La ligue cardiologique belge ASBL créée en 1968 · 2018-05-24 · Statins are among the most...

Systematic Coronary Risk Evaluation (SCORE) charts

Risico op

Cardiovasculaire

Sterfte

=

“Fataal” Risico

Risiconiveaus

Om het risico op een fataal CV voorval te

converteren naar fataal én niet fataal CV voorval:

– X 3 voor ♂

– X 4 voor ♀

Effect van combinatie van risicofactoren samen komt goed tot uiting…

SCORE

2011

Women

High

Risk

Invloed van HDL op risico…

Probleem met SCORE:

In de jongsteleeftijdsgroepen is het

absolute risico altijd laag...

relatieve risico reductie van het primaire eindpunt in

studies met statines:

hoe vroeger de interventie hoe groter het klinisch voordeel

Primary prevention Confirmed CAD Advanced CAD

4S = sec prev post-MI pts with high LDL

Primary Endpoint: Overall Survival

80

82

84

86

88

90

92

94

96

98

100

0 1 2 3 4 5 6

Simvastatin

Placebo

Years since randomization

% S

urv

ivin

g

30%

risk reductionp = 0.0003

The Lancet, Vol 344, November 19, 1994

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69

P < 0.00001

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lative

In

cid

en

ce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

JUPITER = prim prev in subjects with low LDLPrimair eindpunt: MI, CVA, OA, Revascularisatie, CV mortaliteit

Ridker et al, NEJM 2008

Relative Risk Chart

Piepoli F, Hoes W, Agewall S, Albus Chr, Brotons C, Catapano A et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2016;

doi:10.1093/eurheartj/ehw106

ESC Guidelines on CV Prevention



ESC Guidelines on CV prevention

Dutch Lipid Clinic Network diagnostic criteria for Familial Hypercholesterolemia

*Premature =

< 55 years in men

< 60 years in women

points1

2

3

4

5

Som hoogste scorein elk item 1 tem 5 =

anamnese

klinisch onderzoek

labo

>200 mg/dl

>135mg/dl

Haralambos K, Atherosclerosis 2015;240:190-6.



ESC Guidelines on CV prevention

‘Risk modifiers’

Wat houdt ‘familiale geschiedenis’ in?

General principle of prevention:

The higher the risk, the more intense the action should be.

= Healthy lifestyle

Recommended Treatment Targets / Dose in Hypercholesterolemia

Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M ; European Guidelines on cardiovascular disease prevention inclinical practice (version 2012). Eur Heart J. 2012 Jul;33(13):1635-701. doi: 10.1093/eurheartj/ehs092. Epub 2012 May 3.

Erratum in: Eur Heart J. 2012 Sep;33(17):2126

‘Quantitatively’

The PREDIMED trial(Prevención con Dieta Mediterránea)

N Engl J Med 2013.DOI: 10.1056/NEJMoa1200303

Extra-virgin olive oil

‘Qualitatively’

3a.5.8 Dietary patterns

Studying the impact of a total dietary pattern theoretically shows the full preventive potential of diet since it yields

a combined estimate of the impact of several favourable dietary habits. The Mediterranean diet comprises many

of the nutrients and foods that have been discussed previously: high intake of fruits, vegetables, legumes,

wholegrain products, fish and unsaturated fatty acids (especially olive oil); moderate consumption of alcohol

(mostly wine, preferably consumed with meals) and low consumption of (red) meat, dairy products and saturated

fatty acids. A meta-analysis of prospective cohort studies has demonstrated that greater adherence to a

Mediterranean diet is associated with a 10% reduction in CV incidence or mortality [pooled RR 0.90 (95% CI

0.87, 0.93)] and an 8% reduction in all-cause mortality [pooled RR 0.92 (95% CI 0.90, 0.94)].336 An RCT in high-

risk individuals suggested that following a Mediterranean diet over a 5 year period, compared with a control diet,

was related to a 29% lower risk of CVD [RR 0.71 (95% CI 0.56, 0.90)].337

Gaps in evidence

•The biggest challenge in dietary prevention of CVD is to develop more effective strategies to make people

change their diet (both quantitatively and qualitatively) and to maintain that healthy diet and a normal weight.

•Research into the substances in foods that underlie the protective effects is ongoing.

2016 European Guidelines on cardiovascular disease

prevention in clinical practice

http://eurheartj.oxfordjournals.org/content/37/29/2315#ref-336

http://eurheartj.oxfordjournals.org/content/37/29/2315#ref-337

Medicamenteuze Aanpakvan Hypercholesterolemie

Remmen van de cholesterolsynthese

Remmen van de cholesterolopname via de darm

Remmen van de afbraak van de LDL receptor

Statins are among the most studied drugs in CV prevention.

