International Journal of Cardiology 176 (2014) 94–98
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Minimal important difference for 6-minute walk test distances among patients with chronic heart failure Tobias Täger a, Wiebke Hanholz a, Rita Cebola a, Hanna Fröhlich a, Jennifer Franke a, Andreas Doesch a, Hugo A. Katus a, Frank H. Wians Jr. b, Lutz Frankenstein a,⁎ a b
Department of Cardiology, Angiology, Pulmonology, University of Heidelberg, Heidelberg, Germany Department of Pathology, Baylor University Medical Center, Dallas, TX, United States
a r t i c l e
i n f o
Article history: Received 29 April 2013 Received in revised form 7 January 2014 Accepted 24 June 2014 Available online 1 July 2014 Keywords: Heart failure 6-minute walk-test Minimal important difference Biovariability
a b s t r a c t Background: The 6-minute walk test (6WT) is an established tool in the assessment of endurance and prognosis in patients with chronic heart failure (CHF). For these patients there is very limited data on biological variation of 6WT distances. We determined the minimal important difference (MID) for the 6WT in patients with stable systolic CHF. Methods: Two cohorts of patients with stable systolic CHF were included from the outpatients' clinic of the University of Heidelberg. In these cohorts, two 6WT measurements were performed – in cohort 1 (n = 461) 180 days and in cohort 2 (n = 512) 365 days apart. Stability was defined as the absence of clinical events (3 months before the first test, between both tests, and 6 months after the second test) and stability of symptoms (NYHA) between tests. Using a standard error of measurement (SEM)-based approach, we determined the MID for both cohorts. Results: The intraclass correlation coefficient was 0.89 at 180 days and 0.88 at 365 days. The results were consistent for groups stratified for age, gender, etiology of CHF, and individual NYHA class. The MID for the 6WT in stable CHF patients was 35 m and 37 m between presentation and 180 and 365 days, respectively. Conclusion: Submaximal exercise capacity as represented by the 6WT varies little in stable CHF patients for up to 1-year intervals. The MID for changes in 6WT values in patients with stable CHF over a period of 6 to 12 months is ~36 m. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The 6-minute walk test (6WT) was used initially as a measure of reduced exercise endurance in the evaluation of patients with pulmonary disease [1]. Subsequently, this test was rapidly adopted by cardiologists [2] and clinicians in other clinical subspecialties [3,4]. The widespread use of the 6WT in evaluating the degree of heart disease in patients with chronic heart failure (CHF) relates both to its value in the evaluation of therapeutic strategies in the treatment of patients with CHF [5,6] and in predicting the future likelihood of an adverse event (e.g., cardiac decompensation or death) in these patients [5–9]. Consequently, the 6WT is used widely as a non-invasive, easy-toperform, and inexpensive test for identifying patients with CHF who
⁎ Corresponding author at: Department of Cardiology, Angiology, Pulmonology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Tel.: +49 6221 56 3 8895; fax: +49 6221 56 6547. E-mail address: [email protected] (L. Frankenstein).
http://dx.doi.org/10.1016/j.ijcard.2014.06.035 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
are the most suitable for inclusion in clinical trials of new therapeutic strategies and as an endpoint for evaluating the long-term efficacy of these strategies in patients with CHF [10–18]. For pulmonary patients biological variation and MID are known [19–26]. In contrast and despite its widespread use in CHF, there is limited to no information on biological variation or its proxies such as minimal important difference (MID) of 6WT distances in CHF patients. So far, studies in CHF patients addressed either correlation of changes in 6WT distances with other clinical variables or endpoint driven cut-offs for change between 6WT measurements [27–32]. Neither of these approaches represents biological variation. Biological variation can be regarded as the random variation around a homeostatic set point of the respective test result. It is inherent to any biological system and can only be measured in strict absence of any change induced by instability or intervention. Our study sought to close the gap in our knowledge of biological variation and MID for the 6WT in patients with stable systolic CHF. Using a standard error of measurement (SEM)-based approach, we determined the MID for 6WTs from patients with two tests either 180 or 365 days apart.
