Cholesterol Lowering and CV Risk: Meta-analyses

On-Treatment LDL and CHD Events in Statin Trials WOSCOPS - Rx 4S - Rx LIPID - Rx 4S - PBO CARE - Rx LIPID - PBO CARE - PBO WOSCOPS - PBO AFCAPS - PBO AFCAPS - Rx 10 20 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Secondary Prevention Primary Prevention 200 (5.2) ASCOT - PBO ASCOT - Rx PROVE-IT - PRA PROVE-IT - ATV80 TNT - ATV10 Event rate (%) LDL-C achieved, mg/dL (mmol/L) 70 (1.8) HPS - PBO HPS - Rx TNT - ATV80 LaRosa, p 1434, Fig 4 Rosenson p 270, Fig 1 Landmark statin trials in primary and secondary prevention clearly show the relationship between on-treatment low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular (CV) event rate, indicating that larger reductions in LDL-C are associated with greater improvements in morbidity and mortality. TNT, Treating to New Targets; HPS, Heart Protection Study; CARE, Cholesterol and Recurrent Events Trial; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; 4S, Scandinavian Simvastatin Survival Study; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial. Ballantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. Rosensen RS. Expert Opin Emerg Drugs. 2004;9:269-279. LaRosa JC, Grundy SM, Waters DD, et al. N Engl J Med. 2005;352:e-version. Adapted from Rosensen RS. Expert Opin Emerg Drugs. 2004;9:269-279. Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269-279. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

mmol/L LDL-C reduction Second Cycle of the CTT Meta-analysis: Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction No. of events (% pa) Relative risk (CI) per mmol/L LDL-C reduction Statin/more Control/less More vs. less statin PROVE-IT 406 (11.3) 458 (13.1) A to Z 257 (7.2) 282 (8.1) TNT 889 (4.0) 1164 (5.4) IDEAL 938 (5.2) 1106 (6.3) SEARCH 1347 (3.6) 1406 (3.8) Subtotal (5 trials) 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78) P < 0.001 Statin vs. control First cycle (14 trials) 5883 (3.1) 7467 (4.0) 0.78 (0.76 - 0.81) ALLIANCE 254 (5.4) 293 (6.4) 4D 144 (9.0) 162 (10.1) The second cycle of the Cholesterol Treatment Trialists’ (CTT) Collaboration consisted of 2 parts: a meta-analysis of more versus less intensive statin therapy and an updating of the first cycle meta-analysis of statin versus control that added 7 more trials. For the meta-analysis of more versus less intensive statin therapy, 5 studies were included: 2 in patients with acute coronary syndromes (ACS) and 3 in patients with stable coronary disease. The original CTT meta-analysis of statins versus controls included 14 trials, whereas this second cycle included 7 additional trials of statins versus controls: 2 in primary prevention, 2 in patients on hemodialysis, and 1 each in patients with coronary disease, diabetes, and heart failure. In the 5 CTT trials that compared more versus less intensive statin therapy, the overall further reduction in first major vascular events was 28% per 1 mmol/L reduction in LDL-C (95% CI, 22-34; P < 0.0001). When all 26 trials were combined, including the CTT trials from the first cycle as well as the trials comparing statin therapy versus control, the risk of a first major event was reduced by 22% per 1 mmol/L reduction in LDL-C at 1 year (95% CI, 20-24; P < 0.0001). A, atorvastatin; P, pravastatin; S, simvastatin; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; A to Z, Aggrastat to Zocor; TNT, Treating to New Targets; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study group; 4D, Die Deutsche Diabetes Dialyse Studie; AURORA, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non–Insulin-Dependent Diabetes Mellitus; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiac. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. ASPEN 114 (2.7) 136 (3.3) MEGA 102 (0.5) 140 (0.7) JUPITER 105 (0.5) 194 (1.0) GISSI-HF 172 (2.2) 174 (2.2) AURORA 362 (8.1) 368 (8.3) Subtotal (21 trials) 7136 (2.8) 8934 (3.6) 0.79 (0.77 - 0.81) P < 0.001 Total (26 trials) 10973 (3.2) 13350 (4.0) 0.78 (0.76 - 0.80) P < 0.001 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better Difference between more vs. less and statin vs. control: c 1 2 = 4.5, p=0.03 Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681.

mmol/L LDL-C reduction Second Cycle of the CTT Meta-analysis: More vs Less Statin—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction Nonfatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularization Ischemic stroke Hemorrhagic stroke Unknown stroke Any stroke Any major vascular event (5 trials) 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 (0.58 - 0.87) 0.85 (0.63 - 1.15) 0.74 (0.65 - 0.85) P < 0.0001 0.72 (0.55 - 0.95) 0.60 (0.50 - 0.71) 0.78 (0.58 - 1.04) 0.66 (0.60 - 0.73) 0.69 (0.50 - 0.95) 1.39 (0.57 - 3.39) 0.63 (0.24 - 1.66) 0.74 (0.59 - 0.92) P = 0.007 0.72 (0.66 - 0.78) No. of events (% pa) Relative risk (CI) per mmol/L LDL-C reduction More statin Less statin More statin better Less statin better 99% or 95% CI 0.5 0.75 1 1.25 1.5 In the 5 CTT trials that compared more versus less intensive statin therapy, the overall further reduction in first major vascular events was 28% per 1 mmol/L reduction in LDL-C (95% CI, 22-34; P < 0.0001). There were significant proportional reductions of any major coronary event of 26% (P < 0.0001), any coronary revascularization of 34% (P < 0.0001), and any stroke of 26% (P < 0.007) per 1 mmol/L reduction in LDL-C. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681.

mmol/L LDL-C reduction Second Cycle of the CTT Meta-analysis: Statin vs Control—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction No. of events (% pa) Relative risk (CI) per mmol/L LDL-C reduction Statin Control Nonfatal 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) P < 0.001 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 revascularization 3103 (1.2%) 4066 (1.6%) 0.76 (0.73 - 0.80) P < 0.001 Ischemic stroke 987 (0.4%) 1225 (0.5%) 0.80 (0.73 - 0.88) Hemorrhagic stroke When the data from the 21 CTT trials that studied statin therapy versus control were combined, most of the proportional reductions in risk for major vascular events were similar to those seen with LDL-C reductions in the more versus less statin trials. In the statin versus control trials, the 24% reduction in coronary revascularization procedures was significant (P < 0.0001) but not as great as the reduction in revascularization seen in the more versus less statin trials (34%). The reduction in any major coronary event in the statin versus control trials was 24% (P < 0.0001), which was similar to the difference in the more versus less statin trials. The reduction in any stroke of 15% (P < 0.0001) was nonsignificantly less than in the trials of more intensive versus less intensive statin. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. 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) P < 0.001 Any major vascular event (all 21 trials) 7136 (2.8%) 8934 (3.6%) 0.79 (0.77 - 0.81) P < 0.001 0.5 0.75 1 1.25 1.5 99% or 95% CI Statin better Control better Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681.

Meta-analysis of Statin Trials and Fatal and Nonfatal Stroke Log-scale Study 0.1 Active group (%) Control group RR (95% CI) Total: P < 0.0001 (heterogeneity: I2 = 7.3%, P = 0.36) SEARCH JUPITER ASPEN MEGA IDEAL TNT ALLIANCE CARDS PROVE-IT A TO Z ASCOT-LLA ALLHAT-LLT GREACE HPS (with no prior CVD) PROSPER MIRACL GISSI AFCAPS/TexCAPS LIPID (with no prior CVD) Post-CABG CARE (with no prior CVD) WOSCOPS SSSS Sub-total: P < 0.0001 (heterogeneity: I2 = 26.6%, P = 0.12) 4.2 0.4 2.8 1.3 3.4 2.3 2.9 1.5 1.0 1.2 1.7 4.0 3.2 4.7 0.8 0.9 3.3 2.6 1.9 1.4 2.5 4.6 0.7 1.6 3.9 3.1 2.4 4.5 2.1 4.8 0.5 3.5 SPARCL HPS (with prior CVD LIPID (with prior CVD) CARE (with prior CVD) Sub-total: P = 0.03 (heterogeneity: I2 = 0.8%, P = 0.39) 11.2 10.3 9.5 13.5 13.1 10.4 13.3 20.0 Primary prevention of stroke 0.2 1 2 5 10 0.91 (0.77, 1.08) 0.52 (0.34, 0.78) 0.89 (0.56, 1.40) 0.83 (057,1.20) 0.87 (0.70, 1.08) 0.76 (0.60, 0.96) 0.90 (0.58, 1.42) 0.53 (0.31, 0.90) 1.09 (0.59, 2.01) 0.79 (0.48, 1.29) 0.73 (0.56, 0.96) 0.91 (0.76, 1.09) 0.53 (0.24, 1.18) 0.67 (0.57, 0.77) 1.04 (0.82, 1.31) 0.50 (0.25, 1.00) 1.05 (0.56, 1.96) 0.82 (0.41, 1.67) 0.84 (0.67, 1.05) 1.12 (0.58, 2.18) 0.67 (0.44, 1.01) 0.90 (0.61, 1.34) 0.72 (0.51, 1.01) 0.81 (0.75, 0.87) Secondary prevention of stroke 0.82 (0.77, 0.87 0.85 (0.73, 0.99 0.99 (0.81, 1.21) 0.72 (0.46, 1.12) 0.68 (0.37, 1.25) 0.88 (0.78, 0.99) A meta-analysis of randomized controlled design statin trials that recorded data on stroke events (brain infarction and hemorrhage) was conducted. Fatal and nonfatal stroke were reported in 24 trials with 165,792 patients at high risk of stroke. Incidence of all strokes was reduced by 18% (95% CI, 13%-23%; P < 0.0001). The incidence of stroke was reduced significantly in the 20 primary prevention trials (19%; P < 0.0001)and in the 4 secondary prevention trials (12%; P = 0.03). Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453-463. Amarenco P et al. Lancet Neurol. 2009;8:453-463.

