Eligibility mrc bhf heart protection study
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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

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ELIGIBILITY: MRC/BHF Heart Protection Study

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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


Eligibility mrc bhf heart protection study

PRIOR DISEASE at BASELINE


Eligibility mrc bhf heart protection study

AGE & SEX at BASELINE


Eligibility mrc bhf heart protection study

TOTAL & LDL CHOLESTEROL at BASELINE


Eligibility mrc bhf heart protection study

FACTORIAL TREATMENT COMPARISONS


Vitamins average blood vitamin levels during follow up

VITAMINS: Average blood VITAMIN levelsduring follow-up


Eligibility mrc bhf heart protection study

VITAMINS: CAUSE-SPECIFIC MORTALITY

Cause of

VITAMINS

PLACEBO

Rate ratio & 95% CI

death

(10269)

(10267)

VITAMINS better

PLACEBO better

Vascular

Coronary

664

630

Other vascular

214

210

ANY VASCULAR

878

840

5% SE 5

increase

(8.6%)

(8.2%)

(NS)

Non-vascular

Neoplastic

359

345

Respiratory

103

101

Other medical

90

82

Non-medical

16

21

NON-VASCULAR

568

549

4% SE 6

increase

(5.5%)

(5.3%)

(NS)

ALL CAUSES

1446

1389

4% SE 4

increase

(14.1%)

(13.5%)

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: SITE-SPECIFIC CANCER INCIDENCE

VITAMINS

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

VITAMINS better

PLACEBO better

Gastrointestinal

228

223

Respiratory

181

165

Connective tissue

60

68

Genitourinary

247

284

Central nervous system

11

8

Haematological

58

58

Other

3

5

Not specified

42

43

ANY CANCER (except

800

817

2% SE 5

non melanoma skin)

reduction

(7.8%)

(8.0%)

(NS)

Non-melanoma skin

217

228

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: STROKE INCIDENCE

VITAMINS

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

VITAMINS better

PLACEBO better

Type

Ischaemic

345

354

Haemorrhagic

51

53

Unknown

122

115

Severity

Fatal

108

107

Severe

50

43

Moderate

127

135

Mild

158

169

Unknown

68

64

ALL STROKES

511

518

1% SE 6

reduction

(5.0%)

(5.0%)

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: CORONARY EVENTS & REVASCULARISATION

VITAMINS

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

VITAMINS better

PLACEBO better

Major coronary event

Non-fatal MI

464

467

Coronary death

664

630

CORONARY EVENTS

1063

1047

2% SE 4

increase

(10.4%)

(10.2%)

(NS)

Revascularisation

Coronary

623

615

Non-coronary

472

510

REVASCULARISATIONS

1058

1086

3% SE 4

reduction

(10.3%)

(10.6%)

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: MAJOR VASCULAR EVENTS

Vascular

VITAMINS

PLACEBO

Rate ratio & 95% CI

event

(10269)

(10267)

VITAMINS better

PLACEBO better

Major coronary

1063

1047

Any stroke

511

518

Revascularisation

1058

1086

ANY OF ABOVE

2306

2312

0% SE 3

reduction

(22.5%)

(22.5%)

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: MAJOR VASCULAR EVENT

by PRIOR DISEASE

VITAMINS

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

VITAMINS better

PLACEBO better

Previous MI

1155

1094

Other CHD (not MI)

501

550

No prior CHD

CVD

190

194

PVD

376

371

Diabetes

311

332

ALL PATIENTS

2306

2312

0% SE 3

reduction

(22.5%)

(22.5%)

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: MAJOR VASCULAR EVENT by YEAR

Year of

VITAMINS

PLACEBO

Rate ratio & 95% CI

follow-up

(10269)

(10267)

VITAMINS better

PLACEBO better

1

494

(4.8%)

514

(5.0%)

2

466

(4.8%)

449

(4.6%)

3

456

(5.0%)

412

(4.5%)

4

379

(4.4%)

388

(4.5%)

5+

511

(6.3%)

549

(6.7%)

ALL FOLLOW-UP

2306

(22.5%)

2312

(22.5%)

0% SE 3

reduction

(NS)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

VITAMINS: MAJOR VASCULAR EVENT by YEAR

30

25

PLACEBO

20

15

VITAMINS

10

5

0

0

1

2

3

4

5

6

Years of follow-up

2(3)

0(4)

-4(5)

-3(5)

4(8)

People suffering events (%)

Benefit/1000 (SE):

2(18)

