Cholesterol Treatment Trialists CTT Collaboration Slide deck CTT

Cholesterol Treatment Trialists’ (CTT) Collaboration Slide deck

CTT Collaboration: Background* History: • • Founded in 1993 (prior to publication of 4 S 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 4 S S 20 -40 vs. placebo WOSCOPS Target population Entry lipid criteria 4444 Angina or previous MI Total cholesterol 5. 5 -8. 0 mmol/L P 40 vs. placebo 6595 Primary prevention LDL-C at least 4. 0 mmol/L CARE P 40 vs. placebo 4159 Previous MI Total cholesterol <6. 2 mmol/L; LDL-C 3. 0 to 4. 5 mmol/L Post-CABG L 40– 80 vs. L 2· 5– 5 1351 Previous bypass surgery LDL-C 3. 4 -4. 5 mmol/L AFCAPS/Tex. CAPS L 20– 40 vs. placebo 6605 Primary prevention Total cholesterol 4. 65 -6. 82 mmol/L; LDL-C 3. 36 -4. 91 mmol/L LIPID P 40 vs. placebo 9014 Previous MI or hospitalization for unstable angina Total cholesterol 4. 0 -7. 0 mmol/L GISSI-P P 20 vs. no treatment 4271 Recent MI Total cholesterol ≥ 5. 2 mmol/L LIPS F 80 vs. placebo 1677 Previous PCI Total cholesterol 3. 5 -7. 0 mmol/L HPS S 40 vs. placebo 20, 536 CHD, other occlusive arterial disease or DM Non-fasting total cholesterol ≥ 3· 5 mmol/L PROSPER P 40 vs. placebo 5804 History of or risk factors for vascular disease Total cholesterol 4· 0 -9· 0 mmol/L ALLHAT-LLT P 40 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 A 10 vs. placebo 10, 305 Hypertension CVD risk factors Non-fasting total cholesterol ≤ 6· 5 mmol/L ALERT F 40 vs. placebo 2102 Renal transplant patients Total cholesterol 4· 0 -9· 0 mmol/L. CARDS A 10 vs. placebo 2838 Type 2 DM LDL-C ≤ 4. 14 mmol/L *Lancet 2005; 366: 1267– 78 N

Relation between the proportional reduction in MAJOR VASCULAR EVENTS and mean absolute LDL-C reduction in 14 statin trials Proportional reduction in MVE rate (± 1 SE) 50% 40% 30% 20% 10% 0% 0. 5 1. 0 1. 5 2. 0 -10% Reduction in LDL cholesterol (mmol/L) Lancet 2005; 366: 1267 -78

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

CTT Lancet 2010*: more vs less intensive statin therapy Study Treatment comparison PROVE-IT A 80 vs. P 40 A to Z S 40 then S 80 vs. placebo then S 20 TNT A 80 vs. A 10 IDEAL A 80 vs. S 20 -40 SEARCH S 80 vs. S 20 *Lancet 2010; 376: 1670 -81 N Target population Entry lipid criteria 4162 ACS TC ≤ 240 mg/d. L 4497 ACS TC ≤ 250 mg/d. L 10, 001 Prior CHD LDL-C 130 -250 mg/d. L TG ≤ 600 mg/d. L 8888 Prior CHD TG ≤ 600 mg/d. L 12, 064 Prior CHD TC ≥ 4. 5 mmol/L or ≥ 3. 5 if on statins

CTT meta analysis: Proportional reduction in MAJOR VASCULAR EVENTS versus absolute LDL-C reduction 30% TNT Proportional reduction in MVE rate (95% CI) 25% Statin vs. control (21 trials) More vs. Less (5 trials) 20% IDEAL 15% 10% 5% 22% (20%-24%) risk reduction per mmol/L P<0. 0001 PROVE-IT A to Z SEARCH 0% 0. 0 Lancet 2010; 376: 1670 -81 0. 5 Mean LDL cholesterol difference between treatment groups (mmol/L) 1. 0

