MRCBHF 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
• Total cholesterol ? 3.5 mmol/l (? 135mg/dl)
• Statin or vitamins not considered clearly
  indicated or contraindicated by patients own
  doctors

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PRIOR DISEASE at BASELINE
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AGE SEX at BASELINE
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TOTAL LDL CHOLESTEROL at BASELINE
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FACTORIAL TREATMENT COMPARISONS
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VITAMINS Average blood VITAMIN levelsduring
follow-up
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VITAMINS CAUSE-SPECIFIC MORTALITY
VITAMINS
PLACEBO
Rate ratio 95 CI
Cause of
death
(10269)
(10267)
VITAMINS better
PLACEBO better
Vascular
Coronary
664
630
Other vascular
214
210
5 SE 5
878
840
ANY VASCULAR
increase
(8.6)
(8.2)
(NS)
Non-vascular
Neoplastic
359
345
103
101
Respiratory
90
82
Other medical
16
21
Non-medical
4 SE 6
568
549
NON-VASCULAR
increase
(5.5)
(5.3)
(NS)
4 SE 4
1446
1389
ALL CAUSES
increase
(14.1)
(13.5)
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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VITAMINS SITE-SPECIFIC CANCER INCIDENCE
VITAMINS
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
VITAMINS better
PLACEBO better
228
223
Gastrointestinal
181
165
Respiratory
60
68
Connective tissue
247
284
Genitourinary
11
8
Central nervous system
58
58
Haematological
3
5
Other
42
43
Not specified
2 SE 5
800
817
ANY CANCER (except
reduction
non melanoma skin)
(7.8)
(8.0)
(NS)
217
228
Non-melanoma skin
0.4
0.6
0.8
1.0
1.2
1.4
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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
1 SE 6
511
518
ALL STROKES
reduction
(5.0)
(5.0)
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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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
2 SE 4
1063
1047
CORONARY EVENTS
increase
(10.4)
(10.2)
(NS)
Revascularisation
623
615
Coronary
Non-coronary
472
510
3 SE 4
1058
1086
REVASCULARISATIONS
reduction
(10.3)
(10.6)
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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VITAMINS MAJOR VASCULAR EVENTS
VITAMINS
PLACEBO
Rate ratio 95 CI
Vascular
event
(10269)
(10267)
VITAMINS better
PLACEBO better
1063
1047
Major coronary
511
518
Any stroke
1058
1086
Revascularisation
0 SE 3
2306
2312
ANY OF ABOVE
reduction
(22.5)
(22.5)
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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VITAMINS MAJOR VASCULAR EVENT
by PRIOR DISEASE
VITAMINS
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
VITAMINS better
PLACEBO better
1155
1094
Previous MI
501
550
Other CHD (not MI)
No prior CHD
190
194
CVD
376
371
PVD
311
332
Diabetes
0 SE 3
2306
2312
ALL PATIENTS
reduction
(22.5)
(22.5)
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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VITAMINS MAJOR VASCULAR EVENT by YEAR
VITAMINS
PLACEBO
Rate ratio 95 CI
Year of
follow-up
(10269)
(10267)
VITAMINS better
PLACEBO better
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 3
2306
2312
(22.5)
(22.5)
ALL FOLLOW-UP
reduction
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
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People suffering events ()
2(18)
Benefit/1000 (SE)
VITAMINS
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VITAMINS CATARACT and FRACTURES
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VITAMINS COGNITIVE IMPAIRMENT(TICS-m lt22/39) at
Final Follow-up
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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
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STATIN USE Compliance with study simvastatin or
use of non-study statin
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Difference in LDL CHOLESTEROL
(SIMVASTATIN - PLACEBO)
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0.5
Years of follow-up
mmol/l
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
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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
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SIMVASTATIN 40mg daily Safety monitoring
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SIMVASTATIN CAUSE-SPECIFIC MORTALITY
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Cause of
death
(10269)
(10267)
STATIN better
PLACEBO better
Vascular
Coronary
587
707
Other vascular
194
230
17 SE 4
781
937
ANY VASCULAR
reduction
(7.6)
(9.1)
(2Plt0.0001)
Non-vascular
Neoplastic
359
345
90
114
Respiratory
82
90
Other medical
16
21
Non-medical
5 SE 6
547
570
NON-VASCULAR
reduction
(5.3)
(5.6)
(NS)
13 SE 4
1328
1507
ALL CAUSES
reduction
(12.9)
(14.7)
(2Plt0.001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN SITE-SPECIFIC CANCER INCIDENCE
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
STATIN better
PLACEBO better
228
223
Gastrointestinal
179
167
Respiratory
60
68
