Taylor Bradshaw, PharmD, BCACP, Allergan plc
5 Giralda Farms, Madison, NJ 07940
Phone: (314) 568-2092 Email: Taylor.Bradshaw@Allergan.com
This review was sponsored by Allergan plc, Dublin, Ireland. Writing and editorial assistance was provided to the authors by Karen B Chien, PhD of Complete HealthVizion, Inc, Chicago, IL, and funded by Allergan plc. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Allergan plc provided suggestions for topic ideas and authors of this manuscript to Complete HealthVizion. Allergan plc was not involved in the development of the manuscript with the authors or the vendor. Allergan plc had the opportunity to review the final version of the manuscript and provide comments; however, the authors maintained complete control over the content of the paper.
The authors would like to thank Karen B Chien, PhD, of Complete HealthVizion, for assistance with writing and revising the draft manuscript based on detailed feedback from all authors; this assistance was funded by Allergan plc. Primary responsibility for opinions, conclusions, and interpretation of data lies with the authors; all authors approved the final version of the manuscript.
Chronic constipation can occur due to the aging process and can present as a functional gastrointestinal disorder such as constipation-predominant irritable bowel syndrome (IBS-C) or chronic idiopathic constipation (CIC). Constipation results in lower quality of life and increased economic burden. Management of chronic constipation in older adults is critical to avoid unnecessary hospitalizations and potentially fatal complications. This review provides regulatory and clinical updates on the management of chronic constipation in post-acute care facilities (long-term care and assisted living facilities), including bowel-specific updates from the Final Rule on the Requirements of Participation from the Centers for Medicare & Medicaid Services (effective November 28, 2017). Updates on linaclotide use and costs in older adults with chronic constipation are provided, given its existing evidence as an efficacious and well-tolerated monotherapy and the flexibility of a new lower 72 μg daily dose for CIC. Significantly greater percentages of responders were reported with linaclotide compared with placebo in multiple phase 3 clinical trials for both IBS-C and CIC; adverse events, most commonly diarrhea (16%-20%), were typically mild, with only 9% of study participants discontinuing treatment.
Key words: irritable bowel syndrome; constipation-predominant irritable bowel syndrome; chronic idiopathic constipation; long-term care; clinical practice guidelines; linaclotide; Requirements of Participation
The prevalence of constipation in the general population ranges from 2% to 27%, depending on the definition used.1 Approximately 50% of older adults aged 65 years and older experience chronic constipation.2 Of adults aged 65 years and older residing in skilled nursing facilities (SNFs), up to 74% use laxatives for constipation-related conditions, including irritable bowel syndrome (IBS) and chronic constipation.1,2
General risk factors for chronic constipation have been identified and detailed in other reviews; these include female sex, nonwhite race, physical inactivity, low income, low educational level, medications, dietary intake, dehydration, and depression.2-4 However, chronic constipation in older adults is multifaceted. Mechanical, biologic, and macroscopic changes in the gastrointestinal (GI) tract that occur during the aging process can affect bowel structure and function, resulting in slow colonic transit and pelvic floor disease, which may lead to constipation.2 In addition, other psychologic and comorbid factors previously characterized as the “10 Ds” may contribute to the disease
pathology (Box 1).2
Although the causes of constipation may differ between older adults and the general population, characterization by different types of functional GI or bowel disorders is similar and includes functional constipation (ie, chronic idiopathic constipation [CIC]), constipation-predominant IBS (IBS-C), and opioid-induced constipation. The Rome IV guidelines released in 2016 provide an update on the definitions of IBS-C and CIC (Figure 1).5
Constipation symptoms have been found to be correlated with neurologic dysfunction and impaired quality of life, with increasing symptom severity correlating negatively with perceived quality of life.6-9 To improve the quality of health care and patient safety, recent updates have been made to the regulatory requirements for long-term care (LTC) facilities that included maintenance of bowel continence.10 These regulatory changes necessitate a review of the management of constipation, including the available treatment options. This review article provides updated information on guidelines for the management of IBS-C and CIC in the LTC setting, with a focus on the use of linaclotide. Linaclotide is a recently developed medication with potential benefit in older adults; however, it should be noted that there is limited evidence supporting its efficacy and safety in the LTC setting specifically. A review of the available data on linaclotide relevant to older adults is also presented in this article.
