Cholesterol Treatment Trialists’ (CTT) Collaboration Slide deck

CTT Collaboration: Background* History: Founded in 1993 (prior to publication of 4S trial in 1994) Original protocol published in 1995 Trial eligibility for inclusion in CTT: Randomized Principal effects of treatment is modification of blood lipids Unconfounded (i.e. treatment arms differ only by lipid intervention) Recruited at least 1000 participants Scheduled study treatment duration of at least 2 years *American Journal of Cardiology 1995; 75: 1130-4

CTT Collaboration: Analyses* Based on individual participant data (as opposed to tabular data) Intention-to-treat analyses Main results standardised per mmol/L LDL-cholesterol reduction *American Journal of Cardiology 1995; 75: 1130-4

CTT Lancet 2005*: included 14 trials of statin vs control Study Treatment comparison N Target population Entry lipid criteria 4S S20-40 vs. placebo 4444 Angina or previous MI Total cholesterol 5.5-8.0 mmol/L WOSCOPS P40 vs. placebo 6595 Primary prevention LDL-C at least 4.0 mmol/L CARE 4159 Previous MI Total cholesterol <6.2 mmol/L; LDL-C 3.0 to 4.5 mmol/L Post-CABG L40–80 vs. L2·5–5 1351 Previous bypass surgery LDL-C 3.4-4.5 mmol/L AFCAPS/TexCAPS L20–40 vs. placebo 6605 Total cholesterol 4.65-6.82 mmol/L; LDL-C 3.36-4.91 mmol/L LIPID 9014 Previous MI or hospitalization for unstable angina Total cholesterol 4.0-7.0 mmol/L GISSI-P P20 vs. no treatment 4271 Recent MI Total cholesterol ≥ 5.2 mmol/L LIPS F80 vs. placebo 1677 Previous PCI Total cholesterol 3.5-7.0 mmol/L HPS S40 vs. placebo 20,536 CHD, other occlusive arterial disease or DM Non-fasting total cholesterol ≥ 3·5 mmol/L PROSPER 5804 History of or risk factors for vascular disease Total cholesterol 4·0-9·0 mmol/L ALLHAT-LLT P40 vs. usual care 10,355 Hypertension + at least 1 additional CHD risk factor Fasting LDL-C 3.1-4.9 mmol/L (no known CHD); 2.6 to 3.3 mmol/L (known CHD; upper limit 4.1 mmol/L) ASCOT-LLA A10 vs. placebo 10,305 Hypertension CVD risk factors Non-fasting total cholesterol ≤6·5 mmol/L ALERT F40 vs. placebo 2102 Renal transplant patients Total cholesterol 4·0-9·0 mmol/L. CARDS 2838 Type 2 DM LDL-C ≤ 4.14 mmol/L *Lancet 2005; 366: 1267–78

Relation between the proportional reduction in MAJOR VASCULAR EVENTS and mean absolute LDL-C reduction in 14 statin trials 0.5 1.0 1.5 2.0 Reduction in LDL cholesterol (mmol/L) Proportional reduction in MVE rate (±1 SE) -10% 0% 10% 20% 30% 40% 50% Lancet 2005; 366: 1267-78

CTT Lancet 2010*: additional trials of statin vs control Study Treatment comparison N Target population Entry lipid criteria MEGA P 10-20 vs. usual care 8214 Primary prevention TC 220-270 mg/dL JUPITER R 20 vs. placebo 17 802 Primary prevention (but CRP>2 mg/dL) LDL-C <130 mg/dL, TG <500 mg/dL 4D A 20 vs. placebo 1255 Type 2 DM + haemodialysis LDL-C 80-190 mg/dL TG <1000 mg/dL AURORA R 10 vs. placebo 2773 Haemodialysis None ALLIANCE A 10-80 (until LDL <80 mg/dL) vs. usual care 2442 Prior CHD LDL-C 110-200 mg/dL on lipid lowering drugs, 130-250 mg/dL if not ASPEN A 10 vs. placebo 2410 Type 2 DM + CHD or risk factors LDL-C <150, TG ≤445 mg/dL with CHD; LDL-C <159, TG ≤600 mg/dL without GISSI-HF 4574 CHF *Lancet 2010; 376: 1670-81

CTT Lancet 2010*: more vs less intensive statin therapy Study Treatment comparison N Target population Entry lipid criteria PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL A to Z S 40 then S 80 vs. placebo then S 20 4497 TC ≤250 mg/dL TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL IDEAL A 80 vs. S 20-40 8888 SEARCH S 80 vs. S 20 12,064 TC ≥4.5 mmol/L or ≥3.5 if on statins *Lancet 2010; 376: 1670-81

CTT meta analysis: Proportional reduction in MAJOR VASCULAR EVENTS versus absolute LDL-C reduction 30% TNT 25% Statin vs. control (21 trials) More vs. Less (5 trials) 20% IDEAL Proportional reduction in MVE rate (95% CI) 15% 22% (20%-24%) risk reduction per mmol/L P<0.0001 PROVE-IT A to Z 10% 5% SEARCH 0% 0.0 0.5 1.0 Mean LDL cholesterol difference between treatment groups (mmol/L) Lancet 2010; 376: 1670-81

Statin vs control trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction No. of events (% per annum) RR (CI) per mmol/L LDL-C reduction Outcome Statin Control Non-fatal MI 2310 (0.9) 3213 (1.2) 0.74 (0.69 - 0.78) CHD death 1242 (0.5) 1587 (0.6) 0.80 (0.73 - 0.86) Any major coronary event 3380 (1.3) 4539 (1.7) 0.76 (0.73 - 0.79) CABG 816 (0.3) 1126 (0.4) 0.76 (0.69 - 0.83) PTCA 601 (0.2) 775 (0.3) 0.78 (0.69 - 0.89) Unspecified 1686 (0.6) 2165 (0.8) 0.76 (0.70 - 0.83) Any coronary revascularisation 3103 (1.2) 4066 (1.6) 0.76 (0.73 - 0.80) Ischaemic stroke 987 (0.4) 1225 (0.5) 0.80 (0.73 - 0.88) Haemorrhagic stroke 188 (0.1) 163 (0.1) 1.10 (0.86 - 1.42) Unknown stroke 555 (0.2) 629 (0.2) 0.88 (0.76 - 1.02) Any stroke 1730 (0.7) 2017 (0.8) 0.85 (0.80 - 0.90) Any major vascular event 7136 (2.8) 8934 (3.6) 0.79 (0.77 - 0.81) 99% or 95% CI 0.5 0.75 1 1.25 Statin better Control better Lancet 2010; 376: 1670-81

More vs less statin trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction No. of events (% per annum) RR (CI) per mmol/L LDL-C reduction Outcome More statin Less statin Non-fatal MI 1175 (1.3) 1380 (1.5) 0.71 (0.58 - 0.87) CHD death 645 (0.7) 694 (0.7) 0.85 (0.63 - 1.15) Any major coronary event 1725 (1.9) 1973 (2.2) 0.74 (0.65 - 0.85) CABG 637 (0.7) 731 (0.9) 0.72 (0.55 - 0.95) PTCA 1166 (1.3) 1508 (1.8) 0.60 (0.50 - 0.71) Unspecified 447 (0.5) 502 (0.6) 0.78 (0.58 - 1.04) Any coronary revascularisation 2250 (2.6) 2741 (3.2) 0.66 (0.60 - 0.73) Ischaemic stroke 440 (0.5) 526 (0.6) 0.69 (0.50 - 0.95) Haemorrhagic stroke 69 (0.1) 57 (0.1) 1.39 (0.57 - 3.39) Unknown stroke 63 (0.1) 80 (0.1) 0.63 (0.24 - 1.66) Any stroke 572 (0.6) 663 (0.7) 0.74 (0.59 - 0.92) Any major vascular event 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78) 99% or 95% CI 0.5 0.75 1 1.25 More statin better Less statin better Lancet 2010; 376: 1670-81

