Abstract
Objectives
Acute pancreatitis (AP) occurs among patients with pancreas sufficient cystic fibrosis (PS-CF) but is reportedly less common among pancreas insufficient CF (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF.
Methods
MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by use of pancreas enzyme replacement therapy.
Results
A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, p=0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval (CI) 0.10, 1.11, p=0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, p=0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations respectively. In a subset analysis of 1,795 subjects who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, p=0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, p=0.26) for PI-CF.
Conclusions
CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. This observational data supports the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.
Keywords: Cystic fibrosis, CFTR, acute pancreatitis
Introduction
In healthy individuals, the cystic fibrosis transmembrane conductance regulator (CFTR) maintains an alkaline environment in the pancreatic duct which neutralizes acidic chyme and delivers proenzymes to the duodenal lumen. 1-3 In persons with CF, CFTR malfunction results in increased pancreas juice viscosity and acidity leading to ductal obstruction, chronic inflammation, and progressive acinar cell destruction. 1, 4, 5 Ultimately, as acinar cells are damaged the pancreas parenchyma becomes fibrotic, resulting in pancreas exocrine and endocrine insufficiency.1, 4, 5 This process may occur in utero among individuals with severe CFTR gene mutations, but individuals with class V or mild class IV mutations retain apical CFTR activity and may suffer recurrent acute pancreatitis (RAP) until eventually developing chronic pancreatitis over their lifetime.6-8 Accordingly, this subgroup of patients with pancreas sufficient CF (PS-CF) suffering RAP may be appropriate for therapy to decrease episodes of AP in order to reduce or delay the progression to exocrine pancreatic insufficiency (i.e., pancreas insufficient CF (PI-CF)) and/or chronic pancreatitis.
Treatment of CF has evolved to personalized CFTR modulator therapy targeting multiple protein activity defects including synthesis, transport, trafficking, and function of CFTR and continues to progress.1, 9-12 Among patients with PS-CF and recurrent AP, use of CFTR modulators lead to a reduction in the rate of subsequent AP.13-15 Additionally, improved weight and pancreas exocrine function have been described.16-18 Among patients with PI-CF, AP is thought to be rare due to insufficient enzyme production to allow autoactivation within the pancreatic ducts. Therefore, AP in patients with PI-CF is hypothesized to occur at early stages of pancreatic insufficiency, when steatorrhea has occurred, but fecal elastase is still detectable. For example, one study reported a mean fecal elastase of 97mcg/g (normal >200mcg/g) among PI-CF patients who developed AP.19 CFTR modulators may affect pancreatic exocrine function in PI-CF patients. One study showed an increase of fecal elastase from 83mcg/g to 465mcg/g with CFTR modulator therapy.20 Thus, in patients with low fecal elastase, treatment with CFTR modulators may increase pancreas enzyme production. This could potentially explain the increased rate of AP among PI-CF subjects treated with CFTR modulators.20-24
No large studies have investigated the incidence of AP among patients treated with CFTR modulators over time. Therefore, we sought to use a large database to assess the rate of AP among CF patients treated with CFTR modulators. We hypothesized that patients with PS-CF would experience a reduction in AP hospitalizations while on CFTR modulator therapy. We also sought to study the effect of CFTR modulators on PI-CF subjects, hypothesizing that the impact of these medications would be less significant.
Materials and Methods
Data Source:
A retrospective analysis was performed using the MarketScan database from 2012 to 2018 which includes an opportunity sampling of de-identified patients in the United States. MarketScan includes more than 32 billion service records of over 200 million individuals, providing inpatient and outpatient healthcare and medication costs and also compliance measures.25 MarketScan also reports time-sensitive data which allows recruitment to a study cohort subsequent to an intervention, thus providing a robust temporal association compared to other claims databases. The Ohio State University Wexner Medical Center Institutional Review Board deemed this study exempt.
Study Population:
All patients with CF were considered eligible for inclusion, as determined by International Classification of Disease (ICD) version 9 and 10 codes (Supplementary Table 1). To support ongoing use of CFTR modulators, subjects were required to have a minimum of 1 year pharmaceutical coverage in the dataset prior to the date of enrollment. Subjects with less than 3 months of follow up were excluded. Other exclusion criteria included history of pancreas transplant or resection (Figure 1).
