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Repatha

Generic Name: Evolocumab
Class: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors
Chemical Name: Immunoglobulin G, anti-(human neural apoptosis-regulated proteinase 1) (human monoclonal heavy chain), disulfide with human monoclonal light chain, dimer
Molecular Formula: C6242H9648N1668O1996S56
CAS Number: 1256937-27-5

Medically reviewed on May 21, 2018

Introduction

Antilipemic agent; fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9).1 3 6 7 10 11 12 19 34

Uses for Repatha

Prevention of Cardiovascular Events

Used for secondary prevention to reduce risk of MI, stroke, and coronary revascularization in patients with established cardiovascular disease.1 36

Has been shown to substantially reduce the risk of cardiovascular events when added to hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin)-based antilipemic therapy in high-risk patients with clinical atherosclerotic cardiovascular disease (ASCVD).1 36

Statins are first-line antilipemic drugs of choice in patients with clinical ASCVD.350 ACC/AHA cholesterol management guideline states that a nonstatin drug may be added in patients who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely statin intolerant, particularly when evidence from randomized controlled studies suggest the nonstatin drug further reduces ASCVD events when added to statin therapy.350

According to an ACC expert consensus panel, patients who may benefit from the addition of a nonstatin drug (e.g., ezetimibe and/or PCSK9 inhibitor) include those with clinical ASCVD with or without comorbidities (including baseline LDL-cholesterol concentrations >190 mg/dL) who have not met certain thresholds of LDL-cholesterol reduction (e.g., ≥50% reduction in LDL-cholesterol or absolute LDL-cholesterol concentration <70 mg/dL or non-HDL cholesterol concentration <100 mg/dL) despite receiving maximally tolerated statin therapy.37

Select appropriate nonstatin drug based on favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences.37 350

Prior to initiating a nonstatin drug, ensure that patients are treated with maximally tolerated statin therapy first and that lifestyle modifications are intensified/optimized.37 Because true statin intolerance is uncommon, systematically and rigorously evaluate patients for this condition to encourage adherence to evidence-based statin therapy.37

Primary Hyperlipidemia

Used alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe) as an adjunct to diet in patients with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce LDL-cholesterol concentrations.1 2 19 24 39 40

Further reduces LDL-cholesterol concentrations by approximately 50–60% or more when added to other lipid-lowering therapies or when used as monotherapy.1 2 4 18 19 22 23 24 26 31 32 34 37 39 40

Homozygous Familial Hypercholesterolemia

Adjunct to diet and other LDL-cholesterol lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-cholesterol concentrations.1 3 10 Designated an orphan drug by FDA for this use.9

Further reduces LDL-cholesterol concentrations by approximately 30% when used adjunctively with other antilipemic agents.1 3 18 19 23

Appears to be more effective in patients with relatively functional residual LDL-receptor activity.1 3 10 18 (See Actions.)

Repatha Dosage and Administration

General

  • Periodically reinforce adherence to lifestyle modifications.350

  • When monitoring LDL-cholesterol concentrations, note that considerable variation can occur during dosing interval in patients receiving the once-monthly dosage regimen.1

Administration

Sub-Q Administration

Administer sub-Q every 2 weeks or once monthly.1

Commercially available as a prefilled manual syringe, prefilled auto-injector, and single-use on-body infuser pump with prefilled cartridge.1

A monthly dose of 420 mg can be administered using the on-body infuser with prefilled cartridge or by consecutively administering 3 prefilled syringes or auto-injectors within 30 minutes.1 13 Consider patient preference for dosing frequency and injection volume when determining method of administration.1

Injection using a prefilled syringe or auto-injector may take up to 15 seconds to complete; injection using the on-body infuser with prefilled cartridge takes about 9 minutes to complete.1

Instruct patients on proper techniques for self-administration using prefilled syringe or auto-injector or on-body infuser with prefilled cartridge.1 13 15 16 35 If on-body infuser with prefilled cartridge is used in adolescents, adult supervision is necessary.35