T. Täger et al. / International Journal of Cardiology 176 (2014) 94–98
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2.4. MID
2. Materials and methods 2.1. Patients The clinical registry to the ongoing longitudinal observational study on chronic heart failure formed the basis of this study. Patients presenting to the outpatients' clinic of the University of Heidelberg Hospital (UHH), Germany, for assessment of heart failure and/ or evaluation toward cardiac transplantation have been asked to consent to have their data recorded and used for research purposes. The UHH is a 1685-bed tertiary care facility that serves the populace of the Rhein–Neckar region (app. 900,000 persons) in Germany. Recruitment into this longitudinal study has been continuous and prospective. For the present analysis, we retrospectively selected the clinical data from all patients meeting the following clinical and stability criteria: 1) CHF due to chronic systolic dysfunction; 2) no evidence of cardiac decompensation in the 3 months preceding the inclusion visit (V1) of this study where the initial 6WT was performed; 3) a second measurement of 6WT at a separate visit (V2) – either 180 days or 365 days after V1; 4) no evidence of cardiac decompensation between V1 and V2; 5) no change in perceived symptoms or subjective exercise capacity as evidenced by the NYHA functional class between V1 and V2; and 6) absence of any clinical event defined as evidence of cardiac decompensation or all-cause death or cardiac transplantation in the 6 months following V2. The timeline and temporal requirements of the present study are displayed in Fig. 1. If a given patient had more than 2 visits with measurement intervals meeting the requirements for both cohorts, inclusion into both cohorts was considered. This was assumed valid since the “learning effect” had been excluded already at the inclusion into this study at V1 (see below) and all the patients were stable between the two walk tests irrespective of cohorts by protocol definition. The diagnosis of CHF was based on standard clinical criteria, including systolic dysfunction and abnormal echocardiographic findings [33,34]. Systolic dysfunction was defined as a left-ventricular ejection fraction (LVEF) ≤45%. The protocol of the underlying clinical registry to the ongoing longitudinal observational study met the requirements of the Helsinki Declaration and was approved by the UHH Ethics Committee in its original conception in 1996 under the number 198/1996. Consequent modifications due to change in clinical variables/modalities and/or legal requirements have been systematically updated with the UHH Ethics committee ever since.
Within-subject biological variation refers to all biological (nondisease-related) sources of variation that can alter any individual's test results, including, but not limited to: seasonal and geographic variation, gender, and pulsatile and circadian biorhythms [37]. MID represents one way of approaching biological variation and the merits and pitfalls of this approach have been discussed previously [38]. MID can be assessed by either anchor-based methods – requiring reliable endpoints as “anchor” for definition – and distribution-based methods – requiring stable cohorts for derivation of the respective descriptive (distribution) statistics of the cohort. The onestandard error of measurement (one-SEM) value is a proxy for MID [39]. It is both valid and simpler than most other approaches [38,40,41] for the determination of MID. In our study, MID was determined using the one-SEM-based approach developed by Wyrwich et al. [41,42] using the formula:
MID ¼ SD x SQRT ð1−rÞ;
where SD is the population standard deviation and r is the intraclass correlation coefficient (i.e., the degree of absolute agreement among measurements). Descriptive statistics, the population SD, intra-class correlation coefficient, and paired samples t-test values were obtained using MedCalc software version 12.7 (Ostend, Belgium) and the results were displayed using GraphPad Prism version 6.02 for Windows (La Jolla, California, USA). An arbitrary p-value of 0.05 was used to assume statistical significance. 2.5. Ethics and authorship The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [43].
3. Results 3.1. Patient characteristics
2.2. 6WT The 6WT was performed according to a published protocol [7]. To avoid the “learning effect” that occurs when patients have not previously undergone a 6WT [35,36], only patients with a minimum of one 6WT value prior to the 6WT at V1 were included in our study. In general, patients had performed a median of two 6WTs prior to V1 – the first of these prior 6WT dating a median of 352 days before V1.
2.3. Determination of endpoints Endpoints were part of the definition of stability as outlined above. Cardiac decompensation, all-cause mortality, and cardiac transplantation were the predefined endpoints for the purpose of this analysis. They were determined from the patients' clinical records, phone calls to the patient's home or physician, or review of hospital in-patient records. walk-test
walk-test
The clinical characteristics for all patients in cohorts 1 (180-dayinterval) and 2 (365-day-interval) are shown in Table 1. Ischemic heart disease was the underlying etiology in the majority of patients. The mean ejection fraction was relatively low, indicating more advanced heart failure. The distribution of patients was balanced across NYHA functional Classes I–III. The selection of stable cohorts was evidenced by the low event rate. Among the Cohort 1 patients, 40 (8.7%) died during overall follow-up and 35 (7.6%) presented with cardiac decompensation after V2. Among the Cohort 2 patients, 48 (9.4%) died during overall follow-up and 47 (9.2%) presented with cardiac decompensation after V2. For the complete results on endpoints at 1-year, 2year, and 3-year follow-up see Table 2.
Table 1 Patient demographics and 6WT data at approximately 180- and 365-day intervalsa.
Cohort 1
clinically stable
(n=461)
Chacteristic
Cohort 1
Cohort 2
N Age, y Sex:
461 57 ± 12 360 (78.1) 101 (21.9) 27.9 ± 5.0 101 (21.9) 222 (48.2) 137 (29.7) 0 (0.0) 30 ± 11 280 (60.7) 185 ± 16 472 ± 106 414 (89.8) 395 (93.5) 665 (320–1844)
512 57 ± 12 391 (76.4) 121 (23.6) 27.9 ± 5.2 178 (34.8) 211 (41.2) 123 (24.0) 0 (0.0) 33 ± 12 285 (55.7) 366 ± 17 488 ± 107 466 (91.4) 418 (93.7) 734 (371–1364)
BMI, kg/m2 NYHA Class: -180
-90
0
Cohort 2
90
180 Time (days)
270
360
450
540
walk-test
I II III IV
LVEF, % IHD, n (%) No. of days between 6WTs 6WT, m Betablocker ACE-I/AT1-B No. of days of follow-upb
clinically stable
(n=512)
M F
walk-test
Fig. 1. Study outline regarding timeline with respect to stability criteria and measurement intervals.
a All patients had stable CHF; values shown are mean ± SD or mean (% of total) or median (IQR) were appropriate. b After second 6WT measurement. N, number; y, years; M, males; F, females; BMI, body mass index; NYHA, New York Heart Association; LVEF, left-ventricular ejection fraction; IHD, ischemic heart disease.
