Background: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. Methods: We conducted an international, multicenter, randomized, double-blind, prospective trial involving patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis.
We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. Median high-sensitivity C-reactive protein hsCRP was elevated at baseline Table 1 and decreased in the rosuvastatin group at 3 months by The composite cardiac endpoint cardiac death or nonfatal MI occurred in 85 diabetic patients allocated to rosuvastatin 7. For the chosen post hoc composite cardiac endpoint the number needed to treat was Patients randomized to rosuvastatin have a reduced composite cardiac event rate.
The figure shows Kaplan-Meier curved for cardiac events by treatment group. For the primary endpoint chosen in the overall AURORA trial cardiac death, nonfatal MI, fatal or nonfatal stroke , 7 there was a nonsignificant reduction of There was no difference in overall stroke incidence, 38 in the rosuvastatin group versus 20 in the placebo group HR, 1.
Although numerically small numbers, there was an increased incidence of hemorrhagic strokes in the treatment arm compared with placebo arm, 12 versus two respectively, HR, 5. The treatment effect was unchanged when these covariates were included data not shown. There was no significant effect of rosuvastatin on time to death from any cause HR, 0. The proportion of deaths attributable to cardiac disease was Of all cardiac events, As seen in previous studies in patients with end-stage renal disease, there was a high incidence of adverse and serious adverse events.
Most individuals reported multiple events with no significant difference between treatment groups Table 2. Age HR 1. Risk factors for time to first cardiac event in diabetic patients by cox regression analysis adjusted for each other at baseline. This finding parallels the cardiac and definite cardiac events results in the 4D trial. The reduction of cardiac events in diabetic patients observed both in AURORA and 4D show a similar magnitude of risk reduction to a wide range of statin-treated populations, including patients with diabetes and normal, or mildly impaired, renal function.
Although statin treatment failed to show an overall effect on the primary composite cardiovascular endpoint in AURORA and 4D, 6 , 7 a lack of effects on chosen primary composite endpoints in statin trials have also been demonstrated for other patient populations. In patients with chronic heart failure 9 , 10 and in patients with aortic stenosis, 11 lipid lowering was without effect. In populations where statins have failed to show a beneficial effect, the primary endpoints were often complex and consisted of different components for cardiovascular events of which a beneficial effect of statin therapy could be questioned.
Thus, in both end-stage renal disease and advanced chronic heart failure, sudden death is much more common than nonfatal myocardial infarction. Moreover, whereas in patients with atherosclerotic coronary artery disease such as 4S sudden death is likely to be due to occlusive coronary disease, in patients with end-stage renal disease and advanced chronic kidney disease this presumption may not be appropriate.
In AURORA, and in the chronic heart failure trials, the proportion of cardiac deaths due to coronary disease may be relatively small, and thus may have contributed to the negative results. The major issue that emerges from both 4D and AURORA, and from the chronic heart failure trials is the pathophysiology of sudden cardiac death, and the extent to which is it is dependent on atherosclerotic coronary disease. Our observation that statin therapy is associated with a reduction in the composite end-point of cardiac death in the diabetic subgroup, but not the whole, study population in AURORA might be taken to suggest that atherosclerotic coronary disease is a more common cause of sudden cardiac death in patients with diabetes compared with nondiabetic patients with end-stage renal disease.
There is a growing awareness of avoiding a too wide inclusion of endpoints in statin trials. The Study of Heart and Renal Protection SHARP steering committee narrowed the focus for the primary endpoint of the study by excluding previous endpoints of noncoronary coronary events and hemorrhagic stroke. Statin treatment has also lowered stroke incidence in most, but not all trials. Due to a relatively low number of events this could have been a chance finding. In the diabetic populations in AURORA, there was no difference in the total or fatal strokes, but a significant although numerically small increase in hemorrhagic strokes.
A difference of 5 mmHg in systolic BP might explain why 4D patients had increased occurrence of fatal strokes. However, we did not see an association between LDL-C at baseline and coronary events. This is well recognized in hemodialysis patients with inflammation and an inverse relation between atherogenic lipids and cardiovascular risk has been described.
The increased inflammation status in our patients could have masked an association between LDL-C and coronary events. Hemodialysis is associated with an increased inflammation status. CRP in this population was a marker for coronary endpoints paralleling the findings in renal transplant populations. There is underuse of statin treatment in patients with chronic kidney disease partly due to uncertainty of documented effected and partly due to fear of side effects.
We observed one rhabdomyolosis in the placebo arm and none in the rosuvastatin arm. There were few muscle- and liver-related adverse events, and they appeared equally in placebo and treatment arms.
Concerns have been raised about increased risk of cancer in lipid-lowering trials, 11 , 37 but in the diabetes subpopulation examined, no increase in any type of incident cancer was observed in relation to statin treatment.
LDL-C lowering with statins has consistently decreased the occurrence of cardiovascular events in a broad range of patients. Although there was no difference in overall stroke incidence or fatal stroke, there was an increase in hemorrhagic strokes. Learn more about the modernization effort. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.
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The purpose of this study is to see if rosuvastatin helps to reduce the number of heart attacks, strokes and cardiovascular deaths in patients undergoing haemodialysis. Drug Information available for: Rosuvastatin calcium Rosuvastatin. FDA Resources. Arms and Interventions. Outcome Measures. Eligibility Criteria.
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