Importance of Treadmill Exercise Time as an Initial Prognostic Screening Tool in Patients With Systolic Left Ventricular Dysfunction
Background— We sought to determine whether treadmill exercise time may be of value as an initial prognostic screening tool in ambulatory patients with impaired systolic function who are referred for cardiopulmonary exercise testing.
Methods and Results— We studied 2231 adult systolic heart failure patients (27% of whom were women) who underwent cardiopulmonary stress testing using a modified Naughton protocol. We assessed the value of treadmill exercise time for prediction of all-cause death and a composite of death or United Network for Organ Sharing status 1 heart transplantation. During a mean follow-up of 5 years, 742 patients (33%) died. There were 249 United Network for Organ Sharing status 1 heart transplants (11%). Treadmill exercise time was predictive of death and the composite outcome in both women and men, even after accounting for peak oxygen consumption and other clinical covariates (adjusted hazard ratio of lowest versus high sex-specific quartile for prediction of death 1.70, 95% confidence interval 1.05 to 2.75, P=0.03; for prediction of the composite outcome, 1.75, 95% confidence interval 1.15 to 2.66, P=0.009). For a 1-minute change in exercise time, there was a 7% increased hazard of death (eg, comparing 480 to 540 seconds, hazard ratio =1.07, 95% confidence interval 1.02 to 1.12, P=0.004).
Conclusions— Because cardiopulmonary stress testing is not available in every hospital, treadmill exercise time with a modified Naughton protocol may be of value as an initial prognostic screening tool.
Received January 2, 2009; accepted April 15, 2009.
Peak oxygen consumption (V̇o2) remains one of the most powerful single predictors of mortality for heart failure patients with severe systolic left ventricular dysfunction.1–3 Current guidelines suggest ambulatory patients be considered for transplantation when the peak V̇o2 is ≤14 mL · kg−1min−1, or ≤12 mL · kg−1min−1 in the setting of β-blockade.3 Although cardiopulmonary exercise testing routinely is used to determine candidacy for heart transplantation, it is not known whether a simple measurement of treadmill exercise time may be of comparable value as an initial prognostic screening tool. We sought to evaluate whether (1) treadmill exercise time predicts survival in heart failure patients with systolic dysfunction, (2) treadmill exercise time adds incremental prognostic value beyond established risk factors, including peak V̇o2, and (3) a model with treadmill exercise time in addition to established risk factors better classifies risk than a model with established risk factors alone.
Editorial see p 3165
Clinical Perspective on p 3197
We performed an observational prospective cohort study at the Cleveland Clinic involving consecutive patients with left ventricular ejection fraction <40% who underwent cardiopulmonary stress testing between August 1997 and April 2007. We focused specifically on patients who were tested according to the modified Naughton protocol, which was the most common protocol used in our laboratory for this type of patient. Patients were excluded if they were <18 years old or had no US Social Security number. The study was approved by the institutional review board at the Cleveland Clinic, and because all data were collected and recorded as part of routine clinical care, the requirement for informed consent was waived.
All demographic information, medications, medical and surgical history, heart rate, blood pressure, directly measured height and weight, and stress results were obtained at the time of stress testing and prospectively recorded in our electronic database. Biventricular pacemakers were not reported separately from other pacemakers during database entry. Glomerular filtration rate was estimated with the Cockcroft-Gault equation.4 Left ventricular ejection fraction was determined either by echocardiography, left ventriculography, or ECG-gated myocardial perfusion imaging. If a patient underwent >1 metabolic stress test with a modified Naughton protocol, only the first test was considered. Serum laboratory tests within 3 months of the cardiopulmonary study were included, and only the laboratory tests closest to the stress test date were used.
Cardiopulmonary Stress Testing
Cardiopulmonary stress testing was symptom limited, and patients were strongly advised to not use the handrails for support. Details on our laboratory’s protocols have been published previously.5 Briefly, the test was performed with a modified Naughton protocol that increases workload ≈1 metabolic equivalent every 2 minutes.6 Results were recorded on a MedGraphics cardiopulmonary system (Medical Graphics Corp, St Paul, Minnesota). Oxygen consumption, carbon dioxide production, minute ventilation, tidal volume, heart rate, blood pressure, and respiratory rate were obtained at rest, every 30 seconds during exercise, and during recovery. Total duration of exercise, henceforth referred to as treadmill exercise time, was recorded to the nearest second.
