Download PCSK9 Inhibitors Praluent

PCSK9 Inhibitors
Praluent (Alirocumab) and Repatha (Evolocumab)
For the Treatment of Familial Hypercholesterolemia
Policy Number:
MM.04.037
Line(s) of Business:
HMO; PPO; QUEST Integration
Section:
Prescription Drugs
Place of Service:
Outpatient
I.
Original Effective Date:
08/01/2016
Description
Hypercholesterolemia is defined as excessive cholesterol in the bloodstream. An elevation in lowdensity lipoprotein (LDL) cholesterol has been proven to increase risks of cardiovascular events. LDL-C
accumulates in the body primarily by liver production and secondarily by food consumption. The most
common treatment for hypercholesterolemia has been a combination of the use of oral statins and
lifestyle modifications. If desired outcomes are not achieved, additional treatment using drugs in other
classes such as fibrates, nicotinic acid, bile acid sequestrants or ezetimibe may be used.
Familial hypercholesterolemia (FH) is inherited in an autosomal dominant manner; therefore, a parent
who carries an altered gene has a one in two chance of passing it on to each child. One in 500
individuals carries one altered gene and is considered genetically heterozygous. More rarely, a person
inherits the gene mutation from both parents, making them genetically homozygous. Individuals who
are homozygous have a more severe form of hypercholesterolemia, with heart attack and death often
occurring before age 30. Signs and symptoms include high levels of LDL cholesterol (LDL-C) as well as
total cholesterol, a strong family history of high cholesterol and early heart attack, therapy resistant
levels of LDL-C, xanthomas, xanthelasmas, corneal arcus, and sometimes angina. People diagnosed
with homozygous hypercholesterol-emia have fewer treatment options and achieving target
cholesterol levels is rarely attained.
Evolocumab (Repatha) and alirocumab (Praluent) are human monoclonal antibodies that inhibit the
production of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein controlled by its
respective gene that reduces the liver's ability to remove LDL cholesterol before it is released into the
bloodstream. Restricting this protein’s ability to hinder the liver by using PCSK9-inhibiting drugs has
shown to lower LDL-C as much as 52%. Studies to date have shown that adverse events are
manageable.
An assessment of the severity of hypercholesterolemia is determined by performing labs and
documenting a complete family history, which have an impact on treatment choices and outcome of
disease. Evolocumab and alirocumab do not replace current standards of care; rather, they may
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contribute to better health outcomes for those unable to achieve or maintain recommended
cholesterol levels using traditional treatment only.
II.
Criteria/Guidelines
PCSK9 Inhibitors, alirocumab (Praluent) or evolocumab (Repatha) are covered (subject to Limitations
and Administrative Guidelines) when one of the following criteria is met:
A. Documented diagnosis of homozygous familial hypercholesterolemia (HoFH) as defined by clinical
or genetic criteria by the European Atherosclerosis Society (Table 1); OR
B. Documented diagnosis of definite heterozygous familial hypercholesterolemia (HeFH) as defined by
the Dutch Lipid Network (Table 2) or Simon Broome Diagnostic Criteria (Table 3) with
1. the highest cardiovascular (CV) risk as defined by the National Lipid Association Expert Panel
on FH (Table 4); and
2. the inability to reach target LDL-C as defined by the National Lipid Association Guidelines
(Table 5),
a. Despite a meaningful trial of at least two high-intensity statins (Table 6); and
b. Despite maximally tolerated dose of a high-intensity statin (Table 6) and at least one
additional lipid-lowering agent, such as fibrates, nicotinic acid, bile acid sequestrants or
ezetimibe; and
c. Despite lifestyle modifications supporting lipid management as recommended by the
2013 AHA/ACC Guidelines to Reduce Cardiovascular Risk (Table 7); OR
C. Documented diagnosis of clinical atherosclerotic cardiovascular disease (ASCVD) or a cardiovascular
event (Table 8) and the inability to reach target LDL-C as defined by the National Lipid Association
Guidelines (Table 5)
1. Despite a meaningful trial of at least two high-intensity statins (Table 6); and
