Change In 6-minute Walk Distance Research Articles

Results of the Randomized Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction Trial (RAAM-PEF)

BackgroundCardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF). Methods and ResultsIn a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E’, P = .01). ConclusionsAlthough eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined.

Ambulatory Rehabilitation Improves Exercise Capacity in Patients With Pulmonary Hypertension

Background Rehabilitation is a central treatment modality for patients with chronic cardiopulmonary disease. Physical exertion for patients with pulmonary arterial hypertension (PAH) has typically been discouraged. Inpatient pulmonary rehabilitation has been shown to improve exercise capacity in patients with PAH. The present study aimed to evaluate outpatient pulmonary rehabilitation for patients with PAH. Methods and Results Twenty-two patients with PAH or chronic pulmonary thromboembolic disease were allocated to ambulatory rehabilitation (n = 11) or to the control group (n = 11). All patients were stable on PAH-specific medication. The rehabilitation group underwent 24 1-hour sessions of exercise training/rehabilitation over 12 weeks. Primary end points were change in 6-minute walking distance (6MWD) and peak oxygen uptake (VO 2) on cardiopulmonary exercise testing. All of the patients assigned to rehabilitation and 9 control subjects completed the study. In the rehabilitation group, 6MWD increased by 32 m, and in the control group 6MWD decreased by 26 meters ( P = .003). Peak VO 2 increased in the rehabilitation group by 1.1 mL kg −1 min −1 and decreased by 0.5 mL kg −1 min −1 in the control group ( P < .05). Peak work rate during cardiopulmonary exercise test also increased in the rehabilitation group, with borderline significance ( P = .051). Echocardiography and blood N-terminal pro–brain natriuretic peptide levels were unchanged. No adverse events occurred due to the rehabilitation program. Conclusions Ambulatory rehabilitation is a safe and efficacious treatment for patients with pulmonary hypertension already on medical therapy. Clinical Trial Registration clinicaltrials.gov ID: NCT00544726

Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed

In a previous meta-analysis on the approved treatments for pulmonary hypertension, we reported that all therapies caused small changes in 6-minute walk distance over a short period, with minimal effects on hemodynamics and no effect on survival. Since that last review, 10 new clinical trials with about 1,500 patients have been published, which has increased the statistical power of our observations. A systematic review of all clinical trials in pulmonary arterial hypertension was done. The pooled effect of all treatments strategies (relative risk [95% CI], P) now shows a significant reduction of 39% (2%-62%, P = .041) in all-cause mortality. The benefits were confined only to patients with advanced disease for 16 weeks, regardless of which class of drug is used. When considering the effects within each drug family, no class of drug produced a statistically significant reduction in all-cause mortality. The improved survival bore no relationship with the change in 6-minute walk, the primary end point in most of the trials. The impact of vasodilators on long-term survival in pulmonary arterial hypertension remains uncertain. Future trials need to (a) adopt new trial designs that can better address clinical benefits, (b) use new end points that incorporate our best understanding of the disease rather than the ones that are easy to administer, and (c) include longer durations of study and other strategies to clarify if survival is affected.

Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension

In proximal chronic thromboembolic pulmonary hypertension, pulmonary endarterectomy is the treatment of first choice. In general, medical treatment before pulmonary endarterectomy is not indicated. However, selected "high-risk" patients might benefit by optimization of pulmonary hemodynamics. Moreover, in patients whose surgery is delayed owing to limited medical resources, pretreatment may prevent clinical deterioration. The primary objective of this study was to determine whether the dual endothelin-1 antagonist bosentan improves pulmonary hemodynamics and functional capacity in patients with proximal chronic thromboembolic pulmonary hypertension waiting for pulmonary endarterectomy. We used an investigator-initiated, randomized, controlled single-blind study. Patients were randomized to receive bosentan (n = 13) or no bosentan (n = 12) for 16 weeks, next to "best standard of care." The primary end point was change in total pulmonary resistance. Secondary end points included changes in 6-minute walk distance, mean pulmonary artery pressure, and cardiac index. After 16 weeks, the mean differences in change from baseline between the groups were as follows: total pulmonary resistance 299 dynes x s x cm(-5) (P = .004), 6-minute walk distance 33 m (P = .014), mean pulmonary artery pressure 11 mm Hg (P = .005), and cardiac index 0.3 L x min(-1) x m(-2) (P = .08). Treatment with bosentan was safe. After pulmonary endarterectomy, 4 patients died (no-bosentan group: n = 3); the short-term in-hospital postoperative clinical course was similar in both groups of patients. Patients with proximal chronic thromboembolic pulmonary hypertension may benefit hemodynamically and clinically from treatment with bosentan before pulmonary endarterectomy. Individual factors predictive of a beneficial response and whether this influences either morbidity or mortality associated with pulmonary endarterectomy remain to be established.

