Georg Heinze

Risk Assessment of Recurrence in Patients With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism. The Vienna Prediction Model

Background— Predicting the risk of recurrent venous thromboembolism (VTE) in an individual patient is often not feasible. We aimed to develop a simple risk assessment model that improves prediction of the recurrence risk. Methods and Results— In a prospective cohort study, 929 patients with a first unprovoked VTE were followed up for a median of 43.3 months after discontinuation of anticoagulation. We excluded patients with a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects. A total of 176 patients (18.9%) had recurrent VTE. Preselected clinical and laboratory variables (age, sex, location of VTE, body mass index, factor V Leiden, prothrombin G20210A mutation, D-dimer, and in vitro thrombin generation) were analyzed in a Cox proportional hazards model, and those variables that were significantly associated with recurrence were used to compute risk scores. Male sex (hazard ratio versus female sex 1.90, 95% confidence interval 1.31 to 2.75), proximal deep vein thrombosis (hazard ratio versus distal 2.08, 95% confidence interval 1.16 to 3.74), pulmonary embolism (hazard ratio versus distal thrombosis 2.60, 95% confidence interval 1.49 to 4.53), and elevated levels of D-dimer (hazard ratio per doubling 1.27, 95% confidence interval 1.08 to 1.51) were related to a higher recurrence risk. Using these variables, we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient. The model was cross validated, and patients were assigned to different risk categories based on their risk score. Recurrence rates corresponded well with the different risk categories. Conclusions— By use of a simple scoring system, the assessment of the recurrence risk in patients with a first unprovoked VTE and without strong thrombophilic defects can be improved.

Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Type 1 Receptor Antagonist Therapy Is Associated with Prolonged Patient and Graft Survival after Renal Transplantation

Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) reduce cardiovascular death in the general population, but data for renal transplant recipients remain elusive. Similarly, ACEI/ARB have been shown to reduce proteinuria, but data on graft survival are lacking. Therefore a retrospective open cohort study was conducted of 2031 patients who received their first renal allograft at the Medical University of Vienna between 1990 and 2003 and survived at least 3 mo. Patient and graft survival was compared between patients with versus without ACEI and/or ARB therapy. Data were analyzed with and without propensity score models for ACEI/ARB therapy. Medication and comorbidities were analyzed as time-dependent variables in the Cox regression analyses. Ten-year survival rates were 74% in the ACEI/ARB group but only 53% in the noACEI/ARB group (P<0.001). The hazard ratio (HR) of ACEI/ARB use for mortality was 0.57 (95% confidence interval [CI] 0.40 to 0.81) compared with nonuse. Ten-year actual graft survival rate was 59% in ACEI/ARB patients but only 41% in nonusers (P=0.002). The HR of actual graft failure for ACEI/ARB recipients was 0.55 (95% CI 0.43 to 0.70) compared with nonusers; the HR of functional graft survival was 0.56 (95% CI 0.40 to 0.78). Ten-year unadjusted functional graft survival rates were 76% among ACEI/ARB patients and 71% in noACEI/ARB recipients (P=0.57). In summary, the use of ACEI/ARB therapy was associated with longer patient and graft survival after renal transplantation. More frequent use of these medications may reduce the high incidence of death and renal allograft failure in these patients.

Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism

BACKGROUND Excess body weight is a risk factor for a first venous thromboembolism. The impact of excess body weight on risk of recurrent venous thrombosis is uncertain. METHODS We studied 1107 patients for an average of 46 months after a first unprovoked venous thromboembolism and withdrawal of anticoagulant therapy. Excluded were pregnant patients, those requiring long-term antithrombotic treatment, and those who had a previous or secondary thrombosis, natural coagulation inhibitor deficiency, lupus anticoagulant, or cancer. Our study end point was symptomatic recurrent venous thromboembolism. RESULTS A total of 168 patients had recurrent venous thromboembolism. Mean (SD) body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was significantly higher among patients with recurrence than among those without recurrence: 28.5 (6.0) vs 26.9 (5.0) (P = .01). The relationship between excess body weight and recurrence was linear; the adjusted hazard ratio for each 1-point increase in BMI was 1.044 (95% confidence interval [CI], 1.013-1.076) (P < .001). Four years after discontinuation of anticoagulant therapy, the probability of recurrence was 9.3% (95% CI, 6.0%-12.7%) among patients of normal weight and 16.7% (95% CI, 11.0%-22.3%) and 17.5% (95% CI, 13.0%-22.0%) among overweight and obese patients, respectively. Compared with patients of normal weight, the hazard ratio of recurrence adjusted for age, sex, factor V Leiden, prothrombin G20210A mutation, high factor VIII levels, and type of initial venous thromboembolic event was 1.3 (95% CI, 0.9-1.9) (P = .20) among overweight patients and 1.6 (95% CI, 1.1-2.4) (P = .02) among obese individuals. The population attributable risk corresponding to excess body weight was 26.8% (95% CI, 5.3%-48.2%). CONCLUSION Excess body weight is a risk factor of recurrent venous thromboembolism.

