may 20, 2018 lake geneva, wi please complete the ... · duchenne muscular dystrophy 5x more common...

May 20, 2018

Lake Geneva, WI

Please complete the preassessment located in your handout

before the program begins.

This educational activity is jointly provided by

Postgraduate Institute for Medicine

and Spire Learning.

This activity is supported by an independent

educational funding donation provided by Amgen.

Sponsorship and Support

JOINT ACCREDITATION STATEMENT

In support of improving patient care, this activity has been planned and

implemented by the Postgraduate Institute for Medicine and Spire Learning.

Postgraduate Institute for Medicine is jointly accredited by the American

Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy

Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide

continuing education for the healthcare team.

PHYSICIAN CONTINUING MEDICAL EDUCATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of

1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate

with the extent of their participation in the activity.

Accreditation Statement

To receive credit for your participation in this educational activity:

• Read the objectives and other introductory CME information

• Complete the preassessment located in your handout materials

at the start of the activity

• Participate in the PCSK9 inhibitor presentation

• Complete the postassessment/evaluation located in your handout

materials at the conclusion of the activity

Instructions to Receive Credit

Activity Chair:

Ty J. Gluckman, MD, FACC, FAHAMedical Director, Clinical Transformation

Providence Heart and Vascular Institute

Portland, OR

Adjunct Faculty, Ciccarone Center for the Prevention of Heart Disease

The Johns Hopkins Hospital

Baltimore, MD

Dr Gluckman has disclosed the following relationship:

Consulting Fees (Advisory Board): Boehringer Ingelheim

Faculty and Disclosures

Faculty and Disclosures (Cont’d)

Pamela B. Morris, MD, FACC, FACP, FACPM, FAHA, FASPC, FNLAAssociate Professor of Medicine, Cardiology

Director, Preventive Cardiology

Co-director, Women’s Heart Care

Medical University of South Carolina

Charleston, SC

Dr Morris has disclosed the following relationships:

Consulting Fees (Advisory Board): Amgen Inc; Sanofi Regeneron

Contracted Research (Local PI): Amgen Inc; Esperion Therapeutics, Inc

Steering Committee: Esperion Therapeutics, Inc

This educational activity may contain discussion of published and/or

investigational uses of agents that are not indicated by the FDA. The

planners of this activity do not recommend the use of any agent outside

of the labeled indications.

The opinions expressed in the educational activity are those of the faculty

and do not necessarily represent the views of the planners. Please refer

to the official prescribing information for each product for discussion of

approved indications, contraindications, and warnings.

Disclosure of Unlabeled Use

Upon completion of this activity, the participant should be

better able to:

• Summarize the mechanism of LDL-C reduction by inhibition

of PCSK9

• Compare the latest PCSK9 inhibitor clinical trial data on safety,

efficacy, and outcomes

• Identify patients with high LDL-C in whom treatment with PCSK9

inhibitors is appropriate and likely to be beneficial

Learning Objectives

HypercholesterolemiaBurden of Disease and

Guideline Recommendations

90

50

33

20

10

18

7

12

14

36

0 10 20 30 40 50 60 70 80 90 100

All 9 Risk Factors

Lipids

Psychosocial

Abdominal Obesity

Diabetes Mellitus

Hypertension

Alcohol

Exercise

Fruits/Vegetables

Smoking

PAR (%) for a First Myocardial Infarction

N = 15,152 patients and 14,820 controls in 52 countries.

PAR, population attributable risk.

Yusuf S, et al. Lancet. 2004;364:937-952.

Importance of Addressing Hypercholesterolemia

INTERHEART Study

Lifestyle factors = 55% of PAR

LDL-C, low-density lipoprotein cholesterol.

Ripsin CM, et al. JAMA. 1992;267:3317-3325.

Rambjor GS, et al. Lipids. 1996;31:S45-S49.

Jones PJH. Curr Atheroscler Rep. 1999;1:230-235.

Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.

Expert Panel on Detection, Evaluation, and Treatment of

High Blood Cholesterol in Adults. Circulation. 2002;106:3143-3421.

Jenkins DJ, et al. JAMA. 2003;290:502-510.

Lifestyle Interventions to Lower LDL-Cholesterol

Dietary Modification Recommendation ~LDL-C Reduction

Saturated fat <7% calories 8%-10%

Dietary cholesterol <200 mg/d 3%-5%

Plant stanols/sterols Up to 2 g/d 6%-10%

Viscous dietary fiber 5-10 g/d 3%-5%

Soy protein 20-30 g/d 5%-7%

Almonds >10 g/d 1%/10 g

Weight reduction Lose 10 lb (4.5 kg) 5%-8%

Total 30%-45%

Age <75 years

High-intensity statin(Moderate-intensity statin if not candidate

for high-intensity statin)

Moderate-intensity statin

Estimated 10-year ASCVD risk >7.5%

High-intensity statin

Age >75 years OR if not candidate for

high-intensity statin




2013 Blood Cholesterol Guideline Recommendations

Age >21 years

and a candidate

for statin therapy

Clinical

ASCVDYes

No

No

LDL-C >190

mg/dL

DM

Age 40-75

years

Yes

Yes

Yes

Yes

Yes

If diabetic and age <40 or >75

years, consider statin therapy (Expert Opinion)

DM, diabetes mellitus.

Stone NJ, et al. JACC. 2014;63(25 Pt B):2889-2934.

Statin Use in ASCVDGaps in Care

U.S. Prevalence of ASCVD

0

2

4

6

8

10

12

14

16

18

Coronary HeartDisease

CerebrovascularDisease

Peripheral ArterialDisease

Mil

lio

ns

Benjamin EJ, et al. Circulation. 2017;135(10):e146-e603.

Impact of Statins in ASCVD

Secondary Prevention

1. POSCH (1990)

2. 4S (1994)

3. CARE (1996)

4. LIPID (1998)

5. MIRACL (2001)

6. HPS (2002)

7. A to Z (2004)

8. ALLIANCE (2004)

9. PROVE-IT (2004)

10. IDEAL (2005)

11. TNT (2005)6

10

30

5

0

Eve

nt

Rate

(%

)

20

25

15

LDL-C Achieved (mg/dL)

16080 12060 200

Treatment Arm

Control Arm (Placebo)

Control Arm (Active Comparator)

140100 180

1

1

5

911

10

2

2

34

86

11

10

4S, Scandinavian Simvastatin Survival Study; ALLIANCE, Aggressive Lipid-lowering Initiation Abates New Cardiac Events; CARE,

Cholesterol and Recurrent Events; HPS, Heart Protection Study; IDEAL, Incremental Decrease in Events through Aggressive Lipid

Lowering; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; MIRACL, Myocardial Ischemia Reduction with

Aggressive Cholesterol Lowering; POSCH, Program on the Surgical Control of Hyperlipidemia; PROVE-IT, Pravastatin or Atorvastatin

Evaluation and Infection Therapy; TNT, Treating to New Targets.

Adapted from Raymond C, et al. Clev Clin J Med. 2014;81:11-19.

How Are We Doing in Those at Highest Risk?