Statin vs control trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction RR (CI) per mmol/L LDL-C reduction No. of events (% per annum) Control Statin Outcome Non-fatal MI CHD death Any major coronary event 2310 (0. 9) 1242 (0. 5) 3380 (1. 3) 3213 (1. 2) 1587 (0. 6) 4539 (1. 7) 0. 74 (0. 69 - 0. 78) 0. 80 (0. 73 - 0. 86) CABG PTCA Unspecified Any coronary revascularisation 816 (0. 3) 601 (0. 2) 1686 (0. 6) 3103 (1. 2) 1126 (0. 4) 775 (0. 3) 2165 (0. 8) 4066 (1. 6) 0. 76 (0. 69 - 0. 83) 0. 78 (0. 69 - 0. 89) 0. 76 (0. 70 - 0. 83) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 987 (0. 4) 188 (0. 1) 555 (0. 2) 1730 (0. 7) 1225 (0. 5) 163 (0. 1) 629 (0. 2) 2017 (0. 8) 0. 80 (0. 73 - 0. 88) 1. 10 (0. 86 - 1. 42) 0. 88 (0. 76 - 1. 02) Any major vascular event 7136 (2. 8) 8934 (3. 6) 0. 79 (0. 77 - 0. 81) 99% or 95% CI Lancet 2010; 376: 1670 -81 0. 76 (0. 73 - 0. 79) 0. 76 (0. 73 - 0. 80) 0. 85 (0. 80 - 0. 90) 0. 5 0. 75 Statin better 1 1. 25 Control better

More vs less statin trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction RR (CI) per mmol/L LDL-C reduction No. of events (% per annum) More statin Less statin Outcome Non-fatal MI CHD death Any major coronary event 1175 (1. 3) 645 (0. 7) 1725 (1. 9) 1380 (1. 5) 694 (0. 7) 1973 (2. 2) 0. 71 (0. 58 - 0. 87) 0. 85 (0. 63 - 1. 15) CABG PTCA Unspecified Any coronary revascularisation 637 (0. 7) 1166 (1. 3) 447 (0. 5) 2250 (2. 6) 731 (0. 9) 1508 (1. 8) 502 (0. 6) 2741 (3. 2) 0. 72 (0. 55 - 0. 95) 0. 60 (0. 50 - 0. 71) 0. 78 (0. 58 - 1. 04) 440 (0. 5) 69 (0. 1) 63 (0. 1) 572 (0. 6) 526 (0. 6) 57 (0. 1) 80 (0. 1) 663 (0. 7) 0. 69 (0. 50 - 0. 95) 1. 39 (0. 57 - 3. 39) 0. 63 (0. 24 - 1. 66) 3837 (4. 5) 4416 (5. 3) 0. 72 (0. 66 - 0. 78) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any major vascular event 99% or 95% CI Lancet 2010; 376: 1670 -81 0. 74 (0. 65 - 0. 85) 0. 66 (0. 60 - 0. 73) 0. 74 (0. 59 - 0. 92) 0. 5 0. 75 More statin better 1 1. 25 Less statin better

More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C, by baseline LDL cholesterol No. of events (% per annum) More statin Less statin Baseline LDL-C (mmol/L) < 2. 0 RR (CI) per mmol/L LDL-C reduction 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) 3837 (4. 5) 4416 (5. 3) 0. 72 (0. 66 - 0. 78) Total 99% or 95% CI 0. 5 More statin better Lancet 2010; 376: 1670 -81 0. 75 1 1. 25 Less statin better

