Coronary artery disease
Safety and Efficacy of Atorvastatin-Induced Very Low-Density Lipoprotein Cholesterol Levels in Patients With Coronary Heart Disease (a Post Hoc Analysis of the Treating to New Targets [TNT] Study)

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High-dose statin therapy has been demonstrated to provide incremental benefit when low-density lipoprotein (LDL) cholesterol concentrations are lowered well below recommended target levels. This secondary analysis of the Treating to New Targets (TNT) study was conducted to investigate whether the attainment of very low LDL cholesterol levels was associated with a further reduction in major cardiovascular events compared with higher LDL cholesterol concentrations and whether any incremental benefit was achieved without additional safety risk. Patients with coronary heart disease and LDL cholesterol levels <130 mg/dl (3.4 mmol/L) were randomized to therapy with atorvastatin 10 mg/day (n = 5,006) or 80 mg/day (n = 4,995). The primary end point was the occurrence of a first major cardiovascular event. Clinical outcomes and safety data were compared across on-treatment LDL cholesterol quintiles. There was a highly significant reduction in the rate of major cardiovascular events with descending achieved levels of on-treatment LDL cholesterol (p <0.0001 for trend across LDL cholesterol). Analysis of individual components of the primary end point demonstrated similar results. Death from any cause and from noncardiovascular causes was lowest in patients with the lowest on-treatment LDL cholesterol levels. Cardiovascular deaths were also reduced with lower levels of on-treatment LDL cholesterol. There were no clinically important differences in adverse event rates across quintiles. Specifically, no increase in muscle complaints, suicide, hemorrhagic stroke, or cancer deaths was observed at the lowest LDL cholesterol levels. In conclusion, the present analysis adds support to the concept that for patients with established atherosclerotic cardiovascular disease, a further risk reduction without sacrifice of safety can be achieved by reducing LDL cholesterol to very low levels.

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Study design and patients

The study protocol and outcome measures for the TNT trial have been published previously.1, 2 All patients gave written informed consent, and the study was approved by the local research ethics committee or institutional review board at each center. In brief, patients with clinically evident CHD (defined as previous myocardial infarction [MI] or previous or present angina with objective evidence of atherosclerotic CHD and/or those who had undergone coronary revascularization procedures)

Patient population

In the TNT study, 10,001 patients were randomized and given double-blind treatment with atorvastatin 10 or 80 mg. Of these, 9,769 (97.7%) had LDL cholesterol measurements taken after 3 months, and this group was stratified into quintiles (Table 1).

Baseline characteristics across quintiles are listed in Table 2. Patients in the quintile with the lowest levels of on-treatment LDL cholesterol concentrations were slightly more likely to be older, to be men, to have lower systolic and diastolic

Discussion

The present analysis supports the quantitative relation between reduced LDL cholesterol and reduced CHD risk and demonstrates that this association exists even at very low LDL cholesterol levels. In the TNT cohort, there was a consistent and highly significant reduction in the rate of major cardiovascular events with decreasing levels of on-treatment LDL cholesterol, with the lowest event rate observed in patients with LDL cholesterol <64 mg/dl (1.7 mmol/L). The incremental clinical benefit at

Acknowledgment

A full list of TNT investigators has been published previously.1 We acknowledge the contributions made by Andrei Breazna, Liz Cusenza, Sheila Auster, and Miriam Marshood, all employees of Pfizer, in the collection and analysis of the data and John Bilbruck of Envision Pharma, Inc., Horsham, United Kingdom (a medical writer funded by Pfizer), for editorial assistance.

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The Treating to New Targets study was funded by Pfizer, Inc., New York, New York.

Conflicts of interest: Dr. LaRosa has served as a consultant to Pfizer, Inc., New York, New York; Merck Whitehouse Station, New Jersey; Bristol-Myers Squibb, New York, New York; and AstraZeneca, Wilmington, Delaware; and has received lecture fees from Pfizer. Dr. Grundy has consulted with Abbott, Chicago, Illinois; GlaxoSmithKline, Durham, North Carolina, Pfizer, AstraZeneca, and Sanofi-Aventis, Bridgewater, New Jersey; received lecture fees from Merck Schering Plough, Kenilworth, New Jersey; Kos, Edison, New Jersey, Pfizer, GlaxoSmithKline, Lilly, and Bristol-Myers Squibb; and received research support from Abbott and GlaxoSmithKline. Dr. Kastelein has received consulting fees, lecture fees, and grant support from Pfizer, Merck Schering Plough, Bristol-Myers Squibb, and Sankyo, Munich, Germany; Dr. Kostis has served as a consultant to Pfizer, Schering Plough, Berlex, Montville, New Jersey; Taisho, Tokyo, Japan; Forest Laboratories, New York, New York; and Sankyo; received lecture fees from Pfizer, Merck, Bristol-Myers Squibb, AstraZeneca, Sanofi Aventis, and Otsuka, Rockville, Maryland; and received grant support from Pfizer and Schering Plough. Dr. Greten has received consulting and lecturing fees from Pfizer, Merck, Schering Plough, and Kowa Company, Nagoya, Japan.

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