Bias due to withdrawal in long-term randomised trials in COPD: evidence from the TORCH study

Introduction: Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates. Objectives: We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial. Methods: We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal. Results: There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal. Conclusion: Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal. Please cite this paper as: Vestbo J, Anderson JA, Calverley PMA, Celli B, Ferguson GT, Jenkins C, Yates JC, Jones PW. Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study. Clin Respir J 2011; 5: 44–49.     

The diagnostic accuracies of chronic obstructive pulmonary disease (COPD) in general practice: The results of the MAGIC (Manchester Airways Group Identifying COPD) study.

BACKGROUND: Although it is generally accepted that chronic obstructive pulmonary disease (COPD) is underdiagnosed, there is little objective information concerning the size of the problem in the UK. METHOD: Patients from two general practices were offered spirometry if they were aged 30 or older, had reported ever smoking in one of four postal respiratory surveys (1993-2001), and/or reported four or more symptoms or risk factors in 2001 indicating likely obstructive airways disease. RESULTS: Of 2646 subjects invited, 871 attended and 825 had adequate spirometry results for analysis. In all, 163 patients had spirometrically-confirmed COPD; 103 of these (63.2%) had no recorded COPD in their practice records, including 14 out of 31 (45.2%) whose spirometry results classified them as having severe or very severe COPD. CONCLUSION: This study found a considerable under-recording of COPD in two general practices. This may be due to a combination of administrative and diagnostic problems (including the under-use of spirometers), and a reluctance of patients to present with their symptoms. These results have important implications in terms of unmet need and resource utilisation.     

The Japan Morning Surge-1 (JMS-1) study: protocol description.

Morning blood pressure is reported to be more closely related to hypertensive organ damages such as left ventricular mass index, microalbuminuria and silent cerebral infarcts, than blood pressure at other times of the day. Morning blood pressure may play an important role in the pathogenesis of hypertensive target organ damage. Increased sympathetic nerve activity is reported to be one of the mechanisms of morning hypertension; however, there are no available data that show whether strict home blood pressure control, especially in the morning period, can reduce target organ damage. The Japan Morning Surge-1 (JMS-1) study includes hypertensive outpatients with elevated morning systolic blood pressure (>or=135 mmHg) as assessed by self-measured blood pressure monitoring at home. All enrolled patients are under stable antihypertensive medication status. Exclusion criteria are arrhythmia, chronic inflammatory disease, and taking alpha-blockers or beta-blockers. The target number of patients to be enrolled in the JMS-1 study is 600, and the aim is to evaluate differences in the markers of hypertensive target organ damage, such as brain natriuretic peptide and the urinary albumin excretion/creatinine ratio. All of the patients are randomized to an experimental group or a control group, with randomization to be carried out by telephone interviews with the patients' physicians. In the experimental group, patients begin taking additional antihypertensive medication just before going to bed. This consists of doxazosin 1 mg/day, which then is increased to 2 mg/day and 4 mg/day, with a beta-blocker added after a 1-month interval until the morning systolic blood pressure is controlled to less than 135 mmHg. Patients in the control group continue the treatment they are receiving at the enrollment for 6 months. Blood pressure levels, adverse effects, and hypertensive target organ damage before and after the study are evaluated. In the JMS-1 study, we will evaluate whether strict morning blood pressure control by sympathetic nervous system blockade using an alpha-blocker, doxazosin, and with the addition of a beta-blocker if needed, can reduce hypertensive target organ damage.     

Use of a preference-based measure of health (EQ-5D) in COPD and asthma

BACKGROUND: EQ-5D is a generic preference-based measure of health that can help to understand the impact of asthma and chronic obstructive pulmonary disease (COPD). The purpose of this paper was to synthesize literature on the validity and reliability of EQ-5D use in studies of asthma and COPD, and estimate EQ-5D utility scores associated with stage of disease. METHODS: A structured search was conducted in EMBASE and MEDLINE (1988-2007) using keywords relevant to respiratory disease and EQ-5D. Original research studies in asthma or COPD that reported EQ-5D results and/or psychometric properties were included. RESULTS: Studies that reported psychometric properties supported the construct validity, test-retest reliability, and responsiveness of EQ-5D in asthma (seven studies) and COPD (nine studies), although some evidence of ceiling effects were observed in asthma studies. In asthma studies that reported summary scores (n=11), EQ-5D index-based scores ranged from 0.42 (SD 0.30) to 0.93 (SD not reported). In COPD studies (n=8), scores ranged from 0.52 (SD 0.16) to 0.84 (SD 0.15). While few asthma studies reported scores by severity level, sufficient studies in COPD were available to calculate pooled mean utility scores according to GOLD stage: stage I=0.74 (0.62-0.87), stage II=0.74 (0.66-0.83), stage III=0.69 (0.60-0.78) and stage IV=0.61 (0.44-0.77) (most severe). CONCLUSIONS: Evidence generally supported the validity and reliability of EQ-5D in asthma and COPD. Utility scores associated with COPD stage may be useful for modeling health outcomes in economic evaluations of treatments for COPD.     

