Discussion
Our aim was to assess the cost-effectiveness of the PHARMACOP community pharmacists' COPD intervention program. In a 1-year time horizon, the PHARMACOP-intervention would induce a cost saving of €227 per patient, compared to usual care. This was primarily the result of the prevention of 0.07 hospital-treated exacerbations per patient. Therefore, the results of this cost-effectiveness analysis indicate that the PHARMACOP-intervention provides more value for money, combined with increased health gains when compared to usual care, i.e. it is the dominant strategy. Furthermore, long-term projections revealed that when the intervention would be extended to longer periods (up to 12.5 years), a considerable amount of 1.36 hospital-treated exacerbations per patient would be prevented. As we assumed a linear extrapolation of effects, long-term clinical follow-up is necessary to confirm whether this assumption does reflect real-life effectiveness.
Accordingly, Khdour et al. reported a pharmacist's intervention as highly cost-effective with both savings on total costs and gains in effects.Takemura et al. did not report costs but observed comparable effects on adherence and exacerbation rates. Notably, effects of these adherence enhancing interventions are considerable, especially when compared to reduction of exacerbations observed in trials assessing the effectiveness of (new) medication. This may be explained by the possibility that these type of behavior modifying interventions not just alter patients medication adherence but alter healthy behavior as a whole (i.e. "healthy adherer effect"), resulting in a much larger effect. A posthoc analysis from the TORCH-trial illustrates this explanation: patients with high adherence (regardless of whether the patients used medication or placebo) showed marked better outcomes (rate ratio severe exacerbations: 0.58) compared to patients with lower adherence. Moreover, regarding the percentage of patients with >1 exacerbations in the previous year, this was only 33% in the TORCH-trial, while in PHARMACOP this was 54%. As the ECLIPSE-study showed that a higher number of exacerbations in the previous year indicated a higher baseline risk for new exacerbations, more exacerbations could be expected in the PHARMACOP-population, thus larger potential gains. This aligns with the explanation regarding differences in effectiveness of COPD self-management interventions of which some showed positive and some showed disappointing results, depending on the baseline characteristics of the population. While the PHARMACOP-intervention prevented a considerable amount of hospital-treated exacerbations, only little gains on quality of life measures were observed. This as well corresponds with results from a COPD intervention program that focused on adherence. This finding is explained by the discrepancy between the timing of measurement of health status within trials and the relatively short duration of exacerbations.
When comparing the hospital-treated exacerbation rate (0.38 per patient-year) of the PHARMACOP-population to large trials, the rate seems relatively high. For example, in the TORCH-trial the hospitalization rate was 0.2 (SD:0.6) per year and in the UPLIFT-trial 0.15 (SD 0.01). However, hospitalization rates highly depend on type of study and are reported to vary from as low as 0.09 to 2.4 per year. Since co-morbidities such as heart failure increase the risk of hospital treated exacerbations in patients with COPD, and since several co-morbidities are excluded in classical RCTs of COPD (such as TORCH and UPLIFT), the different prevalences of co-morbidities might (partially) explain the higher exacerbation rate in the real-world PHARMACOP-study. Another risk factor for a high exacerbation rate was the winter season in which the trial was performed. In addition, mean CAT score in the PHARMACOP-population was >10, indicating patients with high symptoms according to the new GOLD guidelines. When compared to a previous Belgian cost-effectiveness report in the evaluation of tiotropium, hospitalization rates are more in line (0.36 per year), what might suggest that patients in Belgium are relatively earlier referred to hospital when exacerbations are suspected.
Strengths
This study is the first cost-effectiveness analysis of an intervention directed at improving COPD patients' medication adherence and inhalation technique based on a large RCT. One of the major strengths of this trial was the community care setting in which real-life data were obtained. The vast majority of patients with COPD fill their prescriptions in community pharmacies, where recruitment took place. Our study population - and therefore also the results from the current cost-effectiveness study - is considered representative for the Belgian COPD population using inhaled medication for the maintenance treatment of COPD. The study closely followed and modeled real-life medication distributions among the study population. Using this distribution enabled precise estimates of the economic impact of improving medication adherence for the total population. Therefore, not only the costs for the intervention itself (materials and time of healthcare providers) but also costs related to the extent of medication use, which effects may last for longer periods, were included providing a complete economic picture. Finally, the analysis was reported according to the CHEERS-guidelines for reporting of health-economic evaluations.
Limitations
Though basecase assumptions were well-considered and assessed for robustness in sensitivity analyses, long-term effects related to the programs' future impact on frequency of (severe) exacerbations and costs, remain highly uncertain. Some studies recommend that inhalation instruction should be (frequently) reinforced for continuation of optimal pharmacological effects. Also future changes in healthcare policies and treatments may change current cost-effectiveness estimates. Regarding implementation in the Belgian healthcare system, the varying ability of individual healthcare providers to adopt - and patients to respond to - the interventions has to be considered, which limits generalizability. Regarding generalizability to other countries, differences in country specific healthcare systems, costs and regulations should be taken into account. For example, this study did not take into account indirect costs (productivity), in line with Belgian guidelines, while the Dutch guidelines recommend to take these costs into account indeed.
Long-term projections of our COPD model should be interpreted with caution as e.g. in spite of evidence that decline in lung function is increased by the occurrence of an exacerbation we did not account for this possibility. However, because this decline due to an exacerbation is relatively low in comparison with regular annual lung function decline, for analyses up to 2 years (including the basecase analyses) this is considered only a minor limitation.
Recommendations
As an alternative to addition of new drugs to COPD patients' treatment regimen, optimization of current treatment has to be considered. Pharmaceutical care (i.e. optimization of medication adherence and inhalation technique) as provided by the PHARMACOP-protocol should be embedded in the integral multidisciplinary respiratory care for patients with COPD. Based on the cost-saving strategy, health insurance companies should be stimulated to reimburse these type of interventions. Furthermore, community pharmacists are well positioned - and are recommended - to integrate COPD specific pharmaceutical care as part of their daily practices. Overall, these recommendations are expected to contribute to better patients outcomes and to lower total healthcare costs for the COPD population. In particular, when interventions are performed in the winter season, the season when patients are at highest risk for exacerbations, potential health and cost gains are maximized.