Download 02 PACE Cardiovascular risk - pace

Cardiovascular risk management:
What are the strategic changes?
Prof. John Deanfield
University College London
London, United Kingdom
Death / 100,000 population
Death Rates from All Circulatory Disease in England
1993-2011
180
A fall of 55% since baseline
160
140
Target:
120
40%
100
80
minimum
reduction
from
1995-97
60
40
Immortality
Guaranteed by 2026
20
0
B/L
Progress
target
Source: ONS (ICD9 390-459; ICD10 I00-I99)
Treatment of CVD: Residual Risk
% CV events
100
0
Statins
40%
Residual
Risk
60%
CHD Impact of Early vs Late LDL Lowering
Mendelian Randomisation Studies of 9 Polymorphisms in 6 Genes
Ference J Am Coll Cardiol 2012; 60: 2631–9
Lifetime Risk of Death from CV Disease
Berry NEJM 2012; 366: 321-329
Early intervention
pays long term
dividends
A reasonable next step for ATP IV?
….Consider statins for younger
persons, perhaps starting at 30
in those with risk factors that
convey high lifetime risk (as
opposed to 10 yr risk) for CHD
Pletcher JACC 2010; 56: 637-640
Benefits of further
lowering of causal
factors?
Frequency (%)
30
No Nonsense
Mutation
(n=3278)
50th
Percentile
20
10
0
30
0
50 100 150 200
PCSK9142X
or PCSK9679X
(N=85)
250
300
28%
20
12
P=0.008
8
88%
4
0
No
10
0
Coronary Heart Disease (%)
LDL Cholesterol and Coronary Heart Disease among
Black Subjects by PCSK9142X or PCSK9679X Allele
Yes
PCSK9142X or PCSK9679X
0
50 100 150 200 250 300
LDL Cholesterol in Black Subjects (mg/dl)
Cohen NEJM 2006; 354:1264-72
PCSK9 Monoclonal AB in heFH Patients
% Change in LDL-C from Baseline
0
TC
Non-HDL-C
ApoB
Lp(a)
-10
-20
-30
-40
-50
-60
Stein Lancet 2012; 380: 29-36
Life Course Blood Pressure and Mortality
Harvard Alumni Health Study
Survival from CVD
10
8
6
4
Normal
Stage 1 hypertension
2
20
40
Pre-hypertension
Stage 2 hypertension
60
80
Follow up time (years)
Gray JACC 2011; 58: 2396-403
BP Treatment in Type 2 DM
4733 age 62.2 years intensive vs standard BP treatment over 4.7 years
ACCORD Study Group NEJM 2010;362:1575-1585
Lifetime Risk from Blood Pressure: NICE
Short-term (10-year) risk
underestimates lifetime CV
risk of young people with
hypertension... Lifetime risk
with untreated stage 1
hypertension in this age
group could be substantial.
Lifetime risk assessments
may be a better way to
inform treatment decisions
and evaluate cost
effectiveness of earlier drug
therapy.
Evidence for residual risk from
other risk factors and pathways
Need Treatments for New
Targets
Hazard Ratio
Coronary Heart Disease and HDL-C
3.5
3.0
2.5
N = 302,430
2.0
1.5
1.0
0.8
30
40
50
60
HDL-C (mg/dL)
70
80
The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000
Dalcetrapib in Patients With Recent ACS
Schwartz NEJM 2012; 367: 2089-2099
HDL Trials:Reasons for Failure
• Failure of molecule -Toxicity
-Potency
• Failure of biology
-HDL not on causal pathway
-Wrong pathway for drug
-HDL properties may change
-Wrong stage of disease
HDL : Effects on endothelial
NO production in patients with CAD
Endothelial NO production
[in % of buffer-treated cells]
Healthy
P<0.025
30
sCAD
ACS
20
10
0
-10
-20
25 mg/ml
HDL
50 mg/ml
HDL
100 mg/ml
HDL
Besler C et al. & Landmesser U. J Clin Invest (in press)
Dalcetrapib HDL Function Study
25 dalcetrapib treated
DALCETRAPIB
25 placebo-treated
Serum
collection
PLACEBO
12 wks
Baseline
36 wks
HDL isolation
density ultracentrifugation
Endothelial Nitric Oxide production
ESR spectroscopy
Endothelial anti-apoptotic capacity
Inhibition of caspase-3 expression
Endothelial anti-inflammatory capacity
Inhibition of VCAM-1 expression
Anti-inflammatory
capacity of HDL
Anti-apoptotic
capacity of HDL
Effect of HDL on
NO production
Dalcetrapib and HDL Function
Placebo
Dalcetrapib
Late-stage Drug Development Failure
A major productivity limiting barrier
Late-stage failure
Pre-clinical development
Clinical studies
Cost
$4-11B
Kola & Landis, Nat Rev Drug Disc. 2004
Arrowsmith, Nat Rev Drug Disc, 2011
Bunnage, Nature Chemical Biology, 2011
Arrowsmith, Nature Reviews Drug Disc, 2011
Time
~12yrs
In Search of Fewer independent Risk Factors
Brotman Arch Intern Med. 2005; 165: 138-145
New approaches
to refine target
validation, safety
and efficacy
RCT as an arbiter of molecule efficacy and safety, and target validity
Drug
intervention
Genetics:
natural randomisation
RCT (Phase III)
Mendelian randomisation
Sample
Population
Randomisation
Random allocation of alleles
Protein target: HMGCR
HMG-CoA red inhibitor
LDL-C reduced
CV event
rate lower
Placebo
LDL-C unchanged
Off target
CV event
rate higher
Protein target: HMGCR
HMGCR aa
LDL-C reduced
Genotype AA
LDL-C unchanged
HMGCR variant (rs12916) reduce
CV
event
event
LDL-C
by -0.07 mmol/L,CV
and
risk of
rate
lower
rate
higher
CHD (OR of 0.94; 95%CI: 0.90, 0.98).
JACC 2013
Finding new indications for existing medications
Genetics: natural randomisation
Drug intervention
(IL6R blocker licensed for Rheumatoid arthritis)
Population
Sample
Randomisation (Tocilizumab)
Random allocation of IL6R alleles
Protein target: IL6R
Protein target: IL6R
IL6R- blocker (MAB)
IL6R aa
IL6R AA
Reduced IL6 signalling
IL6 signalling unchanged
CV event
rate lower
CV event
rate higher
Placebo
Reduce IL6 signalling IL6 signalling unchanged
RA disease
activity higher
RA disease
Activity lower
Biomarker
Tocilizumab
IL6R SNP
IL-6

(n=1,446)

(n=29,838)
CRP

(n=3,010)

(n=76,527)
Fibrinogen

(n=409)

(n=52,667)
Soluble IL-6R
Albumin


(n=1,465)
(n=108)


(n=1,454)
(n=5,787)
Haemoglobin

(n=2,072)

(n=17,898)
Finding new indications for existing medications
Drug intervention
Genetics: natural randomisation
(IL6R blocker licensed for Rheumatoid arthritis)
Sample
Swerdlow, Lancet 2012
Randomisation (Tocilizumab)
Protein target: IL6R
IL6R- blocker (MAB)
Placebo
Reduce IL6 signalling
IL6 signalling unchanged
RA disease
Activity lower
RA disease
activity higher
Biomarker
Tocilizumab
IL6R SNP
IL-6

(n=1,446)

(n=29,838)
CRP

(n=3,010)

(n=76,527)
Fibrinogen

(n=409)

(n=52,667)
Soluble IL-6R
Albumin


(n=1,465)
(n=108)


(n=1,454)
(n=5,787)
Haemoglobin

(n=2,072)

(n=17,898)
Harmful effects of first-in-man drugs: On- vs Off-target effects
CETP genetic variant recapitulates the
effects of pharmacological CETP inhibition
on blood lipids, but does not share the BP
raising effect of torcetrapib
CETP
genotypes
Individuals
(studies)
Systolic BP
Drug Randomisation
Mean Difference
(95% CI)
B1B2 v B1B1 46,412 (21)
-0.27 (-0.64, 0.10)
B2B2 v B1B1 29,050 (21)
0.16 (-0.28, 0.60)
-2
Sample
Torcetrapib
Control
0
mmHg
CETP-inhibition
No-CETP inhibition
Change in lipid traits
No change in lipids
BP
(Off-target)
HDL
LDL
TRG
CV Risk Management: What is Needed?
•
•
•
Opportunities from novel therapies to
reduce residual CV risk
Optimal approach will involve lifetime
management of RFs
Better strategies to refine
priorotization of new drug targets
needed