How safe are very low LDL cholesterol levels?

BACKGROUND The original Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction ( PROVE IT-TIMI) 22 trial found that patients with acute coronary syndromes (ACS) treated with more-intensive statin therapy achieved greater reductions in LDL cholesterol and had fewer adverse clinical events than patients treated with standard statin therapy. Despite these encouraging findings, it is not known whether there are safety concerns related to achieving very low LDL cholesterol levels. OBJECTIVES To evaluate the efficacy and safety of using intensive statin therapy to achieve very low LDL cholesterol concentrations in patients with ACS. DESIGN AND INTERVENTION The original PROVE IT-TIMI 22 trial was a prospective, controlled study of patients who had presented with acute myocardial infarction or non-ST-segment elevation ACS in the 10 days before study start. For inclusion, patients with ACS had to have LDL cholesterol less than 6.2 mmol/ l (< 240 mg/dl). Patients were then randomly assigned daily treatment with 80 mg atorvastatin ( intensive therapy) or 40 mg pravastatin ( standard therapy), both with concomitant gatifloxacin or placebo. This substudy analyzed data only from patients who received atorvastatin and achieved LDL cholesterol levels less than 2.59 mmol/ l (< 100 mg/dl). OUTCOME MEASURES The primary endpoint was a composite of death, myocardial infarction and stroke. RESULTS Of the 2,099 patients who received intensive statin therapy, 1,949 had their LDL cholesterol levels recorded at 4-month follow-up. In total, 1,656 patients had LDL cholesterol < 2.59 mmol/ l (< 100 mg/dl): 193 (10.5%) patients had LDL cholesterol of <= 1.04 mmol/ l (<= 40 mg/dl); 631 (34.4%) had levels in the range > 1.04 to <= 1.55 mmol/ l (> 40 to <= 60 mg/ dl); 576 (31.4%) had levels in the range > 1.55 to <= 2.07 mmol/ l (> 60 to <= 80 mg/ dl); and 256 (13.9%) had levels in the range > 2.07 to <= 2.59 mmol/ l (> 80 to <= 100 mg/ dl). With reduction in LDL cholesterol level, there was a trend towards a reduction in the incidence of death, myocardial infarction and stroke ( 20.4%, 20.4%, 22.2% and 26.1%, respectively; P-trend = 0.1). Multivariate analysis showed that, compared with the patients with the highest LDL cholesterol levels, patients in the two groups with the lowest LDL cholesterol had fewer adverse cardiac events ( LDL cholesterol = 1.04 mmol/ l [= 40 mg/ dl], hazard ratio 0.67, 95% CI 0.40 - 0.91; and LDL cholesterol > 1.04 to = 1.55 mmol/ l [> 40 to = 60 mg/ dl], hazard ratio 0.67, 95% CI 0.50 - 0.92). There were no significant differences in the occurrence of rhabdomyolysis, liver-related side effects, adverse ophthalmologic events or strokes between the four groups. Patients with the lowest LDL cholesterol levels were more likely to be male, to be older, and to have diabetes. CONCLUSION In patients with ACS, the risk of complications related to statin therapy is not increased by reducing LDL cholesterol concentrations further than current guidelines recommend, and such reductions decrease the occurrence of adverse cardiovascular events.