Abstract
Objective
To assess the prognostic significance of exercise capacity in patients with ischemic left ventricular (LV) dysfunction eligible for coronary artery bypass surgery (CABG).
Background
Poor exercise capacity is associated with mortality, but it is not known how this influences the benefits and risks of CABG compared to medical therapy.
Methods
In an exploratory analysis physical activity was assessed by questionnaire and 6-minute walk test in 1,212 patients before randomization to CABG (n=610) or medical management (n=602) in the STICH trial. Mortality (n=462) was compared by treatment allocation during 56 (IQR 48 to 68) months follow-up for subjects able (n=682) and unable (n=530) to walk 300m in 6 minutes and with less (Physical Ability Score >55, n= 749) and more (PAS ≤55, n=433) limitation by dyspnea or fatigue.
Results
Compared to medical therapy mortality was lower for patients randomized to CABG who walked ≥300m (HR 0.77, 95% CI 0.59 to 0.99, p=0.038) and those with a PAS >55 (HR 0.79, 95% CI 0.62 to 1.01, p=0.061). Patients unable to walk 300m or with a PAS ≤55 had higher mortality during the first 60 days with CABG (HR 3.24, 95% CI 1.64 to 6.83, p=0.002) and no significant benefit from CABG during total follow-up (HR 0.95, 95% CI 0.75 to 1.19, p=0.626, interaction p=0.167).
Conclusion
These observations suggest that patients with ischemic LV dysfunction and poor exercise capacity have increased early risk, and similar 5 year mortality with CABG compared to medical therapy, while those with better exercise capacity have improved survival with CABG.
Keywords: coronary disease, heart failure, surgery, trials
Background
Impaired exercise or functional capacity has been associated with increased mortality in healthy general populations,(1) in the elderly,(2,3) and in patients with coronary artery disease(4) and heart failure.(5-8) Most of these studies have assessed exercise capacity by treadmill, bicycle ergometry or corridor walking speed over various distances. In patients with heart failure, the 6-minute walk test has been commonly used to evaluate functional capacity, and a low 6-minute walk distance has been associated with increased total mortality and more hospital admissions for heart failure.(5-8) Impaired functional capacity assessed by questionnaire has also been associated with mortality in heart failure populations.(9-12)
Although the long-term prognostic importance of exercise capacity is well known, it is not certain whether assessing the level of exercise limitation provides useful prognostic information in patients with ischemic left ventricular (LV) dysfunction considered for either coronary artery bypass surgery (CABG) or medical therapy only. It is also unclear whether exercise limitation is best assessed by a formal test of functional capacity, or by a health status questionnaire in this setting. The Society for Thoracic surgeons risk score does not include any objective measure of exercise capacity.(13,14) The EuroScore 2 includes a category ‘poor mobility,’ but this is not defined by objective testing.(15)
The Surgical Treatment for Ischemic Heart Failure (STICH) trial randomized 1212 patients with ischemic LV dysfunction and coronary artery disease suitable for bypass grafting to either medical therapy or CABG.(16) The aim of this exploratory analysis was to determine whether low 6-minute walk distance and/or more limiting dyspnea and/or fatigue assessed by questionnaire(17) predicts increased mortality in the STICH study population. In addition we evaluated whether either measure of physical limitation provides useful information on the balance of benefits and risks of CABG compared to medical treatment in these patients.
Methods
Study Population
Eligible patients had coronary artery disease amenable to CABG and an ejection fraction of 35% or less, as determined at each enrolling site. All patients provided written informed consent. The current analysis included 1212 subjects randomised to medical therapy or medical therapy plus CABG. Patients were eligible for medical therapy alone if they did not have ≥50% left main coronary artery stenosis or Canadian Cardiovascular Society (CCS) class III or IV angina.
During the initial evaluation, information was obtained on demographic variables, clinical characteristics, diagnostic investigations and cardiovascular procedures. Clinical variables recorded at baseline include age, gender, history of renal impairment, defined as serum creatinine >1.5mg/dl, diabetes, peripheral vascular disease, number of diseased coronary arteries with diameter stenosis >75%, LV ejection fraction, LV end systolic volume index, degree of mitral regurgitation, heart rate, history of stroke, CCS angina class, New York Heart Association (NYHA) functional class, and physician diagnosis of depression. Quality of life was assessed from the five item European Quality of Life questionnaire (EQ-5D), with a higher score indicating better quality of life.(18) The baseline characteristics of the study population have been reported in detail elsewhere.(19)
The 6-minute Walk Test
The study protocol included a 6-minute walk test for all study participants. Instructions to patients included “Walk for 6 minutes around this course, covering as much ground as possible during that time. Keep going continuously, if possible, but don't worry if you have to slow down and rest.” If the patient did not attempt the test, ‘patient unable’ was recorded in the case report form.
Physical Ability Assessment by Questionnaire
The Kansas City Cardiomyopathy Questionnaire (KCCQ) (17), a health related quality of life instrument, evaluated the effect of heart failure symptoms on quality of life at baseline. For this analysis, the severity of physical limitation was assessed from the following 6 KCCQ questions. Subjects were asked; “Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your ability to do the following activities over the past 2 weeks; 1) showering or bathing; 2) dressing yourself; 3) walking one block on level ground; 4) doing yard work, housework, or carrying groceries; 5) climbing a flight of stairs without stopping; 6) hurrying or jogging (as if to catch a bus).” Possible responses to each question were ‘extremely limited, score =1 ’, ‘quite a bit limited, 2’, ‘moderately limited, 3’, ‘slightly limited, 4’, ‘not limited at all, 5’, or ‘limited for other reasons or did not do the activity’(scored as missing). The Physical Ability Score (PAS) was calculated for each patient by averaging their non-missing responses to the six questions, transforming that number to a 0 to 100 scale by subtracting the lowest possible score and dividing by the range of the scale, and then finally multiplying by 100. If fewer than three of the six questions were answered, the score was considered missing. A PAS of 100 indicates no limitation by fatigue or dyspnea during any activity.
Follow-up and Outcomes
After the baseline assessment, patients were randomly assigned to medical therapy only or to medical therapy plus CABG (16). The primary outcome of the STICH trial was all-cause mortality. Median follow-up of the patients was 56 (IQR 48 to 68) months.
Statistical Analysis
Continuous demographic and baseline variables were summarized using the median and the first and third quartiles, and categorical variables by frequency (n) and percent (%). Between-group comparisons for baseline continuous and ordinal variables were performed using the Kruskal-Wallis test (comparing 3 groups) and the Wilcoxon rank-sum test (comparing 2 groups). Categorical variables were compared between groups using the chi-square test or Fisher's exact test.
Univariate relationships of 6-minute walk distance and PAS with all-cause mortality were examined using the Cox proportional hazards model. The 6-minute walk distance and PAS were analyzed as both continuous variables and categorical variables. Whether or not patients were able to walk ≥300 meters in the 6-minute walk test was used to categorize patients, because a 6-minute walk distance <300m has been associated with increased mortality or CV hospitalization in heart failure or LV systolic dysfunction populations (5,20,21). There is no prior literature which relates PAS and mortality. To dichotomize PAS, a threshold of 55 was chosen because mortality risk decreased with increasing levels of PAS up to approximately 55, with no further gradient of risk for PAS >55. Relative risks were derived from the Cox model and expressed as hazard ratios with associated 95% confidence intervals.
The Cox model was also used to assess the incremental prognostic value of the 6-minute walk and PAS beyond other clinical predictors of mortality identified in previous multivariable analyses using the STICH database. Independent predictors of mortality in these analyses (p<0.05) were: LV end systolic volume index (ESVI), creatinine, moderate or severe mitral regurgitation, age, heart rate, history of stroke, and treatment received.
Event rate plots were created using the Kaplan-Meier method for the following groups: unable to do the 6-minute walk test, walked <300 meters or walked ≥ 300 meters, and for PAS ≤55 and >55. To evaluate the value of combining 6-minute walk and PAS, Kaplan-Meier plots were also generated for subjects who were both able to walk ≥ 300 meters and had a PAS >55, and for subjects who did not meet both of these criteria. The log-rank test was used to examine the randomized treatment comparisons (CABG vs. medical therapy) with respect to all-cause mortality among patients in different exercise capacity groups. The interaction of exercise capacity and randomized treatment with respect to mortality was assessed using the Cox model. Kaplan-Meier plots for all subjects suggested increased mortality for subjects randomized to CABG during the first ~60 days and lower mortality after 2 years.(16) In exploratory analyses to evaluate possible differences in early compared to later mortality by treatment allocation and exercise group, hazard ratios for mortality <60 days, 60 days to 2 years, and >2 years after randomization were calculated.
Results
Baseline Assessments
Clinical characteristics for all patients at baseline are summarized by 6-minute walk distance groups in Table 1. Subjects unable to perform the 6-minute walk test were compared to those who walked <300m or walked ≥300m. Patients who walked ≥300m were younger, more likely to be male, and more likely to be white. Patients from Poland were most likely to do well on the test and those from US/Canada were the least likely to do well. Patients unable to do the 6-minute walk test were more likely to have chronic renal insufficiency, peripheral vascular disease, depression, and lower quality of life. Subjects who walked ≥300m were less likely to have NYHA class ≥III or have 3-vessel coronary artery disease.
Table 1.
