Cholesterol lowering for secondary prevention: What statin dose should we use?

Figures & data

Table 1 Placebo-controlled statin trials which randomized greater than 250 participants

Trial	Study design	Treatment dose	Key eligibility criteria	Control group LDL at baseline/ at follow-up	Treatment group LDL at baseline/at follow-up	LDL subgroup analysis
4S	Secondary prevention, multicenter, median f/u 5.4 years	Simvastatin 20–40 mg	35–70 yrs, prior angina or AMI, fasting total chol 5.5–8.0 mmol/L	4.87/4.92	4.87/3.17	None
WOSCOPS	Primary prevention, one center, mean f/u 4.9 years	Pravastatin 40 mg	45–64 yrs, no prior AMI, fasting LDL chol 4.0–6.0 mmol/L	4.97/not reported	4.97/3.68	Baseline LDL < 4.9 vs > 4.9
CARE	Secondary prevention, multicenter	Pravastatin 40 mg	21–75 yrs, prior AMI, fasting LDL chol 3.0–4.5 mmol/L	3.6/	3.6/2.5	Baseline LDL < 3.2 vs 3.2–3.9 vs 3.91–4.5
AFCAPS/ TexCAPS	Primary prevention, multicenter, mean f/u 5.2 years	Lovastatin 20–40 mg	45–73 yrs (males) or 55–73 (females), no prior AMI, fasting LDL chol 3.4–4.9 mmol/L	3.89/4.04 (at 1 year)	3.89/2.96	None
LIPID	Secondary prevention, multicenter, mean f/u 6.1 years	Pravastatin 40 mg	31–75 yrs, prior AMI or unstable angina, fasting total chol 4–7 mmol/L	3.9/not reported	3.9/reduced by 25% more than placebo group	Baseline LDL < 3.5 vs 3.5–4.5 vs > 4.5
GISSI prevention	Secondary prevention multicenter, mean f/u 23 months	Pravastatin 20 mg	Recent MI (<6 months), total cholestrol > 5.18 mmol/L	3.9/3.8	3.9/3.3	Baseline LDL < 3.4 vs > 3.4
HPS	Primary and secondary prevention, multicenter, mean f/u 5 years	Simvastatin 40 mg	40–80 yrs, with coronary disease, other occlusive arterial disease, or diabetes, with non-fasting tot chol of ≥3.5	3.4/not reported	3.4/(1.0 mmol/L less than placebo)	Baseline LDL < 3.0 vs 3.1–3.4 vs ≥ 3.5
MIRACL	Secondary prevention, multicenter, 16 weeks f/u	Atorvastatin 80 mg	>18 yrs, unstable angina or non-Q-wave AMI	3.2/3.5 (at 16 weeks)	3.2/1.9 (at 16 weeks)	Baseline LDL < 3.1 vs > 3.1
Serruys study (LIPS)	Secondary prevention, multicenter, median f/u 3.9 years	Fluvastatin 80 mg	18–80 yrs, pts with stable or unstable angina or silent ischemia who underwent PCI, tot chol 3.5–7.0 mmol/L	3.4/3.8 (at 6 weeks)	3.4/2.5 (at 6 weeks)	Baseline LDL < 3.4 vs > 3.4
PROSPER	Primary and secondary prevention, multicenter, mean f/u 3.2 years	Pravastatin 40 mg	70–82 yrs, with history of or risk factors for vascular disease	3.8/	3.8/2.8	Baseline LDL < 3.41 vs 3.41–4.11 vs > 4.11
ASCOTTLLA	Primary prevention, multicenter, median f/u 3.3 years	Atorvastatin 10 mg	40–79 yrs, hypertensive pts with at least 3 additional CHD risk factors, non-fasting total chol <6.5 mmol/L	3.44/3.45 (at 6 months; 1,2,3 yr data avail)	3.44/2.21	None
ALLHATLLT	Primary and secondary prevention, multicenter, mean f/u 4.8 years	Pravastatin 40 mg	>55yrs with stage 1 or 2 hypertension & one additional CHD risk, fasting LDL 3.1–4.9 mmol/L for no known CHD vs.. 2.6–3.3 mmol/L for known CHD	3.8/3.3 (at 4 years; data for yr 2 & 6 also avail)	3.8/2.7	Baseline LDL <3.37 vs. > 3.37
ALERT	Primary and secondary prevention, multicenter, mean f/u 5.1 years	Fluvastatin 40 mg	30–75 yrs, prev renal or combined renal and pancreas transplants, tot chol 4.0–9.0 mmol/L in pts with no CHD vs. 4.0–7.0 mmol/L for known CHD	4.1/	4.1/2.8 (at end of study)	None
CARDS	Primary prevention, multicenter, median f/u 3.9 years	Atorvastatin 10 mg	40–75 yrs, with type 2 diabetes and at least one of: retinopathy, albuminuria, current smoking, or hypertension; LDL ≤ 4.14 mmol/L	3.02/3.07 (at 6 months; values at 1,2, and 4 years also avail)	3.04/1.75	-Baseline LDL < 3.1, 39/696 atorvastatin vs. 61/718 placebo, HR 0.63 -Baseline LDL ≥ 3.1, 44/721 atorvastatin vs. 66/695 placebo, HR 0.62
SPARCL	Secondary prevention, multicenter, median f/u 4.9 years	Atorvastatin 80 mg	>18 yrs, prior ischemic or hemorrhagic stroke or TIA, LDL chol 2.6–4.9 mmol/L	3.46/3.32	3.44/1.89	None
FLORIDA	Secondary prevention, multicenter, median f/u 1 year	Fluvastatin 80 mg	>18 yrs, AMI, total chol ≤ 6.5 mmol/L	3.6/3.9	3.5/2.7	None
AVERT	Secondary prevention, multicenter, f/u 18 months	Atorvastatin 80 mg vs. PCI	Stable CAD, stenosis of ≥50% in at least one coronary artery, LDL ≥3.0 mmol/L, triglycerides ≤ 5.6 mmol/L	3.8/3.1	3.7/2.0	None

Table 2 Randomized trials comparing higher dose statin therapy with lower dose statin therapy in patients with coronary artery disease

Trial	Sample size	Comparators	Key eligibility criteria	Key demographics (mean age, % men, mean LDL at baseline)	LDL at follow-up (more intensive therapy arm)	LDL at follow-up (less intensive therapy arm)	Duration of follow-up
Post-CABG	1351	Lovastatin 80 mg vs lovastatin 5 mg	Post CABG 1–11 years before	62 years 92% 3.98 mmol/L	2.4 mmol/L	3.5 mmol/L	4.3 years
REVERSAL	654	Pravastatin 40 mg vs atorvastatin 80 mg	Stable CAD	56 years 72% 3.9 mmol/L	2.04 mmol/L	2.85 mmol/L	18 months
Vascular basis	300	Lovastatin 5 mg vs atorvastatin 80 mg vs atorvastatin 80 mg + antioxidant	Stable CAD	not reported 86% 3.9 mmol/L	2.2 mmol/L	3.2 mmol/L	12 months
PROVE IT-TIMI 22	4,162	Pravastatin 40 mg vs atorvastatin 80 mg	Post ACS	58 years 78% 2.74 mmol/L	1.60 mmol/L	2.46 mmol/L	24 months
A to Z	4,497	Placebo × 4 months then simvastatin 20 mg vs simvastatin 40 mg × 1 month then 80 mg	Post ACS	61 years 76% 2.89 mmol/L	1.71 mmol/L	2.10 mmol/L	24 months
TNT	10,001	Atorvastatin 10 mg vs 80 mg	Stable CAD	61 years 81% 2.6 mmol/L (after run-in)	2.0 mmol/L	2.6 mmol/L	4.9 years
IDEAL	8,888	Simvastatin 20 mg vs atorvastatin 80 mg	Stable CAD	62 years 81% 3.2 mmol/L	2.1 mmol/L	2.7 mmol/L	4.8 years

Figure 1 Association between achieved LDL cholesterol levels and primary outcome in both arms of the higher dose versus lower dose statin trials. The results for the less intensive arm of each trial are expressed on the right of each trial’s line; the results for the more intensive arm of each trial are expressed on the left of each trial’s line.

Figure 2 Event rates with higher dose vs. lower dose statin therapy.