Change In 6-minute Walk Distance Research Articles

Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation

Ex vivo lung perfusion (EVLP) is an effective method to assess and improve the function of otherwise unacceptable lungs, alleviating the shortage of donor lungs. The early results with EVLP have been encouraging, but longer-term results, including functional and patient-reported outcomes, are not well characterized. This retrospective single-center study included all lung transplants performed between September 2008 and December 2012. We investigated whether survival or rate of chronic lung allograft dysfunction (CLAD) differed in recipients of EVLP-treated lungs compared with contemporaneous recipients of conventional donor lungs. We also studied functional (highest forced expiratory volume in 1 second predicted, change in 6-minute walk distance, number of acute rejection episodes) and quality of life outcomes. Of 403 lung transplants that were performed, 63 patients (15.6%) received EVLP-treated allografts. Allograft survival for EVLP and conventional donor lung recipients was 79% vs 85%, 71% vs 73%, and 58% vs 57% at 1, 3, and 5 years after transplant, respectively (log-rank p = not significant). Freedom from CLAD was also similar (log-rank p = 0.53). There were no significant differences in functional outcomes such as highest forced expiratory volume in 1 second predicted (76.5% ± 23.8% vs 75.8% ± 22.8%, p = 0.85), change in 6-minute walk distance (194 ± 108 meters vs 183 ± 126 meters, p = 0.57), or the number of acute rejection episodes (1.5 ± 1.4 vs 1.3 ± 1.3, p = 0.36). The EVLP and conventional donor groups both reported a significantly improved quality of life after transplantation, but there was no intergroup difference. EVLP is a safe and effective method of assessing and using high-risk donor lungs before transplantation and leads to acceptable long-term survival, graft function, and improvements of quality of life that are comparable with conventionally selected donor lungs.

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N = 57); ataluren 20, 20, 40 mg/kg (N = 60); or placebo (N = 57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ = 31.3 meters, post hoc P = 0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Muscle Nerve 50: 477–487, 2014

T.P.5: Timed function tests and other physical function outcomes in Ataluren-treated patients with nonsense mutation Duchenne Muscular Dystrophy (nmDMD)

A Phase 2b, double-blind, placebo-controlled study of ataluren, an investigational drug, assessed change in 6-minute walk distance (6MWD) over 48 weeks in ambulatory males ⩾5 yrs old with nonsense mutation Duchenne muscular dystrophy (nmDMD) and showed evidence of clinical benefit for ataluren 40 mg/kg/day vs placebo. Based on emergent natural history data, 6MWD, timed function tests, and other measures of physical function were analyzed in subgroups of patients who, at baseline, were at high risk of ambulatory decline. An ambulatory decline phase subgroup was retrospectively defined as: ⩾7 to ⩽16 years old, ⩾150 m 6MWD but ⩽80%-predicted 6MWD at baseline, and on a stable dose of corticosteroids. A subgroup of patients with baseline 6MWD

Preoperative change in 6-minute walk distance correlates with early weight loss after sleeve gastrectomy.

Introduction:The 6-minute walk test (6MWT) is an objective preoperative measure of functional capacity and response to intervention in patients with heart or lung disease. In bariatric surgery, there has been no reliable preoperative measure predictive of postoperative success. Here we investigated the impact of bariatric surgery on changes in distance traveled in the 6MWT (the 6MWD) and whether preoperative changes in 6MWD correlated with weight change after surgery.Methods:This is a retrospective study of consecutive patients in which the 6MWT was performed before and after laparoscopic sleeve gastrectomy for weight loss. 6MWD and total weight were measured. Pearson correlation was used to determine association between variables.Results:Of 100 patients who underwent laparoscopic sleeve gastrectomy, 31 patients had a preoperative 6MWT. Thirty patients (97%) were available for follow-up after surgery. Percentage of excess weight loss was 45.7% over an average of 7 months after surgery. There was a weak correlation between the postoperative weight loss and the change in preoperative and postoperative 6MWD (r = 0.28; P = .13). In a subset of patients who demonstrated a change in distance traveled in 2 separate preoperative 6MWD measurements (average 18.5% increase in distance), there was a strong correlation with postoperative weight loss (r = 0.82; P = .02).Conclusions:A demonstrated increase in 6MWD before surgery correlates strongly with early postoperative weight loss after laparoscopic sleeve gastrectomy. A multidisciplinary team that includes a physical therapist is useful in preparing bariatric patients for surgery.