Baseline Characteristics of Study Population by 6-minute Walk Distance Group
| Variable | Unable to Walk (N=168) | Walk <300M (N=362) | Walk ≥300M (N=682) | P-value |
|---|---|---|---|---|
| 6-Minute walk distance (meters) | 225 (162, 270) | 390 (348, 440) | ||
| Age at randomization (years) | 62 (54, 69) | 60 (54, 68) | 59 (53, 66) | 0.005 |
| Male sex | 144 (86%) | 303 (84%) | 617 (90%) | 0.004 |
| Region1 | <0.001 | |||
| Poland | 21 (7%) | 73 (23%) | 225 (70%) | |
| US/Canada | 63 (26%) | 82 (34%) | 98 (40%) | |
| West Europe2 | 28 (25%) | 20 (18%) | 64 (57%) | |
| Other countries2 | 56 (10%) | 187 (35%) | 295 (55%) | |
| Hispanic/Latino/non-white | 62 (37%) | 162 (45%) | 197 (29%) | <0.001 |
| CCS angina class ≥2 | 73 (44%) | 206 (57%) | 304 (45%) | <0.001 |
| NYHA HF class ≥3 | 82 (49%) | 189 (52%) | 176 (26%) | <0.001 |
| Heart rate (beats/minute) | 75 (66, 83) | 75 (68, 83) | 72 (64, 80) | 0.020 |
| LV ejection fraction (%) | 28 (21, 33) | 27 (22, 34) | 28 (23, 34) | 0.128 |
| LV End Systolic Volume Index | 80 (65, 99) | 77 (59, 102) | 80 (61, 101) | 0.614 |
| Atrial flutter or fibrillation | 24 (14%) | 48 (13%) | 81 (12%) | 0.638 |
| Mitral regurgitation (moderate/severe) | 32 (19%) | 70 (20%) | 118 (17%) | 0.651 |
| 3-vessel CAD with ≥75% stenosis | 68 (41%) | 150 (42%) | 224 (33%) | 0.011 |
| Body Mass Index (kg/m2) | 26 (24, 30) | 27 (24, 30) | 27 (24, 30) | 0.212 |
| Chronic renal insufficiency | 36 (21%) | 26 (7%) | 32 (5%) | <0.001 |
| Diabetes | 78 (46%) | 149 (41%) | 251 (37%) | 0.053 |
| History of stroke | 18 (11%) | 27 (8%) | 47 (7%) | 0.244 |
| Peripheral vascular disease | 44 (26%) | 71 (20%) | 69 (10%) | <0.001 |
| Depression | 26 (16%) | 21 (6%) | 29 (4%) | <0.001 |
| Quality of life EQ-5D Score | 0.65 (0.52, 0.81) | 0.69 (0.52, 0.85) | 0.79 (0.66, 1.00) | <0.001 |
Percent of patients in each walking group within a region.
West European countries here include: Austria, Germany, Italy, Sweden, Norway, and United Kingdom. ‘Other countries’ includes other European, Asia-Pacific and South American countries.
Baseline characteristics for the 1182 (97.5%) patients who completed the baseline questionnaire are displayed by physical ability score groups in Table 2. Patients reporting greater physical ability (PAS>55) did significantly better on the 6-minute walk test and were more likely to be male. Patients from Poland tended to report less physical limitation than patients from US/Canada. Patients with more physical limitations on average were more likely to have NYHA heart failure class ≥III, CCS angina class ≥II, lower LV ejection fraction, higher resting heart rate, and a higher rate of atrial flutter or fibrillation, but other markers of severity of cardiac disease were similar. Patients with poorer physical capacity were more likely to have a history of stroke, peripheral vascular disease, depression and lower quality of life.
Table 2.
Baseline Characteristics of Study Population by Physical Ability Score
| Variable | Physical ability score ≤55 (N=433) | Physical ability score >55 (N=749) | P-value |
|---|---|---|---|
| 6-Minute walk distance (meters) | 300 (220, 372) | 361 (285, 427) | <0.001 |
| Age at randomization (years) | 60 (54, 67) | 60 (54, 67) | 0.621 |
| Male sex | 358 (83%) | 680 (91%) | <0.001 |
| Region1 | <0.001 | ||
| Poland | 101 (32%) | 215 (68%) | |
| US/Canada | 101 (42%) | 138 (58%) | |
| West Europe2 | 38 (37%) | 65 (63%) | |
| Other countries2 | 193 (37%) | 331 (63%) | |
| Hispanic/Latino/non-white | 151 (35%) | 262 (35%) | 0.970 |
| CCS angina class ≥2 | 245 (57%) | 325 (43%) | <0.001 |
| NYHA Heart failure class ≥3 | 258 (60%) | 177 (24%) | <0.001 |
| Heart rate (beats/minute) | 76 (68, 84) | 72 (65, 80) | <0.001 |
| LV ejection fraction (%) | 26 (21, 33) | 28 (23, 34) | <0.001 |
| LV End Systolic Volume Index | 81 (63, 104) | 77 (60, 99) | 0.076 |
| Atrial flutter or fibrillation | 69 (16%) | 79 (11%) | <0.001 |
| Mitral regurgitation (moderate/severe) | 77 (18%) | 138 (18%) | 0.803 |
| 3-vessel CAD with ≥75% stenosis | 164 (38%) | 264 (35%) | 0.350 |
| Body Mass Index (kg/m2) | 27 (24, 31) | 27 (24, 30) | 0.198 |
| Chronic renal insufficiency | 41 (10%) | 50 (7%) | 0.084 |
| Diabetes | 182 (42%) | 286 (38%) | 0.192 |
| History of stroke | 41 (10%) | 46 (6%) | 0.035 |
| Peripheral vascular disease | 88 (20%) | 89 (12%) | <0.001 |
| Depression | 40 (9%) | 33 (4%) | <0.001 |
| Quality of life EQ-5D Score | 0.62 (0.52, 0.73) | 0.81 (0.69, 1.00) | <0.001 |
Percent of patients in each physical ability score group within a region.
