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Synopsis: Aggressive LDL cholesterol lowering of at least 45-50% is beneficial and safe in patients with familial hypercholesterolemia.
Sources: Smilde TJ, et al. Lancet. 2001;367:577-581; Durrington PL. Lancet. 2001;367:574.
ASAP, the effect of aggressive vs. conventional Lipid Lowering on Atherosclerosis Progression in Familial Hypercholesterolaemia, is a prospective randomized trial in individuals with familial hypercholesterolemia (FC) treated with aggressive vs. less aggressive statin therapy for 2 years. The primary end point was a change in carotid intima medial thickness (IMT), with a number of secondary end points at 24 months. Eligible patients were untreated (1/3) or were on therapy but still had an LDL-C greater than 175 mg/dL. After a run-in period of 2 months, with baseline measurements of IMT and a variety of lipoproteins, 325 patients (mean age, 48) were randomized to 80 mg of atorvastatin or 40 mg of simvastatin. One-third had overt cardiovascular disease, and one-third were smokers. A resin was added to therapy if total cholesterol remained greater than 320 mg/dL. All individuals were recommended to be on a standard low-fat diet. B-mode ultrasound was used, with measurements of the distal common corotid artery, carotid bifurcation, and the proximal internal carotid artery; IMT was determined for both anterior and posterior walls of the common carotid and bifurcation.
Results: 14% of patients did not complete the protocol for a variety of reasons. There was a low cardiovascular event rate; muscle aches and mild abdominal complaints were common in both groups (there was no placebo arm). Baseline TC was 400 mg/dL, and LDL-C was approximately 320 mg/dL. Lipid levels dropped dramatically. Atorvastatin (A) lowered LDL-C by 50% (P = .0001), with a reduction TC of 42%, TG 29%, and an increase in HDL of 13%. Simvastatin (S) lowered TC by 34%, LDL-C by 41%, TG by 18%, with a comparable increase in HDL-C. There was a marked change in the LDL/HDL ratios in both groups. Twenty-seven percent of A individuals had a fall in LDL-C below 120 mg/dL, but only 7% of the S patients achieved these levels. Lp(a) levels decreased by 15% in both groups. IMT changes were notable. Overall IMT was reduced in the A group but increased in the S group, with highly significant P-values. Thus, regression of carotid IMT was noted in 66% of A patients and 42% of S patients. Overall changes in IMT were correlated with baseline IMT (thicker vessels demonstrated greater changes) and with the percentage of cholesterol reduction. Changes in HDL and Lp(a) did not correlate with changes in IMT. Smilde and associates conclude that aggressive LDL cholesterol lowering of at least 45-50% is warranted in patients with FH to modify IMT progression and produce regression. While HDL did not seem to relate to IMT, triglycerides did; they speculate that triglyceride rich LDL and small dense LDL particles may be favorably altered by aggressive statin therapy and play a role in favorable changes in IMT. They point out that their data are consistent with the Post CABG Trial, which compared a modest vs. high dose of lovastatin in patients with prior bypass surgery, and demonstrated a more favorable effect on slowing progression of saphenous graft disease in the high-dose lovastatin subjects, who achieved a final LDL-C of less than 90 mg/dL. They emphasize that the A subjects in ASAP not only had limited progression but actually reversed atherosclerosis, as assessed by IMT; the data are concordant and correlate LDL-C reduction to favorable changes in IMT. They point out that a yearly IMT progression rate of 0.03 mm or greater increases the risk of future events, based on data in the literature. The 0.07 mm difference in IMT between A and S at 2 years suggests that less effective LDL-C lowering did not achieve sufficiently favorable results in this high-risk subject. They concluded that IMT is an adequate surrogate end point for vascular disease, although there are significant limitations using this marker; "aggressive lipid lowering is indicated, beneficial, and safe in patients with FH."
Comment by Jonathan Abrams, MD
The data in this study are striking, suggesting for the first time that a large number of patients with FH can have their vascular disease stabilized and potentially even regressed. The comparison of 80 mg of atorvastatin to 40 mg of simvastatin is unfair, in one sense, as it is no surprise that greater LDL-C reductions can be achieved with high-dose atorvastatin. As to what is the best end point for lowering LDL cholesterol, the arguments remain: should it be a percentage reduction, achievement of a target level, or simply reaching a specific level, such as 125 mg/dL, as the CARE investigators recommend. This study clearly supports that greater lowering is more favorable, and the fact that IMT actually regressed over 2 years, associated with a 50% reduction in baseline LDL-C, is compatible with much other data. Thus, lower is better, certainly in FH patients, and probably in other individuals at high risk. These would include an elevated LDL-C in individuals who have established vascular disease and/or multiple other CAD risk factors. The absence of a placebo arm in this trial makes it difficult to know whether simvastatin slowed progression; this is likely but is unproven. In that the mean baseline total cholesterol in this FH cohort was 400 mg/dL, and the LDL-C was approximately 320 mg/dL, there is little to dispute over a target of LDL reduction of 50% or even greater.
The role of carotid IMT as a marker for vascular disease and atherosclerosis seems reasonably well founded. Multiple studies have or are using this technique. Meticulous attention to detail is necessary. The slope of change is important, and clearly a negative slope, as seen with the high dose atorvastatin group, is an exciting finding. I am unaware of other regression trials that show that the majority of individuals treated with lipid lowering actually regress as opposed to having stabilized disease and slowed progression. It is reasonable to extrapolate from the FH patients in this trial to high-risk individuals in general, from either a primary or secondary prevention perspective. In patients with established vascular disease, LDL-C should (and can) be brought to below 100 mg/dL and probably even lower. The actual levels achieved in the FH patients are much higher, of course. One can extrapolate from the 2-year differences in LDL and IMT between the simvastatin and atorvastatin groups that reducing high levels of total and LDL cholesterol to levels approaching "normal" is most beneficial for patients with high cardiovascular risk.