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Received: 5 March 2017

Accepted: 6 March 2017

DOI: 10.1002/clc.22713

REVIEWS

PCSK9 inhibitor access barriers—issues and recommendations:
Improving the access process for patients, clinicians
and payers
Seth J. Baum1

| Peter P. Toth2 | James A. Underberg3 | Paul Jellinger4 | Joyce Ross5 |

Katherine Wilemon6
1
Department of Integrated Medical
Sciences, Charles E. Schmidt College of
Medicine, Florida Atlantic University, Boca
Raton, Florida

The proprotein convertase subtilisin/kexin type 9 inhibitors or monoclonal antibodies likely
represent the greatest advance in lipid management in 30 years. In 2015 the US Food and
Drug Administration approved both alirocumab and evolocumab for high-risk patients with

2

CGH Medical Center, Sterling, Illinois, and
Ciccarone Center for the Prevention of Heart
Disease, Johns Hopkins University School of
Medicine, Baltimore, Maryland
3

Center for the Prevention of Cardiovascular
Disease at New York University Langone
Medical Center, New York, New York
4

Center for Diabetes and Endocrine Care, Ft.
Lauderdale, Florida, and University of Miami
Miller School of Medicine, Miami, Florida
5

University of Pennsylvania Health System,
Philadelphia, Pennsylvania

familial hypercholesterolemia (FH) and clinical atherosclerotic cardiovascular disease requiring
additional lowering of low-density lipoprotein cholesterol. Though many lipid specialists, cardiovascular disease prevention experts, endocrinologists, and others prescribed the drugs on label,
they found their directives denied 80% to 90% of the time. The high frequency of denials
prompted the American Society for Preventive Cardiology (ASPC), to gather multiple stakeholder organizations including the American College of Cardiology, National Lipid Association,
American Association of Clinical Endocrinologists (AACE), and FH Foundation for 2 town hall
meetings to identify access issues and implement viable solutions. This article reviews findings
recognized and solutions suggested by experts during these discussions. The article is a product
of the ASPC, along with each author writing as an individual and endorsed by the AACE.

6

The Familial Hypercholesterolemia
Foundation, Pasadena, California
Correspondence
Seth J. Baum, MD, Preventive Cardiology, Inc.
7900 Glades Rd #400 Boca Raton, FL 33434
Email: sjbaum@fpim.org

KEYWORDS

Coronary Artery Disease, Familial Hypercholesterolemia, Hepatocyte, Low-Density
Lipoprotein Cholesterol, Pharmacy Benefits Manager, Proprotein Convertase Subtilisin/Kexin
Type 9

Funding information
Funding for The Town Hall Series came from
an unrestricted grant from Amgen and Sanofi/
Regeneron.

1 | I N T RO D UC T I O N

(HoFH). Understanding that “time is plaque”3 and that PCSK9 mab
offered heretofore unobserved intensive and predictable lowering of

In 2015, the US Food and Drug Administration (FDA) approved

LDL-C incremental to statin therapy, many clinicians in the lipid and

2 novel lipid-lowering drugs, the proprotein convertase subtilisin/

ASCVD prevention and treatment arenas prescribed these medicines

kexin type 9 inhibitors (PCSK9 mab) alirocumab and evolocumab.1,2

according to the label. Nearly ubiquitous denials for these medica-

Treatment indications were clear: for use in addition to diet and

tions were rapidly encountered. In 2016, a Symphony study demon-

maximally tolerated statin therapy in adult patients with heterozy-

strated approximately 80% initial denial rates, with final approvals

gous familial hypercholesterolemia (HeFH) or clinical atherosclerotic

between 25% and 50% for commercial and Medicare patients

cardiovascular disease (ASCVD) requiring further reduction in low-

respectively.4 An FH Foundation survey of impacted individuals

density lipoprotein cholesterol (LDL-C). Evolocumab was given the

assessed patient access to lipid-lowering therapies for FH.5 Data

additional indication for homozygous familial hypercholesterolemia

from 163 participants revealed a 26% overall denial rate of

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original
work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

© 2017 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.
Clinical Cardiology. 2017;1–13.

wileyonlinelibrary.com/journal/clc

1

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BAUM ET AL.

medication coverage; 79% were denials of PCSK9 mab prescriptions,
with 36% of these prescriptions being written for secondary preven-

2 | T H E H I S T OR Y A N D I M P O R T A N C E OF
PCSK9

tion. These and other similar findings demanded deeper inquiry, and
so the American Society for Preventive Cardiology (ASPC) organized

Multiple levels of evidence support the causal role of LDL-C in the

representation from the American College of Cardiology (ACC),

development of atherosclerosis. Most importantly, LDL-C reduction

National Lipid Association (NLA), American Association of Clinical

has been shown in numerous randomized controlled trials (RCTs) to

Endocrinologists (AACE), and the Familial Hypercholesterolemia

reduce the risk of heart attack, stroke, and death.11 Some of the most

(FH) Foundation to convene 2 town halls. Other stakeholders invited

dangerous conditions of high LDL-C are hereditary. Heritable eleva-

to attend these meetings included insurance providers, pharmacy ben-

tions in serum LDL-C are attributable to a variety of genetic poly-

efit managers (PBMs), legislators, and patients. The first town hall, held

morphisms, some more consequential than others. FH is associated

during the annual ASPC congress in September 2016, was structured

with moderately severe and severe elevations in LDL-C in its hetero-

to identify and clarify problems in drug access. The second event, at

zygous and homozygous forms, respectively.12 Importantly, risk for

the 2016 American Heart Association (AHA) scientific sessions, pre-

ASCVD increases in direct proportion to the magnitude of elevation

sented proposed solutions to the previously identified problems. The

in LDL-C exposure.11 According to the classic model developed by

town hall meetings were well attended, demonstrating substantial

Brown and Goldstein, FH is a manifestation of reduced or absent

appreciation and concern among clinicians regarding our inability to

expression of the low-density lipoprotein receptor (LDLR) on the sur-

access PCSK9 mab for our patients.

