Medication discontinuation in the era of elexacaftor/tezacaftor/ivacaftor: an Australian survey and qualitative interview

ABSTRACT

Chloride channel potentiator and corrector elexacaftor/tezacaftor/ivacaftor (ETI) has reduced the burden of disease in people with cystic fibrosis (PwCF) and led to some patients ceasing high‐burden treatment regimens. This study was a prospective survey and qualitative interview that evaluated medications PwCF had ceased after ETI. It demonstrated that a majority of PwCF have ceased medications, which prompts further research to rationalise medication regimens for PwCF.

Treatment regimens in people with cystic fibrosis (PwCF) are often complex and burdensome and have a significant impact on quality of life. Chest physiotherapy and nebulised therapy have been particularly noted as having a high burden. ¹ , ² Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has been able to reduce many of the symptoms experienced by PwCF and has enabled PwCF to cease some of their previously required medications. ³ The SIMPLIFY and CF STORM studies have suggested that patients on ETI are able to cease mucolytic agents without worsening their pulmonary function over the short term. ⁴ , ⁵ The SIMPLIFY‐MCC study also speculates that PwCF with mild lung disease on ETI and mucolytic dornase alfa may even experience deleterious effects; however, additional study is needed. Poor adherence to medication regimens has also been a challenge due to high daily treatment burden, and at times, medications are self‐ceased. ⁶ This study aimed to explore the medications that have been discontinued by Australian PwCF since commencing ETI, as well as patient reasoning and experience in undertaking this self‐management approach.

A mixed‐method descriptive study approach was used involving an online survey followed by qualitative interviews. An email survey relating to medication and treatment changes since commencing ETI therapy was sent to PwCF who are part of the CF Australia (CFA) community in November 2023 and closed 29 December 2023 (Supporting Information Appendix A). Participants >16 years of age and using ETI for at least 1 year were included in the survey. All members registered with CFA received the email from CFA. Quantitative analyses of these data were performed using descriptive statistics using SPSS. From these survey respondents, participants were further invited to participate in semi‐structured interviews. Of the respondents that agreed, all proceeded to have an interview which was used in this study. Survey data of chosen participants were not reviewed prior to selecting them for the interview to reduce any bias of their responses. Interview conduct was guided by qualitative interview template constructed based on clinical insight and qualitative researcher experience (Supporting Information Appendix B). Interviews were conducted via online video calls using the Zoom platform (Zoom Communications Inc., San Jose, CA, USA; Version 517.11) and audio transcripts, which were auto‐translated by Zoom. The qualitative analysis was conducted using NVivo 15 software (Lumivero, Denver, CO, USA). An inductive thematic analysis was performed by one investigator (MC) and cross referenced by another investigator (BS) to ensure consistency in coding and theme derivation. This study was approved by the Human Research Ethics Committee of the Sydney Local Health District (X23‐0188 & STE01697) at Royal Prince Alfred Hospital (Sydney, NSW, Australia).

The respondents (n = 290) had a median age of 41 (range 16–75) years, 44% were male, and their median ETI use duration was 23.5 months (range 6–68 months). Twelve participants opted in for the interviews (median age 36 (18–64) years, and 58% were male).

More than half (59%) of PwCF involved in this study reported having ceased some of their regular CF medications since the commencement of ETI therapy (Fig. 1A). Despite 88% of participants reporting a reduced number of respiratory exacerbations and 90% reporting a reduction in overall symptoms (Fig. 1A), the remaining participants (41%) chose not to cease medications even though they also experienced a reduction in symptoms.

Figure 1.

(A) Survey participants were asked which medications they had ceased based on a preselected list of most common medications. (B) Response of ‘yes’ from email survey regarding two separate questions: ‘Have your symptoms reduced post ETI?’ and ‘Have you ceased any medication after ETI?'. (C) Survey participants were asked to rank different reasons for stopping medications on a scale of little to high importance.

Of those who had ceased medications, mucolytics dornase alpha and hypertonic saline were the most discontinued medications (25% and 22% respectively), based on a preselected list of most common prescribed or over‐the‐counter medications used by pwCF (Fig. 1A). Tobramycin and azithromycin were the next most ceased medication group (15% and 13% respectively), followed by other antibiotics (10%). Creon was the least commonly ceased medication (2%).

As part of the survey, participants were asked how important, on a scale of 1 to 100, ‘symptom reduction’, ‘side effects’, ‘difficulty of administering therapy’ and ‘medical advice’ were in their decision to discontinue medications (Fig. 1C). Survey data indicated that ‘symptom reduction’ was the most common reason PwCF ceased a medication and ‘side effects’ the least common. Medical advice had an average of 67% importance (Fig. 1C).

