ELIGIBILITY: MRC/BHF Heart Protection Study Increased risk of CHD death due to prior disease:...
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![Page 1: ELIGIBILITY: MRC/BHF Heart Protection Study Increased risk of CHD death due to prior disease: Myocardial infarction or other coronary heart disease; Occlusive.](https://reader034.fdocuments.in/reader034/viewer/2022051516/56649ec55503460f94bcfb5e/html5/thumbnails/1.jpg)
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ELIGIBILITY: MRC/BHF Heart Protection Study
• Increased risk of CHD death due to prior disease:
Myocardial infarction or other coronary heart disease;
Occlusive disease of non-coronary arteries; or
Diabetes mellitus or treated hypertension
• Age 40-80 years
• Total cholesterol >3.5 mmol/l (>135mg/dl)
• Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors
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PRIOR DISEASE at BASELINE
Prior disease Number Percentage
Any MI 8510 41%Other CHD 4876 24%No CHD* 7150 35% Cerebrovascular 1820 Peripheral vascular 2701 Diabetes 3982
ALL PATIENTS 20,536 100%
* Overlap between categories within “No CHD” group
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AGE & SEX at BASELINE
Baseline feature Number Percentage
Age (years)<65 9839 48%65-69 4891 24%70-74 4543 22%>74 1263 6%
SexMale 15,454 75%Female 5082 25%
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TOTAL & LDL CHOLESTEROL at BASELINE
Baseline lipids Number Percentage
LDL cholesterol (mmol/l)<3.0 (116 mg/dl) 6793 33%3.0 <3.5 5063 25%3.5 (135 mg/dl) 8680 42%
Total cholesterol (mmol/l)<5.0 (193 mg/dl) 4072 20%5.0 <6.0 7883 38%6.0 (232 mg/dl) 8581 42%
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FACTORIAL TREATMENT COMPARISONS
Simvastatin(40 mg daily)
vs Placebotablets
Vitamins(600 mg E, 250 mg C& 20 mg beta-carotene)
vs Placebocapsules
5 years average duration of follow-up
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VITAMINS: Average blood VITAMIN levelsduring follow-up
Vitamin(mol/l)
VITAMINS PLACEBO Difference
tocopherol 49.5 ± 0.6 27.0 ± 0.2 22.5 ± 0.6
Ascorbate 58.9 ± 1.0 43.2 ± 1.0 15.7 ± 1.4
carotene 1.22 ± 0.03 0.32 ± 0.01 0.89 ± 0.03
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VITAMINS: CAUSE-SPECIFIC MORTALITY
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
Cause ofdeath
Vascular
664 630Coronary214 210Other vascular
(8.6%) (8.2%)5% SE 5increase
878 840
(NS)
ANY VASCULAR
Non-vascular
359 345Neoplastic103 101Respiratory
90 82Other medical16 21Non-medical
(5.5%) (5.3%)4% SE 6increase
568 549
(NS)
NON-VASCULAR
(14.1%) (13.5%)4% SE 4increase
1446 1389
(NS)
ALL CAUSES
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: SITE-SPECIFIC CANCER INCIDENCE
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
228 223Gastrointestinal
181 165Respiratory
60 68Connective tissue
247 284Genitourinary
11 8Central nervous system
58 58Haematological
3 5Other
42 43Not specified
(7.8%) (8.0%)2% SE 5reduction
800 817
(NS)
ANY CANCER (exceptnon melanoma skin)
217 228Non-melanoma skin
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: STROKE INCIDENCE
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
Type
345 354Ischaemic51 53Haemorrhagic
122 115Unknown
Severity
108 107Fatal50 43Severe
127 135Moderate158 169Mild
68 64Unknown
(5.0%) (5.0%)1% SE 6reduction
511 518
(NS)
ALL STROKES
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: CORONARY EVENTS & REVASCULARISATION
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
Major coronary event
464 467Non-fatal MI664 630Coronary death
(10.4%) (10.2%)2% SE 4increase
1063 1047
(NS)
CORONARY EVENTS
Revascularisation
623 615Coronary472 510Non-coronary
(10.3%) (10.6%)3% SE 4reduction
1058 1086
(NS)
REVASCULARISATIONS
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: MAJOR VASCULAR EVENTS
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
Vascularevent
1063 1047Major coronary