face of hepatocytes, leading to: (1) decreased uptake and metabolism

This review documents the development of a novel and highly

of low-density lipoprotein (LDL) particles and (2) elevations in serum

promising drug class, and the barriers to access encountered by clin-

levels of LDL-C.13 Apoprotein B100 (apoB), present in a 1-to-1 rela-

icians and their patients across the United States. Pragmatic, mean-

tionship with all LDL particles, functions as a docking molecule

ingful, and implementable solutions are proposed to improve the
PCSK9 mab access process for patients meeting the prescribing criteria specified by the FDA. Five well-considered definitions for each
of the 5 specifications required to meet the PCSK9 mab’s package
inserts (PIs), as well as sample uniform prior authorization (PA) and

between LDLR and LDL particles. Mutations that cause a reduced
affinity of apoB for LDLR also result in decreased LDL clearance and
constitute a cause of FH.14
Additional heterogeneity in the hereditary basis for FH became
apparent. Abifadel and coworkers identified a third candidate gene

appeals letters are presented. It is important to recognize that

that mapped to the short arm of chromosome 1.15 In 2003, this gene

recent systematic denials for novel medications are not limited to

was identified as coding for PCSK9.16 Using positional cloning, Abifa-

PCSK9 mab; they affect other medicines today, and might impact

del et al. detected 2 mutations in PCSK9 that predispose to the phe-

future innovative therapies as well. Thus, resolving this matter is of

notype of FH.17 The overexpression of PCSK9 was found to

paramount importance to preserve innovation and safeguard patient

correlate with increased serum LDL-C.18 Consistent with this obser-

access to prescribed novel therapies, a foundation of the patientclinician relationship.
A brief discussion of pharmacoeconomics is necessary. Price is
always the “elephant in the room” and therefore must at least be
openly discussed. The list price —not the true negotiated price—for
both PCSK9 mab is approximately $14,000 per year.6 A number of
articles, such as that by Kazi et al,6 have evaluated the cost effectiveness of these medications using questionable criteria such as
quality-adjusted life years (QALYs), a metric abandoned by the
Affordable Care Act7 as well as Europe because of its acknowledged inaccuracies.8 In addition, a number of assumptions made in
relevant pharmacoeconomics analyses proved incorrect, including
an overestimation of the number of FH patients purportedly requiring a PCSK9 mab and an inaccurate forecast by the Institute for
Clinical and Economic Review (ICER) that the drugs would cost the
United States $1.2 billion in the first year after approval, whereas
the actual expenditure was $83 million, just 1.2% of predicted.9
Such prognostications likely precipitated a high level of caution
among payers, causing frequent denials and a challenging appeal

vation, mutations in PCSK9 that cause FH are a gain of function. Following these discoveries, investigators identified loss of function
mutations in PCSK9, which correlated with low serum levels of LDLC and concomitant reduced risk for acute cardiovascular events.19 In
considerable subsequent investigation, PCSK9 emerged as a critical
regulator of LDLR expression, and great effort has therefore been
made to exploit this molecule for therapeutic purposes.
PCSK9 is produced as a zymogen (proPCSK9) by hepatocytes,
and undergoes autocatalytic cleavage so as to facilitate its secretion
and proper folding.20 In the extracellular milieu, mature PCSK9 has
no proteolytic activity; its active site is blocked by its previously
cleaved prosegment.21 Therefore, it serves simply as a binding protein. On hepatocytes, PCSK9 binds to a complex comprising the
LDLR and an LDL particle. This binding occurs between PCSK922
and the epidermal growth factor–like repeat A domain of the
LDLR.23 This polymolecular assembly is incorporated into clathrincoated endosomal vesicles that are brought into the cytosol.24
Within the cytosol, PCSK9 chaperones the LDLR complex into the
lysosome for hydrolytic destruction, thereby reducing the recycling

process.
Integrally involved in drug pricing, yet often overlooked, are

of LDLR to the hepatocyte cell surface and reducing LDL particle

PBMs. Several PBMs control the majority of US prescriptions, nego-

clearance capacity. When PCSK9 is not bound to the LDLR-LDL

tiating deals between pharmaceutical companies and the end

complex, lysosomal enzymes catabolize the LDL particle, but the

10

payers.

Like the payers, PBMs could clearly benefit from the find-

ings and solutions detailed in this article.

LDLR is recycled back to the hepatocyte cell surface to initiate further LDL particle binding, uptake, and degradation. LDLR recycling

3

BAUM ET AL.

can occur up to 150 times.25 This model neatly explains why
gain-of-function and loss-of-function PCSK9 mutations would be
etiologic for elevations and reductions in serum levels of LDL-C,
respectively. PCSK9 also regulates the expression of other lipoprotein cell surface receptors, including the LDL receptor related
protein-1,26 the very low-density lipoprotein receptor, and the apolipoprotein E receptor 2.27 The clinical significance of these latter
interactions is yet to be established.

