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Abstract Rationale In chronic obstructive pulmonary disease (COPD), the benefits of pulmonary rehabilitation (PR) tend to wane over time. Whether maintenance techniques may help sustain the benefits achieved after completion of the initial PR program remains controversial. Objectives To determine whether a long-term (3-yr) maintenance program after PR preserves the short-term effects on outcomes in patients with COPD. Methods This was a multicenter prospective randomized trial including 143 patients with moderate–severe COPD, with 3 years of PR maintenance following an 8-week outpatient PR program. Patients were randomized to maintenance intervention group (IG) and standard monitoring program or control group (CG). The effects on BODE index, 6-minute-walk test distance (6MWD), and health-related quality of life were compared at 12, 24, and 36 months. Measurements and Main Results A total of 138 (96.5%) completed the 8-week program. At this time, all outcomes (BODE, 6MWD, and health-related quality of life) showed clinically and statistically significant improvements (P ≤ 0.001). During the follow-up period, the magnitude of change in 6MWD differed between IG and CG (P = 0.042), with a slight initial increase in the IG during the first year and smaller decline afterward. The BODE index changes differed between baseline and measurements at Month 24 (P = 0.043). At 3 years, the adherence rate of IG patients was 66% and 17% for the CG group (P < 0.001). Conclusions This study shows a 2-year beneficial effect of a program of rehabilitation maintenance on the BODE index and 6MWD when compared with a standard strategy. This effect vanishes after the second year of follow-up. Clinical trial registered with www.clinicaltrials.gov (NCT 01090999)

Abstract Rationale Studies suggest that patients with connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) have a poorer treatment response to therapies for PAH compared with patients with idiopathic PAH (IPAH), but individual randomized controlled trials (RCTs) have been underpowered to examine differences within these subgroups. Objectives To compare the effect of therapy for PAH in CTD-PAH versus IPAH. Methods We obtained individual participant data from phase III placebo-controlled RCTs of therapies for PAH submitted to the U.S. Food and Drug Administration for drug approval. A treatment-by-diagnosis interaction term evaluated differences in treatment response between CTD-PAH and IPAH. Outcomes included change in 6-minute-walk distance (∆6MWD) from baseline to 12 weeks, clinical worsening, and all-cause mortality. Measurements and Main Results The study sample included 827 participants with CTD-PAH and 1,935 with IPAH from 11 RCTs. Patients with CTD-PAH had less improvement in 6MWD when assigned to active treatment versus placebo compared with patients with IPAH (difference in treatment effect on ∆6MWD in CTD-PAH vs. IPAH, −17.3 m; 90% confidence interval, −31.3 to −3.3; P for interaction = 0.043). Treatment was less effective in reducing the occurrence of clinical worsening in CTD-PAH versus IPAH (P for interaction = 0.012), but there was no difference in the placebo-adjusted effect of treatment on mortality (P for interaction = 0.65). Conclusions Treatment for PAH was less effective in CTD-PAH compared with IPAH in terms of increasing 6MWD and preventing clinical worsening. The heterogeneity of treatment response supports the need for identifying therapies that are more effective for CTD-PAH.

Although sex differences exist in the management of acute coronary syndromes, less is known about the management and outcomes of women and men with suspected coronary artery disease being evaluated with noninvasive testing (NIT). We investigated sex-based differences in NIT results and subsequent clinical management in 4,720 women and 4,246 men randomized to CT angiography versus stress testing in the PROMISE trial. Logistic regression models assessed relationships between sex and referral for catheterization, revascularization, and aspirin or statin use. Cox regression models assessed the relationship between sex and the composite of all-cause death, myocardial infarction, or unstable angina. Women more often had normal NITs than men (61.0% vs 49.6%, P < .001) and less often had mild (29.3% vs 35.4%, P < .001), moderate (4.0% vs 6.8%, P < .001), or severe abnormalities (5.7% vs 8.3%, P < .001) found on NIT. Women were less likely to be referred for catheterization than men (7.6% vs 12.6%, adjusted OR 0.75 [0.62-0.90]; P = .002). Of those who underwent catheterization within 90 days of randomization (358 women, 534 men), fewer women than men had obstructive coronary artery disease (40.8% vs 60.9%, P < .001). At a 60-day visit, women were significantly less likely than men to report statin use when indicated (adjusted OR 0.81 [0.73-0.91]; P < .001) but were similarly likely to report aspirin use when indicated (adjusted OR 0.78 [0.56-1.08]; P = .13). Over a median follow-up of 25 months, women had better outcomes than men (adjusted OR 0.73 [0.57-0.94]; P = .017). Although women more frequently had normal NITs compared with men, those with abnormalities on NIT were less likely to be referred for catheterization or to receive statin therapy. The high rates of negative NIT in women, coupled with the better outcomes compared with men, strongly support the need for a sex-specific algorithm to guide NIT and chest pain management.

