Johannes F.E. Mann

Effect of the Angiotensin-Converting–Enzyme Inhibitor Benazepril on the Progression of Chronic Renal Insufficiency

Background Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic nephropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting–enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases. Methods In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46 to 60 ml per minu...

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril : the HOPE randomized trial

The future rate of cardiovascular events can be predicted by several well-established risk factors. Even in the absence of classic risk factors, patients with renal disease have an elevated risk for cardiovascular disease (1, 2). This renalcardiovascular association is well established in patients with advanced renal insufficiency (2). It has also been reported in patients in the Hypertension Detection and Follow-up Program (HDFP) (3), in which a serum creatinine concentration greater than 133 mol/L (1.5 mg/dL) was a strong predictor of cardiovascular disease. However, HDFP included only patients with hypertension. In contrast, a recent analysis of data from the Framingham Study did not detect a relationship between mild renal insufficiency (defined as a serum creatinine concentration of 124 to 265 mol/L [1.4 to 3.0 mg/dL]) and cardiovascular events (4). The Heart Outcomes and Prevention Evaluation (HOPE) study investigated the effects of ramipril and vitamin E on major cardiovascular outcomes in 9297 patients at high risk, including those with serum creatinine concentrations up to 200 mol/L (2.3 mg/dL) (5-7). Our study examined the hypothesis that previous evidence of renal disease (that is, an elevated serum creatinine concentration 124 mol/L [ 1.4 mg/dL]) would independently predict future cardiovascular disease. Since the connection between renal and cardiovascular disease is known to exist in patients with diabetes mellitus and those with hypertension, we analyzed nondiabetic and normotensive patients separately. We also examined whether ramipril continued to be effective in patients with impaired renal function. This was done to determine whether the common clinical practice of withholding angiotensin-converting enzyme (ACE) inhibitors in patients with impaired renal excretory function is justified. Methods Patients The design and primary outcomes of the HOPE study have been described elsewhere (5-7). Briefly, men and women at least 55 years of age from 267 centers were included if they had objective evidence of vascular disease or diabetes combined with another cardiovascular risk factor. The main exclusion criteria were heart failure, intolerance of ACE inhibitors or vitamin E, a serum creatinine concentration greater than 200 mol/L (2.3 mg/dL), or dipstick-positive proteinuria (>1+). Patients were treated with ramipril, vitamin E, or placebo in a double-blind, 2 2 factorial design. Follow-up was 3.5 to 5.5 years (median, 4.5 years), and the primary outcome measure was the incidence of cardiovascular death, myocardial infarction, or stroke. Secondary outcome measures included total mortality, hospitalization for heart failure, and revascularization. At the time of randomization, urine albumin level and creatinine concentration were measured once in all patients at four central laboratories. The ratio of urine albumin to creatinine was calculated, and a value of at least 2 mg/mmol was defined as microalbuminuria. Serum creatinine concentration was measured in all patients at local laboratories at the time of randomization. Renal Insufficiency Recent data suggest that in patients older than 55 years of age, a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) is a good indicator of a glomerular filtration rate less than 80 mL/min (8). Therefore, before beginning this post hoc analysis, we used a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) to differentiate between patients with and those without renal insufficiency. We also estimated creatinine clearance from serum creatinine concentrations by using the CockcroftGault formula (8), which derives the value from creatinine concentration, age, and body weight (140 age [in years] body weight [in kg]/serum creatinine concentration [in mg/dL] 72 [in men] or 0.85 [in women]). For calculated creatinine clearance, an a priori value of 65 mL/min was arbitrarily chosen as a definite indicator of renal insufficiency. Statistical Analysis Baseline serum creatinine values were missing in 10 of 9297 patients who were randomly assigned to receive ramipril, 10 mg/d, or placebo. Only data from the original intention-to-treat analysis (5) were included in our study. We compared baseline characteristics in patients with and those without renal insufficiency by using chi-square tests for discrete variables and t-tests for continuous variables. Because the ratio of albumin to creatinine was not normally distributed, it was compared by using a Wilcoxon test. In the final analysis, time-to-event in each group was estimated by using Cox regression stratified by center; this was done because rates of renal insufficiency varied significantly by center (P=0.006) but event rates did not. Association by center was tested by using logistic regression