Regulatory Guidelines for Management of Constipation in SNF Residents
SNFs caring for older adults are required to be in compliance with Title 42 of the US Code of Federal Regulations (CFR), issued by the Centers for Medicare & Medicaid Services, to receive reimbursement from Medicare or Medicaid programs.10 The Requirements of Participation for LTC facilities, instated in 1989, was most recently updated in October 2016 through a Final Rule, which is currently being implemented in the following three phases: phase 1: by November 28, 2016; phase 2: by November 28, 2017; and phase 3: by November 28, 2019. The revisions aim to improve the quality of health care, service delivery, and patient safety based on recent technologic advances, with the overall goal of reducing procedural burdens on health care providers.
In the Final Rule, LTC facilities are required to develop, implement, and maintain a comprehensive, data-driven Quality Assurance and Performance Improvement program (42 CFR 483.75).10 Several priorities for LTC facilities regarding the care and maintenance of a resident’s bowel function should be considered. Bowel-specific updates in the Final Rule include the provision of services and assistance to residents for the maintenance of continence. Sentinel health events regarding constipation, including the prevalence of fecal impaction and dehydration, have been defined as quality indicators/measures that should occur infrequently at a facility; even one occurrence of an event warrants investigation.11
Facilities should confirm compliance with F-tag 329 (42 CFR 483.25[l], F329) on Unnecessary Drugs12; this rule has been redesignated to F-tag 757 (42 CFR 483.45[d], F757) on Pharmacy Services in the Final Rule, implemented in phase 1.10 It states that duplicate therapy, or multiple medications of the same pharmacologic class/category that substantially duplicate a particular effect of another medication that is being taken, is generally not indicated unless current clinical standards of practice and documented clinical rationale can confirm benefits. Drug effectiveness should be continuously monitored, especially in the case of laxative use, to avoid misuse in those with no formal diagnosis of constipation.13
To define an appropriate individualized care plan for residents with constipation, accurate information on their current bowel status is necessary. The Minimum Data Set (MDS) is a required comprehensive assessment completed upon admission to a Medicare-/Medicaid-certified nursing home. The form gathers information regarding resident status on bladder and bowel function in Section H.14 Bowel function is specifically covered in H0400 (bowel continence), H0500 (bowel toileting program), and H0600 (bowel patterns) (Figure 2).14 Bowel continence is coded on a scale of 0 (always continent) to 3 (always incontinent). The bowel toileting program is coded as yes/no for whether a resident is currently using a toileting program to manage bowel continence. Bowel patterns is coded as yes/no for constipation, with constipation being defined as two or fewer bowel movements for the previous 7 days or as having hard and difficult-to-pass stools regardless of the frequency. This suggests that the MDS nurse in an SNF may be positioned to identify trends in bowel issues and can create a report that identifies residents at risk.
A consultant pharmacist is another critical member of the SNF bowel management team (Table 1). As consultant pharmacists complete drug regimen reviews at least monthly, they are well positioned to identify patients who would be better managed on regimens beyond over-the-counter (OTC) medications. While this is determined on an individual basis, consultant pharmacists can also educate the SNF interdisciplinary team and lead the development of efficient and effective bowel protocols.
SNFs should consider key actions regarding the management of chronic constipation in residents (Box 2). Although the completion of the MDS allows for the planning of care for residents, symptomology may not be fully captured. In addition to documenting the number of bowel movements (or lack thereof), collecting information on episodes of straining, manual maneuvers required, and thorough characterization of stool consistency may also be useful to better characterize the extent of a resident’s constipation. Clinical guidelines may further guide treatment selection and the ongoing maintenance of a resident’s bowel conditions.
