Transcript 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
Any MI
Other CHD
No CHD*
Cerebrovascular
Peripheral vascular
Diabetes
ALL PATIENTS
Number
Percentage
8510
4876
7150
1820
2701
3982
41%
24%
35%
20,536
100%
* Overlap between categories within “No CHD” group
AGE & SEX at BASELINE
Baseline feature
Age (years)
<65
65-69
70-74
>74
Sex
Male
Female
Number
Percentage
9839
4891
4543
1263
48%
24%
22%
6%
15,454
5082
75%
25%
TOTAL & LDL CHOLESTEROL at BASELINE
Baseline lipids
Number
Percentage
LDL cholesterol (mmol/l)
<3.0 (116 mg/dl)
3.0 <3.5
3.5 (135 mg/dl)
6793
5063
8680
33%
25%
42%
Total cholesterol (mmol/l)
<5.0 (193 mg/dl)
5.0 <6.0
6.0 (232 mg/dl)
4072
7883
8581
20%
38%
42%
FACTORIAL TREATMENT COMPARISONS
Simvastatin
(40 mg daily)
vs
Placebo
tablets
Vitamins
(600 mg E, 250 mg C
& 20 mg beta-carotene)
vs
Placebo
capsules
5 years average duration of follow-up
VITAMINS: Average blood VITAMIN levels
during 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
Cause of
death
VITAMINS
(10269)
PLACEBO
(10267)
Rate ratio & 95% CI
VITAMINS better PLACEBO better
Vascular
Coronary
Other vascular
ANY VASCULAR
664
214
630
210
878
(8.6%)
840
(8.2%)
5% SE 5
increase
(NS)
359
103
90
16
345
101
82
21
568
(5.5%)
549
(5.3%)
4% SE 6
increase
(NS)
1446
(14.1%)
1389
(13.5%)
4% SE 4
increase
(NS)
Non-vascular
Neoplastic
Respiratory
Other medical
Non-medical
NON-VASCULAR
ALL CAUSES
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: SITE-SPECIFIC CANCER INCIDENCE
VITAMINS
(10269)
PLACEBO
(10267)
Gastrointestinal
228
223
Respiratory
181
165
60
68
247
284
Central nervous system
11
8
Haematological
58
58
3
5
42
43
800
(7.8%)
817
(8.0%)
Connective tissue
Genitourinary
Other
Not specified
ANY CANCER (except
non melanoma skin)
Non-melanoma skin
217
Rate ratio & 95% CI
VITAMINS better PLACEBO better
2% SE 5
reduction
(NS)
228
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: STROKE INCIDENCE
VITAMINS
(10269)
PLACEBO
(10267)
Rate ratio & 95% CI
VITAMINS better PLACEBO better
Type
Ischaemic
Haemorrhagic
Unknown
345
51
122
354
53
115
108
50
127
158
68
107
43
135
169
64
511
(5.0%)
518
(5.0%)
Severity
Fatal
Severe
Moderate
Mild
Unknown
ALL STROKES
1% SE 6
reduction
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: CORONARY EVENTS & REVASCULARISATION
VITAMINS
(10269)
PLACEBO
(10267)
Rate ratio & 95% CI
VITAMINS better PLACEBO better
Major coronary event
Non-fatal MI
Coronary death
464
664
467
630
1063
(10.4%)
1047
(10.2%)
623
472
615
510
REVASCULARISATIONS 1058
(10.3%)
1086
(10.6%)
CORONARY EVENTS
2% SE 4
increase
(NS)
Revascularisation
Coronary
Non-coronary
3% SE 4
reduction
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: MAJOR VASCULAR EVENTS
Vascular
event
Major coronary
Any stroke
Revascularisation
ANY OF ABOVE
VITAMINS
(10269)
PLACEBO
(10267)
1063
1047
511
518
1058
1086
2306
(22.5%)
Rate ratio & 95% CI
VITAMINS better PLACEBO better
2312
(22.5%)
0% SE 3
reduction
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: MAJOR VASCULAR EVENT
by PRIOR DISEASE
VITAMINS
(10269)
Previous MI
PLACEBO
(10267)
1155
1094
Other CHD (not MI)
501
550
No prior CHD
CVD
190
194
PVD
376
371
Diabetes
311
332
ALL PATIENTS
2306
(22.5%)
Rate ratio & 95% CI
VITAMINS better PLACEBO better
2312
(22.5%)
0% SE 3
reduction
(NS)
0.4
0.6
0.8
1.0
1.2
1.4
VITAMINS: MAJOR VASCULAR EVENT by YEAR
Year of
follow-up
VITAMINS
(10269)
PLACEBO
Rate ratio & 95% CI
(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%)
0.4
0% SE 3
reduction
(NS)
0.6
0.8
1.0
1.2
1.4
VITAMINS: MAJOR VASCULAR EVENT by YEAR
People suffering events (%)
30
25
PLACEBO
20
15
VITAMINS
10
5
0
0
1
2
3
4
5
6
-3(5)
4(8)
2(18)
Years of follow-up
Benefit/1000 (SE):
2(3)
0(4)
-4(5)
VITAMINS: CATARACT and FRACTURES
Outcome
VITAMINS
(10,269)
PLACEBO
(10,267)
P-value
Cataract
379 (3.7%)