for renal insufficiency and Cox regression for events. Center was treated as a fixed effect in these models (9). Multivariate models to predict events were developed by using Cox regression and a backward elimination technique, beginning with univariate significant risk factors, including age; sex; waist-to-hip ratio; body mass index; and history of hypertension, diabetes, coronary artery disease, peripheral vascular disease, smoking, ramipril use, and renal insufficiency. Age, body mass index, waist-to-hip ratio, and blood pressure were treated as continuous variables. All covariates were tested for possible confounding with renal insufficiency, but no such pattern was found. We used Cox regression models to assess the effect of randomization to ramipril after controlling for serum creatinine concentration. Statistical tests for interaction were done in the Cox regression analysis to determine whether the effect of ramipril differed in patients with and those without renal insufficiency. We classified patients according to quartiles of serum creatinine concentration and then determined the effect of renal insufficiency on risk for the primary outcome. To do this, we analyzed the rate of the primary outcome across quartiles using Cox regression and testing linearity of the hazard ratios (HRs). Creatinine clearance was also estimated from serum creatinine concentration by using the CockcroftGault formula (8). Because age is used to calculate this value, age was excluded from all multivariate analyses that included creatinine clearance as a variable. All analyses were done by using SAS software for Unix, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients with Renal Disease As shown in Table 1, 980 patients had a serum creatinine concentration at least 124 mol/L (1.4 mg/dL) and 8307 patients did not. Baseline variables did not differ between the placebo and ramipril subgroups. Compared with patients who had no evidence of renal insufficiency, those with renal insufficiency were older; were more likely to be male; and had a higher baseline prevalence of hypertension, coronary artery disease, peripheral vascular disease, low high-density lipoprotein cholesterol level, and use of antiplatelet and antihypertensive agents. Systolic blood pressure, urine albumin level, and waist-to-hip ratio were also higher in this group. Table 1. Baseline Characteristics of Patients with and Those without Renal Insufficiency Event Rates in Patients with Renal Insufficiency Renal insufficiency was an important predictor of the primary outcome for all patients, as well as for the ramipril and placebo groups separately. The extent to which renal insufficiency was associated with the primary outcome is shown in Figure 1 and Table 2. Most impressive is the fact that cardiovascular and all-cause mortality rates were nearly twice as high in patients with renal insufficiency (HR, 1.90 [95% CI, 1.53 to 2.36] and 1.83 [CI, 1.54 to 2.17], respectively, by Cox regression controlling for ramipril use; P<0.001 for both comparisons), as were hospitalizations for heart failure (HR, 2.11 [CI, 1.56 to 2.81]; P<0.001). This effect of renal insufficiency was also observed when calculated creatinine clearance was used instead of serum creatinine concentration (Table 3). Figure 1. Primary outcome, myocardial infarction, cardiovascular death, and all death for patients with a serum creatinine concentration less than 1.4 mg/dL (<124 mol/L) or at least 1.4 mg/dL ( 124 mol/L). Table 2. Outcomes in Patients with and Those without Renal Insufficiency Table 3. Outcomes in Patients with a Creatinine Clearance 65 mL/min or > 65 mL/min Analysis of the group risk for the primary outcome clearly showed that as serum creatinine concentration increases, so does cardiovascular risk. As shown in Figure 2, the incidence of the primary outcome increased with each quartile of serum creatinine concentration (P<0.001 for linear trend of HR across quartiles). Figure 2. Primary outcome according to quartiles of serum creatinine concentration. P P We performed a multivariate analysis to determine whether the observed relationship between the incidence of the primary outcome and renal insufficiency could be explained by the association of impaired renal function with the variables identified in Table 1. In this analysis, an elevated serum creatinine concentration and microalbuminuria were highly significant, independent renal risk factors for the aggregate primary outcome of cardiovascular death, myocardial infarction, or stroke (HR, 1.40 [CI, 1.16 to 1.69] and 1.59 [CI, 1.37 to 1.84], respectively; P<0.001 for both comparisons). Other factors that independently and significantly predicted the primary outcome measure were coronary artery disease (HR, 1.51 [CI, 1.22 to 1.85]), peripheral vascular disease (HR, 1.49 [CI, 1.29 to 1.70]), diabetes mellitus (HR, 1.42 [CI, 1.23 to 1.65]), male sex (HR, 1.20 [CI, 1.01 to 1.43]), 1-year increase in age (HR

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial

BACKGROUND Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartans effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Chronic Kidney Disease Effects on the Cardiovascular System

Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.

Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention

Since the first description of the association between chronic kidney disease and heart disease, many epidemiological studies have confirmed and extended this finding. As chronic kidney disease progresses, kidney-specific risk factors for cardiovascular events and disease come into play. As a result, the risk for cardiovascular disease is notably increased in individuals with chronic kidney disease. When adjusted for traditional cardiovascular risk factors, impaired kidney function and raised concentrations of albumin in urine increase the risk of cardiovascular disease by two to four times. Yet, cardiovascular disease is frequently underdiagnosed and undertreated in patients with chronic kidney disease. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that needs particular medical attention at an individual level. This view should be incorporated in the development of guidelines and when defining research priorities. Here, we discuss the epidemiology and pathophysiological mechanisms of cardiovascular risk in patients with chronic kidney disease, and discuss methods of prevention.

Urinary Sodium and Potassium Excretion and Risk of Cardiovascular Events

CONTEXT The precise relationship between sodium and potassium intake and cardiovascular (CV) risk remains uncertain, especially in patients with CV disease. OBJECTIVE To determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and CV events in patients with established CV disease or diabetes mellitus. DESIGN, SETTING, AND PATIENTS Observational analyses of 2 cohorts (N = 28,880) included in the ONTARGET and TRANSCEND trials (November 2001-March 2008 from initial recruitment to final follow-up). We estimated 24-hour urinary sodium and potassium excretion from a morning fasting urine sample (Kawasaki formula). We used restricted cubic spline plots to describe the association between sodium and potassium excretion and CV events and mortality, and to identify reference categories for sodium and potassium excretion. We used Cox proportional hazards multivariable models to determine the association of urinary sodium and potassium with CV events and mortality. MAIN OUTCOME MEASURES CV death, myocardial infarction (MI), stroke, and hospitalization for congestive heart failure (CHF). RESULTS At baseline, the mean (SD) estimated 24-hour excretion for sodium was 4.77 g (1.61); and for potassium was 2.19 g (0.57). After a median follow-up of 56 months, the composite outcome occurred in 4729 (16.4%) participants, including 2057 CV deaths, 1412 with MI, 1282 with stroke, and 1213 with hospitalization for CHF. Compared with the reference group with estimated baseline sodium excretion of 4 to 5.99 g per day (n = 14,156; 6.3% participants with CV death, 4.6% with MI, 4.2% with stroke, and 3.8% admitted to hospital with CHF), higher baseline sodium excretion was associated with an increased risk of CV death (9.7% for 7-8 g/day; hazard ratio [HR], 1.53; 95% CI, 1.26-1.86; and 11.2% for >8 g/day; HR, 1.66; 95% CI, 1.31-2.10), MI (6.8%; HR, 1.48; 95% CI, 1.11-1.98 for >8 g/day), stroke (6.6%; HR, 1.48; 95% CI, 1.09-2.01 for >8 g/day), and hospitalization for CHF (6.5%; HR, 1.51; 1.12-2.05 for >8 g/day). Lower sodium excretion was associated with an increased risk of CV death (8.6%; HR, 1.19; 95% CI, 1.02-1.39 for 2-2.99 g/day; 10.6%; HR, 1.37; 95% CI, 1.09-1.73 for <2 g/day), and hospitalization for CHF (5.2%; HR, 1.23; 95% CI, 1.01-1.49 for 2-2.99 g/day) on multivariable analysis. Compared with an estimated potassium excretion of less than 1.5 g per day (n = 2194; 6.2% with stroke), higher potassium excretion was associated with a reduced risk of stroke (4.7% [HR, 0.77; 95% CI, 0.63-0.94] for 1.5-1.99 g/day; 4.3% [HR, 0.73; 95% CI, 0.59-0.90] for 2-2.49 g/day; 3.9% [HR, 0.71; 95% CI, 0.56-0.91] for 2.5-3 g/day; and 3.5% [HR, 0.68; 95% CI, 0.49-0.92] for >3 g/day) on multivariable analysis. CONCLUSIONS The association between estimated sodium excretion and CV events was J-shaped. Compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF. Higher estimated potassium excretion was associated with a reduced risk of stroke.

