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REVIEWS

PCSK9 inhibitor access barriers—issues and recommendations:

Improving the access process for patients, clinicians

and payers

Seth J. Baum

| Peter P. Toth

| James A. Underberg

| Paul Jellinger

| Joyce Ross

Katherine Wilemon

Department of Integrated Medical

Sciences, Charles E. Schmidt College of

Medicine, Florida Atlantic University, Boca

Raton, Florida

CGH Medical Center, Sterling, Illinois, and

Ciccarone Center for the Prevention of Heart

Disease, Johns Hopkins University School of

Medicine, Baltimore, Maryland

Center for the Prevention of Cardiovascular

Disease at New York University Langone

Medical Center, New York, New York

Center for Diabetes and Endocrine Care, Ft.

Lauderdale, Florida, and University of Miami

Miller School of Medicine, Miami, Florida

University of Pennsylvania Health System,

Philadelphia, Pennsylvania

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

Funding information

Funding for The Town Hall Series came from

an unrestricted grant from Amgen and Sanofi/

Regeneron.

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

familial hypercholesterolemia (FH) and clinical atherosclerotic cardiovascular disease requiring

additional lowering of low-density lipoprotein cholesterol. Though many lipid specialists, cardio-

vascular 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 stake-

holder 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.

KEYWORDS

Coronary Artery Disease, Familial Hypercholesterolemia, Hepatocyte, Low-Density

Lipoprotein Cholesterol, Pharmacy Benefits Manager, Proprotein Convertase Subtilisin/Kexin

Type 9

1|INTRODUCTION

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

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

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

1,2

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

maximally tolerated statin therapy in adult patients with heterozy-

gous familial hypercholesterolemia (HeFH) or clinical atherosclerotic

cardiovascular disease (ASCVD) requiring further reduction in low-

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

additional indication for homozygous familial hypercholesterolemia

(HoFH). Understanding that “time is plaque”

and that PCSK9 mab

offered heretofore unobserved intensive and predictable lowering of

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

ASCVD prevention and treatment arenas prescribed these medicines

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

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

strated approximately 80% initial denial rates, with final approvals

between 25% and 50% for commercial and Medicare patients

respectively.

An FH Foundation survey of impacted individuals

assessed patient access to lipid-lowering therapies for FH.

Data

from 163 participants revealed a 26% overall denial rate of

Received: 5 March 2017 Accepted: 6 March 2017

DOI: 10.1002/clc.22713

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.

Clinical Cardiology. 2017;1–13. wileyonlinelibrary.com/journal/clc 1

medication coverage; 79% were denials of PCSK9 mab prescriptions,

with 36% of these prescriptions being written for secondary preven-

tion. These and other similar findings demanded deeper inquiry, and

so the American Society for Preventive Cardiology (ASPC) organized

representation from the American College of Cardiology (ACC),

National Lipid Association (NLA), American Association of Clinical

Endocrinologists (AACE), and the Familial Hypercholesterolemia

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

to attend these meetings included insurance providers, pharmacy ben-

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

during the annual ASPC congress in September 2016, was structured

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

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

sented proposed solutions to the previously identified problems. The

town hall meetings were well attended, demonstrating substantial

appreciation and concern among clinicians regarding our inability to

access PCSK9 mab for our patients.

This review documents the development of a novel and highly

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

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

ingful, and implementable solutions are proposed to improve the

PCSK9 mab access process for patients meeting the prescribing cri-

teria 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

appeals letters are presented. It is important to recognize that

recent systematic denials for novel medications are not limited to

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

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

paramount importance to preserve innovation and safeguard patient

access to prescribed novel therapies, a foundation of the patient-

clinician 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.

A number of

articles, such as that by Kazi et al,

have evaluated the cost effec-

tiveness of these medications using questionable criteria such as

quality-adjusted life years (QALYs), a metric abandoned by the

Affordable Care Act

as well as Europe because of its acknowl-

edged inaccuracies.

