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Intensive Lipid Lowering in Stable Coronary Disease



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Am Fam Physician. 2005 Nov 1;72(9):1876-1878.

Guidelines from the Third Report of the National Cholesterol Education Program Adult Treatment Panel recommend a low-density lipoprotein (LDL) cholesterol level of less than 100 mg per dL (2.6 mmol per L) for patients at high risk of developing coronary heart disease (CHD), with an LDL cholesterol goal of less than 70 mg per dL (1.8 mmol per L). However, much of the evidence supporting this new goal came from studies of patients with acute coronary syndromes. LaRosa and associates prospectively studied the effectiveness and safety of lowering LDL cholesterol levels below 100 mg per dL in patients with stable CHD.

Eligible patients were 35 to 75 years of age with clinically evident CHD. At screening, patients were taken off lipid-regulating medicines. After a washout period of one to eight weeks, patients with LDL cholesterol levels of 130 to 250 mg per dL (3.4 to 6.5 mmol per L) were started on an eight-week run-in period of open-label treatment with 10 mg of atorvastatin (Lipitor) daily. After this, patients with an LDL cholesterol level of less than 130 mg per dL were assigned randomly to receive 10 or 80 mg of atorvastatin daily. Assignments were double-blind, and patients were followed for a median of 4.9 years. A total of 10,001 patients were randomized, and 9,917 completed the study, although all patients were included in the data analysis. Most patients were white (94 percent) and male (81 percent), with an average age of 61 years. Primary endpoints were death from CHD; nonfatal, nonprocedure-related myocardial infarction; cardiac arrest with resuscitation; and fatal or non-fatal stroke. Investigators assessed numerous secondary cardiovascular outcomes and all-cause mortality.

During the run-in phase, the mean LDL cholesterol level was reduced from 152 mg per dL (3.9 mmol per L) to 98 mg per dL (2.5 mmol per L) in the overall patient population. After randomization, the mean LDL was 77 mg per dL (2.0 mmol per L) for patients being treated with 80 mg of atorvastatin and 101 mg per dL (2.6 mmol per L) for patients being treated with 10 mg of atorvastatin. Patients treated with 80 mg of atorvastatin experienced a statistically significant reduction in total cholesterol and triglyceride levels from baseline to week 12. Neither group experienced elevated levels of high-density lipoprotein cholesterol.

Patients treated with 80 mg of atorvastatin experienced 2.2 percent fewer primary events than patients treated with 10 mg of atorvastatin (8.7 versus 10.9 percent, relative reduction of 22 percent). There also were significant reductions in the separate variables of nonfatal myocardial infarction, death from CHD, coronary events, and stroke. Both groups had low rates of cardiovascular events compared with previous studies. There was no difference between the two groups in all-cause mortality. There were significantly more adverse events (8.1 versus 5.8 percent) and discontinuations (7.2 versus 5.3 percent) in the high-dose group. The most common adverse events were myalgias and persistently elevated liver transaminase levels.

The authors conclude that intensive lipid-lowering therapy with 80 mg of atorvastatin daily in patients with stable CHD is associated with substantial clinical benefits. The authors estimate that treating 1,000 patients with an 80-mg dose of atorvastatin would prevent 34 major cardiovascular events over five years.

LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. April 7, 2005;352:1425–35

editor’s note: Before this study, there was only limited evidence that the benefits of high-dose statins on acute coronary syndrome would extend beyond that event. In a connected editorial,1 Pitt raises important questions about the recent trend toward high-dose statin use in patients with stable CHD. Does a 2.2 percent absolute reduction in cardiovascular events justify higher dosages, higher risk, and higher cost? Certainly a reduced coronary disease burden could bring other benefits (e.g., less disability). Most importantly, this study does not answer the question of an all-cause mortality benefit. With high-dose statins, will we once again be lowering rates of one type of demise without prolonging life? This question is vitally important when considering major shifts in our typical care, and it remains unanswered for now.—c.c.

 

REFERENCE

1. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease—is it time to shift our goals? [Editorial] N Engl J Med. 2005;352:1483–4.



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