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  .001) and a 2.2% absolute reduction in the rate of such events. Thus, according to the TNT results, aggressive LDL-C lowering (to 77 mg/dL) will prevent 34 major events in 1000 patients with stable CHD over a 5-year period.6 There appeared to be no significant differences in overall mortality between the 2 treatment groups. However, the trial was not sufficiently powered to detect this outcome.6  Adverse effects. Adverse events occurred in 8.1% of patients in the 80-mg group and in 5.8% of those in the 10-mg group (P .001). Persistent and statistically significant increases in liver enzyme levels developed in 1.2% of study participants who received 80 mg/d of atorvastatin, but in only 0.2% of those who received 10 mg/d (P .001).7 Although there were 26 fewer deaths from CHD in the patients who took 80 mg/d of atorvastatin than there were in those who took 10 mg/d of atorvastatin, there were 31 more deaths from noncardiovascular causes in the 80-mg group than there were in the 10-mg group.6,7 The disparity between the number of noncardiac deaths associated with high and low dosages of atorvastatin deserves evaluation in future similar trials. Nonetheless, the TNT trial has provided the strongest evidence to date that lower is indeed better (Figure). The results of this trial underscore the importance of approaching secondary prevention more aggressively. ACHIEVING GREATEST EFFICACY WITH LEAST RISK Although TNT showed that the highest dosage of atorvastatin results in fewer cardiovascular events than the lowest dosage, long-term adverse effects associated with the high-dosage regimen demand attention. As the editorial that accompanied the published TNT results pointed out, we need to ask whether there is a way to achieve the benefits shown in this trial with less risk.7 Safety of statins. At low to moderate dosages, simvastatin does not appear to be associated with a significant risk of liver function abnormalities. Atorvastatin also appears to be associated with low rates of liver toxicities at moderate dosages. A recent statement from the FDA on the safety of rosuvastatin notes that some evidence suggests a lower risk of myopathy with rosuvastatin at all dosages, compared with other agents that have similar cholesterol-lowering effects.8  REFERENCES: 1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. 2. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versusmoderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. 3. Nissen SE, Tuzcu EM, Schoenhagen P, et al; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080. 4. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics; the alliance study. J Am Coll Cardiol. 2004;44: 1772-1779. 5. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. 6. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. 7. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease—is it time to shift our goals? N Engl J Med. 2005;352: 1483-1484. 8. Galson SK. Center for Drug Evaluation and Research response to petition of Sidney M. Wolfe, MD. Letter. Available at: http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf. Accessed March 15, 2005.