The Six-Minute Walk is a Better Outcome Measure than Treadmill Walking Tests in Therapeutic Trials of Patients with Peripheral Artery Disease

Lower extremity peripheral artery disease (PAD) affects eight million people in the United States (U.S.) and over 200 million men and women worldwide^1,2. PAD will become increasingly common as the U.S. population survives longer with chronic disease. Although intermittent claudication is the most classic symptom of PAD, many patients with PAD are asymptomatic or have exertional leg symptoms other than intermittent claudication^3,4. PAD patients have slower walking speed, poorer walking endurance, and substantially lower physical activity levels compared to people without PAD^3,5. PAD patients also have faster decline in lower extremity functional performance and higher rates of mobility loss, compared to individuals without PAD^6,8. Even PAD patients who are asymptomatic or who have exertional leg symptoms other than intermittent claudication have greater functional impairment, faster functional decline, and higher rates of mobility loss than people without PAD^3,9–11. The functional limitations experienced by people with PAD are associated with loss of independence, loss of mobility in daily life, increased hospitalization rates, and increased mortality^8,12,13,14. Therefore, an important treatment goal in patients with PAD is improving walking performance and preventing mobility loss.

Despite the functional limitations present in PAD, few medical therapies exist for improving walking performance and preventing mobility loss in patients with PAD. There are just two FDA-approved medications, pentoxifylline and cilostazol, for improving walking performance in patients with PAD^15–17. Of these two medications, pentoxifylline is not substantially better than placebo^15,17. Cilostazol provides only modest improvement in treadmill walking performance^16,17. Although supervised treadmill exercise significantly improves walking performance in patients with PAD^18,19, medical insurance typically does not pay for costs of supervised exercise for patients with PAD. Thus, most patients with PAD do not participate in supervised treadmill exercise²⁰.

New medical therapies are needed to improve walking performance and to prevent the adverse outcomes associated with PAD-related functional impairment, such as mobility loss and the ability to continue living independently in one’s community. Emerging therapies for PAD must be tested in rigorous randomized controlled clinical trials. Traditionally, randomized trials have used treadmill walking performance as the primary outcome measure in clinical trials of therapeutic interventions in patients with PAD^21,22. However, there are significant limitations to treadmill walking as an outcome.

Increasingly, the six-minute walk test has been validated as an outcome measure and is increasingly recognized as a meaningful outcome measure in patients with PAD. Among 156 people with PAD who completed both a six-minute walk test and a treadmill test, the six-minute walk test correlated more closely with physical activity levels in the community than treadmill testing²³. Additional evidence shows that the six-minute walk test is not associated with a learning effect when repeated testing is performed in people with PAD^23,24. Changes in six-minute walk performance have been linked to clinically meaningful outcomes such as mortality and mobility loss in patients with PAD²⁵. However, changes in treadmill walking performance have not been linked to clinically meaningful outcomes such as mortality or mobility loss in patients with PAD. This manuscript provides evidence to support the assertion that the six-minute walk is a better outcome than treadmill walking tests in clinical trials of therapeutic interventions in patients with PAD.

Methods of graded treadmill test

A graded treadmill stress test has substantially better test re-test reliability than a constant load treadmill stress test in patients with PAD²⁶. In the graded Gardner-Skinner stress test²⁶, participants begin walking on the treadmill at 2.0 Miles Per Hour (MPH). Grade began at zero and is increased by two percent every two minutes. Participants unable to walk at least 2.0 MPH begin walking at 0.5 MPH and their speed is increased by 0.50 MPH every two minutes until the participant reaches 2.0 MPH. After reaching 2.0 MPH, treadmill grade is increased by two percent every two minutes. The test is conducted by an exercise physiologist and participants have continuous cardiac monitoring with electrocardiograph leads during testing. Participants are asked to continue walk without stopping until they cannot continue because of leg symptoms, exhaustion, or other symptoms. The test is also stopped if evidence of coronary ischemia develops during cardiac monitoring.

Treadmill walking performance has limitations as an outcome measurement in PAD

A summary of the advantages of the six-minute walk test as compared to treadmill testing is shown in Table 1. Treadmill testing in patients with PAD has limitations. First, walking on a treadmill is not representative of walking in daily life^27–29. Second, there is a significant learning effect associated with treadmill walking, in which even PAD patients not receiving therapeutic interventions experience improvement in treadmill walking over time^26,30. This learning effect is particularly problematic for interventions that involve treadmill exercise. Third, meaningful change in treadmill walking performance has not been defined. The six-minute walk circumvents all of these limitations^8,13,25,31. In the following paragraphs, each of these limitations is discussed in further detail and advantages of the six-minute walk test are described.

Table 1.

Advantages of six-minute walk over treadmill walking as an outcome measure in therapeutic trials of peripheral artery disease patients

Characteristic	Treadmill walking outcome	Six-minute walk	Comments
Represents walking during daily life, in the community	No	Yes	Treadmill walking requires balance and that the participant “keep up” with the pace of the treadmill test. Six-minute walk testing takes place in a corridor and is more representative of walking in daily life.
Test-related learning phenomenon	Yes	No	The learning phenomenon is particularly problematic in studies that include a supervised treadmill exercise intervention, in which the participant is trained to the test outcome.
Meaningful clinically important difference has been defined.	No	Yes	Meaningful clinically important difference has been defined for the six-minute walk and helps determine whether a given change in six-minute walk represents a clinically meaningful difference.
Measure has been shown to predict mortality or mobility loss in patients with PAD.	No	Yes	The six-minute walk predicts all-cause mortality, cardiovascular disease mortality, and mobility loss in people with PAD.

Treadmill walking performance does not represent walking in daily life

Walking on a treadmill requires dynamic balance and the ability to maintain a constant rhythmic gait in order to keep up with the treadmill’s constant pace. Patients with PAD frequently touch or hold on to the treadmill rail to maintain balance. Importantly, these skills are intrinsically linked to treadmill walking but do not apply to walking in daily life. Furthermore, among patients with PAD, handrail support is associated with a greater learning effect and longer maximal walking distances, compared to no handrail support³⁰. In addition, patients with PAD have specific impairments in balance and cognitive function^5,32,33 compared to people without PAD that are likely to make the need for good balance and a rhythmic gait on the treadmill particularly difficult to achieve. For example, more severe PAD, as measured by the Rutherford Classification, was associated with progressively increased difficulty with the Timed Up and Go test, a measure of dynamic balance³². Lower ankle brachial index (ABI) values, a measure of presence and severity of PAD, are associated with poorer standing balance⁵. In summary, PAD patients have particular deficiencies in dynamic balance that are likely to make treadmill walking particularly challenging.

Furthermore, in a corridor walk, such as the six-minute walk test, PAD patients who have difficulty walking can slow down, but keep going or even rest temporarily without stopping the test. In contrast, the treadmill test requires PAD participants to maintain or even increase their walking speed. PAD participants who cannot keep up with the treadmill must stop walking, thereby simultaneously ending the treadmill test. This key difference between the six-minute walk and treadmill walking performance is likely to result in longer walking distances in the six-minute walk than on the treadmill, as previously observed in patients with heart failure²⁹.

Several studies of older people and people with chronic disease, similar to patients with PAD, have documented that treadmill walking performance does not accurately represent corridor walking, such as that performed during the six-minute walk test and during daily walking^27–29. For example, Swerts et al studied 12 healthy elderly men and women (age 71–80) and 12 healthy young participants (age 21–37). These two groups of participants underwent a self-paced six-minute walk test and a treadmill walking test, respectively. The treadmill walking test was conducted such that it matched the walking velocity of the corridor walking test. Younger participants had a similar heart rate when they walked on the treadmill compared to when they walked in a corridor at identical speed. In contrast, the elderly participants had higher heart rates when they walked on the treadmill, compared to when they walked in a corridor at identical speed. Both the older and the younger participants had slower step rates, resulting in a longer stride, during treadmill walking as compared to corridor walking performed at identical speed²⁸. In a separate study, Peters et al studied 37 patients (mean age 81.3), including 11 untrained control participants, 16 patients with New York Heart Association class II heart failure and 10 patients with New York Heart Association class III heart failure²⁹. Participants completed a six-minute walk and a treadmill exercise stress test on separate days, with the order of testing randomly determined. In this study, the treadmill stress test was not graded, but started slowly at 1 km/hour and increased in speed by 0.5 km/hour every two minutes²⁹. All participants completed the six-minute walk, but 22% were unable to perform the treadmill stress test. Six participants (17%) walked only very short distances on the treadmill test. On average, the distance achieved on the treadmill test was 27% shorter compared to the six-minute walk. Although their sample sizes were small, together, these studies demonstrate that participants, particularly those who are older and have chronic diseases limiting their walking ability, alter their walking stride-length and demonstrate physiologic evidence of anxiety during treadmill walking and these changes are not present during corridor walking tests, such as the six-minute walk^27–29. However, the higher heart rates observed during treadmill walking may also be related to the fact that treadmill walking requires extra skills that are not necessary when walking in a corridor. Execution of these additional skills requires more energy, which may also explain the higher heart rate at a given speed during treadmill walking, compared to corridor walking. An individual’s ability in the specific skills required for treadmill walking may also contribute to the observation that treadmill walking is less representative of walking in the natural environment than the six-minute walk.

Learning effect associated with treadmill walking performance

Another limitation of treadmill walking is that it is associated with a significant learning effect^21,26,30,34. Even without any therapeutic intervention, patients with PAD typically increase their maximum and pain-free walking distance between baseline and follow-up testing. Recent placebo-controlled drug therapeutic trials in patients with PAD have demonstrated increases in maximal walking time in the placebo or control groups ranging from 17% to 26%^34–36. This phenomenon likely occurs because treadmill walking is an un-natural form of walking. With the practice afforded by repeated treadmill tests at baseline and follow-up, PAD patients improve their treadmill walking performance, even without receiving a therapeutic intervention.

The learning effect associated with treadmill walking is particularly problematic with interventions that include a treadmill exercise intervention. Treadmill exercise interventions train the participant to the treadmill outcome measure and allow participants to become more comfortable with treadmill walking during their treadmill exercise sessions. Consequently, PAD participants get better on the treadmill outcome measure in part because they have “practiced” the outcome as part of their exercise intervention. This ‘training to the outcome’ advantage likely explains some of the gains reported on the treadmill outcome in groups randomized to supervised treadmill exercise interventions.

In contrast to treadmill walking performance, the six-minute walk is not associated with a learning effect when repeated testing is performed in patients with PAD. McDermott et al reported the test re-test reliability of the six-minute walk among 156 PAD participants in who completed the six-minute walk test approximately one to two weeks apart²³. In these PAD participants, the mean value of the six-minute walk during the first measurement was 312.7 meters ± 87.2 and the mean value during the second measurement was 316.2 ± 87.7. The correlation coefficient between the two measures was 0.90 (p<0.001)²³ and the coefficient of variation percent was 8.9%. In a separate study of 64 participants with PAD, the coefficient of variation for two six-minute walk tests performed approximately one week apart was 10.4%²⁴. In summary, the six-minute walk test has excellent test re-test reliability.

Evidence of how PAD participants in a supervised treadmill exercise intervention achieve relatively greater increases in the treadmill walking outcome than the six-minute walk by training to the treadmill outcome is illustrated in two previous trials of exercise interventions that measured change in both treadmill walking and the six-minute walk in response to the exercise intervention^18,37. One of these prior trials studied supervised treadmill exercise in patients with PAD and one studied home-based over-ground walking exercise in patients with PAD. The study with treadmill walking exercise interventions demonstrated greater gains in the treadmill outcome measure than in the six-minute walk test¹⁸. However, the study with a home-based walking exercise intervention that encouraged over ground walking exercise demonstrated relatively greater gains in the six-minute walk than in the treadmill walking measure. For example, the Study to Improve Leg Circulation (SILC) randomized controlled trial demonstrated relative gains in maximal treadmill walking time of 51% among 61 patients with PAD who were randomized to supervised treadmill exercise¹⁸. However, the Group Oriented Arterial Leg Study (GOALS) trial, in which PAD patients were randomized to home-based over-ground walking exercise, demonstrated gains in maximal treadmill walking time of only 19% (Figure 1)³⁷. Relative gains in six-minute walk distance among PAD participants randomized to supervised treadmill exercise were only 6.4% in the SILC trial vs. 12% in the GOALS trial intervention of home-based over ground walking. Findings in the SILC trial were similar to results of a randomized-controlled clinical trial of 61 PAD participants who were randomized to a treadmill exercise intervention vs. a control group. PAD participants in the supervised exercise intervention achieved a 80% improvement in treadmill walking performance (P<0.001) but only a 10% improvement in six-minute walk performance (P=0.003) at eighteen-month follow-up³⁸. Together, these findings suggest that treadmill walking exercise interventions that involve training to the outcome measure of treadmill walking performance ensure that participants become more familiar and comfortable with treadmill walking, because of the “practice” associated with their supervised treadmill exercise intervention. However, only a fraction of this improvement is reflected in improvement in mobility in daily life. It is also important to point out that in both the SILC and GOALS trials, participants randomized to the control groups experienced declines in the six-minute walk test at six-month follow-up, consistent with the natural history of declining walking endurance in patients with PAD^18,37. In contrast, PAD patients randomized to the control groups experienced improvement in their maximum treadmill walking performance at six-month follow-up, likely related to the learning effect associated with the treadmill^18,37.

Figure 1.

Relative changes in six-minute walk and treadmill maximal walking time in clinical trials of exercise, according to whether the trial used treadmill walking exercise vs. over ground walking exercise.

The Six-Minute Walk is a Validated Measure of Walking Endurance in PAD

The six-minute walk test is a well-validated measure of walking endurance that does not require sophisticated equipment or extensive training. Among people with PAD, the six-minute walk improves in response to therapeutic interventions, predicts rates of mobility loss and mortality, and is not associated with a learning effect when repeated testing is performed. Clinically meaningful change in the six-minute walk has been defined for older people without PAD.

Six-minute walk test methods

In contrast to a treadmill stress test, the six-minute walk is inexpensive to perform and does not require highly specialized personnel or sophisticated equipment. However, the six minute walk requires a 100-foot corridor. The six-minute walk also requires a research coordinator who is trained and certified in administration of the six-minute walk and a stopwatch. Participants receive standardized instructions by the certified study coordinator. Participants are advised by the coordinator that the goal of the six-minute walk test is to achieve the greatest distance possible by walking back and forth along the 100-foot corridor for six-minutes. Participants may not talk during the test, except to notify the coordinator of any symptoms they develop. The coordinator calls out each passing minute during the test, with a standardized phrase of encouragement^5–8,13,18. Participants are allowed to rest during the test, but the clock continues to run while the participant rests. At the end of the six-minutes, the distance covered is measured. Certification requires that the research coordinator reads a study manual, practices administering the six-minute walk, and demonstrates proficiency to another individual who has expertise in six-minute walk testing. Use of a checklist for the certifier to document successful administration of each component of the six-minute walk test is recommended.

The Six-Minute Walk is Sensitive to Declines in Walking Endurance that occur in Patients with PAD

In contrast to the learning effect associated with treadmill walking performance, observational studies demonstrate that the six-minute walk detects and quantifies declines in walking endurance among patients with PAD who do not receive interventions. For example, in the Walking and Leg Circulation Study (WALCS), 676 individuals age 55 and older with and without PAD underwent a baseline six-minute walk followed by annual six-minute walk testing for two years⁶. Average annual declines in six-minute walk were 12.6 feet/year among participants without PAD (ABI of 0.90–1.50), 58.8 feet/year among participants with mild PAD and (ABI of 0.51 to < 0.90), and 73.0 feet/year among participants with severe PAD (ABI < 0.50)⁶. In addition, in randomized clinical trials of participants with PAD that measured both the treadmill test and the six-minute walk test at baseline and follow-up, those randomized to the control group who did not receive any therapeutic interventions experienced declines in the six-minute walk of about 11 to 15 meters but simultaneously experienced gains in the treadmill test at six-month follow-up^18,37. Collectively, these findings demonstrate that the six-minute walk is sensitive to declines in walking endurance that occur as part of the natural history of PAD in patients who do not receive therapeutic interventions. In contrast, the treadmill test tends to increase even among PAD patients not receiving therapeutic interventions. This absence of a learning effect associated with the six-minute walk in patients with PAD provides a distinct advantage as compared to treadmill walking performance. The treadmill walking test simply does not reflect the natural history of declining walking performance over time in patients with PAD.

Six-minute walk performance predicts mortality rates and mobility loss in patients with PAD

Among people with PAD, a baseline six-minute walk test predicts rates of all-cause mortality, cardiovascular disease mortality, and mobility loss^8,13. For example, in the WALCS cohort that was prospectively followed to document the natural history of functional decline, measured by the six-minute walk test, PAD participants in the lowest quartile of six-minute walk performance at baseline had a higher rate of all-cause mortality (Hazard Ratio (HR)=2.39, 95% Confidence Interval (CI)= 1.33–4.18) and a higher rate of cardiovascular disease mortality (HR=5.59, 95% CI=1.97–15.90) compared to those in the highest six-minute walk quartile at baseline. Among PAD participants without mobility disability at baseline, defined as the ability to walk up and down a flight of stairs and walk ¼ mile without assistance, PAD participants in the lowest quartile of six-minute walk performance at baseline had significantly higher rates of mobility loss at a median of 50 month follow-up, compared to PAD participants in the highest quartile of six-minute walk at baseline (HR= 9.65, 95% CI= 3.35–27.8). These associations were independent of known and potential confounders including age, sex, race, comorbidities, smoking history, body mass index, and the ankle brachial index. Finally, change in six-minute walk performance has also been linked to mortality and mobility loss in people with PAD²⁵. Among 440 PAD participants in the WALCS cohort who completed a six-minute walk test at baseline and at two-year follow-up, those with greater declines in six-minute walk performance between baseline and two-year follow-up had significantly higher rates of all-cause mortality (hazard ratio=3.56, 95% CI=1.56–7.85), cardiovascular mortality (hazard ratio =2.45, 95% CI=2.45, 95% CI=1.08–5.54), and mobility loss (hazard ratio=3.50, 95% CI=1.56–7.85) compared to those with lesser declines in six-minute walk between baseline and two-year follow-up²⁵. In summary, both a baseline six-minute walk measurement and two-year change in the six-minute walk test predict clinically meaningful outcomes among individuals with PAD. In all of these analyses, the associations were independent of age, sex, race, PAD severity, comorbidities, and other potential confounders^8,13,25. To our knowledge, only one prior longitudinal study related treadmill walking performance to subsequent outcomes³⁹. Although this study demonstrated that poorer baseline exercise capacity, measured by metabolic equivalents (METS), was associated with higher rates of all-cause mortality in patients with PAD, the analyses adjusted only for age. Most likely the association is confounded by PAD severity and presence of comorbid disease. Yet the analyses did not adjust for ankle brachial index or other potential confounders³⁹.

The Six-Minute Walk as a Measure of Improved Walking Endurance in Response to Medications

Clinical trials of exercise in participants with PAD demonstrate that the six-minute walk test consistently successfully quantifies and documents improvement in walking endurance in responsive to exercise interventions. To our knowledge, no prior clinical trials of therapeutic medications in patients with PAD have used the six-minute walk test as an outcome measure. However, the six-minute walk test is frequently used as a primary outcome measure in therapeutic trials of patients with chronic lung disease and pulmonary hypertension^40–42. The Food and Drug Administration (FDA) also considers the six-minute walk a meaningful outcome measure in patients with PAD. An ongoing trial of granulocyte macrophage colony stimulating factor combined with supervised treadmill exercise uses the six-minute walk as a primary outcome measurement⁴³. Future clinical trials of therapeutic medications in patients with PAD should include the six-minute test as an outcome.

Meaningful Changes in the Six-Minute Walk have been defined

Clinically meaningful change in the six-minute walk test has been defined by relating changes in six-minute walk over time to corresponding rates of mobility loss and declines in quality of life across several studies of older people with and without chronic diseases³¹. This study combined a distribution-based method and an anchor-based method to define clinically meaningful change in the six-minute walk³¹. Distribution-based methods rely on the psychometric properties of the six-minute walk to determine small and large effect sizes. Anchor-based methods define a clinical standard to link with a meaningful change, measured using small and large effect sizes in the six-minute walk. Using these methods, a small meaningful change in six minute walk was defined as a change of 20 meters and a large meaningful change in six-minute walk was defined as a change of 50 meters³¹. These defined clinically meaningful changes in the six-minute walk can be used to interpret results of clinical trial that use the six-minute walk as an outcome. In contrast, to our knowledge, no prior studies have defined clinically meaningful changes for treadmill walking performance.

Safety and other considerations

To our knowledge, data on safety of the six-minute walk and treadmill testing in people with PAD have not been reported. However, in our experience conducting more than 7,900 six-minute walk tests in people with PAD, we have had only one serious adverse event, consisting of a fall resulting in a forearm fracture. In our experience conducting over 1,300 treadmill tests in participants with PAD, we have had two participants who required immediate referral to the emergency department. Of these, one developed ventricular tachycardia during the treadmill test and one developed hypotension during the treadmill test. Although treadmill testing can be used as a diagnostic test for PAD⁴⁴, the six-minute walk has not been studied as a diagnostic tool. Finally, there is currently insufficient evidence to calculate the statistical efficiency of the treadmill test vs. the six-minute walk.

Conclusion

Available evidence in patients with PAD demonstrates that walking performance measured by the six-minute walk test better represents walking in daily life than treadmill walking performance. Among patients with PAD, the six-minute walk has excellent test re-test reliability, predicts risk for mortality and mobility loss, is sensitive to the natural history of declines in walking endurance, and detects improved walking endurance in response to therapeutic interventions. Treadmill testing is particularly problematic for clinical trials that use supervised treadmill exercise as a therapeutic intervention, since these trials are training PAD patients specifically to the outcome measurement. Future therapeutic trials of new medications for PAD patients should preferentially use the six-minute walk, rather than treadmill walking performance, as an outcome measure.