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Figure.
Incremental Cost-effectiveness Ratio as a Function of Baseline Cardiovascular Event Rate
Incremental Cost-effectiveness Ratio as a Function of Baseline Cardiovascular Event Rate

Cardiovascular events include myocardial infarction, ischemic stroke, and cardiovascular death. An annual evolocumab list price of $5850 was used. FOURIER indicates the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial.

Table.  
Cost-effectiveness Results at an Evolocumab List Price of $5850 in Patients With Very High-risk Atherosclerotic Cardiovascular Diseasea
Cost-effectiveness Results at an Evolocumab List Price of $5850 in Patients With Very High-risk Atherosclerotic Cardiovascular Diseasea
1.
Sabatine  MS, Giugliano  RP, Keech  AC,  et al; FOURIER Steering Committee and Investigators.  Evolocumab and clinical outcomes in patients with cardiovascular disease.  N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664PubMedGoogle ScholarCrossref
2.
Fonarow  GC, Keech  AC, Pedersen  TR,  et al.  Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease.  JAMA Cardiol. 2017;2(10):1069-1078. doi:10.1001/jamacardio.2017.2762PubMedGoogle ScholarCrossref
3.
Mark  DB, Richman  I, Hlatky  MA.  Proprotein convertase subtilisin/kexin type 9 inhibitor therapy-breakthrough in low-density lipoprotein cholesterol lowering, breakdown in value.  JAMA Cardiol. 2017;2(10):1066-1068. doi:10.1001/jamacardio.2017.2911PubMedGoogle ScholarCrossref
4.
Grundy  SM, Stone  NJ, Bailey  AL,  et al.  AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines  [published online November 8, 2018].  J Am Coll Cardiol. 2018. doi:10.1016/j.jacc.2018.11.003Google Scholar
5.
Arrieta  A, Hong  JC, Khera  R, Virani  SS, Krumholz  HM, Nasir  K.  Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER trial.  JAMA Cardiol. 2017;2(12):1369-1374. doi:10.1001/jamacardio.2017.3655PubMedGoogle ScholarCrossref
6.
Kazi  DS, Penko  J, Coxson  PG,  et al.  Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.  JAMA. 2017;318(8):748-750. doi:10.1001/jama.2017.9924PubMedGoogle ScholarCrossref
7.
Li  S, Peng  Y, Wang  X,  et al.  Cardiovascular events and death after myocardial infarction or ischemic stroke in an older Medicare population.  Clin Cardiol. 2019;42(3):391-399. doi:10.1002/clc.23160PubMedGoogle ScholarCrossref
8.
Kazi  DS, Penko  J, Coxson  PG, Guzman  D, Wei  PC, Bibbins-Domingo  K.  Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY outcomes trial.  Ann Intern Med. 2019;170(4):221-229. doi:10.7326/M18-1776PubMedGoogle ScholarCrossref
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Brief Report
June 5, 2019

Updated Cost-effectiveness Analysis of Evolocumab in Patients With Very High-risk Atherosclerotic Cardiovascular Disease

Author Affiliations
  • 1Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles Medical Center, Los Angeles
  • 2ScHARR School for Health and Related Research, University of Sheffield, Sheffield, England
  • 3Amgen (Europe) GmbH, Zug, Switzerland
  • 4Amgen Inc, Thousand Oaks, California
  • 5The Swedish Institute for Health Economics, Lund, Sweden
  • 6Department of Learning, Informatics, Management and Ethics, Karolinska Institute, Stockholm, Sweden
  • 7Section Editor, JAMA Cardiology
JAMA Cardiol. 2019;4(7):691-695. doi:10.1001/jamacardio.2019.1647
Key Points

Question  What is the cost-effectiveness of evolocumab in patients with very high-risk atherosclerotic cardiovascular disease at its new annual list price of $5850?