In addition, a number of assumptions made in

relevant pharmacoeconomics analyses proved incorrect, including

an overestimation of the number of FH patients purportedly requir-

ing 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.

Such prognostications likely precipitated a high level of caution

among payers, causing frequent denials and a challenging appeal

process.

Integrally involved in drug pricing, yet often overlooked, are

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

tiating deals between pharmaceutical companies and the end

payers.

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

ings and solutions detailed in this article.

2|THE HISTORY AND IMPORTANCE OF

PCSK9

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

development of atherosclerosis. Most importantly, LDL-C reduction

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

reduce the risk of heart attack, stroke, and death.

Some of the most

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

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

morphisms, some more consequential than others. FH is associated

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

zygous and homozygous forms, respectively.

Importantly, risk for

ASCVD increases in direct proportion to the magnitude of elevation

in LDL-C exposure.

According to the classic model developed by

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

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

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

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

levels of LDL-C.

Apoprotein B100 (apoB), present in a 1-to-1 rela-

tionship with all LDL particles, functions as a docking molecule

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.

Additional heterogeneity in the hereditary basis for FH became

apparent. Abifadel and coworkers identified a third candidate gene

that mapped to the short arm of chromosome 1.

In 2003, this gene

was identified as coding for PCSK9.

Using positional cloning, Abifa-

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

notype of FH.

The overexpression of PCSK9 was found to

correlate with increased serum LDL-C.

Consistent with this obser-

vation, mutations in PCSK9 that cause FH are a gain of function. Fol-

lowing these discoveries, investigators identified loss of function

mutations in PCSK9, which correlated with low serum levels of LDL-

C and concomitant reduced risk for acute cardiovascular events.

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.

In the extracellular milieu, mature PCSK9 has

no proteolytic activity; its active site is blocked by its previously

cleaved prosegment.

Therefore, it serves simply as a binding pro-

tein. On hepatocytes, PCSK9 binds to a complex comprising the

LDLR and an LDL particle. This binding occurs between PCSK9

and the epidermal growth factor–like repeat A domain of the

LDLR.

This polymolecular assembly is incorporated into clathrin-

coated endosomal vesicles that are brought into the cytosol.

Within the cytosol, PCSK9 chaperones the LDLR complex into the

lysosome for hydrolytic destruction, thereby reducing the recycling

of LDLR to the hepatocyte cell surface and reducing LDL particle

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

complex, lysosomal enzymes catabolize the LDL particle, but the

LDLR is recycled back to the hepatocyte cell surface to initiate fur-

ther LDL particle binding, uptake, and degradation. LDLR recycling

2BAUM ET AL.

can occur up to 150 times.

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 lipopro-

tein cell surface receptors, including the LDL receptor related

protein-1,

the very low-density lipoprotein receptor, and the apoli-

poprotein E receptor 2.

The clinical significance of these latter

interactions is yet to be established.

Alirocumab and evolocumab are safe and highly efficacious, and

provide substantial incremental LDL-C reductions of between 55%

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

28,29

These therapies constitute an important and vital breakthrough in the

management of patients who cannot achieve guideline-established

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

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

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

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

haps stands out most prominently. Despite FH guidelines that advise

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

often remain too high for those with FH.

Current data from the FH

Foundation’s national CAscade SCreening for Awareness and DEtec-

tion of Familial Hypercholesterolemia (CASCADE FH) registry,

com-

prising 30 leading cardiovascular and academic centers in the United

States, demonstrate frequently insufficient LDL-C reduction. Adults

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

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

181 mg/dL, respectively.

Although 60% of the adult participants

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

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

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

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

preference. Such findings highlight the need for access to additional

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

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

driver of early and aggressive vascular disease.

