REVIEW URRENT C OPINION

Do patients with chronic kidney disease get optimal cardiovascular risk reduction? Mark K. Elliott, Jennifer A. McCaughan, and Damian G. Fogarty

Purpose of review Cardiovascular events are the major cause of death in chronic kidney disease (CKD). Individuals with CKD have a substantially greater risk of cardiovascular disease compared with the general population but have largely been excluded from clinical trials. This review highlights the complex pathogenesis of cardiovascular disease, discusses the evidence for cardiovascular risk reduction and assesses the achievement of cardiovascular treatment targets in CKD. Recent findings There is evidence to support both blood pressure and cholesterol reduction in the CKD population. The risk of bleeding with antiplatelet drugs is high in CKD and these should be used with caution. Although there has been recent interest in targeting nonclassical cardiovascular risk factors in CKD, few trials have demonstrated any significant reduction in cardiovascular risk. Smoking cessation remains important but is poorly studied in CKD with many dialysis patients still smoking. Summary The pathogenesis of cardiovascular disease in CKD differs subtly from that of non-CKD patients. As renal function declines, the role and impact of treating classical risk factors may change and diminish. However, hypertension, hypercholesterolaemia and smoking cessation management should be optimized and may require multiple agents and approaches, particularly as CKD advances. Treatment of hypertension would appear to be one management area in which performance is less than ideal. Future work should focus on new management strategies and drug combinations that tackle the classical risk factors as well as better designed longitudinal and randomized control trials of nonclassical risk factors. Patients with CKD should be included in all cardiovascular intervention studies, given their poor outcomes without interventions. Keywords cardiovascular disease, chronic kidney disease, nonclassical cardiovascular risk factors, risk reduction

INTRODUCTION Cardiovascular disease is the major cause of morbidity and mortality in the chronic kidney disease (CKD) population. Prospective cohort studies have demonstrated a strong association between impaired kidney function, increased risk of cardiovascular events and mortality, with cardiovascular disease as the leading cause of death in CKD patients [1,2]. The magnitude of this effect is now often deemed similar to that associated with a diagnosis of diabetes, though importantly there is a progressive increase in risk with reducing level of kidney function such that amongst dialysis patients the risk of cardiovascular mortality is at least ten-fold that of the general population [3].

PATHOGENESIS OF CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE Many studies have attempted to elucidate the pathophysiology of the increased cardiovascular risk observed in the CKD population (Table 1). Several classical cardiovascular risk factors, such as hypertension and diabetes, are implicated in the cause or Regional Nephrology and Transplantation Unit, Belfast City Hospital, Lisburn Road, Belfast, Northern Ireland, UK Correspondence to Damian G. Fogarty, MD, FRCP, Regional Nephrology and Transplantation Unit, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, BT9 7AB, Northern Ireland, UK. Tel: +44 28 9504 8506; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:267–274 DOI:10.1097/01.mnh.0000444913.78536.b1

1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-nephrolhypertens.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Epidemiology and prevention

KEY POINTS  The pathogenesis of cardiovascular disease in CKD is more complex than in those without CKD, and may involve both classical and nonclassical risk factors.  There is good evidence for optimal blood pressure and lipid lowering therapy in CKD, although the benefit of statins is attenuated in advanced CKD.  Achievement of blood pressure targets decreases with increasing CKD stage, despite high rates of medication use.  Aspirin is associated with high bleeding rates in patients with CKD and its use should be reserved for those at highest risk.  Few trials targeting the nonclassical risk factors have demonstrated a significant reduction in cardiovascular events or mortality.

progression of the primary renal disease, whereas others are consequences of CKD and therefore are overrepresented in this population. Cross-sectional analyses of key study groups, including the Framingham offspring, National Health and Nutrition Examination Survey, and Modification of Diet in Renal Disease study populations, have demonstrated that the prevalence of hypertension, hyperlipidaemia and diabetes is significantly greater in participants with CKD [4–6]. The burden of classical risk factors contributes to, but may not fully account for, the greater cardiovascular risk in CKD. Reduced estimated glomerular filtration rate (eGFR) and increased albuminuria are both independently associated with cardiovascular disease. Two recent meta-analyses have demonstrated that the risk of cardiovascular mortality increases linearly with decreasing eGFR after adjustment for classical cardiovascular risk factors [7,8]. After similar adjustments, albuminuria also correlates with increasing risk of cardiovascular

Table 1. Role of classical and nonclassical risk factors in CKD-related cardiovascular disease Classical risk factors (established)

Nonclassical risk factors (putative)

Hypertension

Hyperhomocysteinaemia

Hyperlipidaemia

Chronic inflammation

Diabetes

Oxidative stress

Smoking

Anaemia

Obesity and inactivity

Mineral bone disease

CKD, chronic kidney disease.

