The Effect of Elexacaftor/Tezacaftor/Ivacaftor on Hospitalizations and Intravenous Antibiotic Use


Eric Walter, MD, MSc1; Jennifer L Bass, MD2

Perm J 2022;26:21.089 • E-pub: 04/05/2022 •

Volume 26, Issue 1

Corresponding Author
Eric Walter, MD, MSc

Author Affiliations
1Kaiser Permanente Northwest, Department of Pulmonary and Critical Care Medicine; Kaiser Permanente Center for Health Research, Portland, OR, USA

2Kaiser Permanente Northwest, Department of Pediatrics; Kaiser Permanente Cystic Fibrosis Clinic, Portland, OR, USA

Author Contributions:
Eric Walter, MD, MSc, participated in the study design, acquisition, and analysis of data, drafting, and submission of the final manuscript. Jennifer L Bass, MD, participated in the study design and drafting of the final manuscript.

Conflicts of Interest: None declared
Funding: Dr. Walter and Dr. Bass both receive partial salary support paid to Kaiser Permanente Northwest from the Cystic Fibrosis Foundation.

The authors would like to thank TaShell Franklin and Clare Ku for their help in data research and Dr. Richard Mularski for his help with critical review of the article.

Copyright Information
© 2022 The Permanente Federation. All rights reserved.


INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective cystic fibrosis transmembrane conductance regulator modulator. It has been shown to improve lung function and decrease pulmonary exacerbations in short-term clinical trials. The effect of ETI on hospitalization and intravenous (IV) antibiotic rates is not known. We performed a single-institution, retrospective review comparing these rates before and after the initiation of ETI.

METHODS: Among patients taking the cystic fibrosis modulator ETI, we compared the cumulative number of days per month hospitalized and cumulative number of days per month on IV antibiotics before and after the initiation of ETI. Electronic medical records from 37 patients were reviewed from 2016 through 2020 to identify demographic data, hospitalizations, and antibiotic use. Results were then stratified by severity of lung disease.

RESULTS: Following the initiation of ETI, there was a decline in days per month hospitalized and on IV antibiotics. The cumulative average number of days per month patients were hospitalized decreased 86% from 27 to 4 after starting ETI. The cumulative average number of days per month on IV antibiotics decreased by 80% (32.5 to 6.4). Most of these reductions occurred among patients with severe lung disease.

DISCUSSION: At our institution, we saw a decline in cystic fibrosis–related hospitalizations and in the use of outpatient IV antibiotics following the initiation of ETI. These reductions were most pronounced among patients with severe lung disease.

CONCLUSION: The initiation of ETI was associated with a decline in days hospitalized and days on IV antibiotics.


Cystic fibrosis (CF) is an autosomal recessive disorder caused by a defect in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.1 There are more than 2000 known mutations, although most do not cause CF disease. CFTR resides on the epithelial cell surface and regulates sodium, bicarbonate, and fluid transport across the apical cell membrane. Defects in CFTR can lead to multisystem disease. The lungs are most often affected as airway epithelial dysfunction causes mucous to be dry, thick, and difficult to clear. This, in turn, can lead to bronchiectasis, chronic infection, and progressive respiratory failure.1,2

In 2019, there were more than 31,000 people living with CF in the United States.3 Advances in CF care have made dramatic improvements in quality of life and life expectancy. Predicted median survival in 2004 was 34 years; this increased to 46 years by 2019.3 Prior to 2011, treatments were primarily focused on airway clearance, pancreatic enzyme replacement, and infection control.4 Over the past decade, CFTR modulator therapies have revolutionized the way CF is treated. These small molecule therapies correct the underlying defect in CF, leading to improved CFTR function. In a 2011 landmark trial, the CFTR modulator ivacaftor substantially increased the percent predicted forced expiratory volume in 1 second (ppFEV1), decreased sweat chloride levels, and reduced the rate of pulmonary exacerbations (PEx) in patients with the G551D mutation.5 It was approved by the US Food and Drug Administration (FDA) in 2012 but was only available to the small percentage of CF patients with the G551D mutation. Since 2011, 3 more modulators have been approved (lumacaftor, tezacaftor, and elexacaftor). Current therapies use combinations of these modulators. Combination therapies have shown benefit in many more patients, including those with the most common CF mutation, Phe508del (over 90% of patients have at least 1 copy of Phe508del). The combination therapy elexacaftor/tezacaftor/ivacaftor (ETI) improved ppFEV1 and quality of life and decreased sweat chloride and PEx over 6 months among patients with at least 1 copy of Phe508del.6 Among patients with 2 copies of Phe508del, ETI improved ppFEV1 and quality of life and decreased sweat chloride over a short, 4-week trial.7 On the basis of these 2 trials, ETI was FDA approved in 2019.

