Ridurre drasticamente il colesterolo si traduce in beneficio clinico? Dall’IMPROVE-IT all’inibizione PCSK9

Dr Carlo SponzilliOspedale San Paolo Polo Universitario

ASST Santi Paolo Carlo - Milano

Chen Z et al., BMJ 1991; 303:276–282

Dati dello studio Shanghai, condotto in 9021 soggetti cinesi con un follow-up di 8–13 anni

Il numero delle morti per cardiopatia ischemica in ciascuno dei gruppi di colesterolo basale è indicato da una linea verticale che rappresenta una deviazione standard

Ris

chio

rel

ativ

o d

i m

ort

ali

tà C

HD

2.00

1.00

0.50

0.25

139 147 155 162 170 178 186

Colesterolo totale medio (mg/dl)

£136 159-178 137-158 ³179 Col. totale basale (mg/dl)

Lo studio Shanghai

4

9 12

18

Studi con statine in prevenzione secondaria: riduzione eventi e C-LDL “on trial”

30

25

20

15

10

5

0

30 50 70 90 100 130 150 170 190 210

4S-P

LIPID-P

CARE-P

CARE-S

LIPID-S

4S-S

HPS-P

HPS-S

PROVE-IT-AT

PROVE-IT-PR

Even

ti C

HD

(%

)

Colesterolo LDL (mg/dL)

Y = 0.1629x – 4.6776

R2 = 0.9029

p < 0.0001

Gli eventi sembrano

azzerarsi per un

C-LDL di 30 mg/dL

O’Keefe et al, JACC, 2004.

IMPROVE-IT

PCSK9 ?

TNT 10TNT 80

A2Z 20 A2Z 80

Risk Pattern for Subsequent CV Events Over a

Range of LDL-C Values1

CV = cardiovascular; CHD = coronary heart disease; MS = metabolic syndrome; IFG = impaired fasting glucose; CVD = CV disease. 1. Robinson JG et al. Am J Cardiol. 2006;98:1405–1408.

CHD + Diabetes

CHD + MS or IFG

CHD – No MS or IFG

Diabetes – No CVD

No Diabetes – No CVD

0 20 40 60 80 100 120 140 160 180 200 LDL, mg/dL

0

10

20

30

40

50

60

70

80

Card

iov

as

cu

lar

Ev

en

t R

ate

, %

Kenichi Tsujita et al J Am Coll Cardiol 2015;66:495–507)

SJ Nicholls et al JAMA. 2016;316(22):2373-2384.

Post Hoc Analysis Examining the Relationship Between Achieved LDL-C Level and Change in Percent Atheroma Volume (GLACOV)

Niacina e statine

AIM – HIGH 2012

Atheroma

Liver

Blood

CholesterolPool (Micelles)

NPC1L1 RemnantReceptors

LDL Receptor

Expression

Cholesterol

HMG-CoA

CMR

CM

Statins

Ezetimibe

X

X

2

1 Reduction of hepatic cholesterol

2 Increased LDL receptor expression

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.

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

LDL-C LDL-C LDL-C

20%

30-45%

STATIN

+As high as

60%

10%

20%

30%

40%

50%

ME

AN

LD

L-C

LO

WE

RIN

G2,3

synthesis absorptionsynthesis

absorptionsynthesis

absorption

As high as 60% LDL-C lowering via dual inhibition

1. Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; 2. Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.;

3. Davidson M et al. J Am Coll Cardiol 2002; 40:2125-34.

CH

AN

GE

OF

SY

NT

HE

SIS

AN

D A

BS

OR

PT

ION

MA

RK

ER

S1

Inhibition of

absorption

Dual inhibition

Statin + EZETROL

Inhibition of synthesis

EZETIMIBE

Primary Endpoint — I TT

Simva — 34.7% 2742 events

EZ/Simva — 32.7% 2572 events

HR 0.936 CI (0.887, 0.988)

p=0.016

Cardiovascular death, MI, documented unstable angina requiring

rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT= 50

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

First, Additional, and Total Primary Endpoint Events During Follow-Up by Randomization Group

Reduction in Total Cardiovascular Events

With Ezetimibe/Simvastatin Post-Acute Coronary

Syndrome:

The IMPROVE-IT Trial

Bohula, E.A. et al. J Am Coll Cardiol. 2017;69(8):911–21.

Atherothrombotic Risk Stratification and Ezetimibe for Secondary Risk Prevention

Effects of Ezetimibe by risk scores in IMPROVE-IT

JACC 2017

FOURIERPrimary Endpoint: Composite of CV Death, MI, Stroke, Hospitalization for UA, or

Coronary Revascularization

HR 0.85 (95% CI 0.79 to 0.92); P < 0.001

Sabatine MS, et al . NEJM 2017

6.0

10.7

14.6

5.3

9.1

12.6

No. at RiskPlacebo 13,780 13,278 12,825 11,871 7,610 3,690 686Evolocumab 13,784 13,351 12,939 12,070 7,771 3,746 689