Figure 1: Study flow diagram.
Pancreas insufficient cystic fibrosis (PI-CF); Pancreas sufficient cystic fibrosis (PS-CF)
Outcomes of Interest:
The primary outcome of interest was hospitalizations for AP. A secondary outcome was to evaluate medication use characteristics.
Definition of Variables:
Study definitions and corresponding ICD codes are presented in Supplementary Table 1. The diagnosis of CF was based on one inpatient diagnosis code or on two outpatient codes, as has been done previously to improve diagnostic accuracy.26, 27 Pancreas insufficiency was defined by prescription of any pancreas enzyme replacement therapy during the preceding 12 months. Subjects who did not receive pancreas enzyme replacement therapy were deemed to be pancreas sufficient. Patients were considered to be on CFTR modulator therapy when it was prescribed and filled, and patients were considered to be off of CFTR modulator therapy when no medications were prescribed or filled for 60 days. After the 60-day period without CFTR modulators subjects were allowed to crossover to the no CFTR modulator cohort. Thus, the time from last CFTR modulator dose to 60 days without CFTR modulators was considered a washout period and this data was not included in the analysis. Varying time periods (10, 30, 60, and 90 days) were used for this washout period which all produced similar findings (Supplementary Table 2). Other variables included age, sex, type of insurance, region of residence, and presence of comorbidities defined by the Charlson Comorbidity Index (CCI).28, 29 Readmissions for AP within 30 days were considered to be part of the index AP and were therefore considered to be the same episode, rather than counted as a different AP event.
Statistical Methods:
Demographics and medication use characteristics were displayed with descriptive statistics such as means with standard deviations (SD) or medians with interquartile ranges (IQR) and ranges for continuous variables and frequencies and percentages for categorical variables. For continuous variables that followed normality assumption (such as age), two sample t-test was used for the bivariate relationships. For continuous variables that displayed distribution skewness, Wilcoxon Rank Sum test was used. Chi-square test (or Fisher’s Exact test when appropriate) was used for the bivariate relationships among categorical variables.
Patient follow-up time was divided into time on and off CFTR modulators. AP admissions were totaled separately for periods of time when on and off CFTR modulators. Generalized linear models with a log-link and Poisson distribution were used to compare AP rates by CFTR modulator status. The outcome was number of distinct AP events with an offset for the log of the patient-years, so that the outcome was a rate, and rate ratios were estimated between groups. The correlation between data from time on and off of CFTR modulators within the same patient was accounted for in the models. Separate models were fit to patients with PI-CF and PS-CF, including unadjusted models followed by multivariable models. The multivariable model for all subjects adjusted for age (as a continuous variable), sex, Charlson comorbidity index, and geographic region while the multivariable model for subjects with prior CFTR modulator use only adjusted for age (due to smaller sample size). Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Significance was defined as a two-sided alpha <0.05.
Results
Baseline Characteristics
A total of 10,417 patients were included, of which 1,795 (17.2%) had some prior CFTR modulator use (Table 1). Patients with CFTR modulator use were younger and more likely to be male compared to those without CFTR modulator use. Insurance plan types and region of residence were different between groups (Table 1). Patients with CFTR modulator use had a lower Charlson comorbidity index (0.4 vs 0.7, p<0.0001). A higher percentage of patients with CFTR modulator use were pancreas insufficient (84.5% vs 59.6%, p<0.0001) compared to those without CFTR modulator use. Among patients with CFTR modulator use, the most commonly used agent was lumacaftor/ivacaftor, followed by ivacaftor alone. Treated patients received CFTR modulators 51% of the time within the study period (standard deviation (SD) 34%).
