Statins vs Coumadin in ESRD
Statins in ESRD
Both the ACC/AHA and KDIGO came out with new recommendations regarding lipid management in late 2013. The ACC/AHA guidelines made no specific recommendations regarding lipid management in ESRD patients. The KDIGO guidelines for lipid management are based on three randomized, controlled trials:
4D (Die Deutsche Diabetes Dialyse Studie). 4D consisted of 1233 patients on hemodialysis that were treated for 4 weeks with atorvastatin 20 mg or placebo and followed for 4 years.
• LDL was reduced to a greater extent in the statin group.
• no difference in the primary endpoint of cardiac death, non-fatal MI and fatal and non-fatal stroke: the RR was 0.92 (95% CI, 0.77-1.1; P=0.37).
• Atorvastatin did have an effect on fatal stroke (RR, 2.02; 95% CI, 1.05-3.93; P=0.04).
• Overall there was no effect on the primary end points or total mortality.
AURORA Study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events). AURORA had similarly negative results, with 2776 patients on hemodialysis randomized to rosuvastatin 10 mg or placebo with 3.8 years of follow-up.
• There was no effect on the primary end point or any component of the primary end point or on all-cause mortality.
SHARP (Study of Heart and Renal Protection). SHARP was the largest and most recent of these studies. This was a randomized trial that assigned 9270 participants aged 40 years or older with CKD to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 4.9 years. ~33% of the patients (n=3023) were receiving maintenance dialysis at randomization.
• This combination treatment did not significantly reduce the risk of primary endpoint in the dialysis subgroup in this study.
A meta-analysis of eighty trials including ~50,000 patients with CKD demonstrated the variable benefits of statin therapy in different CKD stages. Statins reduced all-cause mortality, cardiovascular mortality, and cardiovascular events in patients with CKD not on dialysis but had little or no effect on all-cause mortality (RR, 0.96; 95% CI, 0.88-1.04), cardiovascular mortality (RR, 0.94; 95% CI, 0.82-1.07), or cardiovascular events (RR, 0.95; 95% CI, 0.87-1.03) in persons receiving dialysis.
Overall, there is no evidence for the use of statins in ESRD patients and guidelines suggest not starting a statin on patients who had not already been on one prior to starting dialysis. These trials are disappointing given the huge cardiovascular comorbidity and risk that our patients carry and the large benefit of statins seen in the general population.
Coumadin in ESRD
The use of warfarin (Coumadin) in patients with ESRD is unfortunately very common given the frequency of comorbid conditions such as valvular heart disease and thrombosis seen in this patient population. In many of these situations, the use of warfarin is unavoidable.
Controversy over the use of warfarin arises when considering its use in non-valvular atrial fibrillation (AF). Patients with ESRD are already at increased risk of bleeding and hemorrhagic stroke. Warfarin is a risk factor for vascular calcification through its actions on matrix Gla protein and vascular smooth muscle cell phenotype. Warfarin has also been shown to increase the risk of aortic valve calcification in the general population. We also know that there is greater variability of INR in patients on dialysis and warfarin compared to those on warfarin but not on dialysis.
All these issues make the decision to use warfarin a difficult one. On the other hand, we know that dialysis patients are at increased risk of ischemic stroke and have higher rates of atrial fibrillation than the general population.
There is little evidence to guide the use of warfarin in dialysis patients with AF, and the data that does exist is contradictory.
• A Danish registry study found that the use of warfarin in dialysis patients at high risk for stroke or thromboembolism based on the CHA2DS2-VASc score was associated with significantly lower all-cause mortality.
• Chan et al examined the outcomes of 1671 incident dialysis patients with pre-existing AF treated with warfarin or not. In comparison with nonuse, warfarin use associated with a significantly increased risk for new stroke.
• Shah et al performed a retrospective cohort study of Canadian patients over 65 years of age admitted to hospital with AF. 1626 of these patients were on dialysis. 46% of these dialysis patients were prescribed warfarin. Warfarin use, compared to no warfarin use, was not associated with a lower risk for stroke but was associated with a 44% higher risk for bleeding (adjusted HR, 1.44, 95% CI, 1.13-1.85) after adjusting for potential confounders.
The CHADS2 score in patients on dialysis needs to be interpreted with caution. Two components of this score, hypertension and HF, do not independently predict stroke risk in dialysis patients. This tends to misclassify low stroke risk patients as being high risk. This study by Wizemann et al also demonstrated that warfarin use among patients with pre-existing AF was associated with elevated stroke risk in patients >75 years.
Overall, the data for warfarin use in dialysis patients with AF supports a cautious approach, and we probably should be prescribing warfarin less frequently than we do for these patients given the risks outlined above.
Both Coumadin and statins may not affect long-term outcomes in ESRD patients. You decide which one of them deserves to move to the next round.
Dr. House is a Professor and Chair of the Western University Division of Nephrology in London, Ontario. He completed his training in Physiology and Pharmacology at Western before obtaining his MD and specialist training at the University of Ottawa, as well as a Master's in Epidemiology and Biostatistics at Western. In 2007, he completed a six-month sabbatical in Vicenza, Italy, where he developed an interest in Critical Care Nephrology and Cardiorenal Syndromes. He participated in the Acute Dialysis Quality Initiative (ADQI) consensus conferences on Cardio-Renal Syndromes held in Venice in 2008 and 2012.