More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C, by baseline LDL cholesterol Baseline LDL-C (mmol/L) No. of events (% per annum) RR (CI) per mmol/L LDL-C reduction More statin Less statin < 2.0 704 (4.6) 795 (5.2) 0.71 (0.52 - 0.98) ≥ 2.0 ,<2.5 1189 (4.2) 1317 (4.8) 0.77 (0.64 - 0.94) ≥ 2.5, <3.0 1065 (4.5) 1203 (5.0) 0.81 (0.67 - 0.97) ≥ 3.0, <3.5 517 (4.5) 633 (5.8) 0.61 (0.46 - 0.81) ≥ 3.0 303 (5.7) 398 (7.8) 0.64 (0.47 - 0.86) T otal 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78) 99% or 95% CI 0.5 0.75 1 1.25 More statin better Less statin better Lancet 2010; 376: 1670-81

All trials (statin vs control OR more vs less statin): Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C 0.5 0.75 1 1.25 Control/less better Statin/more Non-fatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke Any major vascular event 3485 (1.0) 1887 (0.5) 5105 (1.4) 1453 (0.4) 1767 (0.5) 2133 (0.6) 5353 (1.5) 1427 (0.4) 257 (0.1) 618 (0.2) 2302 (0.6) 10973 (3.2) 4593 (1.3) 2281 (0.6) 6512 (1.9) 1857 (0.5) 2283 (0.7) 2667 (0.8) 6807 (2.0) 1751 (0.5) 220 (0.1) 709 (0.2) 2680 (0.8) 13350 (4.0) 0.73 (0.69 - 0.78) 0.80 (0.74 - 0.87) 0.76 (0.73 - 0.78) 0.75 (0.69 - 0.82) 0.72 (0.65 - 0.80) 0.76 (0.70 - 0.82) 0.75 (0.72 - 0.78) 0.79 (0.72 - 0.87) 1.12 (0.88 - 1.43) 0.88 (0.76 - 1.01) 0.84 (0.79 - 0.89) 0.78 (0.76 - 0.80) Outcome RR (CI) per mmol/L LDL-C reduction No. of events (% per annum) 99% or 95% CI Lancet 2010; 376: 1670-81

Expected reduction in MAJOR VASCULAR EVENT risk from lowering LDL-C with STATIN therapy Control 20 22% relative risk reduction per mmol/L Statin 15 15% relative risk reduction per 0.5 mmol/L More statin Five year risk of a major vascular event, % 10 Combined evidence: 34% relative risk reduction per 1.5 mmol/L (since 0.78 x 0.85 = 0.66) Or: ~40% relative risk reduction per 2 mmol/L (0.78 x 0.78) 5 1 2 3 4 5 LDL cholesterol, mmol/L

LATEST ANALYSES Including individual data from the CORONA trial and minor updates to other trials (27 trials involving 174 149 participants)

Effect of statin therapy on MAJOR VASCULAR EVENTS by age and sex Events (% p.a.) p-value for Baseline Statin/ Control/ RR (CI) per 1 mmol/L heterogeneity subgroup more statin less statin reduction in LDL-C or trend Age (years) £ 65 6113 (2.9) 7510 (3.6) 0.78 (0.75 - 0.82) > 65, £ 75 4161 (3.7) 5050 (4.6) 0.79 (0.74 - 0.83) p=0.14 > 75 1010 (4.9) 1113 (5.5) 0.87 (0.76 - 0.99) Male 8943 (3.5) 10979 (4.4) 0.78 (0.75 - 0.81) Female 2341 (2.6) 2694 (3.0) 0.84 (0.78 - 0.91) Gender p=0.02 All patients 11284 (3.3) 13673 (4.0) 0.79 (0.77 - 0.81) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse

Effect of statin therapy on MAJOR VASCULAR EVENTS by baseline LDL-C and prior vascular disease Events (% p.a.) p-value for Baseline Statin/ Control/ RR (CI) per 1 mmol/L heterogeneity subgroup more statin less statin reduction in LDL-C or trend < 2.5 2483 (3.8) 2773 (4.3) 0.78 (0.69 - 0.89) ³ 2.5 , < 3.0 1906 (3.4) 2276 (4.0) 0.77 (0.70 - 0.85) 3 , < 3.5 2071 (3.2) 2533 (4.1) 0.76 (0.70 - 0.82) 3.5 4668 (3.0) 5895 (3.9) 0.80 (0.77 - 0.84) Pre-treatment LDL-C (mmol/L) p=0.22 CHD 8671 (4.6) 10426 (5.6) 0.79 (0.76 - 0.82) Non-CHD vascular 707 (3.1) 822 (3.7) 0.83 (0.73 - 0.94) None 1906 (1.4) 2425 (1.8) 0.75 (0.69 - 0.82) History of vascular disease p=0.18 All patients 11284 (3.3) 13673 (4.0) 0.79 (0.77 - 0.81) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse

Effect of statin therapy on MAJOR VASCULAR EVENTS by diabetes, treated hypertension and smoking status Events (% p.a.) p-value for Baseline Statin/ Control/ RR (CI) per 1 mmol/L heterogeneity subgroup more statin less statin reduction in LDL-C or trend Diabetes Type 1 diabetes 145 (4.5) 192 (6.0) 0.77 (0.58 - 1.01) Type 2 diabetes 2593 (4.2) 3028 (5.1) 0.80 (0.74 - 0.86) p=0.78 No diabetes 8484 (3.2) 10378 (4.0) 0.78 (0.76 - 0.82) Treated hypertension Yes 6374 (3.7) 7565 (4.5) 0.80 (0.77 - 0.84) p=0.11 No 4656 (2.8) 5815 (3.5) 0.77 (0.73 - 0.81) Smoking status Current smokers 2303 (3.7) 2922 (4.7) 0.79 (0.73 - 0.85) p=0.88 Non-smokers 8979 (3.2) 10749 (3.9) 0.79 (0.76 - 0.82) All patients 11284 (3.3) 13673 (4.0) 0.79 (0.77 - 0.81) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse

Effect of statin therapy on MAJOR VASCULAR EVENTS by 5-year predicted MVE risk Events (% p.a.) Baseline Statin/ Control/ RR (CI) per 1 mmol/L p-value for subgroup more statin less statin reduction in LDL-C trend < 5% 167 (0.4) 254 (0.6) 0.62 (0.47 - 0.81) ³ 5 , < 10% 606 (1.1) 847 (1.6) 0.69 (0.60 - 0.79) 10 , < 20% 3615 (3.0) 4195 (3.5) 0.79 (0.74 - 0.85) 20 , < 30% 4109 (4.7) 4919 (5.8) 0.81 (0.77 - 0.86) 30% 2787 (7.6) 3458 (9.8) 0.79 (0.74 - 0.84) 5-year MVE risk p=0.04 All patients 11284 (3.3) 13673 (4.0) 0.79 (0.77 - 0.81) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse

Effect of statin therapy on MAJOR VASCULAR EVENTS 30% 5 trials with LDL-c reduction at 1 year >1.1 mmol/L (average: 1.4 mmol/L) 17 trials with LDL-c reduction at 1 year <1.1 mmol/L (average: 0.9 mmol/L) 20% major vascular event rate (95% CI) Proportional reduction in 5 trials with further LDL-c reduction (average: 0.5 mmol/L) 10% 0% 0.0 0.5 1.0 1.5 Mean 1-year LDL cholesterol difference between treatment groups (mmol/L)

Effect of statin therapy on MAJOR VASCULAR EVENTS : 22 trials of statin vs control Events (% p.a.) Statin/ Control/ RR (CI) per 1 mmol/L Year more statin less statin reduction in LDL-C 0-1 year 2221 (3.4) 2459 (3.8) 0.91 (0.85 - 0.97) 1-2 years 1567 (2.6) 2013 (3.4) 0.78 (0.73 - 0.85) 2-3 years 1347 (2.7) 1777 (3.6) 0.76 (0.70 - 0.82) 3-4 years 1046 (2.6) 1437 (3.6) 0.72 (0.66 - 0.79) 4-5 years 810 (2.9) 1009 (3.7) 0.78 (0.71 - 0.87) 5+ years 456 (3.0) 562 (3.9) 0.76 (0.65 - 0.87) All years 7447 (2.9) 9257 (3.6) 0.80 (0.78 - 0.82) Years 1-5+ 5226 (2.7) 6798 (3.6) 0.76 (0.74 - 0.79) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse Test for heterogeneity between RR in first year and RR in years 1-5+: p<0.0001

Effect of statin therapy on MAJOR VASCULAR EVENTS: 5 trials of more vs. less statin Events (% p.a.) Statin/ Control/ RR (CI) per 1 mmol/L Year more statin less statin reduction in LDL-C 0-1 year 1396 (7.4) 1641 (8.8) 0.72 (0.61 - 0.86) 0.72 (0.56 - 0.93) 0.66 (0.49 - 0.89) 0.75 (0.55 - 1.02) 0.69 (0.50 - 0.97) 0.83 (0.54 - 1.27) 0.72 (0.66 - 0.78) 0.72 (0.65 - 0.80) 1-2 years 645 (3.8) 741 (4.4) 2-3 years 499 (3.6) 603 (4.4) 3-4 years 470 (3.6) 522 (4.1) 4-5 years 414 (3.7) 476 (4.4) 5+ years 413 (3.9) 433 (4.1) All years 3837 (4.5) 4416 (5.3) Years 1-5+ 2441 (3.7) 2775 (4.3) 99% or 95% CI 0.5 0.75 1 1.25 LDL-C lowering LDL-C lowering better worse Test for heterogeneity between RR in first year and RR in years 1-5+: NS

Absolute effect of statin therapy on MAJOR VASCULAR EVENTS

Effect of statin therapy on MORTALITY Deaths (% p.a.) Cause-specific Statin/ Control/ RR (CI) per 1 mmol/L mortality more statin less statin reduction in LDL-C Coronary 1902 (0.5) 2290 (0.6) 0.80 (0.74 - 0.87) Other cardiac 1955 (0.5) 2121 (0.6) 0.92 (0.85 - 0.99) Stroke 521 (0.1) 533 (0.1) 0.98 (0.83 - 1.15) Other vascular 420 (0.1) 435 (0.1) 0.95 (0.80 - 1.14) Any vascular 4798 (1.3) 5379 (1.5) 0.88 (0.84 - 0.91) Cancer 1834 (0.5) 1849 (0.5) 0.99 (0.91 - 1.09) Respiratory 257 (0.1) 281 (0.1) 0.86 (0.70 - 1.06) Trauma 137 (0.0) 138 (0.0) 0.97 (0.70 - 1.34) Other non-vascular 856 (0.2) 892 (0.2) 0.94 (0.82 - 1.07) Any non-vascular 3084 (0.8) 3160 (0.9) 0.96 (0.92 - 1.01) Unknown 488 (0.1) 548 (0.1) 0.87 (0.74 - 1.04) Any death 8370 (2.3) 9087 (2.5) 0.91 (0.88 - 0.93) 99% or 95% CI 0.5 0.75 1 1.25 1.5 LDL-C lo w er ing LDL-C lo w er ing better w orse

Effect of statin therapy on SITE-SPECIFIC CANCER Events (% p.a.) Site-specific Statin/ Control/ RR (CI) per 1 mmol/L cancer more statin less statin reduction in LDL-C Large bowel/intestine 549 (0.2) 567 (0.2) 0.95 (0.82 - 1.11) Other GI 665 (0.2) 678 (0.2) 0.99 (0.86 - 1.15) Prostate 923 (0.3) 954 (0.4) 0.97 (0.85 - 1.10) Bladder 315 (0.1) 331 (0.1) 0.94 (0.76 - 1.16) Other GU 406 (0.1) 391 (0.1) 1.05 (0.86 - 1.27) Respiratory 845 (0.2) 847 (0.2) 1.00 (0.88 - 1.14) F emale breast 273 (0.3) 244 (0.3) 1.09 (0.85 - 1.39) Haematological 313 (0.1) 301 (0.1) 1.03 (0.83 - 1.28) Other/unspecified 932 (0.3) 897 (0.2) 1.05 (0.92 - 1.21) Any cancer 5221 (1.5) 5210 (1.5) 1.00 (0.96 - 1.04) 99% or 95% CI 0.5 0.75 1 1.25 1.5 LDL-C lowering LDL-C lowering better worse