TNT: LDL lower than 100 mg/dL provides improved outcomes

Active treatment group had a mean LDL of 77 mg/dL and a 22% reduction in events over those at 100 mg/dL.

ORLANDO – Driving low density lipoprotein levels below 100 mg/dL with atorvastatin significantly improved outcomes compared to what was observed at the 100-mg/dL threshold.

“We have entered a new era in the treatment of established coronary disease,” John LaRosa, MD, president of State University New York Downstate, said at the American College of Cardiology Annual Scientific Session 2005. “These data extend the body of evidence indicating that lowering LDL well below currently recommended levels can further reduce the health care burden associated with cardiovascular and cerebrovascular disability.”

LaRosa presented results from the Treating to New Targets (TNT) study, which randomized 10,001 patients, from 256 sites in 14 countries, to either 10 mg or 80 mg of atorvastatin (Lipitor, Pfizer).

Patients entered the trial after a washout period to remove all lipid lowering therapies, and initially all patients were placed on 10 mg of atorvastatin to reduce their LDL cholesterol to about 100 mg/dL.

After this initial treatment period, half the patients were placed on 80 mg of atorvastatin with the goal of reducing LDL to approximately 75 mg/dL.

The mean age of patients was 61. Most of the patients were white, and about 80% were male. All patients had a history of established coronary disease, about half had hypertension, and 15% had diabetes.

Researchers excluded all patients with LDL >130 mg/dL.

4.9 years of follow up

All patients achieved an LDL of about 101 mg/dL prior to randomization to either low-dose or high-dose atorvastatin. After 4.9 years of follow-up, those patients taking 80 mg of atorvastatin had achieved a mean LDL of 77 mg/dL. Total cholesterol and triglycerides were also significantly improved in the high-dose group, but HDL remained the same between the two arms.

Researchers assessed a primary composite outcome of a first major cardiovascular event, defined as death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest or fatal and nonfatal stroke.

Patients in the high-dose atorvastatin arm had an 8.7% rate of the primary outcome compared to 10.9% in the low-dose group, a significant (P<.001) 22% risk reduction.

“The reduction of LDL below 100 mg/dL also produced significant clinical benefits beyond the coronary vasculature,” LaRosa said. “We singled out stroke because of the potential for severe long-term physical and mental disability and the huge economic burden this presents for society. Intensive therapy with atorvastatin reduced the risk of stroke by 25%.”

Safety

TNT was not powered to detect a difference in mortality, so there was no difference in all-cause mortality between the two groups.

“In a group of 10,000 patients with documented coronary heart disease followed for five years on atorvastatin, cardiovascular death was not the leading cause of death. The leading cause of death in both groups was cancer,” LaRosa said.

Patients taking 80 mg of atorvastatin were more likely to experience an adverse event (8.1% vs. 5.8%, P<.001). “No specific category of events could be identified to account for these differences,” LaRosa said. Treatment-related myalgia was reported in 4.8% of the high-dose group and 4.7% of the low-dose group (P=.72). Two cases of rhabdomyolysis were reported in the high-dose group compared to three in the low-dose group.

In a comment period following LaRosa’s presentation, Carl J. Vaughan, MD, University College Cork in Ireland, said TNT was a “proof of concept” study that confirms what has been shown in PROVE-IT and the Heart Protection Study.“

When we look back at the dozen or so statin trials that we have to date, the overriding message is the absolute importance of bringing statin therapy to patients at risk and to wider populations such as hypertensives and diabetics,” Vaughan said. – by Jeremy Moore

scorecard

For more information:

  • LaRosa JC. Effect of lowering low density lipoprotein cholesterol substantially below currently recommended levels in patients with coronary heart disease: results of the Treating to New Targets study. Late-breaking trial presented at the American College of Cardiology Annual Scientific Session 2005. March 6-9, 2005. Orlando.

ORLANDO – Driving low density lipoprotein levels below 100 mg/dL with atorvastatin significantly improved outcomes compared to what was observed at the 100-mg/dL threshold.

“We have entered a new era in the treatment of established coronary disease,” John LaRosa, MD, president of State University New York Downstate, said at the American College of Cardiology Annual Scientific Session 2005. “These data extend the body of evidence indicating that lowering LDL well below currently recommended levels can further reduce the health care burden associated with cardiovascular and cerebrovascular disability.”

LaRosa presented results from the Treating to New Targets (TNT) study, which randomized 10,001 patients, from 256 sites in 14 countries, to either 10 mg or 80 mg of atorvastatin (Lipitor, Pfizer).

Patients entered the trial after a washout period to remove all lipid lowering therapies, and initially all patients were placed on 10 mg of atorvastatin to reduce their LDL cholesterol to about 100 mg/dL.

After this initial treatment period, half the patients were placed on 80 mg of atorvastatin with the goal of reducing LDL to approximately 75 mg/dL.

The mean age of patients was 61. Most of the patients were white, and about 80% were male. All patients had a history of established coronary disease, about half had hypertension, and 15% had diabetes.

Researchers excluded all patients with LDL >130 mg/dL.

4.9 years of follow up

All patients achieved an LDL of about 101 mg/dL prior to randomization to either low-dose or high-dose atorvastatin. After 4.9 years of follow-up, those patients taking 80 mg of atorvastatin had achieved a mean LDL of 77 mg/dL. Total cholesterol and triglycerides were also significantly improved in the high-dose group, but HDL remained the same between the two arms.

Researchers assessed a primary composite outcome of a first major cardiovascular event, defined as death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest or fatal and nonfatal stroke.

Patients in the high-dose atorvastatin arm had an 8.7% rate of the primary outcome compared to 10.9% in the low-dose group, a significant (P<.001) 22% risk reduction.

“The reduction of LDL below 100 mg/dL also produced significant clinical benefits beyond the coronary vasculature,” LaRosa said. “We singled out stroke because of the potential for severe long-term physical and mental disability and the huge economic burden this presents for society. Intensive therapy with atorvastatin reduced the risk of stroke by 25%.”

Safety

TNT was not powered to detect a difference in mortality, so there was no difference in all-cause mortality between the two groups.

“In a group of 10,000 patients with documented coronary heart disease followed for five years on atorvastatin, cardiovascular death was not the leading cause of death. The leading cause of death in both groups was cancer,” LaRosa said.

Patients taking 80 mg of atorvastatin were more likely to experience an adverse event (8.1% vs. 5.8%, P<.001). “No specific category of events could be identified to account for these differences,” LaRosa said. Treatment-related myalgia was reported in 4.8% of the high-dose group and 4.7% of the low-dose group (P=.72). Two cases of rhabdomyolysis were reported in the high-dose group compared to three in the low-dose group.

In a comment period following LaRosa’s presentation, Carl J. Vaughan, MD, University College Cork in Ireland, said TNT was a “proof of concept” study that confirms what has been shown in PROVE-IT and the Heart Protection Study.“

When we look back at the dozen or so statin trials that we have to date, the overriding message is the absolute importance of bringing statin therapy to patients at risk and to wider populations such as hypertensives and diabetics,” Vaughan said. – by Jeremy Moore

scorecard

For more information:

  • LaRosa JC. Effect of lowering low density lipoprotein cholesterol substantially below currently recommended levels in patients with coronary heart disease: results of the Treating to New Targets study. Late-breaking trial presented at the American College of Cardiology Annual Scientific Session 2005. March 6-9, 2005. Orlando.