Dacheng Liu

Bronchodilator responsiveness in patients with COPD

The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease (COPD) patients, and depends upon the type and dose of bronchodilator and the timing of administration. Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, a 4-yr randomised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function. After wash-out of respiratory medications, patients received 80 μg ipratropium followed by 400 μg salbutamol. Spirometry was performed before and 90 min following ipratropium administration. The criteria used for forced expiratory volume in one second (FEV1) responsiveness were: ≥12% increase over baseline and ≥200 mL; ≥15% increase over baseline; and ≥10% absolute increase in the percentage predicted value. Of the patients, 5,756 had data meeting the criteria for analysis (age 64.5 yrs; 75% male; baseline FEV1 1.10 L (39.3% predicted) and forced vital capacity (FVC) 2.63 L). Compared with baseline, mean improvements were 229 mL in FEV1 and 407 mL in FVC. Of these patients, 53.9% had ≥12% and ≥200 mL improvement in FEV1, 65.6% had ≥15% improvement in FEV1, and 38.6% had ≥10% absolute increase in FEV1 % pred. The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators.

Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease.

RATIONALE 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. OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients. METHODS 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)/FVC <or=70%). Mortality was evaluated during treatment and with follow-up of discontinued patients. Cause of death was adjudicated by an endpoint committee. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality, with the effect being most prominent in the cardiac and respiratory systems.

Exacerbation frequency and course of COPD.

Background 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.

Cause-specific mortality adjudication in the UPLIFT® COPD trial: Findings and recommendations

Mortality 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.

Efficacy of tiotropium in COPD patients from Asia: A subgroup analysis from the UPLIFT trial

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.

Efficacy of Tiotropium in COPD Patients with FEV1 ≥ 60% Participating in the UPLIFT® Trial

Abstract GOLD stage II COPD encompasses patients with FEV1 50–80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV1 <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted from UPLIFT®. Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT® cohort, 1,210 (632 tiotropium, 578 control) had baseline post-bronchodilator FEV1 ≥60% predicted (range 60–78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post-bronchodilator FEV1 decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV1 and FVC improvements for tiotropium versus control were 87–127 mL and 139–186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropium–control) were 2.0–3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of ≥4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 [0.71, 0.96]) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 [0.45, 0.96]). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV1 ≥60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339).

Adverse health consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial

BackgroundThe rate of decline in forced expiratory volume in 1 second (FEV1) is representative of the natural history of COPD. Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints.MethodsRetrospective analysis of UPLIFT® trial (four-year, randomized, double-blind, placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [COPD], n = 5993). Decline of FEV1 was analysed with random co-efficient regression. Patients were categorised according to quartiles based on the rate of decline (RoD) in post-bronchodilator FEV1. The St Georges Respiratory Questionnaire (SGRQ) total score, exacerbations and mortality were assessed within each quartile.ResultsMean (standard error [SE]) post-bronchodilator FEV1 increased in the first quartile (Q1) by 37 (1) mL/year. The other quartiles showed annualised declines in FEV1 (mL/year) as follows: Q2 = 24 (1), Q3 = 59 (1) and Q4 = 125 (2). Age, gender, respiratory medication use at baseline and SGRQ did not distinguish groups. The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers. The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD, but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 (Q1 = 19.5% [tiotropium], 26% [control]; Q4 = 33.8% [tiotropium] and 33.1% [control]). Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile. The group with the largest RoD had the highest mortality.ConclusionPatients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific (or more aggressive) approaches to management may be needed.Trial RegistrationClinicalTrials.gov number, NCT00144339

Bronchodilator responsiveness in patients with COPD (data from the UPLIFT trial).

Vol XIV N.o 4 Julho/Agosto 2008 Resumo No início do estudo, foi realizada espirometria antes e depois de 80 μg de ipratrópio e 400 μg de salbutamol, administrados 90 e 30 minutos antes, respectivamente. A administração de dois broncodilatadores e a sua temporalidade teve como objectivo atingir a broncodilatação máxima ou quase máxima. O FEV1 basal após esta broncodilatação, no estudo UPLIFT, permitiu: – examinar a resposta broncodilatadora aguda numa grande coorte de doentes com DPOC moderada a muito grave; – determinar o que pode ser considerado critério de resposta usando vários critérios de reversibilidade; – avaliar as características dos doentes com e sem reversibilidade. A resposta broncodilatadora em doentes com DPOC (dados do estudo UPLIFT)

Recruiting Patients After Hospital Discharge for Acute Exacerbation of COPD: Challenges and Lessons Learned

Background: Hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased mortality and decreased quality of life. Replicate hospital discharge studies were initiated to examine efficacy and safety of once-daily tiotropium HandiHaler® versus placebo, in addition to usual care, in patients discharged from the hospital after an AECOPD. Methods: Both studies were randomized, placebo-controlled, double-blind, parallel-group, multicenter, with inclusion/exclusion criteria providing a diverse COPD patient cohort hospitalized for ≤14 days with AECOPD. Patients received tiotropium or placebo, initiated within 10 days post-discharge. Target recruitment was 604 patients/study and planned duration was event-driven, ending after 631 clinical outcome events across both studies. Inability to reach targeted site numbers and patient recruitment/retention difficulties led to early study termination. Recruitment/retention challenges and protocol amendment impacts were assessed qualitatively to understand the major issues. Results: Over 18 months, 219 patients were enrolled; 158 were randomized and 61 failed screening. Premature treatment discontinuation occurred in 49(31%) patients, of whom 20(41%) completed health status follow-up. All-cause, 30-day hospital readmission was low (8[5%] patients). A total of 154(98%) patients had a concomitant diagnosis and most took pulmonary medication pre-randomization (143[91%]) and during study treatment (144[92%]). Inclusion/exclusion criteria changes failed to improve recruitment. Recruitment/retention barriers were identified, relating to patient and clinician factors, health care infrastructure, and clinical practices. Conclusions: Although AECOPD hospitalization is clinically important and incurs high costs, significant challenges exist in studying this population in clinical trials after hospitalization. Studies are needed to evaluate effective management of AECOPD patients at high risk of adverse clinical outcomes.