statins and pcsk9 inhibitors for stroke prevention...statins and pcsk9 inhibitors for stroke...

Statins and PCSK9 inhibitors for stroke prevention

Haralampos Milionis

Professor of Internal Medicine

School of Medicine, University of Ioannina

Ioannina, Greece

Every 1 mmol/L reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanism

Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists

Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental

LDL-C lowering on CV outcomes. [To convert, 100 mg/dL=2.59 mmol/L].

CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density

lipoprotein cholesterol.

CTT Collaboration. Lancet 2005:366;1267–78; CTT Collaboration. Lancet 2010;376:1670–81;

Cannon CP, et al. N Engl J Med 2015;372:2387–97.

There is no evidence of any lower LDL-C threshold

CTTC trials (statin)

Niacin

Diet/unsaturated fatty acid

Ileal bypass

Bile acid resin

Ezetimibe

Fibrate

More LDL lowering and risk reduction

Re

du

ctio

n in

CV

eve

nts

(%

)

0

10

20

30

40

50

IMPROVE-IT

10 20 30 40 50 60 70 80

Reduction in LDL-C (mg/dL)

Major Statin trials in Primary Prevention and Risk of Stroke

Barkas F & Milionis H. Semin Neurol 2017;37:286-93

Statins

&

Neuroprotection?

Potential mechanisms whereby

statins may reduce the risk of stroke

P. Amarenco, et al. Arch Med Sci 2007;3:S109-S114

Stroke reduction and

neuroprotection by statins

Vaughan C J , Delanty N Stroke 1999;30:1969-1973

Statins

&

Acute phase of stroke

Acute Statin Therapy, Survival, and

Improved Functional Outcome After

Ischemic Stroke: The North Dublin Population Stroke Study

Association Between Acute Statin

Ni Croinin D. et al. Stroke 2011;42:1021-9

Kaplan-Meier curves indicating 90-day survival according to

statin therapy (prestroke statin treatment, new acute poststroke

statin treatment, and statin-untreated).

Ní Chróinín D et al. Stroke 2011;42:1021-1029

N=448

Treatment with statins and ischemic strokeseverity: Does the dose matter?

Pretreatment with statins is associated with lower stroke severity,

at high as well as at low to moderate doses.

A higher probability of mild stroke severity in the in the propensity

score matched analysis (OR, 2.023, 95%CI 1.248–3.281 for the

low to moderate doses and OR, 3.502, 95% CI 1.477–8.300 for

the high doses of statins)

Martinez-Sanchez P et al. Neurology 2013;80:1800–1805

Statin treatment withdrawal in ischemic stroke: A controlled randomized study

Neurology 2007;69:904–910

Study Design

• Consecutive pts admitted with acute hemispheric stroke <24 hrs duration

• Randomly assigned to:

Continuing statintherapy (atorva 20mg/d) OR

Stopping for 3 days

• Outcome: death, dependency or END

Bianco M et al . Neurology 2007;69:904–910

Results

Bianco M et al. Neurology 2007;69:904–910

4.668.67

Statins

&

Secondary Prevention

Major statin trials in subjects at high CVD risk or with a Hx of CAD and risk of stroke

Barkas F & Milionis H. Semin Neurol 2017;37:286-93

30%

20%

10%

1 2 3 4 5 6 7 yrs

Statin plus Ezetimibe after MI prevents strokes

IMPROVE-IT (N=18,144 ACS patients)

Simvastatin 40 mg

Simvastatin 40mg

& Ezetimibe 10mg

HR = 0.94* (CI 0.89 - 0.99)

NNT= 50/6y

Ischemic stroke:

HR = 0.79*

IMPROVE-IT/ Cannon NEJM 2015

SPARCL: Study design

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

Stroke or TIA in ≤6 months,

no known CHD, LDL-C 100–190 mg/dL

N = 4731

Atorvastatin 80 mg daily

n = 2365

Placebo

n = 2366Randomized

Double blind

Primary end point: Fatal/nonfatal stroke

Secondary end points: Major coronary or CV events

Follow-up: ~5 years (until >540 primary end points)

Time since randomization (years)

SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke

*AdjustedSPARCL Investigators. N Engl J Med. 2006;355:549-59.