VITAMINS


Eligibility mrc bhf heart protection study

VITAMINS: CATARACT and FRACTURES


Eligibility mrc bhf heart protection study

VITAMINS: COGNITIVE IMPAIRMENT(TICS-m <22/39) at Final Follow-up


Vitamins summary of findings

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


Eligibility mrc bhf heart protection study

FACTORIAL TREATMENT COMPARISONS


Statin use compliance with study simvastatin or use of non study statin

STATIN USE: Compliance with study simvastatin or use of non-study statin


Eligibility mrc bhf heart protection study

Difference in LDL CHOLESTEROL

(SIMVASTATIN - PLACEBO)

20

0.5

mmol/l

Years of follow-up

mg/dl

(±SE)

(±SE)

1

2

3

4

5

0.0

0

-0.5

-20

-1.0

-40

-1.5

-60

Average: - 1.0 ± 0.02 mmol/l

-2.0

- 37 ± 0.8 mg/dl

-80


Hps assesses 2 3 of the effect of actually using 40mg simvastatin daily

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


Eligibility mrc bhf heart protection study

SIMVASTATIN 40mg daily: Muscle symptoms


Simvastatin 40mg daily safety monitoring

SIMVASTATIN 40mg daily: Safety monitoring


Eligibility mrc bhf heart protection study

SIMVASTATIN: CAUSE-SPECIFIC MORTALITY

Cause of

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

death

(10269)

(10267)

STATIN better

PLACEBO better

Vascular

Coronary

587

707

Other vascular

194

230

ANY VASCULAR

781

937

17% SE 4

reduction

(7.6%)

(9.1%)

(2P<0.0001)

Non-vascular

Neoplastic

359

345

Respiratory

90

114

Other medical

82

90

Non-medical

16

21

NON-VASCULAR

547

570

5% SE 6

reduction

(5.3%)

(5.6%)

(NS)

ALL CAUSES

1328

1507

13% SE 4

reduction

(12.9%)

(14.7%)

(2P<0.001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: SITE-SPECIFIC CANCER INCIDENCE

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

STATIN better

PLACEBO better

Gastrointestinal

228

223

Respiratory

179

167

Connective tissue

60

68

Genitourinary

259

272

Central nervous system

12

7

Haematological

64

52

Other

6

2

Not specified

36

49

ANY CANCER (except

814

803

0% SE 5

non melanoma skin)

increase

(7.9%)

(7.8%)

(NS)

Non-melanoma skin

243

202

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: STROKE INCIDENCE

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

STATIN better

PLACEBO better

Type

Ischaemic

290

409

Haemorrhagic

51

53

Unknown

103

134

Severity

Fatal

96

119

Severe

42

51

Moderate

107

155

Mild

138

189

Unknown

61

71

ALL STROKES

444

585

25% SE 5

reduction

(4.3%)

(5.7%)

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

STATIN better

PLACEBO better

Major coronary event

Non-fatal MI

357

574

Coronary death

587

707

CORONARY EVENTS

898

1212

27% SE 4

reduction

(8.7%)

(11.8%)

(2P<0.00001)

Revascularisation

Coronary

513

725

Non-coronary

450

532

REVASCULARISATIONS

939

1205

24% SE 4

reduction

(9.1%)

(11.7%)

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENTS

Vascular

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

event

(10269)

(10267)

STATIN better

PLACEBO better

Major coronary

898

1212

Any stroke

444

585

Revascularisation

939

1205

ANY OF ABOVE

2033

2585

24% SE 3

reduction

(19.8%)

(25.2%)

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR

Year of

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

follow-up

(10269)

(10267)

STATIN better

PLACEBO better

1

481

(4.7%)

527

(5.1%)

2

377

(3.9%)

538

(5.6%)

3

359

(3.9%)

509

(5.6%)

4

331

(3.8%)

436

(5.2%)

5+

485

(5.8%)

575

(7.3%)

ALL FOLLOW-UP

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR

30

25

PLACEBO

20

15

SIMVASTATIN

10

5

0

0

1

2

3

4

5

6

Years of follow-up

5(3)

20(4)

35(5)

46(5)

54(7)

People suffering events (%)

Benefit/1000 (SE):

60(18)

SIMVASTATIN


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by PRIOR DISEASE

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

(10269)

(10267)

STATIN better

PLACEBO better

Previous MI

999

(23.5%)

1250

(29.4%)

Other CHD (not MI)

460

(18.9%)

591

(24.2%)

No prior CHD

CVD

172

(18.7%)

212

(23.6%)

PVD

327

(24.7%)

420

(30.5%)

Diabetes

276

(13.8%)

367

(18.6%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT by AGE & SEX

Baseline

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

feature

(10269)

(10267)

STATIN better

PLACEBO better

Age

< 65

831

(16.9%)

1091

(22.1%)

65 - 69

512

(20.9%)

665

(27.2%)

70 - 74

548

(23.8%)

620

(27.7%)

³

75

142

(23.1%)

209

(32.3%)

Sex

Male

1666

(21.6%)

2135

(27.6%)

Female

367

(14.4%)

