Statins for Dialysis Patients Defended Despite Study

by Mitchel L. Zoler

Statin treatment for most dialysis patients with high cholesterol levels still makes sense despite newly published results from a German trial with more than 1,200 patients that suggests statin treatment did not improve outcomes.

"You shouldn't conclude that statin treatment has no benefit, but, rather, that statin treatment needs to start sooner," commented Jeffrey S. Berns, M.D., a nephrologist at the University of Pennsylvania in Philadelphia. "It would be a mistake to say that based on these findings we should not target cholesterol."

"I would be reluctant to consider these trial results as the sole evidence to support or not support the use of statins" in this type of patient, commented Lynda A. Szczech, M.D., director of the Center for Renal Outcomes Research and Health Policy at Duke University in Durham, N.C. "We would be doing our patients a disservice by considering the conclusions from this study definitive."

The controversial statin finding was made in Die Deutsche Diabetes Dialyse Studie (4D), which enrolled 1,255 patients with type 2 diabetes who were receiving maintenance hemodialysis at 178 centers in Germany. Patients were eligible if their baseline serum level of LDL cholesterol was 80-190 mg/dL. Statin therapy at entry was washed out by a 4-week period of drug discontinuation, after which patients were randomized to receive 20 mg atorvastatin daily or placebo, and were then followed for just under 4 years.

Patients in the study were an average of 66 years old, and had diabetes for a mean of about 18 years. The average duration of dialysis at entry was about 8 months. At randomization, the median serum LDL cholesterol level was 121 mg/dL in the atorvastatin group and 125 mg/dL in the placebo group. After 4 weeks of treatment, the median level was 72 mg/dL in the atorvastatin group and 120 mg/dL in the placebo group.

The study's primary end point was the cumulative incidence of death from cardiac causes, fatal stroke, nonfatal MI, or nonfatal stroke. After 1 year of treatment, the incidence of this composite end point was 12.6% in the atorvastatin group and 11.2% in the placebo group, a nonsignificant difference, the German researchers reported. After 3 years, the rate was 31.9% and 30.5% in the two groups, again a nonsignificant difference (N. Engl. J. Med. 2005;353:238-48).

An additional, troubling finding from another primary-end point analysis was that treatment with atorvastatin was associated with a statistically significant, twofold increase in the risk of fatal stroke, compared with placebo. However, the atorvastatin group showed absolutely no increased incidence in the rate of nonfatal strokes. The U.S. experts interviewed dismissed this finding as probably a statistical fluke. "It's hard to understand. There's never been a prior report that statins increase strokes," said Charles A. Herzog, M.D., a cardiologist at the University of Minnesota in Minneapolis whose practice focuses on patients with chronic and end-stage kidney disease.

The authors concluded 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 ... is not warranted." But several U.S. experts drew a sharply different conclusion.

"I've known about these results for a while, but I'm still treating dialysis patients with statins," Dr. Herzog said. "I usually see patients with established coronary disease, and I wouldn't change using a statin for secondary prevention" in dialysis patients, he told this newspaper. "It's a tougher decision for primary prevention patients, but I don't see a  change" for these patients either, he said.

In 2003, a panel of the National Kidney Foundation set guidelines for managing dyslipidemia in patients with chronic kidney disease that called for using lipid-lowering drugs when levels of LDL cholesterol were above 100 mg/dL. The guidelines called for a target level of less than 100 mg/dL (Am. J. Kidney Dis. 2003;41:S1-S3).

Prior to these guidelines, management of cardiovascular disease risk factors in patients on dialysis was notoriously lax. But the 2003 recommendations seemed to have an impact.

"There's no question that the awareness by nephrologists of the cardiovascular disease risk of patients with kidney disease has skyrocketed in the last 5 years," said Dr. Berns, who is also associate chief of the renal electrolyte and hypertension division at Presbyterian Medical Center of the University of Pennsylvania.

Despite the reluctance of experts to use the findings from this single study as a reason to change existing practice, they admitted that the findings raised questions about the way that cardiovascular disease presents in dialysis patients.

"The big issue with patients on dialysis is that we don't understand how they die. It may be arrhythmia, an electrolyte imbalance, or other things that have nothing to do with the protective effect of statins," commented Peter A. McCullough, M.D., chief of the division of nutrition and preventive medicine at William Beaumont Hospital, Royal Oak, Mich. The German finding "calls into question the nature of atherosclerosis in dialysis patients," he said in an interview.

"We'd be naive to think that a cardiovascular event in a patient on dialysis would be identical to a patient who was not on dialysis," Dr. Berns said. "But still, the vast majority of cardiovascular risk in dialysis patients is the result of atherosclerosis. You're expecting a lot from a statin to see a reduction in events in 2-4 years because these patients have so much disease. A longer-duration study may show a different outcome."

"Our understanding of how to lower cardiovascular risk in patients with end-stage renal disease is really in its infancy. This study is a necessary first step in what I hope will be a long line of research to tackle these questions," Dr. Szczech said.