All trials (statin vs control OR more vs less statin): Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL-C No. of events (% per annum) Control/less Statin/more Outcome RR (CI) per mmol/L LDL-C reduction 3485 (1. 0) 1887 (0. 5) 5105 (1. 4) 4593 (1. 3) 2281 (0. 6) 6512 (1. 9) 0. 73 (0. 69 - 0. 78) 0. 80 (0. 74 - 0. 87) 0. 76 (0. 73 - 0. 78) CABG PTCA Unspecified Any coronary revascularisation 1453 (0. 4) 1767 (0. 5) 1857 (0. 5) 2283 (0. 7) 0. 75 (0. 69 - 0. 82) 0. 72 (0. 65 - 0. 80) 2133 (0. 6) 5353 (1. 5) 2667 (0. 8) 6807 (2. 0) 0. 76 (0. 70 - 0. 82) 0. 75 (0. 72 - 0. 78) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 1427 (0. 4) 257 (0. 1) 618 (0. 2) 2302 (0. 6) 1751 (0. 5) 220 (0. 1) 709 (0. 2) 2680 (0. 8) 0. 79 (0. 72 - 0. 87) 1. 12 (0. 88 - 1. 43) 0. 88 (0. 76 - 1. 01) 0. 84 (0. 79 - 0. 89) Any major vascular event 10973 (3. 2) 13350 (4. 0) 0. 78 (0. 76 - 0. 80) Non-fatal MI CHD death Any major coronary event 99% or 95% CI 0. 5 Statin/more better Lancet 2010; 376: 1670 -81 0. 75 1 1. 25 Control/less better

Expected reduction in MAJOR VASCULAR EVENT risk from lowering LDL-C with STATIN therapy 15 Statin 22% relative risk reduction per mmol/L 15% relative risk reduction per 0. 5 mmol/L 10 More statin Or: ~40% relative risk reduction per 2 mmol/L (0. 78 x 0. 78) 5 Combined evidence: 34% relative risk reduction per 1. 5 mmol/L (since 0. 78 x 0. 85 = 0. 66) 0 Five year risk of a major vascular event, % 20 Control 0 1 2 3 LDL cholesterol, mmol/L 4 5

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 Baseline subgroup Events (% p. a. ) Statin/ Control/ more statin less statin RR (CI) per 1 mmol/L reduction in LDL-C p-value for heterogeneity or trend Age (years) £ 65 > 65, £ 75 > 75 6113 (2. 9) 4161 (3. 7) 1010 (4. 9) 7510 (3. 6) 5050 (4. 6) 1113 (5. 5) 0. 78 (0. 75 - 0. 82) 0. 79 (0. 74 - 0. 83) 0. 87 (0. 76 - 0. 99) p=0. 14 Gender Male Female 8943 (3. 5) 10979 (4. 4) 2341 (2. 6) 2694 (3. 0) 0. 78 (0. 75 - 0. 81) 0. 84 (0. 78 - 0. 91) p=0. 02 11284 (3. 3) 13673 (4. 0) 0. 79 (0. 77 - 0. 81) All patients 99% or 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 LDL-C lowering worse

Effect of statin therapy on MAJOR VASCULAR EVENTS by baseline LDL-C and prior vascular disease Baseline subgroup Events (% p. a. ) Statin/ Control/ more statin less statin Pre-treatment LDL-C (mmol/L) 2483 (3. 8) < 2. 5 ³ 2. 5, < 3. 0 1906 (3. 4) ³ 3, < 3. 5 2071 (3. 2) ³ 3. 5 4668 (3. 0) RR (CI) per 1 mmol/L reduction in LDL-C p-value for heterogeneity or trend 2773 (4. 3) 2276 (4. 0) 2533 (4. 1) 5895 (3. 9) 0. 78 (0. 69 - 0. 89) 0. 77 (0. 70 - 0. 85) 0. 76 (0. 70 - 0. 82) 0. 80 (0. 77 - 0. 84) p=0. 22 History of vascular disease 8671 (4. 6) 10426 (5. 6) CHD 707 (3. 1) 822 (3. 7) Non-CHD vascular 1906 (1. 4) 2425 (1. 8) None 0. 79 (0. 76 - 0. 82) 0. 83 (0. 73 - 0. 94) 0. 75 (0. 69 - 0. 82) p=0. 18 All patients 0. 79 (0. 77 - 0. 81) 99% or 11284 (3. 3) 13673 (4. 0) 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 LDL-C lowering worse