Table 1:
Demographics and medication use characteristics of patients with cystic fibrosis included in MarketScan 2012-2018
| CFTR modulator use (n=1,795) |
No CFTR modulator use (n=8,622) |
p-value | |
|---|---|---|---|
| Age (in years) (mean (SD)) | 20.7 (12.9) | 22.6 (16.4) | <0.0001 |
| Age Group (in years) | <0.0001 | ||
| 0-5 | 199 (11.1%) | 1453 (16.9%) | |
| 6-11 | 258 (14.4%) | 1092 (12.7%) | |
| 12-17 | 361 (20.1%) | 1221 (14.2%) | |
| 18-25 | 440 (24.5%) | 1793 (20.8%) | |
| 26-34 | 277 (15.4%) | 1087 (12.6%) | |
| 35+ | 260 (14.5%) | 1976 (22.9%) | |
| Sex | |||
| Male | 948 (52.8%) | 4219 (48.9%) | 0.003 |
| Female | 847 (47.2%) | 4403 (51.1%) | |
| Plan Type | <0.0001 | ||
| Comprehensive | 30 (1.7%) | 139 (1.6%) | |
| EPO | 14 (0.8%) | 93 (1.1%) | |
| HMO | 205 (11.4%) | 917 (10.6%) | |
| POS | 159 (8.9%) | 563 (6.5%) | |
| PPO | 1055 (58.8%) | 5407 (62.7%) | |
| POS with capitation | 8 (0.5%) | 68 (0.8%) | |
| CDHP | 153 (8.5%) | 518 (6.0%) | |
| HDHP | 134 (7.5%) | 513 (6.0%) | |
| Unknown | 37 (2.1%) | 404 (4.7%) | |
| Region | 0.0338 | ||
| Northeast | 342 (19.1%) | 1702 (19.7%) | |
| North central | 480 (26.7%) | 2115 (24.5%) | |
| South | 696 (38.8%) | 3183 (36.9%) | |
| West | 264 (14.7%) | 1457 (16.9%) | |
| Unknown | 13 (0.7%) | 165 (1.9%) | |
| Charlson Comorbidity Index (mean (SD)) | 0.4 (0.7) | 0.7 (1.3) | <0.0001 |
| Alcohol Abuse | 4 (0.2%) | 31 (0.4%) | 0.5014 |
| Any pancreas enzyme use | <0.0001 | ||
| Yes (PI-CF) | 1516 (84.5%) | 5142 (59.6%) | |
| No (PS-CF) | 279 (15.5%) | 3480 (40.4%) | |
| Any CFTR modulator use | 1,795 (100%) | 0 (0.0%) | N/A |
| CFTR Modulator | N/A | ||
| Ivacaftor ONLY | 526 (29.3%) | 0 | |
| Lumacaftor/ivacaftor ONLY | 814 (45.4%) | 0 | |
| Tezacaftor/ivacaftor | 317 (17.7%) | 0 | |
| Ivacaftor and tezacaftor/ivacaftor | 11 (0.6%) | 0 | |
| Lumacaftor/ivacaftor and tezacaftor/ivacaftor | 127 (7.1%) | 0 | |
| Percentage of time on CFTR modulator1 (mean (SD) | 51 (34) | - | N/A |
| Time on CFTR modulators (years)1 | N/A | ||
| Mean (SD) | 1.4 (1.2) | - | |
| Median (IQR) | 1.1 (0.5-2.0) | - | |
| Range | 0.0-6.9 | - | |
| Aggregate time on CFTR modulators (patient-years) | 2,541 | - | N/A |
| Aggregate time without CFTR modulator use (patient years) | 3,708 | 19,254 | N/A |
| Follow up available (years) | <0.0001 | ||
| Mean (SD) | 3.5 (2.2) | 2.2 (1.7) | |
| Median (IQR) | 3.0 (1.4-5.6) | 1.7 (0.9-3.0) | |
| Range | 0.3-7.0 | 0.3-7.0 | |
| Experienced ≥1 admission for AP2 | 22 (1.2%) | 145 (1.7%) | 0.1616 |
| Total acute pancreatitis admissions2 | 31 | 209 | N/A |
Restricted to patients with CFTR modulator use
Based on primary diagnoses (some have multiple admissions)
Consumer-driven health plan (CDHP); Cystic fibrosis transmembrane conductance regulator (CFTR); Exclusive provider organization (EPO); High-deductible health plan (HDHP); Health maintenance organization (HMO); Interquartile range (IQR); Pancreas-Insufficient CF (PI-CF); Point-of-service (POS); Pancreas-sufficient CF (PS-CF); Preferred provider organization (PPO); Standard deviation (SD)
Among the 1,795 subjects with some CFTR modulator use during the study period, 279 (15.5%) were PS-CF (Table 2). Patients with PS-CF were older and more likely to be female compared to PI-CF. Insurance plan types were different between groups, but region of residence was no different (Table 2). Patients with PS-CF had a higher Charlson comorbidity index (0.6 vs 0.3, p<0.0001) compared to PI-CF. Patients with PS-CF spent on average less percentage of the study period on CFTR modulators than did patients with PI-CF (42% vs 53%, p<0.0001). The most commonly used agent among patients with PS-CF was ivacaftor (61%), while lumacaftor/ivacaftor was used most often in PI-CF (51%) (Table 2).
