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Chronic Kidney Disease, Cardiovascular Events, and the Effects of Perindopril-Based Blood Pressure Lowering: Data from the PROGRESS Study

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Chronic Kidney Disease, Cardiovascular Events, and the Effects of Perindopril-Based Blood Pressure Lowering: Data from the PROGRESS Study CLINICAL RESEARCH www.jasn.org Chronic Kidney Disease, Cardiovascular Events, and the Effects of Perindopril-Based Blood Pressure Lowering: Data from the PROGRESS Study Vlado Perkovic,*† Toshiharu Ninomiya,* Hisatomi Arima,* Martin Gallagher,* Meg Jardine,* Alan Cass,*‡ Bruce Neal,* Stephen MacMahon,*‡ and John Chalmers*‡ *George Institute for International Health, University of Sydney, †Royal North Shore Hospital, and ‡Royal Prince Alfred Hospital, Sydney, Australia ABSTRACT Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease, but evidence regarding the effectiveness of interventions to reduce that risk is lacking. The Perindopril Protection against Recurrent Stroke Study (PROGRESS) study enrolled 6105 participants with cerebrovascular disease and randomly allocated them to perindopril-based blood pressure–lowering therapy or placebo. Individuals with CKD were at approximately 1.5-fold greater risk of major vascular events, stroke, and coronary heart disease, and were more than twice as likely to die (all PՅ0.002). Perindopril-based treatment reduced the risk of major vascular events by 30% and stroke by 35% among subjects with CKD, and the absolute effects of treatment were 1.7-fold greater for those with CKD than for those without. Considering patients with CKD and a history of cerebrovascular disease, perindopril prevented one stroke or other cardiovascular event among every 11 patients treated over five years. In conclusion, kidney function should be considered when determining the need for blood pressure lowering therapy in patients with cerebrovascular disease. J Am Soc Nephrol 18: 2766–2772, 2007. doi: 10.1681/ASN.2007020256 Chronic kidney disease (CKD) is being increasingly monly elevated in people with CKD, raising the recognized as a leading public health problem. possibility that BP lowering may offer significant CLINICAL RESEARCH CKD, most commonly defined by a reduction in benefit in this group. BP-lowering agents acting via GFR or the presence of proteinuria, affects 10 to the renin-angiotensin system have been demon- 15% of the adult population in Western countries strated to have renoprotective effects in the protein- and a much higher proportion of individuals who uric subgroup of people with CKD.6,7 The few BP- are older than 65 yr.1,2 lowering trials that have been conducted in a Individuals with CKD are at significantly in- broader range of participants with CKD8–10 have creased risk for cardiovascular events as well as pro- not demonstrated clear benefits for either cardio- gression to end-stage kidney disease. This relation- vascular events or kidney function overall. Subsid- ship has been confirmed in a large number of iary analyses of one large clinical trial11 suggested observational analyses3 and persists after adjust- ment for other known risk factors. There is, how- Received February 28, 2007. Accepted May 24, 2007. ever, a lack of data regarding the effects of interven- Published online ahead of print. Publication date available at tions such as BP lowering on cardiovascular risk in www.jasn.org. the CKD population. Correspondence: Dr. Vlado Perkovic, George Institute for Inter- BP is an important determinant of cardiovascu- national Health, PO Box M201, Sydney, Australia, 2050. Phone: lar risk in the general population,4 in which inter- ϩ612-9993-4523; Fax: ϩ612-9993-4501; E-mail: vperkovic@ ventions that lower BP have been clearly shown to thegeorgeinstitute.org prevent cardiovascular events.5 BP levels are com- Copyright © 2007 by the American Society of Nephrology 2766 ISSN : 1046-6673/1810-2766 J Am Soc Nephrol 18: 2766–2772, 2007 www.jasn.org CLINICAL RESEARCH that angiotensin-converting enzyme inhibitors may produce entry to the study. A total of 1058 participants experienced greater benefits in the presence of CKD. However, a number of major vascular events (some participants experienced more other studies that used agents acting via the RAS and were than one event) during an average of 4 yr of follow up, includ- performed specifically in participants with CKD, all with lim- ing 724 strokes, 268 major coronary heart disease events, and a ited statistical power, failed to demonstrate clear cardiovascu- total of 621 deaths. lar benefits.10,12–14 The baseline characteristics of participants overall and ac- In this report, we describe the results of new analyses cording to the presence of CKD at baseline are shown in Table from the Perindopril Protection against Recurrent Stroke 1. Overall, the participants with CKD at entry were older, more Study (PROGRESS), a large, placebo-controlled trial of a likely to