3|DEFINITIONS FOR PI

The FDA has determined that alirocumab and evolocumab are indi-

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

for treatment of adults with HeFH or clinical atherosclerotic cardio-

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

1,2

Furthermore, evolocumab is indicated “as an adjunct to diet and

other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis)

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,

inconsistencies in interpretation of language in the FDA-approved

prescribing information have resulted in discrepancies in payer

approval and reimbursement practices. Five key definitions within the

PIs require clarification and harmonization to ensure proper access to

these medicines.

The following definitions, with their respective explanations, are

proposed to clarify these FDA-approved indications.

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,

the 2016

ACC Expert Consensus Decision Pathway on the Role of Non-Statin

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

erosclerotic Cardiovascular Disease Risk, NLA Recommendations for

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

American Association of Clinical Endocrinologists (AACE)/American

College of Endocrinology (ACE) 2017 Guidelines for the Management

of Dyslipidemia, uniformly recommend high-intensity statin therapy

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

HeFH, or HoFH.

32–35

Moderate-intensity statin therapy may be con-

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

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

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

mended prior to consideration of nonstatin therapies.

The fact that maximally tolerated statin therapy and statin intol-

erance are not well defined in available guidelines contributes signifi-

cantly to provider and payer inconsistencies when physicians

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

nized that following initiation of statin therapy, some individuals may

experience unacceptable adverse effects, the most commonly

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

versally accepted definition of statin intolerance, most experts make

the diagnosis when patients experience intolerable symptoms that

resolve with discontinuation of therapy and recur with rechallenge.

Typically, at least 2 statins must be tried.

Although not studied in

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

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

Under such circumstances, many experts advocate using statins with

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

even once per week.

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

preferably the guideline-recommended intensity of statin, but may of

necessity be a lower intensity dose or reduced frequency of statin

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

unacceptable adverse effects that resolve with discontinuation of

therapy and recur with rechallenge of 2 to 3 statins, preferably ones

that use different metabolic pathways, with 1 of which being pre-

scribed at the lowest approved dose.

33,36

3.2 |HeFH and HoFH

FH is a common life-threatening genetic disorder characterized by

substantially elevated LDL-C starting before birth.

37,38

The life-long

exposure to elevated LDL-C significantly augments the risk for

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

ASCVD compared to control populations.

Importantly, early detec-

tion and treatment of these patients has been shown to improve out-

comes.

39,40

Most commonly caused by mutations in the LDLR, apoB,

BAUM ET AL.3

or the PCSK9 genes, FH is inherited in an autosomal dominant pat-

tern.

41,42

HeFH affects approximately 1 in 250 individuals around the

world, with some founder populations experiencing a much higher

prevalence.

37,43

Adults with HeFH are typically characterized as hav-

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

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

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

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

supravalvular stenosis.

Recent estimates indicate a prevalence of

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

38,45

Indivi-

duals with HoFH generally have untreated LDL-C values over

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

and HoFH at LDL-C levels particularly between 300 and 500 mg/dL

because of the genotypic and phenotypic heterogeneity of FH.

38,45

Though extremely rare, individuals with HoFH and 2 documented

pathogenic mutations have been identified with untreated LDL-C

levels below 200 mg/dL.

3.2.1 |International Classification of Diseases, 10th

Revision

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

gaps in screening, recognition, and disease classification.

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

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

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

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

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

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

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

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

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

Appropriate utilization of these ICD-10 codes will foster enhanced

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

cade screening.

3.2.2 |Recommended definition 2

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

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

affected or with premature coronary artery disease or with positive

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

PCSK9).”

3.2.3 |Recommended definition 3

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

diagnosed FH, positive genetic testing for 2 LDL-C–raising gene

defects (LDLR, apoB, or PCSK9), or autosomal-recessive FH.”

3.3 |Clinical ASCVD

According to the 2013 ACC/AHA cholesterol guideline, clinical

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

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

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

arterial disease presumed to be of atherosclerotic origin.”