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T. Täger et al. / International Journal of Cardiology 176 (2014) 94–98
Table 2 Endpoint statistics (all-cause mortality and cardiac decompensation rate) for Cohorts 1 and 2 at several time points after the second visit (V2). Time after V2, years
1 2 3 Total F/U, mo
Cohort 1 (n = 461)
Cohort 2 (n = 512)
Deathb
Decompsationb
Deathb
Decocompensationb
2 (0.4) 11 (2.4) 17 (3.7) 40 (8.7)
8 (1.7) 18 (3.9) 21 (4.6) 35 (7.6)
7 (1.4) 8 (1.6) 21 (4.1) 48 (9.4)
18 (3.5) 27 (5.3) 36 (7.0) 47 (9.2)
Table 3 Summary statistics for 6WT values (meters) obtained on patients in Cohorts 1 and 2 at visits 1 (V1) and 2 (V2) ~180- (Cohort 1) and 365-days (Cohort 2) apart. Statistic
Mean Median SD Range r MID
b
Data given as total numbers and percent of the corresponding cohort; F/U, follow-up.
Cohort 2 (n = 512)
V2
V1
V2
472 481 106 50–789 0.8895 35.2
469 478 114 32–914
488 495 107 162–801 0.8828 36.8
483 487 113 50–786
SD, standard deviation; r, intraclass correlation coefficient; MID, minimal important difference.
3.2. 6WT & stability of measurements Overall, 973 6WTs were performed in 683 different patients – thus 393 of the patients had one 6WT measurement counted toward both cohorts. The distribution of 6WT values among Cohort 1 and Cohort 2 patients separate for V1 and V2 is shown in Fig. 2. Summary statistics for 6WT values in each cohort are shown in Table 3, alongside the respective values for SD, r, and MID between 6WT measurements at V1 and V2. For both cohorts, the reliability coefficient as expressed by the intraclass correlation coefficient between 6WT measurements at V1 and V2 was above 0.88 – indicating a high stability of measurement over time. When analyzed separately for the individual subgroups, values for the respective intraclass correlation coefficients were consistent across the different groups with respect to age, gender, etiology of CHF or perceived level of exercise capacity as evidenced by the individual NYHA functional classes. For complete results see Table 4. 3.3. MID The Bland–Altman-Plots of the individual absolute differences of 6WT measurements between visits vs. the respective mean values is depicted in Fig. 3. The MID was 35 m at 180-day follow-up in the 461 patients of Cohort 1 and 37 m at 365-day follow-up in the 512 patients of Cohort 2. 4. Discussion Despite its widespread application in heart failure research, there is very limited information on biological variation in 6WT distances in CHF patients and the 6WT MID has not been reported previously. Comparable data on MID of the 6WT comes mostly from studies in pulmonary patients [19–26] where values vary between 25 m [20] and 80 m [24]. From these studies it would further appear that the prognostic
A
significance of change of 6WT depends on the endpoint chosen, as reported by Polkey et al. [25]. When comparing these studies to ours, a few points need to be noted. First, already the context dependence would preclude direct transfer of their values. Furthermore, the results are population-specific and therefore appropriate for the population specified in the respective studies only. Lastly, virtually all of these studies applied anchor based methods – but both the clinical endpoint defined as anchor and the statistical method used to link the individual change in 6WT to this anchor varied largely. In contrast to these studies, we applied a distribution-based approach and our cohorts were selected for a maximum of stability – virtually eliminating clinical events in the first year of follow-up. We consider this stability a prerequisite for the determination of biological variation. As a consequence, we cannot reproduce the methods of the aforementioned studies from our data. We can, however, put our findings into perspective with the large number of clinical CHF trials that report change in 6WT as a surrogate endpoint following the respective trial intervention. Change between 12–15 m and 104–128 m has been reported in drug trials [15] and device trials [44–48] alike. Most recently, the FAIR-HF trial demonstrated a mean study-treatment effect on 6WT of 35 m [18]. It is here that our study significantly extends current knowledge. It should be remembered that it would be the MID that validates any such trial result. Then again, the consistent demonstration of statistical significance for change of 6WT of a magnitude comparable to or above the MID derived from our data indirectly validates our findings. On the other hand, statistical significance does not necessarily mean clinical significance [49] and Ingle et al. [31] demonstrated that for an intervention study based on gained 6WT distance a smaller gain in 6WT would reach statistical significance with a sufficiently large sample size. In the context of CHF, Ingle et al. [31] are the only other study
B 1000
1000
800
400
600
400
0
0
V2
200
V1
200
V2
600
V1
6-WT (m)
800
6-WT (m)
Cohort 1 (n = 461) V1
Fig. 2. 6-Minute walk test (6WT) values at visit 1 (V1) and visit 2 (V2) at approximately 180 days (A, Cohort 1) or 365 days (B, Cohort 2) between V1 and V2.
