Dual LDL, CRP targets best for reducing clinical events

NEW ORLEANS—A new analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study shows that patients treated with an HMG-CoA reductase inhibitor (statin) who achieve the dual goal of low-density lipoprotein (LDL) cholesterol less than 70 mg/dL and a C-reactive protein (CRP) level less than 2.0 mg/dL have the best clinical outcomes, reported Paul M. Ridker, MD, MPH, at the American Heart Association Scientific Sessions 2004. Achieving both goals was more important than randomization to either aggressive or moderate lipid-lowering therapy in PROVE IT, said Dr. Ridker.

In PROVE IT, 4,162 patients who had been hospitalized for acute coronary syndrome (ACS) within the previous 10 days were randomly assigned to intensive lipid-low-ering therapy with atorvastatin, 80 mg/day, or a moderate lipid-low-ering strategy with pravastatin, 40 mg/day. The mean LDL cholesterol achieved was 62 mg/dL in the patients assigned to atorvastatin versus 95 mg/dL in those assigned to pravastatin.

The primary end point—a composite of all-cause mortality, myocardial infarction (MI), documented unstable angina requiring hospitalization, revascularization, or stroke—

occurred in 22.4% of patients assigned to atorvastatin and 26.3% of those assigned to pravastatin (P = .005) at a mean follow-up of 24 months. The event rates translate into a 16% reduction in risk in patients treated aggressively relative to those treated less aggressively.

As specified in the study protocol, plasma samples were obtained at 30 days, 4 months, and at study closeout to help define the relationship between achieved LDL cholesterol, achieved CRP levels, and the risk of recurrent cardiovascular events. The possibility of further therapeutic benefit among patients who achieved the dual target of LDL cholesterol less than 70 mg/dL and CRP less than 2.0 mg/dL was also explored.

After 30 days of treatment, median LDL levels decreased by 22% in the patients assigned to pravastatin and 51% in those assigned to atorva-statin. At this time, median CRP levels were also significantly lower in the atorvastatin-treated patients compared with the pravastatin-treated patients. When the reduction in the risk of recurrent MI or coronary death was analyzed based on LDL cholesterol and CRP levels, the reduction in risk observed in patients with LDL cholesterol levels less than 70 mg/dL was nearly identical to the reduction in risk in patients with CRP levels lower than 2.0 mg/dL.

Neither agent led to better clinical outcomes once both targets were reached, said Dr. Ridker, director of the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston. The findings represent the first evidence to suggest that lowering CRP level by itself may lower the risk of adverse cardiovascular events.

A second analysis of PROVE IT showed that patients with ACS benefit from high-dose statin therapy almost immediately, and these bene-fits persist over time. Aggressive lipid lowering resulted in a rapid reduction in clinical events, and was also associated with a significant reduction in risk in an analysis that began 6 months after the index ACS, reported Christopher P. Cannon, MD. The PROVE IT results demonstrate “a consistent benefit of high-dose statin therapy across the time continuum following an ACS,” said Dr. Cannon, associate professor of medicine, Harvard Medical School, Boston. The results also suggest that ACS patients “benefit from aggressive lipid-lowering even if they are remote from their index clinical event.”

High-dose atorvastatin resulted in a rapid reduction in clinical events that reached 33% at 30 days for the composite of death, MI, and severe recurrent ischemia (P = .04). The benefits were apparent very early in the course of therapy; event curves began to separate within days after initiation of treatment and continued to separate throughout the first 30 days.

The aggressive strategy also reduced clinical events in the analysis that began 6 months after the index ACS. Compared with standard-dose statin therapy, high-dose treatment was associated with an 18% reduction in the primary end point (P = .037). The event rates from 6 months to 2 years were 15% with high-dose atorvastatin and 17.7% with conventional-dose pravastatin. For the composite end point of death, MI, and severe re-current ischemia, the event rates from 6 months to 2 years were

8.4% with high-dose statin therapy and 11.2% with the standard-dose therapy.