West European countries include: Austria, Germany, Italy, Sweden, Norway, and United Kingdom; Other countries include other European, Asia-Pacific and South American countries.
Mortality by Walk Distance
During follow-up for a median of 56 (IQR 48 to 68) months, there were 462 (38%) deaths. The majority of deaths were from cardiovascular causes (n=369, 80%). Figure 1 displays the Kaplan-Meier estimated mortality rates and hazard ratios by three 6-minute walk distance groups: unable to walk, walked <300m, and walked ≥300m. Patients who walked ≥300m tended to have lower mortality than patients who were not able to walk (HR=0.83, 95% CI= 0.64-1.08) and patients who walked <300m (HR=0.82, 95% CI= 0.67-1.01). Because mortality rates were similar for subjects who were not able to walk or walked <300m in 6 minutes (Figure 1), these two groups were combined for further analysis. The association between mortality and 6-minute walk distance analyzed as a continuous variable was of borderline statistical significance (p=0.051) excluding patients unable to walk, with p=0.045 if patients unable to walk were included with their walking distance set as 0. This association was not significant after multivariable adjustment for other prognostic clinical factors (Table 3).
Figure 1. Mortality by 6 minute walk distance for all subjects.
Kaplan-Meier estimates of total mortality for patients unable to perform the walk test, patients who walked <300m in 6 minutes, and those who walked ≥300m in 6 minutes at baseline.
Table 3.
Hazard Ratios for Mortality by Physical Ability Score and by 6-minute Walk Distance Assessed at Baseline
| Number of patients1 | Number of events1 | HR (95%CI) unadjusted | P value | HR (95%CI) Adjusted for clinical covariates3 | P value | |
|---|---|---|---|---|---|---|
| Total mortality | ||||||
| Physical ability score (continuous)3,4,5,6 | 1182 | 450 | 0.73 (0.62-0.85) | <0.001 | 0.79 (0.67-0.94) | 0.006 |
| Physical ability score >55 (yes/no)6 | 1182 | 450 | 0.77 (0.64-0.93) | 0.008 | 0.81 (0.67-0.98) | 0.026 |
| 6min walk distance (continuous; not including patients unable to walk)5 | 1044 | 388 | 0.91 (0.82-1.00) | 0.051 | 0.94 (0.85-1.04) | 0.233 |
| 6min walk distance (continuous; impute 0 if unable to walk)5 | 1212 | 462 | 0.94 (0.88-0.99) | 0.045 | 0.97 (0.90-1.03) | 0.318 |
| Able to do 6min walk test (yes/no) | 1212 | 462 | 0.89 (0.69-1.14) | 0.336 | 0.96 (0.75-1.24) | 0.771 |
| Able to walk ≥ 300 meters in 6 min walk test (yes/no) | 1212 | 462 | 0.82 (0.69-0.99) | 0.036 | 0.93 (0.77-1.12) | 0.440 |
Number of events refers to the number with an event during follow-up. 6-minute walk test information was available for all 1212 subjects (including 1044 who could perform the walk test and 168 who were unable) and physical ability score was available for 1182 subjects at baseline, which explains the different number of events.
2. Clinical covariates included in the adjusted analyses were LV end systolic volume index, serum creatinine, moderate or severe mitral regurgitation, age, heart rate, history of stroke, and treatment (CABG vs. MED) received.
Physical ability score >55 indicates less limiting symptoms of fatigue and/or dyspnea during daily activities
Risk is decreasing as Physical Ability Score increases up to a value of 55, beyond which the risk is level.
The hazard ratios represent the decrease in risk for a 1 standard deviation increase in Physical Ability Score (25 units) or 6-minute walk distance (117 meters).
Hazard ratios and p values for 6-minute walk groups were similar when analyses were repeated excluding subjects who did not have Physical Ability Score data.
Mortality by Physical Ability Score
PAS (0 to 100) was first analyzed as a continuous variable (Table 3). Each 1 standard deviation (25 units) increase in PAS was associated with a decrease in total mortality risk when PAS changed from 0 to 55 (HR=0.73, 95% CI=0.62-0.85, p<0.001), but there was no further decrease in mortality as PAS increased above 55. Patients with a PAS >55 compared to ≤55 had lower mortality risk (HR=0.77, 95% CI =0.64-0.93, p=0.008) (Figure 2) and this association remained significant after adjusting for other prognostic factors in the multivariable model (Table 3).
Figure 2. Mortality by physical ability score for all subjects.
Kaplan-Meier estimates of total mortality for patients with a physical ability score (PAS) >55 compared to those with a score ≤55 at baseline.
Associations between both physical ability score and 6-minute walk distance, and cardiovascular and non-cardiovascular mortality are reported in Supplemental table 1.