Prior to administration, allow prefilled syringes and auto-injectors to warm to room temperature for ≥30 minutes,1 15 16 and on-body infuser with prefilled cartridges to warm to room temperature for ≥45 minutes.1 35

Inject into abdomen (except for 2-inch area around navel), thigh, or upper arm; rotate injection sites.1 15 16 35 Do not administer into areas that are tender, bruised, erythematous, or indurated, or that have scars or stretch marks.1 15 16 35 Securely attach the on-body infuser with prefilled cartridge to a clean, firm and flat skin surface that is less likely to have body hair or on which body hair can be trimmed; do not use on areas with wrinkles, skin folds, moles, or excessive hair.35

Do not administer with other drugs at the same injection site.1

If a dose is missed, administer as soon as possible within 7 days.1 If a dose is missed in a patient receiving the every-2-week regimen and the missed dose is not administered within 7 days, withhold dose and administer next dose at regularly scheduled time.1 If a dose is missed in a patient receiving the once-monthly regimen and the missed dose is not administered within 7 days, administer a dose and initiate a new dosing schedule starting on that date.1

Contains no preservatives; for single use only.1

Dosage

Pediatric Patients

Dyslipidemias
Homozygous Familial Hypercholesterolemia
Sub-Q

Adolescents ≥13 years of age: 420 mg once monthly (administered using on-body infuser with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).1 13

Monitor serum LDL-cholesterol concentrations 4–8 weeks after initiation of therapy to assess response to drug.1

Adults

Prevention of Cardiovascular Events
Secondary Prevention in Adults with Established Cardiovascular Disease
Sub-Q

140 mg every 2 weeks or 420 mg once monthly (administered using on-body infuser with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).1

When switching between the every-2-week and once-monthly dosage regimens, administer first dose of new regimen on the date of the next scheduled dose of previous regimen.1

Dyslipidemias
Primary Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia)
Sub-Q

140 mg every 2 weeks or 420 mg once monthly (administered using on-body infuser with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).1

When switching between the every-2-week and once-monthly dosage regimens, administer first dose of new regimen on the date of the next scheduled dose of previous regimen.1

Homozygous Familial Hypercholesterolemia
Sub-Q

420 mg once monthly (administered using on-body infuser with prefilled cartridge or as 3 consecutive 140-mg injections within 30 minutes).1

Monitor serum LDL-cholesterol concentrations 4–8 weeks after initiation of therapy to assess response to drug.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.1

Severe hepatic impairment: Data are lacking.1

Renal Impairment

No dosage adjustment necessary.1

Geriatric Patients

No specific dosage recommendations.1

Other Special Populations

Dosage adjustments based on age, body weight, gender, or race not required.1

Cautions for Repatha

Contraindications

  • History of serious hypersensitivity reaction to evolocumab.1 (See Hypersensitivity under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., rash, eczema, erythema, urticaria) reported.1

If manifestations occur, discontinue drug and initiate appropriate treatment.1 Monitor patient until resolution occurs.1

Latex Sensitivity

Some packaging components (i.e., needle covers of prefilled syringes and auto-injectors) contain natural latex proteins in the form of dry natural rubber (latex), and should not be handled by individuals sensitive to latex.1 27 28 29

Immunogenicity

Development of non-neutralizing antibodies to evolocumab reported.1 Long-term effects of continued therapy in the presence of such antibodies not known.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 Weigh potential benefits versus possible risk to fetus.1

Adverse developmental effects not observed in animal studies; however, suppression of humoral immune response observed in infant monkeys exposed in utero to another PCSK9 inhibitor.1

Pregnancy registry at 877-311-8792 or [Web].1

Lactation

Not known whether distributed into human milk.1 Human IgG is distributed into human milk; however, published data suggest that IgG antibodies present in human milk are not substantially distributed into the circulation of neonates and infants.1

Weigh known benefits of breastfeeding against potential adverse effects of the drug on the infant, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in pediatric patients with primary hyperlipidemia or heterozygous familial hypercholesterolemia.1

Safety and efficacy not established in children <13 years of age with homozygous familial hypercholesterolemia.1

Geriatric Use

No overall differences in efficacy or safety relative to younger adults; however, possibility of increased sensitivity cannot be ruled out.1