The Inter-

national Atherosclerosis Society Position Paper: Global Recommenda-

tions for the Management of Dyslipidemia broadens the definition of

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

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

rotic vascular disease.”

Although not specified in this document,

other forms of atherosclerotic vascular disease that have been well-

documented to be associated with a marked increase risk of clinical

ASCVD events include extensive subclinical atherosclerosis of the cor-

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

the aorta.

48–51

3.3.1 |Recommended definition 4

Clinical ASCVD includes acute coronary syndromes, history of MI,

stable or unstable angina, coronary or other arterial revascularization,

stroke, TIA, or peripheral arterial disease presumed to be of athero-

sclerotic origin, as well as other forms of atherosclerotic vascular dis-

ease including significant atherosclerosis of the coronary, carotid,

iliofemoral circulations, and the aorta.

3.4 |Additional lowering of LDL-C

Current guidelines for management of dyslipidemia indicate that

despite maximally tolerated statin therapy, high-risk patients with

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

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

or may have unacceptably high residual levels of atherogenic lipo-

proteins.

32–35

The 2013 ACC/AHA cholesterol guideline defines

adequacy of statin therapy based on anticipated percent reduction

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

ducted by the Cholesterol Treatment Trialists in 2010, in which

statin therapy reduced ASCVD events (Table 1).

The 2016 ACC

Expert Consensus Decision Pathway on the Role of Non-Statin

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

erosclerotic Cardiovascular Disease Risk provided levels of LDL-C,

or thresholds, in terms of both percentage LDL-C reduction from

baseline and absolute on-treatment LDL-C measurement, which if

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

sider in decision making regarding the addition of nonstatin therapy.

These thresholds are not firm triggers for adding medication but

factors that may be considered within the broader context of an

individual patient’s clinical situation (Table 2).

Both the National

Lipid Association Recommendations for Patient-Centered Manage-

ment of Dyslipidemia: Part 1 and the AACE/ACE 2017 Guidelines

for the Management of Dyslipidemia continue to define specific

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

genic lipoproteins (Tables 3 and 4).

34,35

The most recent AACE

Guidelines introduced a new level of extreme risk, with an associ-

ated concomitant recommended LDL-C goal of <55 mg/dL

(Table 4).

3.4.1 |Recommended definition 5

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

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

4BAUM ET AL.

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

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

as specifically defined in any of the current guidelines for these very

high-risk and extreme-risk populations.”

32,33

4|PRIOR AUTHORIZATIONS, STEP

THERAPY, AND THE APPEALS PROCESS

Formulary restrictions

have been employed by insurance providers

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

measures creating barriers to access include the requirement of PAs,

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

appeals process. Happe et al provided a systematic literature review

assessing the impact of managed care formulary restrictions on medi-

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

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

demonstrating a negative correlation between formulary restrictions

and medication adherence outcomes.”

Thus, PAs and other

insurance-based cost-containment strategies are actually undermining

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

challenges created by each of these practices.

4.1 |Prior authorization

The PA has become a nearly universal tool to limit patient access to

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-

courages patient access to newer or more costly drugs. Justification

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

is necessary to avoid potential overuse of medications.

Prior to the

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

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

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

projected. Based on their inaccurate prediction, ICER advised insurers

to use the PA as a primary barrier to access.

This strategy, though

effective, can inadvertently undermine the patient clinician relation-

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

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

Statin Benefit Group

Expected % Reduction in LDL-C Recommended Threshold For Consideration of

Nonstatin Therapies Based on Absolute LDL-C

Levels

High-Intensity Statin

Therapy

Moderate-Intensity Statin

Therapy

Clinical ASCVD

Without comorbidities

≥50% 30 to <50% LDL-C ≥100 mg/dL

With comorbidities

≥50% 30 to <50% LDL-C ≥70 mg/dL

Baseline LDL-C ≥190 mg/dL ≥50% 30 to <50% LDL-C ≥100 mg/dL

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

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

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 (40

)–80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg

Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10–20 mg

Simvastatin 20–40 mg

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 2–4mg

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 RCTs

16–18,46–49,64–75,77

included in CQ1, CQ2, and the Cholesterol Treatment

Trialists 2010 meta-analysis included in CQ3.

