Primary Care COPD Patients Compared with Large Pharmaceutically-Sponsored COPD Studies : An UNLOCK Validation Study
TL;DR: Primary care COPD patients stand out from patients enrolled in LPCS in terms of gender, lung function, quality of life and exacerbations, as hitherto unknown GOLD I exacerbation characteristics are revealed.
Abstract: Background: Guideline recommendations for chronic obstructive pulmonary disease (COPD) are based on the results of large pharmaceutically-sponsored COPD studies (LPCS). There is a paucity of data on disease characteristics at the primary care level, while the majority of COPD patients are treated in primary care. Objective: We aimed to evaluate the external validity of six LPCS (ISOLDE, TRISTAN, TORCH, UPLIFT, ECLIPSE, POET-COPD) on which current guidelines are based, in relation to primary care COPD patients, in order to inform future clinical practice guidelines and trials. Methods: Baseline data of seven primary care databases (n = 3508) from Europe were compared to baseline data of the LPCS. In addition, we examined the proportion of primary care patients eligible to participate in the LPCS, based on inclusion criteria. Results: Overall, patients included in the LPCS were younger (mean difference (MD)-2.4; p = 0.03), predominantly male (MD 12.4; p = 0.1) with worse lung function (FEV1% MD -16.4; p = 1 and >= 2 exacerbations, although results were not statistically significant. Our findings add to the literature, as we revealed hitherto unknown GOLD I exacerbation characteristics, showing 34% of mild patients had >= 1 exacerbations per year and 12% had >= 2 exacerbations per year. The proportion of primary care patients eligible for inclusion in LPCS ranged from 17% (TRISTAN) to 42% (ECLIPSE, UPLIFT). Conclusion: Primary care COPD patients stand out from patients enrolled in LPCS in terms of gender, lung function, quality of life and exacerbations. More research is needed to determine the effect of pharmacological treatment in mild to moderate patients. We encourage future guideline makers to involve primary care populations in their recommendations.
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TL;DR: It is strongly believed that it is always better to avoid a therapeutic step-up progression when it is not needed rather than being forced subsequently into a step-down approach in which the outcome is always unpredictable.
Abstract: Chronic obstructive pulmonary disease (COPD) guidelines and strategies suggest escalating treatment, mainly depending on the severity of airflow obstruction. However, some de-escalation of therapy in COPD would be appropriate, although we still do not know when we should switch, step-up or step-down treatments in our patients. Unfortunately, trials comparing different strategies of step-up and step-down treatment (e.g. treatment initiation with one single agent and then further step-up if symptoms are not controlled versus initial use of double or triple therapy, possibly with lower doses of the individual components, or the role of N-acetylcysteine in combination therapy for a step-down approach) are still lacking. In general, there is a large and often inappropriate use of the inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination. However, the withdrawal of the ICS in COPD patients at low risk of exacerbation can be safe, provided that patients are under regular treatment with long-acting bronchodilators. Maximising the treatment in patients with a degree of clinical instability by including an ICS in the therapeutic regimen is useful to control the disease, but may not be needed during periods of clinical stability. In patients with severe but stable COPD, the withdrawal of the ICS from triple therapy [LABA + long-acting muscarinic antagonist (LAMA) + ICS] is possible, but not when the patient has been hospitalised for an acute exacerbation of COPD. We must still establish how long we should wait before withdrawing the ICS. It is still unclear whether the same is true when only the LABA or the LAMA is withdrawn while continuing treatment with the other bronchodilator and the ICS. In any case, we strongly believe that it is always better to avoid a therapeutic step-up progression when it is not needed rather than being forced subsequently into a step-down approach in which the outcome is always unpredictable.
34 citations
Cites background from "Primary Care COPD Patients Compared..."
...knowledge (UNLOCK) study, 12 % of GOLD I (mild COPD) European patients in primary care were frequent exacerbators (two or more AECOPDs yearly), and 34 % exacerbated at least once yearly [13]....