Little is known about the long-term safety and efficacy of ETI. An open-label extension study showed that improvements in ppFEV1, sweat chloride, and quality of life were maintained up to 48 weeks without emergence of safety concerns.8 The Real World Clinical Outcomes With Novel Modulator Therapy Combinations in People with CF (RECOVER) study is an ongoing observational study evaluating long-term clinical effectiveness and safety of ETI.9 Results are expected in 2024. Kaiser Permanente Northwest is an integrated health care organization that provides care to more than 600,000 members in Oregon and Washington states. Kaiser Permanente Northwest has both adult and pediatric CF-Foundation–accredited care centers. Shortly after our centers began prescribing ETI, we noticed an abrupt decrease in the frequency of admissions for PEx. We hypothesized that the use of ETI was reducing hospitalizations for PEx. We performed a retrospective review of hospitalizations before and after patients started ETI. Additionally, we compared intravenous (IV) antibiotic use before and after ETI. Some of the results have been previously reported in the form of an abstract.10


We conducted a single-center, retrospective cohort study with a waiver of informed consent from the Kaiser Permanente Center for Health Research. Electronic medical records were reviewed from January 2016 through December 2020. Patients who were followed by the Kaiser Permanente Northwest CF Pediatric and Adult Centers on December 31, 2020 with a diagnosis of CF and receiving treatment with ETI were eligible for inclusion. This was a preintervention/postintervention study with the initiation of ETI as the intervention. Demographic data, hospitalization records, and outpatient IV antibiotic usage were reviewed. To control for the year-to-year variability in hospitalizations from years prior to ETI initiation, we used data from 2016 to 2019 as our preinitiation period. Most patients had been followed at the Kaiser Permanente Northwest CF Center for the entire study period. Nine patients were new to the Kaiser Permanente Northwest CF Center since 2016, but information on all hospitalizations from 2016 onward were obtained from their electronic medical records.

The cumulative number of days hospitalized per month for CF-related hospitalizations were compared preintervention and postintervention. Non-CF–related hospitalizations were excluded. For patients who had been followed at our center for at least 5 years, complete outpatient IV antibiotic data were available. For this cohort, we compared the cumulative days on outpatient IV antibiotics per month before and after the intervention. If a patient was started on IV antibiotics while in the hospital, IV antibiotic days were calculated by subtracting hospital days from the total number of IV antibiotic days. If an exacerbation was treated without hospitalization, all IV antibiotic days contributed to the total. Results were stratified between patients with and without severe lung disease, defined as ppFEV1 less than 40% at any time during the study period. This was a descriptive study, and no formal tests of statistical significance were performed.



Figure 1 depicts a flow chart for selection of eligible patients. Of the 67 patients eligible for ETI, 23 were not taking it. Nearly half (n = 11) had declined the medication. Most patients who declined did so because of typical lung function and a lack of symptoms. Six patients were posttransplant, and 4 did not have routine follow-up at our center. Patients who did not have a full 5 years of hospitalization data available (n = 5) and patients taking ETI for less than 3 months (n = 2) were excluded, leaving 37 patients included in the final analysis.

tpj21089 g0001

Figure 1: Flow chart for identification of patient eligibility. KPNW = Kaiser Permanente Northwest; ETI = elexacaftor/tezacaftor/ivacaftor.