Mortality by Treatment Allocation
All baseline characteristics were similar by treatment allocation to CABG or medical therapy.(16) For patients who were able to walk ≥300m, mortality risk was lower if randomized to CABG compared to medical treatment (HR 0.77, 95% CI 0.59 to 0.99, p=0.038) (Figure 3). However, for patients who were not able to walk 300m, mortality was not significantly different for the CABG treatment group and the medical therapy group (HR 0.98, 95% CI 0.75 to 1.27, p=0.871, p for interaction = 0.207) (Figure 3).
Figure 3. Mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by walk distance.
Kaplan-Meier estimates of total mortality for patients randomized to CABG and to medical treatment (MED) with (A) a 6-minute walk distance ≥300m at baseline, and (B) a 6-minute walk distance <300mat baseline or unable to perform the walk test.
A similar difference in mortality by treatment was observed by physical ability score (Figure 4). For subjects with PAS >55, there was a trend for lower mortality if randomized to CABG (HR 0.79, 95% CI 0.62 to 1.01, p=0.061. In contrast, patients with more limiting symptoms (PAS ≤55) had a similar mortality risk when randomized to CABG compared to medical therapy (HR 0.94, 95% CI 0.70 to 1.25, p=0.652, p for interaction = 0.406) (Figure 4).
Figure 4. Mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by physical ability score.
Kaplan-Meier estimates of total mortality for patients randomized to CABG and to medical treatment (MED) with (A) a physical ability score (PAS) >55 at baseline, and (B) a physical ability score ≤55 at baseline.
Combined information from the walk test and the physical activity score are presented in Figure 5. For subjects who walked ≥300m and had a PAS >55 (n=486), mortality risk was lower if randomized to CABG compared to medical therapy (HR 0.71, 95% CI 0.52 to 0.97, p=0.033). In contrast, for all subjects who did not meet both of these criteria (n=726), mortality risk was not significantly different between treatment groups (HR 0.95, 95% CI 0.75, 1.19, p= 0.626, interaction p=0.167). The HR for mortality by treatment allocation were similar for subjects who did not walk 300m and had a PAS ≤55 (n=246, HR 0.97, 95% CI 0.67, 1.40, p= 0.961), those who did not walk 300m and had a PAS >55 (n=263, HR 0.94, 95% CI 0.64, 1.40, p= 0.775), and for subjects who walked 300m and had a PAS ≤55 (n=187, HR 0.92, 95% CI 0.58, 1.44, p= 0.703).
Figure 5. Mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by exercise capacity assessed from both walk distance and physical ability score.
Kaplan-Meier estimates of total mortality for patients randomized to CABG and to medical treatment (MED) with (A) a 6-minute walk distance ≥300m and a physical ability score (PAS)>55 at baseline, and (B) a 6-minute walk distance <300m or a physical ability score ≤55 at baseline.
Kaplan-Meier plots for cardiovascular mortality by treatment allocation for 6-minute walk and PAS groups were similar to those for total mortality. (Supplemental figures 1, 2, 3)
Early and Late Mortality by Treatment
For subjects who could not walk ≥300m or PAS ≤55, the early mortality risk within 60 days after CABG was higher than for patients in the medical therapy group (30 [8.04%] vs. 9 [2.55%] deaths, HR 3.24, 95% CI 1.54 to 6.83). In contrast, for subjects both able to walk ≥300m and with higher PAS >55, there was no significant increase in mortality risk during the first 60 days for subjects randomized to CABG compared to medical therapy (8 [3.38%] vs. 7 [2.81%] deaths, HR 1.21, 95% CI 0.44 to 3.33) (Supplemental Figure 6). Similar time-dependent differences by treatment allocation were observed for cardiovascular mortality (supplemental figures 1 to 3). Hazard ratios for total mortality at <60 days, 60 days to 2 years and > 2 years follow-up by 6-minute walk distance and physical ability score groups are presented in Supplemental Figures 4 to 6.
Discussion
In this study of patients with ischemic LV dysfunction who were candidates for CABG, poor exercise capacity assessed by the 6-minute walk test, or greater limitation of daily activities from fatigue and/or dyspnea assessed by questionnaire, were both associated with increased mortality during follow-up. These findings are consistent with many studies in which low exercise capacity predicts worse outcomes, both in general populations(1-3) and in patients with ischemic heart disease(4) and heart failure.(5-8)
Possible Explanations for Mortality Differences by Treatment
The primary results of the STICH trial (16) reported a trend to lower mortality from all causes (HR 0.86, 95%CI 0.72 to 1.04) and from CV causes (HR 0.81, 95%CI 0.66 to 1.00) for patients with ischemic LV dysfunction randomized to CABG compared to medical therapy. This result is consistent with benefit from CABG for some patients, but it has been uncertain how to identify those likely to have better or worse outcomes with CABG compared to medical therapy. In previous analyses from STICH, neither myocardial ischemia (22), nor viability (23) predicted benefit from CABG compared to medical therapy.
In contrast to the results of this analysis, current clinical practice guidelines suggest ‘sicker’ patients are more likely to benefit from CABG.(24, 25) Exploratory analyses suggest two reasons why patients with low functional capacity may benefit less from CABG compared to medical therapy. First, these patients had a higher early mortality risk with CABG. This increased early CABG related risk extended for longer than 30 days, the time usually chosen to assess surgical mortality. For this reason a 60 day cut level was chosen for exploratory analysis. However interpretation of results is not influenced by whether 30 or 60 days is used to define ‘early’ mortality. Second, higher longer term mortality risk of patients with poor functional capacity may not be reduced by CABG, especially if the increased risk is related to non-cardiac factors. Both 6-minute walk distance and physical ability score were associated with other measures of general health, depressed mood, co-morbidities and quality of life, supporting the conclusion that exercise capacity reflects overall health, in addition to the severity of cardiac disease. In previous studies poor health related quality of life, frailty and disability have been associated with increased mortality in patients with heart failure(9-12) as well as after cardiac surgery.(26)
Comparison of Walk Test and Physical Ability Score
Because the focus of the current study was exercise capacity, only the 6 questions from the KCCQ on dyspnea and/or fatigue during common physical activities were included.(17) The physical activity score was a stronger independent predictor of mortality than the 6-minute walk distance, but this did not translate to better prediction of benefit from CABG compared to medical treatment only. The physical ability score provides complementary information to the 6 minute walk test because it estimates self-reported severity of dyspnea and fatigue during daily activities but does not directly measure exercise capacity. Subjects able to walk ≥300m who also had physical ability scores >55 had the greatest estimated benefit from CABG compared to medical therapy alone.
Study Strengths and Limitations
The STICH trial is the only large randomized clinical trial comparing CABG with medical therapy alone in patients with ischemic LV dysfunction, and the only study which allows a comparison of outcomes for patients with poor compared to better exercise capacity for the two treatment options. Questionnaire and 6-minute walk test information were collected using standard methods for >97% of study participants, results were consistent for the two methods of evaluating functional capacity, and all study participants with functional data were included in the intention to treat analysis.
The study has limitations. Associations between exercise capacity and mortality could be explained, in part, by poorer general health, or by cultural factors associated with country of residence.(27) However, subjects were balanced by randomization to CABG or medical therapy, and an intention to treat analysis was performed, so associations between exercise capacity and demographic variables, co-morbidity, general health and quality of life do not bias evaluation of differences in outcome by treatment allocation for subjects with lower and higher exercise capacity. The reported analyses were post-hoc and statistical tests for interaction did not reach conventional levels of significance. It is therefore possible the observed treatment differences in mortality by exercise group occurred by chance. Time dependent hazard ratios were included to evaluate possible reasons for differences in mortality with CABG compared to medical treatment for each exercise group, and should be considered exploratory. All cause mortality was the primary outcome both for the STICH trial and this analysis. Effects of CABG compared to medical therapy on symptoms and quality of life are also clinically important, but these outcomes are not the focus of this report.
Conclusion
This exploratory analysis from the large international randomized STICH trial suggests patients with ischemic LV dysfunction who could not walk 300m, and those with more limiting symptoms of fatigue and/or dyspnea, have a higher early mortality with CABG and are less likely to benefit during longer follow-up from surgery compared to medical therapy. In contrast, patients with better functional capacity may have a lower mortality over ~5 years if referred for CABG.
Supplementary Material
Supplemental Figure 1: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by walk distance. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m at baseline, and (B) a 6-minute walk distance <300 m at baseline or unable to perform the walk test.
Supplemental Figure 2: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by physical ability score. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) with a physical ability score (PAS) >55 at baseline, and (B) a PAS ≤55 at baseline.
Supplemental Figure 3: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by exercise capacity assessed by both walk distance and physical ability score. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m and a physical ability score (PAS) >55 at baseline, and (B) a 6-minute walk distance <300m or a physical ability score (PAS) ≤ 55 at baseline.
Supplemental Figure 4: Time dependent differences in mortality by treatment allocation stratified by walk distance. Time-dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m at baseline, and (B) a 6-minute walk distance <300m at baseline or unable to perform the walk test.
Supplemental Figure 5: Time dependent differences in mortality by treatment allocation stratified by physical ability score. Time-dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a physical ability score (PAS) >55 at baseline, and (B) a PAS ≤55 at baseline.
Supplemental Figure 6: Time dependent differences in mortality by treatment allocation stratified by exercise capacity assessed from both walk distance and physical ability score. Time dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m and a physical ability score (PAS) >55 at baseline, and (B) a 6-minute walk distance <300m or a physical ability score (PAS) ≤ 55 at baseline.
Condensed Abstract.
In an analysis from the Surgical Treatment for Ischemic Heart Failure Trial exercise capacity was assessed by a six minute walk test and by questionnaire in 1,212 patients with ischemic left ventricular dysfunction before randomization to coronary artery bypass graft surgery (CABG) or medical management. Participants able to walk >300m in six minutes and those less limited by symptoms during exercise had lower mortality during 5 years follow-up if randomized to CABG compared to medical therapy. In contrast participants with poorer exercise capacity had an increased early risk and no mortality benefit with CABG compared to medical therapy.
Acknowledgments
We thank all STICH trial investigators and participants for their contributions.
Funding Sources: The Surgical Treatment for Ischemic Heart Failure (STICH) trial was funded by grants U01HL69015 and U01HL69013 from the National Heart, Lung, and Blood Institute.
List of Abbreviations
- CABG
Coronary Artery Bypass surgery
- CCS
Canadian Cardiovascular Society
- EQ-5D
European Quality of Life questionnaire
- ECG
Electrocardiogram
- ESVI
End Systolic Volume Index
- HR
Hazard Ratio
- IQR
Inter-Quartile Range
- KCCQ
Kansas City Cardiomyopathy Questionnaire
- LV
Left Ventricular
- NYHA
New York Heart Association
- PAS
Physical Ability Score
- STICH
Surgical Treatment for Ischemic Heart Failure trial
Footnotes
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Disclosures
Ralph Stewart: none
Dominika Szalewska: none
Lilin She: none
Kerry L. Lee: none
Mark H. Drazner: none
Barbara Lubiszewska: none
Dragana Kosevic: none
Permyos Ruengsakulrach: none
José C. Nicolau: none
Benoit Coutu: none
Shiv K. Choudhary: none
Daniel B. Mark: none
John Cleland: none
Ileana L. Pina: none
Eric J. Velazquez: none
Andrzej Rynkiewicz: has received consulting fees, lecture fees, and grant support from Amgen, Astra-Zeneca, Boehringer Ingelheim, Pfizer, Servier, Bristol-Myers Squibb, and Sanofi-Aventis. Harvey White: has received research grants from Sanofi Aventis; Eli Lilly; Medicines Company; NIH; Pfizer; Roche; Johnson & Johnson; Schering Plough; Merck Sharpe & Dohme; Astra Zeneca; GlaxoSmithKline; Daiichi Sankyo Pharma Development and Bristol-Myers Squibb and has served on Advisory boards for Merck Sharpe & Dohme, Roche and Regado Biosciences.
Clinical Trial Registration: STICH ClinicalTrials.gov number, NCT00023595 http://clinicaltrials.gov/show/NCT00023595
References
- 1.Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305:50–8. doi: 10.1001/jama.2010.1923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Dumurgier J, Elbaz A, Ducimetiere P, Tavernier B, Alperovitch A, Tzourio C. Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study. BMJ. 2009;339:b4460. doi: 10.1136/bmj.b4460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Newman AB, Simonsick EM, Naydeck BL, et al. Association of Long-Distance Corridor Walk Performance With Mortality, Cardiovascular Disease, Mobility Limitation, and Disability. JAMA. 2006;295:2018–2026. doi: 10.1001/jama.295.17.2018. [DOI] [PubMed] [Google Scholar]
- 4.Matsuzawa Y, Konishi M, Akiyama E, et al. Association Between Gait Speed as a Measure of Frailty and Risk of Cardiovascular Events Following Myocardial Infarction. JACC. 2013;61:1964–1972. doi: 10.1016/j.jacc.2013.02.020. [DOI] [PubMed] [Google Scholar]
- 5.Bittner V, Weiner DH, Yusuf S, et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators. JAMA. 1993;270:1702–1707. [PubMed] [Google Scholar]
- 6.Guazzi M, Dickstein K, Vicenzi M, Arena R. Six-minute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circulation Heart failure. 2009;2:549–55. doi: 10.1161/CIRCHEARTFAILURE.109.881326. [DOI] [PubMed] [Google Scholar]
- 7.Ingle L, Rigby AS, Carroll S, et al. Prognostic value of the 6 min walk test and self-perceived symptom severity in older patients with chronic heart failure. European Heart Journal. 2007;28:560–568. doi: 10.1093/eurheartj/ehl527. [DOI] [PubMed] [Google Scholar]
- 8.Forman DE, Fleg JL, Kitzman DW, et al. 6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol. 2012;60:2653–61. doi: 10.1016/j.jacc.2012.08.1010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chamberlain AM, McNallan SM, Dunlay SM, et al. Physical Health Status Measures Predict All-Cause Mortality in Heart Failure Patients. Circulation Heart failure. 2013;6:669–675. doi: 10.1161/CIRCHEARTFAILURE.112.000291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Koch CG, Li L, Lauer M, Sabik J, Starr NJ, Blackstone EH. Effect of functional health-related quality of life on long-term survival after cardiac surgery. Circulation. 2007;115:692–9. doi: 10.1161/CIRCULATIONAHA.106.640573. [DOI] [PubMed] [Google Scholar]
- 11.Mommersteeg PM, Denollet J, Spertus JA, Pedersen SS. Health status as a risk factor in cardiovascular disease: a systematic review of current evidence. Am Heart J. 2009;157:208–18. doi: 10.1016/j.ahj.2008.09.020. [DOI] [PubMed] [Google Scholar]
- 12.Zuluaga MC, Guallar-Castillon P, Lopez-Garcia E, et al. Generic and disease-specific quality of life as a predictor of long-term mortality in heart failure. Eur J Heart Fail. 2010;12:1372–8. doi: 10.1093/eurjhf/hfq163. [DOI] [PubMed] [Google Scholar]
- 13.Shahian DM, O'Brien SM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1--coronary artery bypass grafting surgery. Ann ThoracSurg. 2009;88:S2–22. doi: 10.1016/j.athoracsur.2009.05.053. [DOI] [PubMed] [Google Scholar]
- 14.Surgeons TSoT STS Risk Calculator. 2012 http://wwwstsorg/quality-research-patient-safety/quality/risk-calculator-and-models.