This study assessed the non-inferiority and safety of regadenoson administration during recovery from inadequate exercise compared with administration without exercise. Patients unable to achieve adequate exercise stress were randomized to regadenoson 0.4 mg either during recovery (Ex-Reg) or 1 hour after inadequate exercise (Regadenoson) (MPI1). All patients also underwent non-exercise regadenoson MPI 1-14 days later (MPI2). The number of segments with reversible perfusion defects (RPDs) detected using single photon emission computerized tomography imaging was categorized. The primary analysis evaluated the majority agreement rate between Ex-Reg and Regadenoson groups. 1,147 patients were randomized. The lower bound of the 95% confidence interval of the difference in agreement rates (−6%) was above the −7.5% non-inferiority margin, demonstrating non-inferiority of Ex-Reg to Regadenoson. Adverse events were numerically less with Ex-Reg (MPI1). In the Ex-Reg group, one patient developed an acute coronary syndrome and another had a myocardial infarction following regadenoson after exercise. Upon review, both had electrocardiographic changes consistent with ischemia prior to regadenoson. Administering regadenoson during recovery from inadequate exercise results in comparable categorization of segments with RPDs and with careful monitoring appears to be well tolerated in patients without signs/symptoms of ischemia during exercise and recovery.

Blunted heart rate response (HRR) to vasodilator stress agents is associated with worse outcomes. There are limited data assessing the effect of impaired HRR to regadenoson among patients with end-stage renal disease (ESRD) undergoing stress myocardial perfusion imaging (MPI). We prospectively followed patients with ESRD enrolled in the ASSUAGE and ASSUAGE-CKD trials. HRR was defined as 100*(peak stress heart rate-resting heart rate)/resting heart rate. Study cohort was dichotomized to blunted and normal HRR groups according to an established median HRR value <28% or ≥28%, which were propensity-score matched based on 22 clinical and imaging covariates. The Primary endpoint was all-cause death. The secondary cardiac-specific endpoints included: (1) the composite endpoint of cardiac death or myocardial infarction; (2) the composite endpoint of cardiac death, myocardial infarction, or late (>90 days) coronary revascularization. There were 303 patients followed for 35 ± 10 months. In the entire cohort, there was a stepwise increase in the rates of death and all secondary endpoints with worsening HRR (P values ≤.001). Blunted HRR (<28%) was associated with increased risk of death (unadjusted hazard ratio 4.10 [1.98-8.46], P < .001) and all secondary endpoints (P ≤ .001). After multivariate adjustment, HRR remained an independent predictor of mortality and secondary endpoints whether used as continuous or dichotomous variable, and added incremental prognostic value for all-cause death (P = .046). Blunted HRR was associated with increased event rate among patients with normal myocardial perfusion (P = .001) and abnormal perfusion (P = .053). In the propensity-matched cohort of 132 patients (66 in each group), blunted HRR was associated with significant increase in all-cause death (21% vs. 5%, HR 5.09 [1.46-17.7], P=.011), and similarly for the secondary endpoints. Blunted HRR (<28%) to regadenoson is a strong and independent predictor of death and cardiovascular events in patients with ESRD and adds incremental prognostic value.