A number of large-scale clinical trials have demonstrated that statins

substantially reduce CV morbidity and mortality in both primary and

secondary prevention.

Statins have also been shown to slow the progression or even promote

regression of coronary atherosclerosis.

Statins

Efficacy in clinical studies

Reiner Z et al., European Heart Journal (2011) 32, 1790

Atheroma

Liver

CholesterolPool (Micelles)

NPC1L1 RemnantReceptors

LDL Receptor

Expression

Cholesterol

HMG-CoA

CMR

CM

Statins X 1

3

1 Inhibition of HMG-CoA reductase activity

2 Reduction of hepatic cholesterol

3 Increased LDL receptor expression

4 Increased clearance of LDL-C

Statin: Mechanism of Action

LDL-C

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NPC1L1 = Niemann-Pick C1-like 1; CMR = chylomicron remnant;

LDL=low-density lipoprotein; CM= chylomicron.

1. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

Cholesterol Pool

2

4

Statins Inhibit Synthesis of Cholesterol1

Blood

Current available evidence “suggests” that the clinical benefit:

-is largely independent of the type of statin

-but depends on the extent of LDL-C lowering.

Statins

Meta-analyses


Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

LaRosa JC et al. N Engl J Med 2005;352:1425-1435

LDL-C achieved mg/dL (mmol/L)

WOSCOPS – Placebo

AFCAPS - Placebo

ASCOT - Placebo

AFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Placebo

LIPID - Rx

4S - Placebo

CARE - Rx

LIPID - Placebo

CARE - Placebo

HPS - Rx

0

5

10

15

20

25

30

40

(1.0)

60

(1.6)

80

(2.1)

100

(2.6)

120

(3.1)

140

(3.6)

160

(4.1)

180

(4.7)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPRA – pravastatinATV - atorvastatin

200

(5.2)

PROVE-IT - PRA

PROVE-IT – ATV

TNT – ATV10

TNT – ATV80

LDL-C tijdens behandelingis sterk gecorreleerd met CV voorvallen.

JUPITER - PlaceboJUPITER - Rx

LDL-C ≈ 35 mg/dL

Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

Median

Change

In Percent

Atheroma

Volume

(%)

Mean LDL-C (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

Relationship between LDL-C and Progression Rate

ASTEROID

rosuvastatin

REVERSALComparison of Percentage of LDL Cholesterol Reduction and

Change in Atheroma Volume: Both Treatment Groups (n=502)

% Change in LDL Cholesterol

Ch

an

ge

in

Ath

ero

ma

Vo

lum

e, m

m3

Adapted from Nissen S. et al., JAMA 2004; 291:1071-80.

50% LDL-C reduction

-15

-10

-5

0

5

10

15

20

-80 -70 -60 -50 -40 -30 -20 -10 0 10 20

Comparison of the Effects of Maximal Dose Atorvastatin and Rosuvastatinpost-analysis of STELLAR

(Van Himbergen et al. J Lipid Res 2000)

Wide interindividual variability in response to therapy for LDL-C

LD

L c

hole

ste

rol change (

%)

Rosuvastatin

40mg

Mean % LDL: -55%

Atorvastatin

80mg

Mean % LDL: -53%

DYSIS (2008–2009)Almost Half of Statin-Treated Patients Were Not at LDL-C Goal

(Based on 2007 ESC Guidelines)1,a

High-risk = patients with preexisting CVD, diabetes, and/or ESC score ≥5%.aStudy population: 22,063 statin-treated outpatients enrolled from 2,954 sites across 11 European countries and Canada. All data were collected from clinical examination and medical charts from single outpatient visits between April 2008 and February 2009.

bLDL-C ≥3 mmol/L (~116 mg/dL) in patients with ESC score <5%, LDL-C ≥2.5 mmol/L (~97 mg/dL) in patients with ESC score ≥5%, diabetes, and/or CVD.DYSIS = Dyslipidemia International Study; CVD = cardiovascular disease; ESC = European Society of Cardiology; LDL=low-density lipoprotein.

1. Gitt AK et al. Eur J Prevent Cardiol. 2011;19:221–230.

All patients were on statin therapy

Pa

tie

nts

No

t a

t L

DL

-C G

oa

l,b

%

(n=21,797) (n=17,583) (n=4,524) (n=10,587)

Cholesterol Absorption Inhibitors

efficacy in clinical studies

Guidelines ESC

Ezetimibe can be used as second-line therapy in

association with statins when the therapeutic target is not

achieved at maximal tolerated statin dose or in patients

intolerant of statins or with contraindications to these drugs.