Findings  This economic analysis determined that incremental cost-effectiveness ratios varied by baseline cardiovascular event rate, ranging from $56 655 per quality-adjusted life-year gained at an event rate of 6.4 events per 100 patient-years to $7667 per quality-adjusted life-year gained at an event rate of 12.3 events per 100 patient-years.

Meaning  The addition of evolocumab to standard background therapy at its current list price meets accepted cost-effectiveness thresholds across a range of risk profiles in the population with very high-risk atherosclerotic cardiovascular disease.

Abstract

Importance  In October 2018, evolocumab was made available at a reduced annual list price of $5850 in the United States. This 60% reduction was aimed at improving patient access by lowering patient copays. Shortly thereafter, the 2018 American College of Cardiology/American Heart Association cholesterol management guideline was released. An updated cost-effectiveness analysis of evolocumab in the United States may be therefore of interest to payers and prescribers.

Objective  To present an updated cost-effectiveness analysis of evolocumab added to standard background therapy compared with standard background therapy alone in patients with very high-risk atherosclerotic cardiovascular disease, reflecting the 2018 ACC/AHA guideline definition and using the new evolocumab list price.

Design, Setting, and Participants  This study used the Markov model originally used in a previous study by Fonarow et al in 2017. A US societal perspective was considered, and a range of baseline cardiovascular event rates were modeled to reflect varying risk profiles in clinical practice within patients with very high-risk atherosclerotic cardiovascular disease.

Exposures  Addition of evolocumab to standard background therapy, including maximally tolerated statin therapy (ie, the maximum intensity of statin therapy a patient can safely receive), with or without ezetimibe.

Main Outcomes and Measures  Major cardiovascular events (myocardial infarction, ischemic stroke, and cardiovascular death), costs, quality-adjusted life-years, and incremental cost-effectiveness ratios.

Results  Evolocumab was associated with both increased costs and improved outcomes when added to standard background therapy. Incremental costs ranged from $22 228 to $3411, depending on the varying level of risk within the defined population. Incremental quality-adjusted life years ranged from 0.39 to 0.44. Incremental cost-effectiveness ratios ranged from $56 655 to $7667 per quality-adjusted life-year gained. For a range of baseline cardiovascular event rates in patients with very high-risk atherosclerotic cardiovascular disease, incremental cost-effectiveness ratios were below the generally accepted willingness-to-pay thresholds. Moreover, the ratios were below the threshold of $50 000 per quality-adjusted life-years gained for any baseline rate of 6.9 or more events per 100 patient-years.

Conclusions and Relevance  At its current list price, the addition of evolocumab to standard background therapy meets accepted cost-effectiveness thresholds across a range of baseline cardiovascular event rates in patients with very high-risk atherosclerotic cardiovascular disease as defined by the 2018 ACC/AHA guideline.

Introduction

Based on the results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) clinical trial,1 Fonarow et al2 evaluated the cost-effectiveness of evolocumab when added to standard background therapy (maximally tolerated statin therapy, or the highest intensity of statin that a patient can safely receive, with or without ezetimibe) in patients with atherosclerotic cardiovascular disease (ASCVD). Previous cost-effectiveness analyses of proprotein convertase/subtilisin type 9 (PCSK9) inhibitors in the United States raised debate on value and access implications.3 In October 2018, evolocumab was made available at a reduced annual list price of $5850 in the United States. This 60% reduction was aimed at improving patient access by lowering patient copays, especially for Medicare beneficiaries. Shortly thereafter, the 2018 American College of Cardiology/American Heart Association Multisociety Clinical Guideline on the Management of Blood Cholesterol (2018 ACC/AHA guideline) recommended PCSK9 inhibitors for, among other patient populations, patients with very high-risk (VHR) ASCVD whose low-density lipoprotein cholesterol levels remain at 70 mg/dL or more (≥1.8 mmol/L; to convert to millimoles per liter, multiply by 0.0259) despite a heart-healthy lifestyle and treatment with standard background therapy.4 Based on the Fonarow et al2 economic model, we present an updated cost-effectiveness analysis of evolocumab added to standard background therapy, compared with standard background therapy alone, in patients with VHR ASCVD, per the 2018 ACC/AHA guideline, using the new evolocumab list price.