511 518Any stroke
1058 1086Revascularisation
(22.5%) (22.5%)0% SE 3reduction
2306 2312
(NS)
ANY OF ABOVE
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: MAJOR VASCULAR EVENTby PRIOR DISEASE
(10269) (10267)VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
1155 1094Previous MI
501 550Other CHD (not MI)
No prior CHD
190 194CVD
376 371PVD
311 332Diabetes
(22.5%) (22.5%)0% SE 3reduction
2306 2312
(NS)
ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: MAJOR VASCULAR EVENT by YEAR
(10269) (10267)
VITAMINS PLACEBO Rate ratio & 95% CI
VITAMINS better PLACEBO better
Year offollow-up
494 514(4.8%) (5.0%)1
466 449(4.8%) (4.6%)2
456 412(5.0%) (4.5%)3
379 388(4.4%) (4.5%)4
511 549(6.3%) (6.7%)5+
0% SE 3reduction(NS)
2306 2312(22.5%) (22.5%)ALL FOLLOW-UP
0.4 0.6 0.8 1.0 1.2 1.4
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VITAMINS: MAJOR VASCULAR EVENT by YEAR
0 1 2 3 4 5 60
5
10
15
20
25
30
Years of follow-up
2(3) 0(4) -4(5)
VITAMINS
PLACEBO
-3(5) 4(8) 2(18)Benefit/1000 (SE):
Pe
op
le s
uff
eri
ng
ev
en
ts (
%)
VITAMINS
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VITAMINS: CATARACT and FRACTURES
Outcome VITAMINS (10,269)
PLACEBO(10,267)
P-value
Cataract 379 (3.7%) 418 (4.1%) NS
FractureOsteoporotic 101 (1.0%) 99 (1.0%) NSAny 234 (2.3%) 237 (2.3%) NS
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VITAMINS: COGNITIVE IMPAIRMENT(TICS-m <22/39) at Final Follow-up
Age (years) atrandomisation
COGNITIVE IMPAIRMENT VITAMINS PLACEBO (7955) (7965)
<65 17.3% 17.7%
65 <70 25.3% 26.0%
70 34.2% 36.5%
ALL PATIENTS 23.4% 24.4%
P-value = 0.1
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VITAMINS: Summary of findings
• This antioxidant vitamin regimen (600mg E, 250mg C & 20mg beta carotene daily) increased blood vitamin levels substantially
• These vitamins appeared to be safe, but did not reduce the 5-year risks of any type of vascular disease, cancer or other major outcome
• Given these results, continued recommendation of supplementation with such vitamins is difficult to justify
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FACTORIAL TREATMENT COMPARISONS
Simvastatin(40 mg daily)
vs Placebotablets
Vitamins(600 mg E, 250 mg C& 20 mg beta-carotene)
vs Placebocapsules
5 years average duration of follow-up
![Page 20: ELIGIBILITY: MRC/BHF Heart Protection Study Increased risk of CHD death due to prior disease: Myocardial infarction or other coronary heart disease; Occlusive.](https://reader034.fdocuments.in/reader034/viewer/2022051516/56649ec55503460f94bcfb5e/html5/thumbnails/20.jpg)
STATIN USE: Compliance with study simvastatin or use of non-study statin
Years offollow-up
Approx. no.of patients
SIMVASTATINallocated
PLACEBO allocated
1 20,000 89% 4%
2 20,000 85% 9%
3 19,000 84% 17%
4 18,500 83% 24%
5 14,500 82% 32%
STUDY AVERAGE 85% 17%
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Difference in LDL CHOLESTEROL
1 2 3 4 5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
-80
-60
-40
-20
0
20Years of follow-upmmol/l
(±SE)mg/dl(±SE)
Average: - 1.0 ± 0.02 mmol/l- 37 ± 0.8 mg/dl
(SIMVASTATIN - PLACEBO)
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HPS assesses 2/3 of the effect of actually using 40mg simvastatin daily
• Average proportions using statin during HPS: 5/6 of active group vs 1/6 of control group
• LDL difference in HPS (active vs control group) is ~2/3 of LDL difference from actually using statin
• Risk reduction in HPS (active vs control group) is ~2/3 of risk reduction from actually using statin
ACTUAL EFFECT = 1.5 x APPARENT EFFECT
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SIMVASTATIN 40mg daily: Muscle symptoms
Muscle pain orweakness
SIMVASTATIN(10,269)
PLACEBO(10,267)
P-value
Ever reported 3380 (33%) 3410 (33%) NS
Stopped tablets 49 (0.5%) 50 (0.5%) NS
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SIMVASTATIN 40mg daily: Safety monitoring