Analysis of 1,174,545 patients from the NCDR PINNACLE registry

evaluating use of statin therapy between 2008-2012

19.5 20 16.1 20.5 18.2 14.4

48.7 49.943.5

45.141.5

34.2

3.1 2.9

4.76.2

5.2

4.3

29.3 27.935.9

29.335.5

47.5

0%

20%

40%

60%

80%

100%

Patients currently

not on statin therapy

Patients on statin therapy

No lipid-lowering therapy

Nonstatin lipid-lowering

therapies only

Statins as sole

lipid-lowering therapy

Both statin and

nonstatin therapies

All groups:

Overall

trend

1,164,497

patients total

Group 3:

LDL-C levels

≥190 mg/dL

3124

patients

Group 1:

Confirmed

ASCVD

1,020,896

patients

Group 2:

Diabetes

74,686

patients

Group 5:

No risk

44,710

patients

Group 4:

10-year ASCVD

≥7.5%

21,081

patients

NCDR, National Cardiovascular Data Registry; PINNACLE, Practice Innovation and Clinical Excellence registry.

Maddox TM, et al. JACC. 2014;64:2183-2192.

Age <75 years



Age >75 years OR if not candidate for

high-intensity statin



Age >21 years

and a candidate

for statin therapy

Clinical

ASCVDYes

Yes

Yes


Intensities of Statin Therapy

*Although simvastatin 80 mg was evaluated in randomized controlled trials, this dose is not recommended.


High Intensity* Moderate Intensity Low Intensity

Lowers LDL-C on

average by >50%

Lowers LDL-C on

average by 30% to <50%

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 2-4 mg

Impact of High-Intensity Statin Therapy in ASCVD

Meta-analysis of 39,612 secondary prevention patients randomized to more

intensive vs less intensive statin regimens for a median of 5.1 years

More intensive statin regimens produce greater reductions in adverse CV events

CV, cardiovascular.

CTT Collaboration. Lancet. 2010;376:1670-1681.

Trend: ꭕ21 = 12.4

0.85 (0.82 – 0.89)

P < 0.0001

Unweighted RR (CI)LDL-C

reduction

(mmol/L)

Events (% per annum)

Statin/more Control/less

More vs less statin

PROVE-IT 0.65 406 (11.3%) 458 (13.1%)

TNT 0.62 889 (4.0%) 1164 (5.4%)

IDEAL 0.55 938 (5.2%) 1106 (6.3%)

SEARCH 0.39 1347 (3.6%) 1406 (3.8%)

A to Z 0.30 257 (7.2%) 282 (8.1%)

Subtotal (5 trials) 0.51 3837/19829 4416/19783

(4.5%) (5.3%)

Use of High-Intensity Statin Therapy in ASCVD

Virani SS, et al. Am J Cardiol. 2015;115(1):21-26.

Cohort study of 972,532 patients with ASCVD receiving care at

130 Veterans Health Administration facilities

Pa

tie

nts

Wit

h A

SC

VD

Rec

eiv

ing

a H

igh

-In

ten

sit

y S

tati

n (

%)

Facility

Statin Use in FHGaps in Care

2.0

1.0

0.8

0.5 0.5 0.5 0.50.4 0.4

0.3

0

0.5

1

1.5

2

2.5

FH Dominantotosclerosis

Adult PCKD Sickle celldisease

Multipleexostoses

Huntington'sdisease

Fragile Xsyndrome

Neuro-fibromatosis

Cysticfibrosis

Duchennemusculardystrophy

5x more common

4x more common

Prevalence of FH Relative to Other ConditionsR

ela

tive P

revale

nce

Prevalence of FH

HoFH: 1:300,000-400,000

HeFH: 1:250

HeFH, heterozygous FH; HoFH, homozygous FH; PCKD, polycystic kidney disease.

Sjouke B, et al. Eur Heart J. 2015;36(9):560-565.

de Ferranti SD, et al. Circulation. 2016;133(11):1067-1072.

Impact of LDL-C on CV Risk in the Presence of FH

Nordestgaard BG, et al. Eur Heart J. 2013;34(45):3478-3490.

P < .001

Impact of Statins in FH

Long-term cohort study of 1707 patients with heterozygous FH

evaluating the effect of statin therapy

Versmissen J, et al. BMJ. 2008;337:a2423.



Analysis of 1,174,545 patients from the NCDR PINNACLE

registry evaluating use of statin therapy between 2008-2012

19.5 20 16.1 20.5 18.2 14.4

48.7 49.943.5

45.141.5

34.2

3.1 2.9

4.76.2

5.2

4.3

29.3 27.935.9

29.335.5

47.5

0%

20%

40%

60%

80%

100%

Patients currently





therapies only

Statins as sole


Both statin and

nonstatin therapies

All groups:

Overall

trend

1,164,497

patients total

Group 3:

LDL-C levels

≥190 mg/dL

3124

patients

Group 1:

Confirmed

ASCVD

1,020,896

patients

Group 2:

Diabetes

74,686

patients

Group 5:

No risk

44,710

patients

Group 4:

10-year ASCVD

≥7.5%

21,081

patients




Age >21 years

and a candidate

for statin therapy

Clinical

ASCVDYes

No

LDL-C >190

mg/dLYes


Use of High-Intensity Statin Therapy in FH

Cross-sectional analysis of 1295 patients with

heterozygous FH enrolled in the CASCADE FH registry

Coronary Artery

Disease

Medications Used Yes No

High-intensity statin 39.3% 46.9%

Low- or moderate-

intensity statin35.9% 27.3%

No statin 24.8% 25.8%

CASCADE FH, Cascade Screening for Awareness and Detection FH Registry.

deGoma EM, et al. Circ Cardiovasc Genet. 2016;9(3):240-249.

On Statin

Therapy?

Medications Used Yes No

Ezetimibe 45.2% 25.2%

Bile acid sequestrant 15.0% 15.0%

Nicotinic acid 14.4% 9.4%

Statin Use in DiabetesGaps in Care

0

5

10

15

20

25

0

1

2

3

4

5

6

7

8

1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09 12 15

Nu

mb

er W

ith D

iab

ete

s (M

illion

s)

Perc

en

tag

e W

ith

Dia

bete

s

Year

Percentage With Diabetes

Number With Diabetes

Prevalence of Diabetes Mellitus

Centers for Disease Control and Prevention, Division of Diabetes Translation National Diabetes Surveillance System.

https://www.cdc.gov/diabetes/statistics/slides/long_term_trends.pdf.

Percentage and absolute numbers of diabetics in the United States

Retrospective meta-analysis of 18,686 patients with

DM randomized to treatment with a statin

Impact of Statins in Diabetes

Cholesterol Treatment Trialists’(CTT) Collaborators. Lancet. 2008;371(9607):117-125.

