Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review

Lars G. Olsson1, Karl Swedberg1,*, Andrew L. Clark2, Klaus K. Witte2 and John G.F. Cleland2

1Department of Medicine, Sahlgrenska University Hospital/Östra, SE-416 85 Göteborg, Sweden
2Department of Academic Cardiology, Castle Hill Hospital, Cottingham, Kingston upon Hull, UK

Received 20 October 2004; revised 23 November 2004; accepted 6 January 2005; online publish-ahead-of-print 17 March 2005.

* Corresponding author. Tel: +46 313434000; fax: +46 31258933. E-mail address: karl.swedberg{at}hjl.gu.se

See page 749 for the editorial comment on this article (doi:10.1093/eurheartj/ehi207)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims The 6 min walk test (6MWT) is commonly used in clinical trials to assess treatments for heart failure, but its ability to distinguish between effective and ineffective treatments is questionable. The aim of this study is to investigate, using a systematic literature review, the utility of the 6MWT as a measure of the effectiveness of treatment in randomized controlled trials of heart failure.

Methods and results A literature search was performed using Medline, EMBASE, CINAHL, and Biological abstracts for randomized controlled trials that measured 6MWT between 1988 and 31 May 2004. A significant increase in 6MWT distance was observed in only 9 of 47 randomized controlled trials of pharmacological therapy; 2 of 6 trials of ACE-inhibitors; 3 of 17 trials of beta-blockers; 1 of 4 trials of digoxin; one trial of ibopamine; one trial of L-arginine; one trial of beriberine; and one trial showed superiority of captopril over flosequinan. A significant increase in 6MWT was observed in four out of six placebo-controlled trials of cardiac resynchronization. Smaller pharmacological trials with fewer centres were more likely to be positive; six out of nine positive pharmacological trials had four or less participating centres, raising the possibility of publication bias. Pharmacological trials including patients with more severe heart failure were more likely to show a significant improvement with therapy than trials of milder heart failure. Five out of seven pharmacological trials that reported an improvement in symptoms also reported an improvement in 6MWT distance. Of 30 pharmacological trials, 29 that reported no improvement in symptoms also reported no improvement in 6MWT. Using mean values in these trials, the age of patients appeared a more important determinant of 6MWT distance than New York Heart Association classification.

Conclusion The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions although it appears useful for the assessment of cardiac resynchronization therapy. The results of the 6MWT were concordant with changes in symptoms, suggesting that it may be used as supportive evidence for symptom benefit. The test may be of greater value in patients with more advanced heart failure, where it may function as a maximal exercise test.

Key Words: Chronic heart failure • Six minute walk test • Submaximal exercise • Systematic review • Randomized controlled trials


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Chronic heart failure is a major health problem.1 During the last 25 years, several new therapies have been introduced that can prolong life and delay hospitalizations for heart failure.25 The prevalence of heart failure is rising partly due to ageing of the population and partly due to increased longevity of even patients with severe heart failure.6 Accordingly, there is growing need for further innovations in care for patients with heart failure and for tools with which to evaluate treatment.

The objective of managing patients with heart failure is generally to improve well being and increase longevity. The relative importance of these outcomes will vary among patients and their circumstances. Evaluating the effects of treatment on mortality usually requires large, long-term trials and, when adequately powered, provides robust evidence of the presence and magnitude of effect. It is generally accepted that there are no adequate surrogate measures for mortality. Evaluating well being in patients with heart failure appears more complex, as the patients perceptions will be coloured by their previous health state, future expectations, mood, intercurrent illnesses, and the way in which they are asked questions. Equally, knowledge of the severity of cardiac dysfunction, age, and prognosis will affect the investigator's assessment, consciously or unconsciously. Accordingly, researchers have turned to surrogate measures in an attempt to identify an accurate, objective, and reproducible method of assessing patients' well-being. Bicycle and treadmill exercise tests have been used to assess the effects of therapy in heart failure for at least 40 years.79 Brief, high-intensity exercise tests may be used to assess cardiorespiratory reserve, while longer, lower intensity protocols can be used to assess submaximal exercise endurance, which is determined by complex interactions among the lungs, heart, circulation, and muscle. However, formal exercise testing, especially when coupled with assessment of gas exchange, is complex to administer, may be a poor measure of limiting symptoms during daily activity, and may have limited reproducibility unless patients and staff are rigorously trained. Moreover, many patients are unable or unwilling to exercise adequately on such equipment and training effects may be substantial. On the other hand, all ambulatory patients can manage a self-paced 6 min walk test (6MWT).10,11 It is simple, inexpensive, and carries important prognostic information.1214 As the patient determines the distance walked and because such activity is familiar, it may be more representative of patients' everyday experience.