Blood enzymes(x upper limit of normal)
SIMVASTATIN(10,269)
PLACEBO(10,267)
Liver: ALT >4 x ULN 43 (0.42%) 32 (0.31%)
Muscle: CK 4 –10 x ULN 19 (0.09%) 13 (0.05%)
CK >10 x ULN 11 (0.11%) 6 (0.06%)
Myopathy* 10 (0.10%) 4 (0.04%)
*Muscle symptoms with CK >10 x ULN
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SIMVASTATIN: CAUSE-SPECIFIC MORTALITY
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Cause ofdeath
Vascular
587 707Coronary194 230Other vascular
(7.6%) (9.1%)17% SE 4reduction
781 937
(2P<0.0001)
ANY VASCULAR
Non-vascular
359 345Neoplastic90 114Respiratory82 90Other medical16 21Non-medical
(5.3%) (5.6%)5% SE 6reduction
547 570
(NS)
NON-VASCULAR
(12.9%) (14.7%)13% SE 4reduction
1328 1507
(2P<0.001)
ALL CAUSES
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: SITE-SPECIFIC CANCER INCIDENCE
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
228 223Gastrointestinal
179 167Respiratory
60 68Connective tissue
259 272Genitourinary
12 7Central nervous system
64 52Haematological
6 2Other
36 49Not specified
(7.9%) (7.8%)0% SE 5increase
814 803
(NS)
ANY CANCER (exceptnon melanoma skin)
243 202Non-melanoma skin
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: STROKE INCIDENCE
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Type
290 409Ischaemic51 53Haemorrhagic
103 134Unknown
Severity
96 119Fatal42 51Severe
107 155Moderate138 189Mild
61 71Unknown
(4.3%) (5.7%)25% SE 5reduction
444 585
(2P<0.00001)
ALL STROKES
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Major coronary event
357 574Non-fatal MI587 707Coronary death
(8.7%) (11.8%)27% SE 4reduction
898 1212
(2P<0.00001)
CORONARY EVENTS
Revascularisation
513 725Coronary450 532Non-coronary
(9.1%) (11.7%)24% SE 4reduction
939 1205
(2P<0.00001)
REVASCULARISATIONS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENTS
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Vascularevent
898 1212Major coronary
444 585Any stroke
939 1205Revascularisation
(19.8%) (25.2%)24% SE 3reduction
2033 2585
(2P<0.00001)
ANY OF ABOVE
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Year offollow-up
481 527(4.7%) (5.1%)1
377 538(3.9%) (5.6%)2
359 509(3.9%) (5.6%)3
331 436(3.8%) (5.2%)4
485 575(5.8%) (7.3%)5+
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL FOLLOW-UP
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR
0 1 2 3 4 5 60
5
10
15
20
25
30
Years of follow-up
5(3) 20(4) 35(5)
SIMVASTATIN
PLACEBO
46(5) 54(7) 60(18)Benefit/1000 (SE):
Pe
op
le s
uff
eri
ng
ev
en
ts (
%)
SIMVASTATIN
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SIMVASTATIN: MAJOR VASCULAR EVENTby PRIOR DISEASE
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
999 1250(23.5%) (29.4%)Previous MI
460 591(18.9%) (24.2%)Other CHD (not MI)
No prior CHD
172 212(18.7%) (23.6%)CVD
327 420(24.7%) (30.5%)PVD
276 367(13.8%) (18.6%)Diabetes
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENT by AGE & SEX
(10269) (10267)
SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
Baselinefeature
Age
831 1091(16.9%) (22.1%)< 65
512 665(20.9%) (27.2%)65 - 69
548 620(23.8%) (27.7%)70 - 74
142 209(23.1%) (32.3%) 75
Sex
1666 2135(21.6%) (27.6%)Male
367 450(14.4%) (17.7%)Female
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: COGNITIVE IMPAIRMENT(TICS-m <22/39) at Final Follow-up
Age (years) atrandomisation
COGNITIVE IMPAIRMENTSIMVASTATIN PLACEBO (8086) (7834)
<65 17.1% 17.8%
65 <70 25.8% 25.4%
70 34.6% 36.2%
ALL PATIENTS 23.7% 24.2%
P-value = 0.4
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SIMVASTATIN: MAJOR VASCULAR EVENTby SMOKING & TREATED HYPERTENSION
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterBaselinefeature
Smoking
406 531(15.7%) (20.6%)Never regular
1298 1638(20.8%) (26.3%)Ex-cigarette
329 416(22.8%) (28.4%)Current
Treated hypertension
942 1195(22.4%) (28.1%)Yes
1091 1390(18.0%) (23.1%)No
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENTby HDL CHOLESTEROL & TRIGLYCERIDES