The primary end points were all-cause mortality and a composite of all-cause mortality or United Network for Organ Sharing (UNOS) status 1 heart transplantation during a mean follow-up of 5 years (maximum for survivors, 11 years). Mortality data were obtained by linking our database with the US Social Security Administration Death Index. We validated this approach previously, yielding a sensitivity of 97%,7 which is equivalent to a 97% follow-up rate. UNOS status 1 heart transplantation was based on Organ Procurement and Transplantation Network data as of June 18, 2008. All events (death or heart transplantation) were censored as of April 1, 2008.
Baseline characteristics were reported as sex-specific quartiles of treadmill exercise time. Continuous variables were expressed as means with SDs, and categorical variables were expressed as frequencies. Serum laboratory tests before October 1999 were systematically unavailable on our electronic database. We used informed imputation to fill in these missing values by constructing regression models for each laboratory measure on all other characteristics of our existing database except for outcome (10% of creatinine clearance, blood urea nitrogen, glucose, and sodium values were imputed, and 15% of serum hemoglobin values were imputed).
We generated Kaplan–Meier plots relating treadmill exercise time and cumulative mortality. We constructed unadjusted and adjusted Cox proportional hazards models to examine the association of treadmill exercise time and outcomes. Possible nonlinear associations were tested with restricted cubic splines. Potentially important interactions were tested. The proportional hazards assumption was tested by scaled Schoenfeld residuals and inspection of hazard ratio plots.
Model discrimination was assessed by calculating the out-of-bag (OOB) c-index for time to event outcomes, an approach that we have used previously.8 The OOB method involves obtaining bootstrap samples from the original cohort and using each sample to compute a prediction model. Each bootstrap sample left out ≈37% of the data, which were referred to as the OOB data. The prediction model was applied to the OOB data to calculate the OOB c-index, a measure that is conceptually similar to the area under a receiver operating curve. The purpose of this method is to perform multiple internal validations with an internal cohort that has been randomly sampled multiple times. This is a more conservative measure than what we have reported in previous work, which was based on 1 assessment of the original data.9 Hence, we would expect that these OOB c-index values would be lower than what we reported previously, because they represent more conservative estimates.
To determine the change in prediction error attributable to each variable, we recalculated the prediction error after random permutation of that variable in the OOB data; a variable with a high degree of importance would be expected to yield a greater change in the OOB c-index. The process was repeated 100 times for each variable.
To address clinical utility, we constructed risk-reclassification figures. We compared 1-year predicted risk estimates based on models of established risk factors with and without the variables in question. We selected categories of risk of 15% based on the current 1-year mortality outcomes after cardiac transplantations.10 We used 2 objective methods to quantify improvement in categories as suggested by Pencina et al11: Net reclassification improvement and integrated discrimination improvement. The net reclassification improvement and integrated discrimination improvement were calculated by comparing an individual patient’s predicted risks at 1 year based on a Cox model 1 versus another Cox model 2. These predicted risks were calculated with a modification of the R function predict(), with censoring at 1 year.
Statistical analysis was performed with SAS version 9.1.3 (SAS Institute Inc, Cary, NC) and R version 2.6.2 (www.R-project.org). We used Harrell’s Design and Hmisc libraries for model construction and assessment, an R macro written by 1 of the authors (HI) for the OOB and change in prediction error analyses, and another R macro written by Lauer and colleagues11a to calculate the observed risks in the reclassification figures. We used an SAS macro written by Pencina et al to calculate the net reclassification improvement and integrated discrimination improvement.11
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
The study cohort consisted of 602 women (27%) and 1629 men (73%). During a mean follow-up of 5 years (maximum for survivors, 11 years), 155 women (26% of the female cohort) and 587 men (36% of the male cohort) died. There were 249 patients (16% women) who underwent heart transplantation as UNOS status 1. Only 4 patients underwent 2 transplantations.
Table 1 shows the baseline characteristics of the 2231 patients according to sex-specific quartiles for treadmill exercise time. Compared with those in the highest quartile, those in the lowest quartile were older; were more likely to have coronary artery disease, diabetes mellitus, implantable cardioverter-defibrillators (ICDs), or pacemakers; and had lower systolic blood pressures, with higher resting heart rates. They also had lower peak V̇o2 and lower peak respiratory exchange ratio. They were less likely to be taking a β-blocker or an ACE inhibitor and more likely to be taking nitrates, hydralazine, angiotensin receptor blockers, diuretics, and antiarrhythmic agents. Laboratory test results were similar, except those in the lowest quartile had higher blood urea nitrogen and lower creatinine clearance.
Figure 1 shows the association of sex-specific quartiles of treadmill exercise time with all-cause mortality. The composite of death and UNOS status 1 heart transplantation yielded similar sex-specific results (online-only Data Supplement Figure I). In both women and men, treadmill exercise time predicted survival (death or death/UNOS status 1 transplantation), with the worst survival in the quartile with the lowest treadmill exercise time. After adjustment for all the variables listed in Table 1, including peak V̇o2, in a Cox proportional hazards model, a shorter exercise time remained associated with an increase hazard of death (Table 2) and of death and UNOS status 1 heart transplantation (online-only Data Supplement Table I). For a 1-minute change in exercise time, there was a 7% increased hazard of death (eg, for a comparison of 480 to 540 seconds, hazard ratio 1.07, 95% confidence interval [CI] 1.02 to 1.12, P=0.004). To determine whether the imputed laboratory values affected our data, we performed a sensitivity analysis leaving out all laboratory variables and found similar results (hazard ratio 1.08, 95% CI 1.03 to 1.13, P=0.002).
We further evaluated the association of treadmill exercise time and survival for the subgroup of patients with peak V̇o2 ≥14 mL · kg−1min−1. Even among these lower-risk patients, lower treadmill exercise time predicted worse outcomes in both women and men (Figure 2; online-only Data Supplement Figure II). In this subset of patients with high peak V̇o2, a 1-minute change in exercise time also yielded a 7% increased hazard of death in a fully adjusted model (ie, for a comparison of 480 to 540 seconds, hazard ratio 1.07, 95% CI 1.00 to 1.14, P=0.04).
The c-indices of the models that contained all variables including exercise time were 0.723 for all-cause death and 0.744 for the composite of death and UNOS status 1 heart transplantation. The OOB c-indices, a more conservative measure, of the models that contained all variables including treadmill exercise time were 0.698 (95% CI 0.670 to 0.726) for all-cause death (Table 3) and 0.727 (95% CI 0.703 to 0.751) for the composite outcome of death and UNOS status 1 heart transplantation (online-only Data Supplement Table II), which indicates moderate discriminatory ability. There were no notable differences between the models that contained clinical variables and either peak V̇o2, treadmill exercise time, or both. Treadmill exercise time was among the top 3 most important contributors to discriminative prediction in both sets of models (Figure 3; online-only Data Supplement Figure III).
To better compare model performance within clinical categories, we classified patients into low-risk (<15%) and high-risk (≥15%) categories of 1-year risk, with these cut points based on the observed national 1-year survival after heart transplantation. We compared models with and without treadmill exercise time by cross-classifying predicted risks, stratified by whether or not the patients died (Figure 4) or developed the composite end point of death or transplantation (online-only Data Supplement Figure IV). If an additional variable were to add no predictive value, all points would fall on the line of identity. A spread around the line indicates modulation of predicted risk; if the variable correctly modulates predicted risk, there should be a greater preponderance of events above the line of identity. Clinical variables and usage of peak V̇o2 (Figure 4A) or treadmill exercise time (Figure 4B) improved net reclassification for the outcome of death and the composite outcome (online-only Data Supplement Figures IV-A and IV-B). However, there were no significant differences in net reclassification between a model with clinical variables and treadmill exercise time versus clinical variables and peak V̇o2 (Figure 4C; online-only Data Supplement Figure IV-C).