Clinical Guidelines, Considerations, and Treatment Limitations for Management of Constipation
The management of chronic constipation in older adults, including maintaining appropriate stool consistency and some degree of bowel movement regularity, can be challenging because disorders present heterogeneously, often existing on a continuous spectrum.5 Constipation can become a severe issue if complications such as fecal impaction and bowel obstruction arise and are left untreated or treated improperly, potentially leading to perforation and even death.15-17 Independent risk factors for fecal impaction include controlled constipation, uncontrolled constipation, the number of medications used, reduced functional capacity, and the occasional use of nonsteroidal anti-inflammatory drugs.18 Fecaloma is defined as fecal impaction due to a hardened mass of stool. In three cases of fecaloma in older patients, perforations and ischemia of the colon resulted in death; these cases occurred in patients aged older than 76 years with a long history of chronic constipation.16 Therefore, it is critical to prevent impaction and early fecaloma in older adults with constipation through careful observation and regular rectal examinations.
Treatment selection depends on the cause of constipation and the severity of symptoms, as well as whether the symptoms are chronic. First-line nonpharmacologic treatment methods include bowel training and biofeedback therapy.19 Bowel training with the help of an educator, which involves lifestyle changes (eg, implementing a daily morning routine of mild physical activity, drinking a hot caffeinated beverage, eating a breakfast rich in soluble fibers), has been shown to improve symptoms.19 Scheduled toileting after meals may be advantageous, with stimulation of the bowel movement from the gastrocolic reflex.20 General changes in diet, including increased fluids and the addition of dietary fiber (eg, polycarbophil, methylcellulose, psyllium) between 20g and 35g per day, are recommended.20 However, even with use of nonpharmacologic interventions, symptoms typically persist, leading to the need for pharmacologic treatments.19,20 It is essential to undertake a careful physical, psychologic, and bowel history prior to implementing laxative use to avoid unnecessary and ineffective treatment.4
Laxative use substantially increases with advanced age, and, as many users continue to have considerable symptoms even with single laxative use, multiple laxative use in nursing home residents remains common.1,4,21 In several reviews of older SNF residents presenting with constipation, laxatives have been the standard treatment, with up to 74% of patients with constipation using daily laxatives and 50% of all laxative users taking multiple laxatives.1,13 One major obstacle to using newer US Food and Drug Administration (FDA)-approved medications and nonconventional solutions beyond laxatives is the difficulty in comparing trials between therapies, particularly for older adults. Furthermore, clinical evidence for efficacy and safety supporting the use of new therapies in older adults is limited due to low enrollment numbers for this population. However, ineffective treatments for constipation in older adults can result in significant increases in health care resource use and costs in the LTC setting.22,23
A 2010 US database study showed that the incidence of LTC use as a health care resource was significantly higher among patients with IBS-C or chronic constipation with treatment failure.22 Results from another 2014 US study using the National Inpatient Sample Database revealed that the number of hospitalizations due to constipation increased by 128.6% between 1997 and 2010, resulting in a total cost of $851,713,263 (2010 USD); older adults aged 65 to 84 years accounted for 38% (1997) and 29% (2010) of the total constipation-related discharges, which were the largest percentages out of all age groups.23
For adult residents in SNFs, Medicare Part A/subacute plans cover the SNF care for the resident; therefore, the SNF is responsible for the accumulated prescription costs.24 After Medicare Part A coverage is exhausted, LTC residents with dual eligibility for both Medicare and Medicaid may have their prescriptions covered fully, with no or minimal out-of-pocket costs for themselves or for the SNF.25
In addition to OTC medication and prescription costs, financial considerations for bowel management in SNF residents include staff time and the potential impact of poor quality outcomes. Treatment using drugs targeting specific mechanisms of action may be advantageous in this setting, when nonpharmacologic interventions and OTC medication use do not sufficiently manage constipation. Linaclotide (a minimally absorbed guanylate cyclase-C receptor agonist) and lubiprostone (a chloride channel activator) have been used to treat older adults with IBS-C and CIC.20,26 The below discussion is focused on the former, providing updates on the efficacy, safety, and cost of linaclotide for IBS-C and CIC and summarizing to date the supporting data for linaclotide use in older adults.
Linaclotide Treatment for IBS-C and CIC
Linaclotide stimulates intestinal fluid secretion and reduces abdominal pain27,28; it is approved by the FDA for the treatment of IBS-C and CIC.29 The indicated oral dose for older adults and the general population with IBS-C is 290 µg once daily; the indicated oral dose for these populations with CIC is 145 µg once daily or 72 μg once daily, based on symptom presentation or tolerability (Figure 3).29,30 Linaclotide can also be administered using a gastrostomy or nasogastric tube.