0.78 (0.69–0.87)

0.77 (0.73–0.81)

0.77 (0.74–0.80)

RR (CI)

0.75 (0.64–0.88)

0.76 (0.72–0.81)

0.76 (0.73–0.80)

0.79 (0.67–0.93)

0.84 (0.76–0.93)

0.83 (0.77–0.88)

0.79 (0.76–0.82)

0.79 (0.72–0.86)

0.79 (0.77–0.81)

0.5 1.0 1.5

979 (10.5%)

3441 (9.6%)

4420 (9.8%)

501 (5.4%)

1116 (3.2%)

1617 (3.7%)

6212 (17.4%)

1782 (19.2%)

7994 (17.8%)

776 (8.3%)

2561 (7.2%)

3337 (7.4%)

407 (4.4%)

933 (2.7%)

1340 (3.0%)

4889 (13.7%)

1465 (15.6%)

6354 (14.1%)

ControlTreatment

Events (%)

491 (5.2%)

2129 (6.0%)

2620 (5.8%)

627 (6.7%)

2807 (7.9%)

3434 (7.6%)

Diabetes

No diabetes

Any major coronary event

Diabetes

No diabetes

Any stroke

No diabetes

Diabetes

Any vascular event

Major vascular event and prior diabetes

Diabetes

No diabetes

Any coronary revascularization

Test for heterogeneity within subgroup:ꭕ21= 0.1; p=0.8




Major coronary event

Coronary revascularization

Stroke

Major vascular event

Treatment better Control better


Estimated 10-year ASCVD risk >7.5%

High-intensity statin



Age >21 years

and a candidate

for statin therapy

Clinical

ASCVDYes

No

No

LDL-C >190

mg/dL

DM

Age 40-75

years

Yes

Yes

If diabetic and age <40 or >75

years, consider statin therapy

(Expert Opinion)



Analysis of 1,174,545 patients from the NCDR PINNACLE

registry evaluating use of statin therapy between 2008-2012

19.5 20 16.1 20.5 18.2 14.4

48.7 49.943.5

45.141.5

34.2

3.1 2.9

4.76.2

5.2

4.3

29.3 27.935.9

29.335.5

47.5

0%

20%

40%

60%

80%

100%

Patients currently





therapies only

Statins as sole


Both statin and

nonstatin therapies

All groups:

Overall

trend

1,164,497

patients total

Group 3:

LDL-C levels

≥190 mg/dL

3124

patients

Group 1:

Confirmed

ASCVD

1,020,896

patients

Group 2:

Diabetes

74,686

patients

Group 5:

No risk

44,710

patients

Group 4:

10-year ASCVD

≥7.5%

21,081

patients

Use of Moderate- to High-Intensity Statin Therapy in DM

Cohort study of 911,444 patients with diabetes mellitus receiving

care at 130 VA Health Administration facilities

Facility

Pa

tie

nts

Wit

h D

M R

ec

eiv

ing

a M

od

era

te t

o H

igh

-In

ten

sit

y S

tati

n (

%)

Facility

Pokharel Y, et al. Clin Cardiol. 2016;39:185-191.

Nonstatin TherapiesTo Reduce CV Risk

For Starters, Repeat Lipid Testing Is Recommended

Anticipated

therapeutic

effect?

No

Assess medication and lifestyle adherence

Initial fasting lipid panel at 4-12 weeks

Reinforce continued adherence

Follow up lipids every 3-12 months

Yes

Indicators of anticipated therapeutic

response and adherence to selected

statin therapy:

• High-intensity statin therapy

reduced LDL-C approximately

>50% from the untreated

baseline

• Moderate-intensity statin therapy

reduced LDL-C approximately 30

to <50% from the untreated

baseline


1.00.750.500.25

CI, confidence interval.

Boekholdt SM, et al. JACC. 2014;64(5):485-494.

Meta-analysis of 38,153 patients from 8 randomized statin trials

Rationale for Pushing LDL-C Levels Even Lower

Major CV and Coronary Event Rates

vs Various LDL-C Levels50

0

Eve

nt

Rate

(%

)

10

<50

4.4

30

40

20

50-70

10.9

70-100

16.0

100-130

16.7

130-160

18.2

160-190

25.2

>190

34.4

LDL-C (mg/dL)

Major Coronary Events

Major CV Events

≥175

<50

LD

L-C

(m

g/d

L)

100-<125

LDL-C Levels

and Risk of CV Events

150-<175

50-<75

75-<100

125-<150

Adjusted Hazard Ratio 95% CI

Guidance on Use of Nonstatin Therapy

Lloyd-Jones DM, et al. JACC. 2017;70(14):1785-1822.

4 statin benefit groups

• Adherence and lifestyle

• Statin intolerance

• Control of other risk factors

• Discussion about non-statin therapies

• Choosing alternative goals of therapy

• Monitoring response to therapy

• Referral to a specialist/nutritionist

• Ezetimibe

• Bile acid sequestrant

• PCSK9 inhibitor

• Other therapies (LDL apheresis,

lomitapide, mipomersen)

All patients with ASCVD

Primary:

>50% reduction in LDL-C

Secondary (may consider):

LDL-C <70 mg/dL

Non-HDL-C <100 mg/dL

PCSK9, proprotein convertase subtilisin/kexin type 9 serine protease.

18,144 ACS patients randomized to simvastatin (40 mg QHS) or

simvastatin/ezetimibe (40 mg/10 mg QHS) for 7 years

*Composite of CV death, MI, unstable angina, coronary revascularization, or stroke.

ACS, acute coronary syndrome; HR, hazard ratio.

Cannon CP, et al. NEJM. 2015;372(25):2387-2397.

Eve

nt

Ra

te*(%

)

40

0

5

35

10

25

15

Years

430 2 51 76

30

20

HR 0.936, P = .016

Simvastatin

Ezetimibe/simvastatin

100

40

8

50

90

60

80

70

72

Me

an

LD

L-C

(m

g/d

L)

Time Since Randomization (Months)

1 48R 36QE 244 6016 9612 84

Median time average

69.5 vs 53.7 mg/dL

Simvastatin

Ezetimibe/simvastatin

Impact of Ezetimibe in ASCVD

IMPROVE-IT Study

Rationale for PCSK9 Inhibitors

*Black subjects (n = 3363), 2.6% prevalence of PCSK9 LOF mutations, 28% reduction in LDL-C, and 88% RR in CHD events.

ARIC, The Atherosclerosis Risk in Communities; LOF, loss of function.

Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272.

Analysis of DNA-sequence variations from the ARIC Study among those with

reduced levels of LDL-C and their impact on coronary events*

Fre

qu

en

cy (

%)

CH

D (

%)

0

10

20

30

0 50 100 150 200 250 300

0

10

20

30

0 50 100 150 200 250 300

No Nonsense

Mutation

(N = 3278)

50th Percentile

PCSK9142X or PCSK9679X

(N = 85)

PCSK9142X or PCSK9679X

Plasma LDL-C in Black Subjects (mg/dL)

No Yes

12

8

4

0

P = .008

PCSK9 promotes the degradation of the

LDL receptor and prevents it from recycling

to the cell membrane

PCSK9 inhibitors are monoclonal antibodies

that bind to PCSK9 and prevent association

between the LDL receptor and PCSK9

Lambert G, et al. J Lipid Res. 2012;53:2515-2524.

Mechanism of Action of PCSK9 Inhibitors

Impact of PCSK9 Inhibition in ASCVD

FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk.

Sabatine MS, et al. N Engl J Med. 2017;376(18):1713-1722.

27,564 high-risk patients with stable ASCVD and a LDL-C >70 mg/dL on

background statin therapy randomized to evolocumab (140 mg/Q2W or

420 mg QMO) or placebo for a median of 26 months

FOURIER Trial

FOURIER Trial—Landmark Analysis

Impact of PCSK9 Inhibition in ASCVD (Cont’d)


FOURIER Trial—Relationship between LDL-C and event rate



Mean LDL-cholesterol achieved was 30 mg/dL

0 10 20 30 40 50 60 70 80 90

Rhabdomyolysis

Cataract

Neurocognitive

Diabetes (new onset)

Muscle-related AE

Injection-site reaction

Allergic reaction

Treatment-related AE

Serious AE

Any AE

Evolocumab

Placebo

FOURIER Trial—Key safety endpoints

Laboratory Result Evolocumab Placebo

Binding Ab 0.3% None

Neutralizing Ab None None


Ab, antibody; AE, adverse event.


FOURIER Trial—Efficacy and safety in patients with an LDL-C <10 mg/dL

11.9

7.87.3

4.4

0

5

10

15

CVD, MI, Stroke,UA, Cor Revasc

CVD, MI, Stroke

≥ 100.4 mg/dL

< 10.3 mg/dL

HR 0.69 (0.49-0.97)

P = .03

HR 0.59 (0.37-0.92)

P = .02

Cardiovascular Efficacy

23.3

3.4

22.8

3.4

0

5

10

15

20

25

30

Serious AE AE (DrugDiscontinued)

≥ 100.4 mg/dL

< 10.3 mg/dL

HR 1.08 (0.63-1.85)

P = .78

HR 0.94 (0.74-1.20)

P = .61

Safety

Cor revasc, coronary revascularization; UA, unstable angina.

Giugliano RP, et al. Lancet. 2017;390(10106):1962-1971.

Impact of PCSK9 Inhibition in ASCVD (Cont’d)P

erc

en

t (%

)

Pe

rce

nt

(%)

Steg PG, et al. Presented at: ACC.18 Scientific Sessions; March 10, 2018; Orlando, FL.

Impact of PCSK9 Inhibition in ACS

ODYSSEY Outcomes Trial

18,924 high-risk patients with an ACS within the preceding 1-12 months and an LDL-C >70 mg/dL on

background high-intensity statin therapy randomized to alirocumab or placebo for a median of 2.8 years


Impact of PCSK9 Inhibition in ACS (Cont’d)


MA

CE

(%

)

Years Since Randomization

Years Since Randomization Years Since Randomization Years Since Randomization

*Nominal P value

CHD, coronary heart disease; MACE, major adverse cardiac events.




Endpoint Alirocumab Placebo HR (95% CI) P value

MACE 903 (9.5%) 1052 (11.1%) 0.85 (0.78-0.93) 0.0003

CHD death 205 (2.2%) 222 (2.3%) 0.92 (0.76-1.11) 0.38

Nonfatal MI 626 (6.6%) 722 (7.6%) 0.86 (0.77-0.96) 0.006

Ischemic stroke 111 (1.2%) 152 (1.6%) 0.73 (0.57-0.93) 0.01

Unstable angina 37 (0.4%) 60 (0.6%) 0.61 (0.41-0.92) 0.02

Death, MI, ischemic stroke 973 (10.3%) 1126 (11.9%) 0.86 (0.79-0.93) 0.0003

Coronary heart disease

death

205 (2.2%) 222 (2.3%) 0.92 (0.76-1.11) 0.38

Cardiovascular death 240 (2.5%) 271 (2.9%) 0.88 (0.71-1.05) 0.15

All-cause death 334 (3.5%) 392 (4.1%) 0.85 (0.73-0.98) 0.026*




0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Any AE

Serious AE

ALT >3x ULN

CK >10x ULN

New onset DM

DM worsening/complications

Allergic reaction

Injection site reaction (local)

Neurocognitive disorder

Cataracts

Hemorrhagic stroke Placebo

Alirocumab

Prescribing a

PCSK9 InhibitorPractical Issues

Alirocumab Evolocumab

Indication

Adjunct to diet and maximum-toleratedstatin for adults with HeFH or clinical

ASCVD who require additional loweringof LDL-C

Adjunct to diet and maximum-toleratedstatin for adults with HeFH or clinical

ASCVD who require additional lowering of LDL-C; HoFH patients on other LLT;

to reduce the risk of myocardial infarction, stroke, and coronary

revascularization in adults with established cardiovascular disease (December 2017)

Dosing75-150 mg SQ Q2W; 300 mg SQ monthly

140 mg or 420 mg SC Q2W;420 mg SC monthly for HoFH

How suppliedSingle-dose prefilled pens and

prefilled glass syringes that deliver75-mg/mL or 150-mg/mL solution

Single-use prefilled syringe orautoinjector that delivers

1 mL of 140-mg/mL solution

Side effectsNasopharyngitis, injection-site reactions;

hypersensitivity reactionsNasopharyngitis, injection-site reactions;

hypersensitivity reactions

Prescribing Information for Approved PCSK9 Inhibitors

LLT, lipid-lowering therapy.

Praluent (alirocumab) [prescribing information]. Bridgewater, NJ: sanofi-aventis US LLC; 2015. Drugs@FDA FDA Approved Drug

Products. July 2015. http://www.accessdata.fda.gov/. Accessed September 8, 2015. Repatha (evolocumab) [prescribing information].

Thousand Oaks, CA: Amgen, Inc; 2015. Drugs@FDA. FDA Approved Drug Products. August 2015. http://www.accessdata.fda.gov/.

Patient TypeLDL-C Reduction on

Maximally Tolerated StatinTherapy Recommendation

ASCVD without comorbidities<50% LDL-C reduction or

LDL-C >70 mg/dL

Ezetimibe 1st;

PCSK9 inhibitor 2nd

ASCVD with comorbidities<50% LDL-C reduction or

LDL-C >70 mg/dL

Ezetimibe* or

PCSK9 inhibitor†

≥21 years with ASCVD and baseline

LDL-C ≥190 mg/dL

<50% LDL-C reduction or

LDL-C >70 mg/dL

Ezetimibe* or

PCSK9 inhibitor†

≥21 years without ASCVD and baseline

LDL-C ≥190 mg/dL


LDL-C >100 mg/dL

Ezetimibe* or

PCSK9 inhibitor†

40-75 years without ASCVD and with DM

and baseline LDL-C 70-189 mg/dL


LDL-C >100 mg/dL

Ezetimibe or bile acid

sequestrant‡

40-75 years without ASCVD or DM

and baseline LDL-C 70-189 mg/dL


LDL-C >100 mg/dL

Ezetimibe or bile acid

sequestrant‡

Populations to Consider for a PCSK9 Inhibitor

*May be preferred if patient requires <25% additional LDL-C reduction or ACS <3 months. †May be preferred if patient requires >25% additional LDL-C reduction. ‡If unable to tolerate ezetimibe and triglycerides <300 mg/dL.

Lloyd-Jones DM, et al. JACC. 2017;70(14)1785-1822.

Populations Most Likely to Benefit

From a PCSK9 Inhibitor

7856 healthy patients treated with rosuvastatin (20 mg/d) to

evaluate the magnitude of LDL-C reduction

-70

80

-90

Ch

an

ge

in

LD

L-C

(%

)

10

50

-30

480012000 7200

-80

70

-10

30

-50

0

40

-40

60

-20

20

-60

2400 60003600

Greatest

Theoretical

Benefit

Least

Theoretical

Benefit

Intermediate

Theoretical

Benefit

N = 2734 (34.8%) N = 1573 (20.0%)N = 3549 (45.2%)

No Reduction/

Increase in LDL-C

<40% Reduction

in LDL-C

40%-60% Reduction

in LDL-C

>60% Reduction

in LDL-C

Ridker PM, et al. Eur Heart J. 2016;37(17):1373-1379.

A Balancing Act With PCSK9 Inhibitors

Direct Costs CV Benefit

Knowles JW, et al. Circulation. 2017;135(22):2204-2206.