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterLipid levelsat entry
HDL cholesterol (mmol/l)
818 1064(22.6%) (29.9%)< 0.9 (35 mg/dl)
560 720(20.0%) (25.1%) 0.9 < 1.1
655 801(17.0%) (20.9%) 1.1 (43 mg/dl)
Triglycerides (mmol/l)
1101 1432(18.3%) (23.7%)< 2.0 (177 mg/dl)
743 939(21.6%) (27.3%) 2.0 < 4.0
189 214(23.2%) (27.1%) 4.0 (354 mg/dl)
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: Average LDL DIFFERENCE(mmol/l ± se) by BASELINE LDL cholesterol
LDL cholesterol(mmol/l) at entry
SIMVASTATIN(10,269)
PLACEBO(10,267)
Difference in LDL
<3.0 (116 mg/dl) 1.8 2.7 -0.9 ± 0.023.0<3.5 2.2 3.2 -1.0 ± 0.033.5 (135 mg/dl) 2.7 3.7 -1.0 ± 0.03
ALL PATIENTS 2.3 3.3 -1.0 ± 0.02
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SIMVASTATIN: Average LDL DIFFERENCE (mg/dl ± se) by BASELINE LDL cholesterol
LDL cholesterol(mg/dl) at entry
SIMVASTATIN(10,269)
PLACEBO(10,267)
Difference in LDL
<116 69 104 -35 ± 0.8116<135 86 123 -37 ± 1.2135 104 143 -39 ± 1.2
ALL PATIENTS 90 127 -37 ± 1.2
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SIMVASTATIN: MAJOR VASCULAR EVENTby LDL & TOTAL CHOLESTEROL
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterLipid levelsat entry
LDL cholesterol (mmol/l)
598 756(17.6%) (22.2%)< 3.0 (116 mg/dl)
484 646(19.0%) (25.7%) 3.0 < 3.5
951 1183(22.0%) (27.2%) 3.5 (135 mg/dl)
Total cholesterol (mmol/l)
360 472(17.7%) (23.1%)< 5.0 (193 mg/dl)
744 964(18.9%) (24.5%) 5.0 < 6.0
929 1149(21.6%) (26.8%)> 6.0 (323 mg/dl)
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENT in upper & lower thirds of baseline LDL
Average LDL cholesterol (mmol/l)
15
20
25
30
1.5 2.0 2.5 3.0 3.5 4.0
Statin-allocated
Placebo-allocated
UpperLDL third
LowerLDL third
% w
ith m
ajo
r va
scu
lar
eve
nts
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SIMVASTATIN: MAJOR VASCULAR EVENTby LDL CHOLESTEROL
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterLipid levelsat entry
LDL cholesterol (mg/dl)
282 358(16.4%) (21.0%)< 100
668 871(18.9%) (24.7%) 100 < 130
1083 1356(21.6%) (26.9%) 130
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENTby CREATININE & VITAMINS
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterBaselinefeature
Creatinine
1851 2317(19.2%) (24.2%)Normal
182 268(28.2%) (39.2%)Elevated
Vitamin allocation
1014 1292(19.7%) (25.2%)Vitamins
1019 1293(19.8%) (25.2%)Placebo
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: MAJOR VASCULAR EVENTby OTHER TREATMENT
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO betterBaselinetreatment
Aspirin
1370 1784(21.1%) (27.4%)Yes663 801(17.5%) (21.3%)No
ACE inhibitor
495 568(24.9%) (28.5%)Yes1538 2017(18.6%) (24.4%)No
Beta-blocker
519 705(19.5%) (26.9%)Yes1514 1880(19.9%) (24.6%)No
Calcium antagonist
788 1023(24.7%) (31.2%)Yes1245 1562(17.6%) (22.4%)No
24% SE 3reduction(2P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
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SIMVASTATIN: Main conclusions
• After allowance for non-compliance, 40mg daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularisation by about one-third
• 5 years of statin treatment typically prevents these “major vascular events” in about:
100 of every 1000 people with previous MI 80 " " " other CHD 70 " " " cerebrovascular disease 70 " " " other arterial disease 70 " " " diabetes (age 40+)
irrespective of cholesterol level (or age, or sex, or other treatments)
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Millions of people with relevant conditions
Region of the world CHD Stroke Diabetes
Established market economies 8.2 9.5 37.9Former Socialist 5.8 4.4 11.0India 6.6 2.7 18.1China 4.5 7.4 10.3Other Asia & Islands 2.4 2.3 13.0
Sub-Sahara Africa 1.1 1.3 3.9
Latin America/Caribbean 2.0 1.6 11.2
Middle East Crescent 3.3 1.6 13.0
World total 34.0 30.9 118.3
WHO Global Health Statistics (1996)
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