Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is complicated by diagnostic challenges, multiple comorbidities, and a poor prognosis. Although considered a relatively rare disease, healthcare costs are substantial and disproportionate to the incidence and prevalence of the disease. The comorbidities associated with IPF not only complicate treatment strategies but also increase the burden for patients via higher costs and undesirable health outcomes. Historically, pharmacologic treatment options for IPF have been limited and are often associated with low efficacy. Two drugs approved for IPF, nintedanib and pirfenidone, offer promise for improving health outcomes and survival during the course of the disease. Considerations of cost and adverse events are important when planning treatment options. Optimizing care through patient-centered care management programs can improve outcomes and health-related quality of life for patients. Such programs emphasize communication between healthcare professionals and patients in order to educate patients on their condition, so they can make informed healthcare decisions. Disease registries can be important tools for optimizing data collection and analysis for a disease with limited incidence and prevalence.
Overall Cost of IPF Care
Am J Manag Care. 2019;25:-S0
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a high mortality rate, a median survival time of 3 to 5 years post diagnosis, and roughly 20% survival at 5 years.1,2 Although IPF is generally considered a rare condition, multiple factors contribute to the substantial and disproportionate costs associated with it. These factors include a high mortality rate, treatment options (including lung transplantation), increased age of patients diagnosed (generally aged ≥60 years), and a variety of comorbidities associated with IPF.3,4
By multiple measures and indices, the costs associated with IPF are substantial. An extensive analysis of claims data from 2000 to 2011 for a Medicare population of 7855 subjects with IPF and 38,856 control subjects aged 65 years and older demonstrated that healthcare utilization and medical costs increase substantially for patients with IPF both before and after diagnosis.5 In the year before diagnosis, healthcare utilization ratios (ie, the ratio of the percentage of the IPF cohort to the percentage of control cohort) for patients in the IPF cohort were significantly higher (P <.01) compared with matched controls in hospitalizations (utilization ratios [95% CI]) (1.8 [1.7-1.9]), emergency department (ED) visits (1.8 [1.7-1.9]), and outpatient visits (1.1 [1.0-1.1]), particularly visits to pulmonologists (5.1 [4.9-5.4]).5
Total annual medical costs were also substantially and significantly greater for the IPF cohort in the year before diagnosis ($10,124 vs $5888; P <.01). Patients in the IPF cohort experienced even greater increases in healthcare utilization and in medical costs throughout the 1-year postdiagnosis study period. The ratios (95% CI) for healthcare utilization measures were all-cause hospitalizations (2.3 [2.3-2.4]; P <.01), ED visits (2.3 [2.2-2.4]; P <.01), outpatient visits (1.1 [1.0-1.1]; P <.01), and visits to pulmonologists (7.1 [6.8-7.5]; P <.01). The total annual medical costs in the 1-year post diagnosis were $20,887 (more than twice the prediagnosis period) for the IPF cohort compared with $8932 for the matched controls (P <.01).5 Using their data, the study authors estimated that the total annual medical costs for Medicare patients with IPF would be more than $3 billion, excluding drug costs, of which $1.8 billion would be attributed to IPF-specific costs.5
High annual medical costs for patients with IPF were also observed in a study using private health insurance claims data. Although the study did not use matched controls, total annual healthcare costs for patients with IPF were in excess of $56,000 over the study period ($61,617 for 2009; $56,949 for 2010; $59,379 for 2011) with respiratory-related annual medical costs accounting for over $21,000 ($21,894 for 2009; $22,117 for 2010; $21,762 for 2011).6
Other measures of healthcare cost and utilization in IPF provide additional perspective. A study utilizing the Nationwide Inpatient Sample database determined that patients with IPF had approximately 7000 hospital admissions unrelated to lung transplant procedures annually, with an average cost per admission of $16,000. The use of mechanical ventilation increased the length of stay (LOS) per hospital admission of patients with IPF by 9.83 days (95% CI, 8.42-11.23; P <.001) compared with admissions with no mechanical ventilation, and showed a corresponding increase in total inpatient costs with mechanical ventilation ($36,911; 95% CI, $32,253-$41,568; P <.001).7 Another study by Yu et al used data from the PharMetrics Integrated Database and found similar results, with the mean LOS for IPF-related hospital admissions of 8 (±10) days with an average cost of $16,812 (±$66,399).8
Various economic and resource parameters from multiple studies illustrate the substantial financial burden that accompanies a diagnosis of IPF. When compared with control groups, patients with IPF consistently encounter higher financial costs and utilize healthcare resources at substantially greater rates, thus magnifying the overall disease burden beyond the relatively low incidence and prevalence.4,5 Importantly, the estimated financial burden of IPF to Medicare (approximately $3 billion) is an underestimate as it does not include medication costs,4,5,9 which may be more than $24,000 and $36,000 for pirfenidone and nintedanib, respectively, based on estimates gleaned from literature review through 2015.9
Implications of IPF-Associated Comorbidities