Effect of statin therapy on MAJOR VASCULAR EVENTS by diabetes, treated hypertension and smoking status Baseline subgroup Diabetes Type 1 diabetes Type 2 diabetes No diabetes Events (% p. a. ) Statin/ Control/ more statin less statin RR (CI) per 1 mmol/L reduction in LDL-C 145 (4. 5) 192 (6. 0) 2593 (4. 2) 3028 (5. 1) 8484 (3. 2) 10378 (4. 0) 0. 77 (0. 58 - 1. 01) 0. 80 (0. 74 - 0. 86) 0. 78 (0. 76 - 0. 82) p=0. 78 7565 (4. 5) 5815 (3. 5) 0. 80 (0. 77 - 0. 84) 0. 77 (0. 73 - 0. 81) p=0. 11 2303 (3. 7) 2922 (4. 7) 8979 (3. 2) 10749 (3. 9) 0. 79 (0. 73 - 0. 85) 0. 79 (0. 76 - 0. 82) p=0. 88 11284 (3. 3) 13673 (4. 0) 0. 79 (0. 77 - 0. 81) Treated hypertension Yes 6374 (3. 7) No 4656 (2. 8) Smoking status Current smokers Non-smokers All patients 99% or 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 LDL-C lowering worse p-value for heterogeneity or trend

Effect of statin therapy on MAJOR VASCULAR EVENTS by 5 -year predicted MVE risk Baseline subgroup 5 -year MVE risk < 5% ³ 5, < 10% ³ 10, < 20% ³ 20, < 30% ³ 30% All patients 99% or Events (% p. a. ) Statin/ Control/ more statin less statin 167 (0. 4) 606 (1. 1) 3615 (3. 0) 4109 (4. 7) 2787 (7. 6) RR (CI) per 1 mmol/L reduction in LDL-C 254 (0. 6) 847 (1. 6) 4195 (3. 5) 4919 (5. 8) 3458 (9. 8) 0. 62 (0. 47 - 0. 81) 0. 69 (0. 60 - 0. 79) 0. 79 (0. 74 - 0. 85) 0. 81 (0. 77 - 0. 86) 0. 79 (0. 74 - 0. 84) 11284 (3. 3) 13673 (4. 0) 0. 79 (0. 77 - 0. 81) 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 LDL-C lowering worse p-value for trend p=0. 04

Effect of statin therapy on MAJOR VASCULAR EVENTS Proportional reduction in major vascular event rate (95% CI) 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% 5 trials with further LDL-c reduction (average: 0. 5 mmol/L) 10% 0% 0. 0 0. 5 1. 0 Mean 1 -year LDL cholesterol difference between treatment groups (mmol/L) 1. 5

Effect of statin therapy on MAJOR VASCULAR EVENTS : 22 trials of statin vs control Year Events (% p. a. ) Statin Control RR (CI) per 1 mmol/L reduction in LDL-C 0 -1 year 1 -2 years 2 -3 years 3 -4 years 4 -5 years 5+ years 2221 (3. 4) 1567 (2. 6) 1347 (2. 7) 1046 (2. 6) 810 (2. 9) 456 (3. 0) 2459 (3. 8) 2013 (3. 4) 1777 (3. 6) 1437 (3. 6) 1009 (3. 7) 562 (3. 9) 0. 91 (0. 85 - 0. 97) 0. 78 (0. 73 - 0. 85) 0. 76 (0. 70 - 0. 82) 0. 72 (0. 66 - 0. 79) 0. 78 (0. 71 - 0. 87) 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 LDL-C lowering better 0. 75 1 1. 25 LDL-C lowering 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 Year Events (% p. a. ) More statin Less statin RR (CI) per 1 mmol/L reduction in LDL-C 0 -1 year 1 -2 years 2 -3 years 3 -4 years 4 -5 years 5+ years 1396 (7. 4) 645 (3. 8) 499 (3. 6) 470 (3. 6) 414 (3. 7) 413 (3. 9) 1641 (8. 8) 741 (4. 4) 603 (4. 4) 522 (4. 1) 476 (4. 4) 433 (4. 1) 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) All years 3837 (4. 5) 4416 (5. 3) 0. 72 (0. 66 - 0. 78) Years 1 -5+ 2441 (3. 7) 2775 (4. 3) 0. 72 (0. 65 - 0. 80) 99% or 95% CI 0. 5 LDL-C lowering better 0. 75 1. 25 1 LDL-C lowering 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 1440 Major vascular events avoided per 10, 000 patients treated for 5 -years 1130 1, 600 1010 1, 400 730 800 1, 200 1, 000 680 540 800 370 400 170 5 -y ris ear k ma of j va sc or ev ular en t 600 310 250 30%+ 20 -29% 200 10 -19% 0 1 1. 5 2 LDL cholesterol reduction (mmol/L) with statin treatment 5 -9%

