VA Sierra Pacific Network (VISN 21) Pharmacy Benefits Management

2019-2020 PGY-2 Quality Improvement Project

Does access to high-cost, potentially life-prolonging therapy lead to positive clinical outcomes and improved quality of life?

Outcomes in VHA Amyloidosis Treatment

Authors

Brandi Gore, PharmD, MHA, PGY-2 Health Outcomes and Analytics Pharmacy Resident
Scott Mambourg, PharmD, BCPS, AAHIVP
Janice Taylor, PharmD, BCPS
Robert Malmstrom, PharmD
Diana Higgins, PharmD
Cherie Dillon, PharmD

Disclosures
The authors of this quality improvement project have nothing to disclose concerning financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation. The presented activities reported in the publication were reviewed by the VA ACOS/R or UNR IRB and found not to constitute research. The contents do not represent the views of the U.S. Department of Veteran Affairs or the United States Government. The project received no funding. This material is the result of work supported with resources and the use of facilities at the VA Sierra Nevada Healthcare System (VASNHCS), Reno, NV. Proprietary information or results of ongoing project may be subject to different interpretations.

Abstract

Primary Objective: To compare clinical outcomes of inotersen (Tegsedi), patisiran (Onpattro), tafamidis (Vyndaqel), and tafamidis meglumine (Vyndamax) in Veterans with amyloidogenic transthyretin amyloidosis (ATTR) polyneuropathy or cardiomyopathy.

Background/Introduction: Amyloidosis is an under-recognized condition with a median survival of 2.5 years. Four new high-cost drugs have been FDA-approved for ATTR polyneuropathy or cardiomyopathy. Based on the average wholesale price, inotersen, patisiran, tafamidis, and tafamidis meglumine costs range from $270,000 to $421,000 annually. There are approximately 5,500 Veterans nationwide with an active amyloidosis diagnosis. This project evaluated patient outcomes of high-cost amyloidosis medications within VHA using descriptive analyses.

Methods: The project was designated as quality improvement by the Institutional Review Board. Baseline demographics (diagnostic classification, age, gender, medication possession ratio) were extracted from the VA Corporate Data Warehouse using Microsoft SQL Server Management Studio. Key observational outcomes (past medication history, symptom onset and progression, objective assessment scores) were collected by reviewing electronic health records. All patients within a specific Veterans Integrated Service Network (VISN), with an approved Prior Authorization Drug Request (PADR) for inotersen, patisiran, and/or tafamidis meglumine were collectively assessed from October 2018 through February 2020.

Results: From October 2018 to February 2020, 276 unique Veterans received amyloidosis treatment from the VHA; 21 (7.6%) of these unique cases fall within the pre-specified VISN. Of the VISN-cohort, diagnostic classification was predominantly cardiomyopathy (71.4%), combination of cardiomyopathy and polyneuropathy (19%), and polyneuropathy (9.5%). Eighteen Veterans (86%) were prescribed tafamidis meglumine and 3 (14%) were prescribed patisiran. Five unique Veterans (23.8%) received alternative amyloidosis treatment before transitioning to tafamidis meglumine or patisiran. The 21 unique Veterans were exclusively male, with an average age of 77 years (range: 68-90 years). The average medication possession ratio, defined as percentage of time with access to medication, was 0.9. The average time receiving VA-treatment was 3.5 months (range: 1-10 months). Objective assessment scores for progression were more commonly found upon baseline assessment than in reassessment screenings. All Veterans continued therapy throughout the assessment period.

Conclusion: During the study period, there were no reported adverse effects for tafamidis meglumine or patisiran. It is difficult to assess how these medications affected cardiomyopathy or polyneuropathy progression, due to the lack of documentation and small sample size. Recommendations for future comparisons with clinical outcomes related to ATTR polyneuropathy or cardiomyopathy include following Veterans over a longer timeframe, as Phase IV trials are still pending completion.

Application to Clinical Practice: This project observed real-world use of clinical guidance in patient selection of these high-cost amyloidosis medications both before and after VA National Criteria for Use were published. Appropriate clinical documentation remains essential to best allocate resources in this patient population

Background

Transthyretin-mediated amyloidosis is a progressive and life-threatening disease, caused by mutations in the gene encoding transthyretin protein, resulting in a variety of polyneuropathy and cardiomyopathy symptoms (1). Median survival in untreated patients is reported to be 2.5 years after diagnosis for transthyretin-mediated amyloidosis caused by pathogenic mutations to the transthyretin gene TTR (ATTRm) caused by TTR Val122Ile and 3.6 years for deposition of wild-type transthyretin protein (2). Response to symptom management remains limited to supportive care, with no guideline-recommended treatment.