Table 2:
Demographics and medication use characteristics of patients with cystic fibrosis who received CFTR modulators between 2012-2018
| PS-CF (n=279) |
PI-CF (n=1516) |
p-value | |
|---|---|---|---|
| Age (in years) (mean (SD)) | 25.7 (15.5) | 19.8 (12.2) | <0.0001 |
| Age Group (in years) | <0.0001 | ||
| 0-5 | 30 (10.8%) | 169 (11.2%) | |
| 6-11 | 22 (7.9%) | 236 (15.6%) | |
| 12-17 | 39 (14.0%) | 322 (21.2%) | |
| 18-25 | 61 (21.9%) | 379 (25.0%) | |
| 26-34 | 56 (20.1%) | 221 (14.6%) | |
| 35+ | 71 (25.5%) | 189 (12.5%) | |
| Sex | 0.0004 | ||
| Male | 120 (43.0%) | 828 (54.6%) | |
| Female | 159 (57.0%) | 688 (45.4%) | |
| Plan Type | 0.0258 | ||
| Comprehensive | 10 (3.6%) | 20 (1.3%) | |
| EPO | 2 (0.7%) | 12 (0.8%) | |
| HMO | 35 (12.5%) | 170 (11.2%) | |
| POS | 19 (6.8%) | 140 (9.2%) | |
| PPO | 158 (56.6%) | 897 (59.2%) | |
| POS with capitation | 1 (0.4%) | 7 (0.5%) | |
| CDHP | 34 (12.2%) | 119 (7.9%) | |
| HDHP | 16 (5.7%) | 118 (7.8%) | |
| Unknown | 4 (1.4%) | 33 (2.2%) | |
| Region | 0.1185 | ||
| Northeast | 65 (23.3%) | 277 (18.3%) | |
| North Central | 79 (28.3%) | 401 (29.5%) | |
| South | 97 (34.8%) | 599 (39.5%) | |
| West | 35 (12.5%) | 229 (15.1%) | |
| Unknown | 3 (1.1%) | 10 (0.7%) | |
| Charlson Comorbidity Index (mean (SD)) | 0.6 (1.0) | 0.3 (0.7) | <0.0001 |
| Alcohol Abuse | 0 (0.0%) | 4 (0.3%) | 1.0000 |
| Any CFTR modulator use | 279 (100.0%) | 1516 (100.0%) | N/A |
| CFTR Modulator | <0.0001 | ||
| Ivacaftor ONLY | 170 (60.9%) | 356 (23.5%) | |
| Lumacaftor/ivacaftor ONLY | 49 (17.6%) | 765 (50.5%) | |
| Tezacaftor/ivacaftor ONLY | 48 (17.2%) | 269 (17.7%) | |
| Ivacaftor AND tezacaftor/ivacaftor | 4 (1.4%) | 7 (0.5%) | |
| Lumacaftor/ivacaftor AND tezacaftor/ivacaftor | 8 (2.9%) | 119 (7.9%) | |
| Percentage of time on CFTR modulator (mean (SD)) | 42 (31) | 53 (34) | <0.0001 |
| Time on CFTR modulators (years) | 0.6841 | ||
| Mean (SD) | 1.4 (1.2) | 1.4 (1.2) | |
| Median (IQR) | 1.2 (0.5-1.9) | 1.0 (0.5-2.0) | |
| Range | 0.0-6.9 | 0.0-6.9 | |
| Aggregate time on CFTR modulators (patient-years) | 402 | 2138 | N/A |
| Aggregate time without CFTR modulator use (patient years) | 699 | 3009 | N/A |
| Follow up available (years) | 0.0001 | ||
| Mean (SD) | 3.9 (2.1) | 3.4 (2.2) | |
| Median (IQR) | 3.9 (2.0-5.9) | 2.9 (1.2-5.5) | |
| Range | 0.3-7.0 | 0.3-7.0 | |
| Experienced ≥1 admission for AP1 | 8 (2.9%) | 14 (0.9%) | 0.007 |
| Total acute pancreatitis admissions1 | 13 | 18 | N/A |
Based on primary diagnoses (some have multiple admissions)
Consumer-driven health plan (CDHP); Cystic fibrosis transmembrane conductance regulator (CFTR); Exclusive provider organization (EPO); High-deductible health plan (HDHP); Health maintenance organization (HMO); Interquartile range (IQR); Pancreas-Insufficient CF (PI-CF); Point-of-service (POS); Pancreas-sufficient CF (PS-CF); Preferred provider organization (PPO); Standard deviation (SD)