Effect of statin therapy on MORTALITY Cause-specific mortality Deaths (% p. a. ) Statin/ Control/ more statin less statin RR (CI) per 1 mmol/L reduction in LDL-C Coronary Other cardiac Stroke Other vascular 1902 (0. 5) 1955 (0. 5) 521 (0. 1) 420 (0. 1) 2290 (0. 6) 2121 (0. 6) 533 (0. 1) 435 (0. 1) 0. 80 (0. 74 - 0. 87) 0. 92 (0. 85 - 0. 99) 0. 98 (0. 83 - 1. 15) 0. 95 (0. 80 - 1. 14) Any vascular 4798 (1. 3) 5379 (1. 5) 0. 88 (0. 84 - 0. 91) Cancer Respiratory Trauma Other non-vascular 1834 (0. 5) 257 (0. 1) 137 (0. 0) 856 (0. 2) 1849 (0. 5) 281 (0. 1) 138 (0. 0) 892 (0. 2) 0. 99 (0. 91 - 1. 09) 0. 86 (0. 70 - 1. 06) 0. 97 (0. 70 - 1. 34) 0. 94 (0. 82 - 1. 07) Any non-vascular 3084 (0. 8) 3160 (0. 9) 0. 96 (0. 92 - 1. 01) 488 (0. 1) 548 (0. 1) 0. 87 (0. 74 - 1. 04) 8370 (2. 3) 9087 (2. 5) 0. 91 (0. 88 - 0. 93) Unknown Any death 99% or 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 1. 5 LDL-C lowering worse

Effect of statin therapy on SITE-SPECIFIC CANCER Site-specific cancer Events (% p. a. ) Statin/ Control/ more statin less statin Large bowel/intestine Other GI Prostate Bladder Other GU Respiratory Female breast Haematological Other/unspecified Any cancer 99% or RR (CI) per 1 mmol/L reduction in LDL-C 549 (0. 2) 665 (0. 2) 923 (0. 3) 315 (0. 1) 406 (0. 1) 845 (0. 2) 273 (0. 3) 313 (0. 1) 932 (0. 3) 567 (0. 2) 678 (0. 2) 954 (0. 4) 331 (0. 1) 391 (0. 1) 847 (0. 2) 244 (0. 3) 301 (0. 1) 897 (0. 2) 0. 95 (0. 82 - 1. 11) 0. 99 (0. 86 - 1. 15) 0. 97 (0. 85 - 1. 10) 0. 94 (0. 76 - 1. 16) 1. 05 (0. 86 - 1. 27) 1. 00 (0. 88 - 1. 14) 1. 09 (0. 85 - 1. 39) 1. 03 (0. 83 - 1. 28) 1. 05 (0. 92 - 1. 21) 5221 (1. 5) 5210 (1. 5) 1. 00 (0. 96 - 1. 04) 95% CI 0. 5 0. 75 LDL-C lowering better 1 1. 25 1. 5 LDL-C lowering worse

Thank you to our funders: