ELIGIBILITY: MRC/BHF Heart Protection Study

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Presentation transcript:

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 Notes: Eligibility for the study was guided chiefly by the "uncertainty principle". Patients were informed at the start of the study that lowering cholesterol was already known to reduce the risk of heart attacks, but that most people among the range of volunteers recruited were not then receiving any kind of cholesterol-lowering treatment. Prior to randomisation, the patient's own doctor was provided with the patient's lipid profile and a summary of existing evidence about cholesterol-lowering therapy, and asked to indicate if -- in their view -- a statin was likely to be needed by the patient (in which case the patient would not be randomised). Subsequently, randomised participants and their doctors were encouraged to start a non-study statin if it was considered to have become indicated (e.g. because of emerging evidence from other trials or changes in the patient's medical condition).

PRIOR DISEASE at BASELINE Notes: Patients included with a history of coronary heart disease were predominantly older individuals, women and those with average or below average cholesterol levels at entry to the study. Those with cerebrovascular disease had a history of a stroke, transient ischaemic attack or carotid artery surgery. Those with peripheral vascular disease had intermittent claudication or a history of aortic or peripheral revascularisation. Patients with diabetes had either type 1 or type 2 diabetes.

AGE & SEX at BASELINE Notes: Men and women aged between about 40 and 80 years were eligible for the study.

TOTAL & LDL CHOLESTEROL at BASELINE Notes: Numbers are based on non-fasting lipid measurements taken at the initial visit prior to any lipid lowering therapy being taken. LDL cholesterol values were directly measured not calculated.

FACTORIAL TREATMENT COMPARISONS Notes: Participants were randomly allocated to receive simvastatin or matching placebo tablets, with the average duration of treatment being 5 years. In addition, using a "2x2 factorial design", half of the patients in each of these groups were randomly allocated to receive vitamins and half were allocated placebo capsules. Assessment of cholesterol-lowering therapy involves comparing the 10,000 allocated active statin versus the 10,000 allocated placebo statin. Likewise, the assessment of antioxidant vitamin supplementation involves comparisons of the 10,000 allocated active vitamins versus the 10,000 allocated placebo vitamins.

VITAMINS: Average blood VITAMIN levels during follow-up Notes: Effects on blood vitamin levels were assessed on non-fasting samples collected from about 5% of participants at baseline and at an average of 3 years of follow-up. Comparisons are based on all those allocated the study vitamins versus all those allocated placebo irrespective of whether or not they were still compliant (with any missing data imputed from the screening values, assuming non-compliance).

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 (8.6%) (8.2%) increase (NS) Non-vascular Neoplastic 359 345 Respiratory 103 101 Other medical 90 82 Non-medical 16 21 NON-VASCULAR 568 549 4% SE 6 Notes: No significant differences were observed between treatment groups either overall or in any prespecified category of vascular or non-vascular mortality. (5.5%) (5.3%) increase (NS) ALL CAUSES 1446 1389 4% SE 4 (14.1%) (13.5%) increase (NS) 0.4 0.6 0.8 1.0 1.2 1.4

VITAMINS: SITE-SPECIFIC CANCER INCIDENCE 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 Notes: none non melanoma skin) (7.8%) (8.0%) reduction (NS) Non-melanoma skin 217 228 0.4 0.6 0.8 1.0 1.2 1.4

VITAMINS: STROKE INCIDENCE 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 Notes: none 511 518 1% SE 6 (5.0%) (5.0%) reduction (NS) 0.4 0.6 0.8 1.0 1.2 1.4

VITAMINS: CORONARY EVENTS & REVASCULARISATION 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 (10.4%) (10.2%) increase (NS) Revascularisation Coronary 623 615 Non-coronary 472 510 REVASCULARISATIONS Notes: none 1058 1086 3% SE 4 (10.3%) (10.6%) reduction (NS) 0.4 0.6 0.8 1.0 1.2 1.4

VITAMINS: MAJOR VASCULAR EVENTS 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 (22.5%) (22.5%) reduction (NS) Notes: No difference is seen between treatment groups in coronary events, strokes or the need for revascularisation. The large number of major vascular events on which this is based allows reliable assessment of the effects of study vitamins on this outcome in different circumstances. 0.4 0.6 0.8 1.0 1.2 1.4

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 Notes: No significant differences were observed between the treatment groups in the numbers of participants suffering a first major vascular event in these prior disease categories. ALL PATIENTS 2306 2312 0% SE 3 (22.5%) (22.5%) reduction (NS) 0.4 0.6 0.8 1.0 1.2 1.4

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 Notes: No significant differences were observed between the treatment groups in the numbers of participants suffering a first major vascular event in the first 2 years or after more prolonged follow-up. (NS) 0.4 0.6 0.8 1.0 1.2 1.4

VITAMINS: MAJOR VASCULAR EVENT by YEAR 1 2 3 4 5 6 10 15 20 25 30 Years of follow-up VITAMINS PLACEBO 4(8) -3(5) People suffering events (%) -4(5) 0(4) 2(3) Notes: This life-table plot provides no evidence of effects beginning to emerge with more prolonged follow-up. Benefit/1000 (SE): 2(18) VITAMINS

VITAMINS: CATARACT and FRACTURES Notes: There was no significant support for the suggestion from observational studies that anti-oxidant vitamins might prevent cataracts or fractures.

VITAMINS: COGNITIVE IMPAIRMENT (TICS-m <22/39) at Final Follow-up Notes: The modified Telephone Interview for Cognitive Status (TICS-m) was used to assess cognitive function, with a score of 22/39 pre-specified as indicating some cognitive impairment. Despite apparent discrimatory power, as illustrated by higher proportions of older individuals scoring below 22, there is no evidence of an effect of vitamins on this measure.

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 Notes: none

FACTORIAL TREATMENT COMPARISONS Notes: Participants were randomly allocated to receive simvastatin or matching placebo tablets, with the average duration of treatment being 5 years. In addition, using a "2x2 factorial design", half of the patients in each of these groups were randomly allocated to receive vitamins and half were allocated placebo capsules. Assessment of cholesterol-lowering therapy involves comparing the 10,000 allocated active statin versus the 10,000 allocated placebo statin. Likewise, the assessment of antioxidant vitamin supplementation involves comparisons of the 10,000 allocated active vitamins versus the 10,000 allocated placebo vitamins.

STATIN USE: Compliance with study simvastatin or use of non-study statin Notes: During the study, each participant's own doctors were free to monitor cholesterol levels and were encouraged to start a non-study statin if they considered it had become indicated. The study simvastatin or placebo could be continued if the non-study statin dose was no greater than simvastatin 40mg daily (or equivalent in lipid-lowering potency of another statin). On average during the study, about one-sixth of participants allocated placebo were prescribed a non-study statin and about one-sixth of those allocated study simvastatin stopped taking statin. So, instead of all of those allocated simvastatin taking it throughout the study and none of those allocated placebo taking a statin, the actual difference between these groups in statin use was only about two-thirds of full compliance. (At the final follow-up 4002 participants were taking a non-study statin, with 53% using simvastatin, 28% atorvastatin, 10% pravastatin, 5% cerivastatin and 4% fluvastatin.)

Difference in LDL CHOLESTEROL (SIMVASTATIN - PLACEBO) 0.5 20 mmol/l Years of follow-up mg/dl (±SE) (±SE) 1 2 3 4 5 0.0 -0.5 -20 -1.0 -40 -1.5 -60 Average: - 1.0 ± 0.02 mmol/l -2.0 Notes: These LDL cholesterol differences are based on intention to treat comparisons, with missing data imputed from initial pre-treatment screening values. Simvastatin 40mg daily produces a reduction in LDL cholesterol of about 1.5 mmol/l in this population. But, with 2/3 average compliance during the study, the average LDL difference was 1.0 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 Notes: none

SIMVASTATIN 40mg daily: Muscle symptoms Notes: Participants were asked about unexplained muscle pain or weakness at each follow-up. On average about 5% of participants reported such symptoms at each visit, but at no time during the study was there any significant difference between those allocated simvastatin or placebo. If participants stopped study medication the reasons for doing so were recorded.

SIMVASTATIN 40mg daily: Safety monitoring Notes: Numbers are of participants ever having values in the ranges shown. Participants were seen regularly at 4 month intervals during the first year and then six monthly during the study. A blood sample was taken at each visit and the liver enzyme alanine transaminase (ALT) routinely measured. In addition, if unexplained muscle pain or weakness was reported (or participants were taking non-study statin treatment as well as study simvastatin or placebo tablets) then creatine kinase (CK) was measured . In addition some CK values were reported by the managing doctor.

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 (7.6%) (9.1%) reduction (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 Notes: There was a significant reduction in total mortality which is chiefly driven by a more definite reduction in vascular mortality with no evidence of any excess of non-vascular mortality. (5.3%) (5.6%) reduction (NS) ALL CAUSES 1328 1507 13% SE 4 (12.9%) (14.7%) reduction (2P<0.001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: SITE-SPECIFIC CANCER INCIDENCE 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 Notes: There were no significant differences between the treatment groups in cancer incidence during the study. non melanoma skin) (7.9%) (7.8%) increase (NS) Non-melanoma skin 243 202 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: STROKE INCIDENCE 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 Notes: There was a clear and definite effect of simvastatin on the incidence of first stroke, with the benefits due chiefly to effects on ischaemic stroke (but with no adverse effect on haemorrhagic stroke). For stroke severity the numbers relate to the most severe stroke that could be classified (so these categories are mutually exclusive). 444 585 25% SE 5 (4.3%) (5.7%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION 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 (8.7%) (11.8%) reduction (2P<0.00001) Revascularisation Coronary 513 725 Non-coronary 450 532 REVASCULARISATIONS Notes: none 939 1205 24% SE 4 (9.1%) (11.7%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTS 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 (19.8%) (25.2%) reduction (2P<0.00001) Notes: Similar proportional reductions in major coronary events, in strokes and in revascularisations yield a very definite effect on the first occurrence of any of these “major vascular events“. The extreme statistical significance of this reduction and the very large number of events and on which it is based, allows reliable assessment of the effects of treatment in various different circumstances. 0.4 0.6 0.8 1.0 1.2 1.4

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 Notes: During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year (even though, by the end of year 3, about one-sixth of simvastatin-allocated participants had stopped their study treatment and about one-sixth of those allocated placebo had started statin therapy). (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR 1 2 3 4 5 6 10 15 20 25 30 Years of follow-up SIMVASTATIN PLACEBO 54(7) 46(5) People suffering events (%) 35(5) 20(4) 5(3) Notes: After the first year, there were highly significant reductions of about one quarter in the event rates during each separate year. This leads to continued divergence of the lines in this life-table plot of the effect of simvastatin on the incidence of a first major vascular event, which implies that benefits would increase with longer duration treatment and follow-up. Benefit/1000 (SE): 60(18) SIMVASTATIN

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%) Notes: There were similar proportional reductions in the numbers of participants suffering a first major vascular event in these prior disease categories 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 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%) Notes: There were similar proportional reductions in risk of major vascular events at different ages, and in women as well as men. 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: COGNITIVE IMPAIRMENT (TICS-m <22/39) at Final Follow-up Notes: The modified Telephone Interview for Cognitive Status (TICS-m) was used to assess cognitive function, with a score of 22/39 pre-specified as indicating some cognitive impairment. Despite apparent discrimatory power, as illustrated by higher proportions of older individuals scoring below 22, there is no evidence of an effect of simvastatin on this measure.

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%) Notes: Similar proportional reductions in risk of major vascular events are seen when participants are subdivided by smoking status or history of treated hypertension. 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 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%) Notes: Similar proportional reductions in risk of major vascular events are seen when participants are subdivided by baseline HDL cholesterol or triglycerides levels. 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 Notes: none

SIMVASTATIN: Average LDL DIFFERENCE (mg/dl ± se) by BASELINE LDL cholesterol Notes: none

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%) Notes: Similar proportional reductions in risk of major vascular events are seen when participants are subdivided by baseline LDL or total cholesterol levels. 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 30 Statin-allocated Placebo-allocated 25 Upper LDL third % with major vascular events 20 Lower LDL third 15 Notes: This apparent continuous association between LDL cholesterol and risk of major vascular event is consistent with the original hypothesis of the study that similar risk reductions would be seen irrrespective of baseline LDL cholesterol. It is also consistent with larger reductions in cholesterol being associated with greater proportional benefits (which is being tested by direct randomised comparisons in on-going studies). 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 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 Notes: Even among the 3421 patients with entry LDL cholesterol levels below 100mg/dl (about 2.6 mmol/l), a similar proportional reduction in risk of major major events is seen to that among participants presenting with higher LDL levels. (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

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 Notes: Patients with known chronic renal failure or creatinine >200 µmol/l were excluded from the study. Participants in the study classified as having elevated creatinine were men with creatinine >130 µmol/l and women >110 µmol/l. There was no evidence of any effect of vitamin allocation on the size of the benefit seen with simvastatin. 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 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%) Notes: Similar proportional reductions in risk of major vascular events are seen among those taking or not taking other commonly prescribed cardioprotective medications. 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 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) Notes: none

Millions of people with relevant conditions Notes: It has been estimated that about 25 million people worldwide are currently being treated with a statin. World Health Organisation statistics indicate that there are about 200 million people worldwide with CHD, stroke, other occlusive vascular disease or diabetes. Consequently, the present findings are directly relevant to starting statin treatment in some tens of millions of people at increased risk of heart attacks and strokes.