Breast Cancer Risk Assessment: Calculating Lifetime Risk ...
The concept of Diabetes & CV risk: A lifetime risk challenge
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Transcript of The concept of Diabetes & CV risk: A lifetime risk challenge
The concept of Diabetes & CV risk:A lifetime risk challenge
The Clinical Significance of LDL-Cholesterol: No Longer a Hypothesis?
John J.P. Kastelein, MD PhDAcademic Medical Center University of AmsterdamDept. Vascular MedicineAmsterdam, The Netherlands
Master Class Lipid InnovationsPrague, Czech RepublicMay 27-28, 2011
Slide lecture prepared and held by:
Presentation topic
Mortality from Ischemic Heart Disease and Cholesterol 3,020 Deaths
Prospective Studies Collaboration. Lancet 2007;370:1829
128
64
32
16
8
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2
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1.0 1.5Usual HDL-C (mmol/L) Usual non-HDL-C (mmol/L) Usual total/HDL-C (mmol/L)
3.0 4.0 5.0 6.0 3.0 4.0 5.0 6.0 7.00.5
A. HDL-C B. non-HDL-C C. Total/HDL-CAge at risk(years)
70-89
60-69
40-69
Age at risk(years)
70-89
60-69
40-69
70-89HR 0.69(0.63-0.74)
60-69HR 0.60(0.56-0.64)
40-69HR 0.56(0.51-0.60)
Age at risk(years)
Discoveryof statins
Discoveryof LDLreceptors
Endo, 1976 Brown andGoldstein,1974
Statins raise LDLreceptors in the liver
Plasma LDL is reduced
Primary prevention trials
Secondary prevention trials
50 70 110 130 150 170 19090 210 % P
atie
nts
with
CH
D E
ven
t
LDL cholesterol
CARE-Rx
4S-Rx
LIPID-PL
4S-PL
CARE-PL
LIPID-Rx
AFCAPS-Rx
WOSCOPS-Rx
WOSCOPS-PL
AFCAPS-PL
25
20
15
10
5
0
ASCOT-PL
ASCOT-Rx
HPS-Rx
HPS-PL
HPS
LRC-PLLRC-Rx
POSCH-PL
POSCH-Rx
non statin trials
Statin trials
(mg/dL)
1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)
TNT-80A
TNT-10A
Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy
Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis
Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–1862
LDL-C Reduction, %4025 30 3515 20
Nonfa
tal M
I and C
HD
D
eath
Rela
tive R
isk
Reduct
ion,
%
–20
100
80
60
40
20
0
LondonOsloMRCLos AngelesUpjohnLRC NHLBIPOSCH4Sa
WOSCOPSa
CAREa
LIPIDa
AF/TexCapsa
HPSa
ALERTa
PROSPERa
ASCOT-LLAa
CARDSa
CTTC: 23% reduction in major vascular events for 1mmol/L lower LDL-C with statins
Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke
Number (%) of patients
Quintile 1<64 mg/dL(114/1722)*
Quintile 264–<77 mg/dL
(529/1403)*
Quintile 377–<90 mg/dL
(1019/968)*
Quintile 490–<106 mg/dL
(1515/515)*
Quintile 5106 mg/dL(1718/266)*
Suicide 1 (0.1) 0 (0.0) 1 (0.1) 1 (0.0) 1 (0.1)
Cancer 21 (1.1) 37 (1.9) 34 (1.7) 32 (1.6) 30 (1.5)
Hemorrhagic stroke† 6 (0.3) 5 (0.3) 6 (0.3) 8 (0.4) 7 (0.4)
*Number of patients: atorvastatin 10 mg/atorvastatin 80 mg†Fatal and non-fatal
Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receivestatin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests
Lancet, 2010; 376; 9756
GREACE: Enzyme Activity in Patients with Raised Liver Enzymes. A) On Statins B) Not On Statins
Lancet, 2010; 376; 9756
Lancet, 2010; 376; 9756
Study Treatment comparison
N Target population
Entry lipid criteria
PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL
A to Z S 40 then S 80 vs. placebo then S 20
4497 ACS TC ≤250 mg/dL
TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL
IDEAL A 80 vs. S 20-40 8888 Prior CHD TG ≤600 mg/dL
SEARCH S 80 vs. S 20 12,064 Prior CHD TC ≥4.5 mmol/L or ≥3.5 if on statins
Second CTT Cycle: More vs Less Intensive Statin Therapy
Study Treatment comparison
