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:

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:

CTT Lancet 2005*: included 14 trials of statin vs control StudyTreatment comparison NTarget populationEntry lipid criteria 4SS20-40 vs. placebo4444Angina or previous MITotal cholesterol mmol/L WOSCOPSP40 vs. placebo6595Primary preventionLDL-C at least 4.0 mmol/L CAREP40 vs. placebo4159Previous MITotal cholesterol <6.2 mmol/L; LDL-C 3.0 to 4.5 mmol/L Post-CABGL40–80 vs. L2·5–51351Previous bypass surgeryLDL-C mmol/L AFCAPS/TexCAPSL20–40 vs. placebo6605Primary preventionTotal cholesterol mmol/L; LDL-C mmol/L LIPIDP40 vs. placebo9014Previous MI or hospitalization for unstable angina Total cholesterol mmol/L GISSI-PP20 vs. no treatment4271Recent MITotal cholesterol ≥ 5.2 mmol/L LIPSF80 vs. placebo1677Previous PCITotal cholesterol mmol/L HPSS40 vs. placebo20,536CHD, other occlusive arterial disease or DM Non-fasting total cholesterol ≥ 3·5 mmol/L PROSPERP40 vs. placebo5804History of or risk factors for vascular disease Total cholesterol 4·0-9·0 mmol/L ALLHAT-LLTP40 vs. usual care10,355Hypertension + at least 1 additional CHD risk factor Fasting LDL-C mmol/L (no known CHD); 2.6 to 3.3 mmol/L (known CHD; upper limit 4.1 mmol/L) ASCOT-LLAA10 vs. placebo10,305Hypertension CVD risk factors Non-fasting total cholesterol ≤6·5 mmol/L ALERTF40 vs. placebo2102Renal transplant patientsTotal cholesterol 4·0-9·0 mmol/L. CARDSA10 vs. placebo2838Type 2 DMLDL-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 Lancet 2005; 366: Reduction in LDL cholesterol (mmol/L) Proportional reduction in MVE rate (±1 SE) -10% 0% 10% 20% 30% 40% 50%

CTT Lancet 2010*: additional trials of statin vs control StudyTreatment comparison NTarget populationEntry lipid criteria MEGAP vs. usual care8214Primary preventionTC mg/dL JUPITERR 20 vs. placebo17 802Primary prevention (but CRP>2 mg/dL) LDL-C <130 mg/dL, TG <500 mg/dL 4DA 20 vs. placebo1255Type 2 DM + haemodialysis LDL-C mg/dL TG <1000 mg/dL AURORAR 10 vs. placebo2773HaemodialysisNone ALLIANCEA (until LDL <80 mg/dL) vs. usual care 2442Prior CHDLDL-C mg/dL on lipid lowering drugs, mg/dL if not ASPENA 10 vs. placebo2410Type 2 DM + CHD or risk factors LDL-C <150, TG ≤445 mg/dL with CHD; LDL-C <159, TG ≤600 mg/dL without GISSI-HFR 10 vs. placebo4574CHFNone *Lancet 2010; 376:

CTT Lancet 2010*: more vs less intensive statin therapy StudyTreatment comparison NTarget populationEntry lipid criteria PROVE-ITA 80 vs. P ACSTC ≤240 mg/dL A to ZS 40 then S 80 vs. placebo then S ACSTC ≤250 mg/dL TNTA 80 vs. A 1010,001Prior CHDLDL-C mg/dL TG ≤600 mg/dL IDEALA 80 vs. S Prior CHDTG ≤600 mg/dL SEARCHS 80 vs. S 2012,064Prior CHDTC ≥4.5 mmol/L or ≥3.5 if on statins *Lancet 2010; 376:

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

Statin vs control trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction Lancet 2010; 376: Outcome Statin Control RR (CI) per mmol/L LDL-C reduction Control betterStatin better 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 No. of events (% per annum) 2310 (0.9) 1242 (0.5) 3380 (1.3) 816 (0.3) 601 (0.2) 1686 (0.6) 3103 (1.2) 987 (0.4) 188 (0.1) 555 (0.2) 1730 (0.7) 7136 (2.8) 3213 (1.2) 1587 (0.6) 4539 (1.7) 1126 (0.4) 775 (0.3) 2165 (0.8) 4066 (1.6) 1225 (0.5) 163 (0.1) 629 (0.2) 2017 (0.8) 8934 (3.6) 0.74 ( ) 0.80 ( ) 0.76 ( ) 0.76 ( ) 0.78 ( ) 0.76 ( ) 0.76 ( ) 0.80 ( ) 1.10 ( ) 0.88 ( ) 0.85 ( ) 0.79 ( ) 99% or 95% CI