Prior to the release of tafamidis (Vyndaqel), tafamidis meglumine (Vyndamax), patisiran (Onpattro), and inotersen (Tegsedi), only off-label treatment modalities were available to reduce TTR synthesis or stabilize TTR tetramers (3). Figure 1 demonstrates the disease progression via aggregation of amyloid fibrils. Tafamidis and tafamidis meglumine are oral transthyretin stabilizers with a labeled indication for amyloid cardiomyopathy and clinical evidence demonstrating slowed progression of peripheral neurologic impairment in amyloid polyneuropathy (2, 4). Patisiran is an injectable medication that reduces TTR synthesis, with a labeled indication for amyloid polyneuropathy; Inotersen is also an injectable with a labeled indication for amyloid polyneuropathy that reduces TTR synthesis, with clinical evidence supporting use in patients with amyloid polyneuropathy and with or without cardiomyopathy (5, 6). There remains no treatment with FDA approved indications for both cardiomyopathy and polyneuropathy.

Figure 1.
Amyloidosis Progression

Based on the average wholesale price, inotersen, patisiran, tafamidis, and tafamidis meglumine costs range from $270,000 to $421,000 annually per patient (Figure 2.). In addition to high cost, limited clinical evidence and limited accessibility presents as a common concern. These medications were not initially part of the original VA National Formulary List, nor were there any specific VA National Criteria for Use (CFU) to navigate the adjudication process for this uncommon condition. The interim process at Veterans Integrated Service Network (VISN) 21—a network of VA health care systems across California, Nevada, Hawaii, the Philippines and U.S. Territories in the Pacific Basin (Figure 3.)— until VA National guidance was released compared clinical outcomes of these four medications in Veterans with amyloid cardiomyopathy and polyneuropathy.

Figure 2.

Figure 3.
VHA categorized by VISN

Methods

Clinical trials were reviewed to determine pertinent quality of life assessments and objective symptom assessments (1, 2, 7, 8, 9, 10, 11, 12, 13, 14, 15). Of the literature reviewed, symptom assessments typically included the 6-minute walk test for cardiomyopathy and either polyneuropathic disability score or familial amyloid polyneuropathy score for polyneuropathy. The Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire were used to screen quality of life assessments in cardiomyopathy; a combination of Neuropathic Impairment Score (Lower Limbs, Modified, Upper Limbs) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy were commonly identified for measuring in polyneuropathy. Upon compilation of reviewed information, contact for permission to use quality of life assessments was sought out for the purposes of this quality improvement project (Table 1.).

Table 1.
Assessment Categories

VA National CFU for inotersen and patisiran were initially published in May 2019, though re-released with tafamidis and tafamidis meglumine in September 2019 to specify cardiomyopathy versus polyneuropathy indication and appropriate starting doses (16, 17, 18). Tafamidis meglumine became the preferred medication for either indication, noting polyneuropathy treatment as an off-label use at this time. Prior to the release of these resources, the review and release of these restricted nonformulary items was variable between hospital locations. Larger health systems within VISN 21 were identified independently to assess for trends in evaluating appropriate treatment candidates. The need to develop a standard VISN 21 Prior Authorization Drug Request (PADR) consult (Figure 4.) for Electronic Health Record (EHR) to couple with the VA National CFU and assist in the documentation process was identified.

Figure 4.
Draft VISN 21 PADR Consult for tafamidis meglumine

Baseline demographics (diagnostic classification, age, gender, medication possession ratio) were extracted from the VA Corporate Data Warehouse using Microsoft SQL Server Management Studio (sample code, Figure 5). To determine the preliminary amyloidosis cohort, Veterans across the entire VA were identified using ICD-9 and ICD-10 codes from outpatient and inpatient encounters, then further limited to VISN 21. Veterans from this cohort who had ever received, or continue to receive any quantity of inotersen, patisiran, tafamidis, or tafamidis meglumine between October 2018 and February 2020 were included. All Veterans receiving VA care within VISN 21 were screened for an approved PADR and documented treatment re-evaluation within the specified timeframe. Veterans were excluded if deceased prior to October 2018, if receiving treatment not prescribed by VISN 21, or if missing PADR preliminary evaluation in the EHR. Key observational outcomes (past medication history, symptom onset and progression, objective assessment scores) were collected by reviewing EHR.

