Incidence of cancer in patients with chronic heart failure: a long-term follow-up study.

AIMS: With improvement in survival of chronic heart failure (HF), the clinical importance of co-morbidity is increasing. The aim of this study was to assess the incidence and risk of cancer and all-cause mortality in a large Danish HF cohort. METHODS AND RESULTS: A total of 9307 outpatients with verified HF without a prior diagnosis of cancer (27% female, mean age 68 years, 89% with LVEF <45%) were included in the study. A diagnosis of any cancer and all-cause mortality was obtained from Danish national registries. Outcome was compared with the general Danish population. Overall and type-specific risk of cancer was analysed in an adjusted Poisson and Cox regression analysis. The 975 diagnoses of cancer in the HF cohort and 330 843 in the background population corresponded to incidence rates per 10 000 patient-years of 188.9 [95% confidence interval (CI) 177.2-200.6] and 63.0 (95% CI 63.0-63.4), respectively. When stratified by age, incidence rates were increased in all age groups in the HF cohort. Risk of any type of cancer was increased, with an incidence rate ratio of 1.24 (95% CI 1.15-1.33, c < 0.0001). Type-specific analysis demonstrated an increased hazard ratio for all major types of cancer except for prostate cancer. All-cause mortality was higher in HF patients with cancer compared with cancer patients from the background population. CONCLUSIONS: Patients with HF have an increased risk of cancer, which persists after the first year after the diagnosis of HF, and their prognosis is worse compared with that of cancer patients without HF.

Effect of extended follow-up in a specialized heart failure clinic on adherence to guideline recommended therapy: NorthStar Adherence Study.

AIMS: The optimal duration of a public heart failure (HF) clinic programme is unknown. This substudy of the NT-proBNP stratified follow-up in outpatient heart failure clinics (NorthStar) trial was designed to evaluate the effect of extended follow-up in an outpatient HF clinic on long-term adherence to guideline-based therapy. METHODS AND RESULTS: Patients with HF with reduced EF on optimal medical therapy (n = 921) were randomized to either extended follow-up in the HF clinic (n = 461) or discharge to primary care (n = 460) and followed for a median of 4.1 years (range: 13 months to 6.1 years). The effect of the HF clinic intervention on treatment adherence (time to at least a 90 day break in treatment) was estimated by drug dispensing from pharmacies of an ACE inhibitor/ARB, beta-blocker (BB), or mineralocorticoid receptor antagonist (MRA). Median age was 69 years, 25% were females, LVEF was 30%, and 90% were in NYHA class II-III. The HF clinic intervention did not reduce time to a 90 day break in treatment with either an ACE inhibitor/ARB [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.34-1.97, P = 0.650], a BB (HR 1.09, 95% CI 0.53-2.66, P = 0.820), or an MRA (HR 1.30, 95% CI 0.85-2.00, P = 0.238). CONCLUSIONS: Extended follow-up in an outpatient HF clinic did not improve long-term adherence to guideline-based therapy, and adherence did not deteriorate when follow-up was shifted from the HF clinic to primary care.

Incidence and predictors of end-stage renal disease in outpatients with systolic heart failure.

BACKGROUND: Renal dysfunction is an important prognostic factor in heart failure (HF), but whether this dysfunction progresses to end-stage renal disease (ESRD) is unknown. Therefore, we examined incidence and predictors of ESRD in outpatients with HF. METHODS AND RESULTS: Patients with systolic HF were identified in The Danish Heart Failure database and new-onset ESRD from the Danish Registry on Dialysis. Renal function was estimated by The Chronic Kidney Disease Epidemiology Collaboration equation and patients grouped by estimated glomerular filtration rate (eGFR)-group I: ≥60 mL/min per 1.73 m(2), group II: 30 to 59 mL/min per 1.73 m(2), group III: 15 to 29 mL/min per 1.73 m(2), group IV: <15 mL/min per 1.73 m(2). Cox hazard models for time to ESRD, to death, and the composite end point of ESRD or death were constructed and predictors of ESRD identified. A total of 8204 patients were included in the analyses. Median age was 70 years (Q, 61-77), 28% were women, median left ventricular ejection fraction was 30% (Q, 24-40), and median eGFR was 68 (Q, 51-85) mL/min per 1.73 m(2). Forty-one patients developed ESRD (1.3/1000 patient-years). Baseline eGFR group II (P<0.001), eGFR group III (P<0.001), eGFR group IV (P<0.001), uncontrolled hypertension (P=0.049), need of diuretics, and age <60 years (P=0.016) were associated with time to ESRD. CONCLUSIONS: ESRD is rare in outpatients with systolic HF and is mainly observed in patients with an eGFR <30 mL/min per 1.73 m(2). A low eGFR, age <60 years, need of diuretics, and uncontrolled hypertension identify patients with an increased risk for ESRD.