268

www.co-nephrolhypertens.com

death. These relationships are maintained in patients without hypertension and diabetes [9,10]. Excess cardiovascular risk is observed early in the course of CKD, for example in the setting of microalbuminuria and before GFR declines, and this is the evidence that shared risk factors at this stage are most likely the dominant contributing factors rather than those risks associated with more advanced renal disease. In addition to atherosclerosis, arteriosclerosis and vascular calcification play important roles in the development of cardiovascular disease in advanced kidney disease [11 ]. Furthermore, the types of cardiovascular death differ, with an important proportion of cardiovascular deaths in dialysis patients attributable to arrhythmias and not to discrete atherosclerotic cardiovascular events [12]. Several additional ‘nonclassical’ risk factors have been implicated in the development of cardiovascular disease in the CKD population such as hyperhomocysteinaemia [13], chronic inflammation [14], oxidative stress [15], anaemia [16] and CKD mineral bone disease [17]. Iatrogenic factors may also play a role in cardiovascular risk. In a recent cohort study, monthly stroke rates were found to peak during the 30 days after starting haemodialysis or peritoneal dialysis [18 ]. This suggests that the process of initiating dialysis [with anticoagulation and rapid changes in blood pressure (BP) and fluid shifts] may be worth exploring as relevant to strokes. The role of these nonclassical risk factors remains poorly defined and potentially overstated as unmeasured classical risk factor exposure may not be adequately captured in the current study designs. &

&

WHAT IS OPTIMAL RISK REDUCTION IN THE NONCHRONIC KIDNEY DISEASE POPULATION? Risk factor modification and antiplatelet therapies are the mainstay of cardiovascular risk reduction in the non-CKD population [19–22]. The goal of primary prevention is to attenuate the development of atherosclerosis in ‘at-risk’ individuals, whereas secondary prevention aims to limit further events in those with established cardiovascular disease. The major modifiable risk factors are smoking, hypertension, dyslipidaemia and diabetes. In a large multinational study, 75% of the acute myocardial infarction (MI) risk was attributable to these four factors [23]. The addition of lifestyle factors such as obesity, diet and physical inactivity increased this proportion to over 90% of attributable risk in the first MI. A similar risk profile has been identified for ischaemic stroke [24]. Volume 23  Number 3  May 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Inadequate cardiovascular risk reduction in CKD Elliott et al.

There is a rich evidence base for cardiovascular risk reduction. Observational trials have demonstrated a reduction in mortality and re-infarction in patients who stop smoking after MI [25]. Reductions in BP [26] and serum cholesterol [27] have been shown to significantly attenuate mortality and vascular events in proportion to the risk factor reduction. This is irrespective of the pretreatment levels or the presence of preexisting cardiovascular disease. Whereas intensive glucose-lowering therapy in type I diabetic patients has been shown to reduce cardiovascular mortality in a primary prevention randomized control trial (RCT) [28], studies in type 2 diabetic patients have produced conflicting results. There is evidence that intensive glucose lowering in this population (to HbA1c 6.5%) reduces the risk of nonfatal MI but has no effect on mortality and is associated with an increased risk of hypoglycaemia [29]. Tight glycaemic control may actually increase mortality in individuals with type 2 diabetes [30]. The established role of antiplatelet therapy is in secondary prevention in the general population. Aspirin is the most widely studied antiplatelet agent and reduces the risk of mortality, MI and ischaemic stroke in patients with known cardiovascular disease but does not confer a survival benefit in those without established cardiovascular morbidity [31]. Betablockers and angiotensin-converting enzyme (ACE) inhibitors are central to secondary risk reduction after MI. ACE inhibitors reduce the rate of re-infarction or death after MI, but have minimal effect on the risk of stroke [32]. The evidence for beta-blockers is based on the studies that precede current reperfusion strategies. A recent observational study suggested that beta blockade does not significantly reduce the rate of cardiovascular events in patients with or without coronary artery disease in the modern era [33]. Primary and secondary prevention strategies have made a significant contribution to the decreasing incidence of cardiovascular disease over the recent decades [34]. This large U.S. study explores the 50% decrease in deaths from coronary disease between 1980 and 2000, and finds that it is evenly attributable to both reductions in major risk factors and the impact of evidence-based medical therapies. Despite this strong evidence and clear clinical guidelines, risk factor modification in some populations remains inadequate with scope for improvement [35].

