Patient oriented treatment for prevention of CVD : New targets · An Academic Research Organization...
Transcript of Patient oriented treatment for prevention of CVD : New targets · An Academic Research Organization...
25/02/2018
Dov Gavish MD
Wolfson hospital
Tel Aviv University
ISRAEL
Patient oriented treatment for
prevention of CVD : New targets
,Individual goals
Multiple factors contribute to increased CV risk
CRP, C-reactive protein; CV, cardiovascular; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride.
1. World Heart Federation. Cardiovascular disease risk factors. www.world-heart-federation.org/cardiovascular-
health/cardiovascular-disease-risk-factors. [Accessed 17 July 2015].
2. Dekker JM, et al. Circulation 2005;112:666–73.
3. Bhatt DL, et al. JAMA 2010;304:1350–7.
4. Lagrand WK, et al. Circulation 1999;100:96–102.
5. Go AS. N Engl J Med 2004;351:1296–305.
Increased CV risk
Prior CV event/manifest
atherosclerosis3
Smoking, physical
inactivity1
Obesity1
Lipid disorders1
(LDL, HDL, TG)
Type 2 diabetes1
Hypertension1
High CRP,4
chronic kidney disease5
Metabolic syndrome2
Age, ethnicity, gender, family history/genetic
variations1
Focus on Critical Steps
• Deposition of cholesterol in the artery wall by LDL
• Oxidation of LDL
• Inflammation
• Attraction of monocytes and/or macrophages and plaque development
Elevated LDL-C: central in the pathogenesis of CVD, increasing risk for a CV event
ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; CETP, cholesteryl ester transfer protein; CRP,
C-reactive protein; CV, cardiovascular; CVD, cardiovascular disease; HDL, high-density lipoprotein; IL-6,
interleukin-6; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); OxPL, oxidized phospholipids.
Jensen MK, et al. Nat Revs Endocrinol 2014;10:659–72.
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Current Guidelines: LDL-C Targets
J Clin Lipidol 2015;9:129-69; EHJ 2016;37:2999-3058; JACC 2016;68:92-105
• Patients whose LDL-C cannot be controlled with
intensive statin therapy ± other current therapies
– High-risk patients (e.g., secondary prevention, diabetic) in
whom we cannot get LDL-C low enough
– Most patients with HeFH
– Almost all patients with HoFH
• Patients who cannot take a statin, or an effective dose
– Statin-intolerant, or for whom a statin is contraindicated
Which patients’ needs are not being met by current therapies?
HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia;
LDL-C, low-density lipoprotein cholesterol.
FDA Briefing Document (EMDAC) June 10 2015.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologicand
MetabolicDrugsAdvisoryCommittee/UCM452354.pdf. [Accessed 9 July 2015].
From: Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic,
epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society
Consensus Panel
Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144 Main approach for LDL reduction
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PCSK9 inhibitor CV outcomes trial
design comparison
*Non-haemorrhagic stroke.1.Sabatine MS, et al. Am Heart J 2016;173:94–101.2.Schwartz GG, et al. Am Heart J 2014;168:682–9.