2. Despite maximally tolerated dose of a high-intensity statin (Table 6) and at least one
additional lipid-lowering agent, such as fibrates, nicotinic acid, bile acid sequestrants or
ezetimibe; and
3. Despite lifestyle modifications supporting lipid management as recommended by the 2013
AHA/ACC Guidelines to Reduce Cardiovascular Risk (Table 7); OR
D. Individual is determined to be statin intolerant by the following:
1. Individual has a condition that is contraindicated for statin therapy, such as:
a. Chronic active liver disease greater than 3 months; and/or
b. Unexplained persistent elevation of serum transaminases; OR
2. Individual is unable to tolerate at least 2 statins, with at least one started at the lowest
starting daily dose; AND
3. Statin dose reduction is attempted for symptom and biomarker abnormality resolution,
rather than discontinuation of statin therapy altogether; AND
4. Intolerable symptoms or abnormal biomarker changes are reversible upon statin
discontinuation, but reproducible by re-challenge of statins; if clinically appropriate. Statin
re-challenge may be appropriate for individuals with all of the following:
a. Symptomatic; and
b. Creatine kinase is less than four times (4) the upper limit of normal per laboratory
reference range or creatine kinase is between four (4) and ten (10) times the upper limit
of normal per laboratory reference range without evidence of rhabdomyolysis; and
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c. AST and/or ALT are less than three (3) times the upper limit of normal per laboratory
reference range; and
d. Symptoms or biomarker abnormalities are not attributable to established
predispositions or conditions recognized to increase the risk of statin intolerance, such
as:
i.
Hypothyroidism; and/or
ii.
Drug interactions; and/or
iii.
Concurrent illness; and/or
iv.
Significant changes in physical activity/exercise; and/or
v.
Underlying muscle disease; OR
5. Individual has significant biomarker abnormalities, defined as:
a. Elevation in alanine (ALT) of greater than three (3) times the upper limit of normal; or
b. Elevation in aspartate aminotransferase (AST) of greater than three (3) times the upper
limit of normal; or
c. Elevation of creatine kinase (CK) of greater than ten (10) times the upper limit of normal
per laboratory reference range; or
d. Elevation of creatine kinase (CK) between four (4) to ten (10) times the upper limit of
normal per laboratory reference range with evidence of rhabdomyolysis.
Note: A meaningful trial for statins is at least six weeks which allows lipid levels to stabilize
and when objective measures can be assessed.
III.
Limitations
A. Patients are not covered for use of PCSK9 inhibitors if they are able to achieve target LDL-C
levels using other lipid-lowering interventions regardless of clinical status.
B. Recommendation is a 4-week dosing regimen and quantities will be limited to an initial three
month supply.
IV.
Administrative Guidelines
A. Precertification is required for the initial three months of therapy. To precertify, please
complete CVS's Drug Review Request form and mail or fax the form as indicated. The following
documentation must be submitted:
1. DNA evidence of homozygous FH and other criteria outlined in table 1; or
2. Documentation of diagnosis of heterozygous FH at highest of CHD unable to reach
target or of statin intolerance including laboratory results and clinical notes that include
a detailed history of previous treatments, including all relevant pharmaceutical agents
including evidence of a meaningful of two high-intensity and maximally tolerated
statins; and
3. Documentation showing patient is at highest risk of CHD and unable to reach target LDLC
B. Precertification is required for continuation of therapy for up to an additional six months.
Clinical notes and laboratory results must be submitted showing, at minimum, a 30% reduction
in patient LDL-cholesterol levels prior to starting treatment with PCSK9 inhibitors.
C. Precertification is required for continuation of therapy for up to an additional 12 months.
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Clinical notes and laboratory results must be submitted showing continued benefit of
treatment measured by continued decrease in LDL-C levels or maintenance of optimum levels
of LDL-C.
HCPCS Codes
J3490/J3590
J3490/J3590
V.
Description
Praluent (Alirocumab)
Repatha (Evolocumab)
Important Reminder
The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not
intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is
intended to discourage or prohibit providing other medical advice or treatment deemed
appropriate by the treating physician.
Benefit determinations are subject to applicable member contract language. To the extent there
are any conflicts between these guidelines and the contract language, the contract language will
control.
This Medical Policy has been developed through consideration of the medical necessity criteria
under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4),
generally accepted standards of medical practice and review of medical literature and government
approval status. HMSA has determined that services not covered under this Medical Policy will not
be medically necessary under Hawaii law in most cases. If a treating physician disagrees with
HMSA’s determination as to medical necessity in a given case, the physician may request that
CVS/caremark reconsider the application of the medical necessity criteria to the case at issue in
light of any supporting documentation.
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Appendices
Table 1 - Criteria for the diagnosis of homozygous familial hypercholesterolemia European Heart J
Genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9, or LDLRAP1 gene locus; or
An untreated LDL-C >13 mmol/L (500 mg/dL) or treated LDL-C ≥8 mmol/L (300 mg/dL)* together with
either:
• Cutaneous or tendon xanthoma before age 10 years; or
• Untreated elevated LDL-C levels consistent with heterozygous FH in both parents
* These LDL-C levels are only indicative, and lower levels, especially in children or in treated patients, do not
exclude HoFH
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Table 2 - World Health Organization aka Dutch Lipid Clinic Network - Diagnostic criteria for the clinical diagnosis
of heterozygous familial hypercholesterolemia
Family History
Criteria
Score
First-degree relative with known premature coronary or vascular
disease; or first-degree relative with known LDL-C >95th percentile
1
First-degree relative with tendon xanthomata and/or arcus cornealis,
or children <18 y with LDL-C >95th percentile
Clinical
History
Patient has premature CAD
2
2
Patient has premature cerebral/peripheral vascular disease
1
Physical
Tendon xanthomata
6
Examination
Arcus cornealis age <45 y
4
LDL-C
>8.5 mmol/L (> 330 mg/dL)
8
6.5-8.4 mmol/L (>250-329 mg/dL)
5
5.0-6.4 mmol/L (>190-249 mg/dL)
3
4.0-4.9 mmol/L (>155-189 mg/dL)
1
Definite FH
Score >8
Probable FH
Score 6-8
Possible FH
Score 3-5
No diagnosis
Score <3
CAD: coronary artery disease; FH: familial hypercholesterolemia; HeFH: heterozygous familial
hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; Premature CAD: male before age
55, women before age 60.
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Table 3 - Simon-Broome criteria for diagnosis of familial hypercholesterolemia
FH
Criteria
Definite
TC >6.7 mmol/L or LDL-C >4.0 mmol/L in a child aged <16 y OR
TC >7.5 mmol/L or LDL-C >4.9 mmol/L in an adult (levels either pretreatment or highest
on-treatment)
PLUS Tendon xanthomas in patient, or in first-degree relative (parent, sibling or child), or in
second-degree relative (grandparent, uncle, or aunt) OR
DNA-based evidence of an LDL-R mutation, familial defective apo B100, or a PCSK9
mutation.
Possible
TC >6.7 mmol/L or LDL-C >4.0 mmol/L in a child aged <16 y OR
TC >7.5 mmol/L or LDL-C >4.9 mmol/L in an adult (levels either pretreatment or highest
on-treatment) AND AT LEAST ONE OF THE FOLLOWING:
o Family history of myocardial infarction: <50 y of age in second-degree relative
or <60 y of age in first-degree relative
o Family history of raised TC: >7.5 mmol/L in adult first-or second-degree relative
or >6.7 mmol/L in child or sibling aged <16 y
Apo: apolipoprotein; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; LDL-R: lowdensity lipoprotein receptor; PCSK9: proprotein convertase subtilisin/kexin type 9; TC: total cholesterol.
