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Renal function, atherothrombosis extent, and outcomes in high-risk patients Raphaelle L. Dumaine, MD, a Gilles Montalescot, MD, PhD,a Ph. Gabriel Steg, MD, b E. Magnus Ohman, MD, c Kim Eagle, MD, d and Deepak L. Bhatt, MD, MPHe on behalf of the REACH Registry Investigators Paris, France; Durham, NC; Ann Arbor, MI; and Boston, MA Background Although prior data showed an association between chronic kidney disease (CKD) and atherothrombotic events, little is known about the risk profile and specific outcomes of atherothrombotic outpatients with CKD. Methods More than 69,000 outpatients at risk of atherothrombotic events were enrolled in the REACH Registry. Creatinine clearance (CrCl) was available for 51,208 patients divided into 4 groups: normal (CrCl ≥90 mL/min, n = 13,949), mild (6089 mL/min, n = 19,474), moderate (30-59 mL/min, n = 15,883), and severe CKD (CrCl <30 mL/min, n = 1902). Baseline characteristics, number of arterial beds overtly affected, medications, overall mortality, cardiovascular death, myocardial infarction, stroke, congestive heart failure, peripheral arterial events, and bleeding events were assessed according to renal function. Results The number of arterial beds affected increased with severity of CKD. However, patients with severe CKD were less likely to receive medications of proven benefit. Severe CKD was an independent correlate of all-cause mortality, cardiovascular mortality, myocardial infarction, congestive heart failure, peripheral arterial revascularization, or amputation. Conclusion One third of outpatients at risk for atherothrombotic events have moderate to severe CKD. They are less likely to receive beneficial therapies despite a higher atherothrombotic burden and worse outcomes. (Am Heart J 2009;158:141-148.e1.) Since the first publication by Lindner et al,1 the development of accelerated atherothrombosis in patients with severe chronic kidney disease (CKD) has been well documented: clinical trials and registries show an association between CKD and adverse cardiovascular (CV) events among both community-based 2,3 and hospitalized unstable patients.4-6 However, little is known about the risk profile, medical management, and outcomes of atherothrombotic outpatients with CKD. The objectives of this study are to assess the prevalence of CKD in patients presenting with risk factors or manifestations of atherothrombotic disease and to describe according to renal function the number of arterial beds involved and type of atherothrombosis, the quality of care delivered, and the prognosis of these patients. From the a Pitié-Salpêtrière University Hospital, Paris, France, b Bichat-Claude Bernard University Hospital, Paris, France, cDuke University, Durham, NC, dUniversity of Michigan Cardiovascular Center, Ann Arbor, MI, and eVA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA. See Appendix (available online) for a complete listing of REACH Registry Investigators. Submitted December 10, 2008; accepted May 2, 2009. Reprint requests: Gilles Montalescot, MD, PhD, Institut de Cardiologie, CHU PitiéSalpêtrière, 47 boul de l'Hôpital, 75013 Paris, France. E-mail: [email protected] 0002-8703/$ - see front matter © 2009 Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.05.011 Methods Study design The REACH Registry is an international, prospective, observational registry designed to provide up to 24 months of clinical follow-up. The design and methodology of the REACH Registry have been published previously.7,8 Briefly, consecutive eligible outpatients aged 45 years, with established coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD), or with at least 3 atherothrombotic risk factors were enrolled. Documented CAD consisted of ≥1 of the following criteria: stable angina or history of unstable angina with established CAD, history of percutaneous or surgical myocardial revascularization, or previous myocardial infarction (MI). Documented CVD consisted of a hospital or neurologist report with the diagnosis of transient ischemic attack or ischemic stroke. Documented PAD consisted of one or both criteria: current intermittent claudication with ankle brachial index (ABI) of <0.9 or a history of intermittent claudication together with a previous and related percutaneous or surgical intervention, including amputation. The risk factors consisted of those that were documented in the medical record or for which patients were receiving treatment at the time of study enrolment: treated diabetes mellitus, diabetic nephropathy, ABI of <0.9, asymptomatic carotid stenosis of ≥70%, carotid intima media thickness exceeding twice that of adjacent sites, systolic blood pressure of ≥150 mm Hg despite therapy for at least 3 months, hypercholesterolemia treated with medication, current smoking of at least 15 cigarettes per day, men aged ≥65 years, or women aged ≥70 years. Patients already in a clinical trial, hospitalized patients, 142 Dumaine et al or those who might have difficulty returning for a follow-up visit were excluded from enrolment. Study sample and data source A total of 69,055 patients were enrolled in 5,473 sites in 44 countries worldwide between December 2003 and June 2004. Creatinine clearance (CrCl) was available in 51,208 patients. Estimates of CrCl were made using the Cockcroft-Gault equation.9 Patients were classified as follows: normal (≥90 mL/ min), mildly impaired (60-89 mL/min), moderately impaired (3059 mL/min), and severely impaired CrCl (<30 mL/min), as defined by the Kidney Disease Outcome Quality Initiative.10 Data regarding baseline characteristics, treatment strategies during follow-up as well as clinical end points were collected centrally using a standardized international case report form completed at the study visit. The protocol of the REACH Registry was submitted to the institutional review board in each country according to local requirements, and signed informed consent was obtained for all patients. The protocol of the present study was submitted to and approved by the REACH Publication Committee in May 2005 before all data were collected. Sources of funding The REACH Registry is sponsored by sanofi-aventis (Paris, France), Bristol-Myers Squibb (Princeton, NJ), and the Waksman Foundation (Tokyo, Japan). The sponsors provide logistical support. All the publication activity is controlled by the REACH Registry Global Publication Committee (see Appendix for details). The REACH Registry enforces a no-ghost-writing policy. All manuscripts in the REACH Registry are prepared by independent authors who are not governed by the funding sponsors and are reviewed by an academic publication committee before submission. The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the article, and its final contents. Statistical analysis Continuous variables are expressed as mean (SD). Categorical variables are expressed as frequencies and percentages. Comparisons between categorical variables were performed using the Pearson χ2 test. For continuous variables, regression analysis was performed to test linear trend between the 4 CrCl groups. Multivariable logistic regression was used for the analysis of 1-year clinical end points, adjusting for clinical differences in atherothrombotic risk factors at baseline: CrCl subgroups, age (as continuous variable), gender, hypertension, diabetes, smoking status, and hypercholesterolemia. Statistical significance was considered as a 2-tailed probability of <.05. Statistical analysis was performed using SAS Software v8 (SAS Institute Inc, Cary, NC). Results Demographics Table I presents baseline characteristics of the patients. Normal CrCl was present in less than one third of the overall population (n = 13,949; 27.2%). Advanced CKD American Heart Journal July 2009 was present in more than one third of the population (34.7%), combining moderate CKD in 15,883 (31.0%) patients and severe CKD in 1902 (3.7%) of the patients. A small majority of patients had mildly reduced renal function, representing 38.0% (n = 19,474) of the population. Chronic kidney disease severity increased with age and social isolation (Table I). Except for age and hypertension, other traditional atherothrombotic risk factors were less frequent as CKD severity increased; patients with the worst renal function were more often female, nonsmokers, had a lower body mass index (BMI), waist circumference, and weight, and were less likely to be treated for diabetes or dyslipidemia (all P < .0001). However, the number of patients with diabetic nephropathy and stage 2 hypertension (blood pressure ≥160/100 mm Hg) was more frequent as CKD severity increased (Table II). Other CV events such as a history of congestive heart failure (CHF), supraventricular tachyarrhythmias, aortic valve stenosis, or abdominal aortic aneurysm were all more frequent as CKD severity increased (all P < .0001) (Table I). Atherothrombotic disease burden and location The extent and severity of vascular disease increased with CKD severity: history of atherothrombotic event at any location, low ankle brachial index (ABI) (<0.9), and asymptomatic carotid stenosis were more frequent as CKD increased (Table II, all P < .05). Atherothrombotic disease screening was not systematically performed among all these high-risk patients; as CKD severity