Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally high blood pressure (ie, hypertension) in the pulmonary artery, with 1000 new cases being diagnosed annually in the United States, based on a 2009 report.1 Because of the complex nature of PAH and its treatments, healthcare providers must closely follow patients with PAH; depending on the stage of the illness, patients should generally be seen by a physician every 3 to 6 months according to the 2009 American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association.1
One treatment regimen for PAH includes the use of endothelin receptor antagonists (ERAs), namely ambrisentan (Letairis) and bosentan (Tracleer). Ambrisentan is a nonsulfonamide, propanoic-class ERA, whereas bosentan is a sulfonamide-class ERA and was the first US Food and Drug Administration (FDA)-approved ERA for the treatment of PAH. Because of the small number of patients and complexity of the disease, payers generally do not manage the treatment of PAH and leave the clinical treatment decisions to providers who manage patients with PAH. By contrast, providers are heavily involved in the treatment of patients with PAH, particularly nurses. Because of concerns regarding the connection between ERAs and liver damage, ERAs were subject to Risk Evaluation and Mitigation Strategy (REMS) requirements imposed by the FDA. For example, the REMS requirements for ERAs involved monthly liver function tests (LFTs) to ensure patient safety; before refilling a patient’s ERA prescription each month, a representative from the specialty pharmacy was required to verify that the patient completed his or her monthly LFT.
More recently, based on clinical trial data and postmarketing safety information, the FDA concluded that the risk of liver injury in patients treated with ambrisentan is low.2 On March 4, 2011, the FDA approved a change to ambrisentan’s prescribing information, removing language concerning the potential risk of liver injury from the product label. As a result, patients taking ambrisentan are no longer required to obtain monthly LFTs as part of the REMS program.2 This change to ambrisentan’s label did not affect the REMS program for bosentan; the FDA’s monthly LFT requirement for bosentan remains in place. The present study explored the impact of the removal of the REMS monthly LFT requirement for payers, providers who treat PAH, and specialty pharmacies.
In June and July 2011, primary research was conducted with 5 commercial payer decision makers (medical and pharmacy directors whose health plans represent 78,345,000 covered lives collectively), 6 nurses managing patients with PAH, and staff from 4 specialty pharmacies to understand the impact of the removal of the monthly LFT requirement for patients taking ambrisentan. Telephone interviews with payers focused on their plans’ management of ERA therapies and the direct cost-savings and time-savings associated with the removal of the monthly LFT requirement.
Each nurse who treats patients with PAH completed a written survey and telephone interview that included questions designed to quantify resource requirements for activities related to LFTs, as well as time-savings and cost-savings resulting from the change in LFT requirements. Similarly, 4 specialty pharmacy representatives were surveyed and interviewed by telephone to obtain costsavings and time-savings associated with activities related to LFTs.
For the purpose of this study, “direct cost-savings,” “time-savings,” and “indirect cost-savings” are defined as follows:
- Direct cost-savings. Savings derived from a reduction in the number of laboratory tests ordered or medical services performed (eg, a reduction in LFTs ordered); these savings are referred to as direct cost-savings because they translate into fewer tests and services billed to payers
- Time-savings. Savings that result from reduced time spent on LFT-related activities (eg, ordering tests, evaluating results, following up with patients)
- Indirect cost-savings. The monetary value associated with the time-savings; indirect cost-savings were derived using US Bureau of Labor Statistics wage data to convert the time-savings (as measured in minutes) to labor-related cost-savings.
Payers. To assess the impact of the change in LFT requirements for ambrisentan, payers were asked a series of questions on topics such as their plan’s coverage and management of PAH and ERAs, as well as the total direct cost-savings and time-savings that the plan would realize from the change in LFT requirements.