Table 4 - Characteristics place FH patient at the highest Cardiovascular Disease Risk
Intensification of treatment and an LDL-C goal < 100 mg/dL (non-HDL-C < 130mg/dL) is recommended
for FH patients with any of these high risk characteristics
Established CHD or other CVD
History of acute myocardial infarction, stroke, peripheral
arterial disease, resuscitated cardiac arrest, cardiovascular
revascularization, stable or unstable angina, transient
ischemic attack, carotid artery stenosis, >50%, aortic
abdominal aneurysm
Smokers
Male current smokers have > 2 fold higher risk than female
smokers – Encourage smoking cessation to reduce risk
Diabetes mellitus
Lifestyle or drug treated diabetes
Family history of very premature onset
CHD
First or second degree male relative onset before age 45
First or second degree female relative onset before age 55
2 or more risk factors
See below
Cardiovascular risk factors in individuals with FH
Risk Factor
Cut-points for risk factors
If > 2 risk factors present intensification of therapy is
recommended
Increasing age
Men > 30 years of age
Women > 40 years of age
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Baseline LDL-C level
>250 mg/dL
Male sex
Male sex
Smoking
Current smoker
Family history of premature onset CHD
First degree male relative onset before age 55
First degree female relative onset before age 65
Metabolic syndrome
3 of 5 characteristics:
Increased waist circumference:
o
Men > 40” (>37” in some populations) and
women>35”
•
Blood pressure > 130 mmHg or > 80 mmHg or drug
treatment
•
Triglycerides > 150 mm/dL or drug treatment
•
Low DL-C:
o
Men < 40 mm/dL and women < 50 mm/dL
•
Elevated glucose > 100 mg/dL or drug treatment
•
Low HDL-C level
HDL-C < 40 mm/dL
Hypertension
Blood pressure > 140 or > 90 mmHg or drug treatment
High lipoprotein (a)
> 50 mm/dL using an isoform insensitive assay
Physical findings
Tendon xanthoma
CHD – coronary heart disease; FH – familial hypercholesterolemia; HDL-C – high density lipoprotein
cholesterol; LDL-C – low density lipoprotein cholesterol
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Table 5 - Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol and levels at which to
consider drug therapy: National Lipid Association Guidelines
Risk
Category
Criteria
•
•
Very high
ASCVD
diabetes mellitus (type 1 or 2) AND
)a
•
≥2 other major ASCVD risk factor(s
or
b
•
Evidence of end-organ damage
High
Consider Drug
Therapy
<100 non-HDL-C, mg/dL
<70 LDL-C, mg/dL
≥100 non-HDL-C, mg/dL ≥70
LDL-C, mg/dL
<130 non-HDL-C, mg/dL
<100 LDL-C, mg/dL
≥130 non-HDL-C, mg/dL
≥100 LDL-C, mg/dL
<130 non-HDL-C, mg/dL
<100 LDL-C, mg/dL
<130 non-HDL-C, mg/dL
<100 LDL-C, mg/dL
≥160 non-HDL-C, mg/dL
≥130 LDL-C, mg/dL
≥190 non-HDL-C, mg/dL
≥160 LDL-C, mg/dL
a
≥3 major ASCVD risk factors
c
Diabetes mellitus (type 1 or 2)
0 or 1 other major ASCVD risk factors, and
No evidence of end-organ damage
d
Chronic kidney disease stage 3B or 4
LDL-C ≥190 mg/dL (severe hypercholesterole
emia)
f
≥10% 10-y hard CHD event risk
Moderate
Low
Treatment Goal
a
2 major ASCVD risk factors
g
Consider other risk indicators
0 or 1 major ASCVD risk factors
g
Consider other risk indicators
ASCVD: atherosclerotic cardiovascular disease; CHD: coronary heart disease; CKD: chronic kidney disease; eGFR: Estimated
glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol.