Patient characteristics of the final cohort are described in Table 1. Just over half of the patients were female (n = 20, 54%). Most patients were adults (n = 31, 83.7%). The median start date for ETI was March 12, 2020 with a range from December 19, 2019 through September 18, 2020. Most patients had commercial insurance (68%). The median ppFEV1 was 56%. Sixteen patients (43%) had severe lung disease.

Patient characteristicsN = 37
Sex, n (%)  
F 20 (54%)
M 18 (46%)
Age distribution, n (%)  
12 to 17 years 6 (16%)
≥18 years 31 (84%)
ETI exposure in months (mean, median) 10.7, 9.8
ETI start date (mean, median) 2/12/20, 3/12/20
Age at start of ETI, median and range 30 (12–72)
Insurance status, n (%)  
Commercial 25 (68%)
Medicare 9 (24%)
Medicaid 2 (5%)
Affordable Care Act 1 (3%)
ppFEV1 prior to starting ETI, mean, rangea 62% (21%–117%)
Number with severe lung disease, n (%)b 16 (43%)

Table 1: Patient characteristics

an = 36 (1 patient unable to perform accurate and reproducible spirometry).

bSevere lung disease defined as ppFEV1 < 40% at any time during the study period.

F = female; M = male; ETI = elexacaftor/tezacaftor/ivacaftor; ppFEV1 = percent predicted forced expiratory volume in 1 second.


There was a decline in the number of days hospitalized following the initiation of ETI. The cumulative average number of days per month patients were hospitalized from 2016 to 2019 was 28.8 (Figure 2). This was relatively stable from 2016 to 2020 until ETI was started. After this, the average number of hospital days dropped to 4 days per month, an 86% reduction. Patients with severe lung disease accounted for most hospital days. Despite having severe lung disease, these patients still had a decrease in hospital days following ETI (Figure 3). In patients with severe lung disease, the average days per month hospitalized decreased to just 1.5 from an average of 22.9, a 93% decrease. The average days per month hospitalized decreased more than 50%, from 6 to 2.5 days per month, among patients without severe lung disease

tpj21089 g00002 copy

Figure 2: The average number of days hospitalized per month shown by year. In 2020 an average of 2 months of exposure time occurred prior to starting ETI and 10 months occurred after starting ETI. ETI = elexacaftor/tezacaftor/ivacaftor.

tpj21089 g0003 copy

Figure 3: The average number of days hospitalized per month shown by year. The black bars represent patients with severe lung disease, and the gray bars represent patients without severe lung disease. Severe lung disease was defined as an FEV1 < 40% at any time from 2016 to 2020. ETI = elexacaftor/tezacaftor/ivacaftor.


Complete IV antibiotic records back to 2016 were available for the 27 patients (73%) who had been followed by our center since 2016. Following the initiation of ETI, outpatient IV antibiotic days decreased (Figure 4). The average number of days per month patients in this group received outpatient IV antibiotics decreased from 32.5 per month preinitiation to 6.4 days per month postinitiation of ETI. This 80% reduction in outpatient IV antibiotic use was similar to the 86% reduction in hospital days. The reduction was most apparent among patients with severe lung disease.

tpj21089 g0004

Figure 4: The average number of outpatient IV antibiotic days per month shown by year. The black bars represent patients with severe lung disease, and the gray bars represent patients without severe lung disease. Severe lung disease was defined as an FEV1 < 40% at any time from 2016 to 2020. ETI = elexacaftor/tezacaftor/ivacaftor.