T. Täger et al. / International Journal of Cardiology 176 (2014) 94–98 Table 4 Intraclass correlation coefficients for subgroups defined by age, gender, diagnosis, or NYHA functional class. Chacteristic
Gender NYHA Class
Age, y Diagnosis
Intraclass correlation coefficient (95% CI)
M F I II III bMedian NMedian IHD Other
Cohort 1
Cohort 2
0.8970 (0.8748–0.9155) 0.8471 (0.7813–0.8943) 0.8581 (0.7964–0.9020) 0.8577 (0.8186–0.8889) 0.8041 (0.7359–0.8562) 0.8835 (0.8516–0.9089) 0.8890 (0.8584–0.9133) 0.8989 (0.8689–0.9223) 0.8794 (0.8483–0.9044)
0.8803 (0.8558–0.9008) 0.8905 (0.8467–0.9223) 0.8591 (0.8151–0.8932) 0.8456 (0.8022–0.8932 0.7634 (0.6783–0.8282) 0.8858 (0.8559–0.9097) 0.8715 (0.8388–0.8979) 0.8691 (0.8298–0.8998) 0.8824 (0.8555–0.9045)
CI, confidence interval; M, males; F, females; NYHA, New York Heart Association; IHD, ischemic heart disease.
ever to directly address stability of measurement. They reported a satisfactory agreement of 6WT measurements when repeated after 1 year in elderly patients (aged N 60 years) with CHF. In their 74 patients with stable symptoms the intraclass correlation coefficient was 0.80. When applying the approach of Wyrwich et al. [41,42] to their data, the resultant MID would be about 55 m. While this supports the MID from our data, our study significantly expands their data both on grounds of age-group, sample size, and stability of measurement as evidenced from a comparison of the intraclass correlation coefficients. While there is no data on biological variation and/or distribution based approaches for 6WT in CHF patients, there are two studies applying anchor based approaches to the link between change in 6WT and endpoints in CHF patients. Spruit et al. [32] reproduced the context dependence of 6WT change in CHF patients noted by Polkey et al. [25] in pulmonary patients. In their study, lack of increasing 6MWD above the median change of the cohort did not significantly affect HF hospitalization-free survival but all-cause hospitalization-free survival. Their cohort median is at 40 m and thus very close to the 36 m found in our study. In extension, Spertus et al. [30] reported that the magnitude of change in 6WT distances significantly depended on subjective change in clinical status. In 320 stable CHF patients their mean change in 6WT was around 4.6 m. This indirectly supports the high stability of 6WT measurements in stable patients found by Ingle et al. [31] and us.
A
4.1. Limitations We cannot completely exclude a pre-selection bias in the selection of patients. Presentation to our CHF outpatients' department depends to a certain extent on referring physicians deeming their patients appropriate for referral at our university hospital clinic. Also, since measures of biological variation are context dependent, our results may not be applicable to other settings. The retrospective nature of our study may further represent a limitation. However, clinical information from all patients referred to our clinic, who consented to have their data included in our CHF Registry, was added to this registry continuously and prospectively. More importantly, the retrospective nature of our study design allowed us to rigorously define stability of CHF. From our understanding this is a prerequisite condition for the determination of MID. Then again, complete stability is difficult to ascertain in CHF. We do not have quality of life data to further validate the stability of our study patients during the time period of our study. We suggest, however, that the absence of any changes in NYHA classification in conjunction with the absence of clinical events over a prolonged period of time beyond our study lends credence to this assumption. In this context, inclusion of NYHA III patients can be debated as there is evidence that serial testing of 6WT might be of limited value in very advanced CHF [27,29]. On the other hand, this evidence relates to patients in NYHA IIIb/IV – patients that were not included in the present analysis. Our NYHA III patients had to meet the stability criteria outlined above and it is our clinical experience that a patient can be stable on a low level of exercise capacity. This notion is further supported by the high intraclass correlation coefficient with values in the range of those reported for stable patients by Ingle et al. [31]. 5. Conclusion Biological variation of 6WT values over 6- and 12-month periods is low for stable CHF patients. The MID for changes in 6WT values in these patients with stable CHF is ~ 36 m for both periods. This finding is relevant for the appropriate clinical follow-up and interpretation of CHF clinical trials that use the 6WT as a surrogate endpoint both for morbidity or mortality. Conflict of interests None.
B 365 days
180 days 200
200
100
100
Difference (m) 6WT
Difference (m) 6WT
97
0
-100
0
-100
-200
-200
200
400
Mean 6WT
600
800
1000
200
400
600
800
Mean 6WT
Fig. 3. Bland–Altman plot for Mean 6WT values (between V1 and V2) at 180 days (A, Cohort 1) or 365 days (B, Cohort 2) follow-up.