Fatal/

nonfat

al

stroke

(%)

0

0 1 2 3 4 5 6

16

12

8

4

16% RRR*

HR 0.84 (0.71–

0.99)

P = 0.03

Placebo

Atorvastatin

NNT = 46

patients

for 5 years

Primary outcome

SPARCL: Reductions in major coronary events

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest

00

10

6

2

1 2 3 4 5 6

Time since randomization (years)

Major

coronary

events*

(%)

35% RRR

HR 0.65 (0.49–

0.87)

P = 0.003

Placebo

Atorvastatin

8

4

• Men and Women1

• Young and Elderly (to 85 yrs)2

• All stroke subtypes3

• Patients with Carotid Artery Disease

(symptomatic – asymptomatic),

Diabetes or Chronic Renal Disease4

Benefit with StatinTreatment in Stroke pts

1: Stroke 2008; 39:2444-8

2: Neurology 2009; 72:688-94

3: Stroke 2009 ; 40:1405-9

4: Stroke 2008: 39:3297-302

SPARCL trial

Post-discharge Statin Therapy

and Outcome After 1st ever

Ischemic Stroke:The Athenian Stroke Registry

Milionis H et al. Neurology 2009;72:1816-22

Post-discharge statin therapy reduces10-yr recurrence after a first-ever acute

ischemic stroke

Milionis et al. Neurology 2009;72:1816–1822

HR

=0.6

5(9

5%

CI

0.3

9 t

o0

.97,

p<

0.0

1)

35%

Post-discharge statin therapy improves 10-yr survival after a first-ever acute

ischemic stroke

HR

=0.4

3 (

95%

CI

0.2

9to

0.6

1,

p<

0.0

1)

Milionis et al. Neurology 2009;72:1816–1822

57%

Forest plots of 90-day outcomes (good functional outcome

and death) with statin treatment at stroke onset, in

observational studies

Ní Chróinín D et al. Stroke 2013;44:448-456

N= 113,148 Good functional outcome

Death

Lipid lowering prevents strokes

Amarenco Lancet Neurol 2009


1.0 20.5

RR for

any stroke type

Treatment better Placebo better

Statins 1° prevention 0.81*


+ Ezetimibe 2° prevention 0.79*

Setting

Risk CategoryVery high:

- CVD (including

Stroke)- DM w/ target-organ lesion or w/ 1 major RF- CRD(GFR<30)- SCORE≥10%

LDL-C <70 or LDL-C >50%

(if 70-135)

High:- ≥1 aggravating RG(TChol>310 mg/dl,BP>180/110 mmHg)

- DM- CRD (GFR 30-59) - SCORE 5-10%,

LDL-C <100 or LDL-C >50%

(if 100-200)

Moderate-Low:

SCORE <5%

LDL-C <115

LDL-C Treatment Targets

Adapted from 2016 European Guidelines on CVD prevention in clinical practice

Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals

CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through

Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.

http://www.escardio.org/about/press/press-releases/esc13-amsterdam/Pages/euroaspire-iv-success-challenges-

secondary-prevention-CVD-europe.aspx. [Accessed 11 May 2015].

Data collected from patients <80 years old with

established CHD, 25% women, mean age 64 years,

one-third <60 years

• EUROASPIRE IV

– n=7998, all patients with

established CHD

– 87% on LLTs, almost

exclusively statins

• Almost 80% of patients on LLTs

failed to reach an LDL-C goal of

<1.8 mmol/L (<70 mg/dL)

42%

79% NOT at goal

79% of patients on LLTs did

NOT achieve an LDL-C

goal of <1.8 mmol/L

(<70 mg/dL)

Only 21% of

patients on

LLTs were at

goal

Aggressive Reduction of LDL-cholesterol

PCSK9 inhibitors

Pro-protein convertase subtilisin-like kexin type 9

(PCSK9) is a secreted protease of 692 amino acids

primarily expressed in the liver, intestine and kidney

36

MECHANISMS OF ACTION OF STATINS AND MAb AGAINST PCSK9

PCSK9: From discovery to therapeutic

Applications – Michel Farnier - Archives of Cardiovascular Disease (2014) 107, 58—66

Statins + PCSK9 inhibitors : may prove synergistic

Mean Percentage Changes in Lipid Parameters with PCSK9 Inhibitors

Robinson JG et al. NEJM 2015;372:1489-99Sabatine MS et al. NEJM 2015;372:1500-9

PCSK9 Inhibition

&

Regression of Atherosclerosis

PCSK9 Inhibition

&

Cardiovascular Outcomes

1.0 20.5

RR

0.51

0.82

Lower Odds Higher Odds

0.84Blacks

Whites 1.06

PCSK9 Loss of Function and Risk of

CHD or Stroke

Kent St et al. Circ Cardiovasc Genet. 2017;10:e001632

Blacks

Whites

Stroke

CHD

Outcome Studies

Evolocumab

Fourier (NCT01764633) Enrolling MI, CVA, or PAD + RF; Rx with atorva ≥ 20 mg or equivalent; LDL > 70 or nonHDL > 100; Endpoint – time to 1st

ASCVD event; Rx w/ 140 Q2W or 420 mg QM vs placebo; n=27,500

Bococizumab

Spire-1 (NCT01975376) Enrolling high risk CVD event; LDL 70-100 or nonHDL 100-130; on LLRx; Randomized to Boco 150 mg SC Q2W vs placebo; n=12,000

Spire-2 (NCT01975389) Same as above except LDL > 100 or nonHDL > 130; n=6300

Alirocumab

ODYSSEY Outcomes (NCT01663402)

Enrolling post-acute MI or hospital UA w/in 12 mon; Rx w/ atorva40/80 mg/d, rosuva 20/40 mg/d or max tolerated; LDL > 70, nonHDL > 100, or apo B > 80; Endpoint – time to ASCVD event; n=18,000

www.clinicaltrials.gov

ODYSSEY Outcomes: Study Design

• Patient population:

– Recent ACS (4-52 wks before randomization*)

– At least one of the following: LDL-C ≥70 mg/dL (1.81 mmol/L), or non-HDL-C ≥100 mg/dL (2.59 mmol/L), or apo B ≥80 mg/dL despite optimal statin treatment

Run-In Period

(up to 16w)

Double-Blind Treatment Period

(~ 2 to 5 years)

R

Background Lipid Treatment: Atorvastatin 40/80mg, rosuvastatin 20/40 mg, or maximal tolerated dose of one of these statins, with non-

statin lipid treatments allowed

Diet: NCEP-ATPIII Therapeutic Lifestyle Changes or equivalent throughout study

• Upon amendment 6 approval only (4-16 weeks prior to amendment 6 approval)

• ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces

cardiovascular morbidity and mortality after ACS.

Until Month 2:

75 mgevery 2w

At Month 2 and beyond:

75 mg or 150 mg every 2w(adjusted at Month 2 in blinded fashion to achieve LDL-C<50 mg/dl)

Placebo (n=9000)

Alirocumab (n=9000)

• Primary endpoint: Composite of

– CHD death

– Non-fatal MI

– Ischemic stroke

– Unstable angina requiring hospitalization

M2

Randomization

Schwartz G.G., et al., American Heart Journal 2014 168:5 (682-689.e1) 43

FOURIER: Study population

• FOURIER: Further cardiovascular OUtcomes Research

with PCSK9 Inhibition in subjects with Elevated Risk

Sabatine MS, et al. Am Heart J 2016;173:94–101.

27,564 patients aged 40–85 years of age

Fasting LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL

Clinically evident cardiovascular disease• History of myocardial infarction

• Non-haemorrhagic stroke

• Symptomatic peripheral artery disease

Plus ≥1 additional CV risk factors

5330 (19.3 %)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Key Subgroups

Subgroup Patients

Overall 27564

Type of disease

MI alone 19113

Stroke alone 3366

PAD alone 1505

Polyvascular disease 3563

Baseline LDL-C

Q1 (<80 mg/dl) 6961

Q2 (80-<92 mg/dl) 6886

Q3 (92-109 mg/dl) 6887

Q4 (>109 mg/dl) 6829

Baseline statin intensity

High 19103

Not high 8461

Ezetimibe

Yes 1440

No 26124

Initial Dosing Regimen

Every 2 weeks 24774

Monthly 2790

PEP HR (95% CI) Key SEP HR (95% CI)

1.0

EvoMab better Pbo better

0.4 2.5 1.0

EvoMab better Pbo better0.4 2.5

All Pinteractions NS

Lipid lowering prevents strokes

Amarenco Lancet Neurol 2009;


FOURIER / Sabatine NEJM 2017

1.0 20.5

RR



Setting


+ Ezetimibe 2° prevention 0.79*

+ Evolocumab 2° prevention 0.79*

Aggressive Reduction of LDL-cholesterol

&

Safety issues?

