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The overwhelming case for LDL-C lowering
Prof Kausik Ray, BSc (hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC
Professor of Cardiovascular Disease Prevention
St Georges University of London
Honorary Consultant Cardiologist St Georges Hospital
4S Primary Endpoint: Total Mortality
Scandinavian Simvastatin Survival Study Group. Lancet. 1994 ;344:1383-1389.
Years Since Randomization
ProportionAlive
Simvastatin
Placebo
0 1 2 3 4 5 60.00
0.80
0.85
0.90
0.95
1.00
30% RiskReduction(P=0.0003)
HPS: Effects of Simvastatin on First Major Vascular Event According to Baseline LDL-C
STATIN PLACEBO(n=10269) (n=10267)
ALL PATIENTS 2033 2585 (19.8%) (25.2%)
Risk ratio and 95% CI
0.4 0.6 0.8 1.0 1.2 1.4
LDL-C (mg/dL)
139 951/4331 1183/4349
< 116 598/3389 756/3404
484/2549 646/2514 116 - 139
STATIN better STATIN worse
24% reductionp<0.0001
Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.
ASCOT-LLA: Primary Prevention in HTN Nonfatal MI and Fatal CHD
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cum
ulati
ve In
cide
nce
(%)
36% reduction
HR = 0.64 (0.50-0.83)
Atorvastatin 10 mg Number of events 100Placebo Number of events 154
p=0.0005
Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58.
3.0%
1.9%
Baseline LDL 132 mg/dl
CARDS-Cumulative Hazard for Primary Endpoint
Relative Risk -37% (95% CI: -52, -17)
Years
328305
694651
10741022
13611306
13921351
AtorvaPlacebo
14281410
Placebo127 events
Atorvastatin10mg83 events
Cum
ulati
ve H
azar
d (%
)
0
5
10
15
0 1 2 3 4 4.75
P=0.001
CTT Collaboration Effects on Major Coronary Events per mmol/L LDL Cholesterol Reduction Subdivided by Baseline Lipid Values
Groups (mmol/L) Events (%)Treatment Control
RR & CI(Treatment : Control)
Total cholesterol:≤5.2 748 (6·9) 940 (8·6)5.2-6.5 1678 (7·0) 2246 (9·4)>6.5 896 (8·8) 1220 (12·1)
LDL cholesterol:≤3.5 1130 (6·8) 1443 (8·7)3.5-4.5 1374 (7·3) 1814 (9·6)>4.5 801 (9·3) 1120 (12·9)
HDL cholesterol:≤0.9 1167 (9·3) 1538 (12·1)0.9-1.1 939 (7·4) 1270 (10·2)>1.1 1207 (6·2) 1595 (8·1)
Triglycerides:≤1.4 1162 (7·3) 1521 (9·6)1.4-2.0 937 (7·1) 1304 (9·8)>2.0 1217 (7·9) 1564 (10·2)
Overall 3337 (7·4) 4420 (9·8)0·77 (0·74 – 0·80)
0·5 1·0 1·5Treatment Control
better better
p < 0·00001
Heterogeneity/trendp-value
p = 0·7
p = 0·5
p = 0·8
p = 0·6
CTT Collaborators. Lancet. 2005; 366:1267-78
Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials
50%
40%
30%
20%
10%
0%
-10%
0.5 1.0 1.5 2.0
Reduction in LDL Cholesterol (mmol/L)
Major Vascular Events
Prop
ortio
nal R
educ
tion
in E
vent
Rat
e (S
E)
Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78
Death/Nonfatal MI
(%)
Months Of Follow-Up
16
12
8
4
00 2 4 6 4 5 6
Stable CAD
ACS
PROVE IT-TIMI 22/ A to Z/ IDEAL
Years
4SCARE
LIPID/ HPS/IDEAL
Only high dose statins have been tested immediately after ACS
All-Cause Death or Major CV Events in All Randomized Subjects
0 3 18 21 24 27 306 9 12 15
% with Event
Months of Follow-up
Pravastatin 40mg(26.3%)
Atorvastatin 80mg(22.4%)
16% RR(P = 0.005)
30
25
20
15
10
5
0
Cannon CP, et al. NEJM 2004;350:1495-504.