Hepatic Impairment

Decreased plasma concentrations in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); however, not clinically important.1 17 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Safety and efficacy not established in patients with severe hepatic impairment.1

Renal Impairment

Renal function not expected to affect pharmacokinetics of evolocumab.1 (See Special Populations under Pharmacokinetics and also see Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nasopharyngitis,1 2 3 24 40 diabetes mellitus,1 36 upper respiratory tract infection,1 3 24 influenza,1 3 24 back pain,1 2 24 39 injection site reactions (e.g., erythema, pain, bruising),1 24 40 cough,1 24 urinary tract infection,1 24 sinusitis,1 24 headache,1 2 24 39 40 myalgia,1 24 40 dizziness,1 24 musculoskeletal pain,1 3 24 40 hypertension,1 24 diarrhea,1 24 40 gastroenteritis.1 3 24

Interactions for Repatha

Specific Drugs

Drug

Interaction

Comments

HMG-CoA reductase inhibitors (statins)

Decreased peak plasma concentration and AUC of evolocumab by approximately 20%; however, not considered clinically important1

No dosage adjustment required1

Repatha Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 72% after sub-Q injection.1

Onset

Following sub-Q administration, maximal suppression of free PCSK9 occurs within 4 hours.1

Plasma Concentrations

Peak plasma concentrations achieved in approximately 3–4 days following single sub-Q dose.1 6

Following multiple dosing, accumulation ratio is approximately two- to threefold; steady-state serum trough concentrations achieved by 12 weeks.1

Special Populations

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), peak plasma concentrations and systemic exposure reduced by approximately 20–30 and 40–50%, respectively.1

In patients with severe renal impairment (i.e., eGFR <30 mL/minute per 1.73 m2) or end-stage renal disease (ESRD) receiving hemodialysis, exposure decreased; however, reductions in PCSK9 concentrations in such patients were similar to those in patients with normal renal function (i.e., eGFR ≥90 mL/minute per 1.73 m2).1

Exposure decreases with increasing body weight, but not considered clinically important.1

Distribution

Extent

Crosses the placenta.1

Not known whether distributed into milk.1

Elimination

Elimination Route

Concentration-dependent.1 At low concentrations, occurs principally through saturable binding to the PCSK9 target; at high concentrations, occurs principally through a nonsaturable proteolytic pathway.1 10

Half-life

Approximately 11–17 days.1

Stability

Storage

Parenteral

Solution for Injection

2–8°C.1 Store in original carton to protect from light.1 Do not shake, freeze, or expose to temperatures >25°C or direct sunlight.1 15 16

May store prefilled syringes and auto-injectors and on-body infusers with prefilled cartridges at room temperature 20–25°C in original carton, but must use within 30 days if stored under these conditions.1 Discard drug if not used within 30 days.1

Actions

  • Fully human IgG2 monoclonal antibody that binds to human PCSK9.1 3 4 6 7 10 11 12 Produced in genetically engineered mammalian (Chinese hamster ovary) cells.1

  • PCSK9 is a serine protease produced principally in the liver.6 7 10 11 12 Major function of PCSK9 is to promote degradation of LDL receptors, the primary receptors responsible for clearing circulating LDL cholesterol.1 17

  • Evolocumab binds specifically and with high affinity to PCSK9; inhibition of PCSK9 increases number of receptors available to clear LDL cholesterol, and consequently reduces plasma concentrations of LDL cholesterol.1 3 6 7 10 17 19

  • Reductions in lipoprotein (a), apolipoprotein B, and other lipid fractions also demonstrated.1 2 3 4 32

  • In patients with homozygous familial hypercholesterolemia, severity of mutation and corresponding residual LDL-receptor activity affects response to evolocumab therapy.1 3 10 Patients with 2 receptor-defective mutations (corresponding to relatively functional LDL-receptor activity) appear to derive the greatest benefit, patients with one negative mutation (corresponding to very little or no LDL-receptor activity) and one defective mutation have a lesser response; those with 2 receptor-negative mutations are not expected to respond at all.1 3 10 (See Homozygous Familial Hypercholesterolemia under Uses.)