More vs less statin trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction Outcome More statin Less statin RR (CI) per mmol/L LDL-C reduction Less statin better More statin better 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 No. of events (% per annum) 1175 (1.3) 645 (0.7) 1725 (1.9) 637 (0.7) 1166 (1.3) 447 (0.5) 2250 (2.6) 440 (0.5) 69 (0.1) 63 (0.1) 572 (0.6) 3837 (4.5) 1380 (1.5) 694 (0.7) 1973 (2.2) 731 (0.9) 1508 (1.8) 502 (0.6) 2741 (3.2) 526 (0.6) 57 (0.1) 80 (0.1) 663 (0.7) 4416 (5.3) 0.71 ( ) 0.85 ( ) 0.74 ( ) 0.72 ( ) 0.60 ( ) 0.78 ( ) 0.66 ( ) 0.69 ( ) 1.39 ( ) 0.63 ( ) 0.74 ( ) 0.72 ( ) Lancet 2010; 376: % or 95% CI

More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C, by baseline LDL cholesterol More statinLess statin RR (CI) per mmol/L LDL-C reduction Less statin better More statin better < 2.0 ≥ 2.0,<2.5 ≥ 2.5, <3.0 ≥ 3.0, <3.5 ≥ 3.0 No. of events (% per annum) 704 (4.6) 795 (5.2)0.71 ( ) 1189 (4.2) 1317 (4.8)0.77 ( ) 1065 (4.5) 1203 (5.0)0.81 ( ) 517 (4.5) 633 (5.8)0.61 ( ) 303 (5.7) 398 (7.8)0.64 ( ) Total 3837 (4.5) 4416 (5.3)0.72 ( ) 99% or 95% CI Lancet 2010; 376: Baseline LDL-C (mmol/L)

All trials (statin vs control OR more vs less statin): Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C Lancet 2010; 376:

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

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

Effect of statin therapy on MAJOR VASCULAR EVENTS by age and sex Baseline subgroup Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C p-value for heterogeneity or trend 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) All patients11284 (3.3)13673 (4.0)0.79 ( ) Male 8943 (3.5)10979 (4.4)0.78 ( ) Female 2341 (2.6) 2694 (3.0)0.84 ( ) Gender p=0.02  (2.9) 7510 (3.6)0.78 ( ) > 65,  (3.7) 5050 (4.6)0.79 ( ) > (4.9) 1113 (5.5)0.87 ( ) Age (years) p=0.14

Effect of statin therapy on MAJOR VASCULAR EVENTS by baseline LDL-C and prior vascular disease Baseline subgroup Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C p-value for heterogeneity or trend 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) All patients11284 (3.3)13673 (4.0)0.79 ( ) < (3.8) 2773 (4.3)0.78 ( )  2.5, < (3.4) 2276 (4.0)0.77 ( )  3, < (3.2) 2533 (4.1)0.76 ( )  (3.0) 5895 (3.9)0.80 ( ) Pre-treatment LDL-C (mmol/L) p=0.22 CHD 8671 (4.6)10426 (5.6)0.79 ( ) Non-CHD vascular 707 (3.1) 822 (3.7)0.83 ( ) None 1906 (1.4) 2425 (1.8)0.75 ( ) History of vascular disease p=0.18

Effect of statin therapy on MAJOR VASCULAR EVENTS by diabetes, treated hypertension and smoking status Baseline subgroup Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C p-value for heterogeneity or trend 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) All patients11284 (3.3)13673 (4.0)0.79 ( ) Type 1 diabetes 145 (4.5) 192 (6.0)0.77 ( ) Type 2 diabetes 2593 (4.2) 3028 (5.1)0.80 ( ) No diabetes 8484 (3.2)10378 (4.0)0.78 ( ) Yes 6374 (3.7) 7565 (4.5)0.80 ( ) No 4656 (2.8) 5815 (3.5)0.77 ( ) Current smokers 2303 (3.7) 2922 (4.7)0.79 ( ) Non-smokers 8979 (3.2)10749 (3.9)0.79 ( ) Diabetes p=0.78 Treated hypertension p=0.11 Smoking status p=0.88