Resource Use Study In COPD (RUSIC): A prospective study to quantify the effects of COPD exacerbations on health care resource use among COPD patients

BACKGROUND:

There is increasing interest in health care resource use (HRU) in Canada, particularly in resources associated with acute exacerbations of chronic obstructive pulmonary disease (COPD).

OBJECTIVE:

To identify HRU due to exacerbations of COPD.

METHODS:

A 52-week, multicentre, prospective, observational study of HRU due to exacerbations in patients with moderate to severe COPD was performed. Patients were recruited from primary care physicians and respirologists in urban and rural centres in Canada.

RESULTS:

In total, 524 subjects (59% men) completed the study. Their mean age was 68.2±9.4 years, with a forced expiratory volume in 1 s of 1.01±0.4 L. Patients had significant comorbidities. There were 691 acute exacerbations of COPD, which occurred in 53% of patients: 119 patients (23%) experienced one acute exacerbation, 70 patients (13%) had two acute exacerbations and 89 patients (17%) had three or more acute exacerbations. Seventy-five patients were admitted to hospital, with an average length of stay of 13.2 days. Fourteen of the patients spent time in an intensive care unit (average length of stay 5.6 days). Factors associated with acute exacerbations of COPD included lower forced expiratory volume in 1 s (P<0.001), high number of respiratory medications prescribed (P=0.037), regular use of oral corticosteroids (OCSs) (P=0.008) and presence of depression (P<0.001). Of the 75 patients hospitalized, only 53 received OCSs, four received referral for rehabilitation and 15 were referred for home care.

CONCLUSIONS:

The present study showed a high prevalence of COPD exacerbations, which likely impacted on HRU. There was evidence of a lack of appropriate management of exacerbations, especially with respect to use of OCSs, and referral for pulmonary rehabilitation and home care.     

The defibrillator in acute myocardial infarction trial (DINAMIT): study protocol

BACKGROUND: The implantable cardioverter/defibrillator (ICD) has been shown to be superior to antiarrhythmic drug therapy for the secondary prevention of sudden cardiac death. Its role in the primary prevention of sudden death after myocardial infarction is unknown.Methods and Results The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) is a randomized, open-label, parallel-group comparison of ICD therapy versus no ICD therapy in selected survivors of acute myocardial infarction. It will test the hypothesis that reduction of sudden arrhythmogenic death by means of the ICD will result in reduction of overall mortality rates in patients at high risk after acute myocardial infarction. Accordingly, this international multicenter study aims to enroll patients shortly after their infarction (day 6 to day 40) who have reduced left ventricular function (left ventricular ejection fraction 相似文献   

The resynchronization therapy in narrow QRS study (RethinQ study): Methods and protocol design

Background Numerous trials have demonstrated the effectiveness of cardiac resynchronization therapy (CRT) as an adjunct to medical therapy for the relief of heart failure (HF) symptoms in patients with a wide QRS duration (QRSd). Current guidelines recommend CRT in patients with an EF <35%, medically refractory NYHA Class III–IV HF and QRSd ≥120 ms. Previous studies have demonstrated QRSd as a marker of electrical dyssynchrony fails to predict response to CRT. In addition, studies have demonstrated significant differences in QRSd post CRT between responders and non-responders. Moreover, smaller non-controlled studies demonstrated that HF patients with a narrow QRSd may benefit from CRT. A growing body of evidence suggests that echocardiographic criteria may be a better method to evaluate mechanical dyssynchrony (MD) which may predict those that will benefit from CRT, particularly those with a narrow QRSd. The Resynchronization Therapy In Narrow QRS (RethinQ) study will evaluate mechanical dyssynchrony using echocardiography (both M mode and TDI) as an eligibility requirement for CRT. Methods The RethinQ study is a prospective, multi-center, randomized, double blind controlled clinical study. The objective of the RethinQ study is to evaluate the effectiveness of CRT in patients with approved ICD indication, advanced HF (NYHA Classification III), narrow QRSd (<130 ms) and evidence of MD measured by echocardiography. Conclusion We hypothesize that patients with narrow QRS <130 ms, advanced HF, and MD as measured by echocardiography will benefit from CRT. An erratum to this article can be found at     