Presumptive FH in

claims adjudication data

N = 5795

Diagnosed ASCVD in

claims adjudication data

N = 415,133

Prescribed

PCSK9i

N = 25,349

Prescribed

PCSK9i

N = 515

Prescribed

Ezetimibe

N = 5442

Prescribed

Ezetimibe

N = 399,603

LDL-C >190 mg/dL

while on LLT

N = 2579

LDL-C >100 mg/dL

while on LLT

N = 1622

LDL-C >190 mg/dL

while on LLT

N = 237

LDL-C >100 mg/dL

while on LLT

N = 27,246

Claims adjudication:

rejected: 150 (63.3%)

Paid: 53 (22.4%)

Abandoned: 34 (14.3%)


rejected: 232 (9.0%)

Paid: 1651 (64.2%)



rejected: 933 (57.5%)

Paid: 426 (26.3%)



rejected: 2244 (8.2%)

Paid: 18,521 (68.0%)

Abandoned: 6481 (23.8%)

Access to Nonstatin Therapy in

Patients at Highest Risk

Analysis of diagnostic information and pharmacy claims adjudication for

1.12 million patients with a claim for either a PCKS9 inhibitor or ezetimibe

A Quantitative Approach to Adding Nonstatin Therapy

Robinson JG, et al. JACC. 2016;68(22):2412-2421.

Very high risk: >30% 10-year ASCVD risk

Clinical ASCVD + diabetes

Clinical ASCVD + familial hypercholesterolemia

Clinical ASCVD + poorly controlled risk factors

Recent acute coronary syndrome (<3 months)

Clinical ASCVD + polyvascular disease

Clinical ASCVD + age >65 years

Clinical ASCVD + multiple recurrent events

Clinical ASCVD + elevated Lp(a)

High risk: 20%-<30% 10-year ASCVD risk

Clinical ASCVD without high-risk features

Familial hypercholesterolemia

Moderate risk: 10%-<20% 10-year ASCVD risk

With or without DM

Navigating the Prior Authorization Process:

Clinical Pearls

• Know the FDA-approved indications

• Prescribe ONLY according to FDA

indications

• Know the definitions of the disease states

in the FDA indications

• Document, document, document

– Disease state

– Previous medications tried

– Description of intolerances

– Response to drug discontinuation

– Response to drug re-challenge

• Use the EHR to support the PA process

• Use online resources to streamline the prior

authorization process

– Insurance benefit information

– PA forms

– Sample letter of medical necessity

– Sample appeals letter

– ICD-10 coding

• Use your care team

– Pharmacist/PharmD

– Specialty Pharmacy

– Advanced Practice Professionals

(NP, PA, etc)

– RN

• Manage patient expectations, particularly

with newer, more expensive medications

– Time to navigate approval process

– Potential for denial

– Appeal process

– Potential for higher co-pays even

if approved

• Teach the patient to support the process

EHR, electronic health record; FDA, Food and Drug Administration; PA, prior authorization.

Medicare Part D Cost-Sharing With PCSK9 Inhibitors

Kazi DS, et al. JAMA Cardiol. 2017;(10):1164-1166.

Coverage sequence• $360 deductible

• Coverage phase

• Coverage gap (donut

hole) when total drug

costs reach $3,310 with

cost-sharing to 45% for

brand-name drug

• Catastrophic coverage

when total costs reach

$4,850 with cost-sharing

reduced to 5% for the

remainder of the year

Analysis of 2575 Part D Medicare Plans Across 50 States

Average out-of-pocket cost of $330/month

($336 for alirocumab and $321 for evolocumab)

Take-Home Messages

• Statins are the most effective traditional LDL-C–lowering medication and

should be used at the maximally tolerated intensity in those at highest risk

(ASCVD, FH, and/or DM)

• Currently approved PCSK9 inhibitors (alirocumab and evolocumab) achieve

significant reductions in LDL-C when used alone or added to statin therapy

• The PCSK9 inhibitor evolocumab significantly and safely reduces the rate

of adverse CV events in patients with stable ASCVD when added to

statin therapy

• The PCSK9 inhibitor alirocumab significantly and safely reduces the rate

of adverse CV events in patients with a recent ACS when added to

statin therapy

• Results from the FOURIER and ODYSSEY Outcomes trials validate the

causality of LDL-C in ASCVD, with incremental benefit associated with

lowering of LDL-C levels well below current targets

Take-Home Messages (Cont’d)

• Between one-half to two-thirds of PCSK9 inhibitor pharmacy claims are

rejected by payers

• For those in whom a PCSK9 inhibitor is approved, there may be significant

out-of-pocket cost for patients, particularly if insured by a government

payer (Medicare/Medicaid)

• Quantitative approaches to estimate CV risk can help determine the

cost-effectiveness of nonstatin therapies (ezetimibe and PCSK9 inhibitors)

• The ASCVD Risk Estimator and Nonstatin Decision Pathway serve as

useful resources to guide decision making around reducing LDL-C

Please complete the

postassessment

and evaluation

located in your meeting handout.

Thank You

Appendix

Cover illustration, The Economist. December 13, 2003.

O’Keefe JH, et al. JACC. 2004;43:2142-2146.

WILD PRIMATES:

Baboon

Howler monkey

Night monkey

Hazda

Inuit

IKung

Pygmy

San

HUNTER-GATHERER

HUMANS:

WILD MAMMALS:

Horse

Boar

Peccary

Black rhinoceros

African elephant

MODERN HUMANS:

Adult American

Adverse Environmental Effects Predominate

50 70 90 110 130 150 170 190 210

Mean Total Cholesterol (mg/dL)

Role of Lipoproteins (LDL-C) in Atherogenesis

Modified from Crawford MH, DiMarco JP, editors: Cardiology, Mosby, London, 2001.

*Includes LDL-C >160 mg/dL, FH of premature ASCVD, lifetime ASCVD risk, CAC >300, ABI <0.9, or hs-CRP >2 mg/L.

ABI, ankle-brachial index; CAC, coronary artery calcification; hs-CRP, high-sensitivity C-reactive protein.Stone NJ, et al. JACC. 2014;63(25 Pt B):2889-2934.


No DM

Primary prevention (no DM, LDL-C 70-189

mg/dL, and not on statin therapy)

Estimate 10-y ASCVD risk every 4-6 y

DM and age <40 or >75 y

or LDL-C <70 mg/dL

<5% 10-y

ASCVD risk

<40 or >75 y and

LDL-C <190 mg/dL

In selected individuals, additional factors*

may be considered to inform treatment

>7.5%

10-y ASCVD

risk

(moderate- or

high-intensity

statin)

Clinician-patient risk discussion

5 to <7.5%

10-y ASCVD

risk

(moderate-

intensity

statin)

*Adjusted heterogeneity test calculated from a Cox model that corrects for nonsex differences between women and men;

1 mmol/L reduction in LDL-C is equivalent to 38.7 mg/dL reduction in LDL-C.

CTT Collaboration. Lancet. 2015;385(9976):1397-1405.