54

Ezetimibe

Inhibits Absorption of Cholesterol in the Small Intestine1

Atheroma

Liver

Blood



LDL Receptor

Expression

Cholesterol

HMG-CoA

CMR

CM

Ezetimibe

X1

3

5

4

2

1 Inhibition of NPC1L1 activity

2 Reduction of cholesterol

transported to the liver



5 Increased clearance of LDL-C

2

Ezetimibe: Mechanism of Action

LDL-C

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant;

LDL=low-density lipoprotein; CM= chylomicron.1. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

Cholesterol Pool

55

Atheroma

Liver



LDL Receptor

Expression

Cholesterol

HMG-CoA

CMR

CM

Statins

Ezetimibe

X

2



3 Increased clearance of plasma LDL-C

Together, ezetimibe in combination

with a statin provides:

LDL-C

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant;

LDL=low-density lipoprotein; CM= chylomicron.

1. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

1 Cholesterol Pool

3

Ezetimibe and Statins

Have Complementary Mechanisms of Action1

Blood

X

Simva — 22.2%

1704 events

EZ/Simva — 20.4%

1544 events

HR 0.90 CI (0.84, 0.97)

p=0.003

NNT= 56

CV Death, Non-fatal MI, or Non-fatal Stroke

7-year event rates

PCSK9 action: LDL receptor degradationProprotein Convertase Subtilisin Kexin Type 9 (=serine-protease)

“PCSK9 inhibition” leads to increase of LDL receptor

with ensuing LDL decrease with 50-70%

Brautbar, A. & Ballantyne, C. M. (2011) Pharmacological strategies for lowering LDL cholesterol:

statins and beyond Nat. Rev. Cardiol. doi:10.1038/nrcardio.2011.2

A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

DESCARTES trial March 29, 2014 NEJM

Bococizumab SPIRE Phase 3

CV Outcomes Program

N= 18,000

SPIRE-1

Study B1481022

(n=12,000)

SPIRE-2

Study B1481038

(n=6,000)

SPIRE-HR

Study 1019 (n=600)SPIRE-LDL

Study 1020 (n=1,930)

SPIRE-FH

Adult HeFH, Study

1021 (n=300)

SPIRE-LL

Study 1045 (n=690)

SPIRE-SI

Statin Intolerant,

Study 1030

(n=150)

Lipid Lowering Program

Bococizumab Phase 3 Clinical ProgramSPIRE – Studies of PCSK9 Inhibition and the Reduction of vascular Events

61

Active StudiesPlanned studies

SPIRE-AI

Study 1046

“Use” Trial For AI

(n=300)

Bococizumab SPIRE Phase 3

CV Outcomes Program

N= 18,000

SPIRE-1

Study B1481022

(n=12,000)

SPIRE-2

Study B1481038

(n=6,000)

SPIRE-HR

Study 1019 (n=600)SPIRE-LDL

Study 1020 (n=1,930)

SPIRE-FH

Adult HeFH, Study

1021 (n=300)

SPIRE-LL

Study 1045 (n=690)

SPIRE-SI

Statin Intolerant,

Study 1030

(n=150)

Lipid Lowering Program

Bococizumab Phase 3 Clinical ProgramSPIRE – Studies of PCSK9 Inhibition and the Reduction of vascular Events

66

Active StudiesPlanned studies

SPIRE-AI

Study 1046

“Use” Trial For AI

(n=300)

NEJM online march 2017

Overview ESC Guidelines: “keep it simple”

! LDL = primary target !

! Statins and Ezetimibe !

Hypertension

Stoffen die hypertensie kunnen uitlokken

Additional slides on special topics relating toCV risk / prevention / treatment of risk factors

Genetic Risk versus LifestylePCSK9 inhibition

Luc Missault, MD, DSc

Cardiologie St Jan Ziekenhuis Brugge

Genetisch risico vs gezonde

levensstijl en coronair risico

Wat houdt ‘familiale geschiedenis’ in?

The upper DNA molecule differs from the lower DNA molecule at a single base-pair location (a C/A polymorphism)

Cytosine Blue

Guanine Yellow

Adenine Green

Thymine Red

A single-nucleotide polymorphism, often abbreviated to SNP (snip),is a variation in a single nucleotide that occurs at a specific position in the genome

"single-nucleotide polymorphism / SNP | Learn Science at Scitable". www.nature.com. Retrieved 2015-11-13.