WHAT IS OPTIMAL RISK REDUCTION IN THE CHRONIC KIDNEY DISEASE POPULATION? The evidence for cardiovascular risk reduction in CKD has largely been extrapolated from trials in

the general population, despite the frequent exclusion of patients with renal impairment [36,37]. The relative lack of RCTs using CKD cohorts has led to a reliance on observational data and subgroup analysis of cardiovascular trials which report participant renal function. The evidence for targeting the classical cardiovascular risk factors in the CKD population is summarized in Table 2. The benefit of antihypertensive therapy in reducing cardiovascular mortality is well established in CKD stages 1–4. A recent meta-analysis reported a reduction in major cardiovascular events by one-sixth per 5 mmHg reduction in systolic blood pressure (SBP), although the vast majority of CKD participants had CKD stage 3 with eGFR 30–60 ml/ min/1.73 m2 [38 ]. The cardiovascular benefit of BP reduction in dialysis is less well established, with an apparent disparity between data from observational and randomized control trials. Observational trials have suggested a U-shaped relationship between BP and mortality in dialysis patients, with a poorer outcome associated with low or normal BPs [45]. However, meta-analyses of RCTs have demonstrated that lowering BP significantly reduces major cardiovascular events in the dialysis population, with the greatest benefit seen in patients who were hypertensive [39,40]. ACE inhibitors and angiotensin receptor blockers (ARBs) have classically been used as first-line agents for the treatment of hypertension in CKD because of the additional benefit of renoprotection and reduction in proteinuria. Whereas the use of ACE inhibitors or ARBs over other antihypertensive agents has been shown to reduce cardiovascular events in CKD patients with proteinuria [46], a reduction in neither mortality nor cardiovascular events has been demonstrated in nonproteinuric CKD patients or those on dialysis [38 ,47–49]. Surprisingly, intensive blockade of the renin–angiotensin–aldosterone system with dual therapy or direct renin antagonists has been associated with poorer cardiovascular outcomes [50,51]. Higher rates of hyperkalaemia, hypotension and deterioration in renal function were observed in patients treated with the direct renin antagonist, which may explain the poorer cardiovascular outcome in this group [51]. Despite the evidence for the beneficial effects of BP reduction in CKD, population surveys have demonstrated suboptimal BP control. In a UK primary care survey of patients with CKD stage 3, 58.1% met national targets for BP control and only 35.9% met the stricter KDOQI target of BP less than 130/80 mmHg [52 ]. Suboptimal control was more common in those with the highest cardiovascular risk. BP control also tends to worsen with increasing

1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

&&

&&

&

www.co-nephrolhypertens.com

269

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Epidemiology and prevention Table 2. Evidence for targeting classical cardiovascular risk factors in CKD Author (year) Ninomiya (2013) [38 ] &&

Heerspink (2009) [39] Agarwal (2009) [40]

n

Intervention

11877

ACEi or CCB

1679

Antihypertensives

Relative risk of cardiovascular events (95% confidence interval)

CKD stage 3a

0.86 (0.78–0.95)

3b–5

0.86 (0.73–1.02)

5D

0.71 (0.55–0.92)

1202

Antihypertensives

5D

0.59 (0.38–0.91)

Upadhyay (2012) [41]

19210

Statin  ezetimibe

5ND

0.77 (0.71–0.83)

5D (HD)

0.96 (0.80–1.15)

Palmer (2012) [42]

35417

Statins

5ND

0.76 (0.73–0.80)

5D

0.95 (0.87–1.03)

Hou (2013) [43 ]

17933

Statins

2–3

0.69 (0.63–0.77)

4

0.78 (0.63–0.96)

5ND

0.82 (0.60–1.11)

&&

Palmer (2013) [44 ]

14003

&&

Antiplatelets

5D

0.93 (0.86–1.00)

5ND

0.84 (0.7–0.99)a 0.82 (0.47–1.42)a

5D

Meta-analyses of randomized controlled trials addressing classical cardiovascular risk factors in the CKD population. ACEi, angiotensin converting enzyme Inhibitor; CCB, calcium channel blocker; CKD, chronic kidney disease; 5ND, nondialysis patients with CKD-5; 5D, patients on dialysis. Data obtained from articles as referenced. a Relative risk of coronary events only.

stage of CKD. In the UK National Diabetes Audit, the proportion of diabetic patients achieving a target SBP of less than 140 mmHg fell with increasing CKD stage and was still lower in patients with albuminuria [53 ]. This finding has been replicated in U.S. studies [54 ,55 ]. The vast majority of individuals with advanced CKD are prescribed antihypertensive therapy; in one study 97.5% of patients with CKD stages 3–5 were receiving BP-lowering drugs, but only 44% had adequate BP control [55 ]. Although this may partially be explained by the inadequate use of combination therapy and, in particular, diuretics, it suggests that the response to antihypertensive treatment may be attenuated by worsening renal function. Several population studies have demonstrated that the rate of resistant hypertension (defined as failure to reach BP target despite the use of three or more agents) is highest in the CKD population and correlates with worsening eGFR and albuminuria [56 ,57 ,58,59 ]. Moreover, resistant hypertension has been associated with an increased risk of cardiovascular events [60 ]. Previous meta-analyses have shown that the lowest risk for kidney disease progression (and we assume cardiovascular events) was demonstrated for current SBP that ranged from 110 to 129 mmHg, with higher levels of SBP associated with a steep increase in the relative risk of renal events. In view of the fact that even in the trials of antihypertensive treatments for CKD patients the mean BPs usually just achieved an SBP of less than 130, this demonstrates how difficult it is to treat hypertension &

