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©2014 MFMER | slide-1
Landmark Lipid Trials and Current Lipid Treatment Guidelines
Francisco Lopez-Jimenez, MD, MScProfessor of Medicine
Chair, Division of Preventive CardiologyCo-Director, Artificial Intelligence in Cardiology
Director of Research, Dan Abraham Healthy Living CenterMayo Clinic, Rochester
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DisclosureRelevant Financial Relationship(s)• None
Off Label Usage• None
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Statins: What is the evidence?
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HOPE-3
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12,705 patients >55 yr (men) or >65 yr(women) with no ASCVD, at least one major CV risk factor. No lipid criteria
P
Rosuvastatin 10 mg/dayI
PlaceboC
CV death, MI, stroke (PCI, CABG, heart failure or h/o cardiac arrestO
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FU: 5.6 years
Event rates: 3.7% (Rosuv) vs 4.8%
(placebo)
Hazard ratio, 0.75; 95% CI 0.64 to 0.91
P ष़ ज़खज़ज़1
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IMPROVE-IT
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18,144 patients with ASCVD, post acute coronary syndrome, LDL 50-100 on RxP
Simvastatin 40 mg + ezetimibe 10 mgI
Simvastatin 40 mg + placeboC
CV death, MI, stroke, hospitalization for UA, PCI or CABGO
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32.7%34.7%
Median time weighted LDL average at FU:69.5 mg/dl vs 53.7 mg/dl (0.4 mmol/l diff)
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FOURIER Trial
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Patients with ASCVD, LDL>70 on statin rxP
Evolocumab 140 mg/Q2W or 240 mg/monthI
PlaceboC
CV death, MI, stroke, hospitalization for UA, PCI or CABGO
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Sabatine et al: N Engl J Med 376:1713, 2017
Main Results
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96108120132144156168Weeks
LDL
chol
este
rol (
mg/
dL) Placebo
Evolocumab
4
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Primary Efficacy End Point
0
20
40
60
80
100
0 6 12 18 24 30 36Months
Cum
ulat
ive
Inci
denc
e (%
)
02468
10121416
0 6 12 18 24 30 36
Hazard ratio, 0.85 (95% CI, 0.79-0.92)P
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HPS3/TIMI55-REVEAL
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30,449 patients with ASCVD, high intensity statin Rx, total cholesterol
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N Engl J Med 377:1217, 2017
First Major Coronary Event
0
20
40
60
80
100
0 1 2 3 4Years of follow-up
Patie
nts
with
eve
nt (%
)
0
5
10
15
0 1 2 3 4
Rate ratio, 0.91 (95% CI, 0.85-0.97)P=0.004
AnacetrapibPlacebo
11.8%
10.8%
ARR=1%NNT=100
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Lipid Guidelines
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Clinical ASCVD, no HF, no CRI on HDAge < 75: High intensity statin Age ≥75: Moderate intensity statin
LDL-C ≥190High intensity statin
Diabetes Mellitus• 10 yr risk ≥7.5%: Moderate to high
intensity statin• Others: Moderate intensity statin
ASCVD Risk ≥7.5%Moderate or high intensity statin + TLC
Use ezetimibe and/or PCSK-9 inhibitors if there is residual
risk, when LDL is above threshold (a.k.a “above goal”)
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Clinical ASCVD
2) High-Risk Conditions: >65 yo, heterozygous FH, hx of HF, prior CABG or PCI, DM, HTN, CKD, current smoking, persistently elevated LDL-C>100 mg/dL.