Interpretation of treatment changes in 6-minute walk distance in patients with COPD

There is uncertainty about the interpretation of changes in the 6-min walk distance (6MWD) in chronic obstructive pulmonary disease (COPD) patients and whether the minimal important difference (MID) for this useful outcome measure exists. Data were used from nine trials enrolling a wide spectrum of COPD patients with 6MWD at baseline and follow-up and used to determine threshold values for important changes in 6MWD using three distribution-based methods. Anchor-based methods to determine a MID were also evaluated. Data were included of 460 COPD patients with a mean+/-sd forced expiratory volume in one second (FEV(1)) of 39.2+/-14.1% predicted and 6MWD of 361+/-112 m at baseline. Threshold values for important effects in 6MWD were between 29 and 42 m, respectively, using the empirical rule effect size and the standardised response mean. The threshold value was 35 m (95% confidence interval 30-42 m) based on the standard error of measurement. Correlations of 6MWD with patient-reported anchors were too low to provide meaningful MID estimates. 6-min walk distance should change by approximately 35 m for patients with moderate to severe chronic obstructive pulmonary disease in order to represent an important effect. This corresponds to a 10% change of baseline 6-min walk distance. The low correlations of 6-min walk distance with patient-reported anchors question whether a minimal important difference exists for the 6-min walk distance.

Continuous Hemodynamic Monitoring in Patients With Pulmonary Arterial Hypertension

The purpose of this study was to determine whether an implantable hemodynamic monitor (IHM) could be used to judge the response of pulmonary arterial hypertension (PAH) patients to changes in therapy. A prospective, non-randomized, multi-center study evaluated physical examination, functional class, echocardiography, brain natriuretic peptide (BNP) levels, exercise capacity assessed by 6-minute walk and cardiopulmonary exercise tests, and quality of life at baseline and at 12 weeks. IHM measurements were continuously available to clinicians between clinic visits. Based on a priori, pre-specified analyses, the relationships between hemodynamic values, PAH treatments and clinical parameters were tracked in an observational fashion. Twenty-four PAH patients underwent IHM implantation prior to a change in PAH therapy. IHM data identified 13 of the 15 patients who improved their 6-minute walk distance by >30 m at 12 weeks (+48 +/- 65 m, p < 0.05), whereas the others walked less (-78 +/- 115 m, not statistically significant). In addition, peak Vo(2), BNP levels and Minnesota Living with Heart Failure Questionnaire scores only improved in the former group. The change in mean pulmonary artery pressure correlated with the change in 6-minute walk distance at 12 weeks (r = -0.71, p < 0.001). Device-related adverse events were comparable to those known to occur with a pacemaker-like device. Changes in ambulatory continuous hemodynamic measurements predicted changes in 6-minute walk distance after the start or addition of PAH therapy. The IHM also identified patients who had improved exercise tolerance, BNP levels and quality of life. The IHM appeared to be well tolerated and allowed rapid hemodynamic feedback between clinic visits.

Ambrisentan for the Treatment of Pulmonary Arterial Hypertension

Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Interaction between Angiotensin Converting Enzyme Insertion/Deletion Genotype and Exercise Training on Knee Extensor Strength in Older Individuals

Prior data in young individuals suggest that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism interacts with exercise to affect athletic performance, but the direction of the genotype effect depends on the outcome assessed (endurance vs. strength). The purpose of this study was to determine whether the ACE I/D genotype influences physical function responses to exercise training in older individuals. Physical function (muscle strength, walking distance, and self-reported disability) was measured before and after an 18-month randomized, controlled exercise trial in 213 older (>or= 60 yrs), obese (BMI >or= 28 kg/m2) men and women. Exercise training consisted of walking and light weight lifting for one hour 3 times/wk. At baseline, there were no associations between ACE I/D genotype and measures of physical function. Following exercise training, individuals with the DD genotype showed greater gains in knee extensor strength compared to II individuals. There was a significant (p = 0.014) interaction between ACE I/D genotype and exercise treatment on percent change in knee strength. In addition, there was a trend towards a greater improvement in physical disability score in DD genotypes (p = 0.13), but changes in 6-minute walk distance were not different between genotype groups. Thus, changes in muscle strength with exercise training in older individuals may be dependent on ACE I/D genotype.

Persistent Depressive Symptoms and Functional Decline Among Patients With Peripheral Arterial Disease

Because depressive symptoms are prevalent among patients with peripheral arterial disease (PAD), our goal was to study the effect of depressive symptoms over time on functional decline among patients with PAD. We conducted a prospective cohort study of 417 patients with PAD followed annually for 2 years. A Geriatric Depression Scale Short Form (GDS-S) score >5 was considered positive for depressive symptoms. Depressive symptom categories based on annual GDS-S measures included persistent, new, resolved, and no depressive symptoms. Outcome variables were change in 6-minute walk distance, 4-meter fast walking velocity, and short physical performance battery (0-12 scale, 12 = best). Results are adjusted for age, sex, race, body mass index, marital status, exercise level, smoking, ankle brachial index, leg symptoms, comorbidities, beta-blocker medication use, anti-depressant medications, and interim medical events. In adjusted analyses, patients with new depressive symptoms had greater annual decline in fast walking velocity compared with that of patients with no depressive symptoms (-0.08 versus -0.01 meters/second per year, p = .02). Patients with persistent depressive symptoms had greater annual decline in 6-minute walk distance (-86.4 versus -41.5 feet/yr, p = .04), fast walking velocity (-0.08 versus -0.01 meters/second per year, p = .004), and short physical performance battery (-0.73 versus -0.18 per year, p = .005) compared with that of patients with no depressive symptoms. Among patients with PAD, persistent and new depressive symptoms are associated with greater annual decline in functional performance. Further study is needed to determine the mechanisms of these associations and whether treatment of depressive symptoms prevents functional decline in persons with PAD.

Sitaxsentan Treatment for Patients With Pulmonary Arterial Hypertension Discontinuing Bosentan

Bosentan, an oral ET(A)/ET(B) receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET(A)-selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan. Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12. With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated. Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan.

Efficacy and safety of sildenafil citrate in Pulmonary Arterial Hypertension (PAH): Results of a multinational, randomized, double-blind, placebo-controlled trial

The purpose of this study was to evaluate the efficacy and safety of sildenafil, a phosphodiesterase 5 inhibitor, in patients with PAH. In this double-blind, placebo-controlled study, 278 patients with PAH were randomized to oral placebo or sildenafil (20, 40, or 80 mg) 3 times daily. The primary endpoint was change in 6-minute walk distance from baseline to Week 12. Secondary endpoints were change from baseline in mean pulmonary artery pressure (MPAP), time from randomization to clinical worsening, and change from baseline in Borg dyspnea score. The 6-minute walk distance increased in all sildenafil groups compared with placebo; mean placebo-corrected treatment effects were 45 m (99% confidence interval [CI], 21–70; P<0.001), 46 m (99% CI, 20–72; P<0.001), and 50 m (99% CI, 23–77; P<0.001) for 20, 40, and 80 mg sildenafil 3 times daily, respectively. All sildenafil doses reduced MPAP at Week 12; mean placebo-corrected treatment effects were −2.7 mmHg (95% CI, −5.4 to −0.1; P=0.021) for 20 mg, −3.0 mmHg (95% CI, −5.3 to −0.7; P=0.006) for 40 mg, and −5.1 mmHg (95% CI, −7.5 to −2.6; P<0.001) for 80 mg sildenafil. Compared with placebo, there were trends towards reductions in the incidence of clinical worsening events (in particular, hospitalizations) and improvement in the level of dyspnea during exercise in the sildenafil-treated groups. Adverse events were of mild to moderate severity, consistent with the natural history of PAH and the established safety profile of sildenafil administered for erectile dysfunction. This study confirms the efficacy and safety of sildenafil in the treatment of patients with PAH.