Analyses were performed using data extracted from the IQVIA PharMetrics® Plus database (October 1, 2015–December 31, 2021) [21]. PharMetrics® Plus contains comprehensive, integrated claims data of over 210 million unique beneficiaries since 2006, of which over 170 million are covered by both medical and pharmacy plans. Data contributors to the database are largely commercial health plans. It is representative of the commercially insured US national population for patients under 65 years of age. It contains a longitudinal view of inpatient and outpatient services, prescription and office/outpatient administered drugs, costs, and detailed enrollment information. Data are de-identified and comply with the requirements of the Health Insurance Portability and Accountability Act; therefore, no institutional review board exemption nor informed consent was required for this study.

This was a retrospective study conducted on commercially insured adult patients with IBS-D who received at least one prescription of rifaximin (550 mg thrice daily) or eluxadoline (100 mg twice daily), regardless of pre-treatment with other IBS-D agents (i.e., antiperistaltics, antispasmodics, mixed opioid agonists/antagonists, and tricyclic agents; Fig. 1) [4]. The index date was defined as the date when the index agent, rifaximin or eluxadoline, was initiated. The index treatment began on the index date, encompassing multiple fills of the index agent, as well as any other IBS-D treatment (excluding rifaximin or eluxadoline) if the other agent was initiated within the days of supply of the initial fill of the index agent. The index treatment ended at the first occurrence of 30 days or more without any prescription fills of the index agent, a prescription fill for a new IBS-D agent (i.e., other than those included in the index treatment), or the end of data availability.

Study design. 1Patients were required to have ≥ 2 IBS-D diagnoses, with ≥ 1 diagnosis during the baseline period. The second IBS-D diagnosis could occur at any time during the patient’s continuous health plan enrollment. 2The TFI is for illustrative purposes; all potential scenarios are not demonstrated. IBS-D irritable bowel syndrome with diarrhea, TFI treatment-free interval

The baseline period was defined as the 12 months prior to the index date. The study period was defined as the 12 months following the index date.

Patients were included in the study if they met the following criteria: (1) ≥ 2 IBS-D diagnoses (International Classification of Disease, Tenth Revision, Clinical Modification [ICD-10-CM] K58.0) on distinct dates; (2) no indicator of hepatic encephalopathy [22] or traveler’s diarrhea (defined as a diagnosis of infectious gastroenteritis [ICD-10-CM A09] or a prescription fill for rifaximin 200 mg); (3) ≥ 1 prescription fill for rifaximin or eluxadoline; (4) ≥ 12 months of continuous health plan enrollment before and after the index date; (5) aged 18–64 years as of the index date (Fig. 2). Patients were excluded from the study if they had claims for simultaneous use of rifaximin and eluxadoline.

Sample selection criteria. HE hepatic encephalopathy, IBS-D irritable bowel syndrome with diarrhea, TD traveler’s diarrhea

All eligible patients were classified into two mutually exclusive cohorts based on the index agent: rifaximin cohort and eluxadoline cohort. Entropy balancing was used to balance key characteristics that may have had an impact on the differences in outcomes across cohorts [23]. Briefly, entropy balancing reweights observations between groups to ensure comparable populations, where weights are assigned to patients in one cohort such that the specified covariate distribution will have the same mean and standard deviation as the other cohort. In this study, patient characteristics from the eluxadoline cohort were weighted to match those in the rifaximin cohort, with the characteristics in the rifaximin cohort remaining the same before and after balancing. Absolute standardized differences (aSD) were reported before and after balancing.

Characteristics used for balancing included those selected a priori on the basis of medical expert input and variables with an aSD ≥ 0.2. These included age, sex, calendar year of index date, healthcare plan type, region, provider type, number of IBS agents during baseline, GI-related and mental health-related diagnoses, baseline procedures, and baseline treatments.

Patient characteristics included age, sex, health plan type, region, and provider specialty, as of the index date. During baseline, medically relevant comorbidities (both GI-related and mental health-related), procedures (i.e., anesthesia, surgery, radiation services and therapies), and treatments were reported.

During the 1-year study period, characteristics of the index treatment were assessed. Specifically, the duration of the index treatment and the number of fills were reported.

Study outcomes included TFIs and all-cause healthcare costs. A TFI was defined as a period of at least 30 consecutive days without any IBS-D treatments observed. In this study, TFI specifically referred to relapses requiring medical attention, and did not include over-the-counter medications or mild symptoms not requiring prescription medications. During the study period, the proportion of patients who achieved a TFI, the duration of the TFI (i.e., ≥ 30 days, ≥ 60 days, ≥ 90 days, ≥ 180 days, ≥ 240 days), and the proportion of patients who remained treatment-free at the end of the study period were reported. All-cause healthcare costs were reported per patient per year (PPPY) and included medical costs (inpatient, outpatient, and emergency department) and pharmacy costs. Costs were measured during the 1-year study period, adjusted for inflation using the US Medical Care consumer price index [24], and reported from the payer’s perspective in 2021 US dollars, reflecting the total amount reimbursed by the payer and the coordination of benefits, excluding deductibles and patient copayments. To assess the impact of initiating treatment with rifaximin instead of eluxadoline, healthcare cost savings (annual and per member per month [PMPM]) of patients with IBS-D were estimated among a simulated healthcare plan of one million commercially insured lives.

For all outcomes, continuous variables were summarized using means, standard deviations, and medians, while categorical variables were summarized using frequency counts and percentages. All measures and outcomes were reported among each cohort separately.

Healthcare costs during the 1-year study period were compared between the rifaximin and eluxadoline cohorts using weighted generalized linear regression models with a Gamma distribution and a log link, using robust standard errors. Mean differences (MD) for the entropy-balanced cohort were reported with 95% confidence intervals (CIs) and p values, with significance considered at the 5% level.