The 6MWT has been used as an outcome measure in clinical trials since 1988, but its ability to distinguish between effective or ineffective interventions in patients with heart failure has not been assessed in detail. The purpose of this review is to evaluate the utility of the 6MWT for the evaluation of therapy in randomized controlled trials of heart failure, features of trial design that may influence its success, and whether or not the results of 6MWT were concordant with other trial outcomes.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
A literature search was performed using Medline, EMBASE, CINAHL, and Biological abstracts. Additional searches were performed using the Science DirectTM database, where the used phrases were ‘walk’ or ‘walking’ in full-text and ‘heart failure’ and ‘ventricular dysfunction’ in the title–abstract–keyword section. Reference lists of papers identified were read to identify additional papers. Additional information was gathered through authors, expert colleagues, and study sponsors. Trials published only in abstract form at scientific meetings were also included.

For inclusion, the trials had to be randomized, blinded (patient, supervisor, or both), report the results of the 6MWT, administer at least daily doses of treatment or have devices implemented, and comprise patients with diagnosed heart failure with or without major left ventricular (systolic) dysfunction who had stable symptoms or were asymptomatic. Trials appearing on the above searches prior to 31 May 2004 were included.

Analysis
For each trial, change in distance walked in 6MWT was noted and whether this was significant compared with the control group. Delta 6MWT was the difference (in meters) between the active and the control group. The impact of repeated baseline tests, intervention type, number of centres involved, study size, blinding, age, and severity of heart failure was analysed together with publication form and presence of diastolic heart failure. In placebo-controlled trials with more than one comparator group, each comparison between active and placebo was treated as a separate analysis for this evaluation. The severity of heart failure was defined as the per cent of patients in different New York Heart Association (NYHA) classes. Trials were analysed according to the number of participating centres: one, two to four, or more than four centres involved. The concordance between 6MWT and maximal exercise testing (ETT), peak oxygen uptake (pVO2), symptoms, and left ventricular ejection fraction (LVEF) was analysed. Positive concordance between two measures was defined as both measures showing significant improvement with therapy. Neutral concordance was defined as both measures showing a non-significant treatment effect. The placebo response was assessed by analysing results after excluding ‘withdrawal’ trials. Trials were also analysed according to whether the intervention was considered effective for the improvement in symptoms or prognosis according to European Society of Cardiology Guidelines or based on large clinical trials reported since the Guidelines were last published.15


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Sixty-three randomized, controlled trials reporting the results of 6MWT published between 1988 and May 2004 were identified. Four papers duplicated results from an already published trial.1619 Two short-term trials were excluded.20,21 One trial decided treatment on symptomatic improvement.22 The Australia–New Zealand Heart Failure Research Collaborative Group trial reported short-term and long-term effects of carvedilol.23,24 Of the remaining 56 trials, 46 were placebo-controlled, 7 parallel active-controlled, and 3 crossover group comparisons with a total of 9861 patients. Forty-nine trials were published in article form and seven as abstracts or in meeting reports. Fifty-three trials evaluated treatment in patients with reduced systolic function and three in patients with preserved systolic function. Seven were single blind and 49 double blind. Forty-six placebo-controlled trials included 102 randomized arms, allowing 58 comparisons against placebo; 10 active-controlled trials included 23 randomized arms, allowing 13 comparisons against control. Trials are listed in Tables 1 and 2. Captopril was compared with ibopamine and placebo in one trial and to flosequinan in another.


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Table 1 Single- or double-blinded placebo-controlled clinical trials
 

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Table 2 Randomized, blinded trials with an active control
 
Placebo response
There were small differences in placebo response between trials reporting more than one baseline test and those that did not (Figure 1A). Trials showing a difference between the active intervention and placebo had a smaller placebo group response (median 8.5 m compared with 24.2 m) (Figure 1B). The placebo response was greater in trials with fewer patients and fewer centres with small differences regarding severity of heart failure (Figure 1C–E).







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Figure 1 (A) Change in mean 6MWT distance in the placebo group in trials performing multiple baseline tests and/or using encouragement; (B) by significant results from an intervention; (C) by number of participating centers; (D) by median placebo group size (n=34); and (E) by per cent patients in NYHA class III/IV.

 
Treatment effects
Twelve out of 46 placebo-controlled trials of pharmacological and non-pharmacological interventions (26%) showed a significant improvement in the 6MWT with intervention and 1 out of 10 trials (10%) showed differences between interventions. Two out of five placebo-controlled trials25,26 (two of six comparisons between active treatment and control) of ACE-inhibitors2729 showed an improvement in 6MWT distance. However, one was a single centre study, which also investigated the effects of ibopamine.25 The only, large multicentre, placebo-controlled trial of an ACE inhibitor failed to show an effect in either of its two active treatment arms, but comprised mostly NYHA II patients.28 One large multicentre study comparing captopril and flosequinan in patients with severe heart failure suggested that the latter was inferior.30 Whether this reflects worsening with flosequinan or improvement with captopril cannot be resolved owing to the lack of a placebo group. The only trial comparing an angiotensin receptor blocker (ARB) with placebo in the absence of an ACE-inhibitor also showed no effect.31 ARBs were compared with enalapril in four active-controlled trials,3235 with no significant differences in exercise capacity or symptoms regardless of agent or dosage.

Only 33638 of 15 placebo-controlled trials23,24,3948 (3 of 20 comparisons) of beta-blockers showed an improvement in 6MWT distance, all with carvedilol (three of eight trials, 3 of 10 comparisons). Only one37 of five comparisons23,24,40,44 in substantial multicentre trials showed a difference. Two trials49,50 comparing metoprolol and carvedilol showed no difference between agents.

Only one51 of four trials5254 of digoxin showed an improvement in 6MWT distance. This trial was a substantial multicentre trial with a withdrawal design. A trial evaluating furosemide withdrawal in elderly patients with preserved systolic function showed no significant changes in distance walked between groups.55 A trial evaluating aerobic exercise showed no significant difference in distance walked between groups.56

The 6MWT distance did not improve in 12 trials30,5767 of agents that are not yet generally accepted as effective. One single-centre trial investigating ibopamine was positive,25 while outcome trials have suggested harm.68 Two single-centre studies, one of L-arginine69 and one of beriberine,70 two interventions for which conclusive evidence of an effect are awaited, were also positive.

Four7174 of six trials75,76 of cardiac resynchronization, two of which were large multicentre trials, showed an improvement in the 6MWT, and results were concordant with the effect on symptoms. In three trials,7779 where bi-ventricular pacing was compared with left ventricular pacing, 6MWT was not significantly improved.

Concordance between changes in 6MWT and changes in other measures
Comparison between 6MWT and other endpoints are listed in Table 3. Overall, there was concordance in 107 of 139 (77%) comparisons, of which 85 showed neutral and 22 showed positive concordances. No trial showed a significant reduction in 6MWT on active therapy compared with control.


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Table 3 Concordance between 6MWT and other endpoints
 
The 6MWT showed positive concordance with symptoms in 9 of 47 trials25,36,37,51,6973 (10 of 62 comparisons), neutral concordance in 33 of 47 trials23,24,28,29,3135,3947,49,50,5254,56,6063,65,67,75,78,79 (48 comparisons), and discordance in 11% of trials. 6MWT was significantly improved while symptoms remained neutral in two trials26,74 (two comparisons) and neutral when symptoms significantly improved in three trials48,66,76 (three comparisons). In placebo-controlled trials where treatments were considered to be effective, symptoms improved in only 9 of 32 and 6MWT in 10 of 34 trials, with a positive concordance in 9 of 32 trials.

The 6MWT showed positive concordance with ETT in 2 of 21 trials51,72 (2 of 25 comparisons), neutral concordance in 13 trials23,24,33,39,43,50,52,5759,62,64,66 (17 comparisons), and discordance in 29% of trials. 6MWT was significantly improved while ETT remained neutral in 2 trials30,38 (two comparisons) and neutral when ETT significantly improved in four trials28,53,76,78 (five comparisons).

The 6MWT showed positive concordance with peak oxygen uptake (pVO2) in 4 of 14 trials7174, neutral concordance in 7 of 14 trials43,47,56,64,7779 (seven comparisons), and discordance in 21% of trials. 6MWT was significantly improved while pVO2 remained neutral in one trial36 (one comparison) and neutral when pVO2 significantly improved in two trials50,76 (two comparisons).

The 6MWT showed positive concordance with LVEF in 6 of 30 trials36,37,51,70,72,74 (6 of 34 comparisons), neutral concordance in 9 of 30 trials3234,47,56,59,60,67,76 (9 comparisons), and discordance in 50% of trials. 6MWT was significantly improved while LVEF remained neutral in no trial and neutral when LVEF improved in 15 trials23,24,3944,4850,53,58,62,75 (19 comparisons).

Standardization
Table 4 shows information concerning the standardization of the trials. Three30,70,74 (20%) of 15 trials41,43,46,58,59,6163,65,66,75,78 (two comparisons) not offering any information about 6MWT methodology showed significant improvements. Two26,69 (40%) of five trials48,52,56 (two of five comparisons) that stated the use of encouragement and 425,38,51,71 (24%) of 17 trials28,3135,39,40,44,49,50,56,60 (five comparisons) stating the use of more than one baseline 6MWT showed significant improvements with 6MWT.


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Table 4 Information regarding standardization in the trials
 
Number of centres and study size
Four25,38,69,70 of 12 single-centre trials27,42,47,49,52,57,64,67,78 (33%) showed a significant improvement in 6MWT (5 of 14 comparisons), 226,36 of 14 trials (14%) (2 of 14 comparisons)29,35,43,45,46,48,50,55,56,59,60,66 with two to four participating centres, and 730,37,51,7174 of 29 multicentre trials (24%) (7 of 39 comparisons).23,24,28,3134,3941,44,53,54,58,6163,65,7577,79 However, the intervention was cardiac resynchronization in four of these seven trials. Only 3 of the remaining 23 multicentre trials (13%) using pharmacological interventions showed an improvement in 6MWT.

All trials except two disclosed information on study group size.61,63 Study group size ranged between 9 and 298 patients, with median size of 52. Five25,26,36,38,69 (17%) out of 29 trials27,29,33,39,42,43,4549,52,53,55,5760,6467,77,78 (6 of 35 comparisons) with study arms below median size showed significant improvement. Eight30,37,51,7074 (32%) out of 25 trials23,24,28,31,32,34,35,40,41,44,50,54,56,62,75,76,79 (6 of 33 comparisons) with study arms above median size showed significant improvement with 6MWT.

Age
All but two trials reported the mean age of the study population.58,75 An inverse relationship between baseline 6MWT and mean age was observed (r=–0.59; P<0.0001) (Figure 2). 6MWT distance improved significantly in two25,26 of six trials27,29,55,57 (three of seven comparisons) where the mean age of the study population was >70 years. These studies evaluated captopril, ibopamine, and perindopril, with none including more than 52 patients per treatment arm.



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Figure 2 Baseline 6MWT distance by age in 37 trials.

 
Severity of heart failure
All but one trial reported information on NYHA class.69 There was a weak inverse relationship between per cent of patients in NYHA class III/IV and baseline 6MWT distance (r=–0.26; P=0.02) as shown in Figure 3. Mean baseline walk test for trials including 100% NYHA class III/IV patients ranged between 243 and 490 m. Ten25,26,30,36,37,7074 (34%) of 29 trials27,32,3942,46,4850,58,6366,7679 (11 of 38 comparisons) that included >50% of patients with NYHA class III/IV showed an improvement in 6MWT distance with treatment [captopril25,30 (two treatment arms), ibopamine,25 perindopril,26 carvedilol36,37 (two treatment arms), beriberine70 (one treatment arm) cardiac resynchronization therapy7174 (four treatment arms)]. Only 238,51 of 25 trials23,24,28,29,31,3335,4345,47,5257,5962,75 (2 of 32 comparisons) that included <50% of patients with NYHA class III/IV showed significant delta 6MWT. These trials evaluated carvedilol38 and digoxin withdrawal.51



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Figure 3 Baseline 6MWT distance by severity of NYHA class (% NYHA III/IV) in 37 trials.

 
Publication form
One38 of seven trials46,58,61,63,65,75 (14%) published as abstracts or meeting reports showed a significantly improved 6MWT compared with 11 of 49 trials published in article form (22%). This trial evaluated carvedilol. Four58,61,63,65 of seven trials evaluated treatment currently not recommended for heart failure patients (57%) compared with 12 of 49 trials in article form (24%).

Trials evaluating treatment in patients with preserved systolic function
Three of 56 trials evaluated treatment in patients with diastolic dysfunction,29,46,55 with none of them showing a significantly improved 6MWT with therapy.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
This review of the utility of the 6MWT for the evaluation of therapy in randomized controlled trials in heart failure indicates uncertainty about the utility of this test. The 6MWT improved in the majority of trials of cardiac resynchronization, a promising intervention. There was no improvement in the majority of studies of ACE-inhibitors and beta-blockers, agents with limited impact on exercise performance. It improved with at least one intervention (ibopamine) that is now generally considered deleterious. However, positive and neutral evaluations by the 6MWT showed a high concordance with the results of symptom assessment and formal exercise testing.