Providers. Provider research focused on the reductions in LFTs ordered and the reduced time spent on LFT-related activities, as well as changes in the frequency of other tests and services associated with LFTs. To capture direct cost data, participants were asked to report each of the following for patients taking ambrisentan before and after the label change:
- Number of patients prescribed ambrisentan
- Frequency and type of LFT ordered
- Frequency and type of additional laboratory tests ordered in conjunction with LFTs
- Frequency and type of services performed in conjunction with LFTs (eg, office visit).
To capture the time-savings and resulting indirect cost-savings realized by providers treating PAH, the nurse participants were asked to estimate the amount of time each type of staff member (ie, physicians, nurses, and administrative staff) spent monthly on 25 LFTrelated activities (Table 1) for their patients taking ambrisentan before and after the label change.
Participants reported the time requirements for each activity using a scale ranging from 0 to 7 (Table 2). To calculate the time saved, the midpoint value of each time range was used, except for the highest range (81+ minutes), which had no end point; the lowest possible value (81 minutes) was used for this range to be conservative. The participants were also asked to rate the overall administrative burden of LFTs on their practice using a scale of 0 to 5, where 0 indicated no burden and 5 indicated significant burden.
Specialty pharmacy research focused on the time-savings associated with the removal of the monthly LFT requirement for patients taking ambrisentan. Participants were not asked about direct cost-savings, because specialty pharmacies do not order tests or provide medical services. Instead, 4 specialty pharmacy participants were asked to estimate the total time that staff members (ie, pharmacists and pharmacy technicians) spent monthly on 3 LFT-related activities for patients taking ambrisentan before and after the label change. These 3 activities involved:
- Communicating with patients regarding LFTs
- Communicating with providers (eg, physician practices) regarding LFTs
- Communicating with payers regarding LFTs.
Interviewees reported the time requirements using a scale ranging from 0 to 5 (Table 3). To calculate the time saved, the midpoint value of each time range was used, except for the highest range (46+ minutes), which had no end point; the lowest possible value (46 minutes) was used for this range to be conservative. In addition, participants were asked to provide the number of patients who were prescribed ambrisentan. Like the providers, specialty pharmacy participants were asked to rate the administrative burden of LFTs on their pharmacy using the same scale of 0 to 5.
Payers. Because of the qualitative nature of the payer interviews, formal data analysis was not required. Interview responses were assessed to tabulate payers’ estimates of overall cost-savings and time-savings attributable to changes in the monthly LFT requirement as a result of the label change, and to identify payers’ coverage and management practices and implications for ERA access.
Providers. Providers completed surveys intended to assess the overall direct cost-savings and time-savings associated with the monthly LFT requirement. Direct cost-savings were calculated by comparing the frequency with which LFTs and other associated tests were performed before and after the label change. Each test included in the survey was identified by a Current Procedural Terminology (CPT®) code (Table 4); the cost associated with each test was based on the Medicare payment rate for 2011.3
Monthly time-savings were reported for physicians, nurses, and administrative staff for 25 LFT-related activities. The time-savings for each activity were summed to illustrate the overall monthly time-savings realized by the facility.
As an extension of the time-savings analysis, the savings in labor costs were calculated based on national wage averages for the respective staff types. Referred to as indirect cost-savings, these figures were calculated using the 2010 US Bureau of Labor Statistics average national hourly wage for office-based physicians ($100.97), administrative staff ($14.31), and specialty nurses ($35.23).4,5 Using the methodology described in a 2010 study,6 a 27% adjustment was added to hourly wages to account for fringe benefits, and opportunity costs were calculated by multiplying each 30-minute increment of time saved by physicians and nurses by $68.97, the 2011 national unadjusted payment rate for a level 3 office visit for an established patient (CPT® code 99213a) under the Medicare physician fee schedule.7
Data on the burden associated with LFTs in the form of direct and indirect cost-savings, as well as timesavings, were calculated on a per-patient per-month (PPPM) basis using the facility’s ambrisentan patient population data reported in the surveys and interviews.
