Hans L. Hillege

Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

Background—For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. Methods and Results—In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P =0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Conclusions—Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.

Renal Function, Neurohormonal Activation, and Survival in Patients With Chronic Heart Failure

BACKGROUND Because renal function is affected by chronic heart failure (CHF) and it relates to both cardiovascular and hemodynamic properties, it should have additional prognostic value. We studied whether renal function is a predictor for mortality in advanced CHF, and we assessed its relative contribution compared with other established risk factors. In addition, we studied the relation between renal function and neurohormonal activation. METHODS AND RESULTS The study population consisted of 1906 patients with CHF who were enrolled in a recent survival trial (Second Prospective Randomized study of Ibopamine on Mortality and Efficacy). In a subgroup of 372 patients, plasma neurohormones were determined. The baseline glomerular filtration rate (GFR(c)) was calculated using the Cockroft Gault equation. GFR(c) was the most powerful predictor of mortality; it was followed by New York Heart Association functional class and the use of angiotensin-converting enzyme inhibitors. Patients in the lowest quartile of GFR(c) values (<44 mL/min) had almost 3 times the risk of mortality (relative risk, 2. 85; P<0.001) of patients in the highest quartile (>76 mL/min). Impaired left ventricular ejection fraction (LVEF) was only modestly predictive (P=0.053). GFR(c) was inversely related with N-terminal atrial natriuretic peptide (ANP; r=-0.53) and, to a lesser extent, with ANP itself (r=-0.35; both P<0.001). CONCLUSIONS Impaired renal function (GFR(c)) is a stronger predictor of mortality than impaired cardiac function (LVEF and New York Heart Association class) in advanced CHF, and it is associated with increased levels of N-terminal ANP. Moreover, impaired renal function was not related to LVEF, which suggests that factors other than reduced cardiac output are causally involved.

Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure

Background— Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. Methods and Results— The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (≤40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 &mgr;mol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. Conclusions— Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.

Lenient versus Strict Rate Control in Patients with Atrial Fibrillation

BACKGROUND Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity

Abstract. Hillege HL, Janssen WMT, Bak AAA, Diercks GFH, Grobbee DE, Crijns HJGM, van Gilst WH, de Zeeuw D, de Jong PE for the PREVEND Study group (University of Groningen and University Hospital Groningen, Groningen; University Medical centre, Utrecht, the Netherlands). Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001; 249: 519–526.

Anemia and Mortality in Heart Failure Patients: A Systematic Review and Meta-Analysis

OBJECTIVES The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF). BACKGROUND Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality. METHODS A systematic literature search in MEDLINE (through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted. RESULTS Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p < 0.001). Lower baseline hemoglobin values were associated with increased crude mortality rates (r = -0.396, p = 0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confidence interval: 1.26 to 1.69, p < 0.001]). Subgroup analysis showed no significant difference between mortality risk of anemia in diastolic or systolic CHF. CONCLUSIONS Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.

Increased Central Venous Pressure Is Associated With Impaired Renal Function and Mortality in a Broad Spectrum of Patients With Cardiovascular Disease

OBJECTIVES We sought to investigate the relationship between increased central venous pressure (CVP), renal function, and mortality in a broad spectrum of cardiovascular patients. BACKGROUND The pathophysiology of impaired renal function in cardiovascular disease is multifactorial. The relative importance of increased CVP has not been addressed previously. METHODS A total of 2,557 patients who underwent right heart catheterization in the University Medical Center Groningen, the Netherlands, between January 1, 1989, and December 31, 2006, were identified, and their data were extracted from electronic databases. Estimated glomerular filtration rate (eGFR) was assessed with the simplified modification of diet in renal disease formula. RESULTS Mean age was 59 +/- 15 years, and 57% were men. Mean eGFR was 65 +/- 24 ml/min/1.73 m(2), with a cardiac index of 2.9 +/- 0.8 l/min/m(2) and CVP of 5.9 +/- 4.3 mm Hg. We found that CVP was associated with cardiac index (r = -0.259, p < 0.0001) and eGFR (r = -0.147, p < 0.0001). Also, cardiac index was associated with eGFR (r = 0.123, p < 0.0001). In multivariate analysis CVP remained associated with eGFR (r = -0.108, p < 0.0001). In a median follow-up time of 10.7 years, 741 (29%) patients died. We found that CVP was an independent predictor of reduced survival (hazard ratio: 1.03 per mm Hg increase, 95% confidence interval: 1.01 to 1.05, p = 0.0032). CONCLUSIONS Increased CVP is associated with impaired renal function and independently related to all-cause mortality in a broad spectrum of patients with cardiovascular disease.

Effect of Moderate or Intensive Disease Management Program on Outcome in Patients With Heart Failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH)

BACKGROUND Heart failure (HF) disease management programs are widely implemented, but data about their effect on outcome have been inconsistent. METHODS The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) was a multicenter, randomized, controlled trial in which 1023 patients were enrolled after hospitalization because of HF. Patients were assigned to 1 of 3 groups: a control group (follow-up by a cardiologist) and 2 intervention groups with additional basic or intensive support by a nurse specializing in management of patients with HF. Patients were studied for 18 months. Primary end points were time to death or rehospitalization because of HF and the number of days lost to death or hospitalization. RESULTS Mean patient age was 71 years; 38% were women; and 50% of patients had mild HF and 50% had moderate to severe HF. During the study, 411 patients (40%) were readmitted because of HF or died from any cause: 42% in the control group, and 41% and 38% in the basic and intensive support groups, respectively (hazard ratio, 0.96 and 0.93, respectively; P = .73 and P = .52, respectively). The number of days lost to death or hospitalization was 39 960 in the control group, 33 731 days for the basic intervention group (P = .81), and 34 268 for the intensive support group (P = .49). All-cause mortality occurred in 29% of patients in the control group, and there was a trend toward lower mortality in the intervention groups combined (hazard ratio, 0.85; 95% confidence interval, 0.66-1.08; P = .18). There were slightly more hospitalizations in the 2 intervention groups (basic intervention group, P = .89; and intensive support group, P = .60). CONCLUSIONS Neither moderate nor intensive disease management by a nurse specializing in management of patients with HF reduced the combined end points of death and hospitalization because of HF compared with standard follow-up. There was a nonsignificant, potentially relevant reduction in mortality, accompanied by a slight increase in the number of short hospitalizations in both intervention groups. Clinical Trial Registry http://trialregister.nl Identifier: NCT 98675639.

Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria

Background—Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). Methods and Results—From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51±12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8±1.0 mmol/L, mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank). Conclusions—In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.

Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction

Abstract Aims. Galectin-3 is an emerging biomarker which has been studied in relatively small heart failure (HF) cohorts with predominantly systolic HF. We studied the prognostic value of base-line galectin-3 in a large HF cohort, with preserved and reduced left ventricular ejection fraction (LVEF), and compared this to other biomarkers. Methods. We studied 592 HF patients who had been hospitalized for HF and were followed for 18 months. The primary end-point was a composite of all-cause mortality and HF hospitalization. Results. A doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62–2.42) for the primary outcome (P < 0.001). After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38 (1.07–1.78; P = 0.015). Galectin-3 levels were correlated with higher IL-6 and CRP levels (P < 0.002). Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value (n = 291); however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone (ROC analysis, P < 0.05). The predictive value of galectin-3 was stronger in patients with preserved LVEF (n = 114) compared to patients with reduced LVEF (P < 0.001). Conclusions. Galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF.