Istanbul, Turkey - Analyses from two large "lower-is-better" cholesterol studies have provided additional support for intensive lipid lowering with high-dose atorvastatin (Lipitor, Pfizer). One analysis showed that aggressive statin therapy reduced the risk of cardiovascular events in coronary heart disease patients with chronic kidney disease and diabetes, while another showed that high-dose statin therapy reduced not only first events but second and third cardiovascular events as well.

These are the findings from two post hoc analyses of the Incremental Decrease in Events Through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) studies, both presented this week here at the 77th European Atherosclerosis Society (EAS) Congress.

"Individuals in TNT who had existing vascular disease, diabetes, and chronic kidney disease brought a lot of pathology into this study," said TNT investigator Dr James Shepherd (University of Glasgow Medical School, Scotland). "These individuals, when they were given treatment to reduce their risk, got major benefit, a 35% reduction in risk. . . . None of the benefits from the aggressive intervention with statins were associated with serious side-effect problems that would influence decisions in clinical practice."

The updated US guidelines issued by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III suggest that LDL-cholesterol levels be reduced below 100 mg/dL, to as low as 70 mg/dL, in patients at high risk for coronary heart disease. TNT, previously reported by heartwire, was conducted in stable coronary heart disease patients to determine whether they, too, should be treated to the lower LDL-cholesterol levels.

In the TNT study, intensive lipid lowering with atorvastatin 80 mg daily provided greater protection from major cardiovascular events compared with low-dose atorvastatin in stable CHD patients. High-dose atorvastatin reduced the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 22% compared with patients treated with atorvastatin 10 mg, a finding previously reported by heartwire.

In TNT, explained Shepherd, approximately 1500 of the patients had diabetes mellitus, and of these, 546 subjects had chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73m². As noted, these patients had significantly more hypertension, CABG surgery, peripheral vascular disease, congestive heart failure, and cerebrovascular accidents than those with normal eGFR.

Investigators showed that among nondiabetic patients, those with chronic kidney disease had a significant 30% greater risk of major cardiovascular events than those with normal eGFR. In addition, among the diabetic patients, those with chronic kidney disease had a similarly significant 32% greater risk of cardiovascular events than patients with normal kidney function. In terms of treatment effects, atorvastatin 80 mg significantly reduced the risk of time to first major cardiovascular events in patients with diabetes and chronic kidney disease, by 35%.

Shepherd said that intensive treatment with the high-dose statin was safe and well tolerated, with just 1.1% of diabetes and chronic kidney disease patients reporting treatment-related myalgias. A small number of patients, 1.5%, had elevated liver enzymes, a common side effect that occurs as physicians push the dose higher. He reiterated, however, that these increases should not concern clinicians looking to aggressively treat stable coronary patients with existing diabetes or with diabetes and chronic kidney disease.

In a second presentation at the EAS meeting, Dr Matti Tikkanen (University of Helsinki, Finland) presented a seldom-seen end point in another post hoc analysis from the IDEAL trial, a comparison of high-dose atorvastatin vs usual-dose simvastatin (Zocor, Merck) in patients with a previous MI. Investigators evaluated the effect of intensive statin therapy with atorvastatin on cardiovascular events beyond the first event during the course of the five-year study.

In IDEAL, the primary end point was missed, a composite of coronary death, nonfatal MI, or cardiac arrest with resuscitation, but investigators pointed to reductions in secondary end points. Based on the other "lower-is-better" trials and the reduction in secondary end points, investigators reported that aggressively lowering LDL cholesterol in patients with a previous MI can provide a benefit without an associated increase in noncardiovascular mortality or other adverse events.

In this new analysis, investigators showed that atorvastatin 80 mg significantly reduced the risk of a second cardiovascular event, one that occurred after the first event was documented, by 24%, and reduced the risk of a third event by 19%.

"Patients who have had multiple cardiovascular events continue to benefit from long-term intensive statin therapy," said Tikkanen. "Physicians treating such patients should ensure that they adhere to sufficiently high-dose statins."