History of MIn = 22,356
PADn = 3640
History of stroke*n = 5330
ODYSSEY OUTCOMES2
N ~ 18,000FOURIER1
N = 27,564
Recent MI< 1 year
An Academic Research Organization of
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Summary of
FOURIER
• LDL-C by 59% (from 2.4 -> 0.8 [0.5, 1.2] mM)
• CV outcomes in patients already on statin therapy
• Evolocumab was safe and well-tolerated
0.0
0.5
1.0
1.5
2.0
2.5
0 4 12 24 48 72 96 120 144 168
LD
L-C
(m
M)
Weeks after randomization
EvolocumabMedian 0.78 mM
IQR [0.49-1.27]
Placebo
59% mean
decline P<0.00001
Absolute↓1.45 mM
(1.42-1.47)
14.6
9.9
12.6
7.9
0
5
10
15
CV death, MI, stroke,UA, cor revasc
CV death, MI, stroke
KM
Rate
(%
) at
3 Y
ears
Placebo
HR 0.80
(0.73-0.88)
P<0.00001
HR 0.85 (0.79-
0.92)
P<0.0001
Sabatine MS et al. New Engl J Med 2017;376:1713-22
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CV Death, MI, Stroke, UA, or Coronary Revasc
Giugliano RP, ESC Congress 2017, Barcelona
8/28/2017
LDL-C (mM)
Adj HR
(95% CI)
<0.5 0.76 (0.64-
0.90)
0.5-1.3 0.85 (0.76-
0.96)
1.3-1.8 0.94 (0.82-
1.09)
1.8-2.6 0.97 (0.86-
1.09)
> 2.6 referent
P =
0.0012
LDL-C (mM) at 4
weeks
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
FOURIER – Sub Analysis
Lessons concerning individuals at an
extreme risk for whom LDL target
should be even lower
An Academic Research Organization of
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27,564
Patients with
Atherosclerosis
Randomized
3,642
Patients with
Symptomatic Lower
Extremity Peripheral
Artery Disease
1,505
Patients with
Symptomatic Lower
Extremity Peripheral
Artery Disease and no
prior MI or Stroke
Patients with Peripheral
Artery Disease57%
Peripheral Revascularization
(Median 3.7 years prior)
26%
955
27%
1,044
42%
1517
27
4%Amputation for
Ischemia
39
4119
69%Intermittent Claudication &
ABI < 0.85 at Baseline
An Academic Research Organization of
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Peripheral Artery Disease and Risk in
Placebo Patients
Days from Randomization
CV
D /
MI / S
tro
ke
adjusted age, sex, race, BMI, diabetes, hypertension, smoking, eGFR, CHF, prior MI,
CABG/PCI, and history of stroke or TIA.
0%
2%
4%
6%
8%
10%
12%
14%
16%
0 180 360 540 720 900Days from Randomization
0%
2%
4%
6%
8%
10%
12%
14%
16%
0 180 360 540 720 900
P=0.0028
7.6%
10.3%
14.9%
P=0.0001
CV
D /
MI / S
tro
ke
7.6%
13.0%Adjusted HR
1.81(1.53 – 2.14)
P<0.001
PAD N=1784
MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N=11996
PAD with MI/Stroke N=1036
PAD no MI/Stroke N=748
An Academic Research Organization of
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CV
De
ath
, M
I o
r S
tro
ke
Placebo
Evolocumab
13.0%
7.6%
9.5%
6.2%
PAD
3.5% ARR
NNT2.5y 29
No PAD
1.4% ARR
NNT2.5y 72
PADN=3,642
27% RRR
HR 0.73
(0.59 – 0.91)
P=0.0040
p-interaction = 0.41
No PAD
N=23,922
HR 0.81
95% CI (0.73 – 0.90)
P<0.001
Days from Randomization
CV Death, MI or Stroke in Patients with
and without Peripheral Artery Disease
0%
2%
4%
6%
8%
10%
12%
14%
0 90 180 270 360 450 540 630 720 810 900
An Academic Research Organization of
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0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900
CV
De
ath
, M
I o
r S
tro
ke
Days from Randomization
Placebo
Evolocumab
10.3%
5.5%
PAD
4.8% ARR
NNT2.5y 21
PAD
(no MI/stroke, N=1505)
43% RRR
HR 0.57
(0.38 – 0.88)
P=0.0095
CV Death, MI or Stroke in Patients with
PAD and no MI or Stroke
Outcome HR 95% CI
MACE 0.57 (0.38–0.88)
CV Death 0.78 (0.39–1.57)
MI 0.66 (0.38–1.14)
Stroke 0.30 (0.11–0.82)
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Conclusion
LDL-C reduction to very low levels should be
considered in patients with PAD, regardless of
history of MI or stroke, to reduce the risk of
MACE and MALE
For more information see simultaneous publication in:
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Background & Objective
