Cardiovascular events are the main causes of death among patients in dialysis with mortality rates ranging from 10 to 20 times higher than in the general population.1 High lipid levels have proven to represent a strong risk factor for cardiovascular diseases onset. However, in hemodialysis patients, a pharmacological intervention for risk factors management presents several issues, such as drug accumulation and clearance (with both dose and time of administration adjustment), and lack of data on drugs efficacy and safety (e.g., an increased risk of hemorrhagic complications with oral anticoagulation).2,3 Statins, a group of lowering lipid drugs, have shown benefit in many clinical trials in reducing the risk of cardiovascular diseases in chronic kidney disease patients. However, statin therapy in dialysis patients, despite showing a similar degree of accumulation to that of healthy individuals and a minimal dialysis clearance, is quite controversial.1,4 Moreover, some studies suggested that both hypercholesterolemia and hypocholesterolemia were associated with an increased risk of death, suggesting a “U-shape” survival curve.1
Up to now, several clinical trials had been performed to assess whether statins could present a beneficial effect in dialysis patients. The SHARP study (Study of Heart and Renal Protection) showed clinical benefit in reducing the incidence of major atherosclerotic events. However, the study was conducted including both dialysis and nondialysis chronic kidney disease patients, and this benefit was not identified in the former group when analyzed alone.5 On the other hand, both the 4D study (Die Deutsche Diabetes Dialyse Studie) and AURORA study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Haemodialysis: An Assessment of Survival and Cardiovascular Events) randomized patients on hemodialysis.6,7 The 4D study showed a reduction rate of all cardiac events combined, without reducing the risk of all cerebrovascular events combined and total mortality, thus not reaching statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke.6 The AURORA study showed that although rosuvastatin reduced LDL cholesterol levels, it had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.7 To date, very few studies have investigated the factors that are related to major cardiovascular event (MACE) in hemodialysis patients who underwent primary percutaneous intervention (PCI), and statin use for secondary prevention is still debated.
Horikoshi et al8 performed a prospective multicenter study, following up on 234 hemodialysis patients who underwent PCI for a median period of 30 months. The study analyzed the time to the first MACE, defined as a combination of all-cause death and nonfatal myocardial infarction, after PCI. According to their findings, patients with statin therapy presented a reduced frequency of MACE (11 vs. 44; P = 0.001). Moreover, this beneficial effect was associated with male gender, elderly, lower BMI and abdominal circumference, hypertension, diabetes, higher levels of high-sensitivity C-reactive-protein, symptomatic heart failure, reduced ejection fraction, nonacute coronary syndrome, and shorter stent length. In this study, the beneficial effect of the statin therapy was beyond the changes in the lipid profile, but it was suggested to be due to their pleiotropic effect. In particular, statins' anti-inflammatory effect is well established, and in hemodialysis patients, it is thought to be achieved by the reduction of inflammation within the artery and plaque stabilization.9–11 In fact, in hemodialysis patients, both LDL and LDL-apoB remain in the blood stream for a longer period, due to a reduced catabolic rate of apoB and liver intake. Therefore, LDL particles are exposed to an increased risk of oxidation or denaturation in the blood vessel, with increased inflammation, endothelial dysfunction, and atherosclerosis progression, which are boosted by diabetes when coexist, even though LDL levels are normal.10,11
Despite advances in clinical research, cardiovascular outcome improvement in hemodialysis patients has taken small steps. The study of Horikoshi et al therefore represents a starting point to give more emphasis to statin therapy for hemodialysis patients who underwent PCI, which is still not recommended by current guidelines, providing a new bullet for a better and more tailored multifactorial intervention for reducing MACEs.12
1. Sun L, Zou L, Chen M, et al. Meta-analysis of statin therapy in maintenance dialysis patients. Ren Fail. 2015;37:1149–1156.
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3. Caturano A, Galiero R, Pafundi PC. Atrial fibrillation and stroke. A review on the use of vitamin K antagonists and novel oral anticoagulants. Medicina (Kaunas). 2019;55:617.
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8. Horikoshi T, Nakamura T, Yoshizaki T, et al. Stratification analysis of statin effect on major adverse cardiac events after percutaneous coronary intervention in patients on hemodialysis. J Cardiovasc Pharmacol. 2021 Oct 6. doi: 10.1097/FJC.0000000000001152.
9. Russo V, Silverio A, Scudiero F, et al. Preadmission statin therapy and clinical outcome in hospitalized patients with COVID-19: an Italian multicenter observational study. J Cardiovasc Pharmacol. 2021;78:e94–e100.
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11. Salvatore T, Pafundi PC, Galiero R, et al. Can metformin exert as an active drug on endothelial dysfunction in diabetic Subjects? Biomedicines. 2020;9:3.
12. Sasso FC, Pafundi PC, Simeon V, et al.; NID-2 Study Group Investigators. Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease. Cardiovasc Diabetol. 2021;20:145.