Application of PCSK9 Inhibitors in Practice
2017; Lippincott Williams & Wilkins; Volume: 121; Issue: 5 Linguagem: Inglês
10.1161/circresaha.117.311532
ISSN1524-4571
AutoresTina M. Kaufman, P. Barton Duell, Jonathan Q. Purnell, Cezary Wójcik, Sergio Fazio, Michael D. Shapiro,
Tópico(s)Pharmaceutical Economics and Policy
ResumoHomeCirculation ResearchVol. 121, No. 5Application of PCSK9 Inhibitors in Practice Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessArticle CommentaryPDF/EPUBApplication of PCSK9 Inhibitors in PracticeChallenges and Opportunities Tina M. Kaufman, P. Barton Duell, Jonathan Q. Purnell, Cezary Wójcik, Sergio Fazio and Michael D. Shapiro Tina M. KaufmanTina M. Kaufman From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. , P. Barton DuellP. Barton Duell From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. , Jonathan Q. PurnellJonathan Q. Purnell From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. , Cezary WójcikCezary Wójcik From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. , Sergio FazioSergio Fazio From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. and Michael D. ShapiroMichael D. Shapiro From the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland. Originally published18 Aug 2017https://doi.org/10.1161/CIRCRESAHA.117.311532Circulation Research. 2017;121:499–501Although the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and development of therapeutic antagonists represent a major triumph of modern clinical medicine, efforts to implement PCSK9 inhibitors (PCSK9i) in patient care have been sobering. This practical guide examines the barriers and opportunities for the successful application of pharmacological inhibition of PCSK9 in clinical practice through introduction of a new model of care delivery—the PCSK9i clinic.A New Era in Lipid-Lowering TherapyHistorically, the foundation of primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has consisted of therapeutic lifestyle changes in combination with pharmacological therapy focused on lipid modulation, specifically low-density lipoprotein cholesterol (LDL-C) lowering.1 In 2015, the Food and Drug Administration (FDA) approved a new class of cholesterol-lowering medications, PCSK9i, to great anticipation. The seminal discovery in 2003 by Abifadel et al2 linked gain-of-function mutations in the PCSK9 gene with autosomal dominant hypercholesterolemia. This finding uncovered PCSK9 as a key player in cholesterol homeostasis, a circulating protein with the strongest influence on plasma LDL-C concentration.3 PCSK9 directly interacts with the low-density lipoprotein receptor and enhances its degradation by targeting it for destruction by the lysosome and halting its efficient recycling. Because PCSK9 causes degradation of the low-density lipoprotein receptor, inhibiting its action prolongs the lifespan of the low-density lipoprotein receptor and leads to profound reductions in plasma LDL-C levels. The ultimate culmination of this work was the regulatory approval of 2 monoclonal antibody inhibitors of PCSK9 (alirocumab and evolocumab). More recently, the randomized, placebo-controlled trial, FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), demonstrated improved ASCVD outcomes when evolocumab was added to background treatment with a statin. The combination of statin plus evolocumab resulted in a significant absolute and relative risk reduction in both the primary composite end point (cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina or coronary revascularization) and the secondary end point (cardiovascular death, myocardial infarction, or stroke).4Alirocumab and evolocumab are FDA approved as adjuncts to diet and maximally tolerated statin therapy in (1) adult patients with heterozygous familial hypercholesterolemia (FH) and (2) patients with clinical ASCVD who require additional LDL-C lowering.5 Evolocumab has additional FDA approval for treatment of homozygous FH. Although statin intolerance is not an official indication for PCSK9i therapy, patients who are unable to take statins may meet criteria for PCSK9 inhibition because their maximally tolerated statin dose is zero (Online Table I). This latter scenario requires detailed and specific documentation of the adverse events associated with statin administration.The indications for PCSK9 inhibition must be balanced with cost. Presently, the expenditure for 1 year of PCSK9i therapy is ≈US $14 600 although pharmacy benefit managers, intermediaries between the payer and the rest of the healthcare system, pay substantially below retail price, as much as 50% less. Clearly, these medications will only be cost effective when allocated to those who are at highest risk. In our center, a prescription for a PCSK9i is considered only as the necessary last resort for a patient who squarely qualifies for it. A critical element of our approach is to scrutinize all the cases that can be treated with less expensive therapies and only proceed with PCSK9i in cases falling within the core of each FDA indication for use. Less than 2% of all patients that we have seen in the last 2 years have been prescribed a PCSK9i, and our practice is made up predominantly of patients with ASCVD and FH-type hypercholesterolemia.Despite the unmet need for additional LDL-C–lowering therapies in these high-risk populations, and initial expectations for widespread use of alirocumab and evolocumab, practice utilization for these agents has been low. There are myriad possible explanations for this observation; however, the single most important deterrent to prescription of these effective new therapies is the difficulty in obtaining coverage by health insurance payers because they face the immense challenge of rationally and intelligently allocating approval of these expensive drugs.According to Symphony Health