Randomised controlled trials of cholesterol reduction in high-risk individuals (LDL-C reduction target ≥50%)
| Study, year Quality score | Population size and characteristics | Intervention (drug class) | Study duration | LDL-C target met? | Mortality benefit? (NNT) | CVD benefit? (NNT) |
| 4 S, 1994 A10 | 4444 CHD | Simvastatin 20–40 mg/day (statin) | 5.4 years | No (LDL-C ↓ 35%) | Yes (RR 0.70; 95% CI 0.58 to 0.85) (30) | Yes (RR 0.66; 95% CI 0.59 to 0.75) (15) |
| CARE, 1996 A50 | 4159 s/p MI | Pravastatin 40 mg/day (statin) | 5 years | No (LDL-C ↓ 32%) | No | Yes (RR 0.76; 95% CI 0.64 to 0.91) (33) |
| LIPID, 1998 A51 | 9014 CHD | Pravastatin 40 mg/day (statin) | 6.1 years | No (LDL-C ↓ 25%) | Yes (RR 0.78; 95% CI 0.69 to 0.87) (32) | Yes (RR 0.76; 95% CI 0.65 to 0.88) (34) |
| GISSI-P, 2000 C (study stopped and modified)52 | 4271 s/p MI | Pravastatin 20 mg/day (statin) | 1.9 years | No (LDL-C ↓ 16%) | No (HR 0.84; 95% CI 0.61 to 1.14) | No (HR 0.90; 95% CI 0.71 to 1.15) |
| LIPS, 2002 A53 | 1677 s/p PCI | Fluvastatin 80 mg/day (statin) | 3.9 years | No (LDL-C ↓ 27%) | No (RR 0.69; 95% CI 0.45 to 1.07) | Yes (RR 0.78; 95% CI 0.64 to 0.95) (19) |
| GREACE, 2002 B (open label)54 | 1600 CHD | Atorvastatin 10–80 mg/day (statin) | 3 years | No (LDL-C ↓ 46%) | Yes (RR 0.57; 95% CI 0.39 to 0.78) (48) | Yes (RR 0.49; 95% CI 0.27 to 0.73) (26) |
| ALLIANCE, 2004 B (open label)6 | 2442 CHD | Atorvastatin 10–80 mg/day (statin) | 4.3 years | No (LDL-C ↓ 11%) | No (HR 0.92; 95% CI 0.72 to 1.18) | Yes (HR 0.83; 95% CI 0.71 to 0.97) (29) |
| SPARCL, 2006 A55 | 4731 s/p TIA or CVA | Atorvastatin 80 mg/day (statin) | 4.9 years | No (LDL-C ↓ 43%) | No (HR 1.03; 95% CI 0.84 to 1.25) | Yes (HR 0.80; 95% CI 0.69 to 0.92) (53) |
| CORONA, 2007 A56 | 5011 >60 years, ischaemic HF | Rosuvastatin 10 mg/day (statin) | 2.7 years | No (LDL-C ↓ 45%) | No (HR 0.95; 95% CI 0.86 to 1.05) | No (HR 0.92; 95% CI 0.83 to 1.02) |
| SEAS, 2008 A7 | 1873 mild to moderate aortic stenosis | Simvastatin 40 mg + ezetimibe 10 mg/day (statin + CAI) | 4.4 years | Yes (LDL-C ↓ 50%) | No (HR 1.04; 95% CI 0.79 to 1.36) | No (HR 0.96; 95% CI 0.83 to 1.12) |
| ENHANCE, 2008 C (small population size)57 | 720 FH on simvastatin 80 mg/day | Ezetimibe 10 mg/day (CAI) | 2 years | No (LDL-C ↓ 17%) | No (OR 2.02; 95% CI 0.18 to 22.38) | No (OR 1.45; 95% CI 0.55 to 3.86) |
| ODYSSEY Long Term, 2015 A58 | 2341 high risk on statin | Alirocumab 150 mg/2 weeks (PCSK9) | 1.5 years | Yes (LDL-C ↓ 62%) | NR | No (OR 0.91; 95% CI 0.61 to 1.35) |
| ODYSSEY COMBO I to 2015 C (small population size, short duration)59 | 316 high risk on statin | Alirocumab 75–150 mg/2 weeks (PCSK9) | 1 year | No (LDL-C ↓ 46%) | NR | No (OR 1.03; 95% CI 0.25 to 4.22) |
| ODYSSEY FH1, 2015 C (small population size)8 | 486 FH | Alirocumab 75–150 mg/2 weeks (PCSK9) | 1.5 years | Yes (LDL-C ↓ 58%) | No (OR 5.06; 95% CI 0.28 to 90.44) | No (OR 1.36; 95% CI 0.36 to 5.19) |
| ODYSSEY FH2, 2015 C (small population size)8 | 249 FH | Alirocumab 75–150 mg/2 weeks (PCSK9) | 1.5 years | Yes (LDL-C ↓ 51%) | No deaths reported | No (OR 0.79; 95% CI 0.07 to 8.84) |
| IMPROVE-IT, 2015 A27 | 18 144 ACS on simvastatin 40 mg/day | Ezetimibe 10 mg/day (CAI) | 6 years | No (LDL-C ↓ 24%) | No (HR 0.99; 95% CI 0.91 to 1.07) | Yes (HR 0.94; 95% CI 0.89 to 0.99) (56) |
| SPIRE 1&2, 2017 B (short study duration)9 | 27 438 high risk on statin | Bococizumab 150 mg/2 weeks (PCSK9) | 1 year | Yes (LDL-C ↓ 64%) | No (HR 1.02; 95% CI 0.79 to 1.31) | No (HR 0.88; 95% CI 0.76 to 1.02) |
| HIJ-PROPER, 2017 B (open label)60 | 1734 ACS on pitavastatin | Ezetimibe 10 mg/day (CAI) | 3.9 years | No (LDL-C ↓ 15%) | No (HR 0.70; 95% CI 0.47 to 1.04) | No (HR 0.89; 95% CI 0.76 to 1.04) |
| FOURIER, 2017 A61 | 27 564 ASCVD on statin | Evolocumab 140 mg/2 weeks or 420 mg/month (PCSK9) | 2.2 years | Yes (LDL-C ↓ 59%) | No (HR 1.04; 95% CI 0.91 to 1.19) | Yes (HR 0.85; 95% CI 0.79 to 0.92) (67) |
| ODYSSEY OUTCOMES,2018 A11 | 18 924 s/p ACS on statin | Alirocumab 75–150 mg/2 weeks (PCSK9) | 2.8 years | Yes (LDL-C ↓ 55%) | Yes (HR 0.85; 95% CI 0.73 to 0.98) (250) | Yes (HR 0.85; 95% CI 0.78 to 0.93) (100) |
ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CAI, cholesterol absorption inhibitor; CHD, coronary heart disease; CVA, cerebrovascular accident; CVD, cardiovascular disease; FH, familial hypercholesterolaemia; HF, heart failure; HR, hazard ratio; LDL-C, low density lipoprotein cholesterol; MI, myocardial infarction; NNT, number needed to treat (to prevent one death or cardiovascular event); NR, not reported; OR, odds ratio; PCI, percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin type nine inhibitors; RR, risk ratio; s/p, status post; statin, HMG-CoA reductase inhibitor; TIA, transient ischaemic attack.