Adding serial N-terminal pro brain natriuretic peptide measurements to optimal clinical management in outpatients with systolic heart failure: a multicentre randomized clinical trial (NorthStar monitoring study).

AIMS: This study was designed to evaluate a new NT-proBNP monitoring concept in outpatients with systolic heart failure (HF). METHODS AND RESULTS: This was a multicentre, prospective randomized open-label blinded endpoint study. A total of 407 systolic HF patients were allocated to either clinical management (n = 208) or clinical management + NT-proBNP monitoring (n = 199) and followed for 2.5 years. If NT-proBNP increased >30%, a clinical checklist was completed and treatment initiated. The patients were matched at randomization and were 73 years old, 25% were females, 85% were NYHA class I-II, LVEF was 30%, and NT-proBNP 1955 pg/mL. NT-proBNP monitoring did not improve outcome, the hazard ratio for the primary composite endpoint (death or a cardiovascular admission) being 0.96 [95% confidence interval (CI) 0.71-1.29, P = 0.766]. NT-proBNP monitoring did not induce a significant change in the pharmacological strategy (P > 0.05 for all comparisons). In patients in whom NT-proBNP increased >30% (25% of the patients) during follow-up, a higher frequency of admission (69% vs. 47%, P = 0.002), a higher number of admission days (14 vs. 5 days, P = 0.003) and number of admissions (2 vs. 1, P = 0.009), and a lower quality of life (P = 0.032) and a poorer functional class (37% vs. 18% in NYHA class III-IV, P < 0.001) were observed. CONCLUSIONS: Adding serial measurements of NT-proBNP to optimal clinical management was not associated with a change in pharmacological strategy and did not improve outcome. However, survivors in whom NT-proBNP increased >30% showed a poorer functional class, clinical outcome, and quality of life. TRIAL REGISTRATION: www.centerwatch: 173491 (NorthStar).

Extended heart failure clinic follow-up in low-risk patients: a randomized clinical trial (NorthStar).

BACKGROUND: Outpatient follow-up in specialized heart failure clinics (HFCs) is recommended by current guidelines and implemented in most European countries, but the optimal duration of HFC programmes has not been established. Nor is it known whether all or only high-risk patients, e.g. identified by NT-proBNP, might benefit from an extended HFC follow-up. METHODS AND RESULTS: In a multi-centre setting, we randomly assigned 921 clinically stable systolic heart failure (HF) outpatients on optimal medical therapy to undergo either an extended follow-up in the HFC (n = 461) or referral back to their general practitioner (GP) (n = 460). The primary composite endpoint was death or a cardiovascular admission. Secondary endpoints included mortality, an HF admission, quality of life, number of days admitted, and number of admissions. The median age of the patients was 69 years; 23% were females; the median left ventricular ejection fraction was 0.30; and the median NT-proBNP was 801 pg/mL; 89% were in NYHA class I-II. The median follow-up was 2.5 years. Time-to-event did not differ between groups (HFC vs. GP) (HR: 1.17, 95% CI: 0.95-1.45, P = 0.149). The two groups did not differ with respect to any of the secondary endpoints at the follow-up (P> 0.05 for all). In high-risk patients identified by NT-proBNP ≥1000 pg/mL, no benefit from HFC follow-up was found (P = 0.721). CONCLUSION: Irrespective of the level of NT-proBNP stable HF patients on optimal medical therapy do not benefit from long-term follow-up in a specialized HFC in a publicly funded universal access healthcare system. Heart failure patients on optimal medical therapy with mild or moderate symptoms are safely managed by their personal GP. TRIAL REGISTRATION: www.Centerwatch.com: 173491 (NorthStar).