Secondary Prevention (>18-75y)
H/O >1 ASCVD Events OR 1 Major ASCVD Event &>1 High Risk Conditions2
Y NVery High Risk Stable ASCVD
Max Tolerated
Statin
High-ModIntensity
Statin
LDL Goal 75y Mod-Hi Statin
2018 ACC/AHA Cholesterol Guidelines
+ means ‘is reasonable’ or ‘may be considered’
1) Major ASCVD Events: Recent ACS (
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Primary Prevention (40-75y)
LDL >190(4.9)
Max Tolerated
Statin
If LDL < 50% Reduction+Ezetimibe
If 30-75y w/ HeFH :LDL>100(2.6)+PCSK9 Inh
(20-75y)
Fast TG 220 (≥5.7) but LDL>130(3.4) +PCSK9 Inh
+ means ‘is reasonable’ or ‘may be considered’
No Risk Assessment
BAS= Bile Acid Sequestrant
2018 ACC/AHA Cholesterol Guidelines
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Primary Prevention (40-75y)
LDL-C 70(1.8)-189(4.9)
Mod Intensity Statin DMY
DM & 40-75y Risk Assessment to consider High
Intensity Statin if High Risk >20%
DM-Specific Risk Enhancers that are Independent of Other Risk Factors in DM
• Long duration (DM2-10 yrs /DM1-20 yrs) • Albuminuria >30 mcg albumin/mg creatinine • eGFR
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Age 0-19yLifestyle
If HeFH Statin
Age 20-39yEstimate Lifetime or 30-
yr RiskLifestyle
If Fam Hx Early ASCVD + LDL>160(4.1) Consider statin
Age 40-75y & LDL>70(1.8)
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Primary Prevention (40-75y)
LDL-C 70(1.8)-189(4.9)
DMN
10 Yr ASCVD Risk
>20%High
>7.5-2.0• ABI50 mg/dL or 125 nmo• ApoB>130 mg/dL
Risk Enhancers
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Primary Prevention (No ASCVD1) 40-75y: Role of CT CAC*
LDL-C 70(1.8)-189(4.9) , No DM
Evaluate Risk Enhancers & Cor Cal CT if uncertain
Moderate Intensity Statin
CAC = 0 (consider no statin, unless DM, FHx early CHD, smoking; ? HeFH) CAC = 1-99 favors statin (esp age> 55) CAC = 100+ and/or 75th percentile, initiate statin therapy
10 Yr ASCVD Risk : Risk >7.5 but
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Quintile 5 Healthiest : Mediterranean Style DietQuintile 1 Unhealthiest : Processed, sodium
ONTARGET & TRANSCEND Trials Circ 2012;126:2705-2712
Primary outcome = CV Death, MI, Stroke, or CHF
What was left out ? The importance of Diet
*Modified Alternative Healthy Eating Index
If you’re not eating healthy, the benefits of a statin are significantly lessened
HR(95%CI)
n=19,055p
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New Cholesterol Guidelines : Helpful Changes 1 LDL-C Goal : Added numbers back in w/ goal 1 favors statin Rx)
5 Ancillary testing : Formal recommendation to check Lp (a) for Fam Hx of premature ASCVD; Check APO B if TG’s > 200
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MACE stratified by statin treatment and coronary artery calcium severity
Mitchell et al JACC 2018 ; 72 (25) 3233-42
CAC 0 CAC 1-100
CAC 101-400 CAC 401+
No StatinStatin
MACE : AMI, CVA, CV Death
Statin : If +CAC, reduced MACE aSHR: 0.76 (95% CI: 0.60-0.95;p = 0.015) If – CAC, No Change aSHR: 1.00 (95% CI: 0.79-1.27; p = 0.99)
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??