3.1 | Maximally tolerated statin therapy
All current guidelines for the management of dyslipidemia in ASCVD
risk reduction, including the 2013 ACC/AHA Blood Cholesterol to
Reduce Atherosclerotic Cardiovascular Risk in Adults,31 the 2016
ACC Expert Consensus Decision Pathway on the Role of Non-Statin
Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk, NLA Recommendations for

Alirocumab and evolocumab are safe and highly efficacious, and

Patient-Centered Management of Dyslipidemia: Part 1, and the

provide substantial incremental LDL-C reductions of between 55%

American Association of Clinical Endocrinologists (AACE)/American

and 60% when used at their maximal FDA-approved doses.28,29

College of Endocrinology (ACE) 2017 Guidelines for the Management

These therapies constitute an important and vital breakthrough in the

of Dyslipidemia, uniformly recommend high-intensity statin therapy

management of patients who cannot achieve guideline-established

for patients with clinical ASCVD, an untreated LDL-C >190 mg/dL,

levels of LDL-C reduction even with high-intensity statin therapy

HeFH, or HoFH.32–35 Moderate-intensity statin therapy may be con-

statin, or for patients with a reduced capacity to tolerate appropriate

sidered in high-risk patients if they are >75 years of age, have a prior

doses of statins and other lipid-lowering medications. Among patients

history of adverse effects on statin therapy, or there is a potential for

urgently requiring a solution to inadequately managed LDL, FH per-

statin-drug interactions. Maximally tolerated statin therapy is recom-

haps stands out most prominently. Despite FH guidelines that advise

mended prior to consideration of nonstatin therapies.

>50% reduction of LDL-C as optimum care, treated LDL-C values

The fact that maximally tolerated statin therapy and statin intol-

often remain too high for those with FH.6 Current data from the FH

erance are not well defined in available guidelines contributes signifi-

Foundation’s national CAscade SCreening for Awareness and DEtec-

cantly to provider and payer inconsistencies when physicians

tion of Familial Hypercholesterolemia (CASCADE FH) registry,30 com-

prescribe PCSK9 mab and other nonstatin agents. It is well recog-

prising 30 leading cardiovascular and academic centers in the United

nized that following initiation of statin therapy, some individuals may

States, demonstrate frequently insufficient LDL-C reduction. Adults

experience unacceptable adverse effects, the most commonly

in the registry with a clinical or genetic diagnosis of HeFH and HoFH

reported being muscle-related symptoms. Though there is not a uni-

have a mean treated LDL-C value of 143 mg/dL (n = 2595) and

versally accepted definition of statin intolerance, most experts make

181 mg/dL, respectively.30 Although 60% of the adult participants

the diagnosis when patients experience intolerable symptoms that

are on 2 or more lipid-lowering therapies, LDL-C continues to be ele-

resolve with discontinuation of therapy and recur with rechallenge.

vated, failing to adequately reduce the risk for ASCVD. Of these indi-

Typically, at least 2 statins must be tried.33 Although not studied in

viduals, 50% report statin intolerance or allergy as the reason for

RCTs, when the lowest dose of multiple statins cannot be tolerated

submaximal statin use, and 23% report either patient or physician

on a daily basis, alternative-dosing strategies can be considered.

preference. Such findings highlight the need for access to additional

Under such circumstances, many experts advocate using statins with

intensive and well-tolerated lipid-lowering therapies in this popula-

long half-lives administered 3 times per week, every other day, or

tion for whom very high LDL-C in utero and beyond is the main

even once per week.33

driver of early and aggressive vascular disease.

3.1.1 | Recommended definition 1
Maximally tolerated statin therapy is defined as the highest tolerated
intensity and frequency of a statin, even if the dose is zero. This is

3 | DEFI NI TIONS F OR PI

preferably the guideline-recommended intensity of statin, but may of
The FDA has determined that alirocumab and evolocumab are indi-

necessity be a lower intensity dose or reduced frequency of statin

cated “as an adjunct to diet and maximally tolerated statin therapy

dosing, or even no statin at all. Statin intolerance can be defined as

for treatment of adults with HeFH or clinical atherosclerotic cardio-

unacceptable adverse effects that resolve with discontinuation of

1,2

vascular disease, who require additional lowering of LDL-C.

Furthermore, evolocumab is indicated “as an adjunct to diet and
other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis)

therapy and recur with rechallenge of 2 to 3 statins, preferably ones
that use different metabolic pathways, with 1 of which being prescribed at the lowest approved dose.33,36

in patients with homozygous familial hypercholesterolemia (HoFH)
who require additional lowering of LDL-C.” Despite specific
evidence-based indications for treatment with these 2 PCSK9 mab,

3.2 | HeFH and HoFH

inconsistencies in interpretation of language in the FDA-approved

FH is a common life-threatening genetic disorder characterized by

prescribing information have resulted in discrepancies in payer

substantially elevated LDL-C starting before birth.37,38 The life-long

approval and reimbursement practices. Five key definitions within the

exposure to elevated LDL-C significantly augments the risk for

PIs require clarification and harmonization to ensure proper access to

ASCVD; those with FH have a 2.5- to 10-fold increased risk for

these medicines.