Prediction of outcome by highly sensitive troponin T in outpatients with chronic systolic left ventricular heart failure.

Our aim was to assess the prognostic impact of a high-sensitivity cardiac troponin T (hs-cTnT) assay in an outpatient population with chronic systolic left ventricular heart failure (HF). Four hundred sixteen patients with chronic HF and left ventricular ejection fraction ≤ 45% were enrolled in a prospective cohort study. In addition to hs-cTnT, plasma amino-terminal pro-B-type natriuretic peptide was measured at baseline. Mean age was 71 years, 29% were women, 62% had coronary artery disease (CAD), mean left ventricular ejection fraction was 31%, and 57% had abnormal level of hs-cTnT. During 4.4 years of follow-up, 211 (51%) patients died. In multivariate Cox regression models, hs-cTnT was categorized as quartiles or dichotomized by the 99th percentile of a healthy population. Adjusted hazard ratios for all-cause mortality for quartiles 2 to 4, with quartile 1 as reference, were 1.4 (95% confidence interval 0.9 to 2.4, p = 0.16) for quartile 2, 1.7 (0.9 to 2.5, p = 0.12) for quartile 3, and 2.6 (1.6 to 4.4, p <0.001) for quartile 4 and 1.7 (1.2 to 2.5, p = 0.003) for abnormal versus normal level of hs-cTnT. In patients without CAD, quartile 4 of hs-cTnT was associated with an adjusted hazard ratio of 6.8. In conclusion, hs-cTnT is increased in most outpatients with chronic systolic HF and carries prognostic information beyond clinical parameters and amino-terminal pro-B-type natriuretic peptide. Increased hs-cTnT indicated a particularly deleterious prognosis in patients without CAD.

Oral glucose tolerance testing in an outpatient heart failure clinic reveals a high proportion of undiagnosed diabetic patients with an adverse prognosis.

AIMS: We evaluated the applicability and prognostic importance of oral glucose tolerance testing (OGTT) among outpatients with systolic heart failure (SHF). METHODS AND RESULTS: Consecutive patients with SHF and left ventricular ejection fraction (LVEF) ≤ 45% referred to a heart failure clinic (n= 413) were included in this study. An OGTT was conducted in patients without a history of diabetes. Information on NYHA class, aetiology of SHF, LVEF, treatment, and biochemical parameters were collected at baseline. The survival status was obtained after a median follow-up time of 591 days. Of the 413 patients, 82 (20%) had known diabetes. Of the remaining 331 patients, 227 (69%) agreed to undergo an OGTT. Among the tested subjects, 136 (60%) were classified as having normal glucose tolerance (NGT), 51 (23%) impaired glucose tolerance (IGT), and 40 (18%) newly diagnosed diabetes. Assuming a similar prevalence of unrecognized diabetes among the patients who refused OGTT, the prevalence of diabetes in the total population was 34%. If only fasting blood glucose had been used, 16 of the 40 newly diagnosed diabetic patients would have been undiagnosed. During follow-up, 24 (29%) patients with known diabetes, 6 (15%) of the newly diagnosed diabetic patients, 9 (18%) of those with IGT, and 13 (9%) patients with NGT died. Patients with diabetes had higher mortality rate compared with non-diabetic patients [multivariate hazard ratio 1.89 (1.02-3.59); P = 0.047]. CONCLUSION: It is feasible to perform diabetes screening using OGTT in outpatients with SHF. A substantial proportion of patients tested were found to have unrecognized diabetes. The presence of diabetes was associated with a higher mortality rate.

High mortality among heart failure patients treated with antidepressants.

BACKGROUND: This study was designed to assess whether pharmacologically treated depression was associated with increased mortality risk in systolic heart failure (SHF) patients. METHODS: Patients (n=3346) with SHF (left ventricular ejection fraction ≤ 0.45) and primarily New York Heart Association (NYHA) classes II-III (78%) were recruited from a clinical database used in 20 heart failure clinics in Denmark. The association between pharmacologically treated depression identified by at least one prescription of an antidepressant and mortality risk was evaluated. RESULTS: Follow-up time was 540 days (range: 30-1600 days). 539 patients died. For 243 patients (7%) an antidepressant had been prescribed at least once. In a Cox Proportional Hazard Model, pharmacologically treated depression was associated with a 49% increased mortality risk (Hazard ratio: 1.49, 95% confidence interval: 1.03-2.16) after adjustment for traditional confounders. Three months after the baseline visit in the heart failure clinic, these patients received lower doses of beta-blockers than patients without antidepressant therapy (p=0.006). Female sex (p<0.001) and NYHA classes III-IV (p=0.007) were associated with the prescription of an antidepressant. CONCLUSIONS: Our analyses suggest that pharmacologically treated depression is associated with a 49% increased mortality risk, and that these high-risk patients receive lower doses of beta-blockers than patients with no antidepressant therapy.