‘Genetic scores’

• Studies van het volledige genoom (GWAS of genome wideassociation studies) hebben aangetoond dat er veel kandidaat SNPsgeassocieerd zijn aan CVD.

• Het effect van een individuele SNP is meestal klein.

• Daarom werden GENETISCHE SCORES ontwikkeld (de som van de SNP’s vermenigvuldigd met hun risicoverhoging).

• Er is nog geen consensus omtrent de te gebruiken SNPs. Er is geen consensus omtrent een ‘standaard’ genetische risicoscore.

• Er is nog evenmin consensus bereikt omtrent een te gebruiken ‘standaard’ methode om het genetisch risico uiteindelijk te berekenen.

After incorporating the genetic risk score into the Framingham risk score,

a total of 380 individuals (30.6%) were reclassified into higher-(188) or lower-risk groups (192).

‘Genetic scores’

• Studies van het volledige genoom hebben aangetoond dat er veel kandidaat SNPs geassocieerd zijn aan CVD.

• Het effect van een individuele SNP is meestal klein.

• Daarom werden GENETISCHE SCORES ontwikkeld (de som van de SNP’s vermenigvuldigd met hun risicoverhoging).

• Er is nog geen consensus omtrent de te gebruiken SNPs. Er is geen consensus omtrent een ‘standaard’ genetische risicoscore.

• Er is nog evenmin consensus bereikt omtrent een te gebruiken ‘standaard’ methode om het genetisch risico uiteindelijk te berekenen.

Genetische scores en CVD risico (1)

• Ook na correctie voor klassieke RF blijft er een associatie tussen risico en bepaalde genetische scores

• Meerdere scores beschreven (delta risk per score eenheid van 1,02 tot 1,49)

• Vooral bij intermediair risico ~ herklassificatie

• Minder igv ‘hoog risico obv klassieke RF’

• studievb: 1 additioneel event per 318 personen (analogie NNT) zou kunnen voorkomen worden indien men een welbepaalde CHZ specifieke score zou toevoegen aan de klassieke risicofactoren

MI GENES trial

Genetische scores en CVD risico (2)

• Bvb een bepaalde genetische score die gebruikt maakt van 27 genetische varianten laat toe om personen te identificeren die het meest baat zouden hebben van een statine in preventie van CVD

• CAVE: klassieke statine studies waren hier niet op gericht en hielden hier geen rekening mee

• Nood aan prospectieve studies in dergelijke groepen (…ethiek)

• Commerciele kits bestaan en het gebruik wordt door sommigen sterk aangeraden (‘strong pressure’; lobbying?)

• Nog geen consensus omtrent: welke genetische merkers te gebruiken? welke genetische score? Voorspellende waarde?

‘Gaps’ in evidence

• Impact van het toevoegen van familiale geschiedenis aan de huidige score risico berekening is nog niet prospectief onderzocht

• Nog geen studies omtrent het bijkomend preventief effect van het incorporeren van een ‘genetische risico score’ aan onze huidige standaard risicoberekening

(hoeveel bijkomende events voorkomen? Kosten effectief?)

Methods:

-Gebruikte genetische score: gebaseerd op 50 verschillende genetische polymorfismen (SNP’s) geassocieerd aan incidentie van coronair lijden

-Geïncludeerd in een berekende polygenische score

-Aldus indeling in 3 groepen met ‘high’, ‘intermediate’ en ‘low’ genetic risk

= minstens 1X/wk

dwz <30 BMI

Favorable

Intermediate

Unfavorable

Results:

Elke individuele lifestyle factor beinvloedt (significant) het risico:

• HR voor non-smoking 0,56

• HR voor no-obesity 0,66

• HR voor fysische activiteit 0,88

• HR voor gezonde voeding 0,91

Results: High genetic risk bleek onafhankelijk te zijn van lifestyle.

High genetic risk betekent een HR 1,91 voor CVD.

Among participants at high genetic risk, favorable lifestyle was associated with a 46% lower

relative risk of coronary events than unfavorable lifestyle (HR 0.54; 95% CI, 0.47 to 0.63).

This corresponded to a reduction in the standardized 10-year incidence of coronary events

from 10.7% for unfavorable lifestyle to 5.1% for favorable lifestyle in ARIC,

from 4.6% to 2.0% in WGHS,

from 8.2% to 5.3% in MDCS.

La ligue cardiologique belge ASBL créée en 1968 · 2018-05-24 · Statins are among the most...

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