a. Major risk factors for ASCVD: (1) Age (male ≥45 y or female ≥55 y). (2) Family history of early CHD (55 years of age in a male first-
degree relative or 65 y of age in a female first-degree relative). (3) Current cigarette smoking. (4) High blood pressure (≥140/≥90
mm Hg, or on blood pressure medication). (5) Low HDL-C (male <40 mg/dL; female <50 mg/dL).
b. End-organ damage indicated by increased albumin-to-creatine ratio (≥30 mg/g), CKD (eGFR, <60 mL/min/1.73 m 2) or
retinopathy.
c. For patients with diabetes plus 1 major ASCVD risk factor, treating to a non-HDL-C goal of <100 mg/dL (LDL-C of <70 mg/dL) is
considered a therapeutic option.
d. For patients with CKD stage 3B (eGFR, 30-44 mL/min/1.73 m2) or stage 4 (eGFR, 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 lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such
patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD.
e. If LDL-C is ≥190 mg/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 hypercholesterol-emia 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 in such patients.
f. High-risk threshold is defined as ≥10% using Adult Treatment Panel III Framingham Risk Score for hard CHD (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 cardiovascular disease (myocardial infarction, CHD death, or stroke) risk
calculation. Clinicians may prefer to use other risk calculators, but should be aware that quantitative risk calculators vary in the
clinical outcomes predicted (e.g., CHD events, ASCVD events, cardiovascular mortality); the risk factors included in their calculation;
and the timeframe for their prediction (e.g., 5 y, 10 y, 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
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interpretation.
g. For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk
stratification.
Table 6 - Statin treatment categorized by intensity using 2013 AHA/ACC cholesterol guidelines
Table 8.
High
Moderate
Low
Daily dose lowers LDL-C, on
Daily dose lowers LDL-C, on
Daily dose lowers LDL-C, on
average, by approximately 30% to
average, by approximately ≥50%
average, by <30%
<50%
Specific statins and doses noted below were evaluated in RCTs and demonstrated a reduction in
major cardiovascular events
Atorvastatin 80 mg
Atorvastatin 10 mg
Pravastatin 10-20 mg
Atorvastatin 40 mg
Lovastatin 20 mg
Rosuvastatin 10 mg
Rosuvastatin 20 mg
Simvastatin 20-40 mg
Pravastatin 40 mg
Lovastatin 40 mg
Fluvastatin 40 mg bid
Statins and doses listed below are approved by FDA, but not tested in reviewed RCTs
Rosuvastatin 40 mg
Atorvastatin 20 mg
Rosuvastatin 5 mg
Pravastatin 80 mg
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg
Simvastatin 10 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
ACC: American College of Cardiology; AHA: American Heart Association; FDA: Food and Drug Administration; LDL- C: lowdensity lipoprotein-cholesterol; RCT: randomized controlled trial.
a. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL trial.
b. Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
recommended by FDA due to the increased risk of myopathy, including rhabdomyolisis.
Table 7 - Summary of Recommendations for Lifestyle Management using 2013AHA/ACC Guidelines on Lifestyle
Management to reduce Cardiovascular Risk
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Table 8 – Clinical ASCVD or Cardiovascular Event
•
•
•
•
•
•
•
Acute coronary syndromes
Myocardial infarction
Stable or unstable angina
Coronary or other arterial revascularization procedure (e.g./percutaneous coronary angioplasty [PTCA],
coronary artery bypass graft [CABG] surgery)
Transient ischemic attack (TIA)
Peripheral arterial disease presumed to be of atherosclerotic origin
Findings from CT angiogram or catheterization consistent with clinical ASCVD
Table 9 - Statin treatment categorized by intensity using 2013 AHA/ACC cholesterol guidelines
Table 8.
