emotional role limitations, and mental health) and has been validated in patients with cardiovascular disease, stroke, and in the general population (24–27). Scores for the SF-36 range from 0 to 100, with higher scores indicating better health status; a difference of 5 to 10 points is considered a clinically important change for an individual subject (smaller differences may be important for group comparisons) (28). In addition, the SF-36 provides summary scales for overall physical and mental health, which are standardized to a population mean of 50 and a standard deviation of 10, and for which individual differences of 2.5 to 5 points are considered clinically meaningful.
In addition to the SF-36, 6 disease-specific modified Likert scales designed specifically for comparison of CAS versus CEA were used to evaluate aspects of functional status and symptoms that may be impacted by 1 or both of the treatments (21,22). The first 3 questions assessed the level of difficulty each patient experienced with walking, eating/swallowing, and driving (1 = no difficulty at all, 2 = mild difficulty, 3 = moderate difficulty, 4 = severe difficulty, 5 = unable to perform this activity). The next 3 questions evaluated how often patients were bothered by headaches, neck pain, and leg pain during the previous week (1 = not at all bothered, 2 = bothered a little bit, 3 = moderately bothered, 4 = bothered quite a bit, 5 = extremely bothered). Two additional questions asked patients to rate their level of pain (0 to 10 scale, in which 0 = no pain and 10 = worst possible pain) and to estimate the number of times pain medications were needed during the past week.
All primary analyses of HRQOL were performed on an intention-to-treat basis. Patients who died during the study were included in the analyses of HRQOL outcomes up until the time of death. Primary findings were based on raw data, and sensitivity analyses were performed using multiple imputation to estimate missing HRQOL scores for surviving patients (29). Covariates used in the multiple imputation models included all of the available HRQOL scores, treatment assignment, and baseline clinical and demographic characteristics. An on-treatment analysis was also performed comparing patients who underwent CAS versus patients who underwent CEA (regardless of initial treatment assignment). Health status scores were compared between the CAS and CEA groups using analysis of covariance for continuous variables and ordinal logistic regression for categorical variables, adjusting for symptomatic status and baseline scores. In addition, to account for the effect of ascertainment bias (in case patients with more severe periprocedural stroke or MI were unable to provide adequate health status data), these analyses were repeated after imputing “worst case scores” to patients with periprocedural events who had missing health status data during follow-up.
For the exploratory analyses of the impact of clinical events on HRQOL, only periprocedural events were considered because there was not a systematic attempt to capture late MI, and rates of late stroke and late MI were extremely low and similar between treatment groups during longer-term follow-up. For each HRQOL outcome, we used multiple linear regression to estimate the independent change associated with the events of interest (stroke, MI, cranial nerve palsy) while adjusting for age, sex, diabetes mellitus, history of cardiovascular disease, and symptomatic status at randomization.
For all analyses, a p value <0.05 was considered statistically significant; no adjustments were performed for multiple comparisons. All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, North Carolina).
Patient population and key clinical outcomes
Between December 2000 and July 2008, 2,502 patients were randomly assigned to either CAS (n = 1,262) or CEA (n = 1,240). Mean age was 69 years, 65% of patients were male, the overwhelming majority of patients had at least 1 cardiovascular risk factor, and >85% of carotid stenoses were at least 70% in severity. Overall, 47% of patients were asymptomatic. As previously reported, rates of the primary composite endpoint were similar for CAS and CEA (7.2% and 6.8%, respectively; p = 0.51) (15). Periprocedural stroke was more common with CAS (4.1% vs. 2.3%, p = 0.01), and periprocedural MI was more common with CEA (2.3% vs. 1.1%, p = 0.03). Cranial nerve palsy was noted in 0.3% and 4.7% of the CAS and CEA patients, respectively (p < 0.01).
The CAS and CEA groups had similar response rates for the HRQOL assessments both at baseline and during follow-up (85% to 90% among surviving patients at all timepoints) (Fig. 1). Results from the analyses of the general health status outcomes are summarized in Table 1 and Figure 2.
At baseline, all SF-36 subscale scores were similar for the 2 groups. Compared with the CEA group, CAS patients had better scores at 2 weeks for 5 of the 8 SF-36 subscales (all p ≤ 0.01), with the role physical subscale demonstrating the greatest difference between treatment groups. By 1-month follow-up, only 3 of the 8 subscales had better scores in the CAS group, and there were no significant differences for any of the SF-36 subscales at 1 year. Findings were unchanged when multiple imputation was used to account for missing data (Online Table 1), when the analyses were repeated according to treatment received (Online Table 2), or when using “worst case scores” for missing health status data among patients experiencing periprocedural events (Online Tables 3 and 4).
