el CIC WHF Cholesterol Roadmap, México ... - Academia El CIC 19 WHF CH… · Lp(a) ≥50 mg/dL. CRP ≥2 mg/L. CCI ≥300 UA. RA, SLE, etc. HIV Without Extra-Risk ASCVD Risk -PCE-≥7.5%

WHF Cholesterol Roadmap, México, September 19th 2018el CICPara Vivir Más y Mejor

Enrique Morales MDWHF/SMC México Ambassador

Mexico City, September 19th 2018

WHF Cholesterol Roadmap


Global Real World EvidenceCholesterol and ASCVD


WHF Cholesterol Roadmap, México, September 19th 2018

ASCVD: Atherosclerotic Cardiovascular Disease

el CICPara Vivir Más y Mejor


Murphy A et al. Global Heart 2017el CICPara Vivir Más y Mejor

Objective 1:

. Analyse the strong evidence that support

the relationship between LDL-cholesterol

-LDL-C- and Atherosclerotic Cardiovascular Disease -ASCVD-.



Objective 2:

. Analyse the strong evidence that support

the relationship between LDL-C reduction and ASCVD prevention.



Objective 3:

. Stablish the rational and key steps

for the World Heart Federation Cholesterol Roadmap implementation in México.



Agenda:

1. What is cholesterol

2. What is the relationship LDL-C/ASCVD

3. What is the benefit of LDL-C reduction

4. What the US/EU Guidelines tell us5. What the WHF Cholesterol Roadmap tell us




Goldstein JL and Brown MS. Cell. 2015; 161:161-172el CICPara Vivir Más y Mejor

1. What is Cholesterol…



What is cholesterol 1/3


Cholesterol is a lipid essential for cell

integrity as steroid and bile acids

production. This lipid is synthetized for the

cells or acquired from lipoproteins though specific receptors vg., LDL and LDL-R.

Brown MS and Goldstein JL. Nobel Lecture 1985

Goldstein JL and Brown MS. Cell. 2015; 161:161-172el CIC

Para Vivir Más y Mejor

Cell

AcetylCoA

HMGCoA

Mevalonate Cholesterol

HMGCoARNucleous

SREBP2Chromosome 5

Cellular cholesterol synthesis

Membranes

ER-Golghi

What is Cholesterol




What is Cholesterol

Hepatocyte

Nucleous

SREBP2Chromosome 19

ACAT2

LDL-C delivering and elimination

Membranes

ER-Golghi






Since the 70 s it is known that the LDL plasma

level required for delivering cholesterol to

cells is 25 mg/dl equivalent to 2.5mg/dl in the

interstitial space; the excess of LDL is accumulated in the subendothelial space.

D Reichl, N Myant, MS Brown and JL Goldstein

The Journal f Clinical Investigation. 1978;61:64-71



50%

100%

150%

200%

00%

HM

GC

oA

Re

du

cta

se

Ac

tiv

ity

pm

ol/

min

/mg

D Reichl, N Myant, MS Brown and JL Goldstein

The Journal f Clinical Investigation. 1978;61:64-71

LDL concentración mg/dL

5 10 15 20 25

Physiologic and Pathologic LDL level

What is Cholesterol

50

100

150

200

00

LD

L-C

le

ve

lin

mg

/dL

an

d A

SC

VD


Response to LDL-Retention Model

What is Cholesterol


Tabas I et al. Circulation. 2007; 116:1832-1844

Goldstein JL and Brown MS. Cell. 2015; 161:161-172

Subendothelial infiltration and retention by matrix proteoglicans

LDL lipid oxidation an apo-B100 lysine modification

Modified LDL is

recognized as DAMP

and endocyted by

macrophages

scavenger receptors




The main mechanism to explain the LDL-C

increase is a quantitative and/or qualitative

defect in the hepatic LDL receptors. In the

current western society the “normal” LDL plasma level is in average 125-150 mg/dl.




Billheimer DW, Stone NJ, Grundy SM

J Clin Invest. 1979;64:524-533

Kovanen PT, Billheimer DW, Goldstein JL et al

Proc Natl Acad Sci USA. 1981;78:1194-1198

LDL production per day in mg/kg -VLDL-IDL-LDL-

15 15 15

LDL-C elimination FCR

1.6 0.8 0.4

LDL plasma

mg/dLLDL plasma

mg/dL

LDL plasma

mg/dL

Dog Chimpance Human

25 50 100

What is Cholesterol


43.6

Total-C

LDL-C

NoHDL-C

41.4

10%

50%

20%

30%

39.1

≥200 mg/dL

≥130 mg/dL

≥160 mg/dL

Carlos Aguilar-Salinas y cols. ENSANUT 2006

00%

40%

Hypercholesterolemia Prevalence in México

What is Cholesterol


2. What is the relationshipLDL-C/ASCVD…



What is the relationship LDL-C/ASCVD


There is an amazing basic, epidemiologic,

clinical and therapeutic evidence that

confirms the direct relation between the

cumulative LDL-C exposure and the burden of atherosclerotic plaque and ASCVD.