The failure of ACE-inhibitors and beta-blockers to improve symptoms or exercise capacity in the majority of comparisons in this review could reflect problems with the size or design of the trials, the inclusion of patients with milder symptoms or an inability of treatment to alter these outcomes. The relative success of the 6MWT in trials of cardiac resynchronization may reflect a selection of patients with more severe symptoms. As in other device clinical research, there may be a problem in maintaining both patient and investigator blind to treatment allocation. The improvement in symptoms but not the 6MWT in MIRACLE ICD may be due to a marked placebo response. This may have been influenced by the inclusion primarily of patients with mild symptoms and ventricular dyssynchrony in MIRACLE ICD II who received an implantable cardioverter defibrillator (ICD) device to reduce risk rather than primarily to improve heart failure symptoms by cardiac resynchronization therapy (CRT).

Part of the rationale for using the 6MWT rather than the bicycle or treadmill exercise in clinical trials is that it is a more natural form of exercise that may better reflect daily activity. The present analysis shows that there is considerable placebo response and, where repetitive tests are performed, evidence of a learning experience10,11,8085. Trials reporting the use of multiple tests prior to randomization were more likely to show differences than those that did not use this approach. However, this may reflect reporting bias, as the methodology in positive trials was reported in greater detail. It is likely that improved standardization of test procedures and conditions would improve the reliability of the test.

Study size was not a major determinant of the ability of the 6MWT to show differences between effective pharmacological treatments and placebo. This finding is at variance with a previous analysis on ETT in ACE-inhibitor trials.7 Large multicentre trials are powered to detect small differences, but with the self-paced, time-limited 6MWT, the environment in which the test is conducted and the person supervising the test may introduce greater variability in test results. These factors may be more easily controlled in single-centre trials, but such trials are often underpowered. With the 6MWT design, there may also be a ‘ceiling’ effect leaving those walking longer at baseline with less room for improvements. In large multicentre trials of pharmacological treatments that are presently considered effective, formal ETT (five of seven comparisons) seemed slightly superior to the 6MWT (three of seven comparisons).

There was little relationship between the 6MWT distance and symptom severity, judged by NYHA class. This may reflect problems with the assessment of NYHA or with the 6MWT. NYHA classification may not be consistent between investigators and is probably influenced by extraneous factors such as knowledge of the patients LVEF and likely prognosis, although it is meant to be a purely functional classification. Moreover, clinical trials often require a certain NYHA classification severity as an entry criterion and this may influence investigator judgement. Age was correlated with 6MWT, perhaps reflecting more problems with balance and joints and reduced skeletal muscle strength. When younger and older patients are matched for the severity of symptoms, older patients have a higher LVEF and lower natriuretic peptide concentrations, implying a contribution of age itself, in addition to cardiac dysfunction, to the subjective severity of symptoms.86

Greater severity of heart failure was the main determinant of whether the walk test performance improved, as has been noted with treadmill exercise.87 Apart from the high success rate in CRT trials, modern pharmacological treatment for heart failure blunts the neurohormonal response to exercise but may improve haemodynamics so that exercise capacity is improved anyway. These effects may be more apparent in patients with severe heart failure. The greater ability of the 6MWT to show differences in patients with more severe heart failure who probably are exercising near their peak oxygen consumption suggests that the 6MWT may also be best viewed as an ETT.84,88,89

There is a widely held belief that exercise testing is a more objective measure of outcome than patient-reported symptoms. It is not clear whether this is true. Encouragement may improve distance walked.90 The outcome of both exercise testing and symptom evaluation are highly dependent on the motivation of the patient and of the person administering the test, and motivation is likely to be affected by whether the patients feels that their symptoms have improved. Ultimately, exercise testing is a surrogate outcome measure for symptoms and, similar to surrogate outcome measures for mortality, may be no substitute for a more direct measurement of the patient perceived and self-rated experience.

Limitations
Sex and different aetiology of heart failure are factors known to influence prognosis and/or response to treatment. Whether this also affects walk test result cannot be resolved, because of the nature of the information presented in these studies.


    Conclusion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions, although it appears useful for the assessment of cardiac resynchronization therapy. Improved standardization of testing may improve performance. The results of the 6MWT were concordant with changes in symptoms, suggesting that it may be used as supportive evidence for symptom benefit. The test may be of greater value in patients with more advanced heart failure, where it may function as an ETT.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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