Is there benefit from an LDL of 2 mmol/L vs 2.6mmol/L in stable CAD?
LaRosa JC, et al. NEJM. 2005; 352:1425-1435Pedersen TR, et al. JAMA. 2005; 294:2437-2445
*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
Years Since Randomization
MCV
E Cu
mul
ative
Haz
ard
(%)
0 1 2 3 4 50
4
8
12
16
HR = 0.87, P=.02
Simvastatin 20/40
Atorvastatin 80
HR = 0.78, P<.0010
5
10
15 Atorvastatin 10 mg
Atorvastatin 80 mg
Maj
or C
V Ev
ent*
(%)
0 1 2 3 4 5 6Time (years)
IDEALIDEAL TNTTNT
-13% RRR
-22% RRR
Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials
50%
40%
30%
20%
10%
0%
-10%
0.5 1.0 1.5 2.0
Reduction in LDL Cholesterol (mmol/L)
Major Vascular Events
Prop
ortio
nal R
educ
tion
in E
vent
Rat
e (S
E)
Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78
TNT
IDEAL
Meta-Analysis of Intensive Statin Therapy LDL Cholesterol by Trial
40
60
80
100
120
140
160
LDL-CTIMI 22
A-to-Z TNT IDEAL Pooled
.
BaselineStandardIntensive
ACS Stable CAD Pooled
4162 4497 10001 8888 27548
25.2% 0% 0% 75.5% 28.2%
Patients
n
Prior Statin Use
Baseline* 108.4 112.9 152 121.5 129.6 (3.32)
Standard* 97.1 101 101 104 101.4 (2.6)
Intensive* 65.5 69.1 77 81 75.4 (1.93)
LDL-
C (m
g/dL
)
Cannon CP, et al. JACC 2006; 48: 438 - 445.
PROVE IT-
High-dose statin better High-dose statin worse
Odds Reduction
Event RatesNo./Total (%)
High Dose Std Dose
-16% 3972/13798 (28.8)
4445/13750 (32.3)
-16% 1097/13798 (8.0)
1288/13750 (9.4)
-12%462/13798
(3.3)520/13750
(3.8)
+3%340/13798
(2.5)331/13750
(2.4)
-6%808/13798
(5.9)857/13750
(6.2)
-18%316/13798
(2.3)381/13750
(2.8)
Coronary Death or Any Cardiovascular Event
Coronary Death or MI
Cardiovascular Death
Non-Cardiovascular Death
Total Mortality
Stroke
0.5 1 2.5
OR 0.8295% CI, 0.71-0.96p=0.012
Odds Ratio (95% CI)
Meta-Analysis of Intensive Statin Therapy - All Endpoints
OR, 0.9495% CI, 0.85-1.04P=0.20
OR, 1.0395% CI, 0.88-1.20p=0.73
OR, 0.8895% CI, 0.78-1.00p=.054
OR, 0.8495% CI, 0.77-0.91p=0.00003
OR, 0.8495% CI, 0.80-0.89P=.0000000000006
Cannon CP, et al. JACC 2006; 48: 438 - 445.
PROVE IT-TIMI 22: Relationship Between Month 4 LDL and Long-Term Risk of Death or Major CV Event
*Adjusted for age, gender, DM, prior MI, baseline LDL
0.80 (0.59, 1.07)
0.67 (0.50, 0.92)
0.61 (0.40, 0.91)
Hazard Ratio
Lower Better Higher Better
Referent
Wiviott SD, Cannon, Ray et al. JACC. 2005
0 1 2
<1.03
> 1.03 -1.54
>1.54 – 2.05
>2.05 – 2.56
0
2
4
6
8
10
12
14
Major CV events CHD death Nonfatal MI Stroke
<1.64 1.64- <1.97 1.97- <2.3 2.3- <2.7 >=2.7
P < 0.0001*
P < 0.01*
P < 0.0001*
P < 0.05*
*P-value for trend across LDL-C
TNT: Incidence of First Major Cardiovascular Events Across Quintiles
LaRosa JC. AJC. 2007, 100, 747-52
% p
atien
ts
Event rates by achieved LDL-C in trials
% with CHD event
Mean LDL-C level at follow-up (mmol/L)
0
5
10
15
20
25
30
2.3 2.8 3.3 3.8 4.4
2° PreventionStable CHD
1° Prevention
1.8
JBS2 ESC GMSATP III
Ray IJCP 2007, 61, 1608-11
Optimal standard
Minimum audit standard
PROVE IT Safety Results: Side Effects
Atorvastatin 80 mg LDL (mmmol/L)
p valueEvent* 2.07-2.59
1.55-2.07
1.04-1.55 <1.04
Myositis or Myalgia (AE) 1.6 3.1 3.2 2.8 NS
CK > 3x ULN 2.3 0.7 1.9 1.0 NS
CK > 10x ULN 0.3 0 0.3 0 NS
Rhabdomyolysis 0 0 0 0 NS
ALT > 3X ULN 3.1 3.0 3.2 3.6 NS
Wiviott, et al. JACC. 2005
Adverse Event Profiles Across Quintiles- TNT
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 5≥106
mg/dL(1718/266)*
Withdrawals due to treatment-associated AEs
122 (6.6) 107 (5.5) 100 (5.0) 106 (5.2) 143 (7.2)
Treatment-associated myalgia
84 (4.6) 85 (4.4) 93 (4.7) 96 (4.7) 104 (5.2)
Persistent† CPK >10 ULN
0 0 0 0 0
Persistent† ALT and/or AST >3 ULN
20 (1.1) 15 (0.8) 18 (0.9) 8 (0.4) 10 (0.5)
*Number of patients: Atorvastatin 10 mg/atorvastatin 80 mg†Occurring twice within 4-10 days
CTT Lancet 2012
Statins increase risk of Dysglycaemia
Sattar N, ……Ray. Lancet 2010; 375: 735-42
Statins and DYSGLYCAEMIA vs CVD Risk
Preiss .... Ray. JAMA 2011;305:2556-64
Prognosis of Patients withNew-Onset T2DM
Waters DD et al. JACC. 2011;
TNT, IDEAL and SPARCL TNT, IDEAL and SPARCL Atorvastatin 80 mg groups
With new-onset T2DM
Without new-onset T2DM
Diabetes at baseline*
With new-onset T2DM
Without new-onset T2DM
Diabetes at baseline*
Incidence of MCVE
n / N (%)
157 / 1,387 (11.3%)
1,884/ 17,472 (10.8%)
832 / 4,761 (17.5%)
76 / 756 (10.1%)
867 / 8,684(10.0%)
358 / 2,359 (15.2%)
Univariate analysis**
(HR=1.03, 95% CI 0.78-1.35, p=0.83)
– – (HR=0.90, 95% CI 0.60-1.34, p=0.59)
– –
Multivariate analysis**
(HR=1.02, 95% CI 0.77-1.35, p=0.69)
– – (HR=0.87, 95% CI 0.58-1.30, p=0.49)
– –
*Patients were excluded from the new-onset T2DM study**MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis
The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD
• ACS
•Pravastatin
– L-CAD
– PACT
•Simvastatin
– A to Z
•Atorvastatin
– MIRACL
– PROVE IT-TIMI 22
•Primary Prev
•Pravastatin
– WOSCOPS
– PROSPER
•Simvastatin
– HPS
•Atorvastatin
– ASCOT
– CARDS
Rosuvastatin
– JUPITER
Lovastatin
– TEXCAPS/AFCAPS
Secondary Prev
Pravastatin CARE LIPID PROSPER
Simvastatin 4S HPS SEARCH
Atorvastatin AVERT TNT IDEAL
Summary
•LDL-C lowering offers similar proportional reductions among those with and without vascular disease
•The magnitude of benefit is related to the degree of LDL-C reduction
•LDL-C lowering is safe in general
•The greatest benefit are in those with the greatest absolute risk