Anitshkow N and Chalatow S. Allg. Pathol. Anat. 1913; 24:1-9


Ference B et al. Eur Heart J. 2017; 38:2459-2472


What is the relationship LDL-C-ASCVD


Ference B et al. J Am Coll Cardiol. 2018; 70:1141-1157

1,250

10,000

2,500

3,500

8,750

6,250

7,500

2%

4%

Age

20 y 40 y 60 y 80 y

Cu

mu

lati

ve

LD

L-C

Ex

po

su

re

mg

/ye

ar

Cu

mu

lativ

e R

isk

of A

MI

log

sc

ale

Su

bc

lin

ica

l

Ph

as

e

Cli

nic

al

Ph

as

e

LDL-C 125mg16%

8%

Impact of LDL-C on ASCVD

5,000 1%Cumulative LDL-C Exposure ThresholdT

ota

l Pla

qu

e B

urd

en


What is the relationship LDL-C-ASCVD



1,250

10,000

2,500

3,500

8,750

6,250

7,500

2%

4%

Age

20 y 40 y 60 y 80 y

Cu

mu

lati

ve

LD

L-C

Ex

po

su

re

mg

/ye

ar

Cu

mu

lativ

e R

isk

of A

MI

log

sc

ale

Su

bc

lin

ica

l

ph

as

e

Cli

nic

al

Ph

as

e

16%

8%

Impact of LDL-C on ASCVD

5,000 1%Cumulative LDL-C Exposure Threshold

100 y

To

tal P

laq

ue

Bu

rde

n

LDL-C 200 vs 125 vs 80 mg/dL


3. What is the benefit of LDL-C reduction…



What is the benefit of LDL-C reduction


In the same way there is an amazing basic,

epidemiologic, genetic, clinical and

therapeutic evidence that confirms the

direct relation between LDL-C reduction and

burden of atherosclerotic plaque and ASCVD reduction.

Endo A et al. FEBS Lett. 1976; 72:323-326




What is benefit of LDL-C reduction

Moments for Cardiovascular Prevention

Ge

ne

tic

Pre

dis

po

sit

ion

Enrique Morales-Villegas. Cardio Prevención Primaria

1ª Edición 2015. Editorial Atheros-CIC

Un

he

alt

hy

En

vir

om

en

t

Ov

erw

eig

ht

an

d O

be

sit

y

Me

tafl

am

ati

on

Ins

uli

n R

es

ista

nc

e

Me

tab

oli

c S

yn

dro

me

Hy

pe

rch

ole

ste

role

mia

Hy

pe

rte

ns

ion

Dia

be

tes

Me

llit

us

Ca

rdio

mio

pa

thy

Pe

rma

ne

nt

Dis

ab

ilit

y

Pre

ma

ture

De

ath

Primordial Primary Secondary and Terciary

Mic

rov

as

cu

lar

Dis

ea

se

Ma

cro

va

sc

ula

r D

ise

as

e


25mg

50mg

75mg

100mg

125mg

150mg

00mg

Hu

ma

n n

ew

bo

rn

Ch

ild

ho

od

Ad

ult

Pla

sm

a L

DL

-C in

mg

/dL

175mg

Kwiterovich PO et al. Lancet. 1973;i:118-122

Descamps OS et al. Atherosclerosis. 2004; 172:287-298

O Keefe JH Jr et al. J Am Coll Cardiol. 2004; 43:2142-2146

What is benefit of LDL-C reduction

Level of LDL-C in Humans

Ad

ole

sc

en

t

Physiologic level

Optimal level

“Normal” level

Vu

lne

rab

ilit

yto

Ath

ero

sc

lero

sis

Genetic

Epigenetic

Ambiental

Others




1,250

10,000

2,500

3,500

8,750

6,250

7,500

2%

4%

Age

20 y 40 y 60 y 80 y

Cu

mu

lati

ve

LD

L-C

Ex

po

su

re

mg

/ye

ar

Cu

mu

lativ

e R

isk

of A

MI

log

sc

ale

Su

bc

lin

ica

l

ph

as

e

Cli

nic

al

Ph

as

e

16%

8%

Timing for LDL-C reduction in Humans

5,000 1%Cumulative LDL-C Exposure Threshold

100 y

To

tal P

laq

ue

Bu

rde

n

LDL-C 125 mg/dL




For life vs for risk LDL-C reduction in Humans

1.00.90.80.70.60.50.4

0.78 -0.76 to 0.80-

RRR: 22% -20 to 24-

0.46 -0.41 to 0.52-

RRR: 54% -48 to 56-Genetic LDL-C Score

46 SNP, N = 376,443

Meta-Analysis of Statin RCTs

27 RCTs, N = 169,138


Ference BA , Majeed F, Panumetcha R et al.