In addition to the direct complications of IPF, comorbidities can contribute to increased mortality risk, increased healthcare utilization, increased healthcare costs, and diminished health-related quality of life for patients.10-13 Common comorbidities may be categorized by organ or physiologic system (Table 110), including pulmonary, cardiovascular, gastrointestinal (GI), endocrine/metabolic, and mental health.10 Patients with IPF often present with multiple comorbidities that can elevate the mortality risk.12 Cardiovascular disease, lung cancer, and diabetes are some of the common comorbidities that significantly increase mortality risk.12,13 Patients may also present with comorbidities before a diagnosis of IPF. Collard et al evaluated claims data for patients during the 6 months before IPF diagnosis (preindex period) and subsequent claims (postindex period) over the study period between January 1, 2001, and September 30, 2008. They found that, compared with a control cohort, patients with IPF were at higher risk in the preindex period for pulmonary hypertension (PH) (relative risk [95% CI]) (15.56 [9.39-25.80]; P <.0001), emphysema (7.11 [95% CI, 5.79-8.73]; P <.0001), pulmonary embolism (6.97 [4.92-9.89]; P <.0001), chronic bronchitis (5.19 [4.50-6.02]; P <.0001), and pulmonary infection (4.20 [3.86—4.57]; P <.0001). The rates of those same comorbidities were also higher in the IPF cohort compared with the control cohort in the postindex period of the study.14
The poor prognosis and progressive nature of IPF can create challenging clinical scenarios for the treatment of comorbidities, with many questions remaining regarding proper management. When considering treatment options for managing comorbidities in patients with IPF, clinicians may need to balance the potential for improving life expectancy and quality of life with the potential for exacerbation of IPF symptoms and/or acceleration of IPF disease progression.15-18 Clinicians should also be aware that many recommendations for comorbidity treatment options are based on studies of patient populations without IPF.19
As research continues, specific recommendations for patients with IPF should evolve for the proper management of lung cancer, PH, and venous thromboembolism (VTE).16,19 With increases in mortality associated with lung cancer treatment options (eg, chemotherapy, radiation, surgery) in IPF, careful consideration of the risks and benefits is warranted.10,16,19 Treatment options for PH in IPF, particularly the role of sildenafil, are not well defined as there have been mixed results from a number of clinical trials using various vasodilator therapies.10,16,17,19 In the treatment of VTE with anticoagulants, no clear agent of choice has been identified, although the use of warfarin is not recommended based on evidence from clinical trials.10,16,17,19 On the other hand, treatment for gastroesophageal reflux disease is generally recommended because the cost of therapy is low and clinical trial results show modest improvements in IPF outcomes with antacid therapies.16,17 The use of continuous positive airway pressure is regularly recommended to treat obstructive sleep apnea, which is common in IPF.10,16,19 As the range of comorbidities in IPF affects a number of organ and physiologic systems, comprehensive approaches that emphasize early detection and prompt management of comorbidities are important for patient care, and research into the most effective treatment options for patients with IPF is warranted.15-17
Evaluating Outcomes Data
In the absence of clinical studies comparing the IPF drugs head-to-head, systematic reviews and network meta-analyses are useful substitutes, and such studies have compared pirfenidone, nintedanib, N-acetylcysteine, and sildenafil.20-25 Despite employing different analytical methods, the systematic reviews and network meta-analyses were fairly consistent in their evaluations of pirfenidone and nintedanib, with some specific differences. The network meta-analysis from Loveman et al found that both pirfenidone and nintedanib significantly reduced the rate of forced vital capacity (FVC) decline when compared with placebo, with nintedanib performing better than pirfenidone in an indirect comparison.25 Canestaro et al concluded that nintedanib and pirfenidone were equally efficacious in slowing decline in percent predicted FVC. They also concluded that the drugs were similar in their effects on respiratory-specific mortality (odds ratio [OR] [95% CI], 0.92 [0.42-2.04]) and all-cause mortality (OR [95% CI], 0.98 [0.53-1.81]).20 In a network meta-analysis from Rochwerg et al, the authors determined that sildenafil, pirfenidone, and nintedanib may extend survival to similar extents.24 A systematic review and meta-analysis by Rogliani and colleagues concluded that pirfenidone and nintedanib significantly reduced FVC decline and the risk of FVC decline of greater than 10%. They also determined that nintedanib was effective in reducing both overall deaths and those due to respiratory causes, as well as in reducing acute exacerbations of IPF.23 The modeling conducted by Chan et al determined that pirfenidone may have a greater numerical impact compared with nintedanib, but the researchers qualified their evaluation by highlighting the overlapping 95% CIs for the drugs.22 On the other hand, the analysis by Fleetwood et al determined that pirfenidone and nintedanib were both effective compared with placebo regarding change from baseline of FVC over 1 year, but only pirfenidone was effective in reducing all-cause mortality over 1 year compared with placebo.21 Although the systematic reviews and meta-analyses provide important data, they underscore the need for direct-comparison clinical trials of the drugs.
