Abstract & Commentary
Comment by Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams is on the Editorial Board of Clinical Cardiology Alert.
Synopsis: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day.
Source: LaRosa JC, et al. Intensive Lipid Lowering With Atorvastatin in Patients With Stable Coronary Disease. N Engl J Med. 2005 (online edition).
The long-awaited Treating to New Targets (TNT) trial assessed 2 doses of atorvastatin in 10,000 subjects with established coronary artery disease, who were followed for an average of 5 years. LDL cholesterol was targeted to a very low level (goal of 75mg/dL), compared to a lower dose of statin, to maintain a LDL cholesterol level of 100mg/dL. The study design and recruitment took place well before the ATP III set a target for LDL < 100mg/dL for patients with vascular disease or those at high risk. More recently, the 2004 white paper from the ATP panel suggested an LDL goal of 70mg/dL for high risk or very high risk subjects.
The mean baseline LDL for the entire cohort was 152mg/dL. All subjects were given open label atorvastatin 10mg to lower LDL to < 130mg/dL, achieving an average of 100mg/dL. Subjects were then randomized to a low and high dose of atorvastatin, 10mg vs 80mg. The study duration was 4.9 years. The primary end point was the first occurrence of a major cardiovascular (CV) event.
Results: The low dose cohort achieved a mean LDL cholesterol of 101mg/dL (TC 178, TG 156, HDL 47); the high dose cohort a mean LDL of 77mg/dl (TC 105, TG 132, HDL 47). There was a 22% reduction of major adverse coronary events (MACE), HR 0.78, P =0.002, and a 25% decrease in stroke, HR 0.75, P =0.02. The MACE rate at 4.9 years was 11% in low-dose patients and 8.7% in the high-dose group. Overall events rates were low. Total mortality was not decreased; a trend for increased non-cardiac deaths was observed, HR 1.25, P = 0.07.
Adverse Effects: There was no increase in rhabdomyolysis or unexpectedly elevated liver function tests.
Comment
The TNT results were anticipated by many, given the emergence of other trial data supporting a lower-is-better strategy. Thus, REVERSAL, PROVE IT-TIMI 22, the post CABG trials, and observational data in acute coronary syndrome populations strongly support a target LDL well under 100mg/dL, which is achievable with aggressive statin therapy. The study population in TNT was at moderate risk, with a mean LDL cholesterol of over 150mg/dL and documented CAD. The actual total risk reduction needs to be considered in this light; the low-dose patients decreased LDL by approximately one third overall from baseline, whereas the high-dose group reduced LDL cholesterol by 50% from baseline. The typical LDL reduction in multiple other statin trails comparing active drug to placebo is 25-30%. The ATP-III white paper of July 2004, suggests the use of aggressive LDL lowering in high-risk populations to a target of 70-80mg/dL. The definition of high risk is in the eye of the beholder. I believe that an individual who has had an established coronary event with an LDL of 150, is in this category. It is likely that we need to be targeting LDL cholesterol to less than 80mg/dL, rather than less than 100 in many subjects with established vascular disease.
The study represents yet another nail in the coffin regarding LDL lowering, particularly in high-risk individuals. Nevertheless, it is far from clear whether such levels should be utilized in lower-risk individuals, such as patients who start out with a relatively low LDL cholesterol, or diabetics and hypertensives without overt vascular disease, who have been shown to benefit from low dose statin therapy without significant LDL cholesterol elevation. The lack of any major adverse events in TNT should be reassuring. Eighty mg of atorvastatin has now been utilized in a number of studies, and appears to be relatively safe. The patient should always be titrated up carefully, with measurements of CK and LFTs from tim4e to time, particularly at the highest dose levels. The results of TNT need to be carefully assessed by the medical community as an important new data base supporting the concept that LDL cholesterol levels should be as low as possible in individuals at increased risk.
Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content