Chronic idiopathic constipation (CIC) is a common and burdensome condition, affecting 10–15% of the population and is likely underreported (1–3). In the United States alone, 8 million patients seek care for chronic constipation from their primary care provider and 2.5 million patients consult with a gastroenterologist (4,5). Standard treatment measures include toileting advice, fiber (bulk-forming laxatives), exercise, and over-the-counter (OTC) osmotic and secretory laxatives (6). Unfortunately, more than 50% of patients fail to respond to standard treatment measures (7–9). As a result, patients with CIC are frequently exposed to repeated laboratory testing, imaging, and colonoscopies (10). Adding to a high degree of variation in care, poorly managed CIC leads to 700,000 emergency department visits and 50,000 hospital admissions each year in the United States. (11–13).
Within the broad armamentarium of treatment options, 4 prescription drugs have been approved by the US Food and Drug Administration (FDA) and are available to treat CIC in adults and recommended in several clinical practice guidelines: lubiprostone (24 μg twice daily), linaclotide (72 or 145 μg daily), plecanatide (3 mg daily), and prucalopride (2 mg daily) (14–16). For patients in whom a prescription drug may be beneficial, the most appropriate drug is ideally chosen in shared decision-making to optimize efficacy and tolerability (17–19). Unfortunately, treatment choice in practice is frequently dictated by insurance coverage rather than expected clinical outcomes (20). In other words, treatment access is the more frequent challenge compared with treatment choice. To physicians, cost is one of the most important determinants of treatment preference for managing chronic conditions more broadly (21). To patients, changes in prescription drug coverage frequently explain treatment discontinuation in CIC (22). Nonetheless, policymakers and physicians lack guidance on whether to focus their efforts on costs vs clinical outcomes both in shared decision-making and at a policy level. Resolving this tension is critical to improving treatment access and reducing variation in care for this common clinical complaint (23–27).
We performed a cost-effectiveness analysis among the currently available FDA-approved CIC prescription drug therapies to inform ranked CIC treatment preferences from patient and insurer perspectives and to explore the relative influence of cost as a determinant of patient and insurer treatment preferences in CIC.
Our study adhered to the CHEERS checklist and guidelines for the conduct of cost-effectiveness analyses established by the Second Panel on Cost-Effectiveness in Health and Medicine (28,29).
Between May and June 2020, we convened a panel of 8 neurogastroenterologists (each with >10 peer-reviewed publications related to disorders of brain–gut interaction and with demonstrated leadership in CIC clinical care) using RAND/UCLA consensus methods to systematically inform model assumptions and inputs (see Supplemental content, Supplementary Digital Content 1 and Table, Supplementary Digital Content 2, https://links.lww.com/AJG/C155, https://links.lww.com/AJG/C156) (30).
Our base-case patient was a 45-year-old commercially insured patient with CIC failing a standard trial of osmotic or bulk-forming laxatives. The following FDA-approved prescription drugs for CIC were included: lubiprostone 24 μg twice daily, linaclotide 72 or 145 μg daily, plecanatide 3 mg daily, and prucalopride 2 mg daily.
We assumed that patients with CIC continued OTC osmotic or bulk-forming laxatives at a stable dose along with typical recommendations on exercise and toileting habits, consistent with clinical practice guidelines and recent national surveys investigating usual care received among patients with CIC (7).
Our study was intended only to evaluate scenarios in which the physician concluded that a prescription drug would be appropriate (but not to study comparative effectiveness between prescription drugs and OTCs or to evaluate the broader subset of patients who respond to OTC laxatives or other disease mechanisms).
Informed by the conduct of our RAND/UCLA panel, we constructed a Markov model (general outline described in Figure 1; full model reported in Figure, Supplementary Digital Content 3, https://links.lww.com/AJG/C157). We assumed that patients remained on treatment as long as no safety events occurred and treatment was well tolerated. Overlapping laxative treatment is common in practice, yet published evidence on expected treatment outcomes with these approaches is lacking. To account for this limitation, we adopted similar assumptions to recent systematic reviews and network meta-analyses in CIC and to the design of registered drug trials in CIC, which allow patients to remain on a stable regimen of laxatives while on the CIC drug (17–19). Individuals were followed in 4-week cycles until the time horizon was reached. Although CIC is a chronic disease, long-term data spanning all drugs unfortunately remain lacking. We adopted the same 12-week timeframe similar to recent systematic reviews and network meta-analyses because this timeframe is reliably supported by clinical trial evidence across all CIC drugs and matches the contemporary required time horizon for registered CIC drug trials to support FDA drug approval (17–19). Sources of model inputs are tabulated in Table 1.