&&

&

&

&

&&

&

&&

270

www.co-nephrolhypertens.com

in these patients. This suggests that the current approach to using antihypertensive agents is not sufficient to achieve optimal BP control in patients with CKD and, given its prominent role in cardiovascular risk reduction, this represents an area of unmet need. Statins reduce cardiovascular mortality in CKD stages 1–4 [41,42,43 ,61]; however, the benefit appears to lessen with increasing CKD stage and their role in end stage renal disease seems diminished compared with earlier stages (see Fig. 1). Two older RCTs in the dialysis population demonstrated no cardiovascular benefit for statins on survival [62,63]; however, the more recent heart and renal protection (SHARP) study showed a 17% reduction in major atherosclerotic events with simvastatin and ezetimibe in patients with advanced CKD, including those on dialysis [64]. However, metaanalyses that present these conflicting results highlight the heterogeneity in these studies [41,42,43 ]. As a consequence of the increasing risk of cardiovascular disease in the latter stages of CKD, although the relative risk reduction for cardiovascular events conferred by lipid-lowering therapy falls as CKD progresses, the absolute risk reduction is comparable between the CKD stages [43 ]. The numbers needed to treat with statin therapy to prevent one cardiovascular event in CKD stage 5 is 46, compared to 36 and 24 for CKD stage 4 and CKD stages 2–3, respectively [43 ]. The U.S. surveys have reported a similar or greater rate of statin use and achievement of &&

&&

&&

&&

Volume 23  Number 3  May 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Inadequate cardiovascular risk reduction in CKD Elliott et al.

Relative risk 1.2 (95% confidence 1 interval) 0.8

0.6

0.4

0.2

0 2–3

4

5 (non-dialysis)

5D

CKD stage

FIGURE 1. The benefit of statins attenuates with increasing CKD stage. Relative risk (RR) of major cardiovascular events in treatment group (statin therapy) versus placebo stratified by CKD stage. These data (RR  95% CI) were plotted on a graph. CI, confidence interval; CKD, chronic kidney disease. Data from Hou et al. [43 ]. &&

cholesterol targets in the CKD population compared to the non-CKD population [54 ,55 ]. While further work is required in different populations, the evidence suggests that optimum cholesterol control can be achieved through the use of statins, although the associated reduction in mortality is attenuated in advanced CKD, perhaps reflecting either different mechanisms or different effectiveness of this treatment. Further work is needed. The use of antiplatelets in CKD is complicated by the complex platelet dysfunction that occurs in uraemia. A recent study in patients after percutaneous coronary stent insertion demonstrated increased baseline platelet activation and an attenuated response to dual antiplatelet therapy in patients with CKD [65 ]. In a large meta-analysis, antiplatelet use in CKD has been shown to reduce the risk of MI, but not mortality or ischaemic stroke, and was associated with a significant increase in minor and major bleeding events [44 ]. The authors concluded that the risks of antiplatelet therapy are likely to outweigh the benefits in patients with early CKD or those without established cardiovascular disease, thus reserving their use for secondary prevention. This mirrors the practice in the general population and is supported by the observational data suggesting an association between clopidogrel use and a reduction in death, MI or stroke in CKD patients after acute coronary syndrome with no increase in bleeding [66 ]. The evidence for other secondary prevention strategies in CKD is limited and is complicated by the fact that patients with severe renal impairment are less likely to receive definitive treatments such as &&

&

&

&&

&

&&

&&

percutaneous stenting [67 ,68 ]. The precise reasons for this are elusive, but one factor may be the concerns amongst physicians that the vascular radiological contrast load may precipitate an acute decline in renal function and even dependence on dialysis. This risk is prominent in the guidelines but may be overstated somewhat as recent work in patients needing intravenous contrast for computed tomography scanning shows that the acute kidney injury (AKI) risk is often related to the degree of illness in the patient under investigation [69 ]. Beta-blockers reduce mortality in patients with CKD and heart failure [70], and observational data has demonstrated an association between the use of ACE inhibitors, ARBs, beta-blockers and aspirin, and reduced short-term and long-term cardiovascular events in CKD patients following MI [71]. Current guidelines support the use of aspirin, ACE inhibitors, statins and beta-blockers for the secondary prevention of cardiovascular disease in CKD patients, regardless of the stage. A systematic review of the literature has reported the underuse of these secondary prevention medications in CKD patients after MI, although there had been an improvement over recent years [72]. Indeed, a more recent observational study of post-percutaneous coronary intervention (PCI) patients in the UK showed that patients with CKD were equally likely to receive statins and beta-blockers, though the use of ACE inhibitors and ARBs was lower in this group [73 ]. It should be noted that patients who are selected to undergo PCI are likely to have less severe kidney disease. Other observational studies demonstrate that treatment rates with secondary prevention