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TL;DR: Risks of coronary heart disease and heart failure were increased in asthma, COPD and ACO and it is suggested that cardiovascular risk factors should be assessed systematically in individuals with obstructive airway disease with the potential to facilitate targeted treatments.
Abstract: Introduction We investigated risk of coronary heart disease and heart failure in phenotypes of obstructive airway disease. Methods Among 91 692 participants in the Copenhagen General Population Study, 42 058 individuals were classified with no respiratory disease, and 11 988 individuals had different phenotypes of obstructive airways disease: asthma with early onset or late-onset, chronic obstructive pulmonary disease (COPD) with forced expiratory volume in one second (FEV1) above or below 50% of predicted value (%p) or asthma-COPD overlap (ACO). Results During a mean follow-up of 5.7 years we registered 3584 admissions for coronary heart disease and 1590 admissions for heart failure. Multivariable Cox regression analyses of time to first admission were used with a two-sided p value of 0.05 as significance level. Compared with no respiratory disease the highest risks of coronary heart disease and heart failure were observed in ACO with late-onset asthma and FEV1 Conclusions Risks of coronary heart disease and heart failure were increased in asthma, COPD and ACO. In asthma, the risk of coronary heart disease depended on presence of allergy. We suggest that cardiovascular risk factors should be assessed systematically in individuals with obstructive airway disease with the potential to facilitate targeted treatments.
30 citations
TL;DR: Compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs, which found rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent.
Abstract: Guidelines for chronic obstructive pulmonary disease (COPD) management are based largely on results from double-blind randomised controlled trials (RCTs) of efficacy. These trials have high internal validity and test whether a drug is efficacious, but they are conducted in highly selected populations that may differ significantly from patients with COPD seen in routine practice.We compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs. We also calculated the proportion of SLS patients who would have been eligible for inclusion in an efficacy RCT by applying the inclusion criteria used in efficacy trials of combination treatments.SLS patients were older, included more females and more current smokers, had more comorbidities (including asthma), and had more often experienced exacerbations prior to inclusion. In the SLS, rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent. A maximum of 30% of patients enrolled in the SLS would have been eligible for a phase IIIa regulatory exacerbation study.Patients in large COPD efficacy RCTs have limited representativeness compared with an effectiveness trial. This should be considered when interpreting efficacy RCT outcomes and their inclusion into guidelines.
29 citations
TL;DR: In a population-based sample, subjects with COPD had a reduced physical performance, a more impaired disease-specific health status and were more socially deprived compared to non-COPD subjects.
Abstract: Chronic obstructive pulmonary disease (COPD) is associated with substantial health impact that may already become apparent in early disease. This study aims to examine the features of subjects with COPD in a Dutch population-based sample and compare their physical status, mental status, and social status to non-COPD subjects. This study made use of Longitudinal Aging Study Amsterdam (LASA) data. Demographics, clinical characteristics, self-reported diseases, post-bronchodilator spirometry, physical, mental, and social status were assessed. A number of 810 subjects (50.5% male, mean age 60.5 ± 2.9 years) were included. Subjects with COPD (n = 68, mean FEV1 67.6 [IQR 60.4–80.4] %.) had a slower walking speed than non-COPD subjects, p = 0.033. When compared to non-COPD subjects, COPD subjects gave a lower rating on their health (physical subscale of SF-12: 15 [IQR 16.0–19.0] vs. 18 [IQR 11.0–17.0] points) and life (EQ5D VAS: 75 [IQR 70.0–90.0] vs. 80 points [IQR 65.0–85.5]) surveys. COPD subjects also had a more impaired disease-specific health status (CAT: 9.5 ± 5.9 vs. 6.7 ± 5.2, respectively), were less likely to have a partner (69% vs. 84%, respectively) and received emotional support less often (24% vs. 36%, respectively) compared to non-COPD subjects (All comparisons p < 0.001). In a population-based sample, subjects with COPD had a reduced physical performance, a more impaired disease-specific health status and were more socially deprived compared to non-COPD subjects. These impairments need to be taken into consideration when setting up a management program for patients with mild COPD. Patients with early-stage chronic lung disease need holistic support to limit the physical, mental and social impacts of the condition. There is more to chronic obstructive pulmonary disease (COPD) than persistent airflow limitation; systemic effects, including loss of muscle strength and higher risk of heart conditions, mental health and social problems can manifest from the early stages. Frits Franssen at CIRO, the Netherlands, and co-workers interviewed 810 participants aged 55–65 from the Longitudinal Aging Study Amsterdam to investigate the physical, mental and social status of COPD sufferers and compare them with healthy controls. Those with COPD were more likely to walk slower, tire easily and perceive themselves as having poor overall health. Socially, COPD patients were less likely to have long-term partners and felt the need for more emotional support than their healthy peers.
