By Peter Laird, MD
Joel Topf is a leading nephrologist who posts excellent commentaries on a wide range of nephrology topics on his blog, Precious Body Fluids. In a post from 2009, he described several studies on cardiovascular prevention using proven pharmaceutical agents for this in the general population including aspirin, blood pressure control and statins.
Statins fail again Statins have a tortured relationship with nephrology. Our patients have accelerated atherosclerosis and they die overwhelmingly of cardiovascular disease. So one of my primary jobs is to continually optimize cardiovascular risk factors to save my patients
Control blood pressure, start an aspirin, and maximize the statin are the lather, rinse, repeat of my world.
That said we have little data that this makes a whit of difference, at least in our dialysis patients.
Only the SHARP study has shown any benefit of statins in CKD patients which was published after Dr. Topf's 2009 post.
Findings
4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe&vs619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74—0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%]vs230 [5·0%]; RR 0·92, 95% CI 0·76—1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%]vs174 [3·8%]; RR 0·75, 95% CI 0·60—0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%]vs 352 [7·6%]; RR 0·79, 95% CI 0·68—0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10&000 patients per year of treatment with this combination (9 [0·2%]vs5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%]vs18 [0·4%]), gallstones (106 [2·3%]vs106 [2·3%]), or cancer (438 [9·4%]vs439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%]vs 612 [13·2%], p=0·13).
Interpretation
Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
There is one common factor that I believe is a fatal flaw in all of the statin trials for CKD patients, the failure to control for the many known non-thrombotic cardiovascular risk factors. CKD patients are much more likely to die from complications related to LVH and disorders of mineral bone metabolism than they are to die from thrombosis of a coronary artery that we commonly call a heart attack. Sadly, none of the statin prevention trials in CKD patients controlled for these factors rendering their results suspect in my opinion.
The FHN short daily dialysis trial showed a significant reduction in LVH between the control group and treatment group. In addtion, the failed nocturnal FHN study did show significant improvement of mineral bone disease factors. Both of these elements are known cardiovascular risks in the dialysis population.Failure to control for these factors in the CKD population is tantamount to failing to control for smoking or a sedentary lifestyle risk factors in studies of cholesterol reduction in the general population.
We would not accept the results of any study that did not control for those confounding factors in the general polation, yet we readily dismiss the known confounding factors for CKD and dialysis patients. My own personal approach is to reduce my ultrafiltration rates with reduced blood flow rates, increased frequency and duration of dialysis and take my statin for cholesterol control. I cannot produce any study that shows that any of these factors with definitively reduce my risk of death by adopting this approach, but I can show the strengths and weaknesses of this approach from both observational studies and from evaluating the deficiencies of the statin trials in CKD patients.
Perhaps someday, the specific cardiovascular pathology known in the dialysis population will be the basis for future studies on this very important topic. Studying daily nocturnal home hemodialysis patients with a well concieved RCT would reduce if not eliminate the confoudning factors of LVH and poor mineral bone disease control prevalent in the conventional in-center hemodialysis population. In the mean time, taking my statin on a daily basis is and will remain part of my own prevention program. I remain convinced it is the correct approach.
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