ELIGIBILITY: MRC/BHF Heart Protection Study

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

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

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%

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%

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

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

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

VITAMINS: SITE-SPECIFIC CANCER INCIDENCE

(10269) (10267)



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

VITAMINS: STROKE INCIDENCE

(10269) (10267)



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

VITAMINS: CORONARY EVENTS & REVASCULARISATION

(10269) (10267)



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

VITAMINS: MAJOR VASCULAR EVENTS

(10269) (10267)



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

VITAMINS: MAJOR VASCULAR EVENTby PRIOR DISEASE

(10269) (10267)VITAMINS PLACEBO Rate ratio & 95% CI


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

VITAMINS: MAJOR VASCULAR EVENT by YEAR

(10269) (10267)



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

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

eve

nts

(%

)

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

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

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

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

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%

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)

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

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

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

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

SIMVASTATIN: SITE-SPECIFIC CANCER INCIDENCE

(10269) (10267)



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

SIMVASTATIN: STROKE INCIDENCE

(10269) (10267)



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

SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION

(10269) (10267)



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

SIMVASTATIN: MAJOR VASCULAR EVENTS

(10269) (10267)



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

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR

(10269) (10267)



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

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

eve

nts

(%

)

SIMVASTATIN: MAJOR VASCULAR EVENTby PRIOR DISEASE

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI


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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENT by AGE & SEX

(10269) (10267)



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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

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

SIMVASTATIN: MAJOR VASCULAR EVENTby SMOKING & TREATED HYPERTENSION


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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTby HDL CHOLESTEROL & TRIGLYCERIDES


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)


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

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

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

SIMVASTATIN: MAJOR VASCULAR EVENTby LDL & TOTAL CHOLESTEROL



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)


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

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

SIMVASTATIN: MAJOR VASCULAR EVENTby LDL CHOLESTEROL



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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTby CREATININE & VITAMINS


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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTby OTHER TREATMENT


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


2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4

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)

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)

ELIGIBILITY: MRC/BHF Heart Protection Study

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