Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure

Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure Usman Baber, MD, Robert D. Toto, MD, and James A. de Lemos, MD, FACC Dallas, TX

Background Although numerous large-scale trials have firmly established the benefits of statins for primary and secondary prevention of coronary artery disease, the role of this class of agents in patients with impaired renal function remains unclear. Methods and Results In the following review, we evaluate current evidence regarding the role of statins in patients with both chronic kidney disease (CKD) and end-stage renal disease (ESRD) on hemodialysis. Although statins do appear to reduce cardiovascular risk in patients with CKD, it remains unclear whether such benefit extends to the ESRD population. Thus far, 1 randomized placebo-controlled trial failed to demonstrate a statistically significant reduction in the primary endpoint of cardiovascular death, stroke, and nonfatal myocardial infarction among patients with ESRD on hemodialysis. This finding contrasts with observational analyses suggesting improved outcomes among patients with ESRD taking statins. Conclusions Risk factors unique to the CKD population, which may not be modifiable with statins, could contribute to the increased cardiovascular morbidity among patients with ESRD. These include alterations in mineral metabolism, elevation in serum homocysteine, and increased oxidative stress. Larger prospective studies are needed to elucidate the role of statins in patients with chronic kidney disease, including those with ESRD on dialysis. Pending further data, we currently recommend using statins in patients with CKD. (Am Heart J 2007;153:47127.) Cardiovascular disease (CVD) is the leading cause of mortality in patients with end-stage renal disease (ESRD), with atherosclerotic heart disease accounting for approximately 55% of all deaths.1 This is likely due to a combination of factors, including a markedly higher prevalence of CVD in this population compared with the general population, an increased risk for adverse outcomes after coronary interventions, and underuse of traditional primary and secondary prevention strategies in patients with ESRD.2 Increased cardiac risk extends to the larger group of patients with chronic kidney disease (CKD) who do not have ESRD. An analysis from the Cardiovascular Health Study demonstrated that the risk of CVD and all-cause mortality increased by 5% and 6%, respectively, for every 10 mL/min per 1.73 m2 decrease in glomerular filtration rate (GFR) in an elderly cohort.3

From the Donald W. Reynolds Cardiovascular Clinical Research Center, and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX. Submitted July 6, 2006; accepted October 28, 2006. Reprint requests: James A. de Lemos, MD, Division of Cardiology, UT Southwestern Medical Center, 5909 Harry Hines Blvd, Rm HA9.133, Dallas, TX 75390-9047. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Published by Mosby, Inc. doi:10.1016/j.ahj.2006.10.042

Because of such excess burden of CVD among patients with renal failure, there is considerable interest in devising strategies to lessen or delay the progression and complications of atherosclerosis in this high-risk group. One strategy would be to use HMG-CoA reductase inhibitors (statins), which have been shown in numerous large-scale, randomized controlled trials to reduce cardiovascular (CV) morbidity and mortality in patients with established coronary artery disease (CAD) or risk factors for CAD. The study populations in these landmark investigations, however, did not include significant numbers of patients with either CKD or ESRD. The following will review the current data on statins in patients with CKD and ESRD.

Statins and moderate CKD Although a robust body of evidence supports the CV benefits of statins in patients with preserved renal function, data are scant among patients with CKD. Most evidence comes from subgroup and post hoc analyses of earlier statin trials. Both the HPS and the ASCOT-LLA trials, for example, demonstrated that statin therapy significantly reduced CV events among patients with impaired renal function.4,5 Renal transplant recipients receiving fluvastatin in the ALERT trial also had

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472 Baber, Toto, and de Lemos

Table I. Statins and CVD risk reduction among different CKD subgroups4-7 Renal disease Elevated creatinine (mg/dL) 1.2bSCrb2.2 Microalbuminuria or proteinuria Renal transplant CKD 2 CKD 3

Statin/dose

End points

Relative risk reduction

Absolute risk reduction

Trial, reference

Simvastatin 40 mg

First major vascular event

28%

11%

HPS 4

Atorvastatin 10 mg

Nonfatal MI and fatal CHD

39%

1.2%

ASCOT-LLA5

Fluvastatin 40 mg Pravastatin 40 mg

Cardiac death or nonfatal MI Fatal/nonfatal CAD, CABG or PTCA Fatal/nonfatal CAD, CABG or PTCA

35% 24%

3.2% 4 %

ALERT 6 PPP 7

32%

6.3%

PPP 7

Pravastatin 40 mg

CKD 2 indicates GFR (mL/min per 1.73m2) between 60 and 89; CKD 3, GFR between 30 and 59 (mL/min per 1.73m2). SCr, Serum creatinine (mg/dL); CHD, coronary heart disease; PTCA, percutaneous transluminal coronary angioplasty.

reductions in the secondary end points of cardiac death and the composite of cardiac death or nonfatal myocardial infarction (MI).6 These studies, however, did not differentiate between mild and more severe levels of renal dysfunction. In contrast, in a post hoc analysis of pooled data from the PPP, a subject-level database combining the results of 3 large-scale statin trials, patients were grouped into 3 categories: normal kidney function (GFR N90 mL/min, n = 2876), mild CKD (GFR 60-89.9 mL/min, n = 12 333), and moderate CKD (30-59.9 mL/min, n = 4491).7 Pravastatin use was associated with a significant 23% relative reduction in the primary end point of time to MI, coronary death, or coronary revascularization in the moderate CKD cohort, a benefit similar to that seen among those with mild CKD and those with normal renal function. 7 Despite similar relative risk reductions between the groups, however, the absolute benefit increased as renal function declined. Those with normal kidney function, for example, had a 2.9% absolute reduction in incidence of the primary end point, compared with 4% reduction in those with mild CKD and 6.3% reduction in those with moderate CKD (Table I).7 The interpretation of the PPP analysis must take into account that GFR was not measured but estimated using either the Cockcroft-Gault or the abbreviated Modified MDRD formulas. These equations have been evaluated in numerous populations and might be less accurate in patients without chronic kidney disease. The MDRD equation tends to underestimate GFR in patients without renal disease, whereas the Cockcroft-Gault formula can overestimate GFR due to the tubular secretion of creatinine.8,9 Despite the potential misclassification of patients into CKD categories, the results of the PPP analysis were consistent regardless of which measure was used to estimate GFR. The evidence from both clinical trials and post hoc subgroup analyses presented above suggest but do not prove that statins do provide significant CV benefits to patients with moderate CKD. Furthermore, because

Table II. Percent reduction in lipids with statins in dialysis patients Statin Simvastatin (20 mg/d)104 Atorvastatin (40 mg/d)114 Atorvastatin (10 mg/d)12 Simvastatin (5 mg/d)13 Pravastatin (10 mg/d)14 Simvastatin (5 mg/d)154

Total cholesterol

Triglyceride

LDL-C

29%

17%

41%

48%

34%

34%

43%

N/A

26%

14%

36%

48%

25%

9%

34%

N/A

21%

21%

31%

N/A

21%

18%

33%

N/A

HS-CRP

HS-CRP, High-sensitivity C-reactive protein. 4These studies included control groups.

these patients have significantly higher rates of CV events than those with normal kidney function, the absolute benefit of treating such high-risk patients is greater than among those with normal renal function.

Statins and ESRD Table II summarizes the effects of statins on lipid measurements and C-reactive protein among patients with ESRD.10-15 The studies listed included patients on either peritoneal or hemodialysis (HD) and suggest that statins lower low-density lipoprotein cholesterol (LDL-C) in patients with ESRD on dialysis from 34% to 43%. To date, however, there is limited data on whether such LDL-C lowering translates into clinical benefit. In a prospective matched cohort study with follow-up through 2 years, the effects of atorvastatin on progression of carotid intima media thickness and changes in dobutamine stress echocardiography findings were compared between patients with CKD (GFR b30 mL/min or dialysis therapy) and those with objective evidence of

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Figure 1

Changes in carotid IMT (mm) at 2 years with atorvastatin in patients with known CAD and no renal disease vs. a cohort with CKD.16

CAD but no renal disease.16 Despite significant reduction in LDL-C in both groups, carotid intima media thickness was favorably influenced only in the group with CAD and normal renal function (Figure 1).16 In contrast, several large observational studies suggest a beneficial role of statins in patients with ESRD. In an analysis involving HD patients from the US Renal Data System Dialysis Morbidity and Mortality Wave 2 study, statin use was independently associated with a 32% reduction in total mortality and a 36% reduction in CV mortality.17 In a similar analysis of HD patients in the United States and Europe, statin prescription was associated with a 31% lower relative risk for mortality and a 23% lower risk for cardiac mortality.18 Such observational studies, however, are limited by selection bias and failure to record duration of statin treatment before enrollment; thus, these studies cannot establish a causal link between statin therapy and reduced mortality. The first randomized placebo-controlled trial of statin administration to patients on HD, the 4-D trial, was recently published.19 In this study, 1255 patients with type 2 diabetes mellitus and ESRD on maintenance HD for b2 years were assigned to receive atorvastatin 20 mg/d or placebo. Atorvastatin reduced LDL-C levels by 42% after 4 weeks of treatment.19 Such LDL-C lowering, however, did not significantly impact the primary end point, a composite of CV death, fatal stroke, nonfatal MI, or nonfatal stroke, which occurred in 37% of patients in the atorvastatin group vs 38% in the placebo group (HR 0.92; 95% CI 0.77-1.10; P = .37).19 The authors of this study concluded that the absence of a benefit of atorvastatin may be explained by additional pathogenic mechanisms of CV disease among dialysis patients. They also stated that lipid-lowering therapy initiated once patients have reached ESRD bmay come

Baber, Toto, and de Lemos 473

too late to translate into consistent improvement of the CV outcome.Q19 Clearly, the findings of this trial were disappointing to a cardiology community that had grown used to a long bwinning streakQ for statins. Thus, the authors’ conclusion that statins do not provide a cardioprotective benefit to diabetic patients on HD merits further scrutiny. First of all, this study was not designed to detect modest treatment effects on the order of 10% to 15% but, rather, was powered for a 27% reduction in the composite primary end point. Thus, the question of whether dialysis patients might derive a smaller yet clinically meaningful benefit from statins remains unanswered based on the results from 4-D. In fact, there was a trend for a beneficial treatment effect among certain individual end points. Cardiac death, for example, was reduced by 19% in the atorvastatin arm (95% CI 0.641.03, P = .08).19 This result is consistent with data from other larger statin trials, such as the HPS (n = 20 536) and the LIPID (n = 9014) trial, in which cardiac death was reduced by 17% and 24%, respectively.4,20 In addition, 4-D did demonstrate a significant 18% risk reduction in favor of atorvastatin for the secondary end point of all cardiac events combined, which included CV death, nonfatal MI, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft (CABG) (HR, 0.82, 95% CI 0.68-0.99, P = .03).19 Although a secondary end point, this finding, when considered together with the 19% relative risk reduction in death from cardiac causes, suggests a beneficial role of atorvastatin among diabetic patients on HD. Other aspects of the study might also explain the lack of a clinical benefit. For example, approximately 50% of patients in the placebo arm and 48% in the treatment arm died. More than half of these deaths were due to non-CV causes, which would not be expected to be modified with statins.19 As prior statin trials have consistently shown a treatment benefit after approximately 1 to 2 years of statin exposure, the patients in 4-D might have died from other noncardiovascular causes before having time to realize benefit from statins. In addition, the results of this study may not be generalizable to all HD patients because the trial only included diabetic patients and did not include any patients on peritoneal dialysis. Diabetic subjects on HD have particularly high mortality rates, compared with other subjects with ESRD.21 In addition, low compliance rates and poor protocol adherence may have masked a larger difference between treatment arms. One other controversial result from 4-D was the observation that fatal stroke was significantly increased in the atorvastatin arm (RR 2.03, 95% CI 1.05-3.93, P = .04), which was a major reason why the benefit in the composite primary end point did not reach statistical significance. However, other data provide conflicting results for statins with regard to stroke prevention in

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CKD patients. In the ALERT trial, for example, there was no significant difference in the incidence of fatal or nonfatal cerebrovascular events between the treatment and placebo arms (RR 1.16 95% CI 0.83-1.63).6 On the other hand, pravastatin did reduce stroke incidence in the CARE subgroup analysis of patients with CKD (RR 0.62, 95% CI 0.39-1.00, P = .051).22 The inconsistent data with regard to a stroke benefit in patients with CKD requires further study. Two additional international trials evaluating the effects of statins on CV end points in CKD patients are ongoing. The SHARP study will test the hypothesis that LDL-C lowering with simvastatin or ezetimibe reduces CV morbidity and mortality among patients with moderate to severe CKD.23 The AURORA trial will evaluate the effects of rosuvastation on CV morbidity and mortality in HD patients.24

Figure 2

Coronary calcium scores in patients with CAD and no renal disease compared to patients on Hemodialysis by age.33

Statin Safety in CKD and ESRD Statins have shown an excellent safety and tolerability record across multiple large clinical trials. For example, elevation of hepatic aminotransferases occurs in 1% to 3% of patients and appears to be transient and doserelated.4,20 An analysis of 30 randomized controlled statin trials demonstrated that among 83 858 patients, there were only 7 cases of rhabdomyloysis in the statin arm versus 5 in the control arm.25 These trials included few patients with CKD and ESRD, and as such, there is considerable reluctance by physicians to prescribe statins to patients with CKD2. Pharmacokinetic data and the available evidence to date suggest that such conservative practice patterns might be overly cautious. Most statins, with the exception of pravastatin, are predominantly eliminated via cytochrome P450 metabolism with renal excretion contributing minimally.26 Moreover, single dosing and chronic dosing studies of atorvastatin, pravastatin, and fluvastatin in CKD patients demonstrate no change in the pharmacokinetic parameters of these drugs, as compared with controls.27-29 This translates into a low incidence of adverse events in clinical studies evaluating statins in patients with CKD and ESRD. In the 4-D trial, for example, there were no cases of rhabdomyolysis or severe liver injury.19 Similarly, the frequency of critical liver enzyme elevation or creatine kinase elevation did not differ significantly among renal transplant recipients and controls in the ALERT trial.6 It is important to note, however, that the polypharmacy which often exists among CKD and ESRD patients might include drugs that interact with cytochorome P450. This, along with the potential down-regulation of cytochrome P450 activity in renal failure, might diminish statin elimination and increase the potential for myopathy.30 Thus, we recommend starting statins in patients with severe CKD or ESRD at moderate evidence-based dosages before titrating up to full dosages.

Mechanisms of atherosclerosis in patients with ESRD The lower-than-anticipated clinical benefit from atorvastatin in the 4-D trial suggests that there may be fundamental differences in atherosclerosis between subjects on dialysis and those with normal renal function or mild CKD. The different atherosclerosis bphenotypeQ in dialysis patients may be less responsive to statins than the phenotype in nondialysis patients. Two principal alterations that exist in uremic patients include increased vascular calcification and a unique, highly atherogenic dyslipidemia that is characterized by hypertriglycedridemia, low high-density lipoprotein cholesterol, and low-normal levels of total cholesterol and LDL-C.31 These and other nonlipid mechanisms might impair the effectiveness of statins in this highrisk population.

Mineral metabolism Alterations in calcium and phosphorus metabolism are well characterized anomalies in patients with advanced CKD and/or ESRD. Such dysregulation predisposes the uremic population to vascular calcification and might partially account for the increased CV and stroke risk in such patients. For example, the prevalence of coronary artery calcification (CAC) is much higher in the ESRD population, and CAC occurs at a much younger age.32,33 In an analysis comparing coronary calcification between patients on HD and patients without renal disease, Braun et al33 demonstrated a 2.5- to 5-fold increase in CAC scores among HD patients (Figure 2). The morphology of the atherosclerotic plaque also appears to differ in the ESRD population, with increased media thickness and heavy calcification, as compared with coronary plaques in patients without ESRD.34 In addition, elevations of serum phosphorus and calcium/phosphorus

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products are associated with increased mortality in the dialysis population.35 These findings might be particularly relevant because it appears that statins have minimal effect on the progression of vascular calcification. Although initial observational studies suggested delayed progression of CAC in patients on statins,36,37 more recent data suggest the relationship between serum lipids, CAC, and statins is more complex. Schmermund et al38 demonstrated no change in CAC progression in patients treated with atorvastatin 80 mg versus atorvastatin 10 mg over 12 months. Similarly, Raggi et al found that intensive statin therapy did not significantly slow progression of CAC over a 12-month period compared to moderate therapy.39 Moreover, there was no correlation between changes in calcification score and LDL-C levels in either of the above studies.38,39

Oxidized low-density lipoprotein Oxidation of low-density lipoprotein (LDL) is required for LDL to be taken up by macrophages via the scavenger receptor, leading to the formation of foam cells, a crucial step in the initiation of atherosclerosis.40 The production of oxidized LDL (OxLDL) is regulated by numerous factors, including oxidative stress, antioxidant concentrations, hypertriglyceridemia, and small-dense LDL-C. In addition to increased oxidative stress,41 HD patients have a dyslipidemia with a predominance of triglyceride-enriched, small-dense LDL particles.42 Such LDL particles undergo conformational changes that impair LDL receptor–mediated uptake.43 The coupling of increasing oxidative stress and impaired clearance of LDL in the uremic population might lead to higher levels of circulating OxLDL in HD patients. Although statins do appear to beneficially affect lipoprotein profiles across all subfractions in uremic patients10-15 the effects on OxLDL are less clear. Both in vitro studies of the effects of statins on LDL susceptibility to oxidation and in vivo studies using more direct measurements of OxLDL have generated inconsistent results.44-47 In a cross-sectional analysis of 687 patients with angiographically proven CAD, those on statin therapy had lower levels of OxLDL compared with those not on statins.45 Toshima et al44 however, found no significant difference in OxLDL levels among patients with coronary heart disease receiving statins compared to those not on therapy. The potential role of statins and their effects on OxLDL need further study in larger prospective analyses of patients with impaired renal function. Elevated homocysteine Elevated total homocysteine (tHcy) is a potential risk factor for atherosclerosis in patients with preserved renal function and may be particularly important in patients with ESRD, who typically have markedly

Baber, Toto, and de Lemos 475

elevated levels of tHcy.48 Mortality risk in dialysis patients increased by 1% to 3% per year for every micromolar-per-liter increase in plasma tHcy.49 Homocysteine-related atherogenesis likely involves impairment of endothelial-dependent vasodilatation via modulation of nitric oxide expression and increased thrombosis risk.50 Because statins do not appear to significantly lower tHcy this may be another characteristic of vascular disease in patients with ESRD that is not modifiable with statins.51

Conclusion The evidence to date suggests comparable relative benefit of statins in patients with moderate CKD versus those with normal renal function but increased absolute benefit due to the high-risk nature of this population. These benefits include reductions in nonfatal MI, major coronary events, coronary revascularization, and possibly, stroke. On the other hand, although observational analyses of HD cohorts suggest improved outcomes among patients taking statins, the only randomized placebo-controlled trial performed to date did not demonstrate significant reduction in the primary end point with atorvastatin, largely because of a surprising (and possibly spurious) excess risk for stroke. Despite certain limitations, this study did demonstrate a 19% relative risk reduction in cardiac death and a significant 18% reduction in all cardiac events combined. In our opinion, although larger studies are needed, the aggregate data to date suggests benefit for statins in patients with CKD. Although such benefit might extend to the ESRD population, the relative magnitude may be lower than in nondialysis patients. Several factors that may contribute to accelerated atherosclerosis in ESRD patients may not be modifiable with statins, including abnormal calcium and phosphate metabolism, and elevated levels of OxLDL and homocysteine. Given the very high absolute risk in patients with CKD and ESRD, even modest risk reductions are likely to result in important benefit. Thus, pending further data, we currently recommend using statins to lower LDL-C in patients with chronic kidney disease in accord with the National Cholesterol Education Program Adult Treatment Panel III guidelines. Statins should be started at moderate doses and uptitrated in CKD patients, and monitoring for adverse events including muscle and liver injury should be performed on a regular basis. Additional studies in chronic kidney disease patients including nondiabetic HD patients are needed before the role of statins in this high-risk population can be fully defined.

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