By Peter Laird, MD
The debate over cholesterol management of dialysis patients is filled with divergent data from several studies. Some studies actually indicate an increased rate of survival with higher cholesterol levels, but these outcomes are clouded by the effect that malnutrition/inflammation has on mortality. In this case, the findings of elevated cholesterol and higher survival are more likely a secondary measure of poor nutrition and higher death rates from the malnutrition/inflammation connection:
Conclusions The inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations. These findings support treatment of hypercholesterolemia in this population.
However, further randomized and controlled studies found no benefits to dialysis patients with statin therapy. The 4D trial was a double blind, placebo controlled RCT evaluating 1255 patient on dialysis that also had Type II diabetes. After four years comparing Artovastin (lipitor) to placebo, there was no difference in mortality even though there were fewer cardiac events due to a higher than expected number of cerebrovascular events. In 2009, many nephrologist believed that the AURORA trial, the second major clinical trial of statins in dialysis patients, settled the issue for good when it likewise found no survival benefit in dialysis patients:
A total of 804 patients had a major cardiovascular event during the followup period, of which 396 were in the rosuvastatin group and 408 were in the placebo group (9.2 and 9.5 events per 100 person-years of followup respectively). There was no significant effect of treatment with rosuvastatin on the primary combined endpoint (HR 0.96; 95% CI 0.84 to 1.11; p = 0.59). There was also no significant effect of treatment with rosuvastatin on the individual components of the primary endpoint. A summary of the AURORA trial results can be found in the Table. The lack of effect of rosuvastatin on the primary endpoint was consistent among all subgroups including those with diabetes, high LDL-C level, elevated hsCRP, hypertension and preexisting CVD. The lack of effect of rosuvastatin on the primary endpoint was also not influenced by overall time on hemodialysis.
The latest study evaluating cholesterol lowering in patients with chronic kidney disease to include dialysis patients is the SHARP trial. It is the first study showing any benefit to cholesterol lowering in this population. Granted, patients not yet on dialysis had a greater benefit than those on dialysis, the results remain provocative.
One of the difficulties of studying the cardiovascular benefits of statins in dialysis patients is that most cardiac events in dialysis patients appear to from a different mechanism of action than plaque rupture and thrombosis leading to acute coronary syndrome and myocardial infarction.
High ultrafiltration rates, short dialysis treatment times, mineral-bone disorders, rapid electrolyte shifts and underlying LVH are all factors leading to myocardial stunning, hybernation and myocardial ischemia during the dialysis procedure. These confounding cardiac factors have never been controlled and eliminated in dialysis patients who have a significantly higher risk of sudden cardiac death. The results of the SHARP trial showing significant benefits in CKD patients not on dialysis should not lead to dismissing the use of statins in dialysis patients from studies not designed to eliminate these other factors. Instead, there is no reason physiologically for an improved clinical outcome especially in daily, home dialysis patients who are at lower risk of LVH, rapid electrolyte shifts and myocardial ischemia than those that are in-center patients.
Before eliminating statin therapy from dialysis patients as many nephrologists now advocate, any further studies should consider Dr. Kjellstrand's Unphysiology theory leading to testing statins in the most stable dialysis population, home dialysis patients on daily, nocturnal dialysis. These patients have documented reversal of LVH and significantly lower mortality than standard in-center patients that the prior cholesterol studies have used as their study population. For myself, I personally believe that statin therapy is just as important in dialysis patients as in any other patient at risk for acute cardiovascular outcomes. It may be the large number of confounding factors leading by a different path to cardiovascular deaths that confounds any benefit of statin therapy. If we are to answer this question definitively, designing a trial in well nourished patients at lower risk of cardiovascular outcomes in the first place might significantly highlight the need not only for statins but optimal dialysis as well.