29 citations
TL;DR: The majority of studies showed that pharmacologic COPD maintenance treatment is cost effective, but most studies poorly represented the cost effectiveness of real-life medication use.
Abstract: Background
Worldwide, chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic lung disease with considerable clinical and socioeconomic impact. Pharmacologic maintenance drugs (such as bronchodilators and inhaled corticosteroids) play an important role in the treatment of COPD. The cost effectiveness of these treatments has been frequently assessed, but studies to date have largely neglected the impact of treatment sequence and the exact stage of disease in which the drugs are used in real life.
27 citations
Cites background from "Primary Care COPD Patients Compared..."
...As a result, less than half of the real-life primary care COPD population (42 %) [53] would be eligible to participate in the UPLIFT trial that was frequently used as basis for CEAs of tiotropium [54, 55]....
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References
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University of Manchester1, University of Barcelona2, St George's Hospital3, University of Marburg4, University of Texas Health Science Center at San Antonio5, Imperial College London6, University of Modena and Reggio Emilia7, University of Michigan8, Hokkaido University9, University of British Columbia10
TL;DR: It is recommended that spirometry is required for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation.
Abstract: Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.
17,023 citations
TL;DR: Representatives from many countries serve as a network for the dissemination and implementation of programs for diagnosis, management, and prevention of COPD.
Abstract: Representatives from many countries serve as a network for the dissemination and implementation of programs for diagnosis, management, and prevention of COPD. The GOLD Board of Directors is grateful to the many GOLD National Leaders who participated in discussions of concepts that appear in GOLD reports.
3,165 citations
TL;DR: The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance, and there were significant benefits in all other outcomes among these patients.
Abstract: We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 μg plus fluticasone propionate at a dose of 500 μg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed. Results Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combinationtherapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P = 0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo). Conclusions The reduction in death from all causes among patients with COPD in the combinationtherapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216.)
3,037 citations
TL;DR: The St George's Respiratory Questionnaire is a standardized self-completed questionnaire for measuring impaired health and perceived well-being in airways disease and the background and rationale for its development are discussed together with an analysis of its performance.
2,621 citations
"Primary Care COPD Patients Compared..." refers methods in this paper
...We used the St Georges Respiratory Questionnaire (SGRQ) which is designed to measure health- related quality of life in patients with asthma and COPD [34]....
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TL;DR: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype, which has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity.
Abstract: BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
2,459 citations
"Primary Care COPD Patients Compared..." refers background in this paper
...Selection for large COPD studies The proportion of patients from primary care that would be eligible to be included in the LPCS ranged from 17% (TRISTAN trial) to 42% (ECLIPSE and UPLIFT study) (Table 7)....
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...In addition to five large trials, we decided to include the ECLIPSE cohort study as well, because this is an important observational study often cited in guidelines, especially with regard to exacerbation frequency patterns....
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...Exacerbation data Individual datasets: UNLOCK studies reporting exacerbation data were compared with baseline data of the ISOLDE, TRISTAN, TORCH, UPLIFT and ECLIPSE studies (Table 3)....
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...The proportion of primary care patients eligible for inclusion in LPCS ranged from 17% (TRISTAN) to 42% (ECLIPSE, UPLIFT)....
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...Overall mean MRC scores were similar in the UNLOCK studies compared to ECLIPSE: 2.1 (0.8) and 2.7 (1.1), respectively....
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