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Elevated central aortic pressure indices (e.g., systolic pressure and pulse pressure) predict cardiovascular (CV) events and mortality in addition to structural changes (e.g., left ventricular hypertrophy, carotid intima-media thickness and reduced glomerular filtration rate). These elevated risks have been shown in multiple studies to be superior to, and in others, at least as high as that associated with brachial pressures. Threshold values for the diagnosis of elevated central arterial pressures have been defined and can be considered target goals of treatment. Measurements of central arterial pressures can be incorporated into the current approaches to hypertension management utilizing currently available non-invasive devices that measure central pressures during the measurement of brachial BP. The objective of this review is to outline the rationale and evidence supporting incorporation of central aortic pressure monitoring into the care of patients with hypertension.

Hand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose-derived regenerative cells (ADRCs) to improve hand function in SSc patients.The Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double-blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small-volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc).Eighty-eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between-group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between-group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC-treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small-volume adipose tissue harvest and ADRC treatment were well tolerated.While the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted.

Background Delivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these limitations. Methods the device was designed to produce similar aerosol particle output to a marketed albuterol MDI and to the albuterol/ipratropium combination in a soft mist inhaler (SMI). Cascade impactor studies were conducted to demonstrate comparable aerodynamic particle size distribution (APSD) metrics. Efficacy was evaluated by pharmacodynamic studies involving spirometry in two separate protocols with adult subjects having COPD (albuterol DBAI vs. albuterol MDI – Study A, albuterol/ipratropium DBAI single arm – Study B). Results The total emitted doses (TED) were 81.9 ± 10.3, 109.3 ± 15.0 and 121.9 ± 7.0 μg/actuation for the DBAI, SMI and MDI respectively, and the fine (respirable) particle doses (FPD) were 56.2 ± 6.0, 61.7 ± 5.5 and 79.4 ± 2.7 μg/actuation. MMADs for albuterol sulfate were 1.93 ± 0.11, 1.75 ± 0.19, and 2.65 ± 0.05 μm for the DBAI, Respimat soft mist inhaler (SMI) and MDI respectively. The corresponding GSDs were 1.96 ± 0.16, 2.79 ± 0.25, and 1.48 ± 0.02 μm. The corresponding respirable fractions were 68.7 ± 3.2%, 57.3 ± 10.5%, and 65.2 ± 2.4%. Spirometric study A enrolled 23 subjects (age 64 ± 7.3 years, 39% male, FEV 1 45 ± 14% predicted). Study B enrolled 23 subjects (age 65 ± 8.6 years, 43% male, FEV1 47 ± 10% predicted). For Study A, FEV1 at 20 min post-dose improved by 120 (167) mL (p = 0.002) for the DBAI device and 109 (183) mL (p = 0.008) for the MDI device (p = 0.86 for between group differences). For Study B, FEV1 (20 min post-dose) improved by 216 (126) mL (p Conclusion The DBAI generated highly respirable aerosols containing albuterol sulfate that were similar to the MDI and SMI in respirable fraction but lower in dose. Subsequent pharmacodynamic studies delivering albuterol sulfate alone and in combination with ipratropium bromide confirmed similar responses for the DBAI compared with the other inhalers, which could possibly be related to a response ceiling. The DBAI breath-activated capability combined with the ability to monitor actual delivery of medication may improve effectiveness by overcoming patient miscoordination.

Objective To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. Background Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. Methods The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II–IV) or heart failure (NYHA Class II–III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. Results Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. −9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (−21.6 + 13.9 vs. −5.5 + 23.8, P = 0.038). Conclusions A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in “no option” CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

Robert Gordon Sorrell,1 Jamie Muhlenfeld,2 John Moffett,2 Gary Stevens,3 Steven Kesten4 1Alabama Orthopedic Center, Birmingham, AL, USA; 2Regenesis Biomedical Inc., Scottsdale, AZ, USA; 3Dynastat Consulting Inc., Bastrop, TX, USA; 4SKC Life Sciences, Carlsbad, CA, USA Background: The incidence of chronic postoperative pain following lumbar spinal surgery has increased with the overall increase in the prevalence of lumbar surgery. This study was conducted to evaluate the analgesic effectiveness of pulsed electromagnetic field (PEMF) therapy in subjects with persistent pain following lumbar surgery. Patients and methods: A randomized, double-blind, sham-controlled, multicenter study in 36 subjects with persistent low-back and/or radiating leg pain after lumbar surgery was conducted. Eligible subjects were randomized (1:1:1) to receive one of two doses of therapy (42-μs or 38-μs pulse width) or treatment with a sham device. Subjects self-treated twice daily for 60days. The primary end point was change in pain intensity (∆PI) using the Numerical Pain Rating Scale between average baseline (Days −5 to −1) and end of treatment (Days 56–60) for lumbar and radiating leg pain. Secondary outcome measures included the Oswestry Disability Index, Beck Depression Inventory-II, Patient Global Impression of Change, and consumption of analgesics. Results: Low-back pain scores for the 42-µs group decreased by 40.2% (p = 0.028), compared to 18.6% for the 38-µs pulse width group (p = 0.037) and 25.6% for the sham group (p = 0.013 per protocol population). Average leg pain scores decreased by 45.0% (42 μs, p = 0.009), 17.0% (38 μs, p = 0.293), and 24.5% (sham, p = 0.065). The proportion of subjects responding to therapy, time to 30% reduction in pain scores, and Patient Global Impression of Change were improved with the PEMF 42-μs device over the sham control, although results were associated with p-values >0.05. Conclusion: PEMF therapy (42-μs pulse width) was associated with trends for a reduction in pain, compared to sham treatment. Secondary endpoints were consistent with an overall beneficial effect of the PEMF 42-μs pulse width device. Keywords: failed back surgery syndrome, lumbar surgery, neuropathic pain, pulsed electromagnetic field therapy, neuromodulation, chronic pain, nociceptive pathways

