Douwe Postmus

The Predictive Value of Short-Term Changes in Hemoglobin Concentration in Patients Presenting With Acute Decompensated Heart Failure

OBJECTIVES The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). BACKGROUND Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. METHODS This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. RESULTS Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. CONCLUSIONS Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.

Hit-And-Run enables efficient weight generation for simulation-based multiple criteria decision analysis

In our previous work published in this journal, we showed how the Hit-And-Run (HAR) procedure enables efficient sampling of criteria weights from a space formed by restricting a simplex with arbitrary linear inequality constraints. In this short communication, we note that the method for generating a basis of the sampling space can be generalized to also handle arbitrary linear equality constraints. This enables the application of HAR to sampling spaces that do not coincide with the simplex, thereby allowing the combined use of imprecise and precise preference statements. In addition, it has come to our attention that one of the methods we proposed for generating a starting point for the Markov chain was flawed. To correct this, we provide an alternative method that is guaranteed to produce a starting point that lies within the interior of the sampling space.

A stochastic multicriteria model for evidence‐based decision making in drug benefit‐risk analysis

Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multi-criteria model that fully takes into account the evidence on efficacy and adverse drug reactions. Our approach is based on the stochastic multi-criteria acceptability analysis methodology, which allows us to compute the typical value judgments that support a decision, to quantify decision uncertainty, and to compute a comprehensive BR profile. We construct a multi-criteria model for the therapeutic group of second-generation antidepressants. We assess fluoxetine and venlafaxine together with placebo according to incidence of treatment response and three common adverse drug reactions by using data from a published study. Our model shows that there are clear trade-offs among the treatment alternatives.

Survival and Quality of Life After Stereotactic or 3D-Conformal Radiotherapy for Inoperable Early-Stage Lung Cancer

PURPOSE To investigate survival and local recurrence after stereotactic ablative radiotherapy (SABR) or three-dimensional conformal radiotherapy (3D-CRT) administered for early-stage primary lung cancer and to investigate longitudinal changes of health-related quality of life (HRQOL) parameters after either treatment. METHODS AND MATERIALS Two prospective cohorts of inoperable patients with T1-2N0M0 primary lung tumors were analyzed. Patients received 70 Gy in 35 fractions with 3D-CRT or 60 Gy in three to eight fractions with SABR. Global quality of life (GQOL), physical functioning (PF), and patient-rated dyspnea were assessed using the respective dimensions of European Organization for Research and Treatment of Cancer Core Questionnaire-C30 and LC13. HRQOL was analyzed using multivariate linear mixed-effects modeling, survival and local control (LC) using the Kaplan-Meier method, Cox proportional hazards analysis, and Fine and Gray multivariate competing risk analysis as appropriate. RESULTS Overall survival (OS) was better after SABR compared with 3D-CRT with a HR of 2.6 (95% confidence interval [CI]: 1.5-4.8; p < 0.01). 3D-CRT conferred a subhazard ratio for LC of 5.0 (95% CI: 1.7-14.7; p < 0.01) compared with SABR. GQOL and PF were stable after SABR (p = 0.21 and p = 0.62, respectively). Dyspnea increased after SABR by 3.2 out of 100 points (95% CI: 1.0-5.3; p < 0.01), which is clinically insignificant. At 1 year, PF decreased by an excess of 8.7 out of 100 points (95% CI: 2.8-14.7; p < 0.01) after 3D-CRT compared with SABR. CONCLUSION In this nonrandomized comparison of two prospective cohorts of medically inoperable patients with Stage I lung cancer, OS and LC were better after SABR. GQOL, PF, and patient-rated dyspnea were stable after SABR, whereas PF decreased after 3D-CRT approaching clinical significance already at 1 year.

Multicriteria benefit-risk assessment using network meta-analysis

OBJECTIVE To enable multicriteria benefit-risk (BR) assessment of any number of alternative treatments using all available evidence from a network of clinical trials. STUDY DESIGN AND SETTING We design a general method for multicriteria decision aiding with criteria measurements from Mixed Treatment Comparison (MTC) analyses. To evaluate the method, we apply it to BR assessment of four second-generation antidepressants and placebo in the setting of a published peer-reviewed systematic review. RESULTS The analysis without preference information shows that placebo is supported by a wide range of possible preferences. Preference information provided by a clinical expert showed that although treatment with antidepressants is warranted for severely depressed patients, for mildly depressed patients placebo is likely to be the best option. It is difficult to choose between the four antidepressants, and the results of the model indicate a high degree of uncertainty. CONCLUSIONS The designed method enables quantitative BR analysis of alternative treatments using all available evidence from a network of clinical trials. The preference-free analysis can be useful in presenting the results of an MTC considering multiple outcomes.

