Aggressive Lipid-Lowering Decreases All-Cause Mortality

Peggy Peck

March 08, 2004

March 8, 2004 (New Orleans) -- Compared with moderate lipid-lowering therapy, aggressive lipid lowering therapy -- reducing low-density lipoprotein (LDL) cholesterol to well below 100 mg/dL -- is associated with a 3.9% reduction in a composite end point of death from any cause as well as nonfatal myocardial infarction, unstable angina requiring hospitalization, revascularization or stroke, according to results reported here at the 53rd annual scientific session of the American College of Cardiology.

Aggressive therapy was also associated with a 16% reduction in the relative event rate compared with moderate treatment.

Christopher Cannon, MD, principal investigator of the Pravastatin or Atorvastatin Evaluation and Infection Therapy--Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22), told Medscape that the study results "finally answer the question: it is all about lower numbers. The lower the LDL, the better the protection." Moreover, he said that the benefit is "not about one drug versus another drug. It is about aggressive treatment versus standard treatment."

Steven Nissen, MD, from the Cleveland Clinic Foundation in Ohio, said the study results were compelling, but he told Medscape, "I disagree with the PROVE-IT investigators. I think this is a drug effect." Dr. Nissen was principal investigator of the Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, which used the "exact same drug regimen." That study, which was reported in November 2003, found that 80 mg atorvastatin stopped progression of plaque as measured by intravascular ultrasound compared with pravastatin treatment.

Dr. Nissen, who was not involved in the PROVE-IT study, said "the findings are even more surprising when you consider that this study was carefully designed to show no difference between these two drugs."

The PROVE-IT study, which was presented here and simultaneously released online by the New England Journal of Medicine, enrolled 4,162 patients who were hospitalized for acute coronary syndromes within 30 days of study entry. Patients were randomized to 40 mg pravastatin (standard therapy) or 80 mg atorvastatin (intensive therapy). After treatment, median the LDL cholesterol level in the pravastatin group was 95 mg/dL while the use of intensive lipid-lowering therapy using atorvastatin lowered LDL cholesterol to a median of 62 mg/dL ( P < .001).

All-cause mortality was reduced by 28% in the aggressive-treatment arm, while death from MI was reduced by 18%. The only end point for which no benefit was reported was stroke, which "was infrequent, but the rates did not differ significantly between the groups," the authors write in their abstract.

At the time of randomization, the median LDL cholesterol level in each group was 106 mg/dL. About 25% of patients (n = 990) were receiving statin therapy prior to randomization and among these patients there was no difference in LDL cholesterol levels with pravastatin therapy, but randomization to atorvastatin "decreased LDL by an additional 32% compared to baseline," said Dr. Cannon.

These results "emphasize the central role of further lipid lowering of [LDL cholesterol] in reducing mortality and morbidity," Dr. Cannon told session attendees.

In a prepared statement, Robert H. Eckel, MD, spokesperson for the American Heart Association, said, "This is the first head-to-head trial comparing clinical events with two statins of proven effectiveness in cardiovascular disease prevention. The group with the greater reduction in LDL...cholesterol had the greater benefit.

Dr. Eckel, who is a professor of physiology at the University of Colorado Health Sciences Center in Denver, noted that it is unclear if higher doses of pravastatin would have achieved similar reductions in LDL cholesterol and similar mortality and morbidity benefits. "But this study represents a segment in a continuing line of research that lowering LDL cholesterol below the currently recommended goal of less than 100 mg/dL will be an important way to further reduce these patients' risk of cardiac death," he added.

The statin benefit was "evident very early, even in the first 30 days of therapy, and was consistent among all subgroups," Eric J. Topol, MD, writes in an accompanying editorial published in the New England Journal of Medicine. Dr. Topol, chairman of cardiology at the Cleveland Clinic Foundation in Ohio, noted that the result was surprising because the trial was designed to "demonstrate noninferiority of pravastatin, as compared with atorvastatin" and because the trial was of fairly short duration -- just 24 months follow-up -- with mixed hard and soft end points that researchers believed would make it "impossible to discern differences between the effects of the two statins."

Dr. Topol adds that the results of PROVE-IT and REVERSAL taken together "herald a shake-up in the field." He concludes that aggressive therapy will result in a "sea change in the prevention and management of atherosclerotic vascular disease."

Another PROVE-IT investigator, Sidney C. Smith Jr., MD, professor of medicine and director of the Center for Cardiovascular Science and Medicine at the University of North Carolina in Chapel Hill, told Medscape that the study clearly demonstrates the benefit of aggressive treatment. But he said it may be difficult to convince clinicians to climb on the aggressive treatment bandwagon.

That may be especially true given recent reports of excess rhabdomyolysis and kidney failure -- including the report of fatal rhabdomyolysis in a 39-year-old woman -- linked to rosuvastatin, which is considered the most potent statin.

Asked if these reports could dampen enthusiasm for aggressive statin treatments, Dr. Cannon said it was unlikely. He noted that the U.S. Food and Drug Administration "carefully reviewed Crestor [rosuvastatin] for more than a year and then studied it for an additional year before approving it -- and it was approved in the face of Baycol." Bayer withdrew cerivastatin (Baycol) from the U.S. market on Aug. 8, 2001, because it was associated with excess and sometimes fatal rhabdomyolysis.

Dr. Cannon added that 3% of the patients in the atorvastatin group had abnormal liver function tests compared with 1% in the pravastatin arm.

Asked about the rhabdomyolysis risk, Dr. Nissen said, "Ask a patient if he or she is more concerned about the 2% risk for an abnormal liver function test versus a 28% reduction in mortality. What do you think the answer will be?"

ACC 53rd Annual Scientific Session: Late-breaking clinical trials. March 8, 2004.

Reviewed by Gary D. Vogin, MD



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