J Am Coll Cardiol. 2015; 65:1552-1561

- 40mg

- 55% risk

- 40mg

- 20% risk


Timing for LDL-C reduction in Humans


4. What the

American/European Guidelines tell us…



1. Framingham 1998, 2001 and 20082. PROCAM 20023. Euro-SCORE 2003 4. QRISK 2007-20145. Reynolds women/men 2007/20086. WHO-ISH Charts 20077. INTERHEART 20118. ACC-AHA Pooled Cohort Equation 20139. Globorisk 2015

Morales-Villegas E.

In Preventive Cardiology. 1st Edition. Ruiz-Mori E Editor

What the Guidelines tell us

ASCVD Risk Estimation Algorithms


What American Guideline tell us


In primary prevention, up to now, ACC/AHA

Guideline recommends to reduce LDL-C

according with the estimated ASCVD risk*.

Healthy lifestyle and statins are the cornerstone to accomplish that goal.

Lloyd Jones DM et al. Lipid Pathway 2017. J Am Coll Cardiol.

* Pooled Cohort Equation AHA/ACC 2013


With Extra-Risk:. ASCVD risk ≥20%

. LDL-C ≥160 mg/dL

. ASCVD RF uncontrolled

. Familial history of ASCVD

. CKD with GFR <60 ml/min/1.73m2

. Lp(a) ≥50 mg/dL

. CRP ≥2 mg/L

. CCI ≥300 UA

. RA, SLE, etc

. HIV

Without Extra-Risk

ASCVD Risk -PCE- ≥7.5%40 to 75 years

70 to 189 mg/dl LDL-C level

Moderate Intensity Statin for:

. LDL-C lowering ≥30% or

. LDL-C level <100 mg/dl

Ezetimibe/Resins

High Intensity Statin for:



Ezetimibe/Resins

What the American Guideline tell us

Lipid Pathway 2017

for Primary

Prevention in non

Diabetic Population

Lloyd Jones DM et al. Lipid Pathway 2017. J Am Coll Cardiol.el CICPara Vivir Más y Mejor

ASCVD Risk

≥7.5%

ASCVD Risk

<7.5%

Diabetes Mellitus40 to 75 years

70 to 189 mg/dl LDL-C level

Moderate Intensity Statin for:

. LDL-C level <100 mg/dl or

. Non-HDL-C <130 mg/dl

Ezetimibe/Resins




. Non-HDL-C <130 mg/dl

Ezetimibe/Resins


Lipid Pathway 2017

for Primary

Prevention in

Diabetic Population




In FH and in secondary ASCVD prevention,

AHA/ACC Guideline recommends to reduce

LDL-C without risk estimation.

Healthy lifestyle, statins and new non-statins

drugs -ezetimibe and Mabs-PCSK9-are the cornerstone to accomplish that goal.


With

ASCVD

Without

ASCVD

Severe Hypercholesterolemia

LDL-C >190 mg/dL20 to 75 years




Ezetimibe/Resins

Evolocumab/Alirocumab

Lomitapide/Mipomersen




Ezetimibe/Resins

Evolocumab/Alirocumab

Lomitapide/Mipomersen



Lipid Pathway 2017

for Severe

Hypercholesterole

mia.


With or Without Extra-Risk

Clinical ASCVD20 to 75 years

High Intensity or MTD Statin for:. LDL-C lowering ≥50% or


. Non-HDL-C level <100 mg/dl

If goal is not reached:

Ezetimibe: if goal gap is <20%

Evolocumab or Alirocumab: if goal gap is ≥20%


Lipid Pathway 2017

for ASCVD

Secondary

Prevention


What the European Guideline tell us


In ASCVD prevention, up to now, European

Guideline recommends to reduce LDL-C

according with the estimated ASCVD risk*.

Healthy lifestyle, statins and new non-statins

drugs are the cornerstone to accomplish that goal.

The Sixth Joint Task Force of the ESC and 10 more Societes

Eur Heart J. 2016; on line May 23, 2016

* SCORE algorithm


Very High Risk:. Clinical ASCVD

. Documented subclinical ASCVD

. DM with organ damage and/or other ASCVD RF

. CKD with GFR <30 ml/min/1.73m2

. ASCVD risk -SCORE- ≥10%

What the European Guideline tell us

The Sixth Joint Task Force of the ESC and 10 more Societies

Eur Heart J. 2016; on line May 23, 2016

LDL-C goal:. <70 mg/dl or

. LDL-C lowering ≥50%

If basal LDL-C level is

70-135 mg/dl.