Adipose derived regenerative cells (ADRCs) are a heterogeneous population of cells including multipotent adipose derived stems cells, other progenitor cells, fibroblasts, T-regulatory cells, and macrophages. Preclinical data exist supporting benefits that are predominantly through angiogenesis, modulation of inflammation, and wound remodeling. Such effects are likely paracrine in nature. The application of autologous ADRCs has been investigated across multiple therapeutic areas. While there are numerous publications, there is a relative lack of double-blind, well-controlled, randomized clinical trials in the literature. Nevertheless, a consistency in outcomes and a consistency with preclinical and laboratory studies suggests a true positive effect. The therapeutic areas reported include orthopedics, autoimmune disease, wounds and reconstruction, cardiology, peripheral vascular disease, genitourinary disorders, gastrointestinal fistulas, and neurology. Case reports have documented wound healing in otherwise intractable wounds such as ischemic- and radiation-related cutaneous ulcers and enterocutaneous fistulas. An open label, 12-patient-study indicated substantial improvement in hand manifestations of scleroderma across multiple endpoints. Post-radical prostatectomy urinary incontinence improved in a study of 11 patients with local delivery of ADRCs. Small studies of intramyocardial delivery have been associated with trends towards benefit. The studies also indicate that same day fat harvest through liposuction, cell processing, and cell delivery is feasible and can be performed with an acceptable safety profile. The objective of this review is to highlight the interest, potential, and trends that support the need to continue evaluation and exploration for the role of ADRCs as a therapeutic agent.

Background: Bronchoscopic thermal vapor ablation (BTVA) reduces lung volumes in emphysema patients by inducing a localized inflammatory response (LIR) leading to a healing process of fibrosis, but may also increase symptoms. Objectives: We sought to evaluate whether the clinical manifestation of LIR correlated with patient outcome. Methods: Respiratory adverse events and inflammatory markers were analyzed from a multicenter trial of BTVA in patients with upper-lobe-predominant emphysema. End points including changes in forced expiratory flow (FEV1), lobar volume, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) and 6-minute-walk distance (6-MWD) were analyzed according to the presence or absence of a respiratory adverse event requiring treatment with an antibiotic or steroid. Results: Forty-four patients received BTVA. Increases of inflammatory markers were observed with a peak between the second and fourth week. Eighteen respiratory adverse events occurred in 16 patients within 30 days of BTVA, requiring antibiotics and/or steroids. These patients had significantly greater lobar volume reduction (65.3 vs. 33.4%, p = 0.007) and a change in residual volume at 12 months (-933 vs. 13 ml, p < 0.001) associated with a greater improvement of exercise capacity and health-related quality of life than patients without respiratory adverse events. Conclusion: Patients with more prominent respiratory symptoms in the first 30 days following BTVA experience greater efficacy. The clinical manifestations of the LIR are predictive of long-term clinical benefits.

To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients.Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions.The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo.Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V0A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

SummaryBackgroundData comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice.MethodsWe performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 μg once daily) + salmeterol (50 μg twice daily) (T + S) to salmeterol + fluticasone (50/500 μg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV1) ≤65% predicted, and thoracic gas volume (TGV) ≥120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET).ResultsIn 309 patients, at baseline, prebronchodilator FEV1 was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p

David MG Halpin,1 Marc Decramer,2 Bartolome Celli,3 Steven Kesten,4 Dacheng Liu,4 Donald P Tashkin51Royal Devon and Exeter Hospital, Devon, UK; 2Respiratory Division, Katholieke Universiteit Leuven, University Hospital, KU Leuven, Belgium; 3Pulmonary Division, Brigham and Women's Hospital, Boston, MA; 4Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; 5Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USABackground: Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD). We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.Methods: This retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo. Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0>0–1, >1–2, and>2). Spirometry and the St George's Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).Results: In total, 5992 patients (mean age 65 years, 75% male) were randomized. Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units). Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium). Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium). The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium). The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.Conclusion: Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increasing rates of hospitalized exacerbations are associated with increasing risk of death.Keywords: chronic obstructive pulmonary disease, exacerbations, forced expiratory volume in one second, health status, tiotropium

Emphysema remains a disabling disease despite current treatment. Novel approaches to the underlying physiological abnormalities responsible for symptom generation are warranted.A review of current hypotheses and preclinical and clinical data on the utility of endoscopic thermal vapor ablation (InterVapor) in the treatment of emphysema.In animal studies, thermal energy in the form of heated water vapor both in healthy and in papain-induced emphysema in dogs and sheep leads to an inflammatory response followed by healing with airway and parenchymal fibrosis. The fibrosis and associated distal atelectasis result in volume reduction. The amount of thermal energy delivered has been based on the amount of target tissue mass determined from a high-resolution computed tomogram. Early human studies indicated the feasibility of InterVapor with 5 cal/g tissue; however, the dose appeared insufficient to induce lobar volume reduction. A study using 10 cal/g to 1 upper lobe (n=44) induced a mean of 46% lobar volume reduction at 12 months along with significant improvements in the physiology and health outcomes.InterVapor induces lung volume reduction in patients with emphysema. The mechanism of action is through a thermally induced inflammatory response followed by healing with subsequent remodeling of tissue (fibrosis and distal atelectasis).

SummaryMortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a Mortality Adjudication Committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

Rationale: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available. Objective: To obtain better insight into the phenomenon of premature discontinuation. Methods: We analyzed the pattern of discontinuation in the UPLIFT-trial. Measurements and main results: Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p < 0.001). Patients discontinuing were characterized by more severe COPD (p < 0.0001), greater number of pack years (p < 0.002), smaller prebronchodilator and post-bronchodilator FEV(1) (p < 0.0001 for both), and worse SGRQ scores < 0.0001). Rates of decline of FEV(1) and SGRQ were greater in non-completers (p < 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV(1), male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related. Conclusion: Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials. (C) 2011 Elsevier Ltd. All rights reserved.

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial. Methods: Subgroup analysis from a randomized, double-blinded, placebo-controlled trial of tiotropium 18 µg daily in COPD. Primary end-point was rate of decline in FEV1. Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m2; post-bronchodilator FEV1: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV1 although annual decline was less in Asian patients. Morning pre-bronchodilator FEV1 and forced vital capacity improved in Asian patients (P

Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease (COPD), relatively little is known about the effect in younger patients. We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year randomised, double blind placebo controlled Understanding Potential Long Term Impact on Function with Tiotropium (UPLIFT) trial. Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of ≤70%, FEV(1)/FVC < 0.70, age ≥40 years, and smoking history of ≥10 pack years. Younger patients had a mean FEV(1) of 1.24 L (39% predicted) and an impaired health-related quality of life (St. George's Respiratory Questionnaire (SGRQ)) compared to the entire UPLIFT population. There were 40.2% women and 51.1% current smokers in the younger age group. Tiotropium was associated with a sustained improvement in spirometry and SGRQ. Mean decline in post-bronchodilator FEV(1) was 58 ml/year (placebo) vs. 38 ml/year (tiotropium) (p = 0.01). Corresponding values for pre-bronchodilator FEV(1) were 41 ml/year (placebo) compared with 34 ml/year (tiotropium) (p = 0.34). The hazard ratio (95%CI) for an exacerbation in the younger age group was 0.87(0.68, 1.13)). The rate of exacerbations was reduced by tiotropium (rate ratio (95%CI) = 0.73(0.56, 0.95)). Tiotropium resulted in sustained bronchodilation, improved quality of life, and a decreased exacerbation rate in younger patients. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV(1), suggesting possible disease modification by tiotropium in younger patients with COPD.

Christopher B Cooper1, Marlon Abrazado1, Daniel Legg2, Steven Kesten21David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Boehringer Ingelheim Pharmaceuticals Inc., Ingelheim, GermanyBackground: Because treadmill exercise testing is more representative of daily activity than cycle testing, we developed treadmill protocols to be used in various clinical settings as part of a two-year, multicenter, chronic obstructive pulmonary disease (COPD) trial evaluating the effect of tiotropium on exercise.Methods: We enrolled 519 COPD patients aged 64.6 ± 8.3 years with a postbronchodilator forced expiratory volume in one second (FEV1) of 1.25 ± 0.42 L, 44.3% ± 11.9% predicted. The patients performed symptom-limited treadmill tests where work rate (W) was increased linearly using speed and grade adjustments every minute. On two subsequent visits, they performed constant W tests to exhaustion at 90% of maximum W from the incremental test.Results: Mean incremental test duration was 522 ± 172 seconds (range 20–890), maximum work rate 66 ± 34 watts. For the first and second constant W tests, both at 61 ± 33 watts, mean endurance times were 317 ± 61 seconds and 341 ± 184 seconds, respectively. The mean of two tests had an intraclass correlation coefficient of 0.85 (P < 0.001). During the second constant W test, 88.2% of subjects stopped exercise because of breathing discomfort; 87.1% for Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II, 88.5% for GOLD Stage III, and 90.2% for GOLD Stage IV.Conclusion: The symptom-limited incremental and constant work treadmill protocol was well tolerated and appeared to be representative of the physiologic limitations of COPD.Keywords: chronic obstructive pulmonary disease, exercise testing, endurance, tiotropium

SummaryBackgroundGender differences may occur in many chronic diseases. We have examined the influence of gender in chronic obstructive pulmonary disease (COPD) on long-term responses to tiotropium.MethodsSubgroup analysis of data from the Understanding the Potential Long-term Impact of Tiotropium (UPLIFT®) trial (4-year, randomized, double-blind, placebo-controlled trial of tiotropium in patients with COPD).ResultsOf 5992 patients, 75% were men and 25% women. Mean age was 65 and 63 years, respectively. Baseline post-bronchodilator forced expiratory volume in 1s (FEV1)=47% predicted(men) and 49% predicted(women). St George’s Respiratory Questionnaire (SGRQ) total score was 44.9 and 48.7units, respectively. At 48 months, improvement in trough FEV1 over control was 92mL(men) and 77mL(women) (p

Background The clinical trial safety database for tiotropium has been augmented with a 4-year trial in patients with COPD, which provides an opportunity to better evaluate the cardiovascular (CV) profile of tiotropium. Methods Trials with the following criteria were considered: ≥ 4 weeks, randomized, double-blind, parallel-group, placebo-controlled. Inclusion/exclusion criteria were similar, including spirometry-confirmed COPD, ≥ 10 pack-year smoking, and age ≥ 40 years. Adverse events were collected throughout each trial using standardized case report forms. Incidence rates (IRs) were determined from the total number of patients with an event divided by total time at risk. Rate ratios (RRs) and 95% CI for tiotropium/placebo were calculated. IRs were determined for all-cause mortality and selected CV events, including a composite CV end point encompassing CV deaths, nonfatal myocardial infarction (MI), nonfatal stroke, and the terms sudden death, sudden cardiac death, and cardiac death. Results There were 19,545 patients randomized: 10,846 (tiotropium) and 8,699 (placebo) from 30 trials. Mean FEV1 = 1.15 ± 0.46 L (41 ± 14% predicted), 76% men, mean age=65 ± 9 years. Cumulative exposure to study drug was 13,146 (tiotropium) and 11,095 (placebo) patient-years. For all-cause mortality, the IR was 3.44 (tiotropium) and 4.10 (placebo) per 100 patient-years (RR [95% CI] = 0.88 [0.77–0.999]). IR for the CV end point was 2.15 (tiotropium) and 2.67 (placebo) per 100 patient-years (RR [95% CI] = 0.83 (0.71–0.98]). The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 (tiotropium) and 1.24 (placebo) per 100 patient-years (RR [95% CI] = 0.77 [0.60–0.98]). For total MI, cardiac failure, and stroke the RRs (95% CI) were 0.78 (0.59–1.02), 0.82 (0.69–0.98), and 1.03 (0.79–1.35), respectively. Conclusion Tiotropium was associated with a reduction in the risk of all-cause mortality, CV mortality, and CV events.

