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Lower LDL Target for Stable CHD Patients?

The cardiovascular benefits of aggressive LDL lowering might come with marginally increased risk for adverse noncardiovascular events.

The National Cholesterol Education Program has introduced an optional LDL-cholesterol goal of <70 mg/dL for patients at very high risk for coronary heart disease, even when baseline levels are <100 mg/dL (Journal Watch Cardiology Sep 3 2004). Adding to the ongoing debate, researchers have conducted a manufacturer-sponsored, double-blind, international trial in which 10,001 patients (mean age, 61; 81% men; 94% white) with clinically evident stable CHD were randomized to receive daily atorvastatin at either 10 mg (LDL goal, 100 mg/dL) or 80 mg (LDL goal, 75 mg/dL). Patients were randomized only if 8-week run-in treatment with open-label 10-mg atorvastatin achieved an LDL level <130 mg/dL.

A significant difference in LDL level emerged between high-dose and low-dose recipients by 12 weeks after randomization, and it was maintained throughout the 5-year study (mean, 77 mg/dL vs. 101 mg/dL, respectively). The incidence of major cardiovascular events was significantly lower in the high-dose group than in the low-dose group (8.7% vs. 10.9%), with significant differences in nonfatal MI (4.9% vs. 6.2%) and stroke (2.3% vs. 3.1%) and a borderline significant difference in CHD death (2.0% vs. 2.5%). Findings were consistent regardless of age and sex.

The high-dose group had significantly higher rates of drug discontinuation (7.2% vs. 5.3% in the low-dose group) and abnormal liver-function tests (1.2% vs. 0.2%) and a borderline significantly higher incidence of death from noncardiovascular causes (3.2% vs. 2.5%). All-cause mortality incidence was nearly identical in the two groups (about 5.7%). Five cases of rhabdomyolysis were reported: two in the high-dose group, three in the low-dose group.

Comment: These findings in stable CHD patients lend support to the case for lower LDL targets. However, the higher incidence of death from noncardiovascular causes in the high-dose group (although perhaps due to chance) prompts an editorialist to call for further research to establish the safety and effectiveness of 80-mg atorvastatin and to ask whether other means of achieving very low LDL levels could prove safer. Another important caveat is that the study subjects, selected for having achieved LDL levels <130 mg/dL while on 10-mg atorvastatin, might have been a group particularly responsive to this statin.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology April 22, 2005

Citation(s):

LaRosa JC et al. for the Treating to New Targets Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005 Apr 7; 352:1425-35.

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• Medline abstract (Free)

Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease — Is it time to shift our goals? N Engl J Med 2005 Apr 7; 352:1483-4.

• Original article (Subscription may be required)
• Medline abstract (Free)