The integrated discrimination improvement (a reclassification measure that is not limited to predetermined categories of risk) for a model with treadmill exercise time was 1.9% (P<0.0001; Figure 4B) for the outcome of death and 3.4% (P<0.001; online-only Data Supplement Figure IV-B) for the composite outcome. There were no significant differences in integrated discrimination improvement between a model with clinical variables and treadmill exercise time versus clinical variables and peak V̇o2 (Figure 4C; online-only Data Supplement Figure IV-C).
In a large cohort of patients with impaired left ventricular systolic function who underwent the same cardiopulmonary stress testing protocol, we found that treadmill exercise time predicted survival and yielded similar prognostic value to peak oxygen consumption (peak V̇o2). Even among low-risk patients with a peak V̇o2 >14 mL · kg−1min−1, those who had a lower treadmill exercise time had markedly worse outcomes. The present findings are consistent with the hypothesis that exercise capacity is a valuable initial prognostic screening tool in patients with systolic left ventricular dysfunction.
The present study expands on previous work demonstrating the prognostic power of exercise capacity.12,13 Exercise capacity (ie, treadmill time or “estimated” metabolic equivalents) is predictive of survival in both healthy adults and those with known coronary artery disease.14–16 Exercise tolerance reflects a number of prognostically important factors, including cardiac function, endothelial function, pulmonary function, oxygen-carrying capacity, and autonomic nervous system balance; however, its usefulness as a prognostic screening tool in patients with systolic left ventricular dysfunction is less established.
Treadmill exercise time has not been used in most heart failure survival models,1,17–19 but it has been explored previously in at least 3 heart failure studies. In the Captopril-Digoxin Research Group report, exercise time on a modified Naughton protocol was deemed to have no significant prognostic value; however, the cohort was relatively healthy, because patients who exercised less than 240 seconds were excluded, and the average exercise time was quite high at 558 seconds.20 In a small study of 60 heart failure patients,21 there was a high degree of correlation between treadmill exercise time and peak V̇o2; however, owing to the small sample size, that study did not have the power to determine prognostic significance. More recently, a cohort of 31 children with idiopathic cardiomyopathy who underwent cardiopulmonary stress testing with a modified Naughton protocol were followed up prospectively for a median of 1282 days, and 20 of them died or underwent heart transplantation.22 Both univariable and multivariable analyses showed treadmill exercise time to be predictive of outcome.22
Can a simple exercise stress test replace cardiopulmonary stress testing for patients being evaluated for heart transplantation? Possibly, but we do not advocate this approach. By both OOB change in c-index and integrated discrimination improvement, we found that peak V̇o2 is a more powerful predictor of mortality than treadmill exercise time. Other researchers have also found measured peak V̇o2 to be a better predictor than either estimated peak V̇o2 or work rate.23,24 Another advantage of cardiopulmonary stress testing is the ability to measure patient effort (ie, respiratory exchange ratio). When patients achieve an adequate level of effort, peak V̇o2 is a reliable and reproducible measurement and does not depend on the use of only 1 exercise protocol. Exercise time may not be as reproducible, based on the results of HF-ACTION (Heart Failure and A Controlled Trial Investigation Outcomes of exercise traiNing), which repeated within 7 days a baseline exercise study in 401 patients with systolic heart failure (87% of whom used a modified Naughton protocol); the study noted that the peak V̇o2 was unchanged, but exercise time increased by 26 seconds on average.25 Cardiopulmonary stress testing can also help identify noncardiac causes for shortness of breath.
However, cardiopulmonary stress testing is not available in every hospital, and therefore, treadmill exercise time may be a reasonable screening tool for physicians to determine prognosis and need for referral to advanced heart failure treatment centers. On the basis of the present data, treadmill exercise times of less than 5 minutes 17 seconds for women and less than 6 minutes for men may be useful cutoff values when a modified Naughton protocol is used, because in the present study cohort, this corresponded to approximately a 15% 1-year mortality rate. Future research in other cohorts will be needed to verify our findings.
