Lower Is Better Redux: What TNT Tells Us About Aggressive Lipid Lowering

For years, cardiologists and primary care physicians have engaged in a spirited debate about the appropriate target for low-density lipoprotein cholesterol (LDL-C) lowering in patients with coronary artery disease. At the heart of the debate has been the question, “Is lower better?” RECENT EVIDENCE THAT LOWER MIGHT BE BETTER Recent studies have suggested, but not proved, that lower levels of LDL-C are better. The Heart Protection Study (HPS) showed that reductions in LDL-C to levels lower than 70 mg/dL produced significant clinical benefit in highrisk patients—including a reduction in myocardial infarctions (MIs) and acute coronary syndromes that require hospitalization—irrespective of baseline cholesterol levels. Moreover, in HPS, no threshold was observed below which lipid lowering did not appear to be beneficial.1 The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study demonstrated that in patients with acute coronary syndromes, more intensive therapy provided greater protection against recurrent events and death than did moderate therapy.2  The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial showed that intensive statin therapy slowed the progression of atherosclerosis as measured by intravascular ultrasonography, but that moderate therapy did not.3  In the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study, aggressive statin therapy outperformed usual care in 2442 patients with coronary heart disease (CHD) enrolled in HMOs; although there was no significant difference in overall mortality, there were fewer cardiovascular events in the aggressive- treatment group.4 In response to HPS, PROVE IT, and other studies, the Coordinating Committee of the Third Adult Treatment Panel of the National Cholesterol Education Program (ATP III) recommended in 2004 that in very high–risk patients, the LDL-C goal be modified from less than 100 mg/dL to less than 70 mg/dL.5  Ongoing studies— including the Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) with simvastatin, and the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study involving atorvastatin—are investigating how far to lower cholesterol levels in patients other than those at very high risk. TNT RESULTS: THE STRONGEST EVIDENCE YET The results of the Treating to New Targets (TNT) trial clearly show the value of aggressive LDL-C lowering in patients with stable CHD. The TNT researchers recruited men and women aged 35 to 75 years who had clinically evident CHD, defined by 1 or more of the following criteria: • Previous MI. • Previous or current angina. • A history of coronary revascularization. After treatment with 10 mg/d of atorvastatin, 10,001 patients who had LDL-C levels of less than 130 mg/dL were randomly assigned to receive either 10 or 80 mg of atorvastatin daily; they were observed for a median of 4.9 years. At the end of this time, the mean LDL-C level was 77 mg/dL in the patients who received 80 mg/d of atorvastatin, compared with 101 mg/dL in those who received 10 mg/d of atorvastatin. Cardiovascular benefits. A major cardiovascular event (defined as death caused by CHD, nonfatal MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke) occurred in 548 patients (10.9%) in the 10-mg group but in only 434 patients (8.7%) in the 80-mg group. This represents a 22% relative reduction in the risk of a major cardiovascular event in those patients who received 80 mg/d of atorvastatin (hazard ratio, 0.78; 95% confidence interval, 0.69 to 0.89; P