The New York Heart Association (NYHA) functional class is a subjective estimate of a patient's functional ability based on symptoms that do not always correlate with the objective estimate of functional capacity, peak oxygen consumption (peak V o 2). In addition, relationships between these 2 measurements have not been examined in the current medical era when patients are using β-blockers, aldosterone antagonists, and cardiac resynchronization therapy (CRT). Using baseline data from the HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing) study, we examined this relationship. One thousand seven hundred fifty-eight patients underwent a symptom-limited metabolic stress test and stopped exercise due to dyspnea or fatigue. The relationship between NYHA functional class and peak V o 2 was examined. In addition, the effects of β-blockers, aldosterone antagonists, and CRT therapy on these relationships were compared. The NYHA II patients have a significantly higher peak V o 2 (16.1 ± 4.6 vs 13.0 ± 4.2 mL/kg per minute), a lower ventilation (Ve)/V co 2 slope (32.8 ± 7.7 vs 36.8 ± 10.4), and a longer duration of exercise (11.0 ± 3.9 vs 8.0 ± 3.4 minutes) than NYHA III/IV patients. Within each functional class, there was no difference in any of the exercise parameters between patients on or off of β-blockers, aldosterone antagonists, or CRT therapy. Finally, with increasing age, a significant difference in peak V o 2, Ve/V co 2 slope, and exercise time was found. For patients being treated with current medical therapy, there still is a difference in true functional capacity between NYHA functional class II and III/IV patients. However, within each NYHA functional class, the presence or absence or contemporary heart failure therapies does not alter exercise parameters.

To assess the safety of symptom-limited exercise testing in patients with New York Heart Association class II-IV heart failure symptoms due to left ventricular systolic dysfunction, we investigated the frequency of all-cause fatal and nonfatal major cardiovascular (CV) events among subjects enrolled in a prospective clinical trial (HF-ACTION). We hypothesized that exercise testing would be safe, as defined by a rate for all-cause death of <0.1 per 1,000 tests and a rate of nonfatal CV events <1.0 per 1,000 tests. Before enrollment and at 3, 12, and 24 months after randomization, subjects were scheduled to complete a symptom-limited graded exercise test with open-circuit spirometry for analysis of expired gases. To ensure the accurate reporting of exercise test–related events, we report deaths and nonfatal major CV events per 1,000 tests at months 3, 12, or 24 after randomization. A total of 2,331 subjects were randomized into HF-ACTION. After randomization, 2,037 subjects completed 4,411 exercise tests. There were no test-related deaths, exacerbation of heart failure or angina requiring hospitalization, myocardial infarctions, strokes, or transient ischemic attacks. There was one episode each of ventricular fibrillation and sustained ventricular tachycardia. There were no exercise test–related implantable cardioverter defibrillator discharges requiring hospitalization. These findings correspond to zero deaths per 1,000 exercise tests and 0.45 nonfatal major CV events per 1,000 exercise tests (95% CI 0.11-1.81). In New York Heart Association class II-IV patients with severe left ventricular systolic dysfunction, we observed that symptom-limited exercise testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests.

There has not been any prospective evaluation of the safety and tolerability of regadenoson (REG)-stress in patients with end-stage renal disease (ESRD). From the pooled database of two identically designed randomized, double-blinded, placebo-controlled clinical trials, ASSUAGE and ASSUAGE-CKD (IV-aminophylline vs placebo following REG-stress), we extracted the placebo-treated subjects to form 2 study groups: ESRD (dialysis or GFR < 15 mL/minute/1.73 m2) and control (GFR ≥ 30). The incidence of REG adverse effects and the hemodynamic and ECG responses to REG-stress were compared. We identified 146 ESRD subjects and 97 controls. There was no significant difference in the incidence of the composite of any REG adverse effect [ESRD 108 (74%) vs control 73 (75%), P = .82]. ESRD patients seem to have excess incidences of diarrhea [42 (29%) vs 14 (14%), P = .009] and fewer events of dizziness [28 (19%) vs 43 (44%), P < .001]. There were no serious adverse events in either group. There was no significant difference in the incidence of ST-segment deviation, tachyarrhythmias, atrioventricular block, or hypotension. This is the first prospective study to confirm the safety and tolerability of REG in patients with ESRD.

