Update PCSK9 trials - Vascular Rounds MUMC · Study drug was administered monthly at home or in the...

Update PCSK9 trials

Vascular Rounds MUMC

16 mei 2017

Frank L.J. Visseren

Disclosures

Voor bijeenkomst mogelijk relevante relaties:

•  Sponsoring of onderzoeksgeld

ZonMw,Wellerdieck-deGoedefonds,Leatarefounda8on,VriendenUMCUtrecht,NederlandseHarts8ch8ng

•  Honorarium of andere (financiële) vergoeding

Geen

•  Aandeelhouder

Nee

•  Andere relatie, namelijk …

Fase II/III klinisch onderzoek met vrijwel alle denkbare lipiden-verlagende middelen (o.a. Sanofi, Medicines Company, Amgen, Pfizer, Eli Lilly, Merck, ISIS) Lidrichtlijncommissies:CVRM,addendumCVRMbijouderen,addendum(erfelijke)dyslipidemie

PCSK9

Proprotein convertase Subtilisin/kexin Type 9 Serine protease

PCSK9; how it started

Affected family members with: •  Total cholesterol >90th percentile •  Tendon xanthomas •  CHD, early MI, Stroke

Nat Genet 2003;34:154-156

NEJM 2016:375:2144-2153

PCSK9-i and incident diabetes

NEJM 2016:375:2144-2153

Mutations in PCSK9-i or HMGCR genes and risk of MI

NEJM 2016:375:2144-2153

Mutations in PCSK9-i or HMGCR genes and risk of MI or DM2

NEJM 2016:375:2144-2153

Mutations in PCSK9-i or HMGCR genes and risk of MI

JAMA 2016;316:2373-2384

GLAGOV trial

GLAGOV trial

Up to 4-week lipid stabilization

period

Assigned to background

statin therapy

Placebo SC every month

Ran

dom

izat

ion

1:1

to s

tudy

dru

g

End

Of S

tudy

Maximum 6 weeks D1 W4 W12 W24 W36 W52 W64 W76 W78 W80 EOS

Study drug was administered monthly at home or in the clinic

Study visits:

Screening and placebo run-in period

•  Clinically indicated coronary angiogram

•  IVUS based on coronary angiogram results

•  SC injection of 3 mL placebo

2–4 weeks

Last dose of

study drug

Last IVUS

procedure

Evolocumab 420 mg SC

every month

JAMA 2016;316:2373-2384

Intravascular Ultrasound (IVUS)

Leading edge of the EEM

Leading edge of the lumen

PAV = Σ(EEMarea – lumenarea)Σ(EEMarea) 100X

JAMA 2016;316:2373-2384

GLAGOV trial

JAMA 2016;316:2373-2384

GLAGOV trial: LDL-c levels

JAMA 2016;316:2373-2384

JAMA 2016;316:2373-2384

GLAGOV: primary and secondary outcomes

GLAGOV trial

JAMA 2016;316:2373-2384

NEJM2017;376:1713-1722

SummaryFOURIER

Robinson JG et al, NEJM 2015;372:1489-1499

Efficacy and safety of alirocumab in reducing lipids and cardiovascular events

(ODYSSEY LONG TERM study)


Efficacy and safety of alirocumab in reducing lipids and cardiovascular events

(ODYSSEY LONG TERM study)

Eur Heart J 2016:37:2981-2989

JAMA Cardiol 2017, online March 14

OSLER longterm follow up

IMPROVE-IT study

Eur Heart J 2016;37:2999-3058

Recommendations Class Level

Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal. I A

In the case of statin intolerance, ezetimibe or bile acid sequestrants, or these combined, should be considered. IIa C

If the goal is not reached, statin combination with a cholesterol absorption inhibitor should be considered. IIa B

If the goal is not reached, statin combination with a bile acid sequestrant may be considered. IIb C

In patients at very high-risk, with persistent high LDL-C despite treatment with maximal tolerated statin dose, in combination with ezetimibe or in patients with statin intolerance, a PCSK9 inhibitor may be considered.

IIb C

ESC guidelines on cardiovascular disease prevention: lipid-lowering therapy

Eur Heart J 2016;37:2315-2381

NEJM2017;376:1430-1440

PCSK9 inhibition by RNAi

NEJM 2017;376:41-51.

ORIONtrial

NEJM2017;376:1430-1440

Vergoedingscriteria PCSK9-i

•  PCSK9-remmingverlaagtLDL-cenverlaagtCVrisicoin2grotetrials>50.000pa8enten

•  FOURIERresultatenbeves8gingen/ondersteunendebestaandevergoedingvoorPCSK9-i.

•  NieuwemanierenvanPCSK9(endusLDL-c)verlaginginaantochtWelkepa8ëntenkomenm.i.metnameinaanmerkingvoor(verdere)LDL-creduc8emetPCSK9-i:

•  pa8ëntenmetprogressievanvaatlijdenondanksop8malelipiden-behandeling.

•  hoogrisicopa8ënten(bv.DM2,FH)dievaatlijdenontwikkelenondanksop8malelipiden-behandelingOFvaatlijdenhebbenenstreefwaardevanLDL-cniethalen.

•  pa8ëntenmet‘cholesterol-ziekte’(FH)diestreefwaardevoorLDL-c(ruim)niethalen

Conclusies

Update PCSK9 trials - Vascular Rounds MUMC · Study drug was administered monthly at home or in the...

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