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Statins and PCSK9 inhibitors for stroke prevention
Haralampos Milionis
Professor of Internal Medicine
School of Medicine, University of Ioannina
Ioannina, Greece
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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)
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Major Statin trials in Primary Prevention and Risk of Stroke
Barkas F & Milionis H. Semin Neurol 2017;37:286-93
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Statins
&
Neuroprotection?
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Potential mechanisms whereby
statins may reduce the risk of stroke
P. Amarenco, et al. Arch Med Sci 2007;3:S109-S114
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Stroke reduction and
neuroprotection by statins
Vaughan C J , Delanty N Stroke 1999;30:1969-1973
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Statins
&
Acute phase of stroke
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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
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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
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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
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Statin treatment withdrawal in ischemic stroke: A controlled randomized study
Neurology 2007;69:904–910
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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
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Results
Bianco M et al. Neurology 2007;69:904–910
4.668.67
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Statins
&
Secondary Prevention
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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
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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
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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)
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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
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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
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• 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
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Post-discharge Statin Therapy
and Outcome After 1st ever
Ischemic Stroke:The Athenian Stroke Registry
Milionis H et al. Neurology 2009;72:1816-22
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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%
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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%
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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
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Lipid lowering prevents strokes
Amarenco Lancet Neurol 2009
IMPROVE-IT/ Cannon NEJM 2015
1.0 20.5
RR for
any stroke type
Treatment better Placebo better
Statins 1° prevention 0.81*
Statins 2° prevention 0.88*
+ Ezetimibe 2° prevention 0.79*
Setting
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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
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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
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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
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Aggressive Reduction of LDL-cholesterol
PCSK9 inhibitors
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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
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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
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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
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PCSK9 Inhibition
&
Regression of Atherosclerosis
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PCSK9 Inhibition
&
Cardiovascular Outcomes
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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
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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
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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
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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 %)
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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
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Lipid lowering prevents strokes
Amarenco Lancet Neurol 2009;
IMPROVE-IT/ Cannon NEJM 2015
FOURIER / Sabatine NEJM 2017
1.0 20.5
RR
Treatment better Placebo better
Statins 1° prevention 0.81*
Setting
Statins 2° prevention 0.88*
+ Ezetimibe 2° prevention 0.79*
+ Evolocumab 2° prevention 0.79*
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Aggressive Reduction of LDL-cholesterol
&
Safety issues?
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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
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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
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Lancet 2017;Aug28
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1.0 20.5
RR
Statins 1° prevention 0.81
Setting
Statins 2° prevention 1.73*
Treatment better Placebo better
1.38+ Ezetimibe 2° prevention
+ Evolocumab 2° prevention 1.16
Lipid lowering may increase
hemorrhagic strokes
Amarenco Lancet Neurol 2009;
IMPROVE-IT/ Cannon NEJM 2015
FOURIER / Sabatine NEJM 2017
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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
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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
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Ischemic Stroke: Multi-modalIntervention
Lipid-lowering
therapy
Lifestyle
Changes
BP controlGlycemic
control
Antiplatelet / Anticoagulant Tx
CVD Risk
Reduction