Do ACE Inhibitors Improve the Response to Exercise Training in Functionally Impaired Older Adults? A Randomized Controlled Trial

Background.Loss of muscle mass and strength with ageing is a major cause for falls, disability, and morbidity in older people. Previous studies have found that angiotensin-converting enzyme inhibitors (ACEi) may improve physical function in older people. It is unclear whether ACEi provide additional benefit when added to a standard exercise training program. We examined the effects of ACEi therapy on physical function in older people undergoing exercise training.Methods.Community-dwelling people aged ≥65 years with functional impairment were recruited through general (family) practices. All participants received progressive exercise training. Participants were randomized to receive either 4 mg perindopril or matching placebo daily for 20 weeks. The primary outcome was between-group change in 6-minute walk distance from baseline to 20 weeks. Secondary outcomes included changes in Short Physical Performance Battery, handgrip and quadriceps strength, self-reported quality of life using the EQ-5D, and functional impairment measured using the Functional Limitations Profile.Results.A total of 170 participants (n = 86 perindopril, n = 84 placebo) were randomized. Mean age was 75.7 (standard deviation [SD] 6.8) years. Baseline 6-minute walk distance was 306 m (SD 99). Both groups increased their walk distance (by 29.6 m perindopril, 36.4 m placebo group) at 20 weeks, but there was no statistically significant treatment effect between groups (−8.6m [95% confidence interval: −30.1, 12.9], p = .43). No statistically significant treatment effects were observed between groups for the secondary outcomes. Adverse events leading to withdrawal were few (n = 0 perindopril, n = 4 placebo).Interpretation.ACE inhibitors did not enhance the effect of exercise training on physical function in functionally impaired older people.

Benefits and costs of home-based pulmonary rehabilitation in chronic obstructive pulmonary disease - a multi-centre randomised controlled equivalence trial

BackgroundPulmonary rehabilitation is widely advocated for people with chronic obstructive pulmonary disease (COPD) to improve exercise capacity, symptoms and quality of life, however only a minority of individuals with COPD are able to participate. Travel and transport are frequently cited as barriers to uptake of centre-based programs. Other models of pulmonary rehabilitation, including home-based programs, have been proposed in order to improve access to this important treatment. Previous studies of home-based pulmonary rehabilitation in COPD have demonstrated improvement in exercise capacity and quality of life, but not all elements of the program were conducted in the home environment. It is uncertain whether a pulmonary rehabilitation program delivered in its entirety at home is cost effective and equally capable of producing benefits in exercise capacity, symptoms and quality of life as a hospital-based program. The aim of this study is to compare the costs and benefits of home-based and hospital-based pulmonary rehabilitation for people with COPD.Methods/DesignThis randomised, controlled, equivalence trial conducted at two centres will recruit 166 individuals with spirometrically confirmed COPD. Participants will be randomly allocated to hospital-based or home-based pulmonary rehabilitation. Hospital programs will follow the traditional outpatient model consisting of twice weekly supervised exercise training and education for eight weeks. Home-based programs will involve one home visit followed by seven weekly telephone calls, using a motivational interviewing approach to enhance exercise participation and facilitate self management. The primary outcome is change in 6-minute walk distance immediately following intervention. Measurements of exercise capacity, physical activity, symptoms and quality of life will be taken at baseline, immediately following the intervention and at 12 months, by a blinded assessor. Completion rates will be compared between programs. Direct healthcare costs and indirect (patient-related) costs will be measured to compare the cost-effectiveness of each program.DiscussionThis trial will identify whether home-based pulmonary rehabilitation can deliver equivalent benefits to centre-based pulmonary rehabilitation in a cost effective manner. The results of this study will contribute new knowledge regarding alternative models of pulmonary rehabilitation and will inform pulmonary rehabilitation guidelines for COPD.Trial registrationClinicalTrials.gov: NCT01423227.

Effectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials)

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor-mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Effect of Spironolactone on Physical Performance in Older People with Self-reported Physical Disability

BackgroundInterventions that improve muscle function may slow decline in physical function and disability in later life. Recent evidence suggests that inhibition of the renin-angiotensin-aldosterone system may maintain muscle function. We evaluated the effect of aldosterone blockade on physical performance in functionally impaired older people without heart failure. MethodsIn this parallel-group, double-blind, randomized, placebo-controlled trial, community-dwelling participants aged ≥65 years with self-reported problems with activities of daily living were randomized to receive 25 mg spironolactone or identical placebo daily for 20 weeks. The primary outcome was change in 6-minute walking distance over 20 weeks. Secondary outcomes were changes in Timed Up and Go test, Incremental Shuttle Walk Test, Functional Limitation Profile, EuroQol EQ-5D, and Hospital Anxiety and Depression Scale over 20 weeks. ResultsParticipants’ mean (standard deviation) age was 75 (6) years. Of the 93% of participants (112/120) who completed the study, 106 remained on medication at 20 weeks. There was no significant difference in change in 6-minute walking distance at 20 weeks between the spironolactone and placebo groups (mean change, −3.2 m; 95% confidence interval, −28.9 to 22.5; P = .81). Quality of life improved significantly at 20 weeks, with an increase in EuroQol EQ-5D score of 0.10 (95% confidence interval, 0.03-0.18; P < .01) in the spironolactone group relative to the placebo group. There were no significant differences in between-group change for other secondary outcomes. ConclusionsSpironolactone was well tolerated but did not improve physical function in older people without heart failure. Quality of life improved significantly, and the possible mechanisms for this require further study.

Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction

Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. clinicaltrials.gov Identifier: NCT00763867.

Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm −5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P =0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm −5 (95% confidence interval, −502 to − 255; P &lt;0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

Treating Anemia in Older Adults With Heart Failure With a Preserved Ejection Fraction With Epoetin Alfa

Background— Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results— Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin ( P &lt;0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P =0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P =0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P =0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions— Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00286182.

The benefits of exercise training in interstitial lung disease: protocol for a multicentre randomised controlled trial

BackgroundInterstitial lung disease encompasses a diverse group of chronic lung conditions characterised by distressing dyspnoea, fatigue, reduced exercise tolerance and poor health-related quality of life. Exercise training is one of the few treatments to induce positive changes in exercise tolerance and symptoms, however there is marked variability in response. The aetiology and severity of interstitial lung disease may influence the response to treatment. The aims of this project are to establish the impact of exercise training across the range of disease severity and to identify whether there is an optimal time for patients with interstitial lung disease to receive exercise training.Methods/DesignOne hundred and sixteen participants with interstitial lung disease recruited from three tertiary institutions will be randomised to either an exercise training group (supervised exercise training twice weekly for eight weeks) or a usual care group (weekly telephone support). The 6-minute walk distance, peripheral muscle strength, health-related quality of life, dyspnoea, anxiety and depression will be measured by a blinded assessor at baseline, immediately following the intervention and at six months following the intervention. The primary outcome will be change in 6-minute walk distance following the intervention, with planned subgroup analyses for participants with idiopathic pulmonary fibrosis, dust-related interstitial lung disease and connective-tissue related interstitial lung disease. The effects of disease severity on outcomes will be evaluated using important markers of disease severity and survival, such as forced vital capacity, carbon monoxide transfer factor and pulmonary hypertension.DiscussionThis trial will provide certainty regarding the role of exercise training in interstitial lung disease and will identify at what time point within the disease process this treatment is most effective. The results from this study will inform and optimise the clinical management of people with interstitial lung disease.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12611000416998

Impact of Neoadjuvant Chemotherapy on Physical Fitness, Physical Activity, and Health-related Quality of Life of Patients With Resectable Esophageal Cancer

Neoadjuvant chemotherapy (NAC) followed by radical surgery is the standard treatment for patients with resectable esophageal squamous cell carcinoma (ESCC) in Japan. However, some adverse events associated with NAC may result in a decrease in physical fitness that may influence the patient's ability to tolerate surgery. The purpose of this study was to evaluate the impact of NAC on physical fitness, physical activity, and health-related quality of life (HRQOL) of patients with ESCC. In this prospective study, we investigated 27 consecutive patients with newly diagnosed resectable ESCC who were scheduled to receive NAC followed by surgery between January 2009 and November 2010. Primary endpoints were change from baseline in physical fitness (knee extensor muscle strength and 6-min walking distance) and physical activity after NAC. A secondary endpoint was change from baseline in HRQOL. Physical fitness and physical activity level after NAC did not differ significantly from those before NAC. With regard to HRQOL, only social functioning was significantly different (P=0.04). The change in physical activity demonstrated a significant correlation with the change in 6-minute walking distance (r=0.45, P=0.02). NAC had no impact on physical fitness and physical activity in patients with ESCC. This result indicated that there was no need for a physiotherapy intervention during NAC to prevent a decline in these parameters.

Baseline NT-proBNP correlates with change in 6-minute walk distance in patients with pulmonary arterial hypertension in the pivotal inhaled treprostinil study TRIUMPH-1

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of disease severity in pulmonary arterial hypertension (PAH). In this study we aimed to determine whether baseline NT-proBNP levels correlate with improvement in 6-minute walk distance (6MWD) in the pivotal randomized, placebo-controlled, double-blind study of the addition of inhaled treprostinil to oral therapy for PAH. A post hoc analysis of data from the TRIUMPH-1 study was performed in patients who had assessments of NT-proBNP levels and baseline and Week 12 6MWD. Least-squares mean analysis was used to compare patients in the highest quartile of baseline NT-proBNP with those in lower quartiles with regard to change from baseline in 6MWD, stratified by treatment. The NT-proBNP within-treatment median changes from baseline to Week 12 were +44 and -72 pg/ml, and the median changes in 6MWD from baseline to Week 12 were +5 and +40 m for the placebo (n = 94) and inhaled treprostinil (n = 84) groups, respectively. Baseline NT-proBNP levels demonstrated a strong interaction with treatment in predicting change from baseline for 6MWD (p < 0.01), indicating that, in the upper quartile (≥1,513.5 pg/ml), patients on inhaled treprostinil had a better response (+64 vs +32 m), whereas patients on placebo fared worse (-13 vs +20 m) when compared with the lower 3 quartiles (<1,513.5 pg/ml). Furthermore, least-squares mean difference in 6MWD between active and placebo groups was +67 and +16 m for the upper and lower 3 quartiles of NT-proBNP, respectively. Greater improvement in 6MWD in actively treated patients with high levels of NT-proBNP enhances understanding of the robustness of clinical response to inhaled treprostinil in more advanced disease.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%- 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Letter by Faul et al Regarding Article, “Percutaneous Femoral Arteriovenous Shunt Creation for Advanced Chronic Obstructive Pulmonary Disease: A Single-Center Safety and Efficacy Study”

To the Editor: We were interested to read the recent article by Bertog et al,1 published in your journal. Bertog et al report, for the first time, significant increases in cardiac output, mixed venous oxygen saturations, oxygen delivery, and functional capacity (significant reductions in New York Heart Association [NYHA] functional class) in patients with severe end-stage chronic obstructive pulmonary disease (COPD) with the use of the novel Rox procedure (percutaneous arteriovenous fistula creation). Their interpretation that “the creation of an arteriovenous shunt in the setting of severe chronic obstructive pulmonary disease did not improve functional capacity” is not convincing, because the data prove the opposite: an improved NYHA functional class, which is not only clinically significant (improved from class III to II) but also statistically significant ( P <0.01). Thus, the idea that an arteriovenous shunt (AVS) does not improve functional capacity is refuted by their data that demonstrate statistically significant improvements in NYHA functional class. Although Bertog et al did not demonstrate a significant change in 6-minute walking distance (6MWD) in …

Repeatability of the Six-Minute Walk Test and Relation to Physical Function in Survivors of a Critical Illness

The Six-Minute Walk Test (6MWT) is widely used as an outcome measure in exercise rehabilitation. However, the repeatability of the 6MWT performed at home in survivors of a critical illness has not been evaluated. The purpose of this study was to evaluate, in survivors of a critical illness: (1) the repeatability of the 6MWT performed at home, (2) the effect on estimates of change in functional exercise capacity if only one 6MWT was performed at follow-up assessments, and (3) the relationship between the physical functioning (PF) score of the 36-Item Short-Form Health Survey questionnaire (SF-36) and the 6MWT. Repeated measures of the 6MWT and SF-36 were obtained. Eligible participants had an intensive care unit (ICU) length of stay of ≥48 hours and were mechanically ventilated for ≥24 hours. Two 6MWTs and the SF-36 were conducted in participants' homes at weeks 1, 8, and 26 after hospital discharge. One hundred seventy-three participants completed the study. The participants had a mean age of 57 years (SD=16), a mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission of 19 (SD=10), a mean ICU length of stay of 9 days (SD=8), and a mean mechanical ventilation time of 140 hours (SD=137). Of the 173 participants, 110 performed two 6MWTs at weeks 1, 8, and 26. There were significant mean increases in 6-minute walk distance in the second test of 15 m (P<.0001) at week 1, 13 m (P<.0001) at week 8, and 9 m (P=.04) at week 26. If only one 6MWT was performed at weeks 8 and 26, the estimate of change in 6-minute walk distance from week 1 was 19 m less (P<.001) at both weeks 8 and 26. There was a moderate to strong correlation between SF-36 PF score and 6-minute walk distance at each assessment (week 1: r=.62, P<.001; week 8: r=.55, P<.001; and week 26: r=.47, P<.001). Some study participants were unable to perform a second 6MWT, and these participants may have differed in important aspects of function compared with those individuals who completed two 6MWTs. In survivors of a critical illness, the 6MWT in the home environment should be performed twice at each assessment to give an accurate reflection of change in exercise capacity over time. The SF-36 PF score was a strong indicator of 6-minute walk distance in early recovery from a critical illness.