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Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. [45] Capasso F, Giunta A, De Simone A, et al. Acute left ventricular dyssynchrony improvement predicts long-term benefit from cardiac resynchronization therapy. Pacing Clin Electrophysiol 2007;30(Suppl. 1):S62–5. [46] Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–80. [47] De Marco T, Wolfel E, Feldman AM, et al. Impact of cardiac resynchronization therapy on exercise performance, functional capacity, and quality of life in systolic heart failure with QRS prolongation: COMPANION trial sub-study. J Card Fail 2008;14:9–18. [48] Provenier F, Jordaens L. Evaluation of six minute walking test in patients with single chamber rate responsive pacemakers. Br Heart J 1994;72:192–6. [49] Beaton DE, Boers M, Wells GA. Many faces of the minimal clinically important difference (MCID): a literature review and directions for future research. Curr Opin Rheumatol 2002;14:109–14.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Minimal important difference for 6-minute walk test distances among patients with chronic heart failure Tobias Täger a, Wiebke Hanholz a, Rita Cebola a, Hanna Fröhlich a, Jennifer Franke a, Andreas Doesch a, Hugo A. Katus a, Frank H. Wians Jr. b, Lutz Frankenstein a,⁎ a b
Department of Cardiology, Angiology, Pulmonology, University of Heidelberg, Heidelberg, Germany Department of Pathology, Baylor University Medical Center, Dallas, TX, United States
a r t i c l e
i n f o
Article history: Received 29 April 2013 Received in revised form 7 January 2014 Accepted 24 June 2014 Available online 1 July 2014 Keywords: Heart failure 6-minute walk-test Minimal important difference Biovariability
a b s t r a c t Background: The 6-minute walk test (6WT) is an established tool in the assessment of endurance and prognosis in patients with chronic heart failure (CHF). For these patients there is very limited data on biological variation of 6WT distances. We determined the minimal important difference (MID) for the 6WT in patients with stable systolic CHF. Methods: Two cohorts of patients with stable systolic CHF were included from the outpatients' clinic of the University of Heidelberg. In these cohorts, two 6WT measurements were performed – in cohort 1 (n = 461) 180 days and in cohort 2 (n = 512) 365 days apart. Stability was defined as the absence of clinical events (3 months before the first test, between both tests, and 6 months after the second test) and stability of symptoms (NYHA) between tests. Using a standard error of measurement (SEM)-based approach, we determined the MID for both cohorts. Results: The intraclass correlation coefficient was 0.89 at 180 days and 0.88 at 365 days. The results were consistent for groups stratified for age, gender, etiology of CHF, and individual NYHA class. The MID for the 6WT in stable CHF patients was 35 m and 37 m between presentation and 180 and 365 days, respectively. Conclusion: Submaximal exercise capacity as represented by the 6WT varies little in stable CHF patients for up to 1-year intervals. The MID for changes in 6WT values in patients with stable CHF over a period of 6 to 12 months is ~36 m. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The 6-minute walk test (6WT) was used initially as a measure of reduced exercise endurance in the evaluation of patients with pulmonary disease [1]. Subsequently, this test was rapidly adopted by cardiologists [2] and clinicians in other clinical subspecialties [3,4]. The widespread use of the 6WT in evaluating the degree of heart disease in patients with chronic heart failure (CHF) relates both to its value in the evaluation of therapeutic strategies in the treatment of patients with CHF [5,6] and in predicting the future likelihood of an adverse event (e.g., cardiac decompensation or death) in these patients [5–9]. Consequently, the 6WT is used widely as a non-invasive, easy-toperform, and inexpensive test for identifying patients with CHF who
⁎ Corresponding author at: Department of Cardiology, Angiology, Pulmonology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Tel.: +49 6221 56 3 8895; fax: +49 6221 56 6547. E-mail address: [email protected] (L. Frankenstein).
http://dx.doi.org/10.1016/j.ijcard.2014.06.035 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
are the most suitable for inclusion in clinical trials of new therapeutic strategies and as an endpoint for evaluating the long-term efficacy of these strategies in patients with CHF [10–18]. For pulmonary patients biological variation and MID are known [19–26]. In contrast and despite its widespread use in CHF, there is limited to no information on biological variation or its proxies such as minimal important difference (MID) of 6WT distances in CHF patients. So far, studies in CHF patients addressed either correlation of changes in 6WT distances with other clinical variables or endpoint driven cut-offs for change between 6WT measurements [27–32]. Neither of these approaches represents biological variation. Biological variation can be regarded as the random variation around a homeostatic set point of the respective test result. It is inherent to any biological system and can only be measured in strict absence of any change induced by instability or intervention. Our study sought to close the gap in our knowledge of biological variation and MID for the 6WT in patients with stable systolic CHF. Using a standard error of measurement (SEM)-based approach, we determined the MID for 6WTs from patients with two tests either 180 or 365 days apart.