Meta-analysis of Statin Trials and Stroke Mortality SEARCH JUPITER CARDS ALLHAT-LLT GREACE HPS PROSPER MIRACL GISSI LIPID CARE WOSCOPS SSSS Sub-total: P = 0.18 (heterogeneity: I2 = 0%, P = 0.48) Study Active group (%) Control group RR (95% CI) Primary prevention of stroke 0.9 0.3 0.1 1.0 0.0 0.8 0.2 0.5 0.6 1.1 0.7 1.2 0.85 (0.60, 1.21) 0.50 (0.13, 2.00) 0.14 (0.02, 1.15) 0.95 (0.65, 1.38) 0.33 (0.01, 8.17) 0.81 (0.62, 1.05) 1.58 (0.81, 3.09) 1.51 (0.25, 9.02) 1.00 (0.25, 3.98) 0.81 (0.46, 1.43) 4.99 (0.58, 42.70) 1.50 (0.42, 5.30) 1.17 (0.54, 2.52) 0.90 (0.76, 1.05) Secondary prevention of stroke SPARCL Total: P = 0.10 (heterogeneity: I2 = 8.1%, P = 0.36) 1.7 0.59 (0.36, 0.97) 0.87 (0.73, 1.03) 1 2 5 10 Log-scale Fatal stroke end points were reported in 14 trials with 107,299 patients. The incidence of fatal stroke was nonsignificantly reduced by 13% (–3 to 27; P = 0.10). Fatal stroke was significantly reduced in the secondary prevention trial SPARCL (RR 0.59;95% CI, 0.36-0.97). Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453-463. Amarenco P et al. Lancet Neurol. 2009;8:453-463.

Stroke Risk and LDL Lowering in Statin Trials Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI, 6.3–33.5%; p<0.009) 1.2 N = 165,732 Post-CABG PROVE-IT 1.1 GISSI PROSPER 1.0 ALLHAT-LLT SEARCH WOSCOPS SPARCL-CS (-) 0.9 IDEAL ALLIANCE LIPID ASPEN SPARCL AFCAPS/TexCAPS 0.8 MEGA Relative Risk of Stroke in Active vs Control Groups (non-log scale) A to Z ASCOT-LLA TNT HPS 0.7 SSSS SPARCL-CS (+) CARE A meta-regression analysis plotted regression lines for 24 trials (165,792 patients; solid line) and for trials of primary prevention (after excluding trials with clearly identified groups of patients in secondary stroke prevention (ie, SPARCL, HPS, LIPID, and CARE subgroups with previous cerebrovascular disease; dotted line). For the analysis of all major statin trials, each 1 mmol/L (39 mg/dL) decrease in concentration of LDL-C equated to a relative risk reduction for stroke of 21.1% (6.3-33.5; P = 0.009). For primary prevention trials, the relative risk reduction per mmol LDL-C was 35.9% (95% CI, 21.7-48.6). In an analysis restricted to patients included in SPARCL with a carotid stenosis at baseline, statin treatment was associated with a 33% reduction in risk of stroke (HR = 0.67; 95% CI, 0.47-0.94; P = 0.02). Plotting the groups with and without carotid stenosis on the meta-regression analysis shows that the SPARCL subgroup with documented atherosclerosis fits perfectly with the regression line, supporting the concept that ischemic stroke subtype, particularly atherothrombotic stroke, is important when evaluating the association between LDL-C and stroke risk. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453-463 0.6 CARDS JUPITER 0.5 GREACE MIRACL 0.4 -10 -15 -20 -25 -30 -35 -40 -45 -50 -55 Between Group Difference in LDL-Cholesterol Reduction, % (active minus control groups) Amarenco P et al. Lancet Neurol. 2009;8:453-463.