Background Ipratropium and albuterol, combined in a single formulation, is widely used as three to four times daily maintenance therapy in COPD. This trial compared tiotropium, once daily, as a potential alternative to patients already taking the ipratropium/albuterol combination. Methods 676 patients with moderate to very severe stable COPD (mean FEV 1 = 39% of predicted) maintained on ipratropium/albuterol were randomized to receive over an 84 day period either tiotropium (18 mcg) each morning, or continue with ipratropium (26 mcg)/albuterol (206 mcg), 2 actuations 4 times daily, using a parallel group, double-blind, double-dummy design. Six-hour spirometry was assessed on study days 1, 22, and 84, along with safety assessments and other efficacy measures. Results In terms of primary outcomes, mean trough FEV 1 at 84 days was larger in the tiotropium arm, as compared with the ipratropium/albuterol arm (difference = 86 ml; 95% CI, 49 to 123 ml, p 1 AUC 0–6 at 84 days was also larger in the tiotropium arm (difference = 17 ml; 95% CI, −21 to 56 ml), this difference being statistically non-inferior to the ipratropium/albuterol arm ( p p = 0.37). Other efficacy measures were similar in the two groups. Lower respiratory adverse events were reported in 40 tiotropium patients vs. 52 ipratropium/albuterol patients. Safety reporting was otherwise similar. Conclusion Patients previously maintained on the ipratropium/albuterol combination taken four times daily can be switched to tiotropium once daily with the reasonable expectation of at least equivalent bronchodilation during daytime hours and superior bronchodilation during early morning hours.

In the 4-year UPLIFT trial, tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease (COPD). Mortality and its causes was a secondary endpoint in UPLIFT.We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients.This study involved a randomized, double-blind trial comparing tiotropium with placebo in patients with COPD (or=40 yr of age; postbronchodilator FEV(1)or=70%; FEV(1)/FVCor=70%). Mortality was evaluated during treatment and with follow-up of discontinued patients. Cause of death was adjudicated by an endpoint committee.A total of 5,993 patients were randomized, 3,006 to placebo and 2,987 to tiotropium. While patients were receiving treatment, there were 792 deaths, with a lower risk in the tiotropium group (hazard ratio, 0.84; 95% confidence interval [CI], 0.73-0.97). Statistical significance was observed at the end of the protocol-defined treatment period (P = 0.034) but not 30 days thereafter (P = 0.086). Adjustment by GOLD stage, sex, age, baseline smoking behavior, and baseline respiratory medications subgroups did not alter the results of the analysis. The most common causes of death adjudicated by an independent end-point committee were lower respiratory, cancer, general disorders, and cardiac disorders. The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 (95% CI, 0.68-1.09) and 0.86 (95% CI, 0.75-0.99), respectively.Treatment with tiotropium over 4 years is associated with decreased mortality, with the effect being most prominent in the cardiac and respiratory systems.

Sparse information exists about chronic obstructive pulmonary disease (COPD) outcomes among different ethnic groups. To determine whether the effect of tiotropium on COPD exacerbation differs between African Americans and Caucasians, we performed a post hoc analysis of African-American (n = 150) and Caucasian (n = 1670) subgroups from a previously reported 6-month trial of tiotropium in patients with moderate-to-very-severe COPD. Compared with placebo, tiotropium reduced the likelihood of having at least 1 exacerbation in the entire group (RR, 0.81; 95% CI, 0.66–0.99, P = 0.037) with no statistically significant difference between African-American and Caucasian subgroups ( P = 0.34). For African Americans, tiotropium significantly reduced the number of antibiotic days for COPD, hospitalizations for exacerbations, and hospitalization days for COPD. For Caucasians, tiotropium significantly reduced the number of exacerbations, exacerbation days, unscheduled clinic visits for COPD, and hospitalizations for exacerbations. Tiotropium reduced the frequencies of antibiotic days and of COPD hospital days to a significantly greater extent in African Americans compared with Caucasians ( P = 0.027 and P = 0.025, respectively). No statistically significant ethnic-related differences were observed in the effect of tiotropium on the frequencies of exacerbations, exacerbation days, systemic corticosteroid days, unscheduled clinic visits, or COPD hospitalizations. Spirometry improved to a similar extent in both subgroups for the entire duration of the 6-month trial. African Americans used fewer respiratory medications than Caucasians in this study. We conclude that tiotropium reduces COPD exacerbations and associated health-care use to a similar extent in African Americans compared with Caucasians.