Several validated instruments are used to measure outcomes, such as exercise performance, dyspnea, and health-related quality of life after pulmonary rehabilitation (PR) in patients with COPD. However, no study has simultaneously compared the responsiveness of the most frequently used outcome measurements after PR. We designed this study to investigate the capacity of several of the most frequently used outcome measurements to detect changes after PR in a population of patients with severe COPD who qualified for lung volume reduction surgery. We evaluated 37 patients with severe COPD (FEV1 < 40%) before and after 6 to 8 weeks of outpatient PR. The following frequently used tools were evaluated: the 6-min walk distance (6MWD); functional dyspnea with the Medical Research Council (MRC) scale; baseline and transitional dyspnea index (BDI/TDI); resting and 6MWD visual analog scale (VAS); quality of life with a generic tool (the Short Form-36 [SF-36]); and two disease-specific tools, the Chronic Respiratory Disease Questionnaire (CRQ) and the St. George's Respiratory Questionnaire (SGRQ). After PR, mean ± SD 6MWD increased in 33 of 37 patients (89%), from 285 ± 97 to 343 ± 92 m (p = 0.009). Improvements were seen also in the MRC scale in 23 of 37 patients (62%; from 2.27 ± 0.8 to 1.86 ± 0.6; p = 0.01); in CRQ dyspnea in 25 of 37 patients (67%; from 3.25 ± 0.9 to 3.90 ± 1.4; p = 0.02); in CRQ mastery in 22 of 37 patients (60%; from 4.37 ± 1.4 to 5.14 ± 1.3; p = 0.01); and in BDI/TDI functional in 24 of 37 patients (64%; from 1.4 ± 0.8 to 0.7 ± 1.1; p = 0.002). There were smaller improvements in the SGRQ in 18 of 37 patients (48%) and in the SF-36 in 19 of 37 patients (51%), but they were not statistically significant. There were good correlations between the dyspnea components of all the tools. The 6MWD change did not correlate with the changes in the other outcomes. Clinically significant changes in the values for those outcome tools were detected in > 50% of patients for the BDI/TDI, 29% of patients for the MRC scale, in 37% of patients for the 6MWD, in 48% of patients for the VAS at peak exercise, in > 50% of patients for the CRQ, and in 40% of patients for the SGRQ. We conclude that the VAS peak exercise, BDI/TDI, and CRQ adequately reflect the beneficial effects of PR. The 6MWD evaluates a unique domain not related to quality of life. Due to their simplicity and sensitivity, VAS at peak exercise, 6MWD, and CRQ may be the best practical tools to evaluate responsiveness to PR.

Patient-reported outcomes are increasingly used to assess the efficacy of new treatments. Understanding relationships between these and clinical measures can facilitate their interpretation. We examined associations between patient-reported measures of health-related quality of life and clinical indicators of disease severity in a large, heterogeneous sample of patients with heart failure. Patient-reported measures, including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol Visual Analog Scale (VAS), and clinical measures, including peak V o 2, 6-minute walk distance, and New York Heart Association (NYHA) class, were assessed at baseline in 2331 patients with heart failure. We used general linear models to regress patient-reported measures on each clinical measure. Final models included for significant sociodemographic variables and 2-way interactions. The KCCQ was correlated with peak V o 2 ( r = .21) and 6-minute walk distance ( r = .27). The VAS was correlated with peak V o 2 ( r = .09) and 6-minute walk distance ( r = .11). Using the KCCQ as the response variable, a 1-SD difference in peak V o 2 (4.7 mL/kg/min) was associated with a 2.86-point difference in the VAS (95% CI, 1.98-3.74) and a 4.75-point difference in the KCCQ (95% CI, 3.78-5.72). A 1-SD difference in 6-minute walk distance (105 m) was associated with a 2.78-point difference in the VAS (95% CI, 1.92-3.64) and a 5.92-point difference in the KCCQ (95% CI, 4.98-6.87); NYHA class III was associated with an 8.26-point lower VAS (95% CI, 6.59-9.93) and a 12.73-point lower KCCQ (95% CI, 10.92-14.53) than NYHA class II. These data may inform deliberations about how to best measure benefits of heart failure interventions, and they generally support the practice of considering a 5-point difference on the KCCQ and a 3-point difference on the VAS to be clinically meaningful.