Patients at higher CV risk may derive greater benefit
from PCSK9 inhibition
Within the broad subgroup of patients w/ prior MI in
FOURIER, we investigated if readily ascertainable clinical
features of the CAD history identified patients:
1) At higher CV risk
2) Who derived greater benefit from PCSK9 inhibition
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Risk of CV Death, MI or Stroke
with Each Risk Factor
10.8%
9.3%
0%
2%
4%
6%
8%
10%
12%
14%
16%
<2 yrs ≥2 yrs
CV
D, M
I o
r S
tro
ke
(3-y
r K
M)
in P
bo
Years from Qualifying MI
HR 1.19
(1.04-1.37)
P=0.01 15.0%
8.2%
0%
2%
4%
6%
8%
10%
12%
14%
16%
≥2 1
# of Prior MIs
HR 2.04
(1.78-2.35)
P<0.001
12.6%
8.9%
0%
2%
4%
6%
8%
10%
12%
14%
16%
Yes No
Multivessel Disease
HR 1.47
(1.27-1.70)
P<0.001
Analyses in placebo arm
An Academic Research Organization of
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Benefit of EvoMab Based on
Time from Qualifying MI Qualifying MI <2 yrs ago
Months after Randomization
CV
De
ath
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
24% RRR
HR 0.76
(95% CI 0.64-0.89)
P<0.001 7.9%
10.8%
Pinteraction=0.18
D 2.9%
NNT 35
Evolocumab
Placebo
8.3%
9.3%
D 1.0%
NNT 101
Qualifying MI ≥2 yrs ago
13% RRR
HR 0.87
(95% CI 0.76-0.99)
P=0.04
0 6 12 18 24 30 36
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Benefit of EvoMab Based on
# of Prior MIs ≥2 Prior MIs
Months after Randomization
CV
De
ath
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
21% RRR
HR 0.79
(95% CI 0.67-0.94)
P=0.006
12.4%
15.0%
Pinteraction=0.57
D 2.6%
NNT 38
Evolocumab
Placebo
6.6%
8.2%
D 1.7%
NNT 60
1 Prior MI
16% RRR
HR 0.84
(95% CI 0.74-0.96)
P=0.008
0 6 12 18 24 30 36
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Benefit of EvoMab Based on
Multivessel DiseaseMultivessel Disease
Months after Randomization
CV
De
ath
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
30% RRR
HR 0.70
(95% CI 0.58-0.84)
P<0.001 9.2%
12.6%
Pinteraction=0.03
D 3.4%
NNT 29
Evolocumab
Placebo7.6%
8.9%
D 1.3%
NNT 78
No Multivessel Disease
11% RRR
HR 0.89
(95% CI 0.79-1.00)
P=0.055
0 6 12 18 24 30 36
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Overlap Between Factors
22,351 patients
w/ prior MI
8402 Pts
<2 y from MI
5618 Pts
w/ MVD
5285 Pts
≥2 MIs
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Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on
# of High-Risk MI Features
Months after Randomization
CV
De
ath
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
Pinteraction=0.11
Evolocumab
Placebo≥1 Feature
22% RRR
2.5% ARR
N=13,973 (63% of prior MI trial population)
High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or residual multivessel disease
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Summary
• Patients (1) closer to their most recent MI,
(2) with multiple prior MIs, or
(3) with multivessel disease
are at 34-90% risk for major vascular events
• These patients experience substantial:
- relative risk reductions (21-30%) and
- absolute risk reductions (2.6-3.4% over 3 yrs)
with intensive LDL-C lowering w/ the PCSK9i evolocumab
These readily ascertainable clinical features offer one
approach to tailoring therapy
26
RESULTSFigure 1: Risk Stratification for MACE with Placebo
# RI 0/1 2 3 4 ≥5
At Risk 747 3015 4468 3444 2106
% Pts 5 22 32 25 15
Events 32 154 278 257 292
Risk Indicators Points
CHF 1
HTN 1
Age ≥ 75 1
DM 1
Prior Stroke 1
Prior CABG 1
PAD 1
eGFR < 60 1
Current Smoking 1
Prior MI 1
Max Possible 10
5.0%
7.8% 8.2%9.8%
19.1%
0%
5%
10%
15%
20%
25%
3Y
r K
M M
AC
E
Low
Risk
Intermediate
Risk
High
Risk
P-trend<0.0001
• The integer-based scheme showed a strong, graded relationship with the rate of CV
death, MI or CVA and the components at 3 yrs in both treatment arms (Fig 1; p-trend
< 0.0001 for all endpoints; c-statistic = 0.61 [0.67 in prior validation set]).