Steven Kesten1, Richard Casaburi2, David Kukafka3, Christopher B Cooper41Boehringer Ingelheim GmbH, Ingelheim, Germany; 2Harbor-UCLA Medical Center, Torrance, CA, USA; 3Northern Colorado Pulmonary Consultants PC, Fort Collins, CO, USA; 4UCLA School of Medicine, Los Angeles, CA, USABackground: Improvements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation. We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation.Methods: COPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a randomized, double-blind, placebo-controlled trial of tiotropium 18 µg daily (tiotropium = 47, placebo = 44). Study drug was administered for 5 weeks prior to, 8 weeks during, and 12 weeks following pulmonary rehabilitation. Patients completed a questionnaire documenting participation in pre-defined activities outside of pulmonary rehabilitation during the 2 weeks prior to each visit. Patients who submitted an activity questionnaire at week 4 and on at least one subsequent visit were included in the analysis. For each patient, the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration.Results: Patients (n = 46) had mean age of 67 years, mean baseline FEV1 of 0.84 L (33% predicted). Mean (SE) increase in duration of activities (minutes during 2 weeks prior to each visit) from week 4 (prior to PR) to week 13 (end of PR) was 145 (84) minutes with tiotropium and 66 (96) minutes with placebo. The increase from week 4 to week 25 (end of follow-up) was 262 (96) and 60 (93) minutes for the respective groups. Increases in activity duration from week 4 to weeks 17, 21, and 25 were statistically significant with tiotropium. No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant.Conclusions: Tiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities.Keywords: activity, chronic obstructive pulmonary disease, exercise, pulmonary rehabilitation, tiotropium

Patients with COPD are frequently prescribed inhaled corticosteroids (ICS); however, it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators. Two 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies of tiotropium 18 μg once daily, compared with salmeterol, 50 μg bid, had been conducted in patients with moderate-to-severe COPD. Efficacy was assessed by spirometry, transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), and exacerbations. Data from both studies were combined to form subgroups with regard to concurrent use of ICS. 796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS. Mean age was 64 years, and pre-bronchodilator FEV1 was 1.06 L (ICS group) and 1.13 L (non-ICS group). Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo (ICS groups: tiotropium 110 ± 20 mL, salmeterol 80 ± 20 mL; non-ICS groups: tiotropium 150 ± 30 mL, salmeterol 110 ± 30 mL; p > 0.05 for tiotropium vs salmeterol). Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium. Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function, irrespective of concurrent use of ICS.

Objectives: The ADVANCE clinical trial sought to define the safety, feasibility and efficacy of an intracoronary infusion of adipose derived regenerative cells in patients admitted with an acute ST-elevation myocardial infarction (STEMI) within 24 hours of successful primary PCI. Methods: In this randomized, double-blind, placebo-controlled trial (n=23, 2:1 randomization), within 24 hours of successful primary PCI following STEMI, a small volume liposuction was performed for fat harvest and ADRC isolation by an automated Celution® System, and intracoronary infusion within 12 hours of the liposuction. Results: 23 patients were enrolled to date (all male, age 58 years, BMI 28 kg/m 2 ). The liposuction procedure data are shown in the table TEMI patients were routinely treated with dual anti platelets and heparin. The decline in hemoglobin following the liposuction procedure from baseline over the 10 hours following the procedure was 10.2% ±7.6 (mean ± SD) Although two patients had >20% of Hb decline at anytime (maximum 20.8%), one of these patients returned to within 10% of baseline by 10 hours without transfusion. The liposuction procedure was completed in all but one patient (terminated early due to hypotension - resolved with termination of procedure). IC infusion of the ADRC suspension was performed successfully in all patients. No impediment of coronary TIMI flow was observed during or following cell infusion of these mesenchymal-like cells. No ventricular arrhythmias were observed during cell infusion. No major adverse cardiac or cerebral events (MACCE) occurred within 30 days of the procedures. Conclusion: Limited liposuction to harvest fat for ADRC stem cell isolation and subsequent intracoronary infusion of these autologous ADRCs can be performed safely in patients with acute STEMI under dual antiplatelets therapy, demonstrating feasibility of the therapeutic application of point-of-care cell therapy using ADRCs.

Study Objectives. To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease (COPD), and to establish previously reported symptomatic efficacy. Design. Randomized, double-blind, placebo-controlled, parallel-group study. Setting. Twelve outpatient investigational centers in the United States. Patients. One hundred ninety-six patients with COPD. Intervention. Patients received either tiotropium 18 μg once/day or placebo, delivered by the HandiHaler device. Measurements and Main Results. Electrocardiography (predose and 5 min postdose) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 μg once/day or placebo. Efficacy measures (spirometry, global COPD ratings, scores on the EuroQol Health Questionnaire [EQ-5D], albuterol inhaler as needed) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies. Mean baseline forced expiratory volume in 1 second (FEV1) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups. No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring. Frequency of premature beats and mean maximal changes in PR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. No patients developed new-onset QT or QTc intervals greater than 500 msec, and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec, 30–60 msec, or greater than 60 msec. At 12 weeks, predose and postdose improvements in FEV1 were 184 and 265 ml, respectively, with tiotropium versus placebo (p

Background The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies. Methods Randomized, double-blind, double-dummy, parallel-group study, comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD. Serial spirometry was performed over 12 h after 12 weeks of treatment. Co-primary endpoints were average (over 12 h) and peak FEV1 at 12 weeks. Results 653 patients were randomized (328 tiotropium, 325 salmeterol): mean age 64 years; 66% male; mean baseline FEV1 1.05 l (37.7% predicted). After 12 weeks, the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol (167 vs. 130 mL, respectively, p=0.03), as was peak FEV1 (262 vs. 216 ml, respectively, p=0.01). The average FEV1 responses from 0–6 h and 6–12 h were higher in the tiotropium group compared with salmeterol (p