Our model tracked efficacy, tolerability, and safety with drug therapy. These data were extracted from recent network meta-analyses, systematic reviews, and integrated analyses of clinical trials and were verified against the FDA medical reviews. Efficacy was defined in a manner approximating the current FDA responder end point to facilitate indirect comparisons among disparate trials using best-available evidence (see Supplemental content, Supplementary Digital Content 1, https://links.lww.com/AJG/C155). Tolerability was defined by modeling treatment discontinuation because of adverse events. No serious adverse events specified in Section 5 (Warnings and Precautions) of the FDA labeling occurred in such excess as to affect our study findings with any drug (31–33). Adherence is important and was assumed to be included in our modeled rates of treatment discontinuation and by our use of intention-to-treat outcomes rather than per-protocol outcomes from underlying clinical trials (22). To avoid double counting, adherence was not modeled separately.
Average wholesale drug prices at retail pharmacies were derived from the US Centers for Medicare and Medicaid Services' National Average Drug Acquisition Cost index (34). CIC-associated healthcare costs from both patient and insurer perspectives were extracted from the “Chronic Constipation and IBS-C Treatment and Outcomes Real-World Research Platform,” a recent nationwide, prospective observational cohort study of insured patients with CIC, containing patient-reported outcomes data link to medical and pharmacy claims information with comparable demographics with our base-case and clinical trial populations with CIC (34). CIC-related direct healthcare costs (from an insurer perspective) and co-pays/out-of-pocket healthcare costs, work productivity/wage losses because of CIC, and childcare/transportation costs to attend healthcare appointments (from a patient perspective) accumulated when treatment was not efficacious or when patients were not receiving prescription drug therapy (34–37).
We tested an assumption that effective treatment of any kind (including OTC laxatives and not specific to prescription drugs) might result in fewer diagnostic tests, procedures, and healthcare visits, specifically to evaluate whether drug prices could even be supported on this basis (34,38,39). All costs were inflation adjusted to November 2020 using the US Bureau of Labor Statistics Consumer Price Index for healthcare and rounded to the nearest whole US dollar (40).
Quality of life
Effectiveness was assessed using quality-adjusted life years (QALYs) calculated as time spent on treatment multiplied by the amount of health assigned to each treatment (defined as health utilities). Health-related quality-of-life (QOL) outcomes measured using PAC-QOL were extracted from integrated clinical trial analyses and the FDA technical reviews and mapped onto health utilities (41). Health utilities in cost-effectiveness studies range from 0 (death) to 1 (full health). In the context of chronic illnesses such as CIC, health gains are typically small but not insignificant. For example, treatment response in CIC adds 0.05 QALY over 1 year compared with treatment nonresponse based on observational cohort studies that validated PAC-QOL (the standard measure of health-related QOL in CIC studies) (42). Over 20 years, a patient with sustained treatment response would gain an entire year of full health (or 1.0 QALY).
Base case and probabilistic sensitivity analysis
Base-case analysis was performed from insurer and patient perspectives in the US health system to determine costs and health gains with each drug. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing incremental costs by incremental health gains to evaluate cost-effectiveness differences between treatments. Lower ICERs represent greater cost-effectiveness, whereas ICERs >$150,000/QALY gained generally represent interventions which are less likely to be deemed cost-effective (43). Rankings were reported on cost-effectiveness to represent possible treatment algorithms with and without lubiprostone. In certain cases, treatments can improve health while incurring greater costs. In these cases, treatment preference was informed by sensitivity analysis. No discount rate was applied because of the short time horizon for this study. Two methods were used to evaluate uncertainty in cost-effectiveness estimates. To assess uncertainty in model estimates based on distributions in source literature, we performed 1-way sensitivity analyses and conducted probabilistic sensitivity analyses using Monte Carlo simulation of 10,000 trials. Acceptability curves were constructed to evaluate the likelihood of each drug being the most cost-effective CIC treatment across a range of willingness-to-pay (WTP) thresholds of up to a WTP threshold of $150,000 to achieve a complete healthy year of life.
Cost-effectiveness and health gains associated with having no prescription drug coverage among patients with documented failure of OTC laxatives
Among the subset of patients with documented failure of OTC laxatives, CIC added $569 in direct healthcare costs from an insurer perspective over 12 weeks. From a patient perspective, patients with CIC and documented failure of OTC laxatives experienced significant nonhealthcare costs and incurred $2,038 in costs over 12 weeks. Consistent with standard types of patient-perspective costs in cost-effectiveness analyses, our patient-perspective cost estimates included co-pays and other out-of-pocket CIC-related healthcare costs, work productivity/wage losses because of CIC, and childcare/transportation costs to attend healthcare appointments. The QALY gained over an entire year of CIC was 0.81 among patients failing standard OTC laxatives without access to prescription medications.