Cu

mu

lati

ve I

ncid

en

ce (

%) Placebo

Evolocumab

0

2

4

6

8

10

12

14

16

0 6 1812 24 3630Months

15%

3.7

6.8

9.9

Fourier Key Secondary Endpoint: Composite of CV Death, MI, or Stroke

HR 0.80 (95% CI 0.73 to 0.88); P < 0.001

No. at RiskPlaceboEvolocumab

Cu

mu

lati

ve I

ncid

en

ce (

%) Placebo

Evolocumab

Months

0

2

4

6

8

9

10

11

0 6 1812 24 3630

1

3

5

7

13,780 13,449 13,142 12,288 7,944 3,893 73113,784 13,501 13,241 12,456 8,094 3,935 724

3.1

5.5

7.9

Sabatine MS, et al . NEJM 2017

20%

FOURIERAssociation of LDL-C Levels and CV Events

P<0.0001 Q4

Q3

Q2

Q1

Q4Q3

Q2

Q1

Placebo

Evolocumab

13%

12%

11%

10%

9%

8%

7%

6%

5%0 20 40 60 80 100 120

Achieved LDL Cholesterol (mg/dL)

Car

dio

vasc

ula

r D

eat

h, M

I, o

r St

roke

Sabatine MS, et al. American College of Cardiology – 66th Annual ScientificSession Late-Breaking Clinical Trial. Washington, D.C. March 17, 2017.

Patients divided by quartile of baseline LDL-C and by treatment arm

Landmark Analysis of Primary Endpoint

Year 1: RRR 12% > Year 1: RRR 19%

Longer duration of treatment and follow up suggests larger risk reduction

Evolocumab

Cu

mu

lati

ve

In

cid

en

ce

(%

)

0%

2%

4%

6%

8%

10%

0 90 180 270 360DaysNo. at Risk

Placebo 13780 13542 13282 13044 12834Evolocumab13784 13563 13358 13137 12950

Placebo

Hazard ratio 0.88

(95% CI, 0.80-0.97)

13524 12467 8080 3928 89113548 12598 8204 3942 888

0%

2%

4%

6%

8%

10%

360 540 720 900 1080

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Days

Placebo

Evolocumab

Hazard ratio 0.81

(95% CI, 0.73-0.89)

Landmark analyses were performed in which patients who were alive and in follow-up at the start of the period of interest formed the group at risk.Sabatine MS, et al . NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664 (Supplementary Figure S4)

Robinson, J.G. et al. J Am Coll Cardiol. 2016;68(22):2412–21.

Association Between the Magnitude of LDL-C Lowering and

Proportional Reduction in Major Cardiovascular Events

FourierLDL-C 9230 mg/dl (3.0 0,78 mmol/L)

ODYSSEY OUTCOMES – Study Design

*Dose titrated up to 150mg Q2W at Month 2 if LDL-C ≥50 mg/dL(1.29 mmol/L) at Month 1 visit.ClinicalTrials.gov. ODYSSEY OUTCOMES Study. http://clinicaltrials.gov/ct2/show/NCT01663402. Accessed May 14, 2015. Schwartz GG, et al. Am Heart J. 2014;168:682-689.e1.

24

Population

• Patients 4-52 weeks post-ACS

• Age ≥ 40

Lipid criteria at entry

• LDL-C ≥70 mg/dL [≥1.81 mmol/L] OR• ApoB ≥80 mg/dL [≥0.8 mmol/L] OR• Non-HDL-C ≥100 mg/dL [≥2.59

mmol/L]

Primary endpoint

• Composite of– CHD death

– Nonfatal MI

– Ischemic stroke

– High-risk UA requiring hospitalization

Double-Blind Treatment Period (64 Months)

n=9000

n=9000

R

Placebo SC

Run-in

Screeningvisit

Injectiontraining

visit

NCEP-ATPIII TLC diet or equivalent

Alirocumab 75 mg with potential ↑ to 150 mg Q2W SC* + placebo PO (single 1-mL injection using prefilled pen for self-administration)

Patients on maximum-tolerated potent statins

atorvastatin 40-80 mg or rosuvastatin 20-40 mg

OR statin intolerant

November 2015: 18,000-Patient ODYSSEY OUTCOMES Trial of Praluent® (alirocumab) Injection Fully Enrolled

CONFIDENTIAL

Robinson, J.G. et al. J Am Coll Cardiol. 2017;69(5):471–82.

Low-Density Lipoprotein Cholesterol Levels <25 mg/dl Following

Alirocumab Treatment: Associated Factors, Exposure, and Safety

Robinson, J.G. et al. J Am Coll Cardiol. 2016;68(22):2412–21.

Determining When to Add Nonstatin Therapy

ACC EXPERT CONSENSUS DECISION PATHWAY 2016

ACC EXPERT CONSENSUS DECISION PATHWAY 2016

ACC EXPERT CONSENSUS DECISION PATHWAY 2016

Recommendations for the pharmacological treatment of hypercholesterolaemia

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

• Il sogno di riuscire quasi ad azzerare gli eventicardiovascolari riducendo il Colesterolo LDL si staavverando

• L’associazione di più farmaci per ottenere la riduzione delle LDL si è dimostrata efficace e sicura

• Importante utilizzare le associazioni giuste con unaprogressione degli interventi identificando i pazienti amaggior rischio

• Il raggiungimento di valori anche molto bassi dicolesterolo LDL si è dimostrata efficace e sicura nelridurre ulteriormente gli eventi cardiovasculari

Conclusioni

Chiedo soprattutto che vengano unificate le

spine elettriche e le unità di misura