Incidence of Acute Pancreatitis
During the study period, there were a total of 240 AP hospitalizations in the whole study population, 31 of which occurred among subjects with some prior CFTR modulator use. In the full study cohort of 10,417 subjects, 145 AP admissions occurred among 3,759 PS-CF patients, of which 2 (1.4%) occurred during CFTR modulator use (Table 3a). Also among 10,417 subjects, there were 95 AP admissions among 6,658 PI-CF subjects, of which 5 (5.3%) occurred during CFTR modulator use (Table 3a). A multivariable model adjusted for age, sex, Charlson comorbidity index, and geographic region found that the rate ratio for AP among subjects with PS-CF was 0.32 (95% confidence interval (CI) 0.10, 0.99, p=0.05) and the rate ratio for PI-CF was 0.37 (95% CI 0.15, 0.92; p=0.03) (Table 3a).
Table 3a:
Rate ratio for time on CFTR modulator versus time not on CFTR modulator among full study population (n=10,417)
| Model | Pancreas Sufficient Cystic Fibrosis (PS-CF) |
Pancreas Insufficient Cystic Fibrosis (PI-CF) |
|---|---|---|
| Observed | 0.33 (0.10, 1.11), p=0.07 | 0.38 (0.16, 0.89), p=0.03 |
| Multivariable (adjusted)* | 0.32 (0.10, 0.99), p=0.05 | 0.37 (0.15, 0.92), p=0.03 |
Adjusted for age (continuous), sex, Charlson comorbidity index, and geographic region
Among 1,795 subjects with some CFTR modulator use during the study period, 13 AP admissions occurred among 279 PS-CF patients, of which 2 (15.4%) occurred during CFTR modulator use (Table 3b). Also among 1,795 subjects with some CFTR modulator use, there were 18 AP admissions among 1,516 PI-CF subjects, of which 5 (27.8%) occurred during CFTR modulator use (Table 3b). A multivariable model adjusting for age found that the rate ratio of AP for PS-CF subjects was 0.36 (95% CI 0.13, 1.01, p=0.05) and the rate ratio for PI-CF was 0.51 (95% CI 0.20, 1.30, p=0.16) (Table 3b).
Table 3b:
Rate ratio for time on CFTR modulator versus time not on CFTR modulator among subjects with some CFTR modulator use (n=1,795)
| Model | Pancreas Sufficient Cystic Fibrosis (PS-CF) |
Pancreas Insufficient Cystic Fibrosis (PI-CF) |
|---|---|---|
| Observed | 0.36 (0.13, 1.01), p=0.05 | 0.53 (0.18, 1.58), p=0.26 |
| Multivariable (adjusted)* | 0.36 (0.13, 1.01), p=0.05 | 0.51 (0.20, 1.30), p=0.16 |
Adjusted for age (continuous)
Prediction of Acute Pancreatitis
The multivariable models were then used to predict the rate of AP hospitalizations per 1,000 patient years of follow up based on CFTR modulator use and pancreas sufficiency (Table 4a and 4b). In the full cohort, untreated patients with PI-CF had an estimated 1.76 (95% CI 0.98, 3.17) AP hospitalizations per 1,000 patient years and untreated patients with PS-CF had an estimated 10.20 (95% CI 6.19, 16.81) AP hospitalizations per 1,000 patient years (Table 4a).