Urine albumin/creatinine ratio, high sensitivity C-reactive protein and N-terminal pro brain natriuretic peptide--three new cardiovascular risk markers--do they improve risk prediction and influence treatment?

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.

Incidence and predictors of hospitalization or death in patients managed in multidisciplinary heart failure clinics.

AIMS: To assess the rates of death or hospitalization in outpatients with heart failure (HF) followed in multidisciplinary, nurse-based HF clinics and to compare the rates with published data from the literature. A second aim was to identify risk factors for death or hospital admission. METHODS AND RESULTS: A total of 4012 consecutive outpatients referred for HF management in 18 Danish HF clinics were included. Clinical data were collected prospectively. Outcome data were obtained from a validated, national registry. Mean follow-up time was 580 days. The mean age of patients was 69 years, 83% had left ventricular systolic dysfunction and 52% had been hospitalized within 90 days prior to referral to the HF clinic. The 6 and 12 month rates of hospitalization or death were 31 and 42%. Hospitalization or death was significantly predicted by age 1.12 (1.05-1.19), diabetes 1.21 (1.03-1.42), serum creatinine 1.03 (1.02-1.04), NYHA III and IV 1.32 (1.15-1.52), and hospitalization prior to referral to the HF clinic 1.81 (1.57-2.08). CONCLUSIONS: Event rates in this cohort were lower than most published data from HF clinic populations. Factors such as advanced age, NYHA class, and prior hospitalization predict poor outcome in patients managed in multidisciplinary HF clinics.

Design and methodology of the NorthStar Study: NT-proBNP stratified follow-up in outpatient heart failure clinics -- a randomized Danish multicenter study.

BACKGROUND: Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. AIMS: The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. METHODS: A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). RESULTS: Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. CONCLUSIONS: This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.

C-reactive protein, insulin resistance and risk of cardiovascular disease: a population-based study.

BACKGROUND: C-reactive protein (CRP), a marker of inflammation, and insulin resistance (IR), a metabolic disorder, are closely related. CRP and IR have both been identified as significant risk factors of cardiovascular disease (CVD) after adjustment for conventional CVD risk factors. It is not clear whether CRP predicts CVD independent of IR. DESIGN: Prospective population-based study. METHODS: Two thousand three hundred and fifty-seven Danish men and women, recruited from the general population, aged 41-72 years, without major CVD at baseline were studied. Traditional and new risk factors were recorded at baseline. CRP was determined by a high-sensitivity assay, and IR was determined by the homoeostasis model assessment (HOMA-IR) method. RESULTS: Over a median follow-up of 9.4 years, the incidence of the prespecified CV event, defined as the composite event of CV death, nonfatal ischaemic heart disease and nonfatal stroke, amounted to 222 cases. In Cox proportional-hazard models, adjusted for age, sex, smoking habit, total cholesterol, waist circumference, levels of triglycerides and high-density lipoprotein-cholesterol, systolic and diastolic blood pressures, physical activity and HOMA-IR, the hazard ratio (95% confidence interval) of a CV event was 1.33 (1.14-1.55; P<0.001) per standard deviation increase in log-transformed CRP level. In the same model, the hazard ratio of a CV event was 1.11 (1.02-1.21; P<0.05) per standard deviation increase in HOMA-IR level. CONCLUSION: In a general Danish population free of major CVD at baseline, both CRP and IR were significantly related to risk of CVD.

Cardiovascular risk prediction by N-terminal pro brain natriuretic peptide and high sensitivity C-reactive protein is affected by age and sex.