Figure 5.
Sample Code from SQL Server Management Studio

Results

By March 2020, only 21 out of 349 Veterans in VISN 21 had received treatment. The most commonly prescribed treatment was Vyndaqel for cardiomyopathy, with treatment duration ranging 1 to 10 months. Ultimately, there were no adverse effects, no deaths, and no patients who discontinued treatment. Baseline quality of life assessments were not documented; however, baseline symptom assessment was completed 90% of the time. Those who completed 6 months of therapy were eligible for reassessment documentation. Of those 9 patients, quality of life assessments was again not documented; 7 had symptoms reassessed.

Table 2.
Baseline Demographics for VISN 21 Cohort

Discussion & Conclusion

It remains unclear whether access to high-cost, potentially life-prolonging therapy will lead to positive clinical outcomes and improved quality of life. The quality improvement results have demonstrated prescribing more and documenting less. Of the 21 patients currently receiving treatment, the current annual cost is approximately $5.6 million. This translates to $99.8 million annually for treatment of the entire VISN 21 cohort.
Without assessing efficacy, through symptom and quality of life assessments-- are these medications making the right impact? Though this project was limited to a small sample size, and short duration, the next steps must include standardizing assessment and reassessment. Adjusting suggested assessment and reassessments will provide more supportive information for patients, providers until long term clinical trial results are available.

References

1. Minamisawa M, Claggett B, Adams D, Kristen AV, Merlini G, Slama MS, Dispenzieri A, Shah AM, Falk RH, Karsten V, Sweetser MT, Chen J, Riese R, Vest J, Solomon SD. Association of Patisiran, an RNA Interference Therapeutic, With Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis. JAMA Cardiol. 2019;4(5)466-472.
2. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018; 379:1007-1016.
3. Gorevic PD, Lachmann HJ, Romain PL. Overview of Amyloidosis. Updated February 2019. Accessed October 2019.
4. Pfizer Inc. Vyndamax/Vyndaqel Package Insert. Updated August 2019. Accessed October 2019.
5. Akcea Therapeutics Inc. Tegsedi Package Insert. Updated October 2019. Accessed October 2019.
6. Alnylam Pharmaceuticals, Inc. Onpattro Package Insert. Updated February 2020. Accessed October 2019.
7. Adams D, Suhr OB, Dyck PJ, Litchy WJ, Leahy RG, Chen J, Gollob J, Coelho T. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurology. 2017; 17:181.
8. Waddington-Cruz M, Ackermann EJ, Polydefkis M, Heitner SB, Dyck PJ, Barroso FA, Wang AK, Berk JL, Dyck PJB, Monia BP, Hughes SG, Tai L, Kwoh JK, Jung SW, Coehlo T, Benson MD, Gertz MA. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018; 25(3): 180-188.
9. Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019; 26(4): 203-209.
10. Waddington-Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016; 23(3): 178-183.
11. Gundapaneni BL, Sultan MB, Keohane DJ, Schwartz JH. Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy. European Journal of Neurology. 2018; 25: 464-468.
12. Keohane D, Schwartz J, Gundapaneni B, Stewart M, Amass L. Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial. Amyloid. 2017; 24(1):30-36.
13. Merlini G, Plante-Bordeneuve V, Judge DP, Schmidt H, Obici L, Perlini S, Packman J, Tripp T, Grogan DR. Effects of Tafamidis on Transthyretin Stabilization and Clinical Outcomes in Patients with Non-Val30Met Transthyretin Amyloidosis. J of Cardiovasc Trans Res. 2013; 6:1011-1020.
14. Suhr OB, Coelho T, Buades J, Pouget J, Concelcao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR, Vaishnaw A, Gollob J, Adams J. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet Journal of Rare Diseases. 2015; 10:109.
15. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan III TH, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Eng J Med. 2018; 379:22-31.
16. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives. Tafamidis meglumine (Vyndaqel) Amyloidosis Cardiomyopathy Criteria for Use. US Department of Veterans Affairs. Published September 2019. Accessed September 2019.
17. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives. Tafamidis meglumine (Vyndaqel) and Patisiran (Onpattro) Treatment of polyneuropathy associated with amyloidosis Criteria for Use. US Department of Veterans Affairs. Published September 2019. Accessed September 2019.
18. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives. Patisiran (Onpattro) and Inotersen (Tegsedi) Criteria for Use. US Department of Veterans Affairs. Published May 2019. Accessed September 2019. 

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