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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
TL;DR: Having another chronic respiratory disease beside COPD showed the highest risk for developing a new exacerbation and several chronic comorbidities were associated with having frequent exacerbations and increased exacerbation risk.
Abstract: COPD often coexists with chronic conditions that may influence disease prognosis. We investigated associations between chronic (co)morbidities and exacerbations in primary care COPD patients. Retrospective cohort study based on 2012–2013 electronic health records from 179 Dutch general practices. Comorbidities from patients with physician-diagnosed COPD were categorized according to International Classification of Primary Care (ICPC) codes. Chi-squared tests, uni- and multivariable logistic, and Cox regression analyses were used to study associations with exacerbations, defined as oral corticosteroid prescriptions. Fourteen thousand six hundred three patients with COPD could be studied (mean age 67 (SD 12) years, 53% male) for two years. At baseline 12,826 (88%) suffered from ≥1 comorbidities, 3263 (22%) from ≥5. The most prevalent comorbidities were hypertension (35%), coronary heart disease (19%), and osteoarthritis (18%). Several comorbidities showed statistically significant associations with frequent (i.e., ≥2/year) exacerbations: heart failure (odds ratio [OR], 95% confidence interval: 1.72; 1.38–2.14), blindness & low vision (OR 1.46; 1.21–1.75), pulmonary cancer (OR 1.85; 1.28–2.67), depression 1.48; 1.14–1.91), prostate disorders (OR 1.50; 1.13–1.98), asthma (OR 1.36; 1.11–1.70), osteoporosis (OR 1.41; 1.11–1.80), diabetes (OR 0.80; 0.66–0.97), dyspepsia (OR 1.25; 1.03–1.50), and peripheral vascular disease (OR 1.20; 1.00–1.45). From all comorbidity categories, having another chronic respiratory disease beside COPD showed the highest risk for developing a new exacerbation (Cox hazard ratio 1.26; 1.17–1.36). Chronic comorbidities are highly prevalent in primary care COPD patients. Several chronic comorbidities were associated with having frequent exacerbations and increased exacerbation risk.

88 citations


Cites background from "Primary Care COPD Patients Compared..."

  • ..., the COPD population without selection of any kind, which is unprecedented and impossible to derive from clinical trial populations [21]....

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Journal ArticleDOI
TL;DR: It is concluded that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD.
Abstract: Introduction: Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of impr ...

82 citations


Cites methods from "Primary Care COPD Patients Compared..."

  • ...Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL....

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  • ...We conclude that the chronic bronchitis phenotype and musculoskeletal symptoms in COPD patients indicate a higher risk of low HRQL....

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  • ...The outcomes of CAT and SGRQ show a fairly good correlation in patients with COPD.7 Many COPD patients suffer from more than one condition,8 and comorbidities are known to influence mortality, morbidity, and hospitalizations as well as HRQL.9–11 The associations of cardiovascular disease, depression, and underweight with poor HRQL are well documented,12–15 although our understanding of these associations remains limited....

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  • ...Depression is common in COPD.8 The finding that depression influenced EQ-5D index in our study is consistent with and confirms previous studies, in which depression in COPD was associated with worse HRQL as assessed using EQ-5D,31 SGRQ,32 and Clinical COPD Questionnaire (CCQ).14 Heart disease influences HRQL when estimated by both the generic instrument SF-12 and the disease-specific instrument SGRQ in COPD.12,15 In our study, both generic and disease-specific HRQL instruments were used, but we were not able to identify an association of cardiovascular disease and lower HRQL. Underweight is associated with worse SGRQ score in COPD,13 but no associations with HRQL were found in the present study....

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  • ...It cannot be excluded that the use of a broad definition of cardiovascular disease may have masked an association between cardiovascular disease and HRQL....

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Journal ArticleDOI
01 Mar 2017-Chest
TL;DR: A multifaceted approach is required to address COPD in women, including greater awareness, minimization of risk, and further elucidation of the sex-specific factors that affect risk, disease progression, and treatment success.

82 citations


Cites background from "Primary Care COPD Patients Compared..."

  • ...There is a need for future trials to include more female participants and to prespecify subanalyses on the basis of sex to study whether biological differences affect the way women respond to medications and therapeutic strategies.(82) In addition, studies should consider the use of sex as a variable in its own right....

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  • ...Analyses suggest that clinical trial populations differ from real-world patients, particularly in sex distribution.(82) There is a need for future trials to include more female participants and to prespecify subanalyses on the basis of sex to study whether biological differences affect the way women respond to medications and therapeutic strategies....

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Journal ArticleDOI
TL;DR: This Commission summarises expert opinion from key stakeholders-patients, caregivers, and medical professionals, as well as representatives from health systems, insurance companies, and industry-to understand barriers to care delivery and propose potential solutions.

77 citations

Journal ArticleDOI
TL;DR: Patients at risk of exacerbation can be identified from routinely available, computerized primary care data and a robust, clinically based model to predict frequent exacerbation risk was developed.
Abstract: This study was funded by an unrestricted grant from the Respiratory Effectiveness Group (REG; www.effectivenessevaluation.org). Access to data from the Optimum Patient Care Research Database was co-funded by Research in Real-Life Ltd (RiRL, Cambridge, UK). The authors would like to thank Dr John Bukowski of WordsWorld Consulting for editorial assistance drafting this manuscript. Additional editorial support was provided by Elizabeth V Hillyer, DVM, funded by RiRL.

66 citations

References
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Journal ArticleDOI
TL;DR: Results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations.
Abstract: BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-tovery-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β 2-agonist is the preferred agent. We investi gated whether the anticholinergic drug tiotropium is superior to the β 2-agonist salmeterol in preventing exacerbations of COPD. METHODS In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we com pared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. RESULTS A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salme terol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (haz ard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P = 0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. CONCLUSIONS These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.)