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RESULTSFigure 3: MACE by Risk Category & Randomized Treatment
• Low-risk pts had a 1.2% ARR, intermediate-risk a 1.9% ARR and high-risk a 3.6% ARR
in MACE at 3 years with EvoMab vs Pbo, translating to a NNT3Yr of 83, 53 and 28,
respectively (Fig 3).
Risk (Score) Low (0/1) Intermediate (2-4) High (≥5)
5.0%
8.6%
19.1%
3.8%
6.7%
15.5%
0%
5%
10%
15%
20%
25%
3Y
r K
M R
ate
of
MA
CE
Pbo EvoMab
P-trend < 0.001 for both treatments
P-interaction = 0.94
HR 0.73 (0.43, 1.23)
ARR 1.2%
HR 0.79 (0.71, 0.89)
ARR 1.9%
HR 0.80 (0.67, 0.95)
ARR 3.6%
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CONCLUSIONS
• In FOURIER, the TIMI Risk Score for Secondary Prevention
(TRS 2ºP):
– Predicted a gradient of risk for major adverse CV events
– Identified high-risk pts w/ ASCVD who demonstrate a pattern of greater
ARR in major CV events with EvoMab, with an NNT3Yr ~ 25 in the
highest risk.
• This strategy may prove useful to personalize the
intensification of secondary preventative therapies.
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Brigham and Women’s Hospital and Harvard Medical School
Cardiovascular Efficacy & Safety of
Evolocumab in Diabetes,
and Risk of Development of Diabetes:
An Analysis from the FOURIER Trial
MS Sabatine, LA Leiter, SD Wiviott, RP Giugliano, P Deedwania, GM De
Ferrari, SA Murphy, JF Kuder, AC Keech, PS Sever, and TR Pedersen,
for the FOURIER Steering Committee & Investigators
European Association for the Study of Diabetes – 53rd Annual Meeting
Clinical Trial Update
September 15, 2017SC-EU-AMG145-00708
Approved September 2017
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Risk of Primary Endpoint
with Diabetes
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
No diabetes at baseline
Diabetes at baseline
Months after Randomization
CV
Dea
th, M
I, S
tro
ke
,
Ho
sp
fo
r U
A,
or
Co
rR
eva
sc
0 6 12 18 24 30 36
Adj Hazard Ratio 1.26
(95% CI 1.13-1.40)
P<0.0001 13.0%
17.1%
Analyses in placebo arm and adj for age, sex, BMI, race, region,
history of MI, stroke, PAD, HTN, smoking, HF, eGFR, lipids,
statin.
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Effect of Evolocumab
on Primary Endpoint
Patients w/o Diabetes at BaselinePatients w/ Diabetes at Baseline
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Months after Randomization
CV
Dea
th, M
I, S
tro
ke
,
Ho
sp
fo
r U
A,
or
Co
rR
eva
sc
0 6 12 18 24 30 360%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Hazard Ratio 0.83
(95% CI 0.75-0.93)
P=0.0008
14.4%
17.1%
0 6 12 18 24 30 36
Hazard Ratio 0.87
(95% CI 0.79-0.96)
P=0.0052
11.4%
13.0%
Pinteraction=0.60
D 2.7%
NNT 37
D 1.6%
NNT 62
Evolocumab
Placebo
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Brigham and Women’s Hospital and Harvard Medical School
Conclusion
Use of evolocumab is particularly clinically efficacious
in ASCVD patients with diabetes,
and evolocumab does not cause diabetes
or worsen glycemia in patients with or without diabetes
in the timeframe we studied.
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0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
Patients with
Baseline LDL-C <70 mg/dL
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke
0 6 12 18 24 30
N=2034
Hazard ratio 0.70
(95% CI, 0.48-1.01)
5.2%
7.7%
Use Ileo femoralis Aorta and Carotids plus CAC
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The best way to reduce inflammation
From: Anti-inflammatory therapies for cardiovascular diseaseEur Heart J. 2014;35(27):1782-1791. doi:10.1093/eurheartj/ehu203
Eur Heart J | Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions
please email: [email protected]
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