The effect of COPD health forecasting on hospitalisation and health care utilisation in patients with mild-to-moderate COPD

Exacerbations are a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) as well as having a large impact on health care utilisation (HCU). They are more frequent during periods of cold weather with a corresponding increase in hospital admissions. It has been hypothesised that COPD exacerbations and admissions can be reduced by predicting periods of cold weather coupled with patients' alerts and education. Healthy Outlook(?) service provided by the Meteorological Office, UK, was used in patients with mild-to-moderate COPD who consented to participate from three primary care practices. Outcome measures included data relating to hospital admissions for acute exacerbations as well as HCU for these patients during the intervention period (1 Nov 2008-31 Mar 2009) and compared for the same patients and same period 12 months earlier (1 Nov 2007-31 Mar 2008). A cost analysis comparing treatment cost per patient for the two periods was also conducted. A total of 157 (34% of target COPD population) patients took part in the project, with five weather alerts generated (first alert reached 150 patients; second reached 146; third reached 138 patients; fourth reached 137 patients; and the fifth reached 125 patients) during the intervention period. There was a non-statistically-significant increase in hospital admissions per patient (0.07-0.076; p = 0.83). The number of general practice visits per patient dropped from 4.9 to 3.8 (p = 0.001), with drop in average number of visits to patients by out-of-hours services from 0.52-0.14 (p = 0.013). The average number of home consultations provided by general practice increased from 0.05 to 0.92 (p = 0.001). Cost per patient increased by an average of ￡142 (95% CI -￡128 to ￡412). This anticipatory care model was not associated with reduction in admissions from COPD exacerbations. Further research is required to fully understand its role in the management of patients with COPD.     

Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study

ObjectivesIt was previously shown that dehydroepiandrosterone (DHEA) reverses chronic hypoxia-induced pulmonary hypertension (PH) in rats, but whether DHEA can improve the clinical and hemodynamic status of patients with PH associated to chronic obstructive pulmonary disease (PH-COPD) has not been studied whereas it is a very severe poorly treated disease.Patients and methodsEight patients with PH-COPD were treated with DHEA (200 mg daily orally) for 3 months. The primary end-point was the change in the 6-minute walk test (6-MWT) distance. Secondary end-points included pulmonary hemodynamics, lung function tests and tolerance of treatment.ResultsThe 6-MWT increased in all cases, from 333 m (median [IQR]) (257; 378) to 390 m (362; 440) (P < 0.05). Mean pulmonary artery pressure decreased from 26 mmHg (25; 27) to 21.5 mmHg (20; 25) (P < 0.05) and pulmonary vascular resistance from 4.2 UI (3.5; 4.4) to 2.6 UI (2.5; 3.8) (P < 0.05). The carbon monoxide diffusing capacity of the lung (DLCO % predicted) increased significantly from 27.4% (20.1; 29.3) to 36.4% (14.6; 39.6) (P < 0.05). DHEA treatment did not change respiratory parameters of gas exchange and the 200 mg per day of DHEA used was perfectly tolerated with no side effect reported.ConclusionDHEA treatment significantly improves 6-MWT distance, pulmonary hemodynamics and DLCO of patients with PH-COPD, without worsening gas exchange, as do other pharmacological treatments of PH (trial registration NCT00581087).     

The economic burden of chronic obstructive pulmonary disease (COPD) in a U.S. Medicare population

RATIONALE: Although the economic burden of COPD has gained attention in recent years, data on the costs of COPD among U.S. Medicare beneficiaries are lacking. METHODS: This study used administrative claims and eligibility records from a large U.S. multi-state Medicare managed care database. Study patients were 65+ years of age with paid claims during 2004. The COPD cohort comprised patients with 1+ inpatient/ER claims or 2+ outpatient claims (>30 days apart) for COPD (ICD-9-CM codes 491.xx, 492.x, 496). The comparison cohort included patients without COPD matched 3:1 to the COPD cohort on age, sex, enrollment months, and Medicare plan. Excess costs of COPD were estimated as the difference in overall health plan payments between the two cohorts during 2004. Attributable costs were calculated using medical claims with listed diagnoses of COPD or other respiratory-related conditions and pharmacy claims for respiratory medications. RESULTS: A total of 8370 patients were included in the COPD cohort and were matched to 25,110 comparison cohort patients. For both groups, mean (SD) age was 78 (8) years, 54% were female, and duration of eligibility was 11 (2) months. COPD patients were more likely to utilize healthcare services and had excess total healthcare costs about $20,500 higher (P<0.0001) than the comparison cohort. Comorbidities were high in the COPD cohort, accounting for 46% of the observed excess cost. The attributable cost of COPD averaged about $6,300; other respiratory-related costs averaged about $4,400. CONCLUSION: In this U.S. Medicare managed care population, COPD posed a substantial burden in terms of both respiratory-related and total healthcare costs. A comparison of these cost-of-illness estimates to those for elderly COPD patients in other countries would be of great interest, given the increasing age of populations in most Western countries.     