BACKGROUND: Previous studies have shown that the urine albumin/creatinine ratio (UACR), high sensitivity C-reactive protein (hsCRP) and N-terminal pro brain natriuretic peptide (Nt-proBNP) predict cardiovascular events in a general population aged 41, 51, 61 or 71 years. This study investigated the impact of age and sex on their prognostic performance in a subgroup of 1994 apparently healthy individuals without diabetes, previous stroke or myocardial infarction, who did not receive any cardiovascular, antidiabetic or lipid-lowering medication. METHODS: In 1993-1994 we recorded cardiovascular risk factors, UACR, hsCRP and Nt-proBNP. The composite cardiovascular endpoint (CEP) of cardiovascular death and non-fatal stroke or myocardial infarction was assessed after 9.5 years. RESULTS: In Cox regression analyses predicting CEP, the effects of log(hsCRP) and log(Nt-proBNP) were modulated by sex (P < 0.05) and age (P < 0.05), respectively. The effect of logUACR was not significantly modulated by age or sex. Log(hsCRP)/SD did not predict CEP in women, but did predict CEP in 41 plus 51-year-old men [hazard ratio (HR) 1.71; 95% confidence interval, 1.1-2.6; P < 0.05] and 61 plus 71-year-old men (HR 1.64; 1.3-2.2; P < 0.001). Log(Nt-proBNP)/SD predicted CEP in 61 plus 71-year-old women (HR 1.74; 1.2-2.5; P < 0.01) and in 61 plus 71-year-old men (HR 1.58; 1.3-2.0; P < 0.001). CONCLUSION: Elevated hsCRP, reflecting early atherosclerosis, predicted CEP even in 41 plus 51-year-old men. Elevated Nt-proBNP, reflecting subclinical cardiovascular damage, predicted CEP in 61 plus 71-year-old subjects. Elevated UACR, reflecting endothelial dysfunction as well as microvascular damage, predicted events independently of age and sex, but primarily in 61 plus 71-year-old subjects.

Losartan versus atenolol on 24-hour ambulatory blood pressure. A LIFE substudy.

OBJECTIVE: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that losartan-based treatment reduced risk of the composite endpoint of cardiovascular death, stroke and myocardial infarction compared with atenolol-based treatment in patients with hypertension and left ventricular hypertrophy with similar office blood pressure (BP) reduction. Our aim was to investigate the effect of losartan- and atenolol-based treatment on 24-h ambulatory BP and heart rate (HR) in LIFE. METHODS: In 110 patients, 24-h ambulatory BP and heart rate were recorded at baseline and 1 year after randomization. RESULTS: Ambulatory BP was comparably reduced throughout the 24-h period after 1 year of losartan- vs atenolol-based antihypertensive treatment. Office and ambulatory BP were comparably reduced in the follow-up period. Early morning surge in BP was similar between groups. Non-dipping status was more frequent in the losartan group (p = 0.01). From baseline to Year 1 the 24-h HR profile for the losartan group was unchanged, but, as expected, there was a significant decrease in daytime HR in the atenolol group, which was not as large during early night-time. CONCLUSION: There were no differences in 24-h BP burden and HR that could explain the difference in outcome in favor of losartan vs atenolol in the LIFE study.

Prognostic usefulness of anemia and N-terminal pro-brain natriuretic peptide in outpatients with systolic heart failure.

N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and anemia are predictors of outcome in systolic heart failure. It is currently unclear how these 2 markers interact in particular with regard to the prognostic information carried by each risk marker. We therefore tested the hypothesis that anemia (World Health Organization criteria, hemoglobin levels <7.5 mmol/L for women and <8.0 mmol/L for men) and NT-pro-BNP are associated and evaluated how a possible association affects the prognostic value of each risk marker. Clinical data from 345 patients with systolic heart failure were obtained prospectively at the baseline visit to our heart failure clinic (inclusion criterion left ventricular ejection fraction <0.45, no exclusion criteria). Follow-up was 30 months (median), and 70 events (mortality) occurred. Prevalence of anemia was 27%. In a multivariate logistic regression model, anemia (p = 0.041) was closely associated with NT-pro-BNP levels above the median (1,381 pg/ml) after adjustment for traditional confounders (left ventricular ejection fraction, age, body mass index, atrial fibrillation, chronic kidney disease). In an adjusted Cox proportional hazard model, the 2 parameters were associated with mortality after adjustment for traditional confounders (hazard ratio for anemia 1.73, 95% confidence interval 1.06 to 2.83, p = 0.029; hazard ratio for NT-pro-BNP >1,381 pg/ml 2.68, 95% confidence interval 1.58 to 4.66, p <0.001). Patients with anemia and high NT-pro-BNP levels had a fivefold increased risk for mortality (hazard ratio 4.77, 95% confidence interval 2.47 to 9.18, p <0.001). In conclusion, anemia is closely associated with NT-pro-BNP in patients with systolic heart failure, and anemia and NT-pro-BNP carry independent prognostic information. Patients with anemia and high levels of NT-pro-BNP have a markedly increased mortality risk.

Effects of body mass index and age on N-terminal pro brain natriuretic peptide are associated with glomerular filtration rate in chronic heart failure patients.

BACKGROUND: Obesity is a state characterized by glomerular hyperfiltration and age-related decreases in glomerular filtration rate (GFR). Body mass index (BMI), age, and GFR are associated with plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) patients. We hypothesized that the effects of BMI and age on plasma concentrations of NT-proBNP are associated with GFR. METHODS: We obtained clinical data and laboratory test results from 345 CHF patients at the baseline visit in our heart failure clinic and examined the hypothesis using multiple linear regression models. RESULTS: Age (P = 0.0184), BMI (P = 0.0098), hemoglobin (P = 0.0043), heart rhythm (P <0.0001), and left ventricular ejection fraction (P <0.0001) were associated with log(NT-proBNP). After adjustment for GFR estimated by the Cockcroft and Gault equation, the parameter estimates for BMI (P = 0.3807) and age (P = 0.7238) changed markedly and became insignificant. In another model, after adjustment for GFR estimated by the 4-component Modification of Diet in Renal Disease formula (eGFR(MDRD)), the parameter estimates for age (P = 0.0674) changed markedly and became insignificant, but BMI (P = 0.0067) remained significant and unchanged. The eGFR(MDRD) is adjusted for body surface area, which may explain the difference. CONCLUSIONS: In CHF patients, the effect of age on NT-proBNP is associated with estimates for GFR derived from serum creatinine, and the significance of the effects of BMI on NT-proBNP depends on the method by which GFR is estimated.

Unrecognized glycometabolic disturbance as measured by hemoglobin A1c is associated with a poor outcome after acute myocardial infarction.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) is a measure of the average blood glucose levels over 2 months and is minimally affected by acute hyperglycemia often observed in myocardial infarction (MI). In a large population of high-risk patients with MI, we examined the prognostic impact of HbA1c in patients with and without a history of diabetes. METHODS: In the OPTIMAAL trial, patients with MI complicated with heart failure were randomized to losartan or captopril. Of the 2841 patients who had HbA1c measured at randomization, 495 (17%) reported a history of diabetes. The remaining patients without diabetes history were stratified into 3 categories according to HbA1c level: HbA1c, <4.9% (n = 1642); HbA1c, 4.9% to 5.1% (n = 432); and HbA1c, >5.1% (n = 272). Mean follow-up time was 2.5 years. RESULTS: Mortality rate during follow-up was 18% in patients with a history of diabetes. Increasing HbA1c levels were associated with higher mortality rate among patients without diabetes history (13% in patients with HbA1c <4.9%, 17% in patients with HbA1c 4.9%-5.1%, 22% in patients with HbA1c >5.1%). Among patients with no prior history of diabetes, a 1% absolute increase in HbA1c level at baseline resulted in a 24% increase in mortality, whereas the level of HbA1c had no impact on mortality among the patients with well-known diabetes (multivariate analyses). CONCLUSIONS: In this high-risk MI population, HbA1c level was a potent predictor of mortality in patients without previously known diabetes.

The relationship between N-terminal pro-brain natriuretic peptide and risk for hospitalization and mortality is curvilinear in patients with chronic heart failure.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) carries prognostic information in patients with chronic heart failure and predicts risk for mortality and cardiovascular events. It is unknown whether NT-proBNP predicts risk for hospitalization for any cause. Furthermore, a clinically useful algorithm for risk stratification based on NT-proBNP as a continuous variable has not yet been described. We therefore evaluated NT-proBNP as a risk marker for mortality and hospitalization and developed a simple algorithm for risk stratification based on NT-proBNP as a continuous variable. METHODS: Data from 345 patients with chronic heart failure were collected prospectively in our heart failure clinic, and the patients were followed for 28 months (median). Seventy patients died, and 201 patients were hospitalized. Cox proportional hazard models for mortality and hospitalization were constructed with NT-proBNP as a dichotomous (median 1381 pg/mL) and a continuous variable (log2 NT-proBNP). RESULTS: Patients with supramedian levels of NT-proBNP had a 2.40-fold (95% CI 1.40-4.10) increased risk for mortality and 1.71-fold (95% CI 1.24-2.36) increased risk for hospitalization. The effect of doubling NT-proBNP on adjusted hazard ratios was 1.56 (95% CI 1.32-1.85) for mortality and 1.19 (95% CI 1.09-1.31) for hospitalization. We observed a curvilinear relationship between NT-proBNP and risk for mortality and hospitalization in the whole range of NT-proBNP. CONCLUSIONS: N-terminal pro-brain natriuretic peptide predicts risk for hospitalization and mortality. A simple algorithm indicates that every time NT-proBNP is doubled, estimated hazard ratio for death increases by a factor of 1.56 (56%) and by a factor of 1.19 (19%) for hospitalization. Finally, the relationship between NT-proBNP and risk is curvilinear if NT-proBNP is considered as a continuous variable.

Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study.

BACKGROUND: There are concerns about highly active antiretroviral therapy (HAART) causing a progressive increase in the risk of ischemic heart disease. We examined this issue in a nationwide cohort study of patients with human immunodeficiency virus (HIV) infection and a population-based control group. METHODS: We determined the rate of first hospitalization for ischemic heart disease in all Danish patients with HIV infection (3953 patients) from 1 January 1995 through 31 December 2004 and compared this rate with that for 373,856 subjects in a population-based control group. Data on first hospitalization for ischemic heart disease and comorbidity were obtained from the Danish National Hospital Registry for all study participants. We used Cox's regression to compute the hospitalization rate ratio as an estimate of relative risk, adjusting for comorbidity. RESULTS: Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81-2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62-2.76), but the relative risk did not further increase in the initial 8 years of HAART. CONCLUSIONS: Compared with the general population, HIV-infected patients receiving HAART have an increased risk of ischemic heart disease, but the relative risk is stable up to 8 years after treatment initiation.

A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure.

OBJECTIVES: This study investigated the effects of rosiglitazone (RSG) on left ventricular ejection fraction (LVEF) in subjects with type 2 diabetes (T2DM) and pre-existing chronic heart failure (CHF) (New York Heart Association [NYHA] functional class I to II). BACKGROUND: Fluid retention is an important consideration in the use of thiazolidinediones in T2DM patients because it could exacerbate symptoms or precipitate decompensation in those with previously stable CHF. METHODS: A total of 224 patients with T2DM and NYHA functional class I to II CHF with LVEF < or =45% were randomized to a 52-week treatment with RSG (4 to 8 mg daily, n = 110) or placebo (PLB) (n = 114) in addition to background antidiabetes therapy. Treatment was uptitrated to achieve target fasting plasma glucose <126 mg/dl; CHF medications were adjusted as appropriate. RESULTS: The LVEF was similar in both groups at baseline (RSG 35.3 +/- 6.2%, PLB 35.7 +/- 7.8%) and after 52 weeks of treatment (mean difference 1.49%, p = 0.1). Glycemic control was significantly better in the RSG group (mean difference in hemoglobin A1c -0.65%, p < 0.0001). There were significantly more adjudicated events in the RSG group of new or worsening edema (RSG n = 28 [25.5%]; PLB n = 10 [8.8%]; p = 0.005) and increased CHF medication (RSG n = 36 [32.7%], PLB n = 20 [17.5%]; p = 0.037), but no significant difference between groups for other adjudicated end points. A similar proportion of patients withdrew from each treatment group because of adverse events. CONCLUSIONS: After 52 weeks of treatment, RSG improved glycemic control but did not adversely affect LVEF in patients with T2DM and NYHA functional class I to II CHF. More fluid-related events occurred with RSG, although these generally did not lead to withdrawal from the study.