Role of Disease Registries in Developing Best Practices
A complicating factor in treating patients with rare diseases, including IPF, is a difficulty associated with administering clinical studies with sufficient numbers of participants. Disease registries are databases that typically combine data from several clinical sites, thus expanding the number of patients to evaluate.26-28 Clinicians can gain valuable information from IPF registries, including data used to make comparisons between nintedanib and pirfenidone in the absence of direct head-to-head clinical trials.21,29-32 IPF registries, such as the Australian IPF Registry and the INSIGHTS-IPF Registry, have been used to investigate the correlation between patient characteristics and health-related quality of life in patients with IPF.33,34 Clinicians, patients, and caregivers should be aware of the multiple, ongoing IPF registry efforts32,35 and consider ways to participate in such programs that best fit their needs and goals, particularly given the potential benefits to IPF research and care.
Applying Strategies to Balance Costs With Improved Outcomes
Collard et al estimated the healthcare costs associated with IPF to be substantial at $3 billion alone for Medicare, excluding medication costs5; it is evident that major drivers of the high healthcare costs are the chronic and debilitating nature of IPF along with the many comorbidities associated with the condition.9,36 Clinicians have touted early diagnosis coupled with assertive treatment of comorbidities to best treat patients with IPF and to reduce costs.37,38 The newest IPF drugs on the market, nintedanib and pirfenidone, are estimated to cost approximately $100,000 per year,39 a high cost burden for patients, Medicare, Medicaid, and private insurers. Published cost-effectiveness analyses can help clinicians and managed care professionals determine whether to add one of the drugs to a patient’s treatment regimen. However, the extent of clinical effectiveness compared with the cost has led to a lack of consensus on the cost-versus-benefit analyses for the drugs, particularly because the available data have mostly come from Europe.40,41
A recent retrospective analysis of nintedanib and pirfenidone in a US population considered the financial burden of the drugs. The average monthly co-pay for nintedanib was $235 (SD $551; range, $0-$8104), while the average monthly co-pay for pirfenidone was $339 (SD $586; range, $0-$4449).42 Considering that patients with IPF are likely to have at least 1 potential comorbidity and multiple prescriptions, the cost to patients can be a burden.