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.

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 less-

than-average response.

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

study.

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.

BAUM ET AL.5

PAs create an undue and often overlooked strain on medical

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

on physician and staff time.”

In 2006, it was estimated that health-

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

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

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

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

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

$85,000 per practitioner.

52–54

Such costs do take a financial toll on

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

care practitioners whose efforts would be better utilized caring for

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

relationship.

Several measures can be taken to ease the burden of the PA on

clinicians and guarantee that appropriate medications are available for

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

assigning case managers with whom doctors’offices can communicate

directly and efficiently, and enabling offices to complete a simplified

and harmonized online PA represent a few potential solutions. Such

changes would lead to shorter times for response and limited waiting

“on hold”for service.

52,54

Keeping in mind that PCSK9 mab are

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

definitely plaque, shortening the time from prescription to acquisition

of medications will likely be clinically meaningful.

Accompanying this article is a template PA form (see Supporting

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

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

payers. The template form follows the definitions presented herein

and, assuming all definitions are met, it is recommended that patients

who meet these requirements be granted access to therapy.

TABLE 3 Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol, and levels at which to consider drug therapy

Risk

Category Criteria

Treatment Goal, Non–HDL-C mg/dL,

LDL-C mg/dL

Consider Drug Therapy, Non–HDL-C

mg/dL, LDL-C mg/dL

Low 0–1 major ASCVD risk factors <30 ≥190

Consider other risk indicators, if known <100 ≥160

Moderate 2 major ASCVD risk factors <130 ≥160

Consider quantitative risk scoring <100 ≥130

Consider other risk indicators

High ≥3 major ASCVD risk factors <130 ≥130

Diabetes mellitus (type 1 or 2)

<100 ≥100

0–1 other major ASCVD risk factors

No evidence of end-organ damage

Chronic kidney disease stage 3B or 4

LDL-C ≥190 mg/dL (severe

hypercholesterolemia)

Quantitative risk score reaching the high-

risk threshold

Very high ASCVD

Diabetes mellitus (type 1 or 2)

≥2 other major ASCVD risk factors <100 ≥100

Evidence of end-organ damage

<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.

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

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.

For patients with CKD stage 3B (GFR 30–44 mL/min/1.73 m

) or stage 4 (GFR 15–29 mL/min/1.73 m

), 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 lipid-

altering 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.

If LDL-C is ≥190 md/dL, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and phar-

macotherapy 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.

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 Fra-

mingham long-term (to age 80 years) CVD (myocardial infarction, CHD death, or stroke) risk calculation. Clinicians may prefer to use the other risk cal-

culators, 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 calcu-

lators 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.

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

6BAUM ET AL.

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.”

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, medica-

tions are divided into tiers, beginning with the least costly prescrip-

tions. 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 medi-

cations. Criteria for moving from a lower to a higher tier can be ther-

apeutic failure, medication intolerance, or inability to treat a

condition appropriately. Thus, step therapy has been aptly dubbed

“fail first”therapy.

Step 1 medications are generally generic products and do not

require prior authorization. Step 2 medications are often branded

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

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

ically require extensive and burdensome PAs and involve substantially

greater costs to patients.

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

costly medication prior to being prescribed what might actually be

the optimal drug for that particular patient undermines the essence

of medical practice from both a personalized and population perspec-

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

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

savings attributed to lower formulary costs may actually be due to

health-averse effects such as nonadherence and diminished access to

medicines.

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 con-

trol and the ability to tailor care to the perceived needs of the indi-

vidual patient.”

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.