Background: In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium. Methods: To evaluate the effect of tiotropium, 18 g/d, on IC, a 4-week, randomized, doubleblind, placebo-controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV1, FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (– 60 and – 15 min) and after study drug (30 min, 60 min, 120 min, and 180 min). Results: Mean age was 64 years; 62% were men. Mean baseline FEV1 was 1.12 L (43% predicted). The mean differences (tiotropium placebo) in FEV1 trough (morning before drug), peak, and area under the curve over 3 h values (adjusted for baseline and center differences) at week 4 were 0.16 L, 0.22 L, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22 L, 0.35 L, and 0.30 L (p < 0.01 for all). Differences in TGV were – 0.54 L, – 0.60 L, and – 0.70 L, respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV1 and lung volumes (FEV1, 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%). Conclusions: Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h. (CHEST 2003; 124:1743–1748)

Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications. Initially, tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties. However, generally such observations have been reported in asthma. A 6-month randomized, double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD. Spirometry was measured over 12h at baseline and at days 15, 57, 116 and 169. Changes over time from baseline were compared relative to changes observed with placebo. A total of 623 patients participated (tiotropium = 209, salmeterol = 213, placebo = 201). The groups were similar in age (mean = 65 years), gender (75% men), and baseline FEV1 (mean = 1.08 +/- 0.37l [40 +/- 12% predicted]). Relative to placebo, both active drugs improved morning pre-drug, peak and average FEV1 and FVC throughout the trial. However, from day 1 to 169, salmeterol was associated with a higher decline in average FEV1 and FVC (0-12h) (difference from placebo: -36 and -115 ml, P0.05), which was most prominent over the 8-12 h period (difference from placebo: -45 and -138 ml, P0.01). Significant declines in peak FVC relative to placebo (-83 ml, P0.05) but not FEV1 (-12ml) were observed with salmeterol. Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial. In conclusion, tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics.

Few studies have measured patients' asthma medication compliance, medication costs, and insurance status. We used a questionnaire assessing details of asthma, medications used, patient costs, and methods used to reduce medication costs to assess these factors. Patients in outpatient clinics, emergency rooms, and inpatient units of two urban Chicago hospitals who had a history of asthma and an age of 18 years or older were eligible for the study. Two hundred subjects completed the questionnaire of which 54 (27%) were self-pay/uninsured, 54 (27%) had public aid, and 92 (46%) had insurance. The public aid group had a significantly higher rate of emergency room services. Eighty-four (42% of all participants) had no costs, including no copayment to obtain their antiasthma medications. Self-pay/uninsured patients more commonly reported delaying filling a prescription, failure to fill a prescription, and taking less than recommended doses than the other two groups. Self-pay/uninsured patients also more commonly reported choosing their pharmacy on the basis of medication costs. Participants with public aid reported their physicians inquired about insurance status, estimated medication costs, advised measures to reduce costs, and gave them free medication samples less often than the other two groups. In conclusion, patients report different methods to reduce their medication costs that vary according to their insurance status. Advice on methods to reduce medication costs and being supplied with medication samples also varied by insurance status according to participants' report.

Background: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. Methods: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 g once daily via dry-powder inhaler, compared with salmeterol, 50 g bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George’s Respiratory Questionnaire (SGRQ). Results: A total of 623 patients participated (tiotropium, n 209; salmeterol, n 213; and placebo, n 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV1 (mean, 1.08 0.37 L; percent predicted, 40 12% [ SD]). Compared with placebo treatment, the mean predose morning FEV1 following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV1 (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, 5.14 U (p < 0.05 vs placebo); salmeterol, 3.54 U (p 0.4 vs placebo); and placebo, 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). Conclusions: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD. (CHEST 2002; 122:47–55)

Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients. Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18 microg once daily (n=356) compared with ipratropium 40 microg q.i.d. (n=179). Screening forced expiratory volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7% of the predicted value) (tiotropium) and 1.18+/-0.37 L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12+/-0.01 L with tiotropium and declined by 0.03+/-0.02 L with ipratropium (p

Objective: To identify patterns of care and associated costs for typical patients with chronic obstructive pulmonary disease (COPD) in a US managed-care setting. Design: Retrospective analysis of administrative data from a proprietary managedcare research database. Patients: 6371 patients with COPD. Methods: A ‘core’ population of enrollees was identified who were continuously eligible for healthcare services (including prescription medications) for at least 12 months and who actively utilized services. From this core population, patients with two or more claims listing International Classification of Diseases, nineth edition, Clinical Modification diagnosis codes for COPD were selected as the COPD study population. The core and COPD study databases were then analyzed to quantify healthcare utilization and charges over the period from October 1995 through September 1996. Results: Approximately one-half of patients with COPD were in the 45- to 64-year age group. The average total healthcare charge for patients with COPD was $US1109 per month (1995/1996 values), compared with $US179 per month for the average patient with healthcare claims. Although only 19% of patients with COPD were hospitalized for COPD, 58% of COPD-attributed healthcare charges were for hospitalizations. Physician visits and tests accounted for another 23% of COPD-attributed healthcare charges, and medications for 9%. Over 25% of patients with COPD had an emergency room visit, compared with 10% of all patients with claims. 40% of patients with COPD received at least one prescription for a respiratory medication during the year. 15% received anticholinergic bronchodilators, 30% received β2-agonist inhalers, 13% received xanthine bron-chodilators, and 14% received inhaled corticosteroids. Patients with COPD had over twice as many medical conditions for which they sought healthcare compared with the average patient with claims. Conclusions: Although COPD has been viewed as a disease of the elderly, it also significantly affects the quality of life of the ‘not so elderly’, and represents a significant cost exposure to commercial health plans in the US. Despite the availability of acceptable clinical guidelines, there are many opportunities to optimize healthcare utilization and the standard of care for patients with COPD, including ensuring that patients receive those medications considered to be first-line treatment for COPD.