Avosentan for Overt Diabetic Nephropathy

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Safety of the combination of valsartan and benazepril in patients with chronic renal disease

Objective Several experimental and clinical studies indicate that the renin system may play a pivotal role in progressing renal disease. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker could provide a higher degree of blockade of the renin-angiotensin system than either agent alone. Such enhanced suppression might be of benefit for patients exhibiting a progressive decline in renal function because of chronic renal disease. Methods A pilot multinational, multicentre, randomized, active-controlled, parallel group open-label study has been conducted in a group of patients with progressive chronic renal failure (creatinine clearance 20–45 ml/min) either with or without proteinuria and hypertension. The primary aim of the study was to investigate the safety and tolerability of the combination of valsartan and benazepril. Patients were randomly assigned to one of three groups: group 1 received valsartan 160 mg once daily (n = 22); group 2 received valsartan 80 mg once daily plus benazepril 5 or 10 mg once daily (n = 42); group 3 received valsartan 160 mg once daily plus benazepril 5 or 10 mg once daily (n = 44). The study lasted for 5 weeks, and in groups 2 and 3 benazepril was added on top of valsartan after the first week of therapy with the angiotensin receptor blocker. Results Serum creatinine increased in all three groups (mean change within a group: 11 μmol/l in group 1, P = 0.045; 9 μmol/l in group 2, P = 0.030; 15 μmol/l in group 3, P = 0.0006). Serum potassium also increased in all three groups of patients (mean change within a group:0.28 mmol/l in group 1, P = 0.28; 0.48 mmol/l in group 2, P = 0.0008; 0.36 mmol/l in group 3, P = 0.02). After 5 weeks of treatment, the largest decrease in blood pressure was observed in group 3 (the mean change from baseline in seated diastolic blood pressure (SDBP) and seated systolic blood pressure (SSBP), respectively, were: −2.0 and −11.5 mmHg in group 1; −7.6 and −15.4 mmHg in group 2; −12.6 and −21.6 mmHg in group 3). In addition, both combination treatments resulted in the reduction of proteinuria. The total number of patients with adverse experiences were 10 (45.5%), 14 (33.3%) and 11 (25%) in groups 1, 2 and 3, respectively. In six patients (5.6%) therapy was discontinued as a result of adverse experiences. Only one patient in each of the combined therapy groups withdrew from the study because of hyperkalaemia and no patients were forced to withdraw because of an increase in serum creatinine, acute renal failure or hospitalization. Conclusions These results indicate that short-term combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker is safe and well tolerated in patients with moderate chronic renal failure.

Changes in Albuminuria Predict Mortality and Morbidity in Patients with Vascular Disease

The degree of albuminuria predicts cardiovascular and renal outcomes, but it is not known whether changes in albuminuria also predict similar outcomes. In two multicenter, multinational, prospective observational studies, a central laboratory measured albuminuria in 23,480 patients with vascular disease or high-risk diabetes. We quantified the association between a greater than or equal to twofold change in albuminuria in spot urine from baseline to 2 years and the incidence of cardiovascular and renal outcomes and all-cause mortality during the subsequent 32 months. A greater than or equal to twofold increase in albuminuria from baseline to 2 years, observed in 28%, associated with nearly 50% higher mortality (HR 1.48; 95% CI 1.32 to 1.66), and a greater than or equal to twofold decrease in albuminuria, observed in 21%, associated with 15% lower mortality (HR 0.85; 95% CI 0.74 to 0.98) compared with those with lesser changes in albuminuria, after adjustment for baseline albuminuria, BP, and other potential confounders. Increases in albuminuria also significantly associated with cardiovascular death, composite cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure), and renal outcomes including dialysis or doubling of serum creatinine (adjusted HR 1.40; 95% CI 1.11 to 1.78). In conclusion, in patients with vascular disease, changes in albuminuria predict mortality and cardiovascular and renal outcomes, independent of baseline albuminuria. This suggests that monitoring albuminuria is a useful strategy to help predict cardiovascular risk.