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Cons
• Good balance between simple and complete• Considers chronic kidney disease• Evidence-based recommendations for
subsets of patients• Less rigid than AHA
Pros ESC Guidelines
• Uses SCORE for risk assessment• Not aggressive enough for middle-age
patients with several risk factors
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Major Atherosclerotic Cardiovascular Disease Risk Factors
Major risk factors Additional risk factors Nontraditional risk factors Advancing age ⇧ Total serum cholesterol level⇧ Non–HDL-C⇧ LDL-CLow HDL-CDiabetes mellitusHypertensionStage 3 or 4 chronic kidney
diseaseCigarette smokingFamily history of ASCVD
Obesity, abdominal obesityFamily history of hyperlipidemia⇧ Small, dense LDL-C⇧Apo B⇧ LDL particle concentrationFasting/postprandial
hypertriglyceridemiaPCOSDyslipidemic triad
⇧ Lipoprotein (a)⇧ Clotting factors⇧ Inflammation markers
(hsCRP; Lp-PLA2)⇧ Homocysteine levelsApo E4 isoform⇧ Uric acid⇧ TG-rich remnants
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Question: How is risk assessed?The 10-year risk of a coronary event (high, intermediate, or low) should be determined by detailed assessment using one or more of the following tools (Grade C; BEL 4, upgraded due to cost-effectiveness):
• Framingham Risk Assessment Tool• MESA 10-year ASCVD Risk with Coronary Artery Calcification Calculator• Reynolds Risk Score, which includes hsCRP and family history of premature ASCVD• UKPDS risk engine to calculate ASCVD risk in individuals with T2DM
When the HDL-C concentration is greater than 60 mg/dL, one risk factor should be subtracted from an individual’s overall risk profile (Grade B; BEL 2).
A classification of elevated TG should be incorporated into risk assessments to aid in treatment decisions (Grade B; BEL 2).
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ASCVD Risk Categories and LDL-C Treatment GoalsRisk
category Risk factors/10-year risk
Treatment goalsLDL-C (mg/dL)
Non-HDL-C (mg/dL)
Apo B (mg/dL)
Extreme risk
– Progressive ASCVD including ACS after achieving an LDL-C
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Cons
• Very comprehensive• Value risk factors beyond “mayor ones”• 5 levels of risk• More information on non-statin options
Pros AACE Guidelines
• Too complex, not simplified. No algorithm • Troublesome handling of risk assessment• Many recommendations not evidence-based
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Only ACC/AHA had no financial conflict of interest
All guidelines link intensity of treatment to level of CVD risk
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Case #1Asymptomatic 61-year-old man with history of NSTMI 2 years ago, treated HTN, no DM; past smoking. ABI 0.70.On atorvastatin 80 mg/day. Good tolerance
LDL 79 (was 120 before the MI), HDL 55, trig 101
What would you recommend to this patient?A. Continue atorvastatin, same doseB. Add ezetimibe 10 mg/dayC. Add PCSK9-iD. Something else
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Case #2Asymptomatic 53-year-old woman, seen for 4th timeSmoked 2 ppd/25 years. Central obesity. Treated HTN, BP 138/89. Mild RA.BMI 31. FBG 115 mg/dLTC 220 LDL 172, HDL 41, trig 101 10-year ASCVD risk 3.9%
What would you recommend to this patient?A. Exercise 150 min/week, lose weight or don’t
come backB. Start atorvastatin 10 mg/dayC. Start atorvastatin 80 mg/dayD. Bariatric surgeryE. Nothing else. She is low risk
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Ezetimibe10 mgPCSK9
Cholesterol Rx
ASCVDYes No
>75 yrs ≤75 yrsMIST
HIST
LDL ≥190DM
ASCVD risk
Mod-High (≥5%) Low (
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Thank You
[email protected]@HeartDrLopez
mailto:[email protected]:[email protected]
Landmark Lipid Trials and Current Lipid Treatment GuidelinesDisclosureSlide Number 3Statins: What is the evidence?Slide Number 5HOPE-3Slide Number 7Slide Number 8IMPROVE-ITSlide Number 10Slide Number 11FOURIER TrialSlide Number 13Main ResultsPrimary Efficacy End PointHPS3/TIMI55-REVEALSlide Number 17First Major Coronary EventLipid GuidelinesSlide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37ConsSlide Number 39�Major Atherosclerotic Cardiovascular Disease Risk FactorsQuestion: How is risk assessed?ASCVD Risk Categories and LDL-C Treatment GoalsConsOnly ACC/AHA had no financial conflict of interestCase #1Case #2Slide Number 47Thank You