Abstract
Evaluation of: Vestbo J, Anderson JA, Calverley PMA et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax 64, 939–943 (2009).
In chronic diseases, adherence to inhaled therapy can impact treatment effectiveness and can influence disease mortality and morbidity. In chronic respiratory diseases in general, and chronic obstructive pulmonary disease (COPD) in particular, adherence to inhaled therapy can potentially influence disease prognosis, as demonstrated in the analyses discussed in this article and a 3-year study assessing the effects of inhaled salmeterol, inhaled fluticasone and an inhaled combination over placebo in patients with moderate-to-severe COPD patients. It is demonstrated that good adherence to inhaled therapy can reduce all-cause mortality and hospital admissions. Such results are very useful in clinical practice to motivate patients to adhere to their inhaled treatment.
Adherence to therapy is an important outcome measure, especially in chronic diseases, and can influence not only treatment effectiveness directly but also disease mortality and morbidity. In trials of chronic respiratory diseases, adherence to inhaled therapies is very difficult to assess because the methods used routinely (self-reported or inhaler canister weighting) are not always reliable, whereas dose-counting devices are costly. Currently, most studies regard good adherence as more than 80% of doses taken over a period of time, however, even this threshold is rather arbitrarily established.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways, related mainly with smoking, which is treated with inhaled bronchodilators and corticosteroids in a step-up approach according to disease severity. Long-acting β2-agonists can be used in less-advanced COPD but are more commonly used in more severe disease, combined with inhaled corticosteroids, such as fluticasone propionate. The effectiveness of such combinations was assessed in stable COPD in both short- and long-duration studies, and improvements in quality of life and exacerbations rates were found Citation[1].
The Towards a Revolution in COPD Health (TORCH) study was a 3-year randomized placebo-controlled study evaluating the effects of salmeterol (SAL) 50 µg twice daily, fluticasone (FP) 500 µg twice daily or their combination (SFC) 50/500 µg twice daily delivered via Diskus on various end points, including all-cause mortality. This study analyzed adherence to long-term inhaled therapy and its impact on mortality and hospital admission for COPD exacerbations (morbidity) Citation[2].
Methods & results
The analysis was performed in a sample of 6112 patients (1524 allocated to placebo, 1521 to SAL, 1534 to FP and 1533 to SFC), with moderate-to-very severe COPD: drug adherence was assessed every 12 weeks with a dose counter quantifying the number of doses left in the Diskus: good adherence was defined as an average adherence to study medication of over 80% for the whole period, whereas poor adherence was defined as no more than 80% adherence Citation[3].
Baseline variables and parameters did not differ among study groups, and 4880 (79.8%) patients were found to have good adherence. Among the 20.2% patients with poor adherence, 12.3% had an adherence rate of less than 70%, and 8% less than 60%. A good adherence rate was higher among the males compared with females (80.3 vs 78.5%). Adherence was not influenced by disease severity (good adherence rates were 81% in moderate COPD, 80% in severe COPD and 77% in very severe COPD) or by inhaled treatment.
Compared with patients with good adherence, patients with poor adherence had a more impaired baseline lung function (lower forced expiratory volume in 1 s [FEV1]) and dyspnea level. The overall 3-year mortality rate in the study was 14.3% and was found to be lower in patients with good adherence (11.3 vs 26.4% in patients with poor adherence). When analyzed according to the study group and good/poor adherence status, good adherence was associated with mortality rates of 10.7% for SAL, 12.9% for FP, 9.5% for SFC and 12% for placebo. In patients with poor adherence, mortality rates were 25.2, 28.7, 24.9 and 26.7% respectively. In a Cox multivariate model after adjusting for region, age, sex, smoking status, lung function, nutritional status, MRC dyspnea score, previous use of inhaled corticosteroids and previous myocardial infarction treatment, good adherence was found to be associated with a 60% mortality risk reduction (hazard ratio [HR]: 0.40; 95% CI: 0.35–0.46; p < 0.001) independent of study therapy; when health-related quality of life was also considered, the HR was 0.41 but the analysis only included the 4678 patients in which the St George’s Respiratory Questionnaire was used. Overall, the rate of severe exacerbations requiring hospital admission was 0.17 per patients per year and did differ in adherent compared with nonadherent patients – 0.15 versus 0.27. In adherent patients, COPD admission rates among the treatment groups were 0.14 (SAL), 0.15 (FP), 0.14 (SFC) and 0.16 (placebo) per patient-year. In patients with poor adherence, admission rates were 0.26, 0.26, 0.25 and 0.36, respectively, per patient-year.
