Elexacaftor/Tezacaftor/Ivacaftor for Cystic Fibrosis: Impact on Hospitalizations and Health Care Resource Utilization in a Universal Health Care Setting

Effective management of cystic fibrosis (CF) poses significant challenges globally. CF care is multifaceted, requiring interdisciplinary efforts from teams of highly skilled health care workers [1]. The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has brought marked improvements in clinical outcomes including pulmonary function, sweat chloride, nutritional status, and quality of life, but its impact on health care resource utilization remains underexplored [2‐4]. People living with cystic fibrosis (pwCF) experience frequent hospitalizations, emergency room visits, and use of prescription medicines, all of which contribute to a high treatment burden from a young age [5]. Hospitalizations are frequently caused by pulmonary exacerbations (pEX), which are associated with a lower quality of life [6]. The complexity of CF care increases with age as comorbidities develop and lung function deteriorates, and increasing complexity is associated with high costs [7].

Treatment of CF in Denmark is centralized at two national CF centers in Copenhagen and Aarhus. The Danish CF care model is centered on “close monitoring and early intervention,” involving frequent hospital visits and preemptive treatment of chronic infections [8]. In addition to pharmacological therapies, treatment regimens include physiotherapy, nutritional management, and sinus surgery. The Danish CF care model has yielded positive outcomes but involves a high treatment burden [8].

The effectiveness of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm) including ETI has been demonstrated in previous studies reporting marked reductions in pEX and all-cause hospitalizations, as well as considerably lower rates of lung transplantation and death [9‐12]. Although lower hospitalization rates after initiation of ETI therapy have been described in US populations, less is known about the impact of ETIs on health care resource utilization in the context of a universal health care system, including the use of non-hospital health care services. High-resolution data from Danish health registries enable comprehensive assessments of real-world health care outcomes, providing insights for health care providers and policymakers. The aim of this study was to assess changes in health care resource utilization before and after initiation of ETI in a nationwide cohort of pwCF.

The study population included 283 individuals aged 12 years or older initiating ETI between 1 September 2020 and 31 December 2022. At least 1 year of follow-up was available for 269 individuals, and complete 2-year follow-up was available for 203 individuals. Median age at ETI initiation was 26 years, 49.1% of individuals were female, and 75.6% were F508del homozygous. Figure 1 shows the study population and number of individuals meeting the inclusion criteria. Population characteristics are shown in Table 1. The number of lung transplant recipients was too small to report due to Danish data protection laws (< 5 individuals).

This study assessed the impact of ETI on hospitalizations and health care resource utilization in a national cohort of pwCF up to 24 months after ETI initiation. We found reductions in the number of elective outpatient hospital contacts and hospitalizations, days in hospital for elective hospitalizations, pharmacy visits, and blood sampling appointments that were sustained 2 years post-ETI initiation. Our results confirm previous findings of reduced hospitalization rates and add evidence of both reduced and sustained utilization of various health care resources in the context of a universal health care system [11, 19].

A substantial drop in elective hospitalizations was observed 6 months post-ETI and was sustained throughout follow-up in terms of reduced number of contacts, days in hospital, and odds ratios. In Denmark, pEX in patients with chronic pulmonary infections are typically treated preemptively with elective 2-week courses of intravenous (IV) antibiotics at regular intervals, facilitated by the close monitoring treatment strategy involving approximately monthly visits [8]. The observed reductions in elective hospitalizations are likely driven by a decreased need for IV antibiotics. However, we were unable to report the rate of pEX specifically, as no validated definition compatible with our data sources was available. The proactive approach to pEX might explain the lack of a significant reduction in acute hospitalizations, as most potential exacerbations are treated at an early stage during elective hospitalizations or at home. A reduced rate of pEX was previously shown in pwCF initiating ETI in the United States [11, 19].