- 15.New EuroScore II interactive calculator. 2011 http://wwweuroscoreorg/calchtml.
- 16.Velazquez EJ, Lee KL, Deja MA, et al. Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction. New England Journal of Medicine. 2011;364:1607–1616. doi: 10.1056/NEJMoa1100356. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol. 2000;35:1245–55. doi: 10.1016/s0735-1097(00)00531-3. [DOI] [PubMed] [Google Scholar]
- 18.Group TE. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. Health policy. 1990;16:199–208. doi: 10.1016/0168-8510(90)90421-9. [DOI] [PubMed] [Google Scholar]
- 19.Jones RH, White H, Velazquez EJ, et al. STICH (Surgical Treatment for Ischemic Heart Failure) trial enrollment. J Am Coll Cardiol. 2010;56:490–8. doi: 10.1016/j.jacc.2009.11.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Roul G, Germain P, Bareiss P. Does the 6-minute walk test predict the prognosis in patients with NYHA class II or III chronic heart failure? Am Heart J. 1998;136:449–57. doi: 10.1016/s0002-8703(98)70219-4. [DOI] [PubMed] [Google Scholar]
- 21.Rostagno C, Olivo G, Comeglio M, et al. Prognostic value of 6-minute walk corridor test in patients with mild to moderate heart failure: comparison with other methods of functional evaluation. Eur J Heart Fail. 2003;5:247–52. doi: 10.1016/s1388-9842(02)00244-1. [DOI] [PubMed] [Google Scholar]
- 22.Panza JA, Holly TA, Asch FM, et al. Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol. 2013;61:1860–70. doi: 10.1016/j.jacc.2013.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. 2011;364:1617–25. doi: 10.1056/NEJMoa1100358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and disability to cardiac surgery risk scores identifies elderly patients at high risk or mortality or major morbidity. Circulation Cardiovascular quality and outcomes. 2012;5:222–8. doi: 10.1161/CIRCOUTCOMES.111.963157. [DOI] [PubMed] [Google Scholar]
- 25.Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/ STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:3097–137. doi: 10.1161/CIR.0b013e3182776f83. [DOI] [PubMed] [Google Scholar]
- 26.Montalescot G, Sechtem U, Achenbach S, et al. ESC guidelines on the management of stable coronary artery disease : the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013. 2013;34:2949–3003. doi: 10.1093/eurheartj/eht296. [DOI] [PubMed] [Google Scholar]
- 27.Stewart R, Held C, Brown R, Vedin O, Hagstrom E, Lonn E, Armstrong P, Granger C, Hochman J, Davies R, Soffer J, Wallentin L, White H. Physical activity in patients with stable coronary heart disease: an international perspective. Eur Heart J. 2013;34:3286–3293. doi: 10.1093/eurheartj/eht258. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplemental Figure 1: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by walk distance. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m at baseline, and (B) a 6-minute walk distance <300 m at baseline or unable to perform the walk test.
Supplemental Figure 2: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by physical ability score. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) with a physical ability score (PAS) >55 at baseline, and (B) a PAS ≤55 at baseline.
Supplemental Figure 3: Cardiovascular mortality for subjects randomized to coronary artery bypass surgery and to medical treatment stratified by exercise capacity assessed by both walk distance and physical ability score. Kaplan-Meier estimates of cardiovascular mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m and a physical ability score (PAS) >55 at baseline, and (B) a 6-minute walk distance <300m or a physical ability score (PAS) ≤ 55 at baseline.
Supplemental Figure 4: Time dependent differences in mortality by treatment allocation stratified by walk distance. Time-dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m at baseline, and (B) a 6-minute walk distance <300m at baseline or unable to perform the walk test.
Supplemental Figure 5: Time dependent differences in mortality by treatment allocation stratified by physical ability score. Time-dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a physical ability score (PAS) >55 at baseline, and (B) a PAS ≤55 at baseline.
Supplemental Figure 6: Time dependent differences in mortality by treatment allocation stratified by exercise capacity assessed from both walk distance and physical ability score. Time dependent hazard ratios for total mortality for patients randomized to CABG and to medical treatment with (A) a 6 minute walk distance (6MW) ≥300m and a physical ability score (PAS) >55 at baseline, and (B) a 6-minute walk distance <300m or a physical ability score (PAS) ≤ 55 at baseline.