Specialty pharmacies. Because the objectives of the provider and the specialty pharmacy surveys and interviews were closely aligned, the analysis of the timesavings and indirect cost-savings was conducted in a similar fashion. Monthly time spent on the 3 LFT-related activities before and after the label change was reported for pharmacists and pharmacy technicians. The timesavings for each activity were summed to illustrate the overall monthly time-savings realized by the pharmacy.
Indirect cost-savings were calculated using the US Bureau of Labor Statistics average national wage for pharmacists ($52.59) and pharmacy technicians ($14.10), as reported in 2010.8 Fringe benefits and opportunity costs were included in the indirect costs, as described earlier. Data on the overall burden associated with LFTs were assessed in the form of indirect cost-savings and timesavings on a PPPM basis.
Although the total impact of PAH on their plans is limited, all payer decision makers interviewed acknowledged the high cost of PAH treatment and management on a per-patient basis. Most payers were also aware of the REMS requirements for ERAs, as well as the ambrisentan label change; however, payers indicated that they generally leave decisions regarding ERA selection and other aspects of PAH treatment to physicians.
The total estimated direct cost-savings averaged $28 PPPM, yet given the high overall PAH treatment costs for payers, the savings PPPM are relatively small. All participating payers indicated that no time-savings would result from the change in LFT requirements, considering that claims processing for LFTs is automated. In addition, the payers reported that REMS requirements did not play a role in their plans’ coverage or management of either ambrisentan or bosentan.
The responses from participating providers who manage patients with PAH indicate that the majority of the savings associated with the ambrisentan label change was driven by an average 69% reduction in LFTs for patients taking ambrisentan. Most of this reduction can be attributed to a decrease in the frequency of administering LFTs for patients taking ambrisentan from once monthly (which was required by the REMS before the label change) to once every 3 months. The reduced frequency of administering LFTs reflects the revised REMS language for ambrisentan, which states that LFTs should be performed at the physician’s discretion; interviewees stated that most patients using ambrisentan now undergo LFTs at their regularly scheduled clinic appointments for PAH—once every 3 months on average. The reduction in LFTs was responsible for direct cost-savings in the form of fewer tests billed to payers, and time-savings in the form of reduced time spent by providers on LFT-related activities.
The average time-savings realized by providers was 12.0 minutes PPPM, representing a 76% average reduction in time spent on LFT-related activities; 1 clinic reported time-savings of 91%. Savings were realized by each provider type (ie, physicians, nurses, and administrative staff), and were most pronounced for nurses, because they are most intensely involved in the daily management of PAH. Results of this study show that nurses saved an average of 8.2 minutes PPPM as a result of the label change for ambrisentan. Table 5 lists the 5 activities for which nurses realized the greatest monthly time-savings, based on 431 patients. These activities represent only 20% of the 25 activities for which nurses were asked to estimate time-savings (Table 1); the wide range of activities in which nurses are involved demonstrates their important role in the management of patients with PAH.
The average direct cost-savings PPPM for the providers interviewed was $10.75; the average PPPM time-savings was 12 minutes, resulting in an indirect cost-savings of $29.75 PPPM. Direct cost-savings were calculated using 2011 Medicare reimbursement rates, as described above. Fringe benefits and opportunity cost adjustments, as described above,6 were included in the indirect cost-savings.
Using the rating scale of 0 to 5, providers rated the overall administrative burden of LFTs on nurses an average of 1.3 after the label change compared with 3.9 before the label change, which supported the significant reduction in time spent on LFT-related activities. The changes in ratings for physicians and administrative staff were comparatively smaller, illustrating that the administrative burden of LFTs is felt largely by nurses.
The results of the interviews with specialty pharmacies indicated that the average time-savings for all specialty pharmacies surveyed was 14.0 minutes PPPM, representing an 86.7% decrease in the amount of time specialty pharmacies spent on LFT-related administrative tasks for patients using ambrisentan. This average time-savings translates to an average indirect cost-savings of $11.97 PPPM among patients using ambrisentan.
The total indirect cost-savings for specialty pharmacies was greater than the time-savings alone, because in some instances the pharmacies were able to shift responsibilities for LFT-related activities from higher-cost staff members, such as pharmacists, to lower-cost staff members, such as pharmacy technicians. Before the label change, the REMS requirement around LFTs mandated that a pharmacist perform patient counseling; some participants reported that with the removal of this requirement for ambrisentan, patient counseling can now be provided by other staff members at a lower cost to the specialty pharmacy.
Using the scale of 0 to 5, participants rated the administrative burden associated with performing LFTrelated tasks on their pharmacy an average of 0.5 after the label change compared with 2.5 before the label change, again illustrating that the label change has reduced the burden of LFTs on specialty pharmacies.
With the removal of the monthly LFT requirement for ambrisentan, providers who treat PAH, specialty pharmacies, and payers have all reported that they realized savings in direct costs or in time spent performing LFT-related activities. Further research could explore the time-savings and cost-savings realized by patients on activities directly and indirectly related to LFTs. The results of this study may underestimate potential time-savings and cost-savings. All the providers who treat PAH and were surveyed have elected to use LabSync, an optional laboratory scheduling and management service offered by Gilead Sciences (the manufacturer of ambrisentan) to help coordinate required laboratory tests for patients taking ambrisentan. Providers who do not participate in LabSync might have seen greater savings than those reported in this study, because nonparticipating providers likely spend more time coordinating their patients’ LFTs.
In addition, this particular analysis provides a snapshot of data based on the number of patients taking ambrisentan that each practice was following at the time the research was conducted. The analysis does not take into account practice growth, or patients who have been switched from bosentan to ambrisentan since the label change. For example, multiple providers indicated that they have switched several patients who were using bosentan to ambrisentan since the label change and will continue to prescribe ambrisentan more frequently for their patients as a result of the reduced burden of LFTs associated with the label change.
The analysis also does not forecast additional savings that may result from future changes in practice patterns for patients using ambrisentan—several practices indicated that they would consider further reducing LFT frequency for patients taking ambrisentan (eg, to once every 6 months or once annually) in the future. Future research would be needed to quantify the impact of changes in ERA prescribing and LFT ordering practices attributable to the label change.
The management of patients with PAH requires extensive coordination between patients, their support system, third-party payers, and healthcare professionals.9 The reductions in time spent on LFT-related activities as reported in this study may enable both providers and specialty pharmacies to devote more of their resources to patient management, education, and counseling.
This potential impact is especially significant for nurses, who typically spend the most time managing patients with PAH. For example, a reduction in time spent on administrative tasks related to LFTs may allow nurses of patients with PAH to spend more time counseling and educating their patients via telephone, as recommended by McLaughlin and colleagues.1 Although further research is needed in this area, several nurses managing PAH surveyed for this study saw a significant reduction in time-consuming activities, including completing standing LFT orders and tracking and obtaining LFT results.
The financial benefits associated with the ambrisentan label change become even greater when the patient’s perspective is taken into account; a separate study conducted with patients indicates that before the label change, the average patient using ambrisentan spent $40 monthly on LFT-related costs, including insurance copayments and costs for transportation to and from testing locations.10 The current study conducted with payers, providers treating PAH, and specialty pharmacies indicates that the ambrisentan label change has resulted in a significant reduction (69% on average) in the frequency of LFTs, and that this has produced time-savings and indirect cost-savings across providers treating PAH and specialty pharmacies surveyed, as well as direct costsavings for payers. The label change for ambrisentan reflects a unique FDA position; the removal of the monthly LFT monitoring requirement is a reflection of ambrisentan’s safety profile,10 and also has led to decreased administrative and cost burden for providers.
It is important to note the limitations of this study. First, the sample size for each stakeholder group involved in this study was small; as a result, the impact of the ambrisentan label change may not be fully reflected in this study’s findings. Second, as discussed above, prescribing trends were not systematically tracked in this study; therefore, the findings reflect only the immediate impact of the removal of the monthly LFT requirement for ambrisentan and do not address long-term implications.
