Target LDL-C Level or Fixed-Dose Treatment for ASCVD

In patients with established atherosclerotic cardiovascular disease (ASCVD), should oral cholesterol medications be dosed to achieve a specific low-density lipoprotein cholesterol (LDLC) level or given as a fixed dose according to the patient's risk profile?

In patients with established ASCVD, evidence supports dosing oral cholesterol-lowering medications to achieve a specific LDL-C target, ideally less than 70 mg/dL (1.81 mmol/L), rather than treatment based solely on risk profile. (Strength of Recommendation [SOR]: A, meta-analysis and randomized controlled trials [RCTs].) A recent consensus guideline recommends fixed-dose statin therapy based on the patient's risk profile. (SOR: C, expert opinion.)

ASCVD

A 2010 meta-analysis of 26 RCTs (N = 169,138) examined the effectiveness of LDL-C lowering with statins. Patients were primarily from high-income regions, male, 50 to 70 years of age, and with or without ASCVD. Interventions included various high-intensity statins. Primary outcomes were cause-specific mortality, major coronary event (death or nonfatal myocardial infarction), coronary revascularization (angioplasty or bypass grafting), stroke, and new cancer diagnosis. A major vascular event was defined as the first occurrence of any major coronary event, coronary revascularization, or stroke.¹

The investigators found that lowering LDL-C resulted in a 22% (95% CI, 20%–24%) relative risk (RR) reduction in major vascular events per 38.7 mg/dL (1.00 mmol/L) LDL-C reduction. Lowering LDL-C from approximately 100 mg/dL (2.59 mmol/L) to 77 mg/dL (1.99 mmol/L) with more intensive statin therapy reduced the absolute risk of major vascular events by 0.8% annually. This corresponds to a number needed to treat (NNT) of 125 to prevent one major vascular event per year. Importantly, these benefits extended even to patients with baseline LDL-C levels less than 77 mg/dL. The investigators found no evidence of increased risks of cancer or nonvascular mortality.¹

A 2016 systematic review and meta-analysis of 49 RCTs (N = 312,175) found a consistent, proportional relationship between the degree of LDL-C lowering and a reduction in major cardiovascular events. The study population included patients treated for primary and secondary prevention. Statins and nonstatin therapies (eg, ezetimibe, bile acid sequestrants, diet) showed similar RR reductions of 23% (RR = 0.77; 95% CI, 0.75–0.79) per 38.7 mg/dL LDL-C reduction. The investigators did not find a lower LDL-C limit to this benefit, including LDL-C levels less than 50 mg/dL (1.29 mmol/L).²

Cardiovascular Disease

A 2015 RCT (N = 18,144) included patients in 39 countries who were 50 years and older with a mean age of 64 years who had been hospitalized for an acute coronary syndrome in the preceding 10 days. The study found that adding ezetimibe to moderate-intensity statin therapy (simvastatin 40 mg, increased to 80 mg if LDL-C was greater than 79 mg/dL [2.05 mmol/L]) led to a statistically significant reduction in LDL-C and major cardiovascular events compared with moderate-intensity statin therapy alone. Over a median of 6 years, the ezetimibe group achieved lower average LDL-C levels (54 vs 70 mg/dL [1.4 vs 1.81 mmol/L]) and had a 2% absolute risk reduction (NNT = 50) in the composite primary end point (hazard ratio [HR] = 0.94; 95% CI, 0.89–0.99). Adverse events did not differ between groups.³