mmol/L LDL-C reduction Second Cycle of the CTT Meta-analysis: Proportional Effects on Cause-Specific Mortality Per Mmol/L LDL-C Reduction No. of deaths(% pa) Relative risk (CI) per mmol/L LDL-C reduction Statin/more Control/less Vascular causes CHD 1887 (0.5%) 2281 (0.6%) 0.80 (0.74 - 0.87) Other cardiac 1446 (0.4%) 1603 (0.4%) 0.89 (0.81 - 0.98) All cardiac 3333 (0.9%) 3884 (1.1%) 0.84 (0.80 - 0.88) Ischemic stroke 153 (0.0%) 139 (0.0%) 1.04 (0.77 - 1.41) Hemorrhagic stroke 102 (0.0%) 89 (0.0%) 1.12 (0.77 - 1.62) Unknown stroke 228 (0.1%) 273 (0.1%) 0.85 (0.66 - 1.08) Stroke 483 (0.1%) 501 (0.1%) 0.96 (0.84 - 1.09) Other vascular 404 (0.1%) 409 (0.1%) 0.98 (0.81 - 1.18) Any vascular 4220 (1.2%) 4794 (1.3%) 0.86 (0.82 - 0.90) Nonvascular Cancer 1781 (0.5%) 1798 (0.5%) 0.99 (0.91 - 1.09) When all CTT trials in the second cycle were combined, a proportional reduction of 10% (95% CI, 7%-13%; P < 0.0001) in all-cause mortality was seen per 1 mmol/L decrease in LDL-C. This risk reduction comprised significant reductions of 14% (95% CI, 10%-18%; P < 0.0001) in vascular mortality and 13% (95% CI, 1%-24%; P < 0.04) in mortality from unknown causes. Reduction in LDL-C did not appear to affect nonvascular mortality risk, and, importantly, there was no effect on cancer mortality. A further analysis looked at cancers by site and found there was no significant difference, and, taking all 26 trials together, there was no evidence of an excess of cancer at all sites combined (RR 1.00 per 1.0 mmol/L LDL reduction; 95% CI, 0.96-1.04; P = 0.9) or at any particular site. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. Respiratory 224 (0.1%) 237 (0.1%) 0.88 (0.70 - 1.11) Trauma 127 (0.0%) 127 (0.0%) 0.98 (0.70 - 1.38) Other nonvascular 811 (0.2%) 832 (0.2%) 0.96 (0.83 - 1.10) Any nonvascular 2943 (0.8%) 2994 (0.8%) 0.97 (0.92 - 1.03) Unknown death 479 (0.1%) 539 (0.1%) 0.87 (0.76 - 0.99) Any death 7642 (2.1%) 8327 (2.3%) 0.90 (0.87 - 0.93) 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better Cholesterol Treatment Trialists Collaboration Lancet. 2010;376:1670-1681.

Meta-analysis of Statin Trials: Effect of Intensive LDL-C Lowering vs StandardStatin Therapy on Fatal and Nonfatal Stroke Intensive arm (%) Conventional arm (%) RR (95% CI) RR (95% CI) Study SEARCH IDEAL TNT ALLIANCE PROVE-IT A to Z Total: P = 0.009 (heterogeneity: I2 = 0%, P = 0.80) 4.2 3.4 2.3 2.9 1.0 1.2 4.6 3.9 3.1 3.2 0.9 1.6 0.91 (0.77, 1.08) 0.87 (0.70, 1.08) 0.76 (0.60, 0.96) 0.90 (0.58, 1.42) 1.09 (0.59, 2.01) 0.79 (0.48, 1.29) 0.87 (0.78, 0.96) Six trials with 42,054 patients assessed the effect of intensive lipid lowering therapy versus standard statin therapy on the incidence of fatal and nonfatal stroke. The outcomes showed a significant effect of intensive statin therapy, with a 13% (reduction in risk (95% CI, 4%-22%; P = 0.009). Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453-463. 0.1 0.2 0.5 1 2 5 10 Log-scale Amarenco P et al. Lancet Neurol. 2009;8:453-463.

The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD Primary Prevention Secondary Prevention ACS Pravastatin L-CAD PACT Simvastatin A to Z Atorvastatin MIRACL PROVE IT-TIMI 22 Pravastatin WOSCOPS PROSPER Simvastatin HPS Atorvastatin ASCOT CARDS Rosuvastatin JUPITER Lovastatin TEXCAPS/AFCAPS Pravastatin CARE LIPID PROSPER Simvastatin 4S HPS SEARCH Atorvastatin AVERT TNT IDEAL Many statin clinical event trials in chronic atherosclerosis have now been undertaken. These demonstrated the benefit of statins in reducing the incidence of recurrent heart attacks and strokes, leaving little doubt on their effectiveness in a broad range of secondary prevention patients at risk for cardiovascular events. Although statin clinical trials in ACS patients have demonstrated short term benefits (MIRACL, L-CAD), the long-term effects of statins in ACS patients remain unknown.