increased, there was a stepwise decrease in the evaluation of ABI (not done in 58.7% vs 59.2% vs 60.1% vs 61.0% among patients with CrCl ≥90 60-89, 30-59, <30 mL/min, respectively) as well as screening for significant carotid stenosis (not done in 48.9% vs 48.6% vs 48.9% vs 51.2%, respectively) (Table II, P < .0001 for all). The number of arterial beds affected by atherothrombotic disease was greater with increasing CKD severity (Table II). Most patients had an atherothrombotic event in a single territory, CAD being the most prevalent atherothrombotic location across all CrCl subgroups. Medications according to renal function Statins, other lipid-lowering therapies, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors were all administered less frequently as renal dysfunction increased (P < .0001 for all, Figure 1). There was a stepwise decrease in the use of aspirin as renal dysfunction increased (71.5%, 69.2%, 64.6%, 61.5% among patients with CrCl ≥90, 60-89, 30-59, <30 mL/min, respectively, P < .0001), as opposed to a stepwise increase in the use of other antiplatelet therapies (22.9%, 24.9%, 25.7%, 27.1%, among patients with CrCl ≥90, 60-89, 3059, <30 mL/min respectively, P < .0001). Oral anticoagulants were used more frequently as CKD severity American Heart Journal Volume 158, Number 1 Dumaine et al 143 Table I. Baseline characteristics on inclusion CrCl (mL/min) (n = 51 208) ≥90 (n = 13 949) 60–89 (n = 19 474) 30–59 (n = 15 883) <30 (n = 1902) P (for trend) Mean age ± SD (y) ≥75 y old (%) Female (%) Weight (kg, mean ± SD) Height (m, mean ± SD) BMI⁎ male (kg/m2, mean± SD) BMI⁎ female (kg/m2, mean ± SD) Waist circumference among men (cm, mean ± SD) Waist circumference among women (cm, mean ± SD) Social isolation (%) Social position (%) Full-time employment Part-time employment Unemployed Retired Incapacity History of CHF (%) History of AF/flutter (%) History of aortic valve stenosis (%) History of abdominal aortic aneurysm (%) Physical and biologic characteristics on inclusion SBP (mm Hg, mean SD) DBP (mm Hg, mean ± SD) Albuminuria† (mg/L, mean ± SD) 61.0 ± 8.7 5.9 25.7 93.7 ± 20.3 1.7 ± 0.1 30.9 ± 5.8 34.4 ± 7.5 105.9 ± 16.0 68.1 ± 8.2 20.6 32.6 78.7 ± 14.6 1.7 ± 0.1 27.3 ± 4.0 29.2 ± 5.5 98.4 ± 13.4 75.2 ± 7.7 54.9 48.1 69.3 ± 13.7 1.6 ± 0.1 25.5 ± 3.9 26.2 ± 4.9 95.0 ± 14.0 78.0 ±10.1 67.6 62.4 63.2 ± 15.3 1.6 ± 0.1 24.5 ± 4.5 24.6 ± 5.1 92.6 ± 15.9 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 105.2 ± 18.2 96.4 ± 16.4 90.3 ± 15.6 86.1 ± 14.8 <.0001 15.7 18.7 25.2 28.9 <.0001 34.2 6.3 6.3 41.6 9.1 12.2 7.8 2.3 1.4 15.2 6.7 6.4 64.7 4.4 12.4 9.8 2.9 2.4 5.1 4.6 7.5 76.9 2.8 18.4 14.1 4.3 3.5 4.6 2.7 8.4 75.1 5.8 29.5 16.4 5.2 4.6 <.0001 <.0001 <.0001 <.0001 137 ± 19 80 ± 11 103.5 ± 507.2 137 ± 19 79 ± 11 81.8 ± 312.0 138 ± 20 76 ± 11 135.3 ± 485.0 138 ± 21 74 ± 12 388.2 ± 1003.8 .14 <.0001 <.000 <.0001 AF, Atrial fibrillation; SBP, systolic blood pressure; DBP, diastolic blood pressure. ⁎ Calculated as weight in kilograms divided by the square of height in meters. † Albuminuria was available in 9480 patients. increased (10.2%, 11.6%, 15.0%, 15.1% from normal to severe CKD, respectively, P < .0001). By contrast with βblockers and ACE inhibitors, other antihypertensive therapies—including angiotensin II receptor blockers (ARBs), diuretics, and calcium-channel blockers—were all prescribed more frequently with increasing CKD severity (all P < .0001, Figure 1). Nitrates were also used more frequently as renal function decreased (21.7%, 24.6%, 28.3%, 31.9% from normal to severe CKD respectively, P < .0001). Medications according to atherothrombotic extent In all grades of CrCl, there was a significant increase in the use of antiplatelet therapy with the extent of atherothrombotic disease (Figure 2). When stratifying by the number of vascular beds involved and by renal function, prescription of at least 1 antiplatelet agent was similar across CrCl subgroups in patients who only had risk factors and no prior manifestation of atherothrombosis. However, in patients with atherothrombotic disease in 1 or 2 locations, there was a stepwise decrease in the use of antiplatelet therapy with increasing of CKD severity. In patients with 3 atherothrombotic locations, these differences were no longer observed (Figure 2). Parallel to the decreased use of antiplatelet agents, there was a stepwise increase in the use of oral anticoagulant medication with the extent of atherothrombotic disease. Oral anticoagulant medication was used more frequently as CKD severity increased, except in polyvascular patients in whom the use of oral anticoagulants was similar, irrespective of the level of renal function (20.8%, 