Effect of statin therapy on MAJOR VASCULAR EVENTS by 5-year predicted MVE risk Baseline subgroup Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C p-value for trend 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) All patients11284 (3.3)13673 (4.0)0.79 ( ) < 5% 167 (0.4) 254 (0.6)0.62 ( )  5, < 10% 606 (1.1) 847 (1.6)0.69 ( )  10, < 20% 3615 (3.0) 4195 (3.5)0.79 ( )  20, < 30% 4109 (4.7) 4919 (5.8)0.81 ( )  30% 2787 (7.6) 3458 (9.8)0.79 ( ) 5-year MVE risk p=0.04

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

Effect of statin therapy on MAJOR VASCULAR EVENTS : 22 trials of statin vs control Year StatinControl RR (CI) per 1 mmol/L reduction in LDL-C 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) 0-1 year 2221 (3.4)2459 (3.8)0.91 ( ) 1-2 years 1567 (2.6)2013 (3.4)0.78 ( ) 2-3 years 1347 (2.7)1777 (3.6)0.76 ( ) 3-4 years 1046 (2.6)1437 (3.6)0.72 ( ) 4-5 years 810 (2.9)1009 (3.7)0.78 ( ) 5+ years 456 (3.0) 562 (3.9)0.76 ( ) All years 7447 (2.9)9257 (3.6)0.80 ( ) Years (2.7)6798 (3.6)0.76 ( ) 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 Year More statinLess statin RR (CI) per 1 mmol/L reduction in LDL-C 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) 0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All years Years 1-5+ Test for heterogeneity between RR in first year and RR in years 1-5+: NS 1396 (7.4)1641 (8.8) 645 (3.8) 741 (4.4) 499 (3.6) 603 (4.4) 470 (3.6) 522 (4.1) 414 (3.7) 476 (4.4) 413 (3.9) 433 (4.1) 3837 (4.5)4416 (5.3) 2441 (3.7)2775 (4.3) 0.72 ( ) 0.72 ( ) 0.66 ( ) 0.75 ( ) 0.69 ( ) 0.83 ( ) 0.72 ( ) 0.72 ( )

Absolute effect of statin therapy on MAJOR VASCULAR EVENTS

Effect of statin therapy on MORTALITY Cause-specific mortality Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C 99% or 95% CI LDL-C lowering worse LDL-C lowering better Deaths (% p.a.) 1902 (0.5)2290 (0.6) Coronary 0.80 ( ) 1955 (0.5)2121 (0.6) Other cardiac 0.92 ( ) 521 (0.1) 533 (0.1) Stroke 0.98 ( ) 420 (0.1) 435 (0.1) Other vascular 0.95 ( ) 4798 (1.3)5379 (1.5) Any vascular 0.88 ( ) 1834 (0.5)1849 (0.5) Cancer 0.99 ( ) 257 (0.1) 281 (0.1) Respiratory 0.86 ( ) 137 (0.0) 138 (0.0) Trauma 0.97 ( ) 856 (0.2) 892 (0.2) Other non-vascular 0.94 ( ) 3084 (0.8)3160 (0.9) Any non-vascular 0.96 ( ) 488 (0.1) 548 (0.1) Unknown 0.87 ( ) 8370 (2.3)9087 (2.5) Any death 0.91 ( )

Effect of statin therapy on SITE-SPECIFIC CANCER Site-specific cancer Statin/ more statin Control/ less statin RR (CI) per 1 mmol/L reduction in LDL-C 99% or 95% CI LDL-C lowering worse LDL-C lowering better Events (% p.a.) 549 (0.2) 567 (0.2)Large bowel/intestine0.95 ( ) 665 (0.2) 678 (0.2) Other GI 0.99 ( ) 923 (0.3) 954 (0.4) Prostate 0.97 ( ) 315 (0.1) 331 (0.1) Bladder 0.94 ( ) 406 (0.1) 391 (0.1) Other GU 1.05 ( ) 845 (0.2) 847 (0.2) Respiratory 1.00 ( ) 273 (0.3) 244 (0.3) Female breast 1.09 ( ) 313 (0.1) 301 (0.1) Haematological 1.03 ( ) 932 (0.3) 897 (0.2)Other/unspecified1.05 ( ) 5221 (1.5)5210 (1.5) Any cancer 1.00 ( )

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