landmark lipid trials and current lipid treatment guidelines · 5 ancillary testing : formal...

©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


DisclosureRelevant Financial Relationship(s)• None

Off Label Usage• None


Statins: What is the evidence?


HOPE-3


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


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


IMPROVE-IT


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


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)


FOURIER Trial


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


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


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


HPS3/TIMI55-REVEAL


30,449 patients with ASCVD, high intensity statin Rx, total cholesterol


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


Lipid Guidelines


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”)


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 (


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



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


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)



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


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


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


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


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)


??


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


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


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).


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


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


Only ACC/AHA had no financial conflict of interest

All guidelines link intensity of treatment to level of CVD risk


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


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


Ezetimibe10 mgPCSK9

Cholesterol Rx

ASCVDYes No

>75 yrs ≤75 yrsMIST

HIST

LDL ≥190DM

ASCVD risk

Mod-High (≥5%) Low (


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

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