Costs and health gains with CIC drugs among patients with documented failure of OTC laxatives
The average wholesale price of CIC drugs over a year exceeds $4,000 under continuous, on-label use (see Table, Supplementary Digital Content 4, https://links.lww.com/AJG/C158). In contrast to network meta-analyses that typically report comparative efficacy end points such as the FDA responder end point, cost-effectiveness analyses typically evaluate health gains measured by changes in health-related QOL. In CIC, PAC-QOL is a validated and standard measure of health-related quality of life, which was assessed in all CIC trials (42). Although lubiprostone had the highest average effectiveness on the PAC-QOL measure among patients in the active treatment arm, differences in effectiveness were small among CIC drugs; the difference in QALY gained was <0.01 over 12 weeks regardless of drug. Furthermore, lubiprostone outcomes were not directly comparable with other treatments because of significant differences in clinical trial design between lubiprostone trials and other drugs.
Cost-effectiveness of CIC drugs from an insurer perspective
Results from base-case analysis including costs, health gains (QALYs), and ICER are reported in Table 2, and cost-effectiveness is reported in Figure 2a. From an insurer perspective, lubiprostone seemed to be the most cost-effective drug at current average wholesale prices (ICER to choose lubiprostone over usual care was $72,053/QALY gained), recognizing that lubiprostone trials were shorter and did not assess bowel movement completeness. For other drugs, insurers preferred to avoid covering CIC prescription drugs even among patients with documented failure of OTC laxatives: average wholesale drug prices outweighed any potential cost-savings due to effective disease management even with an assumption that effective treatment (of any kind) would translate into health gains (see Figures, Supplementary Digital Content 5–19, https://links.lww.com/AJG/C159, https://links.lww.com/AJG/C160, https://links.lww.com/AJG/C161, https://links.lww.com/AJG/C162, https://links.lww.com/AJG/C163, https://links.lww.com/AJG/C164, https://links.lww.com/AJG/C165, https://links.lww.com/AJG/C166, https://links.lww.com/AJG/C167, https://links.lww.com/AJG/C168, https://links.lww.com/AJG/C169, https://links.lww.com/AJG/C170, https://links.lww.com/AJG/C171, https://links.lww.com/AJG/C172, https://links.lww.com/AJG/C173). The ICER to choose linaclotide, plecanatide, or prucalopride exceeded $150,000/QALY gained at their current average wholesale prices compared with usual care.
Cost-effectiveness of CIC prescription drugs from a patient perspective
Results from base-case analysis including costs, health gains (QALYs), and ICER are reported in Table 2, and cost-effectiveness is shown in Figure 2b. From a patient perspective, CIC drugs resulted in decreased overall costs to patients compared with usual care, and all CIC drugs achieved similar gains in health-related QOL based on evidence supported by randomized clinical trials. Plecanatide seemed to be the most cost-effective treatment option from a patient perspective. Prucalopride was more cost-effective than linaclotide in base-case analysis; the ICER to choose linaclotide 145 μg over prucalopride was $222,484/QALY gained.
Determinants of patient treatment preference in sensitivity analysis
Patient preferences were largely driven by expectations on treatment discontinuation and the impact of treatment on QOL, so much so that plecanatide seemed to be the preferred treatment option in sensitivity analysis regardless of comparative differences in efficacy or responder status (see Figures, Supplementary Digital Content 20–34, https://links.lww.com/AJG/C174, https://links.lww.com/AJG/C175, https://links.lww.com/AJG/C176, https://links.lww.com/AJG/C177, https://links.lww.com/AJG/C178, https://links.lww.com/AJG/C179, https://links.lww.com/AJG/C180, https://links.lww.com/AJG/C181, https://links.lww.com/AJG/C182, https://links.lww.com/AJG/C183, https://links.lww.com/AJG/C184, https://links.lww.com/AJG/C185, https://links.lww.com/AJG/C186, https://links.lww.com/AJG/C187, https://links.lww.com/AJG/C188).
Choosing between prucalopride and linaclotide depended highly on the impact of CIC on a patient's work productivity, with a higher expectation that effective CIC treatment could improve work impairment, favoring prucalopride. Expectations on comparative efficacy and tolerability also informed treatment preferences between prucalopride and linaclotide at the 145-μg dose.