450

(17.7%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: COGNITIVE IMPAIRMENT(TICS-m <22/39) at Final Follow-up


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by SMOKING & TREATED HYPERTENSION

Baseline

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

feature

(10269)

(10267)

STATIN better

PLACEBO better

Smoking

Never regular

406

(15.7%)

531

(20.6%)

Ex-cigarette

1298

(20.8%)

1638

(26.3%)

Current

329

(22.8%)

416

(28.4%)

Treated hypertension

Yes

942

(22.4%)

1195

(28.1%)

No

1091

(18.0%)

1390

(23.1%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by HDL CHOLESTEROL & TRIGLYCERIDES

Lipid levels

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

at entry

(10269)

(10267)

STATIN better

PLACEBO better

HDL cholesterol (mmol/l)

< 0.9 (35 mg/dl)

818

(22.6%)

1064

(29.9%)

³

0.9 < 1.1

560

(20.0%)

720

(25.1%)

³

1.1 (43 mg/dl)

655

(17.0%)

801

(20.9%)

Triglycerides (mmol/l)

< 2.0 (177 mg/dl)

1101

(18.3%)

1432

(23.7%)

³

2.0 < 4.0

743

(21.6%)

939

(27.3%)

³

4.0 (354 mg/dl)

189

(23.2%)

214

(27.1%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Simvastatin average ldl difference mmol l se by baseline ldl cholesterol

SIMVASTATIN: Average LDL DIFFERENCE(mmol/l ± se) by BASELINE LDL cholesterol


Simvastatin average ldl difference mg dl se by baseline ldl cholesterol

SIMVASTATIN: Average LDL DIFFERENCE (mg/dl ± se) by BASELINE LDL cholesterol


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by LDL & TOTAL CHOLESTEROL

Lipid levels

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

at entry

(10269)

(10267)

STATIN better

PLACEBO better

LDL cholesterol (mmol/l)

< 3.0 (116 mg/dl)

598

(17.6%)

756

(22.2%)

³

3.0 < 3.5

484

(19.0%)

646

(25.7%)

³

3.5 (135 mg/dl)

951

(22.0%)

1183

(27.2%)

Total cholesterol (mmol/l)

< 5.0 (193 mg/dl)

360

(17.7%)

472

(23.1%)

³

5.0 < 6.0

744

(18.9%)

964

(24.5%)

> 6.0 (323 mg/dl)

929

(21.6%)

1149

(26.8%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Simvastatin major vascular event in upper lower thirds of baseline ldl

Statin-allocated

Placebo-allocated

Upper

LDL third

Lower

LDL third

SIMVASTATIN: MAJOR VASCULAR EVENT in upper & lower thirds of baseline LDL

30

25

% with major vascular events

20

15

1.5

2.0

2.5

3.0

3.5

4.0

Average LDL cholesterol (mmol/l)


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by LDL CHOLESTEROL

Lipid levels

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

at entry

(10269)

(10267)

STATIN better

PLACEBO better

LDL cholesterol (mg/dl)

< 100

282

(16.4%)

358

(21.0%)

³

100 < 130

668

(18.9%)

871

(24.7%)

³

130

1083

(21.6%)

1356

(26.9%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by CREATININE & VITAMINS

Baseline

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

feature

(10269)

(10267)

STATIN better

PLACEBO better

Creatinine

Normal

1851

(19.2%)

2317

(24.2%)

Elevated

182

(28.2%)

268

(39.2%)

Vitamin allocation

Vitamins

1014

(19.7%)

1292

(25.2%)

Placebo

1019

(19.8%)

1293

(25.2%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Eligibility mrc bhf heart protection study

SIMVASTATIN: MAJOR VASCULAR EVENT

by OTHER TREATMENT

Baseline

SIMVASTATIN

PLACEBO

Rate ratio & 95% CI

treatment

(10269)

(10267)

STATIN better

PLACEBO better

Aspirin

Yes

1370

(21.1%)

1784

(27.4%)

No

663

(17.5%)

801

(21.3%)

ACE inhibitor

Yes

495

(24.9%)

568

(28.5%)

No

1538

(18.6%)

2017

(24.4%)

Beta-blocker

Yes

519

(19.5%)

705

(26.9%)

No

1514

(19.9%)

1880

(24.6%)

Calcium antagonist

Yes

788

(24.7%)

1023

(31.2%)

No

1245

(17.6%)

1562

(22.4%)

ALL PATIENTS

2033

(19.8%)

2585

(25.2%)

24% SE 3

reduction

(2P<0.00001)

0.4

0.6

0.8

1.0

1.2

1.4


Simvastatin main conclusions

SIMVASTATIN: Main conclusions

  • After allowance for non-compliance, 40mg daily simvastatin safely reducesthe 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

Millions of people with relevant conditions


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