Thematic analysis of the 12 semi‐structured interviews demonstrated three major themes. Themes and sub‐themes are outlined below, along with representative quotes (Fig. 2).

Figure 2.

Themes and subthemes generated from qualitative analysis of the interview data and representative quotes of each theme.

Treatment burden: Treatment burden was the most common theme raised by interview participants. Participants consistently spoke about their routine CF therapies negatively impacting their lives. In particular, they did not want to sacrifice more time and energy to undertake treatments they may not need, prioritising instead time with friends and family. Participants felt that treatment burden was the main driving factor for wanting to cease medications once they experienced symptom reduction after ETI use. It was clear that participants were heavily impacted by the process of carrying out their treatment regimens, and reducing the time of the regimens was of high importance to them.

Medication cessation: Two major groups within the study population were evident. One group of participants who had ceased medications and one who had not. Participants who had ceased medications largely had done so themselves without consulting their CF practitioners first. The most common feeling was that they could not see any benefit from previous routine therapies, so they discontinued some medications. Often, participants expressed that they had several days of accidentally forgetting medications, then noticing no worsening symptoms. They would normally have expected symptom recurrence prior to ETI use. The other group was those who had not ceased medications. They most commonly reported feeling anxious about symptom recurrence or consequences of ceasing medications, with many mentioning concern regarding the lack of guidelines their clinicians had for medication reduction. Lack of guidance or uncertain advice from medical teams was a common subtheme. Participants felt that CF teams were supportive but were not able to give clear instructions on whether it was safe or not to cease medications.

Improved symptoms since ETI: Participants universally discussed dramatic improvement in symptoms since starting ETI. Increased exercise capacity was very important to participants and seemed to have the most positive impact on their personal lives. Reduced exacerbations in both frequency and intensity were common. Participants felt that they were able to miss more days of therapy before seeing any exacerbations.

Discussion

It was evident in this mixed‐methods study that ETI therapy was resulting in PwCF to be able to discontinue some of their current treatment regimen and reduce the short‐term impact on their lives by reducing treatment burden. Consistent with previous studies, our results both from quantitative and qualitative reviews indicate that the burden of chronic daily treatment was an important factor in the quality of life of PwCF's leading to them trialling medication cessation to improve this. ⁷ Mucolytic therapies were the most frequently ceased medications followed by prophylactic nebulised and/or oral antibiotics. Cessation of mucolytics and/or prophylactic antibiotic use, warrants further study to understand better the longer term effects including on lung function, pulmonary exacerbation frequency and need for antibiotics during exacerbations, particularly in pwCF with established moderate to severe lung disease.

Interestingly, in this study, we identified a large proportion of participants with improved symptom burden after ETI use who chose not to cease any medications after ETI. They were open to awaiting further guidelines and advice from their CF specialist teams. An important finding was that of expressed anxiety about symptom recurrence or consequences which appeared to overwhelm some PwCF who did not cease routine medications despite a reduction in symptoms after commencing treatment with ETI. This highlights the need for clinicians to have a good evidence base around the long‐term outcomes of medication cessation, so that they can appropriately counsel patients and instil confidence in safe medication cessation. Trials such as the SIMPLIFY and STORM will help provide guidance, at least about withdrawing standard mucolytic therapy once a patient is stabilised after ETI administration. ⁴ We acknowledge that there remains a lack of supporting literature that medication cessation is a safe and effective long‐term strategy. Till such time when these trial results inform clinical care, a thoughtful communication approach may be needed that supports patients to make decisions about routine medication cessation, while ensuring that they know and have skills around actions to be taken if any symptoms worsen after ceasing routine CF treatments. Trials that can determine best approaches to de‐prescribe inhaled/nebulised antibiotics or other CF treatments are also needed.

With up to 90% of Australian PwCF eligible for ETI in 2023, this survey is limited as it only incorporates 15% of the ETI‐eligible PwCF recorded in the Australasian CF Data Registry. ⁸ This response rate, however, is similar to several other surveys. ⁹ , ¹⁰ In December 2023, CFA had 6414 lay and medical members. The exact number of adult PwCF who were members of CFA was not available. However, 2223 people opened the communique sent.

Currently, most PwCF are ceasing medications on their own because of respiratory symptom reduction. The longer‐term safety of this has not been assessed, and interim guidelines should be developed so PwCF can do this in a supported way, though there is limited available evidence at this time. This may be best further investigated using harmonised data registries, with PwCF already discontinuing medications despite being apprehensive about doing so. Treatment burden plays a large role in the lives of PwCF, and consumer‐led research shows that this should guide future changes in treatment policies. ¹¹

Supporting information

Data S1 Supporting Information.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.