632 citations


"Primary Care COPD Patients Compared..." refers methods in this paper

  • ...In the UPLIFT [30] and POET-COPD [14] studies, an exacerbation was defined as an increase in or the onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid....

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  • ...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....

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  • ...These studies were published in the year 2000 or later: the ISOLDE [9,24,25], TRISTAN [10], TORCH [11,26–29], UPLIFT [12,30], ECLIPSE [13,31,32] and POET-COPD [14] studies....

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  • ...Furthermore, step-by-step we applied the inclusion criteria of the trials [9,10,14,29,30,32] to the UNLOCK population and calculated the proportion of patients eligible for inclusion....

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Journal ArticleDOI
TL;DR: Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV(1) in patients with GOLD stage II COPD, suggesting that treatment of COPD should begin at an early stage of the disease.

462 citations


"Primary Care COPD Patients Compared..." refers result 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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  • ...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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  • ...Subgroup analysis of UPLIFT showed promising results of tiotropium in GOLD II patients on FEV1 decline [12], but inclusion was limited to patients with FEV1,70%, leading to incomplete representation of GOLD II....

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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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  • ...In the UPLIFT [30] and POET-COPD [14] studies, an exacerbation was defined as an increase in or the onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid....

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Journal ArticleDOI
TL;DR: In this paper, the effect of fluticasone propionate (FP) on exacerbations of chronic obstuctive pulmonary disease (COPD) is associated with worse health status.
Abstract: Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent ( 1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.

420 citations


Additional excerpts

  • ...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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  • ...Characteristic UNLOCK 1 NL UNLOCK 2 UK UNLOCK 3 NL UNLOCK 7 NL ISOLDE 2000 TRISTAN 2003 TORCH 2007 UPLIFT 2008 ECLIPSE 2010 Patients (N) 86 375 1665 902 370 * 361 * 6112 5992 2138 Mean exacerbation rate p/year 1.05 (1.3) 1.32 (1.6) 0.72 (1.1) 0.54 (1.19) 1.90 (2.63)* 1.30 * 1.0 (1.3) 0.85 (0.02)* 0.9 (1.2) $1 in preceding year, % (n/N) 55 (47/85) 59 (222/374) 43 (713/1661) 27 (174/636) 63* - 57 68* 47 $2 in preceding year, % (n,N) 29 (25/85) 33 (124/374) 19 (312/1661) 11 (72/636) - - 32 - 29 Data are baseline data and mean values (SD), unless stated otherwise....

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  • ...Definition of exacerbations: The definition of exacerbation used in the UNLOCK, ISOLDE [9], TRISTAN [10], TORCH [29] and ECLIPSE [32] studies was based on worsening of symptoms and the decision by a patient’s clinician (or by study personnel) to prescribe antibiotics or systemic corticosteroids, alone or in combination....

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  • ...These studies were published in the year 2000 or later: the ISOLDE [9,24,25], TRISTAN [10], TORCH [11,26–29], UPLIFT [12,30], ECLIPSE [13,31,32] and POET-COPD [14] studies....

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  • ...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....

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Journal ArticleDOI
TL;DR: In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages, and is an effective treatment option for patients with GOLD stage II COPD.
Abstract: Background: The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease. Methods: TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV 1 , 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ³ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937). Results: Compared with placebo, SFC improved post-bronchodilator FEV 1 : 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.

339 citations


Additional excerpts

  • ...Subsequent post-hoc analysis of the TORCH trial concluded that a combination of salmeterol and fluticasone propionate reduced exacerbations and FEV1 decline in patients with a FEV1 of 50–60% predicted [28]....

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Journal ArticleDOI
TL;DR: Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials, but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials.
Abstract: Randomised controlled trials (RCTs) must be internally valid (i.e., design and conduct must eliminate the possibility of bias), but to be clinically useful, the result must also be relevant to a definable group of patients in a particular clinical setting (i.e., they must be externally valid). Lack of external validity is the most frequent criticism by clinicians of RCTs, systematic reviews, and guidelines, and is one explanation for the widespread underuse in routine practice of many treatments that have been shown to be beneficial in trials and are recommended in guidelines [1]. Yet medical journals, funding agencies, ethics committees, the pharmaceutical industry, and governmental regulators seem to give external validity a low priority. Admittedly, whereas the determinants of internal validity are intuitive and can generally be worked out from first principles, understanding of the determinants of the external validity of an RCT requires clinical rather than statistical expertise, and often depends on a detailed understanding of the particular clinical condition under study and its management in routine clinical practice. However, reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice. The results of RCTs or systematic reviews will never be relevant to all patients and all settings, but they should be designed and reported in a way that allows clinicians to judge to whom the results can reasonably be applied. Table 1 lists some of the important potential determinants of external validity, each of which is reviewed briefly below. Many of the considerations will only be relevant in certain types of trials, for certain interventions, or in certain clinical settings, but they can each sometimes undermine external validity. Moreover, the list is not exhaustive and requires more detailed annotation and explanation than is possible in this short review. Table 1 Main Issues That Can Affect External Validity and Should Be Addressed in Reports of the Results of Randomised Controlled Trials or Systematic Reviews and Considered by Clinicians Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials [2], but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials. For example, broad eligibility criteria, limited collection of baseline data, and inclusion of centres with a range of expertise and differing patient populations have many advantages, but they can also make it very difficult to generalise the overall average effect of treatment to a particular clinical setting.

321 citations


"Primary Care COPD Patients Compared..." refers background in this paper

  • ...However, reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice [7]....

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