Solution's Integrated Dataverse, new claims for PCSK9i have a final approval rate of only 25% from commercial payers and ≈50% for Medicare.6 The results from other studies have shown similar results, with a 79% to 83% rate of initial medication denials in 2 large cohorts of 44 000 and 45 000 new PCSK9 monoclonal antibody prescriptions and ultimate approval rates of only 43% and 47%.7,8 Other recent data demonstrate that high-risk patients with FH and ASCVD are denied PCSK9i despite evidence that LDL-C lowering is inadequate on optimal statin and additional lipid-lowering therapy.9Initial experience with the prior authorization process has proven to be formidable. More than 50% to 80% of all initial prior authorization requests are denied even when patients meet the FDA-approved indications for therapy and the standard pre-authorization form is appropriately completed with all details. On appeal, however, about half of prior authorization requests are subsequently approved. This process, perhaps by design, is laborious, time consuming, and inefficient. The cynic may suggest that payers rely on the fact that providers lack the time or resources to navigate the approval process although the other side of the coin is that payers must devise filtering processes to avoid frivolous or unwarranted use of these expensive agents. A recent summary report provided theoretical suggestions for overcoming barriers to access to PCSK9i therapy,9 but failure to achieve insurance approval is still a prevalent problem. We and others have learned that access to PCSK9i requires a dedicated team to traverse the complicated labyrinth of prior authorizations, appeals, reappeals, and peer-to-peer reviews. In this context, the proverb "necessity is the mother of invention" rings true. In this report, we describe real-world strategies that have allowed us to provide PCSK9i to most of our qualified patients in need.Birth of the PCSK9i ClinicGiven the challenges in gaining approval for PCSK9i from payers, we have developed and implemented a specialized PCSK9i clinic to improve appropriate access to this therapy. Our PCSK9i clinic team is composed of physicians, a nurse, a medical assistant, a clinical pharmacist, and a physician assistant who coordinates the whole operation. Given our 92% success rate (n=142/153) for ultimately securing approvals for PCSK9i, we offer our PCSK9i clinic experience as a guide and model for all cardiology practices.When a provider in our Center for Preventive Cardiology identifies a PCSK9i-eligible patient, an internal referral to the PCSK9i clinic is made. In addition, we do receive external referrals directly to our PCSK9i clinic, which serves as another source of patients into our Center. The coordinator for the PCSK9i clinic oversees the approval process, provides injection training, and arranges longitudinal management and surveillance while on PCSK9i medications. The initial visit to the PCSK9i clinic is organized into 3 parts, (1) meticulous documentation of all data required for prior authorization submission, (2) general education about PCSK9i, and (3) injection teaching. Some of the more common sources of insurance denial for PCSK9i therapy are presented in Online Table II. We have developed a template for the initial encounter with a patient in the PCSK9i clinic to address these important issues prospectively. The importance of a proper initial encounter note to improve the prospects of approval cannot be overstated.The structure of this initial PCSK9i clinic encounter note includes the following key elements (see also Online Table I):–Detailed medication history: This medication review must include all current and prior lipid-modulating therapies with doses, reasons for discontinuation, dates or length of time when taken, and whether symptoms resolved on discontinuation and returned on rechallenge. Note that most insurance companies require patients to have tried atorvastatin and rosuvastatin at the maximally tolerated doses and ezetimibe before approval of a PCSK9i, a strategy much in line with the 2016 American College of Cardiology Expert Consensus Decision Pathway recommendations.10–Family history: This assessment includes family history of hypercholesterolemia, ASCVD, and tendon xanthomas.–Dutch Lipid Clinic Network Score: If FH is the indication for the PCSK9i, many insurance companies will require a Dutch Lipid Clinic Network score of >8 as evidence for definite FH.–Physical examination: The targeted examination must evaluate for the presence of cutaneous and tendon xanthomas and corneal arcus. Even mild findings should be recorded.–Laboratory evaluation: Laboratory testing must include a recent lipid panel (typically within the last 30 days) with a request for documentation of the highest known (usually off treatment) LDL-C concentration if available.–Indication for PCSK9i therapy: The provider must specify one of the following diagnoses: heterozygous FH, homozygous familial hypercholesterolemia, or ASCVD with inadequate LDL-C lowering despite maximally tolerated lipid-lowering therapy.–The patient's LDL-C goal or target: Use a set of guidelines from a national agency to justify the goal.–Documenting therapeutic lifestyle changes: Coverage for PCSK9i is frequently denied when this documentation is not included. Current smokers will likely be denied by some insurance plans.