A reduced number of outpatient visits was observed at 6, 18, and 24 months post-ETI. Treatment guidelines in Denmark have not officially changed since the introduction of ETI, and it is not known to what extent the reduction was driven by clinicians observing a reduced need for monitoring, or by individuals postponing routine visits due to improved health. The lack of a reduction at 12 months indicates high patient attendance at the first annual post-ETI visit.

In addition to clinical monitoring, physiotherapy offered by the CF centers and ambulatory care in non-CF-specific hospital departments is registered as outpatient contacts, and any changes in the frequency of these contacts will be reflected in the overall figure. The recently published standards of care state that care closer to home with fewer hospital visits may be appropriate but should not compromise quality of care, emphasizing the continued need for a multidisciplinary approach in the treatment of CF [20]. A previous study reported fewer infection-related outpatient visits post-ETI, but evidence concerning the safety of reduced monitoring is scarce [21].

A decreased number of visits to pharmacies and blood sampling appointments was observed in the post-ETI period. Reduced utilization of several routine therapies has previously been reported in pwCF initiating ETI and is the probable reason for the reduction in pharmacy visits [22‐24]. For blood sampling appointments, the OR increased at 6 and 12 months post-ETI but dropped below baseline levels at 18 and 24 months, showing the increased monitoring in the year following ETI initiation. As blood samples might be drawn in relation to pEX, the subsequent reductions at months 18 and 24 might in part reflect fewer exacerbations.

At 24 months post-ETI, no changes were observed in visits to a GP, other specialists, or physiotherapists/chiropractors. However, the sensitivity analysis showed a reduced number of GP visits following ETI treatment when using the month immediately preceding ETI initiation as the baseline level. This difference is likely due to an increasing trend in the number of GP visits before ETI initiation (Supplementary Fig. 1) that was not captured in the pre-ETI average used in the main analysis. Therefore, the number of GP visits post-ETI might be overestimated in the main results, questioning the validity of the increase at 12 months post-ETI.

To our knowledge, no previous studies have assessed changes in GP visits and visits to other specialists or physiotherapists/chiropractors following initiation of ETI. Although the CF centers comprehensively manage the treatment of pwCF directly or through referrals to other hospital departments, > 80% of pwCF visit their GP in a year. Approximately 30% visit other specialists, and 16–20% visit a physiotherapist or chiropractor. Our findings suggest that utilization of non-CF-specific health care resources should be considered when assessing health care resource utilization and associated costs among pwCF.

While ETI was not associated with reduced utilization of several health care resources, we lacked detailed data to determine whether visits were related to CF-specific issues. PwCF also experience health concerns that are not directly related to CF, which may be managed by other health care providers. This might explain the absence of a reduction post-ETI, as such health issues are likely to persist. Additionally, the low absolute number of individuals visiting other specialists or physiotherapists/chiropractors challenges the detection of significant changes. Despite a persistent use of some health care resources, our findings align with previous studies demonstrating overall reductions in health care resource utilization, emphasizing the benefits of ETI and the importance of expanding global access to CFTRm [25].

A strength of this study was the comprehensive data material, enabling assessments of both hospital and non-hospital health care resource utilization with no selection bias in a national CF cohort. Similar studies conducted in the United States have relied on insurance claims and thus limited the sample to subgroups eligible for insurance through their employer or certain government programs. Limitations to be considered include the lack of a validated definition of pEX and data describing reasons for health care contacts. In addition, we were unable to report data on contacts to psychiatric hospitals and psychologists as the number of individuals was too small to report due to national data protection laws. Furthermore, we lacked data on visits to private psychologists and psychiatrists outside the public referral system (i.e., services paid by patients themselves), as well as the number of GP visits related to mental health issues. Mental health remains a top research priority in the CF community, and future studies devoted to utilization of mental health care resources are warranted [26].

In a national CF cohort, we found substantial reductions in number of elective hospitalizations, elective outpatient contacts, number of days in hospital, pharmacy visits, and blood sampling appointments which were sustained two years after ETI initiation. These findings indicate a decreased health care burden, confirming the real-world effectiveness of ETI in the context of universal health care.