Pivotal phase 3 clinical trials have been conducted to assess the efficacy and safety of linaclotide in patients with IBS-C or CIC (Table 2).31-34 In a double-blind, parallel-group, placebo-controlled, randomized, clinical trial of oral linaclotide 290 µg for 26 weeks in 804 patients with IBS-C (n=40; aged ≥65 years), Chey et al31 reported that 33.7% vs 13.9% of linaclotide- vs placebo-treated patients were responders, according to FDA guidance on IBS end point definitions (reporting both ≥30% improvement from baseline in average daily worst abdominal pain score and increase of ≥1 complete spontaneous bowel movement from baseline in the same week for ≥6 out of 12 weeks). Abdominal pain, abdominal bloating, and bowel symptoms were statistically improved with linaclotide vs placebo over 26 weeks.
Another phase 3, double-blind, parallel-group, placebo-controlled trial by Rao et al32 of 800 patients with IBS-C (n=45; aged ≥65 years) on placebo or linaclotide for 12 weeks, followed by a 4-week randomized withdrawal period, found that linaclotide significantly improved abdominal pain and bowel symptoms for at least 12 weeks with no rebound worsening or worsening of symptoms from baseline upon withdrawal. Similar results for efficacy using European Medicines Agency-specified end points were observed in two phase 3, double-blind, multicenter, randomized trials of linaclotide 290 µg for 12 or 26 weeks in patients with IBS-C.33 Results were not analyzed by age in these studies. In two phase 3 placebo-controlled trials evaluating patients with IBS-C by baseline severity of abdominal symptoms, linaclotide improved all abdominal symptoms, global measures, and IBS quality of life in patients with severe symptoms.35 In 26 older women (mean age, 76.4 years) with IBS-C receiving linaclotide 290 μg daily for 12 weeks, abdominal symptoms were reduced, including a greater than 40% reduction in abdominal pain and a greater than 30% reduction in discomfort/bloating.36 Additionally, an increase in weekly spontaneous bowel movements was observed.
In chronic constipation, two phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials were conducted by Lembo et al,34 in which 1276 patients with chronic constipation (n=154; aged ≥65 years) received either linaclotide (145 μg or 290 μg) or placebo. Greater percentages of responders (improvement in frequency of complete spontaneous bowel movements) were observed for linaclotide- vs placebo-treated patients over 12 weeks (Table 2). A meta-analysis by Videlock et al37 that included six randomized placebo-controlled trials examining the effects of linaclotide in adults with IBS-C (by FDA-recommended primary end point) or chronic constipation (by an end point of >3 complete spontaneous bowel movements per week and an increase in ≥1 complete spontaneous bowel movements per week for 75% of weeks) found that linaclotide improved bowel function, reduced abdominal pain, and decreased overall severity compared with placebo. Further, the relative risk for linaclotide 290 μg vs placebo was 1.95 (95% CI, 1.3-2.9) for IBS-C and 4.26 (95% CI, 2.80-6.47) for CIC. Overall, studies on linaclotide in patients aged 65 years or older had approximately 5% and 12% participation for this age group for IBS-C and CIC, respectively. Future studies are needed to confirm efficacy in older adults, as only a small number of patients have been analyzed.38
A longitudinal, claims-linked survey study (including 2052 eligible patients) assessing symptoms, quality of life, and treatment-related patient-reported outcomes, including use of and experience with medications for treating IBS-C and CIC symptoms (Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform), is ongoing beyond clinical trials on efficacy of linaclotide.39 Participants using linaclotide compared to other medications (including polyethylene glycol, GI/proton pump inhibitors, antidepressants and anxiolytics, home remedies, and probiotics) or no medications were more likely to report satisfaction with their bowel movements.40
Linaclotide is well tolerated in multiple age groups across multiple dose ranges, with minimal systemic exposure.29 Evidence suggests that the safety of linaclotide is similar between adult and older adult populations; in the previously mentioned study of 26 older women with IBS-C, 92% completed a 12-week course of treatment, with two withdrawals from adverse events (ie, nausea, diarrhea).36 Caution is advised when prescribing concomitant intestinally absorbed medications with a narrow therapeutic window, such as thyroid-related treatment29; however, phase 3 studies did include patients who were taking concomitant linaclotide and thyroid hormones with normal monitoring. In two studies of patients with CIC (NCT00765882, NCT00730015; data on file), 11.3% of patients treated with placebo and 9.7% of patients treated with linaclotide were also taking concomitant thyroid hormones. In two studies that included patients with IBS-C (NCT00948818, NCT00938717; data on file), 7.3% of patients treated with placebo and 10.4% of patients treated with linaclotide were also taking concomitant thyroid hormones. Further, in two open-label studies of linaclotide that included more than 1200 patients with IBS-C and CIC, approximately 11.3% to 11.4% of the total patient population was taking both linaclotide and thyroid hormones (NCT00730171, NCT00765999; data on file).
