Editorial Cardiovascular Disease Prevention in CKD Related Article, p. 375

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ardiovascular disease risk is increased in patients with chronic kidney disease (CKD), with doubling of the risk for most events (heart failure, myocardial infarction, stroke, atrial fibrillation, and peripheral artery disease).1 Cardiovascular disease accounts for 58% of deaths in this group, and patients aged 30 and 55 years with estimated glomerular filtration rates (eGFRs) of 15-29 mL/min/1.73 m2 will have a loss in life expectancy of 12.5 and 6.2 years, respectively, due to cardiovascular disease. Despite this, patients with CKD for several reasons have received suboptimal preventive care. Recently, KDIGO (Kidney Disease: Improving Global Outcomes) published a new clinical practice guideline on lipid management in CKD. 2 One of the main recommendations was statin treatment in non–dialysis-dependent patients 50 years or older with eGFRs , 60 mL/min/1.73 m 2. Treatment cutoff values were based on 10-year risk for hard coronary events found in a large, but at that time unpublished, Canadian cohort. Cardiovascular disease prevention has been a “problem child” in nephrology for decades, with many aspects unresolved, so the new guideline recommendations were eagerly awaited. In this issue of AJKD, Tonelli et al3 present evidence from the Canadian cohort, which constituted important data for the rationale of the guideline recommendations. They describe the relationships among age, kidney function, and absolute coronary risk in 1.2 million patients having serum creatinine measured for any reason and followed up for a median of 4 years. For patients older than 50 years with CKD, the risk for myocardial infarction or coronary death was more than 10 per 1,000 patient-years for all combinations of sex, eGFR, and albuminuria. This is a commonly used risk cutoff value for deciding whether to start cardiovascular preventive intervention. In contrast, patients younger than 50 years with CKD had coronary risk below this level (except for men aged 40-49 years with eGFRs , 60 mL/min/ 1.73 m2 and increased albuminuria). Clinically, the risk estimates represent highly significant differences with narrow 95% confidence intervals (CIs). Sensitivity analysis including sudden cardiac death or other Address correspondence to Stein Ivar Hallan, MD, PhD, Department of Renal Medicine, St. Olav University Hospital, N-7006 Trondheim, Norway. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.06.005 326

cardiovascular outcomes did not change the main results, neither did subgroup analysis of patients with diabetes or prior cardiovascular disease. Cardiovascular pathophysiology in CKD has distinctive characteristics, including intensive calcification. However, there has been an increasing misconception that patients with CKD are affected mainly by Mönckeberg sclerosis and not a traditional lipid-driven atherosclerosis. There is very little evidence that Mönckeberg sclerosis is an independent nonatherogenic process.4 Most likely Mönckeberg sclerosis and typical CKD vascular pathology should be described as type Vb atherosclerotic lesions, that is, a very advanced lipiddepleted heavy calcified lesion affecting both media and intima layers. Clearly, CKD-specific bone mineral disturbances strongly contribute to calcification of plaques and substantially accelerate the atherosclerotic process. However, cholesterol crystallization seems to be an important trigger for cardiovascular disease pathology in CKD also, thereby creating a strong theoretical rationale for lipid intervention in patients with non–dialysisdependent CKD. What is the clinical evidence that lipid intervention is effective in patients with CKD? Nephrology regrettably is the medical subspecialty with fewest randomized controlled trials, and patients with CKD have been systematically excluded from such studies. Currently, there are only 4 randomized trials on lipid treatment primarily targeting patients with CKD. One included kidney transplant recipients only (ALERT [Assessment of Lescol in Renal Transplantation]),5 2 included dialysis patients only (4D [Die Deutsche Diabetes Dialyse Studie] and AURORA [A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events]),6,7 and only one studied unselected patients with CKD (SHARP [Study of Heart and Renal Protection]: 36%, 42%, 20% and 32% of participants with eGFRs of 30-59, 15-29, ,15 mL/ min/1.73 m2, and on dialysis therapy, respectively).8 In SHARP, patients with CKD with higher traditional risk levels (systolic blood pressure, total cholesterol level, and body mass index) had higher relative risk (RR) reductions, whereas patients with more advanced kidney disease (ie, lower eGFRs) had less effect of the intervention with simvastatin, 20 mg, plus ezetimibe, 10 mg, daily. The overall effect (nonfatal myocardial infarction, coronary death, nonhemorrhagic stroke, or arterial revascularization) was a 22% RR reduction (RR, 0.78; 95% CI, 0.67-0.91) in patients not on dialysis therapy, whereas there was no significant effect in dialysis patients (RR, 0.90; 95% CI, Am J Kidney Dis. 2014;64(3):326-328

Editorial

0.75-1.08).8 This risk reduction probably is somewhat less than in primary prevention of patients without CKD, as summarized in a Cochrane database metaanalysis (RR, 0.70; 95% CI, 0.61-0.79).9 In addition, 2 meta-analyses of post hoc studies reporting results in subgroups of participants with reduced eGFRs (respectively comprising 9 and 20 studies and 20,000 and 45,000 patients) reported very similar treatment effects on major cardiovascular events despite using different methods, with RRs of 0.76 (95% CI, 0.730.80) and 0.78 (95% CI, 0.71-0.86), respectively.10,11 Although such post hoc analysis could be biased, the 2 analyses give consistent results, supporting the view that lipid lowering in patients with non–dialysisdependent CKD is effective. Risk prediction is an important part of preventive medicine and can be performed in several ways. Models incorporating multiple variables can use score sheets or computers to prognosticate future risk for adverse advents. The Framingham models have been used extensively in general medicine, but they do not perform very well in patients with CKD.12 Specific models for patients with CKD therefore have been developed, but discrimination has been modest.13 However, the average cardiovascular risk level in patients with CKD is so high that individual risk prediction might not be necessary. Diabetes has been recognized as a coronary heart disease risk equivalent (or at least very high risk), implying that most patients with diabetes mellitus should receive lipid-lowering therapy.14 The current study by Tonelli et al3 shows that all patients older than 50 years with CKD, even those with eGFRs . 60 mL/min/1.73 m2 (CKD categories G1 A2-3 and G2 A2-3), have a rate of coronary death or nonfatal myocardial infarction higher than 10 per 1,000 person-years. This is an important finding that could simplify risk prediction in patients with CKD and facilitate implementation of preventive interventions. The study has several strengths, including its very large and clinically relevant cohort, use of state-ofthe-art methods for serum creatinine analysis and GFR estimation, and a validated algorithm to find participants with myocardial infarction during followup. However, as noted by the authors, generalizability of this Canadian study could be limited, and of course, broad applicability is critical for the new international lipid guideline. Similar data have not been published previously, but data from general population cohorts in the worldwide CKD Prognosis Consortium can give some information. European cardiovascular prevention guidelines define cardiovascular mortality .5 per 1,000 person years as high risk needing intervention.15 In the 2.1 million CKD Prognosis Consortium cohort cardiovascular death accounted for 36% of deaths, and a total mortality risk of .15 per 1,000 could be used to illustrate an Am J Kidney Dis. 2014;64(3):326-328

equivalent high risk.16 Most patients aged 18-54 years with CKD (except G1 A2, G1 A3, G2 A2, and G3a A1) and all older patients with CKD have total mortality risk above this level and could therefore be eligible for intervention.17 Although not completely comparable, the CKD Prognosis Consortium data support the idea advanced by Tonelli et al3 that patients older than 50 years with CKD are at high risk, whereas only those younger than 50 years with more advanced CKD have sufficiently high risk to justify preventive treatment. Overall, the study by Tonelli et al3 is solid and gives an important contribution to cardiovascular prevention in CKD. The KDIGO work group labeled their main statement on statin treatment of patients older than 50 years with CKD with eGFRs , 60 mL/min/1.73 m2 “grade 1A”; that is, the highest level of evidence and class of recommendation. They also make a “grade 1B” statement that patients older than 50 years with CKD with eGFRs $ 60 mL/min/1.73 m2 should be treated with statins. Grade 1A statements usually imply evidence from multiple randomized trials and grade 1B pertains to evidence from one randomized trial or nonrandomized trials18; however, KDIGO has chosen a less stringent definition. The former recommendation is strong (based on SHARP and post hoc analysis), but the latter is an extrapolation of the good efficacy of statins in general population-based studies to patients with CKD stages 1-2. Although these patients are at increased risk, we should be careful with such strong recommendations because statins have not been tested in this population. In summary, in the current article, Tonelli et al3 provide good evidence on how we easily can use age, eGFR, and albuminuria to select patients with CKD with very high cardiovascular risk. This evidence is used in the recent KDIGO lipid guideline, which advocates statin treatment in patients older than 50 years with CKD. However, the guidelines should be used with some caution given the limited amount of evidence for statins in kidney medicine. Stein Ivar Hallan, MD, PhD St. Olav University Hospital and Norwegian University of Science and Technology Trondheim, Norway

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The author declares that he has no relevant financial interests.

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Stein Ivar Hallan 2. Tonelli M, Wanner C; for the Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Intern Med. 2014;160:182-189. 3. Tonelli M, Muntner P, Lloyd A, et al; Alberta Kidney Disease Network. Impact of age on the association between CKD and the risk of future coronary events. Am J Kidney Dis. 2014;64:375-382. 4. McCullough PA, Agrawal V, Danielewicz E, Abela GS. Accelerated atherosclerotic calcification and Mönckeberg’s sclerosis: a continuum of advanced vascular pathology in chronic kidney disease. Clin J Am Soc Nephrol. 2008;3:1585-1598. 5. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:2024-2031. 6. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-248. 7. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407. 8. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-2192. 9. Taylor F, Ward K, Moore TH, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816. 10. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157:263-275.

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11. Utsunomiya Y, Koda T, Kado T, et al. Incidence of pediatric IgA nephropathy. Pediatr Nephrol. 2003;18:511-515. 12. Weiner DE, Tighiouart H, Elsayed EF, et al. The Framingham predictive instrument in chronic kidney disease. J Am Coll Cardiol. 2007;50:217-224. 13. Tangri N, Kitsios GD, Inker LA, et al. Risk prediction models for patients with chronic kidney disease: a systematic review. Ann Intern Med. 2013;158:596-603. 14. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234. 15. Chronic Kidney Disease Prognosis Consortium; Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with allcause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375: 2073-2081. 16. Perk J, De Backer G, Gohlke H, et al; European Association for Cardiovascular P; Rehabilitation and Guidelines ESCCfP. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33:1635-1701. 17. Hallan SI, Matsushita K, Sang Y, et al; Chronic Kidney Disease Prognosis Consortium. Age and association of kidney measures with mortality and end-stage renal disease. JAMA. 2012;308:2349-2360. 18. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009;301:831-841.

Am J Kidney Dis. 2014;64(3):326-328

Cardiovascular disease prevention in CKD.

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