418 (4.1%)
NS
Fracture
Osteoporotic
Any
101 (1.0%)
234 (2.3%)
99 (1.0%)
237 (2.3%)
NS
NS
VITAMINS: COGNITIVE IMPAIRMENT
(TICS-m <22/39) at Final Follow-up
Age (years) at
randomisation
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
Placebo
tablets
Vitamins
(600 mg E, 250 mg C
& 20 mg beta-carotene)
vs
Placebo
capsules
5 years average duration of follow-up
STATIN USE: Compliance with study
simvastatin or use of non-study statin
Years of
follow-up
Approx. no. SIMVASTATIN PLACEBO
of patients
allocated
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%
85%
17%
STUDY AVERAGE
Difference in LDL CHOLESTEROL
(SIMVASTATIN - PLACEBO)
mmol/l
(±SE)
20
0.5
0.0
Years of follow-up
1
2
3
4
5
mg/dl
(±SE)
0
-0.5
-20
-1.0
-40
-1.5
-60
-2.0
Average: - 1.0 ± 0.02 mmol/l
- 37 ± 0.8 mg/dl
-80
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 or
weakness
Ever reported
Stopped tablets
SIMVASTATIN PLACEBO
(10,269)
(10,267)
P-value
3380 (33%)
3410 (33%)
NS
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
CK >10 x ULN
Myopathy*
19 (0.09%)
11 (0.11%)
10 (0.10%)
13 (0.05%)
6 (0.06%)
4 (0.04%)
*Muscle symptoms with CK >10 x ULN
SIMVASTATIN: CAUSE-SPECIFIC MORTALITY
Cause of
death
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
Vascular
Coronary
Other vascular
ANY VASCULAR
587
194
707
230
781
(7.6%)
937
(9.1%)
359
90
82
16
345
114
90
21
547
(5.3%)
570
(5.6%)
1328
(12.9%)
1507
(14.7%)
17% SE 4
reduction
(2P<0.0001)
Non-vascular
Neoplastic
Respiratory
Other medical
Non-medical
NON-VASCULAR
ALL CAUSES
5% SE 6
reduction
(NS)
13% SE 4
reduction
(2P<0.001)
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: SITE-SPECIFIC CANCER INCIDENCE
SIMVASTATIN PLACEBO
(10269)
(10267)
Gastrointestinal
228
223
Respiratory
179
167
60
68
259
272
Central nervous system
12
7
Haematological
64
52
6
2
36
49
814
(7.9%)
803
(7.8%)
Connective tissue
Genitourinary
Other
Not specified
ANY CANCER (except
non melanoma skin)
Non-melanoma skin
243
Rate ratio & 95% CI
STATIN better PLACEBO better
0% SE 5
increase
(NS)
202
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: STROKE INCIDENCE
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
Type
Ischaemic
Haemorrhagic
Unknown
290
51
103
409
53
134
96
42
107
138
61
119
51
155
189
71
444
(4.3%)
585
(5.7%)
Severity
Fatal
Severe
Moderate
Mild
Unknown
ALL STROKES
25% SE 5
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
Major coronary event
Non-fatal MI
Coronary death
CORONARY EVENTS
357
587
898
(8.7%)
574
707
1212
(11.8%)
27% SE 4
reduction
(2P<0.00001)
Revascularisation
Coronary
Non-coronary
REVASCULARISATIONS
513
450
939
(9.1%)
725
532
1205
(11.7%)
24% SE 4
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENTS
Vascular
event
SIMVASTATIN PLACEBO
(10269)
(10267)
Major coronary
898
1212
Any stroke
444
585
Revascularisation
939
1205
2033
(19.8%)
2585
(25.2%)
ANY OF ABOVE
Rate ratio & 95% CI
STATIN better PLACEBO better
24% SE 3
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR
Year of
follow-up
SIMVASTATIN PLACEBO
(10269)
(10267)
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
Rate ratio & 95% CI
STATIN better PLACEBO better
2033 (19.8%) 2585 (25.2%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR
People suffering events (%)
30
25
PLACEBO
20
15
SIMVASTATIN
10
5
0
0
1
2
3
4
5
6
46(5)
54(7)
60(18)
Years of follow-up
Benefit/1000 (SE):
5(3)
20(4)
35(5)
SIMVASTATIN: MAJOR VASCULAR EVENT
by PRIOR DISEASE
SIMVASTATIN PLACEBO
(10269)
(10267)
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
Rate ratio & 95% CI
STATIN better PLACEBO better
2033 (19.8%) 2585 (25.2%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT by AGE & SEX
Baseline
feature
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
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%)
 75
142 (23.1%)