Probabilistic sensitivity analysis
Our primary analyses excluded lubiprostone because of differences in clinical trial end points compared with other drugs. Usual care without prescription drugs was the preferred CIC management strategy across all WTP thresholds from an insurer perspective (see Figure, Supplementary Digital Content 35, https://links.lww.com/AJG/C189). From a patient perspective, plecanatide was the preferred CIC management strategy (see Figure, Supplementary Digital Content 36, https://links.lww.com/AJG/C190).
The optimal cost-effective treatment algorithm from an insurer perspective was to deny access to prescription drugs regardless of whether patients failed OTC laxatives (Figure 4).
From a patient perspective, the optimal algorithm was to start with plecanatide, followed generally by prucalopride. Informed by our sensitivity analyses, linaclotide could be favored over prucalopride among (i) the subset of patients with low CIC-related work impairment or (ii) patients in whom linaclotide might be favored based on expected clinical outcomes at the individual patient level (recognizing that biomarkers are presently lacking to inform this decision) (Figure 3). The optimal cost-effective starting dose of linaclotide was 145 μg. Lubiprostone was excluded from these rankings because of differences in the clinical trial design and end points with this drug.
To our knowledge, we performed the first cost-effectiveness analysis to determine ranked CIC treatment preferences and to identify key determinants that explain the divergence between insurer and patient treatment preferences among the subset of patients with CIC who were failing standard OTC laxatives. The optimal cost-effective treatment algorithm from an insurer perspective was to consider covering lubiprostone but, otherwise, to deny prescription drug coverage, consistent with the experience of most gastroenterologists in practice in the absence of negotiated drug rebates or discounts. From a patient perspective, the cost-effective prescription drug algorithm among patients failing standard OTCs started with plecanatide, followed by choosing between prucalopride and linaclotide starting at the 145-μg dose (favoring prucalopride among patients whose work productivity is affected by their disease). Lubiprostone of 24 μg twice daily could be considered, recognizing differences in clinical trial end points amenable to shared decision-making. The patient algorithm was largely driven by expected treatment discontinuation rates and effects of treatment on health-related QOL.
Cost is a critical and necessary component toward managing chronic conditions in modern healthcare (20,44,45). In the United States, CIC drugs cost >$4,000 annually, with consistent use according to the label at their average wholesale prices. Our study found that cost was at least as important as clinical efficacy to patients and insurers, substantiated by our findings that (i) cost-related drivers were largely found to drive treatment factors in sensitivity analysis and (ii) effectiveness was remarkably similar among therapies (all drugs added 0.02 QALYs over the 12-week time horizon, translating into an additional week of full health over the course of 1 year). As a result, the inclusion of cost as a consideration in ranking therapies led to different treatment algorithms in our study compared with those reported in 2 recent network meta-analyses on CIC drugs (17,18). Aligning cost-effective treatment algorithms with ideal clinical outcomes requires that specific cost determinants be addressed both in shared decision-making and at a policy level.
From an insurer perspective, drug rebates passed to insurers may exert profound effects on prescription drug coverage and formulary tier (45,46). In addition, identifying patient subgroups in future studies in whom prescription drug therapy results in decreased healthcare utilization would also affect insurer treatment preferences, noting growing evidence of an association between treatment response and healthcare utilization in CIC (47). Our model suggests that insurers would have increasing preference toward drug therapy among subgroups of patients with greater healthcare utilization such as those typically referred to gastroenterology, contingent on the assumption that effective disease management (regardless of treatment specifics) might actually reduce healthcare utilization (7,34). We also found that clinicians should guide the choice between prucalopride and linaclotide and that an algorithmic approach to insurance coverage determinations is suboptimal, given variation in treatment preferences in sensitivity analysis. Further efforts to identify biomarkers to assist clinicians and patients in choosing between guanylate cyclase-C agonists (such as linaclotide) and serotonin receptor antagonists (such as prucalopride) are clearly needed.
From a patient perspective among patients failing standard OTC laxatives, expectations on comparative tolerability and treatment effects related to QOL seem to be more important than comparative differences in efficacy in choosing an appropriate treatment. Incorporating these considerations together in our model led plecanatide to be the preferred CIC treatment from a patient perspective, recognizing differences between preferred therapies in our model compared with the recent network meta-analyses that informed the inputs for our model. Chronic constipation is also consistently associated with impaired work productivity, which in turn seems to be an important factor to patients in choosing among treatments (48,49). What our study ultimately finds is that the most important question may not simply be “Which drug is most likely to yield the greatest symptom relief?” Instead, the more pertinent questions driving treatment preference may be “How might symptom relief improve QOL and ability to be productive in the workplace?” Strategies to routinely incorporate costs into shared decision-making may improve adherence and treatment outcomes in managing this common and chronic disease in this subset of patients failing standard OTC laxatives (44,50,51).