Third, savings realized by patients were not captured in the study. Finally, this study focused only on the time-savings and cost-savings associated with patients taking ambrisentan; it did not address how the resources required for these patients compare with the resources required for patients who are prescribed bosentan. The exact impact of the label change likely will vary based on each stakeholder’s mix of patients taking ambrisentan and bosentan.
The limitations of this study potentially could be addressed by expanding the scope of future research efforts in this area—for example, by including a more robust sample of all relevant stakeholders (patients, payers, providers, and specialty pharmacies), by conducting a longitudinal analysis that tracks savings over time, or by examining differences in resources for patients taking ambrisentan versus those taking other ERAs.
The FDA’s removal of the REMS requirements for monthly LFTs for patients using the ERA ambrisentan has resulted in considerable cost-savings and time-savings for providers and specialty pharmacies, and modest cost-savings for payers. Nurses in particular realized significant time-savings resulting from the reduction in LFTs for patients receiving ambrisentan. Further research could explore the cost-savings and time-savings realized by patients on activities directly and indirectly related to the reduced requirement for LFTs associated with the use of ambrisentan.
Study Funding This study was supported by funding from Gilead Sciences, Inc.
Author Disclosure Statement
Ms Durst has reported no conflict of interest related to this study. Mr Carlsen, Ms Kuchinski, Ms Harner, Mr Neves, Ms Harris, and Ms Traiger have served as Consultants to Gilead Sciences, Inc.
- McLaughlin VV, Archer SL, Badesch DB, et al, for the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension developed in collaboration with the American College of Chest Physicians, American Thoracic Society, and the Pulmonary Hypertension Association. Circulation. 2009;119:2250-2294.
- US Food and Drug Administration. FDA Drug Safety Communication: Liver injury warning to be removed from Letairis (ambrisentan) tablets. March 4, 2011. www.fda.gov/Drugs/DrugSafety/ucm245852.htm. Accessed August 4, 2011.
- Centers for Medicare & Medicaid Services. Clinical Laboratory Fee Schedule: 11CLABMAR. March 2011. www.cms.gov/ClinicalLabFeeSched/02_clinlab.asp. Accessed August 4, 2011.
- US Bureau of Labor Statistics. May 2010 national industry-specific occupational employment and wage estimates NAICS 621100-offices of physicians. May 17, 2011. www.bls.gov/oes/current/naics4_621100.htm. Accessed March 16, 2012.
- US Bureau of Labor Statistics. May 2010 national industry-specific occupational employment and wage estimates, NAICS 622300-specialty (except psychiatric and substance abuse) hospitals. May 17, 2011. www.bls.gov/oes/current/naics4_622300.htm. Accessed March 16, 2012.
- Raper JL, Willig JH, Lin HY, et al. Uncompensated medical provider costs associated with prior authorization for prescription medications in an HIV clinic. Clin Infect Dis. 2010;51:718-724.
- Centers for Medicare & Medicaid Services. Physician fee schedule, relative value files-RVU11C. July 2011. www.cms.gov/PhysicianFeeSched/PFSRVF/itemdetail.asp?filterType=none&filterByDID=-99&sortByDID=1&sortOrder=descending&itemID=CMS1247894&intNumPerPage=10. Accessed August 4, 2011.
- US Bureau of Labor Statistics. May 2010 national occupational employment and wage estimates, United States, April 6, 2011. www.bls.gov/oes/current/oes_nat.htm#29-0000. Accessed August 4, 2011.
- Housten-Harris T. The nurse specialist and practical issues in the care of pulmonary arterial hypertension patients. Int J Clin Pract Suppl. 2007;(158):10-18.
- Gilead Sciences. US FDA removes warning about potential liver injury from boxed warning of prescribing information for Gilead’s Letairis. Press release, March 4, 2011. www.gilead.com/pr_1535940. Accessed August 10, 2011.