Treating to New Targets (TNT) study

• Treating to New Targets (TNT) study:
  • in the run-in phase of the study, 15,464 patients with stable CHD and a mean LDL cholesterol level at baseline of 3.4 to 6.5 mmol per litre (130 to 250 mg per decilitre) entered an eight-week period of open-label treatment with 10 mg of atorvastatin per day
    • at the end of the run-in phase, 10,001 patients with an LDL cholesterol level of less than 3.4 mmol per litre (130 mg per decilitre; mean, 2.6 mmol per litre (99 mg per decilitre)) were randomly assigned in a double-blind fashion to continue to take 10 mg of atorvastatin per day or to receive 80 mg of atorvastatin per day
    • study results:
      • after a median follow-up of 4.9 years
        • patients who received 10 mg of atorvastatin per day had an LDL cholesterol level of 2.6 mmol per litre
        • patients who had received received 80 mg of atorvastatin per day had an LDL cholesterol level of 2.0 mmol per litre
        • the atorvastatin 80mg was associated with:
          • a relative reduction in the risk of a major cardiovascular event, including death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, and fatal or nonfatal stroke, of 22 percent (P<0.001)
          • when considering the composite end point with the 80-mg dose of atorvastatin, as compared with the 10-mg dose
            • there was a 22 percent relative reduction in the risk of nonfatal non-procedure-related myocardial infarction (P=0.004) and a 25 percent relative reduction in the risk of fatal or nonfatal stroke P=0.02) in the atorvastatin 80mg group
          • there was no reduction in overall mortality comparing the atorvastatin 10mg and atorvastatin 80mg groups
          • there was an increase in the incidence of persistent elevations in liver-enzyme levels (1.2 percent, as compared with 0.2 percent in the group given 10 mg of atorvastatin; P<0.001); there was no significant increase in creatine kinase levels or the incidence of myalgia or rhabdomyolysis
          • the study authors concluded that 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. However there was no significant difference in overall mortality comparing the two treatment groups
            • the number of deaths from CHD was reduced by 26 among patients assigned to 80 mg of atorvastatin per day, as compared with those assigned to receive 10 mg of atorvastatin; however the number of deaths from noncardiovascular causes in this group was increased by 31. This increase in deaths noncardiovascular causes in the 80mg atorvastatin group may have been due to chance but it has been noted "...Until the safety and effectiveness of an 80-mg daily dose of atorvastatin have been established, patients and their physicians will need to carefully weigh the benefits of a reduction in the risk of cardiovascular events, including myocardial infarction and stroke, with their attendant disability, against the uncertainty of an increase in the risk of death from noncardiovascular causes .."(2)

Notes:

• a prespecified secondary endpoint analysis was undertaken comparing the two atorvastatin doses and risk of stroke (3):
  • the study found that among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose
    • cerebrovascular events
      • 3.9% (atorvastatin 80mg per day); 5% (atorvastatin 10mg per day)
      • RRR 23% (95% CI 7 to 35); NNT 89 (57 to 593)
  • an increase in hemorrhagic stroke was not seen at low LDL-C levels. However there was a 6 fold increase in consecutive abnormal LFTs (1.2% v 0.2%)

Reference:

1. La Rosa JC et al.Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35.
2. Pitt B. Editorial - Low-Density Lipoprotein Cholesterol in Patients with Stable Coronary Heart Disease - Is It Time to Shift Our Goals?N Engl J Med 2005.
3. Waters DD et al. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol. 2006 Nov 7;48(9):1793-9.