Table 4a:
Estimated acute pancreatitis rates per 1,000 patient-years from multivariable model* incorporating full study population (n=10,417)
| Pancreas Sufficient Cystic Fibrosis (PS-CF) |
Pancreas Insufficient Cystic Fibrosis (PI-CF) |
|
|---|---|---|
| On CFTR Modulator, AP per 1000 patient years (95% CI) | 3.26 (0.94, 11.33) | 0.66 (0.26, 1.68) |
| Not on CFTR Modulator, AP per 1000 patient years (95% CI) | 10.20 (6.19, 16.81) | 1.76 (0.98, 3.17) |
Adjusted for age, sex, Charlson comorbidity index, and geographic region
Acute pancreatitis (AP)
Table 4b:
Estimated acute pancreatitis rates per 1,000 patient-years from multivariable model* among subjects with some CFTR modulator use (n=1,795)
| Pancreas Sufficient Cystic Fibrosis (PS-CF) |
Pancreas Insufficient Cystic Fibrosis (PI-CF) |
|
|---|---|---|
| On CFTR Modulator, AP per 1000 patient years (95% CI) | 4.65 (0.87, 24.78) | 0.34 (0.08, 1.43) |
| Not on CFTR Modulator, AP per 1000 patient years (95% CI) | 12.93 (3.47, 48.14) | 0.67 (0.15, 3.02) |
Adjusted for age (continuous)
Acute pancreatitis (AP)
The highest and lowest rates were seen in the model restricted to subjects with some prior CFTR modulator exposure of 1,795 subjects. AP rates ranged from 12.93 (95% CI 3.47, 48.14) admissions per 1,000 patient years among PS-CF subjects who were no longer using CFTR modulators to 0.34 (95% CI 0.08, 1.43) admissions per 1,000 patient years among PI-CF subjects during CFTR modulator use (Table 4b).
Discussion
Utilizing a large administrative database study, we found that the use of CFTR modulators in patients with CF was associated with a significant reduction in the incidence of hospitalizations for AP. While the relative reduction in AP hospitalizations was greater among PS-CF subjects, the effect was also significant in those with PI-CF. In a subset analysis of patients who had some CFTR modulator use, the relative reduction in AP hospitalizations remained similar for PS-CF. These findings support further evaluation of the use of CFTR modulator therapies to reduce AP admissions in subjects with CF.
The cystic fibrosis transmembrane conductance regulator (CFTR) ion channel is primarily expressed on the apical plasma membrane. Through Cl- and HCO3- secretion, it regulates the amount and volume of pancreatic ductal secretions. 1-3 Additionally, CFTR participates in complex epithelial cell signaling and mitochondrial function pathways, and possibly also acinar cell function.30-32 CFTR passes through many checkpoints before delivery to the apical plasma membrane, and CFTR mutations are categorized broadly into 6 classes based on the effect of the mutation.33, 34 Cystic fibrosis (CF) severity is generally determined by mutation class. However, disease modifiers such as bacterial colonization and toxin exposure may influence the course of the disease among patients with some residual CFTR function.5, 35, 36
While AP is more common in PS-CF subjects compared to PI-CF subjects, we identified that 58 (0.9%) PI-CF subjects had at least one episode of AP. This is an important finding and suggests that AP among PI-CF patients may not be as rare as previously described in the literature. AP in patients with PI-CF treated with CFTR modulators is hypothesized to occur due to an increase in pancreas enzyme production without improvement in pancreatic ductal fluid, tipping the balance towards ductal obstruction, premature activation of trypsinogen, and acute pancreatitis.24 Our study demonstrated that patients with PI-CF exhibited a reduced risk of developing AP while on CFTR modulators. One possible hypothesis for this is that CFTR modulators may result in increased bicarbonate secretion, which would reduce the risk of premature autoactivation of trypsinogen within the pancreatic duct.37
The previously reported incidence of AP among untreated PS-CF patients of between 1-2% was confirmed in this study.7, 19 It is notable that the PS-CF cohort exhibited a decreased risk of AP while on CFTR modulator therapy, as this could ultimately lead to prolonged exocrine function, improved nutritional status, and reduced risk of developing, or prolonging the progression to, chronic pancreatitis and exocrine pancreatic insufficiency.11, 16-18 CFTR modulator therapy is expensive, with one study suggesting that a 40% decline in medication cost would be needed for the therapy to become cost-effective, assuming each quality-adjusted life year to be valued at $500,000.38 However, if CFTR modulators can reduce hospitalizations for AP in subjects with CF, reduce the need for pancreas enzyme replacement therapy, and alter the natural history of the disease then their cost may be more justifiable. Further cost-benefit analyses are warranted, and should take into account the degree of baseline exocrine pancreatic function.