Renal Function Trajectories and Clinical Outcomes in Acute Heart Failure

Background— Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes. Methods and Results— We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen >35 mg/dL and increase in creatinine >0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. Conclusions— Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

The COACH risk engine: a multistate model for predicting survival and hospitalization in patients with heart failure

Several models for predicting the prognosis of heart failure (HF) patients have been developed, but all of them focus on a single outcome variable, such as all‐cause mortality. The purpose of this study was to develop a multistate model for simultaneously predicting survival and HF‐related hospitalization in patients discharged alive from hospital after recovery from acute HF.

Plasma Procalcitonin Is Associated with Obesity, Insulin Resistance, and the Metabolic Syndrome

CONTEXT Procalcitonin, a well-known biomarker of sepsis and bacterial infections, is produced by adipose tissue and has potential as a marker for chronic low-grade inflammation. OBJECTIVES The objective of this study was to investigate whether plasma procalcitonin levels in the normal range are associated with obesity, insulin resistance, and metabolic syndrome (MS) in the general population. METHODS Plasma procalcitonin (0.006-0.1 ng/ml) was measured in 3197 men and 3638 women (aged 28-75 yr) of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study using an ultrasensitive immunoluminometric assay. MS was defined according to Adult Treatment Panel III criteria. RESULTS Median (interquartile range) plasma procalcitonin was 0.018 (0.015-0.022) ng/ml in men and 0.014 (0.012-0.017) ng/ml in women (P < 0.001). Plasma procalcitonin was positively associated with body mass index and waist circumference. In both sexes, cross-sectional associations of plasma procalcitonin with insulin resistance and components of the MS remained significant after adjustment for age, body mass index, waist circumference, and other covariates. The age-adjusted odds ratio (OR) for MS was 3.2 [95% confidence interval (CI) = 2.5-4.2) in men and 4.1 (95% CI = 3.0-5.5) in women, when comparing the highest with the lowest quartile of plasma procalcitonin. The multivariate-adjusted OR for MS was 1.9 (95% CI = 1.4-2.6) in men and 2.3 (95% CI = 1.6-3.3) in women. The multivariate-adjusted OR for insulin resistance was 3.3 (95% CI = 2.4-4.3) in men and 2.5 (95% CI = 1.9-3.4) in women. CONCLUSIONS Elevated plasma procalcitonin levels in the normal range are associated with measures of obesity, insulin resistance, and MS in the general population.

A trial-based economic evaluation of 2 nurse-led disease management programs in heart failure

BACKGROUND Although previously conducted meta-analyses suggest that nurse-led disease management programs in heart failure (HF) can improve patient outcomes, uncertainty regarding the cost-effectiveness of such programs remains. METHODS To compare the relative merits of 2 variants of a nurse-led disease management program (basic or intensive support by a nurse specialized in the management of patients with HF) against care as usual (routine follow-up by a cardiologist), a trial-based economic evaluation was conducted alongside the COACH study. RESULTS In terms of costs per life-year, basic support was found to dominate care as usual, whereas the incremental cost-effectiveness ratio between intensive support and basic support was found to be equal to €532,762 per life-year; in terms of costs per quality-adjusted life-year (QALY), basic support was found to dominate both care as usual and intensive support. An assessment of the uncertainty surrounding these findings showed that, at a threshold value of €20,000 per life-year/€20,000 per QALY, basic support was found to have a probability of 69/62% of being optimal against 17/30% and 14/8% for care as usual and intensive support, respectively. The results of our subgroup analysis suggest that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF would be optimal if the willingness-to-pay threshold exceeds €45,345 per life-year/€59,289 per QALY. CONCLUSIONS Although the differences in costs and effects among the 3 study groups were not statistically significant, from a decision-making perspective, basic support still had a relatively large probability of generating the highest health outcomes at the lowest costs. Our results also substantiated that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF could further improve health outcomes at slightly higher costs.

Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality

Background Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide–degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). Methods and Results We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. Conclusions Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD.