Cardiovascular Risk in Uremic Patients: Darkness after AURORA

Keywords:

• cardiovascular risk
• uremia
• AURORA trial
• lipids
• stains

The recently published “A study to evaluate the use of rosuvastatin in subjects on regular hemodialysis: An assessment of survival and cardiovascular events (AURORA)” (Fellström et al., Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialisis. N Engl J Med. 2009;360:1395–1407) was designed to investigate the effects of statin therapy in patients undergoing regular hemodialysis treatment. The final conclusions were that, in patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.^[1] The lack of a benefit of rosuvastatin was observed despite a mean 43% reduction in the LDL cholesterol level at three months, and there was no benefit at any baseline LDL cholesterol level. This is a striking result, especially when compared with the results of JUPITER trial, where in a group of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.^[2]

Patients undergoing renal replacement therapy have a greatly increased risk of premature cardiovascular disease.^[3] However, the pattern of cardiovascular disease in such patients differs from that in the general population, and although the risk of myocardial infarction is increased, other cardiovascular events, such as sudden cardiac death and heart failure, predominate.^[4] Most striking, the relationship between cardiovascular events incidence and classical cardiovascular risk factors is inconsistent, inverse, or, even more commonly, U-shaped.^[5,6] In a prospective study, Degoulet et al.^[7] made the unexpected—and at first counterintuitive—observation that in dialysis patients, low cholesterol concentrations were associated with high mortality. In a cohort of 823 patients who were admitted for dialysis, Liu et al.^[8] found in the overall cohort that an increased serum cholesterol was associated with a decreased risk for all-cause mortality, whereas in the absence of inflammation/malnutrition (22% of the cohort with serum albumin >3.6 mg/dL, C-reactive protein <10 mg/L, and IL-6 <3.09 pg/mL), an increment in baseline serum cholesterol was associated with increased mortality, as it is in the general population. This study also demonstrates that the predictive value of cholesterol is confounded by concomitant inflammation (see below). As low-density lipoprotein (LDL) cholesterol levels may be low or normal in patients with advanced renal disease, there is particular uncertainty regarding the use of lipid-lowering therapy.^[9]

The review of the medical evidence supports the concept that patients with chronic renal failure have accelerated atherosclerosis in part because of greater numbers of atherosclerotic risk factors and a variety of pathobiologic processes that accelerate many facets, including ingress of cholesterol into the vessel wall, expression of adhesion molecules, recruitment of inflammatory cells, oxidation and modification of LDL cholesterol, high serum homocysteine levels, activation and migration of vascular smooth muscle cells, transformation of vascular smooth muscle cells into osteoblast-like cells, secretion of calcium pyrophosphate crystals, fibrosis, and both inward and outward remodelling.^[10–12]

An issue of transcendental importance in the pathogenesis of atherosclerosis in chronic renal failure is the disorders of bone metabolism. Increasing serum phosphorus levels, through the normal range in the general population, those with symptomatic atherosclerosis, and all stages of chronic kidney disease, has been linked to higher rates of cardiovascular events and death.^[13–15] Previous studies showed that vascular calcification is markedly enhanced in end-stage renal disease and associated with cardiovascular and all-cause mortality.^[16] In these patients, the increased coronary artery disease found by electron-beam computed tomography has been associated with advanced age; duration of dialysis; phosphorus levels; and the conventional cardiovascular risk factors including diabetes, elevated LDL cholesterol, depressed HDL cholesterol, and elevated triglycerides.^[17]

Thus, it can be suggested that the special pathogenesis of cardiovascular disease in chronic renal failure may have influenced the results of the AURORA trial. Nevertheless, two small nonrandomized studies using statins (hepatic hydroxymethyl glutaryl–CoA reductase inhibitors) demonstrated attenuation of progression in coronary artery calcifications associated with LDL cholesterol reduction.^[18,19] On the other hand, five randomized, prospective, comparative trials of statins in the general population did not exclude patients on the basis of glomerular filtration rate, attempting to show attenuation or reversal of coronary arterial calcifications. All of these trials, which totaled 2273 patients, failed to demonstrate that LDL cholesterol reduction can modify the rate of progression of coronary artery calcifications, which is, on average, approximately 25% per year; however, in the larger studies with sufficient follow-up time, as expected, there has been a reduction in cardiovascular events associated with LDL cholesterol reduction with statins.^[20]