Statin therapy in secondary prevention significantly reduces the risk of adverse

CV events among men and women

Impact of Statins in ASCVD

Meta-analysis of 174,179 patients from 27 trials

evaluating the impact of statin therapy on CV risk

26.3

13.710.9

22.4

12.0

8.7

0

10

20

30

40

Patients

Experiencin

g

Majo

r C

VD

Events

(%

)

PROVE IT-TIMI 221 IDEAL2 TNT3

N

LDL-C mg/dL

4162 8888 10,001

95 62 104 81 101 77

There Still Exists Substantial Residual Risk

1. Cannon CP, et al. N Engl J Med. 2004;350(15):1495-1504.

2. Pedersen TR, et al. JAMA. 2005;294(19):2437-2445.

3. LaRosa JC, et al. N Engl J Med. 2005;352(14):1425-1435.

Standard statin therapy

High-intensity statin therapy

Is It Even Possible to Get There?

Subgroup analysis of 18,677 patients assigned to high-dose statin

1500

1000

500

00 50 100 150 200 250

Fre

quency

>40% of patients fail to achieve a LDL-C <70 mg/dL

Mean = 69,217

SD = 26,95

N = 18.661

Boekholdt SM, et al. JACC. 2014;64(5):485-494.

Cumulative Incidence for Recurrent MI,

CHD Events, and All-Cause Mortality

Serban MC, et al. JACC. 2017;69(11):1386-1395.

Adherence to High-Intensity Statins Following an

MI Hospitalization

Pattern of Statin Use After Discharge for MI

(Among Medicare Beneficiaries 66 to 75 Years (N = 29,932))

Colantonio LD, et al. JAMA Cardiol. 2017;2(8):890-895.

Spectrum of Hypercholesterolemia

FCH, familial combined hyperlipidemia; FHBL, familial hypobetalipoproteinemia.

1. NCEP ATP III. Circulation. 2002;106(25):3143-3421.

2. Glueck CJ, et al. J Lab Clin Med. 1976;88(6):941-957.

3. Cohen JC, et al. N Engl J Med. 2006;354(12):1264-1272.

4. Pauciullo P, et al. Atherosclerosis. 2009;203(1):320-324.

5. Brown MS, et al. Science. 1986;232(4746):34-47.

LD

L-c

ho

les

tero

l (m

g/d

L)

0

100

200

300

700

Newborns1FHBL2

PCSK9 LOF Mutants3

FH Heterozygotes5

FH Homozygotes5

FCH4

Gidding SS, et al. Circulation. 2015;132(22):2167-2192.

Known Mechanisms Causing FH

Overlap of Clinical and Mutation Diagnosis of FH

Mutation without

clinical diagnosis

Clinical diagnosis

without mutation

Clin

ical D

iagnosis

Muta

tion d

iagnosis

Patient: treat LDL

Family: monitor LDL and consider treatment

Patient: treat LDL

Family: mutation test, monitor LDL, and consider

treatment

Patient: monitor LDL and consider treatment

Family: monitor LDL and consider treatment


ApoB, apolipoprotein B; DNA, deoxyribonucleic acid; LDL-R, LDL-receptor.


Diagnosis of FH—Dutch Lipid Clinic Network Criteria

Criteria Points

Family History

1st-degree relative with known premature

vascular disease OR

1st-degree relative with known LDL-C

>95th percentile

1

Clinical History

Patient with premature coronary artery

disease2

Patient with premature cerebrovascular or

peripheral vascular disease1

Physical Examination

Tendinous xanthomata 6

Arcus cornealis prior to age 45 years 4

Criteria Points

Cholesterol Levels

>330 8

250-329 5

190-249 3

155-189 1

DNA analysis

Functional mutation in the LDL-R, ApoB,

or PCSK9 gene8

Diagnosis Total

Definite FH >8

Probable FH 6-8

Possible FH 3-5

Unlikely FH <3

Cross-sectional analysis of 1295 patients with

heterozygous FH enrolled in the CASCADE FH registry


deGoma EM, et al. Circ Cardiovasc Genet. 2016;9(3):240-249.

60%

50%

40%

30%

20%

10%

0%

<30% 30-50% >50%

LDL-C Reduction, Treated vs Untreated

On nonstatin therapy

On statin therapy ± nonstatin therapy 30%

25%

20%

15%

10%

5%

0%

Treated LDL-C (mg/dL)

On nonstatin therapy

On statin therapy ± nonstatin therapy

Cardiovascular Risks Associated With

Diabetes Mellitus

Emerging Risk Factors Collaboration. Lancet. 2010;375(9733):2215-2222.

Meta-analysis of 102 clinical trials evaluating the risk of CV

events due to DM

ASCVD Risk Estimator

Web Version: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

iTunes: https://itunes.apple.com/us/app/ascvd-risk-estimator/id808875968?mt=8

Google Play: https://play.google.com/store/apps/details?id=org.acc.cvrisk&hl=en

http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

https://itunes.apple.com/us/app/ascvd-risk-estimator/id808875968?mt=8

https://play.google.com/store/apps/details?id=org.acc.cvrisk&hl=en

Nonstatin Therapy—Cholesterol Absorption Inhibitors

Ezetimibe

Bile Acid Sequestrant

3806 men with primary hypercholesterolemia randomized to

cholestyramine (24 g) or placebo for 7.4 years

Lipid LRC-CPPT

CHD, coronary heart disease; LRC-CPPT, Lipid Research Clinics-Coronary Primary Prevention Trial;

RRR, relative risk reduction.

The LRC-CPPT Investigators. JAMA. 1984;251(3):351-364.

Impact of Bile Acid Sequestrants in

Hypercholesterolemia

Placebo

8.6

Cholestyramine

7.0

P < .05

19% RRR

9

6

3

Rate

of

MI

or

CH

D D

ea

th (

%)

0

Nonstatin Therapy—Nicotinic Acid

HDL

Serum VLDL

results in reduced

lipolysis to LDL

Serum LDL

VLDL

VLDL

secretion

ApoB

Hepatocyte Systemic Circulation

Mobilization of FFA

TG

synthesis

VLDL

LDL

FFA, free fatty acids; TG, triglycerides; VLDL, very-low‒density lipoprotein.McKenney JM. Selecting Successful Lipid-lowering Treatments presentation, 2002. http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14. Accessed October 31, 2017.

ApoB

http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14

Impact of Nicotinic Acid in ASCVD

Time (Years)

Pri

ma

ry O

utc

om

e (

%)*

0

10

20

0 1 2 3 4

Monotherapy

Combination Therapy

HR 1.02, P = .79

16.2%

16.4%

3414 patients with established CV disease randomized to niacin or

placebo for a mean of 3 years*

Atherothrombosis Intervention in Metabolic Syndrome With AIM-HIGH Trial

*CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization;

AIM-HIGH, Low HDL/High Triglycerides: Impact of Global Health Outcomes.

AIM-HIGH Investigators. N Engl J Med. 2011;365(24):2255-2267.

Impact of of Nicotinic Acid in ASCVD (Cont’d)

25,673 patients with established CV disease randomized to extended release

niacin plus laropiprant or placebo for a median of 3.9 years*

HPS2-THRIVE Trial

0 1 2 3 4

Years of Follow-up

0

10

15

Ma

jor

Va

sc

ula

r E

ve

nts

(%

)

15.0%

14.5%

5

Niacin/Laropiprant

Placebo

HR 0.96, P = .29

*The study was stopped prematurely.

HPS2-THRIVE, Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events.

HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371(3):203-212.

Temporal Impact of PCSK9 Inhibition

Koren MJ, et al. Postgrad Med. 2015;127(2):125-132.