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 cau-

tion, and failure should be clearly defined. Finally, it is emphasized

that “rationale and rules should be explicit and transparent.”Evi-

dently, many payers have not embraced these recommendations.

Consequently, patients commonly experience unnecessary delays in

acquiring the medications their clinicians have prescribed. Often they

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

access may be life threatening.

Patients with ASCVD and FH are at particularly high risk for

future cardiovascular events.

All cholesterol guidelines emphasize

the importance of aggressive statin therapy in such patients. Failure

to achieve adequate LDL-C reduction and intolerance to medications

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

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

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

suffer long wait times before receiving their prescribed medicines.

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

son reviewed several scenarios based on level of ethical burden to

justify step therapy.

They specifically pointed to statin therapy (at a

time when many of the statins were still branded and therefore

TABLE 4 Atherosclerotic cardiovascular disease risk categories and low-density lipoprotein treatment goals

Risk Category Risk Factors

/10-Year Risk

Treatment Goals

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

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

HeFH

High risk ≥2 risk factors and 10-year risk 10%–20% <100 <130 <90

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.

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.

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

BAUM ET AL.7

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.

Restricting access to more

expensive medications, including branded products or novel thera-

pies, has the immediate impact of reducing cost. Looking at the long-

term, however, we again witness something concerning. Coverage

gaps (through formulary restrictions) can lead to worse patient out-

comes.

59,60

Clearly, plan exclusions that deny patients entire classes

of medications, such as the PCSK9 mab, should be eschewed.

4.3 |Appeals

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

insurance provider’s decision regarding a prescribed therapeutic. In

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

tion. As noted above, the Symphony report

found that greater than

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

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

vately insured patients ultimately gained approval.

These appeals

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

patient care to unnecessary administrative encumbrances. Multiple

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

vider representatives, and resubmissions of prolific paperwork are

commonplace in the appeal process. Tracking all appeals, providing

identifiable and accessible case managers, and creating electronic sys-

tems for appeals are obvious steps insurers could take to streamline

this process.

Recent evidence suggests a possible bias in the PCSK9 mab

approval/denial, process. Unpublished data from Baum et al

corrob-

orate the FH Foundation’s national CASCADE FH Registry

findings

of high denial rates. This study evaluated results from International

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

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

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

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

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

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

and ezetimibe use was similar between rejected and approved

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

ment nearly pathognomonic for clinical ASCVD, implying inconsistent

adjudication. Many of the initial rejections were later overturned,

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

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

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

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

patients’outcomes need to be explored.

Clinicians must frequently intervene with insurance providers,

advocating on behalf of patients, but unfortunately eroding valuable

time and energy. There is also an unrecognized potential economic

risk some physicians must bear. Blue Cross Blue Shield of North Car-

olina, for example, specifies on its website

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 con-

flict 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).

5|CONCLUSION

Unnecessary PCSK9 mab access barriers have been identified, and

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

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

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

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

their interpretation that has challenged patient access, even for

appropriate individuals as documented by Kolata in the New York

Times, and others in their exposés.

63–65

This article provides defini-

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

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

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

management and prevention. The ASPC recommends that all

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

nitions provided herein, along with the prior authorization template

and appeals letter. Without these process improvements, impaired

patient access to potentially life-saving therapy will persist.

Conflicts of Interest

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

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

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

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

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

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

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

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

Contracted Research, Steering Committee Member. Amarin: Consult-

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

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

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

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

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

Pfizer: Research Payments, Contracted Research Akcea: Honoraria,

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

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

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

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

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

8BAUM ET AL.

Honorarium Speaker, Kowa: Honorarium Speaker, Ackea: Honorarium

Consultant, Abbvie: Honorarium Speaker, Sanofi/Regeneron: Hono-

rarium Speaker, AstraZeneca: Honorarium Speaker.

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SUPPORTING INFORMATION

Additional Supporting Information may be found online in the sup-

porting 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

10 BAUM ET AL.

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