A reduction in AP among patients with PS-CF has been previously reported. In the largest single center study to date, there were 13 episodes of AP among 15 patients during the 2 years leading up to CFTR modulator initiation, but only 5 episodes of AP in available follow up (45.3 patient-years) after initiating CFTR modulators.13 The rate ratio in the above study was 0.25, which is lower than our study, where we observed a rate ratio of 0.33 in the complete cohort. The previous study included only PS-CF subjects with prior AP, suggesting greater benefit from CFTR modulators compared to patients with PS-CF without prior AP. In our study PS-CF subjects received CFTR modulators for shorter periods compared to PI-CF subjects yet AP occurred much less frequently in PS-CF subjects while on modulator therapy. This suggests a major protective effect of the therapy when acinar cell function is still preserved.
Our study has several limitations inherent to the use of an administrative database, including reliance on ICD coding and possible bias due to insurance type. While ICD coding validation studies in CF are lacking, CF is a very specific diagnosis with major clinical implications so the likelihood of accurate coding for identification of CF is high. The diagnosis of pancreas insufficiency relied on prescription of pancreas enzyme therapy rather than laboratory data, but this definition is commonly used in practice and research because assessing pancreas function is not uniform.39 This assumption carries the risk of mis-classifying PS-CF patients as PI-CF if pancreas enzyme treatment was prescribed during the study period. However, approximately 2/3 of the study population was categorized as PI-CF, which suggests that if any mis-categorization was present, it erred on the side of an overly specific allocation to PI-CF. The low incidence of AP in the cohort and inability to determine AP hospitalizations previous to the study period could result in a type II error. Lastly, genetic mutations were not included in the dataset so a secondary analysis of AP incidence according to mutation classifications was not possible.
Despite these potential limitations, our study has many strengths. The use of a large database which allows extraction of more granular data allowed for a robust characterization of AP in a large cohort of patients with CF. We were able to study the effect of CFTR modulators on the occurrence of AP in CF patients with or without pancreas insufficiency in a time-sensitive manner which approximates a cause-and-effect association, especially since we could compare the effect of CFTR modulators by assessing the risk of AP in treated and untreated patients with CF. Additionally, the use of a time varying covariate analysis allowed for considerable patient-years of follow up which highlighted the effect of CFTR modulator therapy on the risk of AP. This approach also allowed patients to serve as their own controls simulating a cross-over study, partially controlling for genotype and propensity to develop AP which would be otherwise challenging to perform outside of a large database or longitudinal patient registry. Even the subgroup analysis of patients with prior CFTR modulator use included 6,248 patient-years of follow-up, which is multiple times greater than any previously published study evaluating the incidence of AP in this population.
Conclusion
In this large database analysis, we demonstrated that the use of CFTR modulators is associated with a significant reduction in the rate of subsequent AP hospitalizations among patients with CF. Patients with CF could benefit from therapy with CFTR modulators to reduce the risk of AP, and this includes patients who already suffer from pancreas insufficiency. A prospective study of CFTR modulator therapy among subjects with CF to determine pancreas outcomes including AP and exocrine and endocrine function as well as a cost-analysis should be performed.
Supplementary Material
Study Highlights.
WHAT IS KNOWN
Individuals with cystic fibrosis (CF) may experience acute pancreatitis
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators affect the risk of pancreatitis in individuals with CF
WHAT IS NEW HERE
Acute pancreatitis occurs in pancreas sufficient and insufficient subjects with CF
CFTR modulator use is associated with a reduction in pancreatitis hospitalizations among subjects with CF
Financial support:
The project described was supported by Award Number UL1TR002733 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Footnotes
Potential competing interests: The authors declare that they have no potential conflicts.
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