be female and have preexisting coronary disease, but perindopril-based BP-lowering regimen in people with pre- less likely to have diabetes, with lower body mass index and vious cerebrovascular disease. The aims of this analysis were diastolic BP but higher systolic BP. Participants with CKD re- to examine the relationship between CKD and cardiovascu- ceived single-drug therapy (perindopril versus single placebo) lar events in participants with cerebrovascular disease and more frequently than those without CKD (60 versus 54%; P Ͻ to assess the effects of the BP-lowering regimen on cardio- 0.0001). vascular events in the subgroup of participants with CKD at baseline. Effects of Kidney Function on the Risk for Cardiovascular Events An increased risk for cardiovascular events was observed in RESULTS the participants with CKD at baseline (Figure 1), with an overall hazard ratio (HR) of 1.58 for major cardiovascular A total of 6105 participants were recruited from 172 centers in events (95% confidence interval [CI] 1.34 to 1.79; P Ͻ 10 countries, and baseline kidney function was available for 0.0001). After adjustment for a number of relevant covari- 6071 (99.4%). A total of 1757 (28.9%) participants had CKD at ates (age, gender, smoking, diabetes, systolic BP, body mass Table 1. Baseline characteristics of participants overall and according to kidney function at study entrya Overall CrCl <60 ml/min CrCl >60 ml/min Characteristic Pb (4314 ؍ n) (1757 ؍ n) (6071 ؍ n) Age (yr; mean Ϯ SD) 64 Ϯ 10 70 Ϯ 861Ϯ 9 Ͻ0.0001 Women (%) 30 45 25 Ͻ0.0001 Asian (%)c 38 37 39 0.4 Creatinine (␮mol/L; median ͓IQR͔) 88 (75 to 100) 102 (88 to 120) 83 (71 to 95) Ͻ0.0001 Creatinine clearance (ml/min; median ͓IQR͔) 72 (58 to 89) 50 (45 to 56) 81 (70 to 96) Ͻ0.0001 Body mass index (kg/m2; 26 Ϯ 424Ϯ 326Ϯ 4 Ͻ0.0001 mean Ϯ SD) Systolic BP (mmHg; mean Ϯ SD) 147 Ϯ 19 149 Ϯ 20 146 Ϯ 19 Ͻ0.0001 Diastolic BP (mmHg; mean Ϯ SD) 86 Ϯ 11 84 Ϯ 11 86 Ϯ 11 Ͻ0.0001 Medical history (%) ischemic stroke 70 71 70 0.6 hemorrhagic stoke 11 10 11 0.04 stroke of unknown type 5 7 4 Ͻ0.0001 transient ischemic attack 22 22 23 0.5 coronary heart diseased 16 20 15 0.01 diabetes 13 11 13 0.01 current smoker 20 16 22 Ͻ0.0001 Medication (%) antihypertensive therapye 50 53 49 0.002 antiplatelet therapy 72 73 72 0.3 oral anticoagulants 9 10 9 0.4 lipid-lowering therapy 14 12 15 0.006 Study treatment regimen (%) active therapy 50 51 50 0.3 combination therapy or double placebos 58 54 60 Ͻ0.0001 aIQR, interquartile range. bDifferences between patients with and without CKD. cParticipants recruited from People’s Republic of China or Japan. dHistory of myocardial infarction or coronary revascularization or of angina (supported by documented electrocardiographic or angiographic evidence). eCurrent treated hypertension. J Am Soc Nephrol 18: 2766–2772, 2007 PROGRESS: BP Lowering in CKD 2767 CLINICAL RESEARCH www.jasn.org Figure 1. Proportion of participants who experienced major vascular events during follow-up according to baseline kidney function. index, active versus placebo therapy, and single- versus dual- agent therapy), CKD was associated with an HR of 1.29 for major cardiovascular events (95% CI 1.11 to 1.49; P ϭ 0.001). The risk for stroke was similarly increased, with a crude HR of 1.49 (95% CI 1.28 to 1.73; P Ͻ 0.0001) and an adjusted HR of 1.21 (95% CI 1.01 to 1.45; P ϭ 0.04). For coronary heart disease, a crude HR of 1.48 (95% CI 1.15 to 1.90; P ϭ 0.002) and an adjusted HR of 1.42 (95% CI 1.05 to 1.91; P ϭ 0.02) were observed. The risk for both total mor- tality (crude HR 2.27 [95% CI 1.94 to 2.66; P Ͻ 0.0001]; adjusted HR 1.43 [95% CI 1.18 to 1.73; P ϭ 0.0003]) and cardiovascular mortality (crude HR 2.13 [95% CI 1.74 to 2.61; P ϭ 0.006]; adjusted HR 1.48 [95% CI 1.16 to 1.90; P ϭ 0.002]) were also increased in the presence of CKD. A more detailed breakdown in the relationship between kidney function at baseline and subsequent cardiovascular events and death is shown in Figure 2, demonstrating a progressive increase in the risk for each end point with decreasing levels of kidney function. Effects of Perindopril-Based Therapy on Cardiovascular Events According to Kidney Function The administration of a perindopril-based BP-lowering reg- imen produced similar reductions in the risk for major car- diovascular events at all levels of baseline kidney function (Figures 3 and 4). The hazard ratio (HR) for major cardio- vascular events was reduced by 30% (95% CI 14 to 42%) in participants with CKD at baseline, compared with 26% in ϭ people without CKD (95% CI 14 to 37%; P 0.9 for homo- Figure 2. Crude and adjusted (adjusted for baseline age, gen- geneity). Individuals with CKD also had similar reductions der, smoking, diabetes, systolic BP, study treatment, and combi- in the HR for stroke and coronary heart disease (Figure 4) as nation therapy) risk for major cardiovascular events, stroke, coro- participants with better kidney function.
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