High Risk:. Total cholesterol >310 mg/dl

. Blood pressure >180/110 mmHg

. DM without organ damage or other ACVD RF

. CKD with GFR 30 to 59 ml/min/1.73m2

. ASCVD risk -SCORE- 5 to <10%

LDL-C goal:. <100 mg/dl or

. LDL-C lowering ≥50%

If basal LDL-C level is

100-200 mg/dl.

Moderate Risk:. ASCVD risk -SCORE- 1 to <5%

Low Risk:. ASCVD risk -SCORE- <1%

LDL-C goal:. <115 mg/dl.


5. What the WHF Cholesterol

Roadmap tell us. The WHF Decalog.



Risk Based Approach to LDL-C

Cholesterol Roadmap

ASCVD Risk EstimationPrimary Health Care

Primary PreventionUse Risk Charts

Secondary PreventionRisk Charts not necessary

Familial Hypercholesterolemia

Source: WHF Cholesterol 2017el CICPara Vivir Más y Mejor

Murphy A et al. Global Heart 2017

Patient Pathway of

Cholesterol Treatment for Primary Prevention



Patient Pathway of

Cholesterol Treatment for Secondary Prevention



Patient Pathway of

Cholesterol Treatment

for Familial Hypercholesterolemia


The WHF Decalog



1.- Make Cholesterol a National Priority

Cholesterol Roadmap

• Make cholesterol a priority and listed

as a major condition within national

cardiovascular disease strategies.


2.- Increase public awareness

Cholesterol Roadmap

• Inform the public, health professionals,

journalists, policy makers, decision

makers… of the burden and ASCVD

risk of cholesterol.


3.- Training for Health Care Personnel

Cholesterol Roadmap

• All health care professionals who are in

contact with people at risk of ASCVD

should have access to training in risk

estimation, treatment and control of

hypercholesterolemia and ASCVD risk

according with Guidelines.


4.- Incentive for Performance

Cholesterol Roadmap

• Provide financial incentives to health

professionals responsible for risk

estimation, prevention, treatment and

control of hypercholesterolemia and

ASCVD risk.


5.- Deliver a patient-centered care

Cholesterol Roadmap

• Identify, support and promote a

nationally recognized pathway of care

for health care professionals.


6.- Monitoring and Follow up

Cholesterol Roadmap

• Identify and promote a clear management plan for

follow-up and adherence.

• Support patients to adhere to medications and

lifestyle changes.

• Identify the healthcare team responsible for

adherence including primary care and health

clinics professionals, pharmacists, community led

programs etc…


7.- Acces to Good Quality Medicine

Cholesterol Roadmap

• Governments should provide free or

subsidized good quality medication to

patients.

• Eliminate taxes on pharmaceuticals on

certain medications -efficient statins-.


8.- Invest in tools and resources

Cholesterol Roadmap

• Governments should invest in tools to

enable patients to self-manage their

cholesterol:

• Patient monitoring devices

• Phone applications (app)

• Reminders


9.- Investigate Gaps

Cholesterol Roadmap

• Health systems should identify existing

professional capacity to identify the gap

in practice, and provide targeted

training to health care professionals.


10.- Fight Poor Quality Medicines

Cholesterol Roadmap

• Health systems should identify and

erradicate poor quality medicines,

including “miracle” products and

alternative remedies.


Make Your Action Plan

Cholesterol Roadmap

• Step 1: Conduct your situational analysis to guide

your priority agenda.

• Step 2: Identify your 1-3 priorities:• What can be your greatest impact with minimum resources?

• What is your rational for change?

• Step 3: Follow a pathway to implementation:• Develop your action plan and project outline for

implementation.

• Make a commitment


Source: WHO. A Roadmap to Implementation Health 2020 – the Experience of San Marino

A situation analysis will inform you of current gaps and identify your priorities...

What is your specific focus? Your defined objectives? What do you hope to achieve?

Where will you begin? Will you pilot the programme in advance? What are the key stages of development? What resources do you

need to begin and to continue? human, financial, equipment & facilities? Who are your leadership

team? Do you have administrative support? How will you define and plan your goals? Who are your

stakeholders? What role will they have? How will you engage and maintain your relationships?How can you consolidate

and strengthen political will and buy in from stakeholders? How important is advocacy in your objectives?

How will you monitor and

evaluate your success?

WH

F I

mp

lem

en

tati

on

Pa

thw

ay


Documents

el CIC WHF Cholesterol Roadmap, México ... - Academia El CIC 19 WHF CH… · Lp(a) ≥50 mg/dL. CRP ≥2 mg/L. CCI ≥300 UA. RA, SLE, etc. HIV Without Extra-Risk ASCVD Risk -PCE-≥7.5%