Several limitations should be considered when interpreting our findings. Importantly, our study was designed solely to investigate cost-related barriers to care among patients with CIC in whom a prescription drug might be reasonably considered and was not intended to imply that CIC prescriptions are more effective than OTC laxatives. Our study was also not intended to imply that prescription drugs generate cost-savings to insurers or patients. Instead, we found that current drug prices are largely not supported even if one assumes that effective disease management might broadly improve QOL, reduce work productivity losses, and improve reduce healthcare costs and utilization (regardless of whether effective management is achieved by prescription drugs or OTCs). There are several evidence gaps in the clinical literature as noted in recent clinical practice guidelines performed according to GRADE methodology: CIC is a chronic disease but head-to-head, long-term data are lacking; overlapping treatments are common in practice but poorly studied in the literature; and there are nuanced differences in clinical trial end points and study populations among drugs (14–16). We addressed most of these problems by conducting a RAND/UCLA expert consensus panel to inform model design, noting rather comparable final model assumptions between our study and recent network meta-analyses and stability in our findings in sensitivity analysis. Although lubiprostone seemed preferred in exploratory analysis, its efficacy end point did not incorporate the sensation of completeness with bowel movements and trials lasted only 4 weeks. Furthermore, no significant improvement in health-related quality of life was found with lubiprostone vs placebo in phase III trials on the PAC-QOL endpoint (52).
Cost, in addition to improvement in quality of life, should be routinely incorporated into shared decision-making in CIC. Cost should also be addressed at a policy level so that patients and physicians can move from navigating barriers in treatment access toward truly optimizing treatment choice.
CONFLICTS OF INTEREST
Guarantor of the article: Eric Shah, MD, MBA, FACG.
Specific author contributions: All authors were involved in the study concept and design and interpretation of data. The modified Delphi panel included study authors except C.A.S., who informed design of this method as a methodologist with expertise in RAND/UCLA Appropriateness Method panels. E.D.S. authored the initial draft of the manuscript and performed statistical analysis, and all authors critically revised the manuscript and approved the final copy.
Financial support: E.D.S. is supported by the AGA Research Foundation's 2019 American Gastroenterological Association-Shire Research Scholar Award in Functional GI and Motility Disorders.
Potential competing interests: E.D.S. received virtual conference registration reimbursement from Bausch Health unrelated to chronic idiopathic constipation or irritable bowel syndrome. K.S. has received research support from Takeda, AstraZeneca, and Gelesis, has served as a consultant or advisor board member for Shire, Synergy, Boston Pharmaceuticals, and Arena Pharmaceuticals, and has served as a speaker for Shire. W.D.C. is a consultant for Allergan, Biomerica, IM Health, Ironwood, Outpost, QOL Medical, Ritter, Salix, and Urovant and has research grants from Commonwealth Diagnostics, Ironwood, QOL Medical, Salix, Urovant, Vibrant, and Zespri. A.L. is a consultant for Allergan, Salix, Ironwood, Takeda, Bayer, and Ardelyx. D.M.B. has served as a consultant, advisor, and/or speaker for Ironwood, Allergan (Abbvie), Salix, Takeda, and Alfasigma; as consultant for Abbvie, BMS, Celgene, Lilly, Janssen, Pfizer, Prometheus, and Takeda; and as speaker for CME activities for Abbvie, Celgene, Janssen, Pfizer, and Takeda; and has received grant support from Abbvie, Janssen, Pfizer, and Takeda and equity interest from Colonary Concepts. The other authors have no disclosures.
WHAT IS KNOWN
- ✓ Chronic idiopathic constipation (CIC) is a common and burdensome illness. The US Food and Drug Administration has approved 4 prescription drugs to treat CIC.
- ✓ The relative influence of costs and clinical outcomes on CIC treatment preferences to both patients and insurers is unknown.
WHAT IS NEW HERE
- ✓ Using cost-effectiveness methodology, we found that prescription drug prices are the major barrier from an insurance perspective to cost-effective treatment with CIC prescription drugs among patient failing standard over-the-counter laxatives—even if one assumes that effective disease management might improve outcomes and reduce healthcare costs.
- ✓ From a patient perspective, the cost-effective algorithm started with plecanatide, followed by either prucalopride or linaclotide starting at the 145 μg dose. This algorithm was driven by expectations on comparative drug tolerability and treatment effects on quality of life.
- ✓ Costs and quality-of-life considerations should be routinely incorporated into shared decision-making in CIC and by policymakers to maximize appropriate treatment choice.
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