Optimizing Patient Care
Care management programs
IPF presents to clinicians as a challenging disease state that is further complicated by the multiple comorbidities affecting several organ and physiologic systems. This complexity lends itself to multidisciplinary team approaches for managing patients with chronic diseases.36,43,44 The first step in optimizing patient care is for clinicians to be familiar with and be able to apply the current IPF practice guidelines.17 Knowledge of and appropriate management of comorbidities is also necessary. Assertive treatment after diagnosis, rather than waiting to treat until after symptoms progress, may benefit patients.36,43 Treatment of patients with IPF through multidisciplinary teams may improve patient outcomes, including improved patient survival, decreased ED visits, and reduced respiratory-related hospitalizations.36,43-48 Patient-centered care management programs can improve health outcomes while reducing healthcare costs. Owens outlined characteristics of an IPF care management program that emphasizes communication among healthcare professionals and patients, patient counseling, and professional support (Table 2).36
Patient Education, Therapy Expectations, and Improving Adherence to Therapy
Addressing the needs of patients and their caregivers is an important component to management of IPF. A patient-centered approach to treating IPF can be helpful in optimizing patient outcomes. With the progressive nature of and poor prognosis associated with IPF, a focus on patient quality of life is important. Patients and their caregivers want to be educated on disease prognosis and expected outcomes of therapy to make informed decisions regarding treatment.49-53 Additionally, monitoring for adverse events (AEs) and adherence to therapy is important in managing costs. Patients may choose to stop taking a medication due to AEs instead of seeking follow-up to address complications and lead to a change in therapy or reduction in dosage. Preliminary results from a retrospective study with data presented in abstract form revealed a discontinuation rate of 26.0% versus 19.5% when comparing pirfenidone with nintedanib therapy.54 Providers need to consider potential reasons for nonadherence and address them with patients. Ultimately, patients with IPF face the prospect of a progressively worsening disease with low 5-year survival rates. Personalized communication with patients and caregivers is essential to best care for patients throughout the natural arc of the disease, including end-of-life care.43,48 As the percentage of patients with IPF with palliative care referrals appears to be very low, planning for palliative care is considered one of the unmet needs in IPF.55 Palliative care has the goal of advance care planning, relief of physical and psychological burden, and patient and caregiver education.56 The literature supports the opportunity for earlier consideration of referral to palliative care.43,48,56 Of note, high intensity hospital care (intensive care unit [ICU] admissions) occurred in more than 1 in 3 patients within 4 months of their first clinic visit at a lung disease specialty center, but only 3.8% of admitted patients had been referred for palliative care prior to their admission.57 In addition, an analysis of a larger cohort of subjects at a specialty lung center determined that the percentage of patients with IPF descendants with a formal palliative care referral was only 13.7% (38 of 277 subjects).58 Given that the majority of deaths occur in ICU settings, the need for earlier referral and further study of the adequacy of end-of-life management in IPF is needed. Clinicians treating patients with IPF, therefore, should be prepared to communicate with the patient and their caregivers to make palliative care plans.43,48,56
Optimizing Pharmaceutical Care
The complexity of IPF, including the numerous comorbidities typically associated with the condition, provide opportunity to optimize the pharmaceutical care necessary to treat patients with IPF. Polypharmacy would likely be an issue for pharmacists to manage in order to optimize pharmacologic therapies as well as to prevent drug—drug interactions. With pirfenidone being metabolized by the CYP1A2 isoenzyme59,60 and nintedanib a substrate for P-gp and CYP3A4,59,61 pharmacists should be aware of the potential for drug—drug interactions when managing patients with IPF. Of particular importance is the use of proton pump inhibitors in patients with gastroesophageal reflux disease; omeprazole and esomeprazole are CYP1A2 inhibitors and therefore may increase pirfenidone exposure. Counseling patients on common AEs, such as photosensitivity with use of pirfenidone and the consequent importance of sunscreen selection, is also necessary to keep them informed and to manage expectations. Furthermore, drug management by pharmacists could help improve compliance and therapeutic outcomes for patients with IPF, as these are particularly critical issues for this disease state given the high cost of new therapies.62,63 Pharmacists may also be in a position to work with patients and the healthcare team to address potential negative impacts of high drug therapy costs. The concept of financial toxicity, most recently and most commonly applied to oncology care,64,65 may also be a consideration for patients with IPF.66
Patients with IPF can experience multiple comorbidities, low survival rates, loss of quality of life, and substantial medical costs. However, the antifibrotic drugs nintedanib and pirfenidone may offer hope in mitigating the progression of this debilitating disease. Multidisciplinary healthcare approaches that focus on early diagnosis and assertive treatment of IPF, before disease progression, may help improve health outcomes while managing costs. Care management programs can be important components of such approaches, particularly for monitoring and treating comorbidities. Pharmacists can be integral to effective disease management for patients with IPF by being involved in medication therapy management, monitoring and avoiding drug—drug interactions, improving medication adherence, and assisting with approaches to mitigate the financial burden of drug therapies. Disease registries may be underused resources that can be beneficial in developing best practices by serving as useful resources for the storage of large datasets for subsequent analyses.Author affiliation: Consultant, Birmingham, AL.
Funding source: This activity is supported by an educational grant from Genentech, Inc.
Author disclosure: Dr Morrow has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address correspondence to: Thomasmorrowmd@hotmail.com.
Medical writing and editorial support: Thomas J. Cook, PhD, RPh.
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