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Treatment response in COPD: does FEV1 say it all? A post hoc analysis of the CRYSTAL study.

ABSTRACT: The association between clinically relevant changes in patient-reported outcomes (PROs) and forced expiratory volume in 1?s (FEV1) in patients with chronic obstructive pulmonary disease (COPD) has rarely been investigated. Using CRYSTAL, a 12-week open-label study in symptomatic, nonfrequently exacerbating patients with moderate COPD, we assessed at baseline the correlations between several PROs (Baseline Dyspnoea Index, modified Medical Research Council dyspnoea scale, COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ)), and between FEV1 and PROs. Associations between clinically relevant responses in FEV1, CAT, CCQ and Transition Dyspnoea Index (TDI) at week 12 were also assessed. Using data from 4324 patients, a strong correlation was observed between CAT and CCQ (rs=0.793) at baseline, with moderate or weak correlations between other PROs, and no correlation between FEV1 and any PRO. At week 12, 2774 (64.2%) patients were responders regarding TDI, CAT or CCQ, with 583 (13.5%) responding using all three measures. In comparison, 3235 (74.8%) were responders regarding FEV1, TDI, CAT or CCQ, with 307 (7.1%) responding concerning all four parameters. Increases in lung function were accompanied by clinically relevant improvements of PROs in a minority of patients. Our results also suggest that PROs are not interchangeable. Thus, the observed treatment success in a clinical trial may depend on the selected parameters.

SUBMITTER: Kostikas K

PROVIDER: S-EPMC6387992 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Treatment response in COPD: does FEV1 say it all? A post hoc analysis of the CRYSTAL study.

Kostikas Konstantinos K Greulich Timm T Mackay Alexander J AJ Lossi Nadine S NS Aalamian-Mattheis Maryam M Nunez Xavier X Pagano Veronica A VA Patalano Francesco F Clemens Andreas A Vogelmeier Claus F CF

ERJ open research 20190225 1

The association between clinically relevant changes in patient-reported outcomes (PROs) and forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD) has rarely been investigated. Using CRYSTAL, a 12-week open-label study in symptomatic, nonfrequently exacerbating patients with moderate COPD, we assessed at baseline the correlations between several PROs (Baseline Dyspnoea Index, modified Medical Research Council dyspnoea scale, COPD Assessmen ...[more]

PMID: 30815470

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Project description:BACKGROUND:The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes. METHODS:FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations. In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50??g once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use. RESULTS:This post-hoc analysis included 2557 men and 805 women. Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ?2 exacerbations in the previous year. Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively). Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively). Results were similar for all (mild/moderate/severe) exacerbations. Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women. The smaller sample size for women may account for some observed discrepancies in treatment responses. CONCLUSIONS:Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC. Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis. TRIAL REGISTRATION:Post hoc analysis of the FLAME study. ClinicalTrials.gov number: NCT01782326 . Registered 1 February 2013.

Project description:Purpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience "mild" exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone.Patients and methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ?2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of >2 and >4 short-acting ?2-agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George's Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models.Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both >2 and >4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p<0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ?1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections.Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as "mild". Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions.

Project description:BackgroundChronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned.MethodsThe association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data.ResultsA statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms.ConclusionsWe have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Project description:BACKGROUND:Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1?s (FEV1) preceding the first reported symptom and after the start of an exacerbation. METHODS:WISDOM was a multinational, randomized, double-blind, active-controlled, 52-week study in patients with severe-to-very severe COPD. Patients received triple therapy (long-acting muscarinic antagonist and long-acting ?2-agonist/inhaled corticosteroid [ICS]) for 6?weeks, and were randomized to continue triple therapy or stepwise withdrawal of the ICS (dual bronchodilator group). After suitable training, patients performed daily spirometry at home using a portable, battery-operated spirometer. In the present post hoc analysis, patients who continued to perform daily home spirometry and completed at least one measurement per week for a 56-day period before and after the start of a moderate or severe exacerbation were included. Missing values were imputed by linear interpolation (intermittent), backfilling (beginning) or carry forward (end). Exacerbation onset was the first day of a reported symptom of exacerbation. RESULTS:Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV1 measure per week for the 8?weeks before and after the event and are included in this analysis. Mean daily FEV1 began to decline from approximately 2?weeks before the onset of symptoms of an exacerbation, dropping from 0.907?L (mean Days -?56 to -?36 before the exacerbation) to 0.860?L on the first day of the exacerbation. After the exacerbation, mean FEV1 improved but did not return to pre-exacerbation levels (mean Days 36-56 after the exacerbation, 0.875?L). The pattern of FEV1 changes around exacerbations was similar in the triple therapy and dual bronchodilator groups, and a similar pattern was seen in moderate and severe exacerbations when analysed separately. CONCLUSIONS:Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8?weeks after the event. TRIAL REGISTRATION:WISDOM (ClinicalTrials.gov number, NCT00975195 ).

Project description:BackgroundIn the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood.MethodsThe gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome.ResultsThe per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p?<?0.05) and higher prevalence of HIV (10% vs 6%, p?=?0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p???0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p?=?0.008) and MGIT media (HR 1.19, p?<?0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p?<?0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p?=?0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women.ConclusionsGender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

Project description:IntroductionAmerican Diabetes Association consensus guidelines emphasize individualized treatment in the management of type 2 diabetes mellitus (T2DM). Early glycemic response is a clinical marker that may predict longer term efficacy for individual patients and provide a clinical tool to enhance personalized treatment. This analysis evaluated whether glycemic response measured at week 12 ("early") could serve as a reliable predictor of glycemic control at weeks 24 and 52 of therapy in patients with T2DM.MethodsWe used data from 3 randomized, controlled clinical trials that evaluated patients with T2DM treated with 3 commonly prescribed glucose-lowering medications: metformin (n = 597), sulfonylurea (n = 626), and insulin glargine (n = 1046). The gradient boosting method was used to identify predictors of subsequent response; predictive accuracy was represented by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Treatment success at weeks 24 and 52 was assessed for each patient and defined as achieving a glycated hemoglobin (HbA1c) level of <7.0% or a reduction from baseline of ≥1.0%.ResultsThe predictive parameters (sensitivity, specificity, PPV, and NPV) for improvements in HbA1c at week 24 for metformin were 0.83, 0.81, 0.44, and 0.96; for sulfonylurea, 0.79, 0.94, 0.71, and 0.96; and for insulin glargine, 0.67, 0.89, 0.65, and 0.90. The predictive parameters for improvements in HbA1c at week 52 for metformin were 0.73, 0.84, 0.56, and 0.92 and for sulfonylurea, 0.45, 0.94, 0.74, and 0.82.ConclusionHigh predictive values identified in this analysis support "early" response as an appropriate tool for predicting treatment success at weeks 24 and 52. The high NPV (lack of early glycemic response) appears to be an effective indicator of the likely need for change in (or intensification of) therapy. These data support the current guideline recommendations that clinicians evaluate therapeutic responses to pharmacologic interventions with metformin, sulfonylureas, or insulin glargine as early as week 12.

Dataset Information

Treatment response in COPD: does FEV1 say it all? A post hoc analysis of the CRYSTAL study.

Publications

Treatment response in COPD: does FEV<sub>1</sub> say it all? A <i>post hoc</i> analysis of the CRYSTAL study.

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