1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

&&

&

www.co-nephrolhypertens.com

271

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Epidemiology and prevention

medications remains significantly lower in patients with CKD compared with those with normal function, and rates are lowest for patients with CKD stages 4–5 [67 ,68 ]. Given that traditional risk factors do not fully account for the increased risk of cardiovascular mortality in CKD, there has been interest in addressing the nonclassical risk factors to improve the prognosis in patients with renal impairment (summarized in Table 3). Plasma homocysteine levels can be lowered using folate or other B vitamins. Whereas one meta-analysis found that folate treatment in patients with advanced kidney disease significantly reduced the risk of cardiovascular events [74], subsequent meta-analyses have not supported this finding and no RCT has demonstrated a beneficial effect for homocysteine-lowering agents [75,76]. However, RCTs using folate or B vitamins are weakened by the fact that the control group are commonly exposed to the treatment agent in food fortification or nutritional supplements. Several strategies have been employed in an attempt to attenuate the cardiovascular risk associated with CKD mineral-bone disease. Cinacalcet is a calcimimetic used to treat secondary hyperparathyroidism. A large observational trial reported a reduced risk of cardiovascular mortality in haemodialysis patients taking cinacalcet, and there is evidence that the drug attenuates the progression of vascular calcification [78,79]. However, cinacalcet was not found to reduce the risk of death or cardiovascular events in a multicentre RCT of haemodialysis patients with secondary hyperparathyroidism [80]. Moreover, a large meta-analysis demonstrated no reduction in cardiovascular or all-cause mortality with cinacalcet in patients with CKD and indeed substantial side effects, with nausea and hypocalcaemia [77 ]. Recent trials of phosphate binders &&

&&

&&

such as sevelamer have reported some promising results. Sevelamer has been associated with relative stabilization of coronary artery calcification in dialysis patients [81], and has been shown in small RCTs to reduce mortality in both predialysis and dialysis populations [82,83 ]. The mechanism of this beneficial effect is not clear, given that sevelamer treatment was also associated with lower plasma-Creactive protein (CRP), an improved lipid profile and a reduced rate of dialysis inception. Further, largescale RCTs are required to assess the benefit of phosphate binders in minimizing cardiovascular risk in CKD. &&

CONCLUSION The pathogenesis of cardiovascular disease in CKD is complex, involving both classical and nonclassical risk factors. From the evidence available, it is clear that BP and cholesterol-lowering strategies significantly reduce the risk of cardiovascular disease in CKD; however, the benefit is attenuated in advanced CKD. BP control is suboptimal in many stages of CKD, despite high treatment rates, suggesting the need for a different approach and potentially further basic research on the underlying pathogenesis of hypertension with a view to different therapeutic targets. Similarly, the diminished benefit of statins on cardiovascular outcomes in dialysis reflects how a differing disease process may require specific treatments. The use of aspirin in CKD is complicated by uraemia-associated platelet dysfunction and an increased risk of bleeding. Aspirin should, therefore, be reserved for patients with the greatest cardiovascular risk. Trials focussing on the nonclassical risk factors for cardiovascular disease in CKD have largely been disappointing to date.

Table 3. Evidence for targeting nonclassical risk factors in CKD n

Author (year)

Intervention

CKD stage

Relative risk of cardiovascular events (95% confidence interval)

Qin (2011) [74]

3886

Folic acid

4–5

0.85 (0.76–0.96)

Jardine (2012) [75]

4697

Folic acid

3–5

1.01 (0.83–1.23)

Pan (2012) [76]

4836

Homocysteine-lowering therapy

7446

Cinacalcet

Palmer (2013) [77 ] &&

5

0.91 (0.71–1.05)

5ND

0.91 (0.74–1.12)

5D

0.94 (0.74–1.10)

3–5

0.29 (0.06–1.48)a,b

5D

0.97 (0.89–1.05)b

Meta-analyses of randomized controlled trials addressing nonclassical cardiovascular risk factors in the CKD population. 5ND, nondialysis patients with CKD-5; 5D, patients on dialysis; CKD, chronic kidney disease. Data obtained from articles as referenced. a Imprecise effects on cardiovascular mortality in low-quality evidence for small numbers of patients with CKD stages 3–5. b Relative risk of cardiovascular mortality.

272

www.co-nephrolhypertens.com

Volume 23  Number 3  May 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Inadequate cardiovascular risk reduction in CKD Elliott et al.

Acknowledgements No funding was received for this work from any commercial organization or from the National Institutes of Health, the Wellcome Trust, and the Howard Hughes Medical Institute. J.A.M. is in receipt of a Kidney Research UK Fellowship. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hajhosseiny R, Khavandi K, Goldsmith DJ. Cardiovascular disease in chronic kidney disease: untying the Gordian knot. Int J Clin Pract 2013; 67:14–31. 2. Perazella MA, Khan S. Increased mortality in chronic kidney disease: a call to action. Am J Med Sci 2006; 331:150–153. 3. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998; 9 (12 Suppl.):S16–S23. 4. Parikh NI, Hwang SJ, Larson MG, et al. Cardiovascular disease risk factors in chronic kidney disease: overall burden and rates of treatment and control. Arch Intern Med 2006; 166:1884–1891. 5. Coresh J, Wei GL, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med 2001; 161:1207–1216. 6. Sarnak MJ, Coronado BE, Greene T, et al. Cardiovascular disease risk factors in chronic renal insufficiency. Clin Nephrol 2002; 57:327–335. 7. Van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011; 79:1341–1352. 8. Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375:2073–2081. 9. Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380:1662–1673. 10. Mahmoodi BK, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet 2012; 380:1649– 1661. 11. Moody WE, Edwards NC, Chue CD, et al. Arterial disease in chronic kidney & disease. Heart 2013; 99:365–372. This review summarizes the different pathogenesis of cardiovascular disease in CKD and highlights the importance of arteriosclerosis over atherosclerosis. 12. U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013. 13. Perna AF, Ingrosso D, Violetti E, et al. Hyperhomocysteinemia in uremia – a red flag in a disrupted circuit. Semin Dial 2009; 22:351–356. 14. Swaminathan S, Shah SV. Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease. Kidney Int 2011; 80:453–463. 15. Del Vecchio L, Locatelli F, Carini M. What we know about oxidative stress in patients with chronic kidney disease on dialysis – clinical effects, potential treatment, and prevention. Semin Dial 2011; 24:56–64. 16. Ho¨rl WH. Anaemia management and mortality risk in chronic kidney disease. Nat Rev Nephrol 2013; 9:291–301. 17. Eddington H, Kalra PA. The association of chronic kidney disease-mineral bone disorder and cardiovascular risk. J Ren Care 2010; 36 (Suppl. 1):61– 67. 18. Murray AM, Seliger S, Lakshminarayan K, et al. Incidence of stroke before and & after dialysis initiation in older patients. J Am Soc Nephrol 2013; 24:1166– 1173. This observational study demonstrates a peak in stroke rates in the month after initiation of hemodialysis and peritoneal dialysis. 19. British Cardiac Society; British Hypertension Society; Diabetes UK; HEART UK; Primary Care Cardiovascular Society; Stroke Association. JBS. 2 Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Suppl. 5):v1–v52.

20. Scottish Intercollegiate Guidelines Network. Clinical guidelines: risk estimation and the prevention of cardiovascular disease. Edinburgh: SIGN; 2007. 21. Perk J, De Backer G, Gohlke H, et al. 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. 22. National Institute for Health and Care Excellence. MI: Secondary Prevention. CG48. London: National Institute for Health and Care Excellence; 2013. 23. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 2004; 364:937–952. 24. O’Donnell MJ, Xavier D, Liu L, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a casecontrol study. Lancet 2010; 376:112–123. 25. Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane Database Syst Rev 2004; CD003041. 26. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338:b1665. 27. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816. 28. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643–2653. 29. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011; 343:d4169. 30. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. 31. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849–1860. 32. Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355:1575–1581. 33. Bangalore S, Steg G, Deedwania P, et al. b-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012; 308:1340–1349. 34. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med 2007; 356:2388–2398. 35. Kotseva K, Wood D, De Backer G, et al. EUROASPIRE III. Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: cross-sectional survey in 12 European countries. Eur J Cardiovasc Prev Rehabil 2010; 17:530–540. 36. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006; 296:1377–1384. 37. Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int 2006; 70:2021–2030. 38. Ninomiya T, Perkovic V, Turnbull F, et al. Blood pressure lowering and major && cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013; 347:f5680. This meta-analysis demonstrates that lowering blood pressure is effective in reducing cardiovascular events in patients with moderate CKD, and that no one group of antihypertensive agents offers an advantage over another. 39. Heerspink HJ, Ninomiya T, Zoungas S, et al. Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet 2009; 373:1009–1015. 40. Agarwal R, Sinha AD. Cardiovascular protection with antihypertensive drugs in dialysis patients: systematic review and meta-analysis. Hypertension 2009; 53:860–866. 41. Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012; 157:251–262. 42. Palmer SC, Craig JC, Navaneethan SD, et al. 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. 43. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and && renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J 2013; 34:1807–1817. This meta-analysis finds that statin therapy reduces cardiovascular events in patients with CKD, including those on dialysis. 44. Palmer SC, Di Micco L, Razavian M, et al. Antiplatelet agents for chronic && kidney disease. Cochrane Database Syst Rev 2013; 2:CD008834. This Cochrane review finds that aspirin therapy reduces the risk of myocardial infarction in patients with CKD but increases the risk of significant bleeding. The authors conclude that the risks of aspirin therapy outweigh the benefits in patients with early CKD or those with low cardiovascular risk.

1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-nephrolhypertens.com

273

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Epidemiology and prevention 45. Lacson E, Lazarus JM. The association between blood pressure and mortality in ESRD – not different from the general population? Semin Dial 2007; 20:510–517. 46. Balamuthusamy S, Srinivasan L, Verma M, et al. Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis. Am Heart J 2008; 155:791–805. 47. Rakugi H, Ogihara T, Umemoto S, et al. Combination therapy for hypertension in patients with CKD: a subanalysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. Hypertens Res 2013; 36:947–958. 48. Rahman M, Ford CE, Cutler JA, et al. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol 2012; 7:989–1002. 49. Iseki K, Arima H, Kohagura K, et al. Effects of angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial. Nephrol Dial Transplant 2013; 28:1579–1589. 50. Chan KE, Ikizler TA, Gamboa JL, et al. Combined angiotensin-converting enzyme inhibition and receptor blockade associate with increased risk of cardiovascular death in hemodialysis patients. Kidney Int 2011; 80:978–985. 51. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367:2204–2213. 52. Fraser SD, Roderick PJ, McIntyre NJ, et al. Suboptimal blood pressure control & in chronic kidney disease stage 3: baseline data from a cohort study in primary care. BMC Fam Pract 2013; 14:88. This UK primary care cohort study found suboptimal achievement of blood pressure targets in patients with CKD 3. Patients with diabetes and albuminuria had the poorest rates of control. 53. Hill CJ, Cardwell CR, Patterson CC, et al. Chronic kidney disease and & diabetes in the National Health Service: a cross-sectional survey of the UK National Diabetes Audit. Diabet Med 2014; 31:448–454; doi: 10.1111/ dme.12312. [Epub ahead of print] In this UK diabetic audit, achievement of blood pressure targets decreased with advancing CKD stage. 54. Kuznik A, Mardekian J, Tarasenko L. Evaluation of cardiovascular disease && burden and therapeutic goal attainment in US adults with chronic kidney disease: an analysis of national health and nutritional examination survey data, 2001–2010. BMC Nephrol 2013; 14:132. This U.S. survey found worsening attainment of blood pressure targets with advancing CKD stage. In contrast, lipid targets were comparable regardless of the CKD status. The use of both antihypertensive and lipid-lowering agents increased with CKD stage. 55. Foster MC, Rawlings AM, Marrett E, et al. Cardiovascular risk factor burden, & treatment, and control among adults with chronic kidney disease in the United States. Am Heart J 2013; 166:150–156. This U.S. survey demonstrates poor cardiovascular risk factor control in patients with CKD, despite high reported medication use. 56. Sim JJ, Bhandari SK, Shi J, et al. Characteristics of resistant hypertension in a & large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc 2013; 88:1099–1107. In this study, resistant hypertension was positively correlated with kidney disease status. 57. Tanner RM, Calhoun DA, Bell EK, et al. Prevalence of apparent treatment&& resistant hypertension among individuals with CKD. Clin J Am Soc Nephrol 2013; 8:1583–1590. This article demonstrates increasing rates of resistant hypertension with advancing CKD stage. 58. Ito H, Mifune M, Abe M, et al. Hypertension resistant to antihypertensive agents commonly occurs with the progression of diabetic nephropathy in Japanese patients with type 2 diabetes mellitus: a prospective observational study. BMC Nephrol 2012; 13:48. doi: 10.1186/1471-2369-13-48. 59. Lithovius R, Harjutsalo V, Forsblom C, et al. Antihypertensive treatment and & resistant hypertension in patients with type 1 diabetes by stages of diabetic nephropathy. Diabetes Care 2013; 37:709–717. doi: 10.2337/dc13-2023. In this study, uncontrolled hypertension and resistant hypertension in type 1 diabetes was found to increase with worsening diabetic nephropathy. 60. De Nicola L, Gabbai FB, Agarwal R, et al. Prevalence and prognostic role of && resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol 2013; 61:2461–2467. In this prospective study of hypertensive CKD patients, true resistant hypertension was associated with increased cardiovascular risk. 61. 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. 62. Wanner C, Krane V, Ma¨rz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238–248. 63. Fellstro¨m BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:1395–1407. 64. Baigent C, Landray MJ, Reith C. 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. doi: 10.1016/S0140-6736(11)60739-3.