20.7%, 25.1%, 22.5%, among patients with CrCl ≥90, 60-89, 3059, <30 mL/min, respectively, P = not significant). The stepwise decrease in the prescription of statins with the increase of CKD severity was observed irrespective of the number of beds affected (data not shown). Use of other medications of proven benefit increased with the number of atherothrombotic beds affected among all CrCl subgroups: β-blockers (eg, among patients with severe CKD, β-blockers were prescribed among 34.9%, 48.5%, 56.7%, 51.0%, of patients with no, 1, 2, or 3 atherothrombotic locations, respectively, P < .001), at least 1 antiplatelet agent (53.2%, 78.6%, 81.3%, 88.2%), or double antiplatelet therapy (2.4%, 13.4%, 19.3%, 22.0%) (P < .001 for all). These medications of proven benefit, however, remained significantly less prescribed among patients with the most severe CKD compared with patients with American Heart Journal July 2009 144 Dumaine et al Table II. Atherothrombotic characteristics on inclusion CrCl (mL/min) (n = 51 208) ≥90 (n = 13 949) 60–89 (n = 19 474) 30–59 (n = 15 883) <30 (n = 1902) P (for trend) Atherothrombotic risk factors ≥65 y old, men (%) ≥70 y old, women (%) Current smoker (%) Treated diabetes (%) Diabetic nephropathy (%) Yes Unknown History of hypertension (%) BP >140/90 mm Hg (%) Hypertension stage 1 (160/100 > BP > 140/90 mm Hg) Hypertension stage 2 (BP ≥160/100 mm Hg) Treated hypercholesterolemia (%) ABI <0.9 (%) Yes Unknown Asymptomatic carotid stenosis ≥70% Yes Unknown Carotid intimal-media thickness (mm, mean ± SD) ABI (mean ± SD) Ischemic disease history (%) TIA Ischemic stroke Stable angina Unstable angina MI PCI CABG Lower limb artery angioplasty or bypass grafting Lower limb amputation Carotid surgery No. of atherothrombotic locations 0 (risk factor only) 1 2 3 Location of atherothrombotic disease Risk factors only CAD only CVD only PAD only CAD + CVD CAD + PAD CVD + PAD CAD + CVD + PAD 32.3 23.1 21.8 48.9 67.8 50.2 15.2 40.2 90.0 79.4 9.8 39.3 84.8 86.4 8.1 42.3 <.0001 <.0001 <.0001 <.0001 <.0001 12.8 18.5 82.1 9.9 19.0 81.1 12.5 19.4 84.6 21.6 17.8 88.6 32.4 33.0 33.0 29.7 16.7 16.0 16.5 19.4 78.5 74.3 70.0 65.7 8.4 58.7 9.0 59.2 11.1 60.1 13.6 61.0 3.7 48.9 1.3 ± 0.7 4.6 48.6 1.3 ± 0.6 5.9 48.9 1.5 ± 0.7 7.3 51.2 1.5 ± 0.7 .17 0.9 ± 0.2 0.9 ± 0.2 0.9 ± 0.2 0.8 ± 0.2 <.0001 10.0 16.1 29.7 13.8 33.8 28.4 19.4 5.4 12.1 19.7 30.6 12.9 31.4 26.4 20.3 6.1 15.1 22.5 30.6 11.9 30.6 22.9 21.6 6.8 17.0 22.5 32.4 13.0 33.9 19.4 23.6 8.8 <.0001 <.0001 .02 <.0001 <.0001 <.0001 <.0001 <.0001 1.6 3.2 1.7 4.2 1.8 5.7 2.9 6.1 <.0001 <.0001 <.0001 22.0 64.9 11.9 1.3 18.5 66.7 13.3 1.5 17.9 63.3 16.8 2.0 15.8 61.8 19.8 2.7 22.0 48.3 13.0 3.7 6.7 4.3 0.9 1.3 18.5 46.1 16.3 4.3 7.8 4.4 1.2 1.5 17.9 41.5 17.3 4.5 10.2 5.1 1.5 2.0 15.8 39.7 16.8 5.3 11.3 7.5 1.0 2.7 <.0001 <.0001 <.0001 <.0001 <.0001 <.0001 BP, Blood pressure; TIA, transient ischemic attack; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft. better renal function, especially in patients with atherothrombosis in 1 or 2 locations. At the 2 extremes of atherothrombotic extent, that is, among patients with risk factors only or among patients with 3 diseased locations, prescription patterns changed: β-blockers were prescribed more frequently as CKD severity increased (eg, among patients with risk factors only, 27.5%, 28.4%, 30.4%, 34.9% in subgroups with CrCl ≥90, 60-89, 30-59, <30 mL/min, respectively, P = .001), and antiplatelet therapy administration did not differ across all CrCl subgroups (54.2%, 55.0%, 54.7%, 53.2% from normal to severe CKD severity, respectively, P = .86). American Heart Journal Volume 158, Number 1 Figure 1 Main medications used depending on renal function. RX, Therapies; HTN, antihypertensive. Figure 2 Antiplatelet therapy prescription stratified by number of atherothrombotic beds affected and creatinine clearance subgroups. One-year atherothrombotic and bleeding events There was an increase in the risk of mortality from any cause, CV death, nonfatal MI, and amputation with increase in CKD severity (Figure 3). There was also a trend toward an increase in non-fatal stroke as renal function decreased, without reaching significance (Figure 3). Finally, hospitalization for CHF occurred more frequently with worsening of CKD (3.7%, 3.0%, 4.1%, 6.2% from normal to severe CKD, respectively, P < .001). Bleeding leading to hospitalization and transfusion was also significantly more frequent as renal function worsened (0.9%, 0.8%, 1.0%, 1.4% from normal to severe CKD respectively, P = .04). Dumaine et al 145 Figure 3 Main adverse atherothrombotic events involving the 3 arterial beds at 1 year among creatinine clearance