The effectiveness of a bronchial drainage technique (ELTGOL) in COPD exacerbations

Background and objective:   Exacerbations of COPD are often characterized by increased mucus production that is difficult to treat and worsens patients' outcome. This study evaluated the efficacy of a chest physiotherapy technique (expiration with the glottis open in the lateral posture, ELTGOL) during acute exacerbations of COPD using as outcome measures sputum volume, length of hospitalization, reduction in dyspnoea (Borg score), improvement in quality of life (assessed by the St George Respiratory Questionnaire) and incidence of COPD exacerbations during follow up.
Methods:   The study recruited 59 patients hospitalized for the treatment of acute exacerbation of COPD, who were randomly assigned to a control group and an intervention group. The control group was treated with standard medical therapy while the intervention group was treated with ELTGOL plus medical therapy. A subgroup of patients was followed for 6 months to verify the effects on COPD exacerbations and need for hospitalizations.
Results:   At the time of hospital discharge there was no significant difference between the two groups in the outcome measures, with the exception of the Borg score, which was significantly improved in the ELTGOL group (4.3 ± 1.5 in the control group vs 3.0 ± 1.8 in the ELTGOL group, P  = 0.004). After 6 months there was no significant difference in the other measured parameters between a subset of the groups available for follow up. During follow up, the ELTGOL group had numerically fewer exacerbations and less need for hospitalization though differences were not statistically significant.
Conclusions:   Chest physiotherapy using the ELTGOL technique has a limited role in patients with mild exacerbation of moderate to severe COPD with a tendency towards fewer exacerbations and hospitalizations.     

The relative survival of COPD patients on long-term oxygen therapy in Australia: A comparative study

OBJECTIVE: The survival of patients with COPD on long-term oxygen therapy (LTOT) has been studied using both univariate and multivariate procedures. There has been only one previous report of relative survival. Relative survival takes into account the risk of death due to increasing age. The objective of this study was to determine the relative survival of a group of South Australian patients prescribed home oxygen therapy for COPD. METHODOLOGY: A method proposed by Hakulinen was used to determine relative survival. The results were compared with the relative survival of a similar group of French COPD patients. RESULTS: A total of 505 COPD patients (249 males, 256 females) were included in the survival analysis. Relative survival corrected for life expectancy was 78.1%, 56.7%, 23.1% and 1.1% at 1, 2, 5 and 10 years, respectively, which was less than that reported in a recent French study of comparable patients. Our patients were similar with respect to age, severity of hypoxaemia and oxygen usage to those in the French study. CONCLUSIONS: Using relative survival analysis, Australian LTOT patients with COPD have worse outcomes than some European patients. Factors contributing to the excess mortality in South Australian COPD patients need to be investigated.     

The COPD Biomarker Qualification Consortium (CBQC)

Abstract

Knowledge about the pathogenesis and pathophysiology of chronic obstructive pulmonary disease (COPD) has advanced dramatically over the last 30 years. Unfortunately, this has had little impact in terms of new treatments. Over the same time frame, only one new class of medication for COPD has been introduced. Even worse, the rate at which new treatments are being developed is slowing. The development of new tools for the assessment of new treatments has not kept pace with understanding of the disease. In part, this is because drug development tools require a regulatory review, and no interested party has been in a position to undertake such a process. In order to facilitate the development of novel tools to assess new treatments, the Food and Drug Administration, in collaboration with the COPD Foundation, the National Heart Lung and Blood Institute and scientists from the pharmaceutical industry and academia conducted a workshop to survey the available information that could contribute to new tools. Based on this, a collaborative project, the COPD Biomarkers Qualification Consortium, was initiated. The Consortium in now actively preparing integrated data sets from existing resources that can address the problem of drug development tools for COPD.