TNT - Any benefit to atorvostatin 80 mg versus 10 mg in patient's with CHD?

From TNT study:
N Engl J Med. 2005 Apr 7;352(14):1425-35

Research Design and Methods: A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke.





Primary efficacy outcome measure: Time to first occurrence of a major cardiovascular event.

Defined as: CHD death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke.

Article's Conclusions: 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. This occurred with a greater incidence of elevated aminotransferase levels.

Analysis
Figure 2 appears to show a significant reduction in mean levels of LDL, Total cholesterol, and Triglycerides. In fact only total cholesterol (P<0.001) and triglycerides(P<0.001) were significantly reduced. There is no P value given for LDL. In the absence of this, the assumption is that the reduction was not significant. There was no significant change in mean HDL values.

There was a 22% relative reduction in the primary composite measure. Looking at the individual components we have:
CHD Death: HR 0.80[0.61-1.03] P=0.09
Non-fatal non-procedure-related myocardial infarction: HR 0.78[0.66-0.93] P=0.004
Resuscitated cardiac arrest: HR 0.96[0.56-1.67] P=0.89
Fatal/Non-fatal stroke: HR 0.75[0.59-0.96] P=0.02

There is a significant reduction with regards to Fatal/non-fatal stroke and non-fatal non-procedure-related MI. There is no significant change in CHD death. In fact there is no signifcant change in Death from any cause: HR 1.01 (0.85-1.19) P=0.92.

What about adverse events? 80 mg (8.1%) vs 10 mg (5.8%) P<0.001. The bulk of this appears to be due to a persistent increase in AST/ALT. This translates into a roughly 40% increase in adverse events.

What are we left with? A significant reduction in fatal/non-fatal stroke and non-fatal MI. However there is no improvement in all-cause mortality or CHD mortality specifically (This is in contrast to a study such as the Jupiter Study in which there appears to be a definite improvement in mortality with 20mg of statin versus placebo in paient's with a high CRP.) Furthermore, there is a 40% increase in adverse events.

I would say therefore that the data is weak in support using atorvostatin 80 mg a day for all patients with CHD. It may be useful for some at moderate or high risk of stroke. A review of this study as well as its substudy on diabetes points to the importance of examining specific outcomes (i.e. MI, stroke, death, PAD, etc.) versus composite outcomes (i.e. major cardiovascular events, cerebrovascular events, etc.), because when the outcomes are grouped together the true benefit can be misleading.