ASCVD compared to control populations.39 Importantly, early detec-

The following definitions, with their respective explanations, are
proposed to clarify these FDA-approved indications.

tion and treatment of these patients has been shown to improve outcomes.39,40 Most commonly caused by mutations in the LDLR, apoB,

4

BAUM ET AL.

or the PCSK9 genes, FH is inherited in an autosomal dominant pat41,42

revascularization, stroke, TIA [transient ischemic attack], or peripheral

HeFH affects approximately 1 in 250 individuals around the

arterial disease presumed to be of atherosclerotic origin.”31 The Inter-

world, with some founder populations experiencing a much higher

national Atherosclerosis Society Position Paper: Global Recommenda-

prevalence.37,43 Adults with HeFH are typically characterized as hav-

tions for the Management of Dyslipidemia broadens the definition of

ing untreated LDL-C values over 190 mg/dL, whereas children and

established ASCVD to include “a history of CHD, stroke, peripheral

44

adolescents have untreated LDL-C values over 160 mg/dL.

arterial disease, carotid artery disease, and other forms of atheroscle-

Although much less common, HoFH is far more severe and poses an

rotic vascular disease.”47 Although not specified in this document,

extremely high risk of early ASCVD as well as aortic valvular and

other forms of atherosclerotic vascular disease that have been well-

supravalvular stenosis.38 Recent estimates indicate a prevalence of

documented to be associated with a marked increase risk of clinical

tern.

38,45

Indivi-

ASCVD events include extensive subclinical atherosclerosis of the cor-

duals with HoFH generally have untreated LDL-C values over

onary, carotid, or iliofemoral circulations, as well as atherosclerosis of

500 mg/dL; however, there is a substantial overlap between HeFH

the aorta.48–51

1 in 160 000 to 1 in 300 000 for HoFH.

and HoFH at LDL-C levels particularly between 300 and 500 mg/dL
because of the genotypic and phenotypic heterogeneity of FH.38,45

3.3.1 | Recommended definition 4

Though extremely rare, individuals with HoFH and 2 documented

Clinical ASCVD includes acute coronary syndromes, history of MI,

pathogenic mutations have been identified with untreated LDL-C

stable or unstable angina, coronary or other arterial revascularization,

levels below 200 mg/dL.38

stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin, as well as other forms of atherosclerotic vascular dis-

3.2.1 | International Classification of Diseases, 10th
Revision

ease including significant atherosclerosis of the coronary, carotid,
iliofemoral circulations, and the aorta.

codes
According to the 2013 consensus statement published by the
European Atherosclerosis Society, more than 90% of individuals with
FH in the United States have not been identified, a consequence of

3.4 | Additional lowering of LDL-C
Current guidelines for management of dyslipidemia indicate that

Previous

despite maximally tolerated statin therapy, high-risk patients with

International Classification of Diseases, 9th Revision codes for “pure

clinical ASCVD, HeFH, or HoFH may not achieve anticipated lower-

hypercholesterolemia” have been applied to both FH and non-FH

ing of LDL-C, or non–high-density lipoprotein cholesterol (HDL-C),

patients, contributing to broad misconceptions that the risk and man-

or may have unacceptably high residual levels of atherogenic lipo-

agement of FH are similar to those of lifestyle-induced hypercholes-

proteins.32–35 The 2013 ACC/AHA cholesterol guideline defines

terolemia. To rectify this problem, the FH Foundation and the NLA

adequacy of statin therapy based on anticipated percent reduction

37

gaps in screening, recognition, and disease classification.

applied for specific International Classification of Diseases, 10th Revi-

in LDL-C as calculated from RCTs included in the meta-analysis con-

sion (ICD-10) codes with the Centers for Medicare and Medicaid Ser-

ducted by the Cholesterol Treatment Trialists in 2010, in which

vices. Effective since October 2016, there is now a specific code for

statin therapy reduced ASCVD events (Table 1).11 The 2016 ACC

FH (E78.01) as well as a code for family history of FH (Z83.42).

Expert Consensus Decision Pathway on the Role of Non-Statin

Appropriate utilization of these ICD-10 codes will foster enhanced

Therapies for LDL-Cholesterol Lowering in the Management of Ath-

FH classification, identification, and much-needed family-based cas-

erosclerotic Cardiovascular Disease Risk provided levels of LDL-C,

cade screening.

or thresholds, in terms of both percentage LDL-C reduction from
baseline and absolute on-treatment LDL-C measurement, which if

3.2.2 | Recommended definition 2

not achieved by adherent patients would serve as factors to con-

“HeFH is defined as untreated LDL-C ≥160 mg/dL for children and

sider in decision making regarding the addition of nonstatin therapy.

≥190 mg/dL for adults and with 1 first-degree relative similarly

These thresholds are not firm triggers for adding medication but

affected or with premature coronary artery disease or with positive

factors that may be considered within the broader context of an

genetic testing for an LDL-C–raising gene defect (LDLR, apoB, or

individual patient’s clinical situation (Table 2).33 Both the National

PCSK9).”46

Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1 and the AACE/ACE 2017 Guidelines

3.2.3 | Recommended definition 3

for the Management of Dyslipidemia continue to define specific

“HoFH is defined as LDL-C ≥400 mg/dL and ≥1 parent with clinically

LDL-C and non–HDL-C goals based on absolute levels of athero-

diagnosed FH, positive genetic testing for 2 LDL-C–raising gene
defects (LDLR, apoB, or PCSK9), or autosomal-recessive FH.”46

genic lipoproteins (Tables 3 and 4).34,35 The most recent AACE
Guidelines introduced a new level of extreme risk, with an associated concomitant recommended LDL-C goal of <55 mg/dL
(Table 4).

3.3 | Clinical ASCVD
According to the 2013 ACC/AHA cholesterol guideline, clinical

3.4.1 | Recommended definition 5

ASCVD “includes acute coronary syndromes, history of MI [myocardial

“Patients with clinical ASCVD, HeFH, or HoFH who may require addi-

infarction], stable or unstable angina, coronary or other arterial

tional lowering of LDL-C include those with less than expected

5

BAUM ET AL.

TABLE 1

High-, moderate-, and low-intensity statin therapy (used in the RCTs reviewed by the expert panel)1

High-Intensity Statin Therapy

Moderate-Intensity Statin Therapy

Low-Intensity Statin Therapy

Daily dose lowers LDL-C, on average, by
approximately ≥50%

Daily dose lowers LDL-C, on average, by
approximately 30% to <50%

Daily dose lowers LDL-C, on average, by
<30%

Atorvastatin (402)–80 mg

Atorvastatin 10 (20) mg

Simvastatin 10 mg

Rosuvastatin 20 (40) mg

Rosuvastatin (5) 10 mg

Pravastatin 10–20 mg

Simvastatin 20–40 mg3

Lovastatin 20 mg

Pravastatin 40 (80) mg

Fluvastatin 20–40 mg

Lovastatin 40 mg

Pitavastatin 1 mg

Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
Abbreviations: BID, twice daily; CQ, critical question; FDA, Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; RCTs, randomized
controlled trials.
Boldface type indicates specific statins and doses that were evaluated in RCTs16–18,46–49,64–75,77 included in CQ1, CQ2, and the Cholesterol Treatment
Trialists 2010 meta-analysis included in CQ3.20 All of these RCTs demonstrated a reduction in major cardiovascular events. Italic type indicates statins
and doses that have been approved by the FDA but were not tested in the RCTs reviewed.
1

Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biological basis for a lessthan-average response.

2

Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental Decrease through Aggressive Lip Lowering)
study.47

3

Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of
the increased risk of myopathy, including rhabdomyolysis.

percent reduction in LDL-C or residual absolute levels of LDL-C,

our ability to properly care for patients. This section reveals various

non–HDL-C, or apoB that exceed goals for atherogenic lipoproteins

challenges created by each of these practices.53

as specifically defined in any of the current guidelines for these very
high-risk and extreme-risk populations.”32,33

4.1 | Prior authorization
The PA has become a nearly universal tool to limit patient access to

4 | PRIOR AUTHORIZATIONS, STEP
T H E R A P Y , A N D TH E A P P E A L S P R O C E S S

medications. PAs require that healthcare practitioners collect specific
data deemed necessary for medication approval. Complex paperwork
(up to 17 pages in the case of the PCSK9 mab) often delays or dis-

Formulary restrictions52 have been employed by insurance providers

courages patient access to newer or more costly drugs. Justification

as a strategy to limit use of more costly medications. Three principal

of the PA process by payers includes the assertion that this process

measures creating barriers to access include the requirement of PAs,

is necessary to avoid potential overuse of medications.10 Prior to the

step therapy (commonly dubbed “fail first”), and a burdensome

FDA’s approval of the PCSK9 mab, ICER predicted that the medica-

appeals process. Happe et al provided a systematic literature review

tions would cost insurers $1.2 billion within their first year on the

assessing the impact of managed care formulary restrictions on medi-

market. The actual cost was $83 million, just 1.2% of what had been

cation adherence, clinical outcomes, economic outcomes, and health-

projected. Based on their inaccurate prediction, ICER advised insurers

care resource utilization, concluding, “There is a strong evidence base

to use the PA as a primary barrier to access.3 This strategy, though

demonstrating a negative correlation between formulary restrictions

effective, can inadvertently undermine the patient clinician relation-

and medication adherence outcomes.”53 Thus, PAs and other

ship, which is in part based on access to therapies appropriately pre-

insurance-based cost-containment strategies are actually undermining

scribed by a clinician and deemed essential to the care of a patient.

TABLE 2

2016 ACC Expert Consensus Decision Pathway on the role of nonstatin therapies for LDL-C lowering in the management of
atherosclerotic cardiovascular disease risk: recommended thresholds for consideration of net ASCVD risk reduction benefit for the addition of
nonstatin therapies
Expected % Reduction in LDL-C
High-Intensity Statin
Therapy

Moderate-Intensity Statin
Therapy

Recommended Threshold For Consideration of
Nonstatin Therapies Based on Absolute LDL-C
Levels

Without comorbidities1

≥50%

30 to <50%

LDL-C ≥100 mg/dL

With comorbidities1

≥50%

30 to <50%

LDL-C ≥70 mg/dL

Baseline LDL-C ≥190 mg/dL

≥50%

30 to <50%

LDL-C ≥100 mg/dL

Statin Benefit Group
Clinical ASCVD

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

6

BAUM ET AL.

