On-Treatment LDL and CHD Events in Statin Trials 2 Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269-279. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435

Cholesterol Lowering and CV Risk: Meta-analyses

2

On-Treatment LDL and CHD Events in Statin Trials

Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269-279.LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

WOSCOPS - Rx

4S - Rx

LIPID - Rx

4S - PBO

CARE - Rx

LIPID - PBO

CARE - PBO

WOSCOPS - PBO

AFCAPS - PBOAFCAPS - Rx WOSCOPS - Rx

0

10

20

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Secondary Prevention

Primary Prevention

200(5.2)

ASCOT - PBOASCOT - Rx

PROVE-IT - PRA

PROVE-IT - ATV80

TNT - ATV10Eve

nt r

ate

(%)

LDL-C achieved, mg/dL (mmol/L)

70(1.8)

HPS - PBO

HPS - Rx

TNT - ATV80

3

Second Cycle of the CTT Meta-analysis: Proportional Effects on Major VascularEvents Per Mmol/L LDL-C Reduction

0.5 0.75 1 1.25 1.5

Relative risk (CI) permmol/L LDL-C reduction

Statin/more better Control/less 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

5883 (3.1)

257 (7.2)406 (11.3)

254 (5.4)

114 (2.7)

889 (4.0)

144 (9.0)

102 (0.5)

938 (5.2)1347 (3.6)

105 (0.5)172 (2.2)362 (8.1)

7467 (4.0)

282 (8.1)458 (13.1)

293 (6.4)

136 (3.3)

1164 (5.4)

162 (10.1)

140 (0.7)

1106 (6.3)1406 (3.8)

194 (1.0)174 (2.2)368 (8.3)

0.78 (0.76 - 0.81)

Subtotal (21 trials) 7136 (2.8) 8934 (3.6) 0.79 (0.77 - 0.81)P < 0.001

Subtotal (5 trials) 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78)P < 0.001

Total (26 trials) 10973 (3.2) 13350 (4.0) 0.78 (0.76 - 0.80)P < 0.001

Difference between more vs. less and statin vs. control:c

12= 4.5, p=0.03

99% or 95% CI

No. of events (% pa)

Statin/more Control/less

Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681.

4

Second Cycle of the CTT Meta-analysis:More vs Less Statin—Proportional Effects onMajor Vascular Events Per Mmol/L LDL-C Reduction


Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unspecified

Any coronary revascularization

Ischemic stroke

Hemorrhagic stroke

Unknown stroke

Any stroke

Any major vascular event(5 trials)

1175 (1.3%)

645 (0.7%)

1725 (1.9%)

637 (0.7%)

1166 (1.3%)

447 (0.5%)

2250 (2.6%)

440 (0.5%)

69 (0.1%)

63 (0.1%)

572 (0.6%)

3837 (4.5%)

1380 (1.5%)

694 (0.7%)

1973 (2.2%)

731 (0.9%)

1508 (1.8%)

502 (0.6%)

2741 (3.2%)

526 (0.6%)

57 (0.1%)

80 (0.1%)

663 (0.7%)

4416 (5.3%)

0.71 (0.58 - 0.87)

0.85 (0.63 - 1.15)

0.74 (0.65 - 0.85)P < 0.00010.72 (0.55 - 0.95)

0.60 (0.50 - 0.71)

0.78 (0.58 - 1.04)

0.66 (0.60 - 0.73)P < 0.00010.69 (0.50 - 0.95)

1.39 (0.57 - 3.39)

0.63 (0.24 - 1.66)

0.74 (0.59 - 0.92)P = 0.0070.72 (0.66 - 0.78)

No. of events (% pa) Relative risk (CI) permmol/L LDL-C reductionMore statin Less statin

More statin better Less statin better99% or 95% CI

0.5 0.75 1 1.25 1.5

5

Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unspecified

Any coronary revascularization

Ischemic stroke

Hemorrhagic stroke

Unknown stroke

Any stroke

Any major vascular event(all 21 trials)

2310 (0.9%)

1242 (0.5%)

3380 (1.3%)

816 (0.3%)

601 (0.2%)

1686 (0.6%)

3103 (1.2%)

987 (0.4%)

188 (0.1%)

555 (0.2%)

1730 (0.7%)

7136 (2.8%)

3213 (1.2%)

1587 (0.6%)

4539 (1.7%)

1126 (0.4%)

775 (0.3%)

2165 (0.8%)

4066 (1.6%)

1225 (0.5%)

163 (0.1%)

629 (0.2%)

2017 (0.8%)

8934 (3.6%)

0.74 (0.69 - 0.78)

0.80 (0.73 - 0.86)

0.76 (0.73 - 0.79)P < 0.0010.76 (0.69 - 0.83)

0.78 (0.69 - 0.89)

0.76 (0.70 - 0.83)

0.76 (0.73 - 0.80)P < 0.0010.80 (0.73 - 0.88)

1.10 (0.86 - 1.42)

0.88 (0.76 - 1.02)

0.85 (0.80 - 0.90)P < 0.0010.79 (0.77 - 0.81)P < 0.001

Second Cycle of the CTT Meta-analysis: Statin vs Control—Proportional Effects onMajor Vascular Events Per Mmol/L LDL-C Reduction

No. of events (% pa)

Statin ControlRelative risk (CI) per

mmol/L LDL-C reduction

Statin better Control better

99% or 95% CI


0.5 0.75 1 1.25 1.5

6

Meta-analysis of Statin Trials and Fatal and Nonfatal Stroke

Amarenco P et al. Lancet Neurol. 2009;8:453-463.