T. Täger et al. / International Journal of Cardiology 176 (2014) 94–98
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2.4. MID
2. Materials and methods 2.1. Patients The clinical registry to the ongoing longitudinal observational study on chronic heart failure formed the basis of this study. Patients presenting to the outpatients' clinic of the University of Heidelberg Hospital (UHH), Germany, for assessment of heart failure and/ or evaluation toward cardiac transplantation have been asked to consent to have their data recorded and used for research purposes. The UHH is a 1685-bed tertiary care facility that serves the populace of the Rhein–Neckar region (app. 900,000 persons) in Germany. Recruitment into this longitudinal study has been continuous and prospective. For the present analysis, we retrospectively selected the clinical data from all patients meeting the following clinical and stability criteria: 1) CHF due to chronic systolic dysfunction; 2) no evidence of cardiac decompensation in the 3 months preceding the inclusion visit (V1) of this study where the initial 6WT was performed; 3) a second measurement of 6WT at a separate visit (V2) – either 180 days or 365 days after V1; 4) no evidence of cardiac decompensation between V1 and V2; 5) no change in perceived symptoms or subjective exercise capacity as evidenced by the NYHA functional class between V1 and V2; and 6) absence of any clinical event defined as evidence of cardiac decompensation or all-cause death or cardiac transplantation in the 6 months following V2. The timeline and temporal requirements of the present study are displayed in Fig. 1. If a given patient had more than 2 visits with measurement intervals meeting the requirements for both cohorts, inclusion into both cohorts was considered. This was assumed valid since the “learning effect” had been excluded already at the inclusion into this study at V1 (see below) and all the patients were stable between the two walk tests irrespective of cohorts by protocol definition. The diagnosis of CHF was based on standard clinical criteria, including systolic dysfunction and abnormal echocardiographic findings [33,34]. Systolic dysfunction was defined as a left-ventricular ejection fraction (LVEF) ≤45%. The protocol of the underlying clinical registry to the ongoing longitudinal observational study met the requirements of the Helsinki Declaration and was approved by the UHH Ethics Committee in its original conception in 1996 under the number 198/1996. Consequent modifications due to change in clinical variables/modalities and/or legal requirements have been systematically updated with the UHH Ethics committee ever since.
Within-subject biological variation refers to all biological (nondisease-related) sources of variation that can alter any individual's test results, including, but not limited to: seasonal and geographic variation, gender, and pulsatile and circadian biorhythms [37]. MID represents one way of approaching biological variation and the merits and pitfalls of this approach have been discussed previously [38]. MID can be assessed by either anchor-based methods – requiring reliable endpoints as “anchor” for definition – and distribution-based methods – requiring stable cohorts for derivation of the respective descriptive (distribution) statistics of the cohort. The onestandard error of measurement (one-SEM) value is a proxy for MID [39]. It is both valid and simpler than most other approaches [38,40,41] for the determination of MID. In our study, MID was determined using the one-SEM-based approach developed by Wyrwich et al. [41,42] using the formula:
MID ¼ SD x SQRT ð1−rÞ;
where SD is the population standard deviation and r is the intraclass correlation coefficient (i.e., the degree of absolute agreement among measurements). Descriptive statistics, the population SD, intra-class correlation coefficient, and paired samples t-test values were obtained using MedCalc software version 12.7 (Ostend, Belgium) and the results were displayed using GraphPad Prism version 6.02 for Windows (La Jolla, California, USA). An arbitrary p-value of 0.05 was used to assume statistical significance. 2.5. Ethics and authorship The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [43].
3. Results 3.1. Patient characteristics
2.2. 6WT The 6WT was performed according to a published protocol [7]. To avoid the “learning effect” that occurs when patients have not previously undergone a 6WT [35,36], only patients with a minimum of one 6WT value prior to the 6WT at V1 were included in our study. In general, patients had performed a median of two 6WTs prior to V1 – the first of these prior 6WT dating a median of 352 days before V1.
2.3. Determination of endpoints Endpoints were part of the definition of stability as outlined above. Cardiac decompensation, all-cause mortality, and cardiac transplantation were the predefined endpoints for the purpose of this analysis. They were determined from the patients' clinical records, phone calls to the patient's home or physician, or review of hospital in-patient records. walk-test
walk-test
The clinical characteristics for all patients in cohorts 1 (180-dayinterval) and 2 (365-day-interval) are shown in Table 1. Ischemic heart disease was the underlying etiology in the majority of patients. The mean ejection fraction was relatively low, indicating more advanced heart failure. The distribution of patients was balanced across NYHA functional Classes I–III. The selection of stable cohorts was evidenced by the low event rate. Among the Cohort 1 patients, 40 (8.7%) died during overall follow-up and 35 (7.6%) presented with cardiac decompensation after V2. Among the Cohort 2 patients, 48 (9.4%) died during overall follow-up and 47 (9.2%) presented with cardiac decompensation after V2. For the complete results on endpoints at 1-year, 2year, and 3-year follow-up see Table 2.
Table 1 Patient demographics and 6WT data at approximately 180- and 365-day intervalsa.