Advice to Patients

  • Importance of reading manufacturer’s patient information13 and instructions for use15 16 35 prior to starting therapy and each time the prescription is refilled.1

  • Importance of discontinuing evolocumab and promptly seeking medical attention if any signs or symptoms of serious hypersensitivity (e.g., severe pruritus, rash, or redness; swollen face; difficulty breathing) occur.1 13 (See Hypersensitivity under Cautions.)

  • Importance of instructing patients and/or caregivers on the preparation and sub-Q administration of evolocumab, including use of the prefilled syringes and auto-injectors and on-body infusers with prefilled cartridges.1 Importance of informing patients that injection of evolocumab using the prefilled syringe or auto-injector may take up to 15 seconds to complete, and that injection of the drug using on-body infuser with prefilled cartridge takes about 9 minutes to complete.1 Importance of informing patients that adult supervision is necessary if the on-body infuser is used in adolescent patients.35

  • Importance of patients informing their clinician if they have an allergy to latex.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 13

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 13 (See Pregnancy under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Evolocumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

140 mg/mL

Repatha (available as single-use prefilled syringes and auto-injectors)

Amgen

420 mg/3.5 mL

Repatha (available as single-use Pushtronex system consisting of on-body infusor with prefilled cartridge)

Amgen

AHFS DI Essentials. © Copyright 2018, Selected Revisions May 21, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Amgen Inc. Repatha (evolocumab) injection prescribing information. Thousand Oaks, CA; 2017 Dec.

2. Raal FJ, Stein EA, Dufour R et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385:331-40. http://www.ncbi.nlm.nih.gov/pubmed/25282519?dopt=AbstractPlus

3. Raal FJ, Honarpour N, Blom DJ et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385:341-50. http://www.ncbi.nlm.nih.gov/pubmed/25282520?dopt=AbstractPlus

4. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1500-9. http://www.ncbi.nlm.nih.gov/pubmed/25773607?dopt=AbstractPlus

5. . Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991; 303:893-6. http://www.ncbi.nlm.nih.gov/pubmed/1933004?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1671226&blobtype=pdf

6. Cicero AF, Colletti A, Borghi C. Profile of evolocumab and its potential in the treatment of hyperlipidemia. Drug Des Devel Ther. 2015; 9:3073-82. http://www.ncbi.nlm.nih.gov/pubmed/26109850?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4474387&blobtype=pdf

7. Reiner Z. Management of patients with familial hypercholesterolaemia. Nat Rev Cardiol. 2015; 12:565-75. http://www.ncbi.nlm.nih.gov/pubmed/26076948?dopt=AbstractPlus

8. Ito MK, McGowan MP, Moriarty PM et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3 Suppl):S38-45.

9. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed [2014 01 10].

10. Page MM, Watts GF. Evolocumab in the treatment of dyslipidemia: pre-clinical and clinical pharmacology. Expert Opin Drug Metab Toxicol. 2015; 11:1505-15. http://www.ncbi.nlm.nih.gov/pubmed/26293511?dopt=AbstractPlus

11. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis. 2014; 107:58-66. http://www.ncbi.nlm.nih.gov/pubmed/24373748?dopt=AbstractPlus

12. Gouni-Berthold I, Berthold HK. PCSK9 antibodies for the treatment of hypercholesterolemia. Nutrients. 2014; 6:5517-33. http://www.ncbi.nlm.nih.gov/pubmed/25470376?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4276981&blobtype=pdf

13. Amgen Inc. Repatha (evolocumab) injection patient information. Thousand Oaks, CA; 2017 Dec.

14. Marais AD, Blom DJ. Recent advances in the treatment of homozygous familial hypercholesterolaemia. Curr Opin Lipidol. 2013; 24:288-94. http://www.ncbi.nlm.nih.gov/pubmed/23839331?dopt=AbstractPlus

15. Amgen Inc. Repatha (evolocumab) injection single-use prefilled SureClick autoinjector instructions for use. Thousand Oaks, CA; 2016 Nov.

16. Amgen Inc. Repatha (evolocumab) injection single-use prefilled syringe instructions for use. Thousand Oaks, CA; 2016 Jul.

17. Markham A. Evolocumab: First Global Approval. Drugs. 2015; 75:1567-73. http://www.ncbi.nlm.nih.gov/pubmed/26323342?dopt=AbstractPlus

18. US Food and Drug Administration. Summary Review: BLA# 125522. From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125522Orig1s000SumR.pdf

19. . Evolocumab (Repatha)--a second PCSK9 inhibitor to lower LDL-Cholesterol. Med Lett Drugs Ther. 2015; 57:140-1. http://www.ncbi.nlm.nih.gov/pubmed/26445204?dopt=AbstractPlus

20. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL 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 Atherosclerosis Society (EAS). Eur Heart J. 2011; 32:1769-818. http://www.ncbi.nlm.nih.gov/pubmed/21712404?dopt=AbstractPlus

22. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015; 373:1588-91. http://www.ncbi.nlm.nih.gov/pubmed/26444323?dopt=AbstractPlus

23. White CM. Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab. Ann Pharmacother. 2015; 49:1327-35. http://www.ncbi.nlm.nih.gov/pubmed/26424774?dopt=AbstractPlus

24. Blom DJ, Hala T, Bolognese M et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370:1809-19. http://www.ncbi.nlm.nih.gov/pubmed/24678979?dopt=AbstractPlus

26. Doggrell SA, Lynch KA. Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely? Evaluation of Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-1509, and Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1488-99. Expert Opin Biol Ther. 2015; :1-5.

27. Food and Drug Administration. Natural rubber-containing medical devices; user labeling. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1997; 62:51021-30.

28. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.

29. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.

30. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372:2387-97. http://www.ncbi.nlm.nih.gov/pubmed/26039521?dopt=AbstractPlus

31. Navarese EP, Kolodziejczak M, Schulze V et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015; 163:40-51. http://www.ncbi.nlm.nih.gov/pubmed/25915661?dopt=AbstractPlus

32. Reviewers' comments (personal observations) on evolocumab.

33. US Food and Drug Administration. Briefing document from the endocrinologic and metabolic drugs advisory committee. June 10, 2015. From FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM450072.pdf

34. Amgen. Thousand Oaks, CA: Personal Communication.

35. Amgen Inc. Repatha (evolocumab) injection Pushtronex system instructions for use. Thousand Oaks, CA; 2017 Jan.

36. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017; 376:1713-1722. http://www.ncbi.nlm.nih.gov/pubmed/28304224?dopt=AbstractPlus

37. Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 2017 Focused Update of 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: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017; 70:1785-1822. http://www.ncbi.nlm.nih.gov/pubmed/28886926?dopt=AbstractPlus

38. Giugliano RP, Mach F, Zavitz K et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017; 377:633-643. http://www.ncbi.nlm.nih.gov/pubmed/28813214?dopt=AbstractPlus

39. Robinson JG, Nedergaard BS, Rogers WJ et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014; 311:1870-82. http://www.ncbi.nlm.nih.gov/pubmed/24825642?dopt=AbstractPlus

40. Koren MJ, Lundqvist P, Bolognese M et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63:2531-2540. http://www.ncbi.nlm.nih.gov/pubmed/24691094?dopt=AbstractPlus

41. Nissen SE, Stroes E, Dent-Acosta RE et al. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016; 315:1580-90. http://www.ncbi.nlm.nih.gov/pubmed/27039291?dopt=AbstractPlus

42. Stroes E, Colquhoun D, Sullivan D et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63:2541-2548. http://www.ncbi.nlm.nih.gov/pubmed/24694531?dopt=AbstractPlus

248. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm

269. Grundy SM, Cleeman JI, Bairey Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004; 110: 227-39.

350. 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. J Am Coll Cardiol. 2014; 63:2889-934. http://www.ncbi.nlm.nih.gov/pubmed/24239923?dopt=AbstractPlus

352. Eckel RH, Jakicic JM, Ard JD et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2960-84. http://www.ncbi.nlm.nih.gov/pubmed/24239922?dopt=AbstractPlus

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