Methods

We used the previously published Fonarow et al2 Markov model, which considered a US societal perspective and assumed a lifetime horizon to capture the progression of ASCVD. The model was used to assess subsequent major cardiovascular (CV) events as a function of age, sex, low-density lipoprotein cholesterol level, and CV event history. Model outcomes included major CV events (myocardial infarction, ischemic stroke, and CV death), costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Institutional review board approval was not required because this was a model-based analysis, and no human participants were involved.

The previously published inputs for ASCVD costs, utilities, and evolocumab intervention effects from the original model were used in this updated analysis.2 Accordingly, total costs and total QALYs determined by the model for standard background therapy remain unchanged from the original article2 when baseline CV event rates are aligned. This updated analysis, however, incorporated new data for 2 key model parameters: (1) an evolocumab annual list price of $5850, reflecting the 60% reduction, and (2) a baseline CV event rate in a clinical practice population in the United States, reflecting the definition of patients with VHR ASCVD in the 2018 ACC/AHA guideline.4

Because the 2018 ACC/AHA guideline has been recently published,4 there is an understandable lack of real-world evidence for patients with VHR ASCVD. We therefore modeled a range of plausible baseline CV event rates to represent patients with varying risk profiles within the VHR population. In the FOURIER clinical trial,1 the baseline CV event rate for patients at VHR was approximately 2-fold that for patients who were not at VHR. The lower bound of the baseline CV event rate range in this analysis was anchored by a rate of 6.4 events per 100 patient-years, using the original population in Fonarow et al,2 referred to as patients in US clinical practice. These event rates integrated total CV events, including recurrent events. The upper bound was calculated at 12.3 events per 100 patient-years by multiplying the rate of patients in US clinical practice by the rate ratio of patients at VHR to those not at VHR observed in the FOURIER clinical trial. Finally, a scenario analysis considering a baseline CV event rate of 4.4 events per 100 patient-years, representing FOURIER clinical trial patients at VHR, was considered. Excel 2016 (Microsoft) was used for all statistical analyses.

Results

Evolocumab was associated with both increased costs and improved outcomes when added to standard background therapy compared with standard background therapy alone, including maximally tolerated statin therapy with or without ezetimibe (Table). Incremental costs varied across the spectrum of CV risk modeled within the population with VHR ASCVD, ranging from $22 228 for a baseline CV event rate of 6.4 events per 100 patient-years to $3411 for a baseline CV event rate of 12.3 events per 100 patient-years. Incremental QALYs gained ranged from 0.39 to 0.44, respectively. The ICERs therefore ranged from $56 655 to $7667 per QALY gained, respectively. Of note, the ICER of $56 665 reflects the original patients in US clinical practice per Fonarow et al2 after only the reduction in the price of evolocumab to $5850 is considered, before modeling any increase in baseline CV event rate to characterize the spectrum of increased risk across the patients at VHR.

For the range of baseline CV event rates in patients with VHR ASCVD in clinical practice, all ICERs were within what the 2018 ACC/AHA guideline considers a high or intermediate value (<$50 000 to <$150 000 per QALY gained).4 Moreover, most ICERs were below $50 000 per QALY gained (the high value), corresponding to baseline CV event rate of 6.9 or more events per 100 patient-years (Figure).

If standard background therapy included maximally tolerated statin therapy with ezetimibe, ICERs would range from $59 331 to $10 584, depending on the varying level of risk within the population at VHR. In the conservative scenario analysis in which a baseline CV event rate of 4.4 events per 100 patient-years was considered, based on the FOURIER clinical trial observed rates for patients at VHR, the ICER was $91 610 (Table).

Discussion

We present an updated cost-effectiveness analysis of evolocumab added to standard background therapy, compared with standard background therapy alone, in patients with VHR ASCVD per the 2018 ACC/AHA guideline, using the new evolocumab list price. As noted in the 2018 ACC/AHA guideline, at any given price, the value of PCSK9 inhibitors will be improved by selecting patients at higher risk for the occurrence of CV events.4 At its new annual list price of $5850, the addition of evolocumab to standard background therapy in patients with VHR ASCVD yields ICERs that meet currently accepted cost-effectiveness thresholds and are consistent with providing high-value care.

This updated cost-effectiveness analysis may be useful for payers, clinicians, and those informing the appropriate use of lipid-lowering therapies in the United States, particularly in light of the current access and reimbursement barriers. The 2018 ACC/AHA guideline questioned the value of PCSK9 inhibitors, likely because mid-2018 prices were considered. Likewise, previously published cost-effectiveness analyses of evolocumab based on the FOURIER clinical trial estimated ICERs that were above the generally accepted willingness-to-pay thresholds; however, these analyses were not specifically conducted in patients with VHR ASCVD and did not reflect the current evolocumab list price.5,6 For instance, the base case ICER in Fonarow et al2 is reduced by 79% to an ICER of $56 665 as a result of the decrease in annual list price of 60%. The reduction in list price improved the cost-effectiveness for patients with ASCVD before characterizing patients at VHR, for whom baseline CV event rates would be higher. Despite the improvement in value at the new current list price, a comprehensive disease management approach including a heart-healthy lifestyle across the life course and adherence to standard background therapy, as per current guidelines, should be applied.

A strength of this analysis is that it offers ICERs across a range of baseline CV event rates as a proxy for patients with varying risk profiles within the VHR population. Despite the understandably limited real-world evidence in this very recently defined population, the range of baseline CV event rates considered in this study is plausible and supported by the available literature. For instance, a recent study in Medicare patients at VHR with a history of recent myocardial infarction or ischemic stroke reported a composite 1-year rate of acute coronary syndrome, ischemic stroke, or death of 38.2 events per 100 patient-years.7 In that study, the 1-year rate of nonfatal myocardial infarction or ischemic stroke was approximately 9 events per 100 patient-years, even before capturing CV death. On the other hand, a recent evaluation of a PCSK9 inhibitor in a subgroup of patients at VHR in the United States applied a baseline CV event rate of 7.2 events per 100 patient-years.8 These results highlight the importance of future analyses that more precisely quantify the baseline CV event rates estimated from patients with VHR ASCVD in the real world to further understand the cost-effectiveness of evolocumab.

Limitations

There are potential limitations to this study, and the findings should be interpreted within the context of the data inputs, event rates, and modeling assumptions used. The event rate range for patients with VHR ASCVD was estimated using available data from the FOURIER clinical trial and patients in US clinical practice. The results are based on the assumption that clinical benefits of treatment extend beyond the period with direct follow-up. If the levels of persistence with and adherence to evolocumab therapy differ from those modeled, costs, and clinical effectiveness may differ.

Conclusions

At its current list price, the addition of evolocumab to standard background therapy meets accepted cost-effectiveness thresholds across a range of baseline CV event rates in patients with VHR ASCVD in the United States, with very high risk defined by the 2018 ACC/AHA guideline. This updated cost-effectiveness analysis may be informative for payers, health systems, and clinicians regarding the appropriate use and value of lipid-lowering therapies in the United States.

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Article Information

Accepted for Publication: April 10, 2019.

Published Online: June 5, 2019. doi:10.1001/jamacardio.2019.1647

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Corresponding Author: Gregg C. Fonarow, MD, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles Medical Center, 10833 Le Conte Ave, Los Angeles, CA, 90095 (gfonarow@mednet.ucla.edu).

Author Contributions: Drs Fonarow and Villa had full access to all data and take responsibility for the integrity of data and the accuracy of data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Fonarow, van Hout, Villa, Arellano.

Drafting of the manuscript: Fonarow, Villa, Arellano.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: van Hout, Villa.

Obtained funding: Arellano.

Administrative, technical, or material support: Villa, Arellano.

Supervision: Fonarow, van Hout, Lindgren.

Conflict of Interest Disclosures: Dr Fonarow reports consulting for Abbott, Amgen, Bayer, Janssen, and Novartis. Dr van Hout reports consulting for Amgen. Drs Villa and Arellano are employees and stockholders of Amgen Inc. Dr Lindgren reports consulting and/or advisory board participation for Amgen, Janssen, MSD, Novartis, and Sanofi. No other disclosures were reported.

Funding/Support: This study was sponsored by Amgen Inc.

Role of the Funder/Sponsor: The sponsor provided funding for the study and, via employee coauthors, input into the design and conduct of the study; collection, management, and analysis of the data; and interpretation of the data. The sponsor reviewed and approved the manuscript prior to submission, but the coauthors prepared, provided final approval for, and decided to submit the manuscript for publication.

Disclaimer: Dr Gregg C. Fonarow is Section Editor of JAMA Cardiology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Meeting Presentation: This article was presented at the National Lipid Association Scientific Sessions; Miami, Florida; May 18, 2019.

Data Sharing Statement: Qualified researchers may request data from Amgen clinical studies. Complete details: https://www.amgen.com/datasharing.

Additional Contributions: We thank Cathryn M. Carter, MS, Amgen Inc, for medical writing support; she received compensation as an employee of Amgen Inc.

References
1.
Sabatine  MS, Giugliano  RP, Keech  AC,  et al; FOURIER Steering Committee and Investigators.  Evolocumab and clinical outcomes in patients with cardiovascular disease.  N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664PubMedGoogle ScholarCrossref
2.
Fonarow  GC, Keech  AC, Pedersen  TR,  et al.  Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease.  JAMA Cardiol. 2017;2(10):1069-1078. doi:10.1001/jamacardio.2017.2762PubMedGoogle ScholarCrossref
3.
Mark  DB, Richman  I, Hlatky  MA.  Proprotein convertase subtilisin/kexin type 9 inhibitor therapy-breakthrough in low-density lipoprotein cholesterol lowering, breakdown in value.  JAMA Cardiol. 2017;2(10):1066-1068. doi:10.1001/jamacardio.2017.2911PubMedGoogle ScholarCrossref
4.
Grundy  SM, Stone  NJ, Bailey  AL,  et al.  AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines  [published online November 8, 2018].  J Am Coll Cardiol. 2018. doi:10.1016/j.jacc.2018.11.003Google Scholar
5.
Arrieta  A, Hong  JC, Khera  R, Virani  SS, Krumholz  HM, Nasir  K.  Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER trial.  JAMA Cardiol. 2017;2(12):1369-1374. doi:10.1001/jamacardio.2017.3655PubMedGoogle ScholarCrossref
6.
Kazi  DS, Penko  J, Coxson  PG,  et al.  Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial.  JAMA. 2017;318(8):748-750. doi:10.1001/jama.2017.9924PubMedGoogle ScholarCrossref
7.
Li  S, Peng  Y, Wang  X,  et al.  Cardiovascular events and death after myocardial infarction or ischemic stroke in an older Medicare population.  Clin Cardiol. 2019;42(3):391-399. doi:10.1002/clc.23160PubMedGoogle ScholarCrossref
8.
Kazi  DS, Penko  J, Coxson  PG, Guzman  D, Wei  PC, Bibbins-Domingo  K.  Cost-effectiveness of alirocumab: a just-in-time analysis based on the ODYSSEY outcomes trial.  Ann Intern Med. 2019;170(4):221-229. doi:10.7326/M18-1776PubMedGoogle ScholarCrossref
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