Boston, MA - Final results of the Deutsche Diabetes Dialyse Studie (4D), confirming the previously reported surprising finding of no benefit on cardiovascular death, nonfatal MI, or stroke from treatment with atorvastatin in patients with type 2 diabetes on hemodialysis, are published in the July 21, 2005 issue of the New England Journal of Medicine [ 1 ].
The findings, previously presented in preliminary fashion at the American Society of Nephrology meeting in 2004 and then in final form at the XLII Congress of the European Renal Association/European Dialysis and Transplant Association (ERA/EDTA) in Istanbul in June 2005, were reported previously by renalwire .
"The message is that atorvastatin did not reduce the primary composite end point of cardiovascular disease," principal investigator Dr Christoph Wanner (University of WÂ¿rzburg, Germany) told renalwire . "This was an unexpected result," he said. There was a high rate of death from other competing events and sudden cardiac death, which is not affected by statin therapy, he added.
However, they did see a higher rate of stroke in the atorvastatin-treated group. "In no statin study so far was stroke higher—in fact, stroke was reduced," he said. "So we may have a particular group of patients where the pathophysiology of vascular disease is different, causing other findings. When you read the . . . results, we state that the stroke rate in the atorvastatin group was double that in the placebo group, and this diluted the primary end point."
The 4D trial findings are in contrast to other evidence in the literature—most recently, for example, a paper published in the American Journal of Kidney Diseases in January [ 2 ]. In that paper, researchers, led by Dr Eric W Young (University of Michigan, Ann Arbor), used data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) to compare outcomes in hemodialysis patients receiving a statin vs those not treated. They reported significant reductions in both cardiovascular and noncardiovascular mortality risk associated with statin treatment.
4D was a double-blind, placebo-controlled trial that randomized 1255 patients with type 2 diabetes on hemodialysis to receive 20 mg of atorvastatin or placebo. After four weeks, LDL cholesterol in the atorvastatin group was reduced by 42% vs 1.3% with placebo.
However, over a median follow-up of four years, this reduction in LDL did not translate into a difference in the primary end point of cardiovascular death, nonfatal MI, or stroke.
4D: Primary end point
Treatment had no effect on individual components of the primary end point except for fatal stroke, which was significantly increased by atorvastatin treatment (RR 2.03 [95% CI 1.05-3.93], p=0.04).
Patients randomized to atorvastatin had a reduced rate of all cardiac events combined that reached nominal significance (p=0.03), but there was no reduction in all cerebrovascular events combined or in total mortality.
Sudden cardiac deaths, which would not be expected to be affected by statin therapy, accounted for 83 of 149 deaths from cardiac causes in the placebo group and 77 of the 121 cardiac deaths in the atorvastatin group, the paper notes.
"We conclude that in persons with type 2 diabetes mellitus who are receiving maintenance hemodialysis and have LDL cholesterol values between 80 and 190 mg/dL, routine treatment with a statin to reduce the primary composite end point of death from cardiac causes, myocardial infarction, and stroke is not warranted," Wanner et al write. "The initiation of lipid-lowering therapy in patients with type 2 diabetes mellitus who already have end-stage renal disease may come too late to translate into consistent improvement in cardiovascular outcome."
Asked how these findings have been received, Wanner said that in general, nephrologists have been understanding of the results. "They have discovered in recent years so many nontraditional cardiovascular risk factors—such as homocysteine, fibrinogen, Lp(a), a high inflammation rate—are all important in contributing to CV death, and these risk factors cannot be influenced by a statin."
The findings have also been presented at two cardiology meetings, he added. Cardiologists found the results interesting, he said, but wanted more data to help explain why, in this very high-risk group of patients where so many events were occurring, the drug was not helpful. "Actually they were not negative, they were interested, and since there are two major trials ongoing with a total of 12 000 patients, they are now eager to see the next results," Wanner said.
A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) is a randomized trial comparing treatment with rosuvastatin (10 mg/day) with placebo in preventing CV death, nonfatal MI, or nonfatal stroke in 2700 patients with end-stage renal disease undergoing hemodialysis. Enrollment is complete on this study, and results are expected in about two years, Wanner said.
Another study, the Study of Heart and Renal Protection (SHARP), which has a target enrollment of some 9000 patients with chronic kidney disease but without established coronary disease, is testing the effect of treatment with a combination of simvastatin (20 mg/day) and the cholesterol-absorption inhibitor ezetimibe (10 mg/day) on subsequent vascular events.
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Cite this: 4D trial published: No benefit of atorvastatin in patients with diabetes undergoing hemodialysis - Medscape - Jul 20, 2005.