It has been clearly demonstrated that inflammation is closely associated with cardiovascular risk in chronic renal disease patients.^[21] Many aspects of dialysis treatment can contribute to inflammation, such as vascular access,^[22] back leak of dialysate,^[23] and exposure of blood to non-biologic surfaces.^[24] While the role of inflammation in patients receiving replacement therapy for end-stage renal disease is less well defined, as patients approach dialysis, the prevalence of inflammation increases,^[25,26] and cytokine and acute phase protein levels are associated both with the prevalence of vascular disease in these patients as well as future progression of vascular disease.^[27] In this regard, the JUPITER trial assessed the effects of rosuvastatin versus placebo on rates of cardiovascular events during a maximum follow-up of five years (median 1.9 years), according to on-treatment concentrations of LDL cholesterol (≥1.8 mmol/L or <1.8 mmol/L) and high sensitivity CRP (≥2 mg/L or <2 mg/L) in a group of non-uremic patients. A 65% reduction in vascular events was found in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and high sensitivity CRP less than 2 mg/L, versus a 33% reduction in those who achieved one or neither target.^[28] Thus, rosuvastatin seems to be able of reducing both serum lipids and inflammation—as measured by highly sensitive CRP—though these effects do not reduce cardiovascular events in hemodialysis patients.

KDOQI Guidelines for Management of Dyslipemia in chronic kidney disease state that the risk of coronary artery disease events is markedly increased in this group of patients and, therefore, patients with chronic renal failure should be considered to have a risk equivalent to that of coronary artery disease. This risk category in the ATP III Guidelines includes patients with known ACVD, patients with diabetes, and patients with an expected 10-year risk of CHD ≥20%. These statement was settled on the evidence that patients with chronic kidney disease have an expected 10-year coronary ischemic disease CHD risk ≥20%. Thus, pending the results of specific trials in this population such as the ongoing SHARP (Study of Heart and Renal Protection) study, which aims to provide some evidence for or against statin treatment in lower grade CKD,^[29] the recommendations were based on the evidence from the general population.^[30] The question remains, Should these recommendations be changed after the Aurora Trial?

The first clue is whether the results of the AURORA trial are applicable to all uremic patients. The patients included in this study were men and women 50 to 80 years of age who had end-stage renal disease and had been treated with regular hemodialysis or hemofiltration for at least three months before starting treatment with rosuvastatin. Thus, no patient with stage II–IV of chronic kidney disease was recruited, and only patients with end-stage V renal disease were studied.^[1] There are extreme differences between mild or moderate renal failure and patients surviving renal death through renal replacement therapy, as uremic derangements are a continuum that worsens as the severity of renal failure increases. In this regard, the results of AURORA trial can only be applied to patients treated with hemodialysis or hemofiltration. There is no reason to exclude patients with milder degrees of chronic renal failure from the possible benefits of statin treatment. The same could be agreed about uremic patients after transplantation who have not completely recovered renal function, but these results also cast some doubts in this issue.

In the subgroup analyses of AURORA, there was no benefit at any baseline LDL cholesterol level or in groups with preexisting cardiovascular disease, regardless of the lipid level. Because about one-fourth of patients were diabetic and 40% have previous cardiovascular disease, the lack of positive results suggests that therapeutic inertia could be acceptable in hemodialysis patients even for secondary prevention of cardiovascular disease. These results resemble those of the 4-D trial where the benefit of statins in diabetic patients receiving hemodialysis were examined. In spite of a 42% reduction of LDL cholesterol levels, atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke (in fact, there was even a increase in the risk of stroke in the treated group).^[31] Nevertheless, in the perspective of the results of previous trials with lipid-lowering drugs in the general population, patients currently treated should continue the therapy unless untoward effects were discovered, as withdrawal of statins might increase event rates in patients with acute coronary syndromes.^[32] Starting treatment with statins in these patients after a new cardiovascular event should be cautiously evaluated by the physician and discussed with the patient when lipid levels were low, but when the patient showed high lipid levels, for the general population, statins should be prescribed. The cost of treatment and their potential untoward effects (i.e., myopathy) should be taken into account.^[33]

Moreover, some criticisms have been raised on the design of the trial:

• the study may not have had sufficient statistical power because event rates in the placebo group in AURORA were lower than expected;

• approximately 50% of subjects discontinued treatment; and

• the trial may have excluded patients who were most likely to benefit from statin treatment, as enrollment was limited to patients who had not been treated with statins during the previous six months, a group that probably included patients with previous cardiovascular events or other evidence of increased risk.^[34]

We dare to drawn some conclusions from the cumulated experience, including the conclusions of the AURORA study. First, stage II–IV chronic renal failure patients should be still considered as high-risk cardiovascular patients and treated with statins whenever LDL cholesterol levels be higher than 100 mg/dL. Second, uremic patients treated with hemodialysis do not need to receive preventive treatment with statins for the associated cardiovascular risk. Finally, there is no compulsory reason to avoid the treatment with statins in this later kind of patients when coronary artery disease, cerebrovascular disease, or diabetes mellitus is also present.

ACKNOWLEDGMENTS

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.