Subodh K. Agrawal, MD

Interventional Cardiologist at Athens Heart Center, P. C.Fellow of American College of Cardiology

Board Certified in•Internal Medicine,•Cardiovascular Diseases•Interventional Cardiology•Sleep Medicine

Special interests:•Coronary Artery Disease•Sleep Disorders•Healthcare Education•Improving Quality of US Healthcare System

Medical School:Sawai Man Singh Medical School

Residency:Emory University Hospital

Fellowship:Emory University Hospital

Cholesterol countdoun.com Survey

Support for LDL Causality in ASCVD

Observational data

Interventional data

Genetic studies

Experimental data

.

Lipids Remain a Key Modifiable Risk Factor

Lipids Remain a Key Modifiable Risk Factor

6

NCDR, National Cardiovascular Data Registry; PINNACLE, Practice Innovation and Clinical Excellence registry. Maddox TM, et al. JACC. 2014;64:2183-2192.

19.5

20

16.1

20.5

18.2

14.4

48.7

49.9 43.

5

45.1 41.

5 34.2

3.1

2.9 4.

7

6.2 5.

24.3

29.3

27.9 35.

9

29.3 35.

5 47.5

0%

20%

40%

60%

100%

80%

Analysis of 1,174,545 patients from the NCDRPINNACLE registry evaluating use of statin

therapy between 2008-2012

Patients currently not on statin therapy

No lipid-lowering therapy

Nonstatin lipid-lowering therapies only

Patients on statintherapy

Statins as solelipid-loweringtherapy

Both statin and nonstatintherapies

Allgroups: Overall trend

1,164,497patients total

Group 3:LDL-C levels≥190 mg/dL

3124patients

Group 1: Confirmed ASCVD1,020,896patients

Group2:Diabetes74,686

patients

Group 5:No risk44,710

patients

Group 4:10-year ASCVD

≥7.5%21,081

patients

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 Rates50

0

Even

t Rat

e(%

)

10 4.4

30

40

20

10.9

16.0 16.7 18.2

25.2

34.4

<50 50-70 70-100100-130130-160160-190 >190

LDL-C (mg/dL)

vs Various LDL-C LevelsMajor Coronary EventsMajor CV Events

<50

LDL-

C(m

g/dL

)

LDL-C Levelsand Risk of CV Events

≥175

150-<175

125-<150

100-<125

75-<100

50-<75

0.25 0.50 0.75 1.0Adjusted Hazard Ratio 95% CI

20

Guidance on Use of Nonstatin Therapy

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

All patients with ASCVD on statin

Primary:>50% reduction in LDL-C

Secondary (may consider):

LDL-C <70 mg/dLNon-HDL-C <100 mg/dL

Ezetimibe or a PCSK9 inhibitor are the onlynon-statinsrecommended

24

Fourier Trial: PrimaryOutcome

10

0 6 12 18 24 30 36

Placebo Evolocumab

15% RRR

NNT = 67

12%

10%

8%

6%

4%

2%

0%

Sabatine MS et al. N Engl J Med 2017; 376:1713-1722 Months

14%

16%

Odyssey Trial – PrimaryOutcome

11

RRR = 15%

NNT = 63

ACC Scientific Sessions 2018

Odyssey: All Cause Mortality

12

RRR = 15%

NNT = 166

ACC Scientific Sessions 2018

Alirocumab Evolocumab

Indication

• Adjunct to diet and maximum- tolerated statin for adults with HeFH or clinical ASCVD who require additional loweringof LDL-C

• To reduce risk of CVE in adults with established CVD

• Adjunct to diet, alone or in combination with other LLT, for adults with primary hyperlipidemia (including HeFH) to reduce LDL-C

• Adjunct to diet and other LDL-lowering therapies in patients with HoFH who require additional lowering of LDL-C

Dosing • 75-150 mg SQ Q2W• 300 mg SQ monthly

• 140 mg SC Q2W• 420 mg SC monthly

How supplied

• Single-dose prefilled pens or syringes

• 75-mg/mL or 150-mg/mL

• Single-use prefilled syringe or autoinjector

• 1 mL of 140-mg/mL or 420 mg/3.5 mL

Side effects• Nasopharyngitis• Injection-site reactions• Hypersensitivity reactions

• Nasopharyngitis• Injection-site reactions• Hypersensitivity reactions

Approved PCSK9 Inhibitors

http://www.pdr.net/drug-summary/Praluent-alirocumab-3765. Accessed May 8, 2018. http://www.pdr.net/drug-summary/Repatha-evolocumab-3781. Accessed May 2018.

11.9

7.87.3

4.4

0

5

10

15

CVD, MI, Stroke, UA, Cor Revasc

CVD, MI, Stroke

Cardiovascular Efficacy

23.3

3.4

22.8

3.4

0

5

10

15

20

25

30

Serious AE

Safety

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

FOURIER Trial—Efficacy and Safety in Patients With LDL-C <10 mg/dL

Perc

ent(

%)

Perc

ent(

%)

LDL > 100 LDL < 10 LDL > 100 LDL < 10

AE (Drug Discontinued)

When to Consider a PCSK9 Inhibitor

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

Patient Type

ASCVD without comorbidities

LDL-C Reduction on Maximally Tolerated Statin

<50% LDL-C reduction or LDL-C>70 mg/dL

Therapy Recommendation

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 baselineLDL-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

<50% LDL-C reduction or LDL-C>100 mg/dL

Ezetimibe* or PCSK9 inhibitor†

40-75 years without ASCVD andwith DM and baseline LDL-C 70-189 mg/dL

<50% LDL-C reduction or LDL-C>100 mg/dL

Ezetimibe or bile acid sequestrant‡

40-75 years without ASCVD or DMand baseline LDL-C 70-189 mg/dL

<50% LDL-C reduction or LDL-C>100 mg/dL

Ezetimibe or bile acid sequestrant‡

Common Reasons for PCSK9 Denial: A Veritable Laundry List

16Kaufman TM, Duell PB, et al. Circ Res. 2017;121(5):499-501.

Patient has not tried ezetimibe Re-challenge with statin not documented in

statin-intolerant patient Patient has not tried a bile acid sequestrant LDL <100 mg/dL with ASCVD or <130mg/dL

without ASCVD Requires 80% compliance in fill history from

pharmacy over 12-month period Nutrition intervention not documented Triglycerides >400 mg/dL

Most recent lab results (≤ 30 days) including lipid paneland lipoprotein (a)

Highest documented LDL-C concentration (ideally off treatment)

Evidence of subclinical atherosclerosis (coronary artery calcium, CIMT, ankle brachial index) or clinical ASCVD(MI, stroke, angina, angiographic evidence, ischemia testing, arterial revascularization)

Clear specification of diagnosis for which PCSK9 inhibitor therapy is being prescribed

Kaufman TM, Duell PB, et al. Circ Res. 2017;121(5):499-501

Required Documentation for PCSK9 Prior Authorization (PA)

Strategies to Improve PCSK9 Inhibitor Access: A Team-Based

Approach Have a dedicated team to deal with prior authorizations,

appeals, re-appeals, and peer-to-peer reviews

Multidisciplinary team of physicians, a nurse, a medical assistant, a clinical pharmacist, and a physician assistant (the “PCSK9 inhibitor Clinic”)- Coordinator oversees the approval process, provides

injection training, and arranges longitudinal management and surveillance

- 92% success rate (n=142/153)

Key to successful PCSK9 inhibitor PAapproval Meticulous documentation of all data required for PA

Kaufman TM, Duell PB, et al. Circ Res. 2017;121(5):499-501. .57

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

ScreenedN=19,212

RandomizedN=8179

(43% of screened)

Icosapent EthylN=4089 (100%)

PlaceboN=4090 (100%)

N=3684Completed Study(90.1%)

N=3630

Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-It)

23

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

Completed Study(88.8%)

Countries 11Sites 473

Actual vs. potential total follow-up time (%) 93.6% Known vital status 4083(99.9%)

Actual vs. potential total follow-up time (%) 92.9% Known vital status 4077(99.7%)

1. Age ≥45 years with established CVD (Secondary Prevention Cohort) or≥50 years with diabetes with ≥1 additional risk factor for CVD (Primary Prevention Cohort)

2. Fasting TG levels ≥150 mg/dL and <500 mg/dL*

3. LDL-C >40 mg/dL and ≤100 mg/dL and on stable statin therapy (± ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization

*Due to the variability of triglycerides, a 10% allowance existing in the initial protocol, which permitted patients to be enrolled with qualifying triglycerides ≥135 mg/dL. protocol amendment 1 (May 2013) changed the lower limit of

acceptable triglycerides from 150 mg/dL to 200 mg/dL, with no variability allowance.