–Additional factors to support necessity for aggressive LDL-C reduction with PCSK9i: In patients with elevated lipoprotein (a) or a diagnosis of ASCVD based on atherosclerosis imaging (eg, coronary artery calcium), it is useful to include excerpts from the primary scientific literature and national guidelines to support the contention that the patient is at high risk for ASCVD events and requires aggressive LDL-C lowering.A lipid panel is ordered at the first visit in the PCSK9i clinic because most insurance companies will require laboratories within 30 days of the initial request. The patient is asked to sign a letter of consent granting permission to the coordinator to act as their representative to file future appeals and communications on approval or denial of requested medications. Although seemingly a small detail, this step is of utmost importance because significant delays can ensue when this provision is not in place as some insurance companies require patients to file appeals themselves or have signed written permission for others to do so on their behalf.Practicalities of the PCSK9i Approval ProcessThe process of identifying potential patients who may benefit from PCSK9i therapy and providing general education, injection teaching, and documentation is straightforward. The real challenge with PCSK9i is navigating the prior authorization process. Our approach to the PCSK9i approval process is delineated in Online Figure I.Even with ultimate approval of PCSK9i therapy from the payer, the financial burden imposed on the patient with high copays and out-of-pocket maximums (or the "doughnut hole" of Medicare) is frequently another serious barrier to treatment (Online Table III). Fortunately, there are several viable options to defray patient liability, including institution-specific medication assistance programs, the Patient Access Network, Amgen Safety Net Foundation, and commercially sponsored discount and copay cards.Within our practice, this model has significantly enhanced and streamlined the prescribing process for providers. Any potential obstacles are identified within the context of a PCSK9i clinic visit with the coordinator and addressed before submission of the prior authorization request. This model has quickly evolved into an effective platform that can be generalized to essentially any other specialty medication. Implementation of this practice has enhanced medication approval rates, provider efficiency and productivity, and the satisfaction of both patient and referring physician. The creation and implementation of a PCSK9i clinic have transformed a formidable challenge into an opportunity for process and quality improvement and added value to our program.Compared with the specialty pharmacy-based model, the PCSK9i clinic model keeps the approval process in the hands of the clinical specialists, who are better equipped to address the nuances of lipid management, to act as patient advocates, and to maximize scholarly opportunities. Appealing inappropriate denials is an important part of the process of accessing PCSK9i. In taking the steps that we outline in this practical guide, providers can expect to have a high level of success in accessing PCSK9i for their patients without having to remove current lipid-lowering therapies.ConclusionsClinical trials of monoclonal antibodies targeting PCSK9 have demonstrated remarkable efficacy in LDL-C reduction with an excellent short-term safety and tolerability profile. More recently, the results of a large randomized placebo-controlled outcomes trial demonstrated the superiority of adding a PCSK9i to a statin versus statin monotherapy in patients with stable ASCVD. The ability to substantially lower LDL-C is an unmet clinical need in several patient populations, including those with FH, statin intolerance, and in those with established ASCVD with inadequate LDL-C lowering on conventional lipid-lowering therapy. The FDA approval of this novel class of LDL-C–lowering agents generated enthusiasm and angst. Perhaps surprising to many were the unanticipated barriers to PCSK9i access. Out of necessity, a new model for patient evaluation and management for this novel therapeutic class arose, the PCSK9i clinic. We propose a framework for the PCSK9i clinic as an efficient means to evaluate, manage, and gain access to an important therapeutic that has the potential to provide significant additional LDL-C lowering in a substantial proportion of patients at risk for ASCVD events.AcknowledgmentsWe gratefully acknowledge Bruce Warden, PharmD, Victoria Simeon, RN, and Kelsey Kyle, MA, for their help in the daily operations of the PCSK9i clinic.Sources of FundingWe are grateful for the support from the Knight Cardiovascular Institute of Oregon Health & Science University.DisclosuresP.B. Duell has received compensation for advisory activities from the following companies: Amgen, Esperion, Kastle, Merck, Retrophin, and Sanofi. J.Q. Purnell has received compensation for advisory activities from Novo Nordisk. C. Wójcik has received compensation for advisory activities from Sanofi. S. Fazio has received compensation for advisory activities from the following companies: Amgen, Merck, Kowa, Aegerion, Pfizer, and Amarin. M.D. Shapiro has received compensation for advisory activities from the following companies: Akcea, Alexion, Amgen, Bracco, and GE Health Care. T.M. Kaufman reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA.117.311532/-/DC1.Correspondence to Michael D. Shapiro, DO, Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239. E-mail [email protected]References1. 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Shapiro M, Tavori H and Fazio S (2018) PCSK9, Circulation Research, 122:10, (1420-1438), Online publication date: 11-May-2018. Wójcik C (2017) Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease, Postgraduate Medicine, 10.1080/00325481.2017.1376570, 129:8, (801-810), Online publication date: 17-Nov-2017. August 18, 2017Vol 121, Issue 5 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.311532PMID: 28819040 Originally publishedAugust 18, 2017 Keywordscholesterol, LDLangina, unstablepatient careinsurance, healthsecondary preventionPDF download Advertisement SubjectsQuality and Outcomes
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