60

80

120

140

180

200

20

0

160

40

100

LD

L-C

Mean

% C

han

ge

Time (h)

0 500 1000 1500 2000 2500

-50

-40

-20

-10

0

-60

-70

-30

Fre

e/T

ota

l P

CS

K9 C

on

c.

(ng

/mL

)

To

tal A

liro

cu

ma

b (

ng

/mL

) x

0.0

1

Total alirocumab Free PCSK9 LDL-C


968 patients with angiographic symptomatic CAD on statin therapy with

LDL-C >80 mg/dL randomized to evolocumab (420 mg) or placebo for

76 weeks to assess change in percent atheroma volume

GLAGOV Trial

Evolocumab

• 61% in LDL-C (P

< .001)

• 1% absolute in

PAV (P < .001)

CAD, coronary artery disease; GLAGOV, Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured

by Intravascular Ultrasound; PAV, percent atheroma volume.

Nicholls SJ, et al. JAMA. 2016;316(22):2373-2384.

Giugliano RP, et al. Lancet. 2012;380(9858):2007-2017.

LD

L-C

Mean

(+

/-S

E)

%

C

han

ge

Fro

m B

aselin

e

Temporal Impact of PCSK9 Inhibition

631 patients on statin therapy with LDL-C >85 mg/dL

randomized to varying regimens of evolocumab

Baseline Week 2 Week 6 Week 10Week 4 Week 8 Week 12

-90

-60

-40

-10

0

10

-100

-20

-30

-50

-70

-80

AMG 145 105 mg every 2 weeks (n = 79) AMG 145 140 mg every 2 weeks (n = 78)

Placebo every 2 weeks (n = 79) AMG 145 70 mg every 2 weeks (n = 79)

Baseline Week 2 Week 6 Week 10Week 4 Week 8 Week 12

-90

-60

-40

-10

0

10

-100

-20

-30

-50

-70

-80

AMG 145 350 mg every 4 weeks (n = 79) AMG 145 420 mg every 4 weeks (n = 80)

Placebo every 4 weeks (n = 77) AMG 145 280 mg every 4 weeks (n = 79)


End Point Evolocumab Placebo HR (95% CI)/P value

CV death, MI, stroke, UA, or revasc. 12.6% 14.6% 0.85 (0.79-0.92)

CV death, MI, or stroke 7.9% 9.9% 0.80 (0.73-0.88)

CV death 2.5% 2.4% 1.05 (0.88-1.25)

MI 4.4% 6.3% 0.73 (0.65-0.82)

Stroke 2.2% 2.6% 0.79 (0.66-0.95)

Hospitalization for UA 2.2% 2.3% 0.99 (0.82-1.18)

Coronary revascularization 7.0% 9.2% 0.78 (0.71-0.86)

All-cause death 4.8% 4.3% 1.04 (0.91-1.19)

FOURIER Trial—Key primary and secondary efficacy endpoints


Giugliano RP. Presented at: ESC Congress 2017, August 28, 2017; Barcelona, Spain.

FOURIER Trial—How low is too low?

Ra

te o

f C

V D

ea

th, N

on

fata

l M

I,

or

No

nfa

tal S

tro

ke

(%

)

LDL (mM) at 4 Weeks

LDL-C

(mM)

LDL-C

(mg/dL)

<0.5 <20

0.5-1.3 20-49

1.3-1.8 50-69

1.8-2.6 70-99

>2.5 >100


Besseling J, et al. JACC. 2016;68(3):252-260.

Retrospective cohort study of 1559 patients with heterozygous FH

evaluating the effect of statin therapy on CV outcomes

Support for Statin Therapy in FH

Impact of PCSK9 Inhibitors in FH

Pooled analysis of 2 trials randomizing 735 FH patients on maximally

tolerated statin therapy to alirocumab or placebo for 24 weeks

ODYSSEY FHI and FHII Trials

LDL-C

reductions

maintained

over 52 weeks

Alirocumab

75/150 mg Q2W

Placebo

Kastelein JJ, et al. Eur Heart J. 2015;36(43):2996-3003.

FH I FH II20

% C

ha

ng

e in

LD

L-C

Fro

m

Bas

eli

ne

to

We

ek

24

(S

E)

-60

-20

-70

-50

10

-40

0

-10

-30

-48.7-48.8

N = 166N = 322

2.8

9.1

N = 81N = 163

LS Mean Difference (SE) vs Placebo

43.4%

had dose

increase at

week 12

38.6%

had dose

increase at

week 12

-57.9% (2.7)

P < .0001

-51.4% (3.4)

P < .0001

Impact of PCSK9 Inhibitors in FH (Cont’d)

331 patients with heterozygous FH on stable statin therapy but with

inadequate LDL control randomized to evolocumab or placebo for 12 weeks

RUTHERFORD-2 Trial

*P < .001; SE, standard error.

Raal FJ, et al. Lancet. 2015;385(9965):331-340.

% L

DL

-C C

ha

ng

e ±

SE

Fro

m

Bas

eli

ne

to

We

ek

12

Evolocumab 140 mg Q2W

(N = 110)

Placebo Q2W

(N = 54)

Placebo QM

(N = 55)

-56

-61

6

-2

-60

-20

-70

-50

10

-40

0

-10

-30

-59%*-61%*

Evolocumab 420 mg QM

(N = 110)

Mean Percentage Reduction From Baseline in

LDL-C Level According to Mutation Status

Defesche JC, et al. J Clin Lipidol. 2017; Epub ahead of print.

Week 24

AACE and ACE LDL-C Targets in Diabetes

Risk Category Risk Factors* † LDL-C Goal

Low risk 0 risk factors <130 mg/dL

Moderate risk ≤2 risk factors and 10-year risk <10% <100 mg/dL

High risk≥2 risk factors and 10-year risk 10%-20%;

DM/CKD 3/4 with no other risk factors <100 mg/dL

Very high riskEstablished or recent hospitalization for ACS; ASCVD;

10-year risk >20%; DM/CKD 3/4 with ≥1 risk factor(s); HeFH <70 mg/dL

Extreme risk

Progressive ASCVD including UA in patients with LDL-C

<70 mg/dL; ASCVD in patients with DM, CKD 3/4, or HeFH;

premature ASCVD (<55 years male, <65 years female)

<55 mg/dL

AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology. *High LDL-C, polycystic ovary syndrome, cigarette smoking, HTN, low HDL-C (<40 mg/dL), family history of CAD, chronic

renal disease stage 3/4, evidence of coronary artery calcification, and age (men ≥45 years; women ≥55 years). Subtract 1

risk factor if the person has high HDL-C. † Framingham risk scoring is applied to determine 10-year risk.

Jellinger PS, et al. Endocr Pract. 2017;23(Suppl 2):1-87.

ACC Expert Consensus on Nonstatin Therapy for ASCVD

Optional nonstatin

medications to consider

Patient has ≥50% LDL-C reduction (may consider LDL-C <70 mg/dL or

non-HDL-C <100 mg/dL) on maximally tolerated statin therapy

Consider ezetimibe first

1 2

NO

Consider adding or replacing

with PCSK9 inhibitor second

Continue to monitor adherence

to medications and lifestyle, and

LDL-C response to therapy

NO

Patients with stable clinical ASCVD without

comorbidities on statin for secondary prevention



NO



1. Address statin adherence

2. Intensify lifestyle (may consider phytosterols)

3. Increase to high-intensity statin if not already taking

4. Evaluate for statin intolerance if unable to tolerate moderate-intensity

statin. Consider referral to lipid specialist if statin intolerant

5. Control other risk factors

CLINICIAN-PATIENT DISCUSSION FACTORS TO CONSIDER

1. Potential for additional ASCVD risk reduction from addition of

nonstatin therapy to lower LDL-C

2. Potential for AEs or drug-drug interactions from addition of

nonstatin therapy

3. Patient preferences

YES

YES

Decision for no

additional medication

YES

Continue to monitor adherence

to medications and lifestyle, and


Consider either ezetimibe or PCSK9 inhibitor as initial non-statin agent,

and addition of other agent second if needed

NO

Patients with stable clinical ASCVD with comorbidities

on statin for secondary prevention



NO





3. Increase to high-intensity statin if not already taking

4. Evaluate for statin intolerance if unable to tolerate moderate-intensity

statin.‡ Consider referral to lipid specialist if statin intolerant



1. Potential for additional ASCVD risk reduction from addition of

nonstatin therapy to lower LDL-C

2. Potential for AEs or drug-drug interactions from addition of

nonstatin therapy



non-HDL-C <100 mg/dL) on maximally tolerated statin therapyNO YES

Decision for no

additional medication

YES

YES

Optional nonstatin medications to consider

Consider either ezetimibe or PCSK9 inhibitor as

initial nonstatin agent,

and addition of other agent second if neededConsider ezetimibe first Consider adding or replacing

with PCSK9 inhibitor second


ACC Expert Consensus on Nonstatin Therapy for FH

Continue to monitor adherence to

medications and lifestyle, and LDL-C

response to therapy

NO

NO

Referral to lipid specialist recommended



Optional non-statin medications to consider

NO

NO

YES

YES

YES

YES

Decision for no additional

medication

Patients without clinical ASCVD and with baseline LDL-C ≥190 mg/dL not due to

secondary causes on statin for secondary prevention



1. Address statin adherence2. Intensify lifestyle (may consider phytosterols)3. Increase to high-intensity statin if not already taking

4. Evaluate for statin intolerance if unable to tolerate moderate-intensity statin Referral to lipid specialist recommended if statin intolerant

5. Control other risk factors6. Consider referral to lipid specialist and RDN for all patients




1. Potential for additional ASCVD risk reduction from addition of nonstatin therapy to lower LDL-C

2. Potential for AEs or drug-drug interactions from addition of nonstatin therapy3. Patient preferences

Consider either ezetimibe or PCSK9 inhibitor as initial non-statin agent,


1. Repeat clinician-patient discussion2. Add other nonstatin medication(s) above3. Consider referral to lipid specialist and Registered Dietitian Nutritionist



Consider either ezetimibe or PCSK9 inhibitor as initial nonstatin agent,



ACC Expert Consensus on Nonstatin Therapy for DM

Continue to monitor adherence to

medications and lifestyle, and


Consider either ezetimibe

NO

NO

Decision for no additional

medication

YES

Optional nonstatin

medications to consider

Patients aged 40-75 years without clinical ASCVD and with diabetes and baseline

LDL-C 70-189 mg/dL, on statin for primary prevention

Patient has ≥50% LDL-C reduction (may consider LDL-C <100 mg/dL or may consider

non-HDL-C <130 mg/dL in patients with diabetes) on maximally tolerated statin

Patient has ≥50% LDL-C reduction (may consider LDL-C <100 mg/dL or may consider

non-HDL-C <130 mg/dL) in patients with diabetes) on maximally tolerated statin



3. Evaluate for statin intolerance if unable to tolerate moderate-intensity statin†

Consider referral to lipid specialist if statin intolerant



1. Potential for additional ASCVD risk reduction from addition of nonstatin therapy to lower

LDL-C

2. Potential for AEs or drug-drug interactions from addition of nonstatin therapy


For the small proportion of patients in this group with 10-year ASCVD risk <7.5% and no other

high-risk features, starting with moderate-intensity statin to achieve 30%-49% LDL-C reduction

(may consider LDL-C <100 mg/dL or non-HDL-C <130 mg/dL) is acceptable. If this level of LDL-C

reduction is not achieved, consider increasing to high-intensity statin

YES

Consider ezetimibe


NLA Expert Panel PCSK9 Inhibitor Recommendations

DisorderLDL-C/Non-HDL-C

Threshold for Rx mg/dL

Strength of

Evidence

Quality of

Evidence

ASCVD + additional risk factors ≥70 / ≥100 A High

Progressive ASCVD ≥70 / ≥100 B Moderate

LDL-C ≥190, 40-79 years

No uncontrolled RF or key additional risk

markers

≥100 / ≥130 B Moderate

LDL-C ≥190, 40-79 years

Uncontrolled RF or key additional risk markers≥70 / ≥100 B Moderate

LDL-C ≥190, 18-39 years

Uncontrolled RF or key additional risk markers

or FH causing mutation

≥100 / ≥130 E Low

Homozygous FH phenotype ≥70 / ≥100 B Moderate

ASCVD + statin intolerance Clinical judgement C Low

NLF, National Lipid Association; RF, risk factors; Rx, prescription.

Orringer CE, et al. J Clin Lipidol. 2017;11(4):880-890.

Modelled Need for a PCSK9 Inhibitor in ASCVD

Simulation model based on 105,269 medical and pharmacy claims to

estimate the percentage of patients with ASCVD needing a PCSK9

inhibitor when oral LLT is intensified first

Cannon CP, et al. JAMA Cardiol. 2017;2:959-966.

Phase 2 double-blind study of 501 patients at high CV risk randomized to inclisiran,

a PCSK9 RNA synthesis inhibitor (at 6 different doses) vs placebo for 180 days

Inclisiran

Ray KK, et al. N Engl J Med. 2017;376(15):1430-1440.

Bempedoic Acid

ATP, adenosine triphosphate.

Ballantyne CM, et al. Am J Cardiol. 2016;117(12):1928-1933.

Phase 2b double-blind study of 134 hypercholesterolemic patients on stable

background statin therapy randomized to the ATP citrate lyase inhibitor,

bempedoic acid (120 mg or 180 mg daily) or placebo for 12 weeks

-30

-25

-20

-15

-10

-5

0

Background statin plusbempedoic acid (120mg), n = 41

Background statin plusbempedoic acid (180mg), n = 43

Background statin plusplacebo, n = 43

Me

an

LD

L-C

Re

du

cti

on

(%

)

2.5

An

nu

al

Co

st,

$ (

Bil

lio

ns)

0Start evolocumab

in all FOURIER-

eligible pts

0.5

2.0

Start evolocumab

in pts with LDL-C

≥70 mg/dL

$950 Million

$112 Million

$838 Million

$2.08 Billion

1.5

1.0

Titrate all pts on

moderate statin to high-

intensity statin, start

ezetimibe in all pts not

on ezetimibe

Titrate statin and

ezetimibe, start

evolocumab in pts with

LDL-C ≥70 mg/dL

• 631,855 patients with ASCVD, ~25%

eligible for FOURIER, with LDL-C ≥70

mg/dL

• Only 48% on high-intensity statin, 2.6%

on ezetimibe + statin

Modelled Costs With Different LDL-C Lowering Regimens

Estimated cost of different LDL-C lowering regimens for patients

with ASCVD within the Veterans Affairs System

Pts, patients.

Virani SS, et al. Circulation. 2017;135(25):2572-2574.

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