subgroups. Figure 4 Association between severe chronic kidney disease and adverse outcomes at 1-year follow-up. *Adjusted risk of outcome for severely impaired creatinine clearance versus normal renal function as detailed in the Methods section. In multivariate analysis, severe CKD was independently associated with all-cause mortality, as well as CV mortality (Figure 4). Severe CKD was also an independent correlate of several other end points at 1-year follow-up: nonfatal MI, hospitalization for CHF, as well as PAD revascularization and amputation. In addition, the lowest quartile of CrCl was independently associated with bleeding leading to hospitalization and/or transfusion (Figure 4). Moderately and severely impaired renal functions were independently correlated with the triple composite end point including CV death/MI/stroke (OR 1.89, 95% CI 1.53-2.34, for CrCl <30 mL/min; OR 1.17, 95% CI 1.01-1.34, for CrCl 30-59 mL/min compared with CrCl ≥90 mL/min). Similarly, decreased renal function was 146 Dumaine et al also an independent correlate for the quadruple end point of CV death/MI/stroke/hospitalization (OR 1.54, 95% CI 1.33-1.78, for CrCl <30 mL/min; OR 1.11, 95% CI 1.02-1.21, for CrCl 30-59 mL/min compared with CrCl ≥90 mL/min). Discussion Prior US community-based studies have demonstrated a graded association between the risk of adverse CV outcomes and renal dysfunction.2,3 The present study builds on these results and provides extensive information from the largest database available regarding the prevalence of CKD among stable outpatients with or at risk of atherothrombosis. Associations are also highlighted between renal function and number and type of arterial beds affected, risk profile, medical management, and clinical outcomes among this broad population of >51,000 outpatients. In the current REACH Registry population, prevalence of CKD is high, and less than one third of this population at risk of atherothrombotic events has normal CrCl levels. Most of these stable outpatients already have mild CKD, and more than one third have more severe CKD. In the large US community-based Kaiser Permanente Renal Registry,3 16.8% of the population had moderate CKD and 0.8% had severe CKD after exclusion of kidney transplant recipients or patients receiving maintenance dialysis at entry. In comparison, among the present population, there is a 2-fold increase in the prevalence of CKD with 31.0% and 3.7% of patients having moderate and severe CKD, respectively. These frequencies are as high as those observed among prospective4 or retrospective studies5,6 of patients hospitalized for acute coronary syndromes. This might reflect the strength of the link between the degree of renal dysfunction and the level of the “vascular risk” of the atherothrombotic patient. This emphasizes the need to incorporate renal function evaluation in the management of any patient with atherothrombosis risk or manifestation, including stable outpatients. As severity of CKD increases, there is a stepwise increase in the risk of prior manifestation of atherothrombosis in any of the 3 main arterial beds (CAD, CVD, PAD). Distribution of atherothrombosis locations is similar among all CrCl subgroups, with CAD as the most prevalent location, then CVD, and finally PAD. There is a gradation in the number of arterial beds affected with the severity of CKD; prevalence of prior manifestations in multiple locations of atherothrombosis is almost 2-fold higher in patients with severe CKD than in patients with normal CrCl. Despite the high atherothrombotic risk of these patients, screening for assessment of significant carotid stenosis or abnormal ABI is not performed in most patients; half of the patients did not undergo assessment for significant carotid stenosis, and in 60% of patients, ABI American Heart Journal July 2009 was not estimated. As albuminuria quantification is usually recommended among hypertensive or diabetic patients, to stratify the risk and guide the “aggressivity” of the medical management, discovery of advanced renal dysfunction in a patient at risk of atherothrombosis should be interpreted as an additional major risk factor, leading to a more systematic assessment of the whole arterial bed. Patients with the most severe CKD are also at higher risk of further atherothrombotic events at 1-year follow-up. Of these outpatients, severe CKD is not only independently associated with CV events such as CV death, MI, or acute coronary syndromes, as in previous observations,2,3 but is also an independent correlate of PAD revascularization, amputation, CHF, or significant bleeding. The risk of heart failure was mainly observed in CAD patients with marked renal dysfunction, a triple association of serious concern. Medical management was different depending on the number of arterial beds affected as well as renal function. The lower prescription of ACE inhibitors among patients with renal dysfunction was in part counterbalanced by an increase of ARB's prescription among these patients. Overall, other medications of proven benefit in different settings of atherothrombosis such as antiplatelet therapies, statins, and β-blockers, were prescribed less frequently among patients with CKD. Some confounders may explain in part this observation, for instance, more limited financial resources among patients with CKD who are more likely to be unemployed or retired. However, the same underutilization has been previously observed in other settings, for instance, among patients with acute coronary syndromes during their inhospital stay4,6,11; in this setting, underutilizations of these medications may have been related in part to unstable hemodynamics, comorbidities, and a higher propensity for bleeding. Overall, even if confounders may explain in part the lower prescription of beneficial therapies, the present observation in stable outpatients underscores the need for optimization of prevention of atherothrombotic events among CKD patients. Interestingly, when stratifying by the extent of arterial disease, in each CrCl subgroup, there was a stepwise increase in the prescription of β-blockers, antiplatelet therapy, and ACE inhibitors as the number of arterial beds involved increased. This may be related to the larger number of physicians involved in the patient's care when several atherothrombotic locations are involved, or the higher concern from the physician in charge as atherothrombotic events increase in frequency and diversity. The use of oral anticoagulants increased gradually with the number of arterial beds affected and the increase of CKD severity. This may relate in part to the higher incidence of atrial fibrillation observed with increasing severity of CKD. The large prescription of oral anticoagulants may partly explain the decrease in prescription of antiplatelet agents, as the gradual increase in oral anticoagulant prescription with renal American Heart Journal Volume 158, Number 1 function decrease is paralleled by a gradual decrease in administration of antiplatelet agents. The association between this treatment strategy and the observed increased risk of bleeding in the CKD population warrants further specific investigation. The observed underuse of statin therapy among patients with CKD, irrespective of the number of arterial beds affected, remains challenging as there is no definitive restriction in the use of statins among patients with CKD. The “paradoxical” association of lower cholesterol levels among patients with severe CKD and poor outcomes has been previously reported; poor outcome does not seem to relate to low cholesterol levels per se but to associated bias such as concomitant systemic inflammation and malnutrition.12 Statin therapy has proven to be of benefit in patients with nonsevere CKD,13-15 but not in patients on chronic haemodialysis.16,17 This suggests that statin therapy may be beneficial in CKD patients, at least when started early enough in the evolution of the disease.18 The results of the ongoing SHARP randomized trial (ClinicalTrials.gov number, NCT00125593)19 of simvastatin in addition to ezetimibe versus placebo in a large population of patients with mild to severe CKD is awaited to draw more definitive conclusion. The present analysis has several limitations. Most of them are inherent to the nature of a registry. Data collection and patients' recruitment may have been biased by unknown cofounders, highly dependent on the investigating center. However, the large size of the current international multicenter registry may have diluted these potential biases. Despite the diversity and extent of recruitment worldwide, some important ethnic groups, including African and Chinese populations, were underrepresented in the REACH Registry. The present findings may thus not be extrapolated to these particular groups. While it can be argued that, at times, absolute differences between CrCl subgroups represented only a few percentages, it is noteworthy that these differences are significant, repeated among almost all studied end point, and particularly marked when the subgroup of patients with the worst renal function is compared with patients with normal renal function. In conclusion, CKD is frequent among stable outpatients at high atherothrombotic risk, with one third of this population presenting with moderate to severe kidney dysfunction. There is a gradual association between CKD severity and the number of arterial atherothrombotic beds affected, translating into a higher risk of atherothrombotic events among patients with severe CKD, particularly in patients with disease in 3 arterial beds. Despite this association between CKD and atherothrombotic events, patients with renal dysfunction are less likely to undergo extensive vascular risk assessment and to receive beneficial therapies, especially if they present with limited atherothrombotic disease. Focus should be made toward greater screening for CKD among patients at high Dumaine et al 147 atherothrombotic risk and optimization of medical management to improve primary and secondary prevention. Acknowledgements We thank the REACH Editorial Support Group for providing editorial help. The REACH Registry is endorsed by the World Heart Federation. Statistical evaluations were performed by Alain-Jean Richard, Sanofi-Aventis, Paris, France. Disclosures Dr R. Dumaine had full access to the data of the present study and takes responsibility for the integrity of the data and accuracy of the data analysis. The authors are fully responsible for the content and editorial decisions for this manuscript. Dr Dumaine has no disclosure information to declare. Dr Montalescot discloses the following relationships: Grant support – sanofi-aventis (Paris, France), Eli Lilly (Indianapolis, IN), Guerbet (Villepinte, France), Pfizer (New York, NY), and Bristol-Myers Squibb (New York, NY); Consulting fees – sanofi-aventis, Eli Lilly, BristolMyers Suibb, Merck Sharpe & Dohme (Whitehouse Station, NJ), Proctor & Gamble (Cincinnati, OH), AstraZeneca (London, United Kingdom), GlaxoSmithKline (Uxbridge, United Kingdom), Medicines Company (Parsippany, NJ), and Schering-Plough (Kenilworth, NJ); Lecture fees – sanofi-aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, GlaxoSmithKline and Nycomed (Zurich, Switzerland). Dr Steg discloses the following relationships: Research Grant – sanofi-aventis; Speakers bureau – BoehringerIngelheim (Ingelheim, Germany), Bristol-Myers Suibb, GlaxoSmithKline, Nycomed, sanofi-aventis, Servier (Suresnes, France), ZLB-Behring (King of Prussia, PA); Consulting/advisory board – AstraZeneca, BoehringerIngelheim, Bristol-Myers Suibb, GlaxoSmithKline, Merck Sharpe & Dohme, Nycomed, sanofi-aventis, Servier, Takeda (Osaka, Japan), The Medicines Company. Dr Ohman discloses the following relationships: Grant support – Bristol-Myers Squibb, sanofi-aventis, ScheringPlough, Millennium Pharmaceuticals (Cambridge, MA), Eli Lilly, Berlex (Wayne, NJ); Consulting fees – Inovise (Beaverton, OR) and Savacor (Los Angeles, CA); Shareholder – Inovise, Savacor and Medtronic (Minneapolis, MN); Speaker's Bureau – CV Therapeutics (Palo Alto, CA) and Schering Plough. Dr Eagle discloses the following relationships: Grant support – Biosite (San Diego, CA), Bristol-Myers Squibb, Cardiac Sciences (Bothell, WA), Blue Cross Blue Shield of Michigan (Detroit, MI), Hewlett Foundation (Menlo Park, CA), Mardigian Fund (Detroit, MI), Pfizer, sanofi-aventis, Varbedian Fund (Ann Arbor, MI); Consulting fees – NIH NHLBI (Bethesda, MD), Pfizer, sanofi-aventis, Robert Wood Johnson Foundation (Princeton, NJ). 148 Dumaine et al Dr. Bhatt discloses the following relationships: Research Grants (directly to the institution) – Bristol Myers Squibb, Eisai (Tokyo, Japan), Ethicon (Somerville, NJ), sanofi-aventis, The Medicines Company; Honoraria (currently donated to non-profits) – Astra Zeneca, Bristol Myers Squibb, Centocor (Horsham, PA), DaiichiSankyo (Tokyo, Japan), Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix (Tucson, AZ), PDL (Incline Village, NV), sanofi-aventis, Schering Plough, The Medicines Company, TNS Healthcare (London, United Kingdom); Speaker's bureau (not current, over 2 years ago) – Bristol Myers Squibb, sanofi-aventis, The Medicines Company; Consultant/Advisory Board (currently donated to non-profits) – Astra Zeneca, Bristol Myers Squibb, Cardax (Aiea, HI), Centocor, Cogentus (Menlo Park, CA), Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson (Raritan, NJ), McNeil (Raritan, NJ), Medtronic, Millennium, Otsuka (Tokyo, Japan), Paringenix, PDL, Portola (San Francisco, CA), sanofi-aventis, Schering Plough, The Medicines Company, TNS Healthcare, Vertex (Cambridge, MA); Expert testimony regarding clopidogrel (the compensation was donated to a non-profit organization). References 1. Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290: 697-701. 2. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47-55. 3. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305. 4. Dumaine R, Collet JP, Tanguy ML, et al. Prognostic significance of renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study). Am J Cardiol 2004;94:1543-7. 5. Gibson CM, Dumaine RL, Gelfand EV, et al. Association of glomerular filtration rate on presentation with subsequent mortality in non ST-segment elevation acute coronary syndrome; observations in 13,307 patients in five TIMI trials. Eur Heart J 2004;25: 1998-2005. American Heart Journal July 2009 6. Santopinto JJ, Fox KA, Goldberg RJ, et al. Creatinine clearance and adverse hospital outcomes in patients with acute coronary syndromes: findings from the global registry of acute coronary events (GRACE). Heart 2003;89:1003-8. 7. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180-9. 8. Ohman EM, Bhatt DL, Steg PG, et al. The REduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events-study design. Am Heart J 2006;151:786. e1-786.e10. 9. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. 10. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089-100. 11. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with endstage renal disease and an acute myocardial infarction. J Am Coll Cardiol 2003;42:201-8. 12. Liu Y, Coresh J, Eustace JA, et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004;291:451-9. 13. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7-22. 14. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58. 15. Tonelli M, Moye L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003;138:98-104. 16. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238-48. 17. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407. 18. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45: S1-S153. 19. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003;84:S207-10. American Heart Journal Volume 158, Number 1 Appendix A. REACH Registry Global Publication Committee Mark Alberts, MD, Northwestern University Medical School, Chicago; Deepak L. Bhatt, MD, VA Boston Healthcare System and Brigham and Women's Hospital, Boston, Massachusetts(chair); Ralph D'Agostino, MD, Boston University, Boston; Kim Eagle, MD, University of Michigan, Ann Arbor, Michigan; Shinya Goto, MD, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Alan T. Hirsch, MD, Minneapolis Heart Institute Foundation and Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis; Chiau-Suong Liau, MD, PhD, Taiwan University Hospital and College of Medicine, Taipei; Jean-Louis Mas, MD, Centre Raymond Garcin, Paris, France; E. Magnus Ohman, MD, Duke University Medical Center, Durham, NC; Joachim Röther, MD, Klinikum Minden, Minden, Germany; Sidney C. Smith, MD, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; P. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris, France (chair); Peter W. F. Wilson, MD, Emory University School of Medicine, Dept of Medicine, Cardiology Division Atlanta, Georgia. National Coordinators Australia: Christopher Reid, Victoria. Austria: Franz Aichner, Linz; Thomas Wascher, Graz. Belgium: Patrice Laloux, Mont-Godinne. Brazil: Denilson Campos de Albuquerque, Rio de Janeiro. Bulgaria: Julia Djorgova, Dumaine et al 148.e1 Sofia. Canada: Eric A. Cohen, Toronto, Ontario. Chile: Ramon Corbalan, Santiago. China: Chuanzhen LV, Frederiksberg. Finland: Ilkka Tierala, Helsinki. France: Jean-Louis Mas, Patrice Cacoub and Gilles Montalescot, Paris. Germany: Klaus Parhofer, Munich; Uwe Zeymer, Ludwigshafen; Joachim Röther, Minden. Greece: Moses Elisaf, Ioannina. Interlatina (Guatemala): Romulo Lopez, Guatemala City. Hong Kong: Juliana Chan, Shatin. Hungary: György Pfliegler, Debrecen. Indonesia: Bambang Sutrisna, Jakarta. Israel: Avi Porath, Beer Sheva. Japan: Yasuo Ikeda, Tokyo. Lebanon: Ismail Khalil, Beirut. Lithuania: Ruta Babarskiene, Kaunas. Malaysia: Robaayah Zambahari, Kuala Lumpur. Mexico: Efrain Gaxiola, Jalisco. The Netherlands: Don Poldermans, Rotterdam. Philippines: Maria Teresa B. Abola, Quezon City. Portugal: Victor Gil, Amadora. Romania: Constantin Popa, Bucharest. Russia: Yuri Belenkov and Elizaveta Panchenko, Moscow. Saudi Arabia: Hassan ChamsiPasha, Jeddah. Singapore: Yeo Tiong Cheng, Singapore. South Korea: Oh Dong-Joo, Seoul. Spain: Carmen Suarez, Madrid. Switzerland: Iris Baumgartner, Bern. Taiwan: Chiau-Suong Liau, Taipei. Thailand: Piyamitr Sritara, Bangkok. United Arab Emirates: Wael Al Mahmeed, Abu Dhabi. United Kingdom: Jonathan Morrell, Hastings. Ukraine: Vira Tseluyko, Kharkov. United States: Mark Alberts, Chicago, IL; Robert M. Califf, Durham, NC; Christopher P. Cannon, Boston, MA; Kim Eagle, Ann Arbor, MI; Alan T. Hirsch, Minneapolis, MN. The list of REACH Registry investigators is accessible online at www.reach-registry.org.