Cohort 1
clinically stable
(n=461)
Chacteristic
Cohort 1
Cohort 2
N Age, y Sex:
461 57 ± 12 360 (78.1) 101 (21.9) 27.9 ± 5.0 101 (21.9) 222 (48.2) 137 (29.7) 0 (0.0) 30 ± 11 280 (60.7) 185 ± 16 472 ± 106 414 (89.8) 395 (93.5) 665 (320–1844)
512 57 ± 12 391 (76.4) 121 (23.6) 27.9 ± 5.2 178 (34.8) 211 (41.2) 123 (24.0) 0 (0.0) 33 ± 12 285 (55.7) 366 ± 17 488 ± 107 466 (91.4) 418 (93.7) 734 (371–1364)
BMI, kg/m2 NYHA Class: -180
-90
0
Cohort 2
90
180 Time (days)
270
360
450
540
walk-test
I II III IV
LVEF, % IHD, n (%) No. of days between 6WTs 6WT, m Betablocker ACE-I/AT1-B No. of days of follow-upb
clinically stable
(n=512)
M F
walk-test
Fig. 1. Study outline regarding timeline with respect to stability criteria and measurement intervals.
a All patients had stable CHF; values shown are mean ± SD or mean (% of total) or median (IQR) were appropriate. b After second 6WT measurement. N, number; y, years; M, males; F, females; BMI, body mass index; NYHA, New York Heart Association; LVEF, left-ventricular ejection fraction; IHD, ischemic heart disease.
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Table 2 Endpoint statistics (all-cause mortality and cardiac decompensation rate) for Cohorts 1 and 2 at several time points after the second visit (V2). Time after V2, years
1 2 3 Total F/U, mo
Cohort 1 (n = 461)
Cohort 2 (n = 512)
Deathb
Decompsationb
Deathb
Decocompensationb
2 (0.4) 11 (2.4) 17 (3.7) 40 (8.7)
8 (1.7) 18 (3.9) 21 (4.6) 35 (7.6)
7 (1.4) 8 (1.6) 21 (4.1) 48 (9.4)
18 (3.5) 27 (5.3) 36 (7.0) 47 (9.2)
Table 3 Summary statistics for 6WT values (meters) obtained on patients in Cohorts 1 and 2 at visits 1 (V1) and 2 (V2) ~180- (Cohort 1) and 365-days (Cohort 2) apart. Statistic
Mean Median SD Range r MID
b
Data given as total numbers and percent of the corresponding cohort; F/U, follow-up.
Cohort 2 (n = 512)
V2
V1
V2
472 481 106 50–789 0.8895 35.2
469 478 114 32–914
488 495 107 162–801 0.8828 36.8
483 487 113 50–786
SD, standard deviation; r, intraclass correlation coefficient; MID, minimal important difference.
3.2. 6WT & stability of measurements Overall, 973 6WTs were performed in 683 different patients – thus 393 of the patients had one 6WT measurement counted toward both cohorts. The distribution of 6WT values among Cohort 1 and Cohort 2 patients separate for V1 and V2 is shown in Fig. 2. Summary statistics for 6WT values in each cohort are shown in Table 3, alongside the respective values for SD, r, and MID between 6WT measurements at V1 and V2. For both cohorts, the reliability coefficient as expressed by the intraclass correlation coefficient between 6WT measurements at V1 and V2 was above 0.88 – indicating a high stability of measurement over time. When analyzed separately for the individual subgroups, values for the respective intraclass correlation coefficients were consistent across the different groups with respect to age, gender, etiology of CHF or perceived level of exercise capacity as evidenced by the individual NYHA functional classes. For complete results see Table 4. 3.3. MID The Bland–Altman-Plots of the individual absolute differences of 6WT measurements between visits vs. the respective mean values is depicted in Fig. 3. The MID was 35 m at 180-day follow-up in the 461 patients of Cohort 1 and 37 m at 365-day follow-up in the 512 patients of Cohort 2. 4. Discussion Despite its widespread application in heart failure research, there is very limited information on biological variation in 6WT distances in CHF patients and the 6WT MID has not been reported previously. Comparable data on MID of the 6WT comes mostly from studies in pulmonary patients [19–26] where values vary between 25 m [20] and 80 m [24]. From these studies it would further appear that the prognostic
A
significance of change of 6WT depends on the endpoint chosen, as reported by Polkey et al. [25]. When comparing these studies to ours, a few points need to be noted. First, already the context dependence would preclude direct transfer of their values. Furthermore, the results are population-specific and therefore appropriate for the population specified in the respective studies only. Lastly, virtually all of these studies applied anchor based methods – but both the clinical endpoint defined as anchor and the statistical method used to link the individual change in 6WT to this anchor varied largely. In contrast to these studies, we applied a distribution-based approach and our cohorts were selected for a maximum of stability – virtually eliminating clinical events in the first year of follow-up. We consider this stability a prerequisite for the determination of biological variation. As a consequence, we cannot reproduce the methods of the aforementioned studies from our data. We can, however, put our findings into perspective with the large number of clinical CHF trials that report change in 6WT as a surrogate endpoint following the respective trial intervention. Change between 12–15 m and 104–128 m has been reported in drug trials [15] and device trials [44–48] alike. Most recently, the FAIR-HF trial demonstrated a mean study-treatment effect on 6WT of 35 m [18]. It is here that our study significantly extends current knowledge. It should be remembered that it would be the MID that validates any such trial result. Then again, the consistent demonstration of statistical significance for change of 6WT of a magnitude comparable to or above the MID derived from our data indirectly validates our findings. On the other hand, statistical significance does not necessarily mean clinical significance [49] and Ingle et al. [31] demonstrated that for an intervention study based on gained 6WT distance a smaller gain in 6WT would reach statistical significance with a sufficiently large sample size. In the context of CHF, Ingle et al. [31] are the only other study
B 1000
1000
800
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600
400
0
0
V2
200
V1
200
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V1
6-WT (m)
800
6-WT (m)
Cohort 1 (n = 461) V1
Fig. 2. 6-Minute walk test (6WT) values at visit 1 (V1) and visit 2 (V2) at approximately 180 days (A, Cohort 1) or 365 days (B, Cohort 2) between V1 and V2.