N Target population Entry lipid criteria
ALLIANCE A 10-80 (until LDL <80 mg/dL) vs. usual care
2442 Prior CHD LDL-C 110-200 mg/dL on lipid lowering drugs, 130-250 mg/dL if not
4D A 20 vs. placebo 1255 Type 2 DM + haemodialysis
LDL-C 80-190 mg/dLTG <1000 mg/dL
ASPEN A 10 vs. placebo 2410 Type 2 DM + CHD or risk factors
LDL-C <150, TG ≤445 mg/dL with CHD; LDL-C <159, TG ≤600 mg/dL without
MEGA P 10-20 vs. usual care
8214 Primary prevention TC 220-270 mg/dL
JUPITER R 20 vs. placebo 17 802 Primary prevention (but CRP>2 mg/dL)
LDL-C <130 mg/dL, TG <500 mg/dL
GISSI-HF R 10 vs. placebo 4574 CHF None
AURORA R 10 vs. placebo 2773 Haemodialysis None
Second CTT Cycle: Additional Trials of Statin vs Control
Absolute Effect of Statin Therapy onMAJOR VASCULAR EVENTS
0 1 2 3 4 5
05
1015
20
LDL cholesterol, mmol/L
Fiv
e ye
ar r
isk
of a
maj
orva
scul
ar e
vent
, %
Control
21% relative riskreduction per mmol/LStatin
15% relative riskreduction per 0.5 mmol/LMore statin
Combined evidence:~33% relative risk reductionper 1.5 mmol/L
Less statin
Proportional Effects on MAJOR VASCULAR EVENTS per mmol/L Reduction in LDL Cholesterol
0.4 0.6 0.8 1 1.2 1.4
No. of events (% pa)Statin/
More statinContr ol/
Relative risk (CI)
Statin/morestatin better
Control/lessstatin better
Nonfatal MI
CHD death
Any major coronary event
CABG
PTCA
Unspecified
Any coronary revascularisation
Ischaemic stroke
Haemorrhagic stroke
Unknown stroke
Any stroke
Any major vascular event
3485 (1.0)
1887 (0.5)
5105 (1.4)
1453 (0.4)
1767 (0.5)
2133 (0.6)
5353 (1.5)
1427 (0.4)
257 (0.1)
618 (0.2)
2302 (0.6)
10973 (3.2)
4593 (1.3)
2281 (0.6)
6512 (1.9)
1857 (0.5)
2283 (0.7)
2667 (0.8)
6807 (2.0)
1751 (0.5)
220 (0.1)
709 (0.2)
2680 (0.8)
13350 (4.0)
0.73 (0.69 - 0.78)
0.80 (0.74 - 0.87)
0.76 (0.73 - 0.78)
0.75 (0.69 - 0.82)
0.72 (0.65 - 0.80)
0.76 (0.70 - 0.82)
0.75 (0.72 - 0.78)
0.79 (0.72 - 0.87)
1.12 (0.88 - 1.43)
0.88 (0.76 - 1.01)
0.84 (0.79 - 0.89)
0.78 (0.76 - 0.80)
99% or 95% CI
Proportional effects on ALL CAUSE MORTALITY per mmol/L LDL-C Reduction
0.5 0.75 1 1.25 1.5
No. of events (% pa)Statin/
More statinControl/
Less statinRelative risk (CI)
Statin/morestatin better
Control/lessstatin better
Statin vs control
More vs less statin
First cycle (14 trials)
A to Z PROVE-IT
ALLIANCE
ASPEN
TNT
4D
MEGA
IDEAL SEARCH
JUPITER GISSI-HF AURORA
3832 (1.9)
104 (2.7)50 (1.2)
121 (2.3)
70 (1.6)
284 (1.2)
297 (16.8)
63 (0.3)
366 (1.8)964 (2.4)
198 (1.0)657 (8.2)
636 (13.5)
4354 (2.2)
130 (3.4)69 (1.7)
127 (2.4)
68 (1.6)
282 (1.1)
320 (17.9)
82 (0.4)
374 (1.8)970 (2.4)
247 (1.2)644 (8.0)
660 (14.0)
0.88 (0.84 - 0.91)
Subtotal (21 trials) 5874 (2.2) 6502 (2.4) 0.90 (0.87 - 0.93)
Subtotal (5 trials) 1768 (1.9) 1825 (2.0) 0.94 (0.82 - 1.08)
Total (26 trials) 7642 (2.1) 8327 (2.3) 0.90 (0.87 - 0.93)
Difference between more vs less and statin vs control:c12= 0.4, p=0.53
99% or 95% CI
Proportional Effects on CANCER INCIDENCE per mmol/L Reduction in LDL Cholesterol
0.5 0.75 1 1.25 1.5
No. of patients
Statin/More statin
ControlLess statin
Relative risk (CI)
Statin/morestatin better
Control/lessstatin better
0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All groups
982 (1.2%)1088 (1.3%)982 (1.4%)873 (1.4%)680 (1.3%)455 (1.5%)
5060 (6.0%)
997 (1.2%)1056 (1.3%)999 (1.4%)878 (1.4%)645 (1.3%)489 (1.6%)
5064 (6.0%)
0.98 (0.87 - 1.11)1.03 (0.92 - 1.16)0.98 (0.86 - 1.10)0.97 (0.85 - 1.10)1.05 (0.90 - 1.22)0.98 (0.80 - 1.21)1.00 (0.96 - 1.04)
Trend c12= 0.01; p=0.94
99% or 95% CI