In clinical trials of linaclotide, the majority of adverse events were GI related and included diarrhea, abdominal pain, flatulence, and abdominal distension (Table 3).29 Discontinuations due to adverse events in patients with IBS-C taking linaclotide and placebo were 9% and 3%, respectively.29 Although diarrhea occurred in 16% to 20% of patients in phase 3 clinical trials of linaclotide, the majority of cases were mild or moderate in severity.29,31 The risk of diarrhea with linaclotide vs placebo was higher for those with IBS-C than for those with chronic constipation in the previously mentioned meta-analysis by Videlock et al.37 Due to the frequency and risk of diarrhea occurrences, caution should be exercised when considering the use of linaclotide in the LTC population. If dehydration due to diarrhea is observed in a LTC resident upon use of linaclotide, it is recommended to suspend linaclotide use and rehydrate the resident.29
Linaclotide is typically covered as a second- or third-tier medication on most Medicare Part D formularies, with a retail price for available doses ranging from $300 to $500 for a 30-day supply.41 Linaclotide has a higher copay than generics and preferred brand-name prescription drugs for the treatment of constipation; there are no direct data on the cost-effectiveness of linaclotide in the LTC setting, and there are limited data from small sample sizes in older patients.
In a retrospective claims analysis that included a Medicare-insured outpatient population (n=432; mean age, 67.8 ± 12.6 years), pre- and post-linaclotide treatment data showed that, following the initiation of linaclotide, there were significant reductions in per-patient per-month costs for GI-related (pre-linaclotide, $27; post-linaclotide, $14) and IBS- or constipation-related (pre-linaclotide, $10; post-linaclotide, $7) medical office visits (P≤.001 for both).42 However, GI-related and IBS- or constipation-related pharmacy costs per patient per month significantly increased upon linaclotide treatment initiation (costs were the same for both: pre-linaclotide, $34; post-linaclotide, $116; P<.001). Although pharmacy costs are expected to increase with the introduction of a new prescription treatment vs OTC or generic treatments, there were medical costs that were substantially decreased following linaclotide initiation. The authors noted that this was suggestive of a positive effect on patients’ engagement with their health care.
Clinical and regulatory guidelines for managing constipation in older LTC residents are constantly evolving, with improvements to bowel regimens and programs to ensure patient safety and reduce resource and cost burdens observed. Considering the complete picture of constipation symptomology during the review of a resident’s medical history and individual treatment plan may provide a clearer perspective on the most appropriate, most effective choice of therapy. The proper management of constipation in older LTC residents is critical, as untreated symptoms can become life threatening. Many residents are on daily or multiple laxatives yet have no noticeable improvement in their symptoms or quality of life. Therapies with the potential for long-term use, including linaclotide, may be tolerable and effective alternatives for those who have not been effectively managed with standard therapies, especially from a risk management perspective. Linaclotide appears to be cost-effective vs no treatment and may result in some reduced health care resource use. However, interpretation of the data acquired from clinical trials and retrospective claims analyses should consider that insufficient numbers of older adults were available for evaluating their responses compared to younger patients. Future studies of linaclotide use in older adults may benefit from assessing treatment efficacy through impact on toileting time and bowel protocol.
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