Connective tissue
259
272
Genitourinary
12
7
Central nervous system
64
52
Haematological
6
2
Other
36
49
Not specified
0 SE 5
814
803
ANY CANCER (except
increase
non melanoma skin)
(7.9)
(7.8)
(NS)
243
202
Non-melanoma skin
0.4
0.6
0.8
1.0
1.2
1.4
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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
25 SE 5
444
585
ALL STROKES
reduction
(4.3)
(5.7)
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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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
27 SE 4
898
1212
CORONARY EVENTS
reduction
(8.7)
(11.8)
(2Plt0.00001)
Revascularisation
513
725
Coronary
Non-coronary
450
532
24 SE 4
939
1205
REVASCULARISATIONS
reduction
(9.1)
(11.7)
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENTS
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Vascular
event
(10269)
(10267)
STATIN better
PLACEBO better
898
1212
Major coronary
444
585
Any stroke
939
1205
Revascularisation
24 SE 3
2033
2585
ANY OF ABOVE
reduction
(19.8)
(25.2)
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENT by YEAR
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Year of
follow-up
(10269)
(10267)
STATIN better
PLACEBO better
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 3
2033
2585
(19.8)
(25.2)
ALL FOLLOW-UP
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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People suffering events ()
60(18)
Benefit/1000 (SE)
SIMVASTATIN
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SIMVASTATIN MAJOR VASCULAR EVENT
by PRIOR DISEASE
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
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 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENT by AGE SEX
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Baseline
feature
(10269)
(10267)
STATIN better
PLACEBO better
Age
831
1091
(16.9)
(22.1)
lt 65
512
665
(20.9)
(27.2)
65 - 69
548
620
(23.8)
(27.7)
70 - 74
142
209
(23.1)
(32.3)
³
75
Sex
1666
2135
(21.6)
(27.6)
Male
367
450
(14.4)
(17.7)
Female
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN COGNITIVE IMPAIRMENT(TICS-m lt22/39)
at Final Follow-up
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SIMVASTATIN MAJOR VASCULAR EVENT
by SMOKING TREATED HYPERTENSION
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Baseline
feature
(10269)
(10267)
STATIN better
PLACEBO better
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 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENT
by HDL CHOLESTEROL TRIGLYCERIDES
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Lipid levels
at entry
(10269)
(10267)
STATIN better
PLACEBO better
HDL cholesterol (mmol/l)
818
1064
(22.6)
(29.9)
lt 0.9 (35 mg/dl)
560
720
(20.0)
(25.1)
³
0.9 lt 1.1
655
801
(17.0)
(20.9)
³
1.1 (43 mg/dl)
Triglycerides (mmol/l)
1101
1432
(18.3)
(23.7)
lt 2.0 (177 mg/dl)
743
939
(21.6)
(27.3)
³
2.0 lt 4.0
189
214
(23.2)
(27.1)
³
4.0 (354 mg/dl)
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
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
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SIMVASTATIN Average LDL DIFFERENCE (mg/dl se)
by BASELINE LDL cholesterol
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SIMVASTATIN MAJOR VASCULAR EVENT
by LDL TOTAL CHOLESTEROL
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Lipid levels
at entry
(10269)
(10267)
STATIN better
PLACEBO better
LDL cholesterol (mmol/l)
598
756
(17.6)
(22.2)
lt 3.0 (116 mg/dl)
484
646
(19.0)
(25.7)
³
3.0 lt 3.5
951
1183
(22.0)
(27.2)
³
3.5 (135 mg/dl)
Total cholesterol (mmol/l)
360
472
(17.7)
(23.1)
lt 5.0 (193 mg/dl)
744
964
(18.9)
(24.5)
³
5.0 lt 6.0
929
1149
(21.6)
(26.8)
gt 6.0 (323 mg/dl)
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
40
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)
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SIMVASTATIN MAJOR VASCULAR EVENT
by LDL CHOLESTEROL
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Lipid levels
at entry
(10269)
(10267)
STATIN better
PLACEBO better
LDL cholesterol (mg/dl)
282
358
(16.4)
(21.0)
lt 100
668
871
(18.9)
(24.7)
³
100 lt 130
1083
1356
(21.6)
(26.9)
³
130
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
42
SIMVASTATIN MAJOR VASCULAR EVENT
by CREATININE VITAMINS
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Baseline
feature
(10269)
(10267)
STATIN better
PLACEBO better
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 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENT
by OTHER TREATMENT
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Baseline
treatment
(10269)
(10267)
STATIN better
PLACEBO better
Aspirin
Yes
1370
1784
(21.1)
(27.4)
No
663
801
(17.5)
(21.3)
ACE inhibitor
Yes
495
568
(24.9)
(28.5)
No
1538
2017
(18.6)
(24.4)
Beta-blocker
Yes
519
705
(19.5)
(26.9)
No
1514
1880
(19.9)
(24.6)
Calcium antagonist
Yes
788
1023
(24.7)
(31.2)
No
1245
1562
(17.6)
(22.4)
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
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
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