Good adherence was associated with a 44% reduction in admissions rate (rate ratio: 0.56; 95% CI: 0.48–0.65; p < 0.001), after adjusting for region, age, sex, smoking status, lung function, nutritional status, prior exacerbations and treatment, and independent of study treatment; when SGRQ scores were considered, the rate ratio was 0.54. In nonadherent patients, the absolute risk reduction for SFC compared with placebo was 1.77%, and 2.54% in adherent patients, whereas the relative risk reduction was 6.6% compared with 21.2%.
Discussion
This analysis demonstrates that on a long-term basis, good adherence to inhaled therapy reduces all-cause mortality and morbidity in patients with moderate-to-very severe COPD. Adherence to inhaled therapy was found to exert the most significant effect on all-cause mortality, good adherence being associated with a 60% reduction in death risk and, for the same inhaled medication, good adherence was associated with a mortality rate that was less than half that found in nonadherent patients (e.g., adherent to SFC 12% vs nonadherent to SFC 24.9%). Interestingly, the same trend was reported in the placebo group as well. However, it was not reported if good adherence or poor adherence impacted significantly on COPD-related mortality.
Adherence to inhaled therapy did impact COPD severe exacerbation rate, which was significantly lower in adherent patients – combination therapy being associated with the lowest exacerbation rate per patient per year and placebo nonadherent patients having the highest exacerbations rate.
Such results are confirmatory for the effects of long-term adherence but might also be influenced by the overall high rate of good adherence of approximately 80% in the analyzed sample.
Expert commentary & five-year view
Other studies attempted to examine adherence to inhaled therapy and their predictors with various methods. For example, the Lung Health Study, a 5-year randomized placebo-controlled study, evaluated the effects of smoking-cessation intervention and bronchodilator therapy (ipratropium bromide) in cigarette smokers with less severe (mild-to-moderate) COPD, and having the primary end point of lung function decline, adherence to inhaled therapy was assessed every 4 months for a duration of 2 years by self-report methods, canister weighting and medication event-monitoring device. Nearly 70% of participants reported at least satisfactory or better adherence after the first 4 months and this was found to decline to approximately 60% by the end of study period. The best adherence rates were found in patients who were married, older, with more impaired lung function and fewer hospitalizations Citation[4].
The present study focused on the effects of adherence on mortality and morbidity but did not analyze predictors of good or poor adherence. Such aspects are particularly interesting and clinically useful, not necessarily for good adherence but, rather, for poor adherence, as by identifying such factors, interventions to address them and, consequently, inappropriate adherence may result in adherence improvement. However, all in all, the results of this analysis are very relevant and can be used in clinical practice to encourage sustained good adherence among COPD patients.
Key issues
• Inhaled therapies are the mainstay of treatment in stable chronic obstructive pulmonary disease (COPD).
• Adherence to inhaled therapy is difficult to evaluate as the methods commonly used with other formulations (self-reported adherence, counting of the remaining drug doses) usually overestimate it, whereas the most reliable methods (dose-dispensing monitoring devices) are costly.
• In COPD, which is a chronic disease, adherence to therapy can impact significantly on disease mortality and morbidity.
• Good adherence with inhaled therapy may result in mortality and hospitalization risk reduction.
• Poor adherence and its predictors remain an important issue to be assessed.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Calverley P, Pauwels R, Vestbo J et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet361(9356), 449–456 (2003).
- Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med.356(8), 775–789 (2007).
- Vestbo J, Anderson JA, Calverley PM et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax64(11), 939–943 (2009).
- Rand CS, Cowles MK, Wise RA, Connett J. Long-term metered-dose inhaler adherence in a clinical trial. The Lung Health Study Research Group. Am. J. Respir. Crit. Care Med.2(152), 580–588 (1995).