Dr. Ardhanari is affiliated with the Division of Cardiovascular Medicine at University of Missouri – Columbia School of Medicine in Ciolumbia, MO. Dr. Whaley-Connell is a nephrologist affiliated with the Harry S. Truman Memorial VA Medical Center and the Division of Nephrology and Hypertension at University of Missouri – Columbia School of Medicine in Columbia, MO, and Co-Chair of the Kidney Early Evaluation Program (KEEP), which is a national and international screening program for the National Kidney Foundation (NKF) in the detection of chronic kidney disease in the general community.
Drs. Ardhanari and Whaley-Connell review the clinical trials looking at Statins in ESRD. A team that surprised many with a win over Coumadin in ESRD during the first round NephMadness matchup.
It is clear that dyslipidemia is associated with atherosclerotic vascular disease and an increased risk of adverse cardiovascular events. There are a number of randomized controlled trials to demonstrate that statins offer substantial cardiovascular benefits; however, there has been a lack of large RCTs to demonstrate a substantial benefit in those with CKD. Despite this lack of positive data and although CKD is one of the major risk factors for CV disease, patients with CKD are generally undertreated. This reluctance stems from several factors. These include cholesterol lowering effect of malnutrition and inflammation, and the risk of rhabdomyolysis with fibrates.
Although there is limited evidence that patients with CKD have substantial benefit from statins the same benefits are not translated to those patients with ESKD. The KDGIO recommends not to initiate statins in patients with dialysis dependent CKD. This is based on the results from 4 RCTs as follows.
- 4D study: Multicenter, randomized, double-blind, prospective study with 1255 patients with type 2 diabetes on maintenance hemodialysis randomly assigned to receive atorvastatin 20 mg daily or placebo. There was a significant decrease (42%) in LDL cholesterol in four months that was maintained throughout the followup of 4 years. At 4 years followup there were fewer combined cardiac events and increased risk of fatal stroke but there was no statistically significant effect on cardiovascular death, non-fatal MI and non-fatal stroke. There were no reported cases of rhabdomyolysis or severe liver disease in the subjects.
- This study is similar to CARDS trial that studied the effect of Atorvastatin 10 mg daily vs placebo in patients with DM and no other cardiovascular risk factors. At 4 years the study had demonstrated that there is a significant reduction in the cardiovascular events and mortality. However, in 4D study the subjects on enrollment had other comorbid conditions that include prior MI, CHF, PVD and stroke. These characteristics puts these patients on a higher risk category and in real world scenario could have been treated with aggressive dose of statin and 20 mg daily is a moderate intensity statin. Whether this could have contributed to the difference is unclear although the followup duration of 4 years is similar.
- AURORA study: Unlike the 4D study, AURORA was designed to recruit less sick patients undergoing hemodialysis. Subjects were randomly assigned to Rosuvastatin 10 mg daily vs placebo. The study demonstrated there was no significant effect on cardiovascular death, non-fatal MI or non-fatal stroke despite significant decrease in LDL cholesterol levels in the statin group. There were also no statistically significant serious adverse event in the statin group and the increased risk of stroke in patients with the statin group observed in the 4D study is not observed in the AURORA study. However, this study still included nearly one-fourth of the subjects with diabetes and about 40% had prior cardiovascular disease in each arm of the study.
- SHARP study: 9270 patients with CKD both on (n=3023; 33% – 27% HD and 6% PD) and not on (n=6247) dialysis and without any known h/o MI, ischemic stroke and need for coronary revascularization were randomized to a combination of simvastatin 20 mg -ezetimibe 10 mg daily vs placebo with a followup of 4.9 years. Nearly one-third of patients not on dialysis on enrollment began dialysis during the trial and one-third of them doing so in the first year of enrollment. Results demonstrate significant decrease in major atherosclerotic events in both dialysis dependent and non-dialysis dependent patients. However, there is no statistically significant difference in the primary outcome on patients that are dialysis dependent that was attributed to the heterogeneity of the dialysis dependent vs non-dialysis dependent patients and also to the lower compliance rate for the study drug in the dialysis group. When the findings from multiple trials from SHARP, 4D and AURORA are weighed together the benefit of statins in dialysis dependent patients was uncertain.
Overall, hemodialysis in patients with ESRD imparts distinct hemodynamic and biochemical alterations. Specifically in relation to dyslipidemia, hemodialysis may impart an altered cholesterol phenotype resulting from decreased hepatic triglyceride lipase leading to accumulation of triglyceride rich LDL, decreased apolipoprotein CII/CIII ratio impairing the lipoprotein lipase resulting in accumulation of VLDL, and lower levels of apolipoprotein AI and AII lead to lower HDL. Increased carbamylation of LDL particles from cyanate (a product that accumulates as urea dissociates in patients with CKD) accelerates atherosclerosis. They are also prone to have vascular stiffness, calcification, structural heart disease, and sympathetic over-activity that can contribute to increased cardiovascular mortality and complicate interpretation of recent trial data in this difficult population.
It is undeniable that patients with CKD are at a very high risk of cardiovascular morbidity and mortality. Hemodialysis further heightens the risk and so it is compelling for the clinician to treat these high risk patients aggressively. However, RCTs to date have not shown any significant benefits with statins in these patients. This can be attributed to less aggressive statin therapy in the trials, altered cholesterol phenotype and added vascular pathology that makes statins not as effective as it is in non-dialysis population and poor compliance and fear of statin related side effects. Despite this, it would seem prudent that at least conservative management may be beneficial in this difficult to treat population.