Results for the disease-specific Likert scales are summarized in Figures 3 and 4⇓⇓. At 2 weeks, CAS patients reported less difficulty eating or swallowing, less difficulty driving, and less impairment from headaches and neck pain as compared with CEA patients. However, CAS patients also reported more difficulty walking and more impairment from leg pain. By the 1-month follow-up visit, CAS patients continued to experience less difficulty eating or swallowing and less impairment from headaches and neck pain, but more limitations from leg pain than patients in the CEA group. There were no significant differences in any of the other disease-specific measures at 1 month, and no differences between the groups for any measure by the 12-month assessment. These results were unchanged when multiple imputation was used to account for missing data (Online Figs. 1 and 2), or for the on-treatment analysis (Online Figs. 3 and 4).
For ratings of overall pain on a 0 to 10 scale, CAS and CEA patients reported similar scores at baseline (mean score 3.1 vs. 3.0, p = 0.23). At the 2-week assessment, CAS patients reported significantly lower pain scores than CEA patients (mean 2.9 vs. 3.1, p < 0.01), but these differences were no longer present by the 1-month assessment (mean 3.0 vs. 3.1, p = 0.16) and the 12-month assessment (mean 3.0 vs. 3.0, p = 0.86). Similarly, CAS patients reported less need for pain medications during the week preceding the 2-week assessment (odds ratio: 0.64 vs. CEA patients, confidence interval: 0.54 to 0.76, p < 0.01), but there was no difference between the groups at the 1-month evaluation (odds ratio: 1.01, 95% confidence interval: 0.85 to 1.21, p = 0.90) or 12-month evaluation (odds ratio: 1.06, 95% confidence interval: 0.88 to 1.27, p = 0.57).
Impact of periprocedural stroke and MI events on HRQOL
The results of the exploratory analyses to estimate the impact of periprocedural events on 1-year health status domains are summarized in Table 2. Patients who had a periprocedural stroke reported worse HRQOL scores at 1 year for 7 of 8 domains of the SF-36 when compared with patients who had no periprocedural events. In contrast, periprocedural MI was associated with worse general health perception at 1 year, but no differences in any other health status domains. Cranial nerve palsy was not associated with a sustained impact on HRQOL.
In this pre-specified substudy of the CREST study, we found that patients undergoing CAS had better HRQOL during the first month after carotid revascularization relative to patients undergoing CEA. These benefits were most pronounced for measures of overall physical function and pain. In addition, disease-specific measures demonstrated that limitations related to ambulation and leg discomfort were more common after CAS, whereas limitations related to eating and neck discomfort were more common after CEA. All of these differences between CAS and CEA were modest in magnitude and were no longer present at 1-year follow-up.
Exploratory analyses of the impact of periprocedural events on health status revealed a strong and consistent impairment of HRQOL at 1 year among those patients who experienced a periprocedural stroke when compared with patients who did not. For most scales, these differences exceeded values generally considered to be clinically meaningful. In contrast, there was minimal or no long-term impairment in health status among patients who had a periprocedural MI or cranial nerve palsy. To date, this is the largest study comparing recovery patterns among patients randomly allocated to either CAS or CEA and the first study to directly evaluate the impact of periprocedural events on HRQOL after carotid revascularization.
These results are consistent with previous results from 1 nonrandomized evaluation of CAS and CEA (20), and are also similar to findings from the SAPPHIRE (Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy) randomized clinical trial (6). In the quality of life substudy of the SAPPHIRE study, patients reported fewer symptoms and less impairment of physical function at the 2-week visit when undergoing CAS versus CEA, but these differences were no longer apparent at 1 month (21). The present analysis from the CREST study demonstrated somewhat greater functional status benefits of CAS over CEA at 2 weeks, and in contrast to the SAPPHIRE study, these differences were largely maintained at the 1-month follow-up visit for both generic and disease-specific assessments.
There are several potential explanations for the differences between the CREST study and the SAPPHIRE study results. First, the CREST study enrolled nearly 8 times as many patients as the SAPPHIRE study, and the additional quality of life differences in the CREST study may simply reflect its greater statistical power. Alternatively, the differences between trials may be explained by differences in patient populations, as patients in the SAPPHIRE trial had a greater burden of comorbidity due to the enrollment requirement of high surgical risk. As a result, the healthier patient population in the CREST study may have experienced a more benign recovery period, which would allow differences in health status after CAS versus CEA to be more readily detected. Regardless of the underlying mechanisms, HRQOL outcomes were similar for the 2 treatment groups during longer-term follow-up for both the CREST study and SAPPHIRE study populations.
In addition to the pre-specified analyses comparing CAS versus CEA, we performed post-hoc analyses to explore in greater depth the impact of early events on late health status. These exploratory analyses demonstrated that health status at 1 year was influenced by the occurrence of periprocedural stroke, but not by either MI or cranial nerve palsy. These findings are not particularly surprising. Most studies of stroke have found persistent disability in 15% to 30% of surviving patients (30,31), which would be expected to result in impaired physical function, role function, and general health perception. In contrast, after the initial short-term recovery phase, patients with MI generally have health status that is similar to the general population unless the MI is large and associated with clinical heart failure or a protracted recovery period (32,33). Notwithstanding the results of our analysis, MI should not be construed as a benign event as it has been associated with a poor long-term prognosis in multiple settings (34–36).