No apparent detrimental effects associated with very low LDL-C

[To convert, 100 mg/dL=2.59 mmol/L].

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHF, congestive heart failure; CK,

creatine kinase; CV, cardiovascular; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

1. Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411–6; 2. Hsia J, et al. J Am Coll Cardiol 2011;57:1666–75; 3. Giugliano

RP, et al. Presented at European Society of Cardiology, London, 2015.

PROVE-IT TIMI 221 IMPROVE-IT3JUPITER2

Atorvastatin 80 mg vs

pravastatin 40 mg

Simvastatin 40 mg ±

ezetimibe 10 mg

Rosuvastatin 20 mg vs

placebo

• ≤40 mg/dL

• >40–60 mg/dL

• >60–80 mg/dL

• >80–100 mg/dL

• <30 mg/dL

• 30–50 mg/dL

• 50–70 mg/dL

• ≥70 mg/dL

• <50 mg/dL

• >50 mg/dL

Hemorrhagic stroke, liver-

related events, muscle-

related events, retinal AEs,

trauma/suicide, study drug

discontinuation due to AEs

Study drug discontinuation

due to AEs, myalgias with

CK↑, hemorrhagic stroke,

AST/ALT >3x, neuro-

cognitive AEs, gall bladder

AEs, cancer, CHF causing

hospitalization, non-CV death

All treatment-emergent

AEs

No difference in the frequency of adverse events was reported between

patient groups with differing LDL-C levels

Yes YesNo

Study

treatment

History

of CVD?

LDL-C

groups

Safety

endpoints

assessed

Safety

Evolocumab

(N=13,769)

Placebo

(N=13,756)

Adverse events (%)

Any 77.4 77.4

Serious 24.8 24.7

Allergic reaction 3.1 2.9

Injection-site reaction 2.1 1.6

Treatment-related and led to d/c of study drug 1.6 1.5

Muscle-related 5.0 4.8

Cataract 1.7 1.8

Diabetes (new-onset) 8.1 7.7

Neurocognitive 1.6 1.5

Laboratory results (%)

Binding Ab 0.3 n/a

Neutralizing Ab none n/a

New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

Lancet 2017;Aug28

1.0 20.5

RR

Statins 1° prevention 0.81

Setting



1.38+ Ezetimibe 2° prevention

+ Evolocumab 2° prevention 1.16

Lipid lowering may increase

hemorrhagic strokes

Amarenco Lancet Neurol 2009;


FOURIER / Sabatine NEJM 2017

Statins and cognitionCurrent knowledge

Regulatory authorities

UK: MHRA warning in 2009

USA: FDA warning in 2012

PROSPER and HPS: no cognitive effects

4 RCT of statins for Alzheimer’s: no effects

PROSPER: Trompet J Neurol 2010; HPS: Lancet 2002

Alzheimers: McGuinness / Cochrane 2014

“ Given the weight of evidence against adverse effects

of statin therapy on memory or other aspects of

cognition, .... it would now be appropriate ... to

consider their removal from lists of potential adverse

effects on the drug labels.” (Collins Lancet 2016)

Courtesy of P. Michel

Lipid lowering and strokeSummary of scientific data

Statins: significant reduction of stroke (1° and 2° prev.)

1 mmol/L LDL reduction = 21-26% stroke ↓

↑ Risk of hemorrhagic stroke in 2° prev. ???

Amarenco Lancet Neurol 2009; IMPROVE-IT/ Cannon NEJM 2015

*CTTC Lancet 2010; FOURIER / Sabatine NEJM 2017

No ↑ risk of

hemorrhagic

stroke; no cogn.

problems

Adding ezetimibe: 21% stroke ↓

Adding evolocumab : 21% stroke ↓

Courtesy of P. Michel

Ischemic Stroke: Multi-modalIntervention

Lipid-lowering

therapy

Lifestyle

Changes

BP controlGlycemic

control

Antiplatelet / Anticoagulant Tx

CVD Risk

Reduction

statins and pcsk9 inhibitors for stroke prevention...statins and pcsk9 inhibitors for stroke...

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