The purpose of this study was to examine the psychological functioning and quality of life (QOL) of lung transplant candidates and recipients.The following measures were completed by 36 lung transplant candidates (the pretransplant group [PRE]) and 73 recipients (the posttransplant group [POST]): the Rand-36 Item Health Survey 1.0 (RAND-36), visual analog scale of overall QOL (OQOL), Brief Symptoms Inventory (BSI), Derogatis Sexual Functioning Inventory (DSFI), Hospital Anxiety and Depression Scale (HAD), Rosenberg Self-Esteem Scale (RSES), and Body Cathexis Scale (BC).Compared to the PRE, POST patients had significantly better scores on the following measures: RAND-36 total, physical health, role limitations due to physical health, general health, vitality, and social functioning subscales (all p0.0001); visual analog scale of OQOL (p0.0001); BSI (p0.05); BC (p0.05); HAD anxiety (p0.05) and depression (p0.0001); and RSES (p0.05). Despite better scores, some areas did not differ between the PRE and the POST, and many patients continued to experience impairments in psychological functioning. Specifically, the RAND-36 emotional health and role limitations due to emotional health subscale scores did not differ between the PRE and the POST and they remained lower than published norms. A significant proportion of patients in both groups (44% of PRE patients and 28% of POST patients) had borderline or clinical levels of anxiety (ie, the HAD). Finally, PRE and POST mean scores were significantly lower than published norms on the RSES (p0.05) and the body image scale of the DSFI (p0.05).Although lung transplant recipients have better general, physical, and psychological health than their pretransplant counterparts, the present research suggests that both groups experience impairment in several areas of psychological functioning. Future research into the QOL of the lung transplant population should be aimed at recognizing, intervening, and improving patients' psychological and emotional well-being.

A meta-analysis of randomized controlled asthma drug therapy trials published in the English literature from January 1991 to June 1995 was performed to estimate the magnitude and direction of the placebo effect in stable ambulatory asthmatic patients. Among placebo groups, the mean absolute increase in forced expiratory volume in 1 sec (FEV1), weighted for sample size and variance, was 0.11 L/min, and the mean percent increase in FEV1 was 4.81%. The corresponding placebo group changes in peak expiratory flow (PEF) were in an opposite direction to those of FEV1; there was a mean absolute decrease of 2.24 L/min, and a mean percent decrease of 4.21%. Changes for active treatment groups were greater in magnitude. However, there were no statistically significant differences in mean changes comparing the placebo groups to the treatment groups, for any of the outcome measures. Mean increases in PEF and FEV1 exceeded 10% in 5 of 33 placebo groups, as compared to 13 of 33 active treatment groups. In conclusion, in well-designed long-term drug therapy studies in stable asthmatics the pooled placebo effect is small but measurable, with FEV1 and PEF showing different directions of response. Moreover, a modest number of patients receiving placebo have changes in pulmonary function that might be interpreted as clinically significant.

End-stage lung disease (ESLD) generally refers to disorders that lead to progressive deterioration in objective measures of lung function, limitation of physical activity, inability to independently perform basic tasks of daily living, and usually premature mortality. These diseases may be accompanied by a variety of comorbid conditions that complicate therapy and contribute to morbidity and mortality. While attempts have been made to define the pulmonary function predictors of life expectancy in patients with ESLD, such as the degree of airway obstruction as reflected by forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for carbon monoxide, little effort has been expended in studying the impact of comorbidities on morbidity and mortality. Recently,2,3 indices have been designed to quantify various comorbid conditions in an attempt to predict mortality in these patients, with variable success. While some of the comorbid conditions occur as a result of the underlying disease process, such as cystic fibrosis (CF) affecting pancreatic function, others may occur due to a common risk factor such as smoking. Deterioration in a patient with ESLD may occur as a result of progression of the underlying lung disease, side effects of therapy, or decompensation due to the comorbid condition(s), all of which influence the therapeutic intervention(s) required and have a marked impact on survival.4 As older patients with less functional reserve survive longer, the issue of comorbid conditions is becoming increasingly important. In this article, we review the available literature on some of the more common comorbidities in ESLD (Table I).

A young woman with primary pulmonary hypertension presented with interstitial lung disease approximately 5 years after successful treatment with IV prostacyclin. The pathology was consistent with nonspecific interstitial pneumonitis and was unresponsive to steroids and immunosuppressive medications. We speculate that further cases of this syndrome may be reported as more patients are living beyond 5 years with prostacyclin.

Background Approximately 4 million persons in the United States are chronically infected with hepatitis C and morbidity due to this disease is increasingly observed in transplant recipients. While knowledge of hepatitis C in liver and kidney transplantation is advancing, little information is available concerning hepatitis C and lung transplantation. We surveyed lung transplant programs about policies regarding testing for hepatitis C, transplantation of hepatitis C-infected candidates, and the use of organs from seropositive donors. Methods A written questionnaire was sent to all United Network of Organ Sharing (UNOS) approved lung transplant programs. Results Fifty-nine of 89 (66%) surveys were returned, including 49 from active programs, capturing 81% of lung transplants performed within UNOS prior to January 1998. All programs screen candidates for hepatitis C. The estimated median seropositivity rate among candidates was 1.9%. Thirty-three of 46 (72%) programs consider seropositive patients for transplantation and most use virologic and/or histologic data to determine candidacy. All donors are screened for hepatitis C. Twenty-six of 47 (55%) programs accept lungs from seropositive donors and many restrict the use of organs from seropositive donors to infected recipients. Few programs routinely test recipients for hepatitis C, and policies for monitoring those with known infection are variable. Conclusions Lung transplant candidates and donors are tested routinely for hepatitis C. The majority of programs are willing to accept infected candidates and seropositive donors. Post-transplant follow-up of hepatitis C is variable and prospective studies are needed to evaluate the impact of hepatitis C on lung transplant recipients.