Conversely, the lack of association between cranial nerve palsy and quality of life was somewhat unexpected, as ∼5% have been reported to be persistent after CEA in previous studies (with rates ranging from 3% to 23%) (37). The effects of cranial nerve injury can be quite variable, however, ranging from complete facial palsy to mild paresthesias of the tongue. It is also possible that the SF-36 was insensitive to the degree of disability and HRQOL impairment caused by cranial nerve palsies in the CREST study population.
It may seem counterintuitive that overall health status and quality of life did not differ after CAS or CEA despite the higher rate of stroke after CAS and the significant impact of stroke on 1-year HRQOL in the study population. It is important to note, however, that the vast majority of patients (>95% in both treatment groups) did not experience a stroke—thus limiting the impact of such events on any between-group measures of HRQOL. Indeed, a trial powered to detect a 0.5 point difference in role physical function (the expected between-group difference based on the CREST study results) would require randomization of >200,000 patients.
Although 1-year HRQOL did not differ between the CAS and CEA groups, some patients may favor 1 or the other approach to carotid revascularization according to their individual values and preferences. Given the greater impact of stroke on late health status and the fact that stroke prevention is the principal indication for carotid revascularization, many patients may prefer CEA over CAS, because CEA minimizes the risk of such events. Conversely, patients at very low risk of periprocedural stroke (e.g., younger, asymptomatic patients) may consider the more rapid recovery and lesser health status impairment during the first month after revascularization to be a compelling argument for CAS.
As with any clinical trial, the results of our study may not be generalizable to all patients who are candidates for carotid revascularization. Nonetheless, the large number of sites and operators included in the CREST study suggests that our results should apply to many other centers and operators who are able to meet the volume and training criteria required for CREST study certification (15,23). In addition, ∼10% of the CREST study patients did not receive their assigned revascularization procedure, mainly related to patients who were enrolled on the basis of noninvasive carotid imaging and were subsequently found to be anatomically unsuitable for CAS—many of whom then underwent CEA. The effect of such treatment crossovers would be expected to dilute any true treatment differences, however, and the similarity of our intention-to-treat and on-treatment results suggests that the extent of bias introduced was small. Finally, some quality of life data were missing at each follow-up timepoint. Nonetheless, the response rates were quite high considering the patient population, and it is reassuring that the results were unchanged in analyses incorporating multiply imputed data.
Among patients with clinical indications and anatomy suitable for either surgical or percutaneous carotid revascularization, CAS was associated with better HRQOL during the early recovery period as compared with CEA. These differences were less pronounced at 1 month than at 2 weeks and were no longer present after 1 year. Although stroke was more common after CAS than after CEA and was associated with clinically important health status impairment throughout follow-up, the small absolute difference in event rates did not result in a detectable difference in long-term HRQOL between the 2 treatments. These health status data, in conjunction with evidence (from CREST and other trials) regarding the absolute and relative risk of important clinical events, should help to better inform patients and clinicians regarding the risks and benefits of CAS versus CEA, and thus help guide patient-centered decision making.
For supplementary figures and tables, please see the online version of this article.
This study is supported by the National Institute of Neurological Disorders and Stroke (NINDS) and by the National Institutes of Health (R01 NS 038384), with supplemental funding from Abbott Vascular Solutions (formerly Guidant), including donations of Accunet and Acculink systems equivalent to ∼15% of the total study cost for the CREST study centers in Canada and to the CREST study centers in the U.S. that were at Veterans Affairs sites. Dr. Cohen has received research support from Boston Scientific, Abbott Vascular, Medtronic, Edwards Lifesciences, MedRad, Merck/Schering-Plough, and Eli Lilly-Daiichi Sankyo; is a consultant to Merck/Schering-Plough, Eli Lilly, Medtronic, and Cordis; and has served on the Speakers' Bureau for Eli Lilly and The Medicines Company. Dr. Stolker has served on the Speakers' Bureau for AstraZeneca. Dr. Magnuson has received research support from Eli Lilly-Daiichi Sankyo, Sanofi-Aventis, and Bristol-Myers Squibb; and has received honoraria from Sanofi-Aventis. Dr. Aronow has served on the Speakers' Bureau/Advisory Board for Medtronic. Dr. Goldstein has served as consultant and Advisory Board member for Abbott and ACT-1 Trial Clinical Oversight Committee. Dr. Roubin has received royalties from Abbott Vascular, Inc. and Cook, Inc. Dr. Howard has served as consultant and Advisory Board member for Bayer Healthcare and is a member of the ARRIVE Executive Committee. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- carotid artery stenting
- carotid endarterectomy
- confidence interval
- health-related quality of life
- myocardial infarction
- odds ratio
- Medical Outcomes Study Short-Form 36
- Received March 11, 2011.
- Revision received May 6, 2011.
- Accepted May 24, 2011.
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