T. Täger et al. / International Journal of Cardiology 176 (2014) 94–98 Table 4 Intraclass correlation coefficients for subgroups defined by age, gender, diagnosis, or NYHA functional class. Chacteristic
Gender NYHA Class
Age, y Diagnosis
Intraclass correlation coefficient (95% CI)
M F I II III bMedian NMedian IHD Other
Cohort 1
Cohort 2
0.8970 (0.8748–0.9155) 0.8471 (0.7813–0.8943) 0.8581 (0.7964–0.9020) 0.8577 (0.8186–0.8889) 0.8041 (0.7359–0.8562) 0.8835 (0.8516–0.9089) 0.8890 (0.8584–0.9133) 0.8989 (0.8689–0.9223) 0.8794 (0.8483–0.9044)
0.8803 (0.8558–0.9008) 0.8905 (0.8467–0.9223) 0.8591 (0.8151–0.8932) 0.8456 (0.8022–0.8932 0.7634 (0.6783–0.8282) 0.8858 (0.8559–0.9097) 0.8715 (0.8388–0.8979) 0.8691 (0.8298–0.8998) 0.8824 (0.8555–0.9045)
CI, confidence interval; M, males; F, females; NYHA, New York Heart Association; IHD, ischemic heart disease.
ever to directly address stability of measurement. They reported a satisfactory agreement of 6WT measurements when repeated after 1 year in elderly patients (aged N 60 years) with CHF. In their 74 patients with stable symptoms the intraclass correlation coefficient was 0.80. When applying the approach of Wyrwich et al. [41,42] to their data, the resultant MID would be about 55 m. While this supports the MID from our data, our study significantly expands their data both on grounds of age-group, sample size, and stability of measurement as evidenced from a comparison of the intraclass correlation coefficients. While there is no data on biological variation and/or distribution based approaches for 6WT in CHF patients, there are two studies applying anchor based approaches to the link between change in 6WT and endpoints in CHF patients. Spruit et al. [32] reproduced the context dependence of 6WT change in CHF patients noted by Polkey et al. [25] in pulmonary patients. In their study, lack of increasing 6MWD above the median change of the cohort did not significantly affect HF hospitalization-free survival but all-cause hospitalization-free survival. Their cohort median is at 40 m and thus very close to the 36 m found in our study. In extension, Spertus et al. [30] reported that the magnitude of change in 6WT distances significantly depended on subjective change in clinical status. In 320 stable CHF patients their mean change in 6WT was around 4.6 m. This indirectly supports the high stability of 6WT measurements in stable patients found by Ingle et al. [31] and us.
A
4.1. Limitations We cannot completely exclude a pre-selection bias in the selection of patients. Presentation to our CHF outpatients' department depends to a certain extent on referring physicians deeming their patients appropriate for referral at our university hospital clinic. Also, since measures of biological variation are context dependent, our results may not be applicable to other settings. The retrospective nature of our study may further represent a limitation. However, clinical information from all patients referred to our clinic, who consented to have their data included in our CHF Registry, was added to this registry continuously and prospectively. More importantly, the retrospective nature of our study design allowed us to rigorously define stability of CHF. From our understanding this is a prerequisite condition for the determination of MID. Then again, complete stability is difficult to ascertain in CHF. We do not have quality of life data to further validate the stability of our study patients during the time period of our study. We suggest, however, that the absence of any changes in NYHA classification in conjunction with the absence of clinical events over a prolonged period of time beyond our study lends credence to this assumption. In this context, inclusion of NYHA III patients can be debated as there is evidence that serial testing of 6WT might be of limited value in very advanced CHF [27,29]. On the other hand, this evidence relates to patients in NYHA IIIb/IV – patients that were not included in the present analysis. Our NYHA III patients had to meet the stability criteria outlined above and it is our clinical experience that a patient can be stable on a low level of exercise capacity. This notion is further supported by the high intraclass correlation coefficient with values in the range of those reported for stable patients by Ingle et al. [31]. 5. Conclusion Biological variation of 6WT values over 6- and 12-month periods is low for stable CHF patients. The MID for changes in 6WT values in these patients with stable CHF is ~ 36 m for both periods. This finding is relevant for the appropriate clinical follow-up and interpretation of CHF clinical trials that use the 6WT as a surrogate endpoint both for morbidity or mortality. Conflict of interests None.
B 365 days
180 days 200
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100
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Difference (m) 6WT
97
0
-100
0
-100
-200
-200
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400
Mean 6WT
600
800
1000
200
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Mean 6WT
Fig. 3. Bland–Altman plot for Mean 6WT values (between V1 and V2) at 180 days (A, Cohort 1) or 365 days (B, Cohort 2) follow-up.
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