We appreciate Dr. Nicholls's comments and agree that the agents studied in the Armed Forces Regression Study (AFREGS), particularly niacin, have not traditionally been well tolerated. With newer formulations of niacin and proper patient instruction, adherence has been much improved (1). Until newer agents have undergone more rigorous study and review, niacin remains the single most effective agent to increase HDL cholesterol level. Whether its well-established clinical benefits are derived from changes in quantity or quality of HDL or low-density lipoprotein cholesterol remains controversial, and unfortunately lipoprotein subtyping was not performed in the AFREGS population.

Although fibrinogen levels did not change with therapy, such a small study cannot exclude modulation of inflammation by study drugs. We examined fibrinogen and leukocyte count in several subsets of patients in AFREGS and could not find evidence of any greater benefit in patients with increased inflammation, or evidence that therapy significantly altered levels of fibrinogen or leukocytes.

In terms of assessing atherosclerotic burden, we agree with Dr. Nicholls that intravascular ultrasonography is a tremendous advance and provides significantly better plaque characterization than angiography (2). It unfortunately remains slightly more invasive, is time-consuming, and is not widely available. It is also important to note that despite the limits of angiography, the AFREGS results and the results of other quantitative coronary angiography studies do not dramatically differ in magnitude from those of recent studies using intravascular ultrasonography (3). In particular, in the REVERSAL (REVERSal of Atherosclerosis with Lipitor) study, a 1.4% difference in percentage of obstructive volume was seen between high- and moderate-dose statins (4). When the suggested 2% progression of atherosclerosis in patients not receiving final angiography in AFREGS is used, the difference in progression between treatment groups remains approximately 2% (0.6% reduction with combination therapy compared with a 1.5% progression in patients receiving placebo), with even stronger statistical significance.

The use of combination therapy without a statin, despite our favorable results, cannot be generally recommended for the secondary prevention of cardiovascular disease. The proven benefit of statins in the reduction of clinical events, including myocardial infarction, stroke, and death, is too significant to totally disregard. Guidelines mainly recommend targeted HDL treatment if goal levels are not achieved with diet, lifestyle, and statins (5). For primary prevention, however, the data are less clear, and further studies will be necessary to establish the most effective treatment strategy.