Inhaled Low‐Dose Iloprost for Pulmonary Hypertension: A Prospective, Multicenter, Open‐Label Study

Inhaled iloprost (average >30 µg/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low-dose iloprost given intravenously was equally effective as high-dose iloprost in the therapy of systemic sclerosis. Patients with pulmonary hypertension will benefit from inhalation of low-dose iloprost. Sixty-two patients with PH were enrolled and initiated with neubulizedlow-dose iloprost (2.5 µg per inhalation, 6× daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), and hemodynamic parameters. Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO-FCIII-IV at baseline), 4 because of protocol change, and 2 patients lost during follow-up. In the remaining 48 patients, 6MWD was increased from 356 ± 98 meters to 414 ± 99 meters (P < 0.001) and WHO-FC improved significantly (P = 0.006) after 24-week inhalation therapy. Cardiac output, cardiac index, and mixed venous oxygen saturation improved significantly compared with baseline (n = 34, P < 0.05). Most of the hemodynamic parameters improved significantly in patients in WHO-FC II (P < 0.05) but not in patients in WHO-FCIII-IV. Low-dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO-FCI-II but not in patients with WHO-FCIII-IV, suggesting the importance of early treatment in patients with advanced disease stages.

Percutaneous Femoral Arteriovenous Shunt Creation for Advanced Chronic Obstructive Pulmonary Disease

Advanced chronic obstructive pulmonary disease causes a significant reduction in functional capacity because of dyspnea and fatigue, partially related to hypoxemia and compromised oxygen delivery. Percutaneous creation of an arteriovenous shunt may increase oxygen delivery and, hence, improve patients' functional capacity. This is a prospective, single-center, proof-of-concept pilot study. Patients with advanced chronic obstructive pulmonary disease underwent percutaneous arteriovenous shunt creation. End points were the change in 6-minute walking distance; quality of life, measured by St George's Respiratory Questionnaire; and physiological parameters at 12-week follow-up. Fifteen patients underwent percutaneous arteriovenous shunt creation. Cardiac output and oxygen delivery increased significantly from 4.1 L/min at baseline to 5.9 L/min at 12 weeks (P<0.01) and from 751 mL/min at baseline to 972 mL/min at 12 weeks (P<0.01), respectively; however, there was a trend toward a significant decrease in the 6-minute walking distance between baseline (338 m) and 12-week follow-up (294 m) (P=0.07). There was no significant difference in the St George's Respiratory Questionnaire score, oxygen saturation, or lung function tests. Lower extremity edema, venous stenosis, right heart failure, and deep venous thrombosis occurred in 10, 7, 4, and 4 patients, respectively. Though it causes a significant increase in cardiac output and oxygen delivery , the creation of an arteriovenous shunt in the setting of severe chronic obstructive pulmonary disease did not improve functional capacity or quality of life. A significant number of adverse events occurred. This concept cannot be recommended for routine clinical use in unselected patients with advanced chronic obstructive pulmonary disease.

Relationships between changes in patient-reported health status and functional capacity in outpatients with heart failure

Heart failure trials use a variety of measures of functional capacity and quality of life. Lack of formal assessments of the relationships between changes in multiple aspects of patient-reported health status and measures of functional capacity over time limits the ability to compare results across studies. Using data from HF-ACTION (N = 2331), we used the Pearson correlation coefficients and predicted change scores from linear mixed-effects modeling to demonstrate the associations between changes in patient-reported health status measured with the EQ-5D visual analog scale and the Kansas City Cardiomyopathy Questionnaire (KCCQ) and changes in peak VO(2) and 6-minute walk distance at 3 and 12 months. We examined a 5-point change in KCCQ within individuals to provide a framework for interpreting changes in these measures. After adjustment for baseline characteristics, correlations between changes in the visual analog scale and changes in peak VO(2) and 6-minute walk distance ranged from 0.13 to 0.28, and correlations between changes in the KCCQ overall and subscale scores and changes in peak VO(2) and 6-minute walk distance ranged from 0.18 to 0.34. A 5-point change in KCCQ was associated with a 2.50-mL kg(-1) min(-1) change in peak VO(2) (95% CI 2.21-2.86) and a 112-m change in 6-minute walk distance (95% CI 96-134). Changes in patient-reported health status are not highly correlated with changes in functional capacity. Our findings generally support the current practice of considering a 5-point change in the KCCQ within individuals to be clinically meaningful.