We report the results of a single-institution, retrospective study to examine the effect of ETI on hospital admission rates and IV antibiotic use among patients with CF. The original 2 pivotal trials examining ETI were short-term trials of 24 weeks6 and 4 weeks7. Our study reports longer-term outcomes with patients on ETI for an average of 10 months. Over this period, we saw an 86% reduction in days hospitalized and an 80% reduction in days on outpatient IV antibiotics after ETI was started. Our population was, on average, sicker than those in the randomized controlled trials, suggesting the benefit exists even in patients with severe lung disease. We prescribe ETI in patients with an FEV1 lower than trial enrollment criteria, as others have done.4,11 Trial patients were required to have an FEV1 of 40% or more at screening. In our study, 6 patients (16%) had an FEV1 < 40% at the time ETI was initiated, and 16 (43%) had an FEV1 < 40% at some time since 2016. Our patients were also hospitalized more often than were trial participants. Middleton et al reported an estimated annualized rate of PEx leading to hospitalization of 0.34 events per patient per year in those on placebo.6 Prior to starting ETI, our patients had approximately 1.0 PEx leading to hospitalizations per patient per year. This finding was heavily driven by patients with severe lung disease. Despite our population being sicker overall, ETI reduced hospitalizations to a level similar to those seen by Middleton. Hospitalization event rates after starting ETI were 0.09 events per year in our study, compared with 0.07 events per year among study drug participants in the trial.

Improvement in CFTR function addresses the underlying problem with CF. However, it is not expected to repair the sequelae of CF such as bronchiectasis. When first approved, there were questions about how well ETI would work in patients with severe lung disease. Among our patients, we saw that the bulk of the reduction in hospital and IV antibiotic days occurred among patients with severe lung disease. Striking examples of improvement include 3 patients with chronic hypoxic respiratory failure and severe lung disease with a ppFEV1 ranging from 21 to 33%. From 2016 to 2019, they averaged a cumulative 18 days per month in the hospital. After starting ETI, none of them were hospitalized in 2020.

While clearly effective, ETI is expensive, with a wholesale acquisition cost of approximately $312,000 per year.12 Reducing PEx, admissions, and IV antibiotic use may offset some of the cost of ETI. For adults, estimated PEx costs requiring IV antibiotics vary between $57,000 (for patients with ppFEV1 ≥ 70%) to $130,000 (for patient with ppFEV1 < 40%).12,13 This estimate does not differentiate between those who were or were not hospitalized. Among the 27 patients in our cohort for whom we have a full 5 years of exacerbation data (both hospitalization and on outpatient IV antibiotics), there were an average of 40 exacerbations per year prior to starting ETI. After accounting for FEV1, this represents an estimated annual cost of exacerbations of $3.4 million dollars. The 2020 estimated cost for ETI for these 27 patients was approximately $8.7 million. Thus, the reduction in PEx following starting ETI potentially offset 40% of ETI costs. Upward of 70% of these savings were attributed to reducing treatment need among patients with severe lung disease.

To our knowledge, this is the largest study looking at real-world use of ETI. O’Shea and colleagues reported the effect of ETI in 14 patients with severe lung disease in Dublin, Ireland. Over an average follow-up period of 5 months, monthly exacerbations decreased approximately 86%.11 Our results, in a larger population of patients and over an average of 10 months of follow-up, showed a similar reduction. The ongoing RECOVER study will provide additional information when available.9

Our study has several limitations. It is likely that the COVID-19 pandemic affected health care utilization because patients wished to stay out of the hospital. However, we feel that ETI initiation decreased hospitalizations. If pulmonary exacerbations were occurring at the same rate as they were prior to starting therapy and patients were just declining admission, we would have expected to see a rise in home IV antibiotic use. Instead, we saw very similar reductions in both hospitalizations and IV antibiotic use. Comparing hospitalization and IV antibiotic use between those who started ETI and those who did not would help control for the effect of COVID-19. However, these 2 groups were not similar. Those who started ETI were not as healthy as were those who declined (mean FEV1 62% versus 92%). We are a small CF center, and this is a single-institution study; our results may not be applicable to other centers. However, our results are similar to others.11 Our size is also a strength of our study. Kaiser Permanente is an integrated health care organization. Our electronic medical records allowed us to identify all hospitalizations over a 5-year period, and excellent pharmacy support allowed us to track ETI initiation and adherence.


Our study suggests that the initiation of ETI was associated with a reduction in hospital days and days on outpatient IV antibiotics at our institution. This effect was seen among all patients but was most notable among patients with severe lung disease.

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