N = 165,732

Log-scale

Study

0.1

Active group(%)

Control group(%)

RR(95% CI)

Total: P < 0.0001 (heterogeneity: I2 = 7.3%, P = 0.36)

SEARCHJUPITERASPENMEGAIDEALTNTALLIANCECARDSPROVE-ITA TO ZASCOT-LLAALLHAT-LLTGREACEHPS (with no prior CVD)PROSPERMIRACLGISSIAFCAPS/TexCAPSLIPID (with no prior CVD)Post-CABGCARE (with no prior CVD)WOSCOPSSSSS

Sub-total: P < 0.0001 (heterogeneity: I2 = 26.6%, P = 0.12)

4.20.42.81.33.42.32.91.51.01.21.74.01.23.24.70.80.90.43.32.61.91.42.5

4.60.73.21.63.93.13.22.80.91.62.44.52.14.84.51.60.90.53.92.42.81.53.5

SPARCLHPS (with prior CVDLIPID (with prior CVD)CARE (with prior CVD)

Sub-total: P = 0.03 (heterogeneity: I2 = 0.8%, P = 0.39)

11.210.39.513.5

13.110.413.320.0

Primary prevention of stroke

0.2 0.5 1 2 5 10

0.91 (0.77, 1.08)0.52 (0.34, 0.78)0.89 (0.56, 1.40)0.83 (057,1.20)0.87 (0.70, 1.08)0.76 (0.60, 0.96)0.90 (0.58, 1.42)0.53 (0.31, 0.90)1.09 (0.59, 2.01)0.79 (0.48, 1.29)0.73 (0.56, 0.96)0.91 (0.76, 1.09)0.53 (0.24, 1.18)0.67 (0.57, 0.77)1.04 (0.82, 1.31)0.50 (0.25, 1.00)1.05 (0.56, 1.96)0.82 (0.41, 1.67)0.84 (0.67, 1.05)1.12 (0.58, 2.18)0.67 (0.44, 1.01)0.90 (0.61, 1.34)0.72 (0.51, 1.01)

0.81 (0.75, 0.87)

Secondary prevention of stroke

0.82 (0.77, 0.87

0.85 (0.73, 0.990.99 (0.81, 1.21)0.72 (0.46, 1.12)0.68 (0.37, 1.25)

0.88 (0.78, 0.99)

RR(95% CI)

7

Meta-analysis of Statin Trials and Stroke Mortality


SEARCHJUPITERCARDSALLHAT-LLTGREACEHPSPROSPERMIRACLGISSILIPIDCAREWOSCOPSSSSS

Sub-total: P = 0.18 (heterogeneity: I2 = 0%, P = 0.48)

Study

Active group

(%)

Control group

(%)RR

(95% CI)

Primary prevention of stroke

0.90.30.11.00.00.90.80.20.20.50.20.20.6

1.10.70.51.10.11.20.50.10.20.60.10.10.5

0.85 (0.60, 1.21)0.50 (0.13, 2.00)0.14 (0.02, 1.15)0.95 (0.65, 1.38)0.33 (0.01, 8.17)0.81 (0.62, 1.05)1.58 (0.81, 3.09)1.51 (0.25, 9.02)1.00 (0.25, 3.98)0.81 (0.46, 1.43)4.99 (0.58, 42.70)1.50 (0.42, 5.30)1.17 (0.54, 2.52)

0.90 (0.76, 1.05)

RR(95% CI)

Secondary prevention of stroke

SPARCL

Total: P = 0.10 (heterogeneity: I2 = 8.1%, P = 0.36)

1.0 1.7 0.59 (0.36, 0.97)

0.87 (0.73, 1.03)

10.50.20.1 2 5 10Log-scale

8

Stroke Risk and LDL Lowering inStatin Trials

Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI, 6.3–33.5%; p<0.009)

N = 165,732


1.1

1.2

1.0

0.9

0.8

0.7

0.6

0.5

0.4

-15-10 -20 -30 -35-25 -40 -45 -50 -55

Between Group Difference in LDL-Cholesterol Reduction, %(active minus control groups)

Rel

ativ

e R

isk

of

Str

oke

in

Act

ive

vs C

on

tro

l G

rou

ps

(no

n-l

og

sca

le)

LIPID

TNT

GISSI PROSPERPROVE-IT

Post-CABG

SPARCL-CS (-)

SPARCL

SPARCL-CS (+)

WOSCOPSASPEN

ALLHAT-LLTSEARCH

IDEALALLIANCE

CARE

CARDS

GREACEJUPITER

MIRACL

MEGA A to ZAFCAPS/TexCAPS

HPSASCOT-LLA

SSSS

00

Documents

On-Treatment LDL and CHD Events in Statin Trials 2 Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269-279. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435