TABLE 3

Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol, and levels at which to consider drug therapy

Risk
Category

Criteria

Low

0–1 major ASCVD risk factors

<30

≥190

Consider other risk indicators, if known

<100

≥160

Moderate

Treatment Goal, Non–HDL-C mg/dL,
LDL-C mg/dL

Consider Drug Therapy, Non–HDL-C
mg/dL, LDL-C mg/dL

2 major ASCVD risk factors

<130

≥160

Consider quantitative risk scoring

<100

≥130

<130

≥130

<100

≥100

Consider other risk indicators1
High

≥3 major ASCVD risk factors
2

Diabetes mellitus (type 1 or 2)

0–1 other major ASCVD risk factors
No evidence of end-organ damage
Chronic kidney disease stage 3B or 43
LDL-C ≥190 mg/dL (severe
hypercholesterolemia)4
Quantitative risk score reaching the highrisk threshold5
Very high

ASCVD
Diabetes mellitus (type 1 or 2)
≥2 other major ASCVD risk factors

<100

≥100

Evidence of end-organ damage6

<70

≥70

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cardiovascular disease;
GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
For patients with ASCVD or diabetes mellitus, consideration should be given to use of moderate or high-intensity statin therapy, irrespective of baseline
atherogenic cholesterol levels.
1

For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk stratification.

2

For patients with diabetes plus 1 major ASCVD risk factor, treating to a non–HDL-C goal of <100 mg/dL (LDL-C <70 mg/dL) is considered a therapeutic
option.

3

For patients with CKD stage 3B (GFR 30–44 mL/min/1.73 m2) or stage 4 (GFR 15–29 mL/min/1.73 m2), risk calculators should not be used because
they may underestimate risk. Stage 5 CKD (or on hemodialysis) is a very high-risk condition, but results from randomized controlled trials of lipidaltering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy
have been designed for stage 5 CKD.

4

If LDL-C is ≥190 md/dL, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and pharmacotherapy are recommended for adults with the severe hypercholesterolemia phenotype. If it is not possible to attain desirable levels of atherogenic
cholesterol, a reduction of at least 50% is recommended. For familial hypercholesterolemia patients with multiple or poorly controlled other major
ASCVD risk factors, clinicians may consider attaining even lower levels of atherogenic cholesterol. Risk calculators should not be used such patients.

5

High-risk threshold is defined as ≥10% using the Adult Treatment Panel III Framingham Risk Score for hard CDH (myocardial infarction or CHD death),
≥15% using the 2013 Pooled Cohort Equations for hard ASCVD (myocardial infarction, stroke, or death from CHD or stroke), or ≥45% using the Framingham long-term (to age 80 years) CVD (myocardial infarction, CHD death, or stroke) risk calculation. Clinicians may prefer to use the other risk calculators, but should be aware that quantitative risk calculators vary in the clinical outcomes predicted (eg, CHD events, ASVCD events, cardiovascular
mortality), the risk factors included in their calculation, and the timeframe for their prediction (eg, 5 years, 10 years, or long term or lifetime). Such calculators may omit certain risk indicators that can be very important in individual patients, provide only an approximate risk estimate, and require clinical
judgment for interpretation.

6

End-organ damage indicated by increased albumin/creatinine ratio (≥30 mg/g), CKD, or retinopathy.

PAs create an undue and often overlooked strain on medical

patients. Creating payer websites to expedite the process of the PA,

practices. A 2013 study found that the “PA is a measurable burden

assigning case managers with whom doctors’ offices can communicate

on physician and staff time.”52 In 2006, it was estimated that health-

directly and efficiently, and enabling offices to complete a simplified

care practitioners spent 1.1 hours per week, nursing 13.1 hours per

and harmonized online PA represent a few potential solutions. Such

week, and clerical staff 5.6 hours per week on PAs. In 2009, total

changes would lead to shorter times for response and limited waiting

healthcare system costs for PAs were estimated to be $23 to $31 bil-

“on hold” for service.52,54 Keeping in mind that PCSK9 mab are

lion per year. Latest national surveys confirm that the cost per year

intended for the highest-risk patient population in whom time is most

to healthcare practitioners has risen to between $83,000 and

definitely plaque, shortening the time from prescription to acquisition

$85,000 per practitioner.52–54 Such costs do take a financial toll on

of medications will likely be clinically meaningful.

clinicians, but much more importantly, they drain time from health-

Accompanying this article is a template PA form (see Supporting

care practitioners whose efforts would be better utilized caring for

Information, Appendix 1, in the online version of this article) pro-

their patients. In this regard, PAs hamper an optimal patient–clinician

posed to serve as a universal guidance for review and application by

relationship.

payers. The template form follows the definitions presented herein

Several measures can be taken to ease the burden of the PA on
clinicians and guarantee that appropriate medications are available for

and, assuming all definitions are met, it is recommended that patients
who meet these requirements be granted access to therapy.

7

BAUM ET AL.

TABLE 4

Atherosclerotic cardiovascular disease risk categories and low-density lipoprotein treatment goals
Treatment Goals
1

2

Risk Category

Risk Factors /10-Year Risk

LDL-C (mg/dL)

Non–HDL-C (mg/dL)

Apo B (mg/dL)

Extreme risk

a.Progressive ASCVD including unstable angina in individuals
after achieving an LDL-C <70 mg/dL
b.Established clinical cardiovascular disease in individuals with
DM, CKD 3/4, or HeFH History of premature ASCVD (<55
male, <65 female)

<55

<80

<70

Very high risk

Established or recent hospitalization for ACS, coronary,
carotid or peripheral vascular disease, 10-year risk >20%

<70

<100

<80

<100

<130

<90

Diabetes or CKD 3/4 with 1 or more risk factor(s)
HeFH
High risk

≥2 risk factors and 10-year risk 10%–20%
Diabetes or CKD 3/4 with no other risk factors

Moderate risk

≤2 risk factors and 10-year risk <10%

<100

<130

<90

Low risk

0 risk factors

<130

<160

NR

Abbreviations: ACS, acute coronary syndrome; APO B, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease;
DM, diabetes mellitus; HDL-C , high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein
cholesterol; MESA, Multi-ethnic Study of Atherosclerosis; NR, not recommended; UKPDS, United Kingdom Prospective Diabetes Study.
1

Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥140/90 mm Hg or on
hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male, first-degree relative younger than 55 years; in
female, first-degree relative younger than 65 years), CKD stage 3/4, evidence of coronary artery calcification and age (men ≥45; women ≥55 years).
Subtract 1 risk factor if the person has high HDL-C.

2

Framingham risk scoring is applied to determine 10-year risk.

4.2 | STEP therapy
Step therapy has been defined as “a prior authorization program that
encourages the use of less costly yet effective medications before
more costly medications are approved for coverage.”55 It has been
designed, however, to lower prescription drug costs. Ostensibly, it
also provides practitioners with optimal pathways to utilize different
classes of drugs when treating particular conditions. Frequently
though, it prioritizes the utilization of generic medications (assumed
to be less costly) over branded medications.
Step therapy is ubiquitous in medical practice. Typically, medications are divided into tiers, beginning with the least costly prescriptions. Clinicians are required to begin with the first tier; they cannot
progress to the second and third tiers until they have documented
proof that their patients have failed long trials with lower-tier medications. Criteria for moving from a lower to a higher tier can be therapeutic failure, medication intolerance, or inability to treat a

health-averse effects such as nonadherence and diminished access to
medicines.56 In a review published in 2014 by Rahul K. Nayak and
Steven D. Pearson, CEO of ICER, step therapy is acknowledged to
have the “potential to create conflict between the goals of cost control and the ability to tailor care to the perceived needs of the individual patient.”57 In an article on the ethics of a fail first policy, the
authors outline guidelines that should be followed to ensure that
patients are protected and receive timely and appropriate access to
needed medications.57 They admonish that cost saving should be
weighed against long-term outcomes. First step drugs should also be
clinically appropriate, and failure should never lead to clinical harm.
Opting out on clinical grounds should be quick and easy, they caution, and failure should be clearly defined. Finally, it is emphasized
that “rationale and rules should be explicit and transparent.” Evidently, many payers have not embraced these recommendations.
Consequently, patients commonly experience unnecessary delays in

condition appropriately. Thus, step therapy has been aptly dubbed

acquiring the medications their clinicians have prescribed. Often they

“fail first” therapy.

are denied. With regard to the PCSK9 mab, such delays in drug

Step 1 medications are generally generic products and do not

access may be life threatening.

require prior authorization. Step 2 medications are often branded

Patients with ASCVD and FH are at particularly high risk for

drugs that are preferred by a particular payer, insurer, or heath care

future cardiovascular events.29 All cholesterol guidelines emphasize

system. Step 3 medications are brands that are not preferred and typ-

the importance of aggressive statin therapy in such patients. Failure

ically require extensive and burdensome PAs and involve substantially

to achieve adequate LDL-C reduction and intolerance to medications

greater costs to patients.

are indications to utilize nonstatin therapies. As time is plaque in

Step therapy’s requirement for a patient to try and fail a less

high-risk patients, they need access to nonstatin therapy quickly and

costly medication prior to being prescribed what might actually be

hindrance free. This typically does not occur; instead, patients usually

the optimal drug for that particular patient undermines the essence

suffer long wait times before receiving their prescribed medicines.

of medical practice from both a personalized and population perspec-

Often, they never obtain them. Examining this issue, Nayak and Pear-

tive. Though this custom can reduce short-term prescription costs, it

son reviewed several scenarios based on level of ethical burden to

may have a negative impact on long-term patient outcomes. In fact,

justify step therapy.57 They specifically pointed to statin therapy (at a

savings attributed to lower formulary costs may actually be due to

time when many of the statins were still branded and therefore

8

BAUM ET AL.

costly) as requiring a high ethical burden to justify step therapy. With
PCSK9 mab now available and indicated for patients with clinical
ASCVD and/or FH, this same standard should apply. Patients who
require additional LDL-C lowering, despite maximally tolerated statin
therapy, should be treated swiftly and aggressively as uniformly
recommended by current professional society cholesterol guidelines.
Step therapy should not be a barrier.
Finally, it is important to note that formulary construction itself
has been used for cost containment.58 Restricting access to more
expensive medications, including branded products or novel therapies, has the immediate impact of reducing cost. Looking at the longterm, however, we again witness something concerning. Coverage
gaps (through formulary restrictions) can lead to worse patient out-

risk some physicians must bear. Blue Cross Blue Shield of North Carolina, for example, specifies on its website62 that when the value of a
dispute exceeds $1000, physicians must personally pay a $250 dollar
filing fee to initiate any second appeal. This establishes a clear conflict of interest; the doctor must pay the insurance provider to obtain
a valid prescription that has already been written. Given the high
denial rate for the PCSK9 mab, such a requirement clearly represents
an untenable financial barrier for physicians.
Accompanying this article is a appeals template letter providing
guidance to clinicians and payers to improve appeal success and
patient access to prescribed therapy (see Supporting Information,
Appendix 2, in the online version of this article).

comes.59,60 Clearly, plan exclusions that deny patients entire classes
of medications, such as the PCSK9 mab, should be eschewed.

5 | CONC LU SION
Unnecessary PCSK9 mab access barriers have been identified, and

4.3 | Appeals

cogent solutions have been recommended. It is only with clear guid-

The appeals process enables clinicians to petition for a change in an

ance to all invested parties, including patients, clinicians, payers, and

insurance provider’s decision regarding a prescribed therapeutic. In

PBMs, that appropriate access to PCSK9 mab will be achieved. As

the case of PCSK9 mab, appeals are the norm rather than the excep-

outlined above, the PIs for alirocumab and evolocumab are clear. It is

5

tion. As noted above, the Symphony report found that greater than

their interpretation that has challenged patient access, even for

80% of initial prescriptions for PCSK9 mab are denied. Of these initial

appropriate individuals as documented by Kolata in the New York

denials, after extensive appeals, 46.6% of Medicare and 26.7% of pri-

Times, and others in their exposés.63–65 This article provides defini-

vately insured patients ultimately gained approval.5 These appeals

tions for each of the 5 key elements of the PI—maximally tolerated

force a doctor’s office’s time, energy, and focus to be redirected from

statin therapy, HeFH, HoFH, clinical ASCVD, and the need for addi-

patient care to unnecessary administrative encumbrances. Multiple

tional lowering of LDL-C—proposed by individual experts in ASCVD

hour-long phone calls often trying simply to identify the proper pro-

management and prevention. The ASPC recommends that all

vider representatives, and resubmissions of prolific paperwork are

invested parties review, evaluate, and incorporate in practice the defi-

commonplace in the appeal process. Tracking all appeals, providing

nitions provided herein, along with the prior authorization template

identifiable and accessible case managers, and creating electronic sys-

and appeals letter. Without these process improvements, impaired

tems for appeals are obvious steps insurers could take to streamline

patient access to potentially life-saving therapy will persist.

this process.
Recent evidence suggests a possible bias in the PCSK9 mab
approval/denial, process. Unpublished data from Baum et al61 corrob30

orate the FH Foundation’s national CASCADE FH Registry

Conflicts of Interest

findings

Seth J. Baum, MD—Scientific Advisory Boards: Amgen, Regeneron,

of high denial rates. This study evaluated results from International

Sanofi, Akcea, Ionis Speaker: Amgen, Merck, BI, Lilly. Research:

Marketing Services (IMS) Formulary Impact Analyzer data, a system

Regeneron, Amgen, Esperion, BI, Regenex, Madrigal, Gemphire. Peter

designed to assess formularies’ impacts on patient, linked to longitu-

P. Toth, MD, PhD—Speaker’s Bureau: Amarin, Amgen, Kowa, Merck,

dinal prescriptions point-of-sale data for both PCSK9 mab over the

Regeneron, Sanofi. Consultant: Amarin, Amgen, Gemphire, Merck,

course of 1 year. A summary of findings reveals an unprecedented

Regeneron, Sanofi James A. Underberg, MD—Amgen: Honoraria,

high initial rejection rate for PCSK9 mab therapies, suggesting a seri-

Consulting Fees, Advisory Board, Consultant, Speakers Bureau. Alex-

ous flaw in the utilization management process. A history of statin

ion:, Honoraria, Speakers Bureau. Aegerion: Research Payments ,

and ezetimibe use was similar between rejected and approved

Contracted Research, Steering Committee Member. Amarin: Consult-

patients, as was the use of P2Y12 platelet inhibitor therapy, a treat-

ing Fees, Consultant. Sanofi: Honoraria, Speaker Bureau, Advisory

ment nearly pathognomonic for clinical ASCVD, implying inconsistent

Board. Regeneron: Honoraria, Speaker Bureau, Advisory Board. Invi-

adjudication. Many of the initial rejections were later overturned,

tae: Honoraria, Advisory Board. True Heath Diagnostics: Honoraria,

suggesting a flawed initial review process. Finally, when federal over-

Speaker Bureau. Kowa: Consulting fees, Advisory Board. Kastle: Hon-

sight is involved (eg, Medicare), initial and final approval rates are sig-

oraria, Consulting Fees, Advisory Board, Speaker Bureau, Consultant.

nificantly higher. Thus, the processes of approval/denial for the

Pfizer: Research Payments, Contracted Research Akcea: Honoraria,

PCSK9 mab as well as the impact of these high denial rates on

Advisory Board. Paul Jellinger, MD—Novo Nordisk: Speaking and

patients’ outcomes need to be explored.61

teaching. Merck: Speaking and teaching. Boehringer-Ingelheim:

Clinicians must frequently intervene with insurance providers,

Speaking and teaching. Astra-Zeneca: Speaking and teaching. Jans-

advocating on behalf of patients, but unfortunately eroding valuable

sen: Speaking and teaching. Amgen: Speaking and teaching; Advisory

time and energy. There is also an unrecognized potential economic

committee. Joyce Ross, ARNP—Amarin: Honorarium Speaker, Amgen:

BAUM ET AL.

Honorarium Speaker, Kowa: Honorarium Speaker, Ackea: Honorarium
Consultant, Abbvie: Honorarium Speaker, Sanofi/Regeneron: Honorarium Speaker, AstraZeneca: Honorarium Speaker.

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S U P P O R T I N G I N F O R M A T I ON
Additional Supporting Information may be found online in the supporting information tab for this article.

How to cite this article: Baum SJ, Toth PP, Underberg JA,
Jellinger P, Ross J and Wilemon K. PCSK9 inhibitor access
barriers—issues and recommendations: Improving the access
process for patients, clinicians and payers, Clin Cardiol, 2017.
https://doi.org/10.1002/clc.22713

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