274

www.co-nephrolhypertens.com

65. Gremmel T, Mu¨ller M, Steiner S, et al. Chronic kidney disease is associated with increased platelet activation and poor response to antiplatelet therapy. Nephrol Dial Transplant 2013; 28:2116–2122. This in-vitro study demonstrated that patients with CKD had increased baseline platelet activation and a reduced response to dual antiplatelet therapy compared with patients without CKD. 66. Lin TH, Lai WT, Hsin HT, et al. Effects of clopidogrel on mortality, cardio& vascular and bleeding outcomes in patients with chronic kidney disease – data from Taiwan Acute Coronary Syndrome Full Spectrum Registry. PLoS One 2013; 8:e71917. This Taiwanese study found that clopidogrel reduced mortality and cardiovascular events in CKD patients after acute coronary syndrome, without an increased bleeding rate. 67. Nauta ST, van Domburg RT, Nuis RJ, et al. Decline in 20-year mortality after && myocardial infarction in patients with chronic kidney disease: evolution from the prethrombolysis to the percutaneous coronary intervention era. Kidney Int 2013; 84:353–358. This study demonstrates that patients with CKD stages 4–5 are less likely to receive reperfusion therapy, aspirin, beta-blockers or statins after myocardial infarction. 68. Vo¨ller H, Gitt A, Jannowitz C, et al. Treatment patterns, risk factor control and && functional capacity in patients with cardiovascular and chronic kidney disease in the cardiac rehabilitation setting. Eur J Prev Cardiol 2014; doi:10.1177/ 2047487313482285. [Epub ahead of print] In this article, compared with patients with normal renal function, patients with CKD were less likely to receive PCI, statins, beta-blockers, antiplatelets or ACE inhibitors in the cardiac rehabilitation setting. 69. McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material&& induced nephropathy: causal or coincident phenomenon? Radiology 2013; 267:106–118. doi: 10.1148/radiol.12121823. In this retrospective study of patients undergoing CT scans, the incidence of acute kidney injury was not found to be different between patients who received contrast agents and those who did not. 70. Badve SV, Roberts MA, Hawley CM, et al. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58:1152–1161. 71. Bae EH, Lim SY, Cho KH, et al. GFR and cardiovascular outcomes after acute myocardial infarction: results from the Korea Acute Myocardial Infarction Registry. Am J Kidney Dis 2012; 59:795–802. 72. Cardinal H, Madore F. [Are cardioprotective drugs underused after a myocardial infarction in patients who suffer from chronic kidney disease?]. Nephrol Ther 2010; 6:162–170. 73. Zachariah D, Brown R, Kanagala P, et al. The impact of age and chronic kidney & disease on secondary prevention post primary percutaneous coronary intervention (PPCI). QJM 2013; 107:185–192. In this UK study, the uptake of secondary prevention medications was high after PCI, irrespective of age or CKD. 74. Qin X, Huo Y, Langman CB, et al. Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis. Clin J Am Soc Nephrol 2011; 6:482–488. 75. Jardine MJ, Kang A, Zoungas S, et al. The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis. BMJ 2012; 344:e3533. 76. Pan Y, Guo LL, Cai LL, et al. Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials. Br J Nutr 2012; 108:400–407. 77. Palmer SC, Nistor I, Craig JC, et al. Cinacalcet in patients with chronic kidney && disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med 2013; 10:e1001436. This meta-analysis found that cinacalcet did not significantly reduce all-cause or cardiovascular mortality in patients with CKD. 78. Block GA, Zaun D, Smits G, et al. Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients. Kidney Int 2010; 78:578–589. 79. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011; 26: 1327–1339. 80. Chertow GM, Block GA, Correa-Rotter R, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482–2494. 81. Kakuta T, Tanaka R, Hyodo T, et al. Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients. Am J Kidney Dis 2011; 57:422–431. 82. Di Iorio B, Bellasi A, Russo D, INDEPENDENT Study Investigators. Mortality in kidney disease patients treated with phosphate binders: a randomized study. Clin J Am Soc Nephrol 2012; 7:487–493. 83. Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in && incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am J Kidney Dis 2013; 62:771–778. This small randomized controlled trial found that sevelamer versus calcium carbonate significantly reduced arrhythmia-related and all-cause cardiovascular mortality in haemodialysis patients. &

Volume 23  Number 3  May 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.