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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