24

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

One or more of the following:1. Documented coronary artery disease2. Documented cerebrovascular or carotid disease3. Documented peripheral artery disease

Inclusion Criteria: Secondary PreventionCohort

25

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

1.Diabetes mellitus requiring medication AND

2.≥50 years of age AND

3.≥1 additional risk factor for CVD

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

Inclusion Criteria: Primary Prevention Cohort

1. Severe (NYHA class IV) heart failure

2. Severe liver disease

3. History of pancreatitis

4. Hypersensitivity to fish and/or shellfish

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

Key Exclusion Criteria

Primary End Point: CV Death, MI, Stroke,Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%Placebo

28.3%

Patie

nts w

ith a

n Ev

ent(

%)

0 1 20

10

20

30 Hazard Ratio, 0.75(95% CI, 0.68–0.83)

P=0.00000001

5.3% ARR24.8%RRR

NNT = 21

Years since Randomization

3 4 5

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

Key Secondary End Point: CV Death, MI, Stroke

Hazard Ratio, 0.74(95% CI, 0.65–0.83)P=0.0000006

20.0%

16.2%

Icosapent Ethyl

Placebo

Patie

nts w

ith a

n Ev

ent(

%)

0 1 2 3 4Years since Randomization

50

10

20

30

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

3.6% ARR26.5% RRRNNT = 28

Most Frequent Adverse Events

Preferred TermIcosapent Ethyl

(N=4089)Placebo

(N=4090) P-valueDiarrhea 367 (9.0%) 453 (11.1%) 0.002

Peripheral edema 267 (6.5%) 203 (5.0%) 0.002

Constipation 221 (5.4%) 149 (3.6%) <0.001

Atrial fibrillation 215 (5.3%) 159 (3.9%) 0.003

Anemia 191 (4.7%) 236 (5.8%)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

0.03

REDUCE-It Conclusions

32

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med 2019; 380:11-22

Compared with placebo, icosapent ethyl 4g/day significantly reduced important CV events by 25%, including: 20% reduction in death due to cardiovascular causes 31% reduction in heart attack 28% reduction in stroke

Low rate of adverse effects, including: Small but significant increase in atrial fibrillation/flutter Non-statistically significant increase in serious bleeding

Consistent efficacy across multiple subgroups Including baseline triglycerides from 135-500 mg/dL Including secondary and primary prevention cohorts

There are 3 Different Omega-3 fatty acids

33

Alpha-linoleic acid (ALA)Plant sourceC-18

Eicosapentaenoic acid (EPA)Marine sourceC-20

Docosahexaenoic Acid(DHA)Marine sourceC-22

ALA EPA

DHA

Alpha-linolenic Acid: Sources

34

Food Serving Alpha-linolenic acid (g)

Walnuts, English 1 ounce 2.6

Flaxseeds 1 tablespoon 2.2

Walnut Oil 1 tablespoon 1.4

Canola Oil 1 tablespoon 1.2

Soybean Oil 1 tablespoon 0.9

Walnuts, Black 1 ounce 0.6

Olive Oil 1 tablespoon 0.1

Broccoli, raw 1 cup, chopped 0.1

Food Serving EPA (g) DHA (g)

Herring, Pacific, cooked 3 ounces 1.06 .75

Salmon, Atlantic, cooked 3 ounces .28 .95

Oysters, Pacific, cooked 3 ounces .75 .43

Salmon, sockeye, cooked 3 ounces .45 .60

Tuna, white, packed in water 3 ounces .20 .54

Crab, dungeness, cooked 3 ounces .24 .10

Shrimp, cooked 3 ounces .15 .12

Cod, Pacific, cooked 3 ounces .09 .15

EPA and DHA: Sources

35

Reducing Lifetime Exposure to High LDL Levels Will Reduce Atherosclerosis and its Complications