High
Moderate
Low
Daily dose lowers LDL-C, on
Daily dose lowers LDL-C, on
Daily dose lowers LDL-C, on
average, by approximately 30% to
average, by approximately ≥50%
average, by <30%
<50%
Specific statins and doses noted below were evaluated in RCTs and demonstrated a reduction in
major cardiovascular events
Atorvastatin 80 mg
Atorvastatin 10 mg
Pravastatin 10-20 mg
Atorvastatin 40 mg
Lovastatin 20 mg
Rosuvastatin 10 mg
Rosuvastatin 20 mg
Simvastatin 20-40 mg
Pravastatin 40 mg
Lovastatin 40 mg
Fluvastatin 40 mg bid
Statins and doses listed below are approved by FDA, but not tested in reviewed RCTs
Rosuvastatin 40 mg
Atorvastatin 20 mg
Rosuvastatin 5 mg
Pravastatin 80 mg
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg
Simvastatin 10 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
ACC: American College of Cardiology; AHA: American Heart Association; FDA: Food and Drug Administration; LDL- C: lowdensity lipoprotein-cholesterol; RCT: randomized controlled trial.
a. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL trial.
b. Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
recommended by FDA due to the increased risk of myopathy, including rhabdomyolisis.
VI.
References
1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Specialty Pharmacy
Report. Generic Name: Alirocumab, Brand Name: Praluent. TEC Specialty Pharmacy Report April
2015; Report 7.
2. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Specialty Pharmacy
Report. Generic Name: Evolocumab, Brand Name: Repatha (proposed). TEC Specialty Pharmacy
Report April 2015; Report 7.
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3. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et. al., Homozygous familial
hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical
management. A position paper from the Consensus Panel on Familial Hypercholesterolemia of the
European Atherosclerosis Society. European Heart Journal. 2014. 35, 2146-2157.
http://dx.doi.org/10.1093/eurheartj/ehu274. First published online: 22 July 2014 (Table 1).
4. European Association for Cardiovascular P, Rehabilitation, Reiner Z, et al. ESC/EAS Guidelines for
the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the
European Society of Cardiology (ESC) and the European Atheroscler-osis Society (EAS). Eur Heart J.
Jul 2011;32(14):1769-1818.
5. Guyton JR, Bays HE, Grundy SM, Jacobson TA. The National Lipid Association Statin Intolerance, An
assessment by the Statin Intolerance Panel: 2014 update. Journal of Clinical Lipidology. 2014 MayJun;8 (3 Suppl): S72-81.
6. O'Riordan M. IMPROVE-IT: 'Modest' Benefit When Adding Ezetimibe to Statins in Post-ACS
Patients. Nov 17, 2014. Available from: http://www.medscape.com/viewarticle/835030#vp_2
7. Robinson, JG. Management of familial hypercholesterolemia: a review of the recommendations
from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care
Pharm. 2013; 19: 139-49.
8. Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and evidence for
treatment: Recommendations from the National Lipid Association Expert Panel on Familial
Hypercholesterolemia. Journal of Clinical Lipidology. 2011. 5: S19-S29.
9. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and
cardiovascular events. New England Journal of Medicine. 2015 April 16; 372 (16):1489-99.
10. Sabatine MS, Giugliano RP Wiviott, SD, et al. Efficacy and safety of evolocumab in reducing lipids
and cardiovascular events. New England Journal of Medicine. 2015 April 16; 372 (16):1500-9.
11. Stein EA, Mellis, S Yancopoulos, GD et al. Effect of a monoclonal antibody to PCSK9 on LDL
cholesterol. The New England Journal of Medicine. 2012 Mar 22; 366 (12):1108-18.
12. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129:
S1-S45.
13. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin
therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology
and Management. European Heart Journal. 2015 Feb 18.
14. Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for
low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. Journal of
Clinical Lipidology. 2014 Jan-Feb; 8 (1):18-28.