Background Immunosuppression and chronic lung disease are known risk factors for mycobacterial infection and might be expected to develop with an increased frequency in lung transplant recipients. We therefore sought to document the incidence and type of mycobacterial infections in a large lung transplant program. Methods A retrospective review of 219 transplant procedures (60 single lung transplants and 159 double lung transplants) in 210 patients was conducted. All patients had scheduled surveillance bronchoscopies at 3, 6, 9, 12, 18, and 24 months, and yearly thereafter. BAL samples were processed routinely for mycobacterium. Results Eight patients (3.8%) had evidence of infection (5 men, 3 women; age range, 26 to 63 years). The reasons for transplant were obstructive lung disease (six), cystic fibrosis (one), and pulmonary fibrosis (one). Five recipients had infection in their native lungs; two of five cultured mycobacterium from BAL following transplantation. At least four of five patients had nontuberculous mycobacterium (one showed acid fast bacilli and granuloma on a biopsy specimen that was not sent for culture). None of the five developed disease (mean follow-up = 22 months; range, 3 to 30 months). The organisms were Mycobacterium avium complex (three), Mycobacterium xenopi (one), and unidentified (one). Of the three remaining patients who developed infection after transplantation, one grew Mycobacterium chelonae and the others grew Mycobacterium tuberculosis (both received double lung transplants and had no evidence of mycobacterium in their native lungs). The only definite symptomatic disease occurred in the patients with M tuberculosis, one of whom had evidence of dissemination. The patients with M tuberculosis responded to standard treatment. There have been no deaths due to mycobacterium. Conclusion Mycobacterial disease rarely occurs following lung transplantation. Cultures for mycobacterium in surveillance BALs in the absence of symptoms are likely unnecessary.

Objective Lung volume reduction surgery (LVRS) represents a potential breakthrough in the management of advanced emphysema, although questions remain about clinical and economic implications of widespread application of LVRS. In this report, we describe hospital costs, excluding physicians' fees, for LVRS. Design Hospital charges were obtained from billing records and converted to costs by applying multiple cost-to-charge ratios. Setting A large, urban academic medical center. Patients Fifty-two consecutive patients who received bilateral LVRS through a median sternotomy between April 1995 and August 1996. Results Median hospital stay was 10 days (mean=14.8±12.8 days; range=3 to 48 days), including 2 days (mean=6±9.2 days; range=1 to 35 days) in the ICU. One hospital death occurred. Hospital costs per case ranged from $11,712 to $121,829, with mean costs of $30,976 and median costs of $19,771. Costs were related significantly to duration of ICU stay and length of hospitalization. Patients who accrued the highest costs were significantly older than the remainder of the sample (69.3 years vs 62.4 years). Conclusions Hospital costs of LVRS vary significantly but are related directly to hospital stay. Identification of factors associated with prolonged stays can be used in assessing benefits and risks of LVRS against utilization of health-care dollars.

To evaluate the acute effects of noninvasive positive pressure ventilation (NPPV) in patients with stable chronic respiratory failure secondary to cystic fibrosis.Eight patients (29+/-5 years of age) with severe airflow limitation (mean FEV1, 24+/-3% predicted) and chronic respiratory failure (PaO2=67+/-15 mm Hg and PaCO2=50+/-4 mm Hg) were evaluated.Tidal volume, respiratory rate, minute ventilation, oxygen saturation, and transcutaneous CO2 (TcCO2) measurements were made over a 20-min period before and after the application of NPPV (inspiratory pressure of 10 to 12 cm H2O and expiratory pressure of 4 to 6 cm H2O).NPPV increased saturation from 88+/-2% to 90+/-1% (p0.05) and decreased TcCO2 from 51+/-3 mm Hg to 50+/-2 mm Hg (p0.05). Tidal volume increased from 219+/-20 mL to 256+/-37 mL (p=not significant [NS]) and respiratory rate decreased from 24+/-2 to 18+/-1 (p0.01). Minute ventilation decreased from 5.3+/-0.8 L/min to 4.6+/-0.6 L/min (p=0.08). There was no change in duty cycle (32+/-5% to 34+/-5%, p=NS). In two patients, esophageal pressure measurements were also recorded. There was a decrease in pressure from -21+/-1 cm H2O to -11+/-2 cm H2O and -14+/-1 cm H2O to -7+/-1 cm H2O.In patients with stable, severe cystic fibrosis, NPPV (1) acutely improves gas exchange, (2) decreases minute ventilation, suggesting either a reduction in CO2 production or an increase in alveolar ventilation, and (3) reduces work of breathing.

Objective Quality of life (QOL) studies of lung transplant recipients indicate that there are improvements following transplantation. More recently, there has been some suggestion that certain QOL issues are different for men and women. The purpose of the present study was to examine changes in QOL, body satisfaction, and sexual functioning in women lung transplant recipients. Study population Seven prelung transplant (PRE) and 34 postlung transplant (POST) women. Main outcome measures The RAND-36 Health Survey, Body Cathexis Scale, Derogatis Sexual Functioning Inventory, Hospital Depression and Anxiety Scale, Rosenberg Self-Esteen Scale, and an open-ended questionnaire. Results Higher scores were found in the POST group with respect to general health and role limitations due to physical health. We were unable to detect significant differences between the groups with respect to emotional well-being, role limitations due to emotional health, and social functioning. There were significant differences between the PRE and the POST body satisfaction scores. Although there was no significant difference in overall sexual functioning, recipients in the PRE group reported higher sex drive. Eleven of the POST recipients (52%;) scored below the 10th percentile in overall sexual functioning. Conclusions Overall QOL improves following lung transplantation; however, the lack of differences in many domains of QOL raises the concern that women lung transplant recipients may continue to have significant impairments, including those regarding sexuality and body satisfaction.