209 (32.3%)
Sex
Male
Female
ALL PATIENTS
1666 (21.6%) 2135 (27.6%)
367 (14.4%)
450 (17.7%)
2033 (19.8%) 2585 (25.2%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: COGNITIVE IMPAIRMENT
(TICS-m <22/39) at Final Follow-up
Age (years) at
randomisation
COGNITIVE IMPAIRMENT
SIMVASTATIN 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 EVENT
by SMOKING & TREATED HYPERTENSION
Baseline
feature
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
Smoking
Never regular
Ex-cigarette
Current
406 (15.7%)
531 (20.6%)
1298 (20.8%) 1638 (26.3%)
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%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT
by HDL CHOLESTEROL & TRIGLYCERIDES
Lipid levels
at entry
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
HDL cholesterol (mmol/l)
< 0.9 (35 mg/dl)
818 (22.6%) 1064 (29.9%)
 0.9 < 1.1
560 (20.0%)
720 (25.1%)
 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%)
 2.0 < 4.0
743 (21.6%)
939 (27.3%)
 4.0 (354 mg/dl)
189 (23.2%)
214 (27.1%)
ALL PATIENTS
2033 (19.8%) 2585 (25.2%)
0.4
24% SE 3
reduction
(2P<0.00001)
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 PLACEBO
(10,269)
(10,267)
Difference
in LDL
<3.0 (116 mg/dl)
1.8
2.7
-0.9 ± 0.02
3.0<3.5
2.2
3.2
-1.0 ± 0.03
3.5 (135 mg/dl)
2.7
3.7
-1.0 ± 0.03
2.3
3.3
-1.0 ± 0.02
ALL PATIENTS
SIMVASTATIN: Average LDL DIFFERENCE
(mg/dl ± se) by BASELINE LDL cholesterol
LDL cholesterol
(mg/dl) at entry
SIMVASTATIN PLACEBO
(10,269)
(10,267)
Difference
in LDL
<116
69
104
-35 ± 0.8
116<135
86
123
-37 ± 1.2
104
143
-39 ± 1.2
90
127
-37 ± 1.2
135
ALL PATIENTS
SIMVASTATIN: MAJOR VASCULAR EVENT
by LDL & TOTAL CHOLESTEROL
Lipid levels
at entry
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
LDL cholesterol (mmol/l)
< 3.0 (116 mg/dl)
598 (17.6%)
756 (22.2%)
 3.0 < 3.5
484 (19.0%)
646 (25.7%)
 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%)
 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%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
% with major vascular events
SIMVASTATIN: MAJOR VASCULAR EVENT
in upper & lower thirds of baseline LDL
30
Statin-allocated
Placebo-allocated
25
20
Upper
LDL third
Lower
LDL third
15
1.5 2.0 2.5 3.0 3.5 4.0
Average LDL cholesterol (mmol/l)
SIMVASTATIN: MAJOR VASCULAR EVENT
by LDL CHOLESTEROL
Lipid levels
at entry
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
LDL cholesterol (mg/dl)
< 100
282 (16.4%)
358 (21.0%)
 100 < 130
668 (18.9%)
871 (24.7%)
 130
ALL PATIENTS
1083 (21.6%) 1356 (26.9%)
2033 (19.8%) 2585 (25.2%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT
by CREATININE & VITAMINS
Baseline
feature
SIMVASTATIN PLACEBO
(10269)
(10267)
Rate ratio & 95% CI
STATIN better PLACEBO better
Creatinine
Normal
Elevated
1851 (19.2%) 2317 (24.2%)
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%)
0.4
24% SE 3
reduction
(2P<0.00001)
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: MAJOR VASCULAR EVENT
by OTHER TREATMENT
Baseline
treatment
SIMVASTATIN PLACEBO
(10269)
(10267)
Aspirin
Yes
No
1370 (21.1%) 1784 (27.4%)
663 (17.5%)
801 (21.3%)
ACE inhibitor
Yes
No
495 (24.9%)
568 (28.5%)
1538 (18.6%) 2017 (24.4%)
Beta-blocker
Yes
No
519 (19.5%)
705 (26.9%)
1514 (19.9%) 1880 (24.6%)
Calcium antagonist
Yes
No
788 (24.7%) 1023 (31.2%)
1245 (17.6%) 1562 (22.4%)
ALL PATIENTS
2033 (19.8%) 2585 (25.2%)
0.4
Rate ratio & 95% CI
STATIN better PLACEBO better
24% SE 3
reduction
(2P<0.00001)
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
Established market economies
Former Socialist
India
China
Other Asia & Islands
Sub-Sahara Africa
Latin America/Caribbean
Middle East Crescent
World total
CHD Stroke Diabetes
8.2
5.8
6.6
4.5
2.4
1.1
2.0
3.3
9.5
4.4
2.7
7.4
2.3
1.3
1.6
1.6
37.9
11.0
18.1
10.3
13.0
3.9
11.2
13.0
34.0
30.9
118.3
WHO Global Health Statistics (1996)