The strengths of the present study include a large sample size with a large number of hard events, prospective data collection, adequate power to present sex-specific results,26,27 and the recording of treadmill exercise time to the nearest second. All end points were determined by query of databases outside our center. Deaths were determined by Social Security files, whereas UNOS 1 transplantation was determined by direct query of UNOS files. Of note, 20% of patients who experienced UNOS 1 transplantation underwent transplantation outside our center; thus, an ascertainment bias based on consideration of only events known to Cleveland Clinic information systems was avoided. Body mass index was calculated on the basis of direct measures of height and weight. We adjusted for >35 clinical/demographic variables, which included sex, peak V̇o2, and coronary artery disease, and still found a longer exercise time interval to be associated with a lower hazard of death. We also used both traditional (c-index) and contemporary statistical discrimination and reclassification methods11 to assess model performance.
The c-index values reported here are lower than those we reported previously for a similar cohort.9 We now have adopted a more sophisticated and conservative method (OOB c-index) than what we used previously. This approach effectively simulates numerous internal validations, and as expected, model performance would be worse if applied to the entire original data set.
Limitations include that this was a single-center study with only patients who could ambulate on a treadmill. Because the cohort included patients from 1997, there were only a few patients who used aldosterone antagonists, there was modest β-blocker usage, and ≈25% of patients had an ICD. However, these proportions all compare favorably to what is seen in registries that have been published recently.28–31 Biventricular pacemakers were not reported separately during database entry, but most are identified in the ICD category, because at our institution, biventricular pacemakers are almost always implanted with an ICD. Therefore, when adjusting for all possible confounding variables, we included those with an ICD alone and with an ICD combined with a biventricular pacemaker. Laboratory tests such as measurement of B-type natriuretic peptides were not included in the baseline characteristics because they were not routinely obtained at our center between 1997 and 2007. Although B-type natriuretic peptide has prognostic value, it has not been used in other heart failure survival models.17,32–35 Like all epidemiological studies, we also cannot account for variables that change with time that may have an impact on death, such as patients receiving an ICD after the cardiopulmonary stress test or changes in medication with time. However, this limitation is inherent in all studies that have confirmed the value of cardiopulmonary stress testing as a prognostic tool. We also did not compare treadmill exercise time to indices of ventilatory inefficiency such as the V̇e/V̇co2 slope, Petco2, oscillatory ventilation, and oxygen uptake efficiency slope, which are more powerful risk predictors than peak V̇o2. These indices require minute-by-minute measurements that were not available in the present database.
Despite these limitations, we found that treadmill exercise time is a powerful and independent predictor of outcomes in both women and men with impaired left ventricular systolic function, even after accounting for peak oxygen consumption. These findings have potentially important implications for our understanding of the clinical pathophysiology of systolic cardiac dysfunction, as well as for finding optimal pathways to screen heart failure patients for possible transplantation. Because cardiopulmonary stress testing is not available in every hospital, treadmill exercise time with a modified Naughton protocol may be of value as an initial prognostic screening tool.
Sources of Funding
This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. It was also supported in part by American Heart Association Scientist Development Grant 0730307N and National Heart, Lung, and Blood Institute CAN #8324207.
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Physicians often refer patients with advanced heart failure for exercise testing with metabolic gas exchange measurements to assess suitability for cardiac transplantation. Peak oxygen consumption and other metabolic measures are known to be powerful predictors of mortality. We asked whether treadmill exercise time according to a standardized protocol might be comparable to peak oxygen consumption for assessment of prognosis. We analyzed the outcomes of 2231 patients with systolic heart failure who all underwent metabolic exercise stress testing on a modified Naughton protocol. During a mean follow-up of 5 years, 742 patients (33%) died, and 249 patients (11%) underwent heart transplantation urgently. We found that after accounting for baseline clinical characteristics, treadmill exercise time performed similarly to peak oxygen consumption for predicting poor outcome. For a 1-minute change in exercise time, there was a 7% increased hazard of death (eg, comparing 480 to 540 seconds, hazard ratio =1.07, 95% confidence interval 1.02 to 1.12, P=0.004). Mortality rates were particularly high for women who exercised less than 5 minutes and 17 seconds and for men who exercised less than 6 minutes. Our findings suggest that treadmill exercise time may be valuable as an initial prognostic screening tool in patients with advanced heart failure.
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