Treating to New Targets Study - TNT

Description:

The goal of the trial was to evaluate treatment of patients to a target low-density lipoprotein (LDL) goal below guideline recommended therapy of 100 mg/dl among patients with stable coronary heart disease (CHD).

Hypothesis:

Treatment with high-dose atorvastatin to achieve an LDL well below 100 mg/dl will be associated with a reduction in cardiovascular events compared with treatment with low-dose atorvastatin to achieve an LDL of 100 mg/dl among patients with stable CHD.

Study Design

Patients Screened: 18,469
Patients Enrolled: 10,003
Mean Follow Up: Median 4.9 years
Mean Patient Age: Mean age 60.3 years
Female: 19

Patient Populations:

Age 35-75 years, clinically evident CHD, LDL between 130 and 250 mg/dl, and triglycerides ≤600 mg/dl

Primary Endpoints:

Major cardiovascular event, defined as CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke

Secondary Endpoints:

Major coronary events, cerebrovascular events, hospitalization for congestive heart failure, all-cause mortality, peripheral artery disease, any cardiovascular event, and any coronary event

Drug/Procedures Used:

All patients received atorvastatin 10 mg during an eight-week open-label, run-in period. Following the run-in period, patients were randomized to either atorvastatin 80 mg (n=4,995) or atorvastatin 10 mg (n=5,006). The two dose groups were selected to achieve an average LDL level of 75 mg/dl and 100 mg/dl, respectively.

Principal Findings:

Baseline clinical characteristics were similar between the treatment groups, with an average LDL of 152 mg/dl prior to the run-in period and 98 mg/dl following the run-in period. On treatment, mean LDL levels were 77 mg/dl in the 80 mg atorvastatin group and 101 mg/dl in the 10 mg atorvastatin group (p<0.001). Decreases in both total cholesterol and triglycerides were larger in the 80 mg group (p<0.001), with no difference in change in high-density lipoprotein (HDL).

The primary composite endpoint of major cardiovascular event occurred less frequently in the 80 mg group (8.7% vs. 10.9%, hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.69-0.89, p<0.001). Among the components of the composite, nonfatal myocardial infarction (MI) was lower in the 80 mg group (4.9% vs. 6.2%, HR 0.78, p=0.004), as was stroke (2.3% vs. 3.1%, HR 0.75, p=0.02), and death from CHD trended lower (2.0% vs. 2.5%, HR 0.80, p=0.09) with no difference in resuscitation after cardiac arrest (0.5% each, p=0.89).

Among the secondary endpoints, the 80 mg group had lower rates of cerebrovascular events (3.9% vs. 5.0%, HR 0.77, p=0.007), major coronary events (6.7% vs. 8.3%, HR 0.80, p=0.002), and hospitalization for congestive heart failure (2.4% vs. 3.3%, HR 0.74, p=0.01). There was no difference in all-cause mortality (5.7% vs. 5.6%, HR 1.01, p=0.92) or peripheral artery disease (5.5% vs. 5.6%, HR 0.97, p=0.76).

Persistent elevations in liver aminotransferase levels were more frequent in the 80 mg group than the 10 mg group (1.2% vs. 0.2%, p<0.001). Treatment-related adverse events were also higher in the 80 mg group (8.1% vs. 5.8%, p<0.001), as was study drug discontinuation due to adverse events (7.2% vs. 5.3%, p<0.001). There was no difference by treatment group in persistent creatine kinase elevations, myalgia, or rhabdomyolysis.

Interpretation:

Among patients with stable CHD, treatment with high-dose atorvastatin to achieve an LDL below 100 mg/dl was associated with a reduction in the primary endpoint of major cardiovascular events at five years compared with treatment with low-dose atorvastatin to achieve an LDL of approximately 100 mg/dl.

In the recently published PROVE-IT/TIMI 22 trial, aggressive LDL lowering with atorvastatin 80 mg was associated with a reduction in cardiovascular events compared with standard LDL lowering with pravastatin in patients with acute coronary syndrome. Findings from the present study suggest that aggressive lipid lowering to LDL levels <75 mg/dl also reduces cardiovascular events in patients with stable coronary artery disease.

The overall safety profile was consistent with other large atorvastatin trials, and was likely relatively low due to the exclusion of the 131 patients with abnormal liver-function tests or myalgia during the run-in phase. Despite the exclusion of these patients, persistent abnormal liver-function tests were more frequent in the 80 mg atorvastatin group, suggesting that close monitoring is warranted in patients treated with this dose.

References:

Larosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005 Mar 8; [Epub ahead of print].

Presented by Dr. John C. LaRosa at the March 2005 ACC Annual Scientific Session, Orlando, FL.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Resuscitation, Creatine Kinase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Heptanoic Acids, Heart Arrest, Rhabdomyolysis, Lipoproteins, LDL, Pyrroles, Heart Failure, Pravastatin, Transaminases, Confidence Intervals, Triglycerides, Lipoproteins, HDL, Myalgia


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