An overview of the objectives of and the approaches to propensity score analyses

The assessment of treatment effects from observational studies may be biased with patients not randomly allocated to the experimental or control group. One way to overcome this conceptual shortcoming in the design of such studies is the use of propensity scores to adjust for differences of the characteristics between patients treated with experimental and control interventions. The propensity score is defined as the probability that a patient received the experimental intervention conditional on pre-treatment characteristics at baseline. Here, we review how propensity scores are estimated and how they can help in adjusting the treatment effect for baseline imbalances. We further discuss how to evaluate adequate overlap of baseline characteristics between patient groups, provide guidelines for variable selection and model building in modelling the propensity score, and review different methods of propensity score adjustments. We conclude that propensity analyses may help in evaluating the comparability of patients in observational studies, and may account for more potential confounding factors than conventional covariate adjustment approaches. However, bias due to unmeasured confounding cannot be corrected for.

Risk prediction models

Prognostic research focuses on the prediction of the future course of a given disease in probability terms. Prognostication is performed by clinical decision makers by using risk prediction models that allow us to estimate the probability that a specific event occurs in a given patient over a predefined time period conditional on prognostic factors (predictors). Before application in clinical practice, risk prediction models should be properly validated by assessing their discrimination and calibration, or explained variation. Reclassification analyses allow us to evaluate the gain in risk prediction by using a new model compared with an established one. We discuss the concepts of developing and validating risk prediction models by means of two examples, the Framingham risk calculator for prediction of coronary heart disease (CHD), and the recently published Renal Risk Score to predict progression of chronic kidney disease (CKD).

Uveal and capsular biocompatibility of hydrophilic acrylic, hydrophobic acrylic, and silicone intraocular lenses

Purpose: To evaluate the long‐term response of 6 types of 3‐piece intraocular lenses (IOLs) by assessing the cellular reaction on the anterior IOL surface, the behavior of posterior and anterior capsule fibrosis, and flare. Setting: Department of Ophthalmology, Medical School, University of Vienna, Vienna, Austria. Methods: One hundred eighty eyes were prospectively randomized to receive 1 of 6 IOLs: hydrophilic acrylic Hydroview® (Bausch & Lomb) or MemoryLens® (ORC); hydrophobic acrylic AcrySof® MA60BM (Alcon) or AMO Sensar AR40® (Allergan); hydrophobic silicone CeeOn® 920 or CeeOn 911A (Pharmacia). The patients had standardized cataract surgery, postoperative medication, and follow‐up. One year after surgery, 155 eyes were assessed. The cellular reaction was evaluated by specular microscopy of the anterior IOL surface. Anterior and posterior capsule opacification (PCO) was assessed semiquantitatively by biomicroscopy. Flare was measured with a Kowa FC‐1000 laser flare‐cell meter. Results: Regarding uveal biocompatibility, the hydrophobic acrylic IOLs showed the highest incidence of late foreign‐body cell reaction (AcrySof, 30%; AR40, 17%) followed by the hydrophilic acrylic (MemoryLens, 8%; Hydroview, 4%) and silicone (CeeOn 920, 4%; CeeOn 911A, 0%) (P = .0044). In all cases, the cellular reaction was low grade and clinically insignificant. Regarding capsular biocompatibility, some eyes developed lens epithelial cell (LEC) outgrowth on the anterior IOL surface. The highest incidence was in the hydrophilic acrylic group (Hydroview, 85%; MemoryLens, 27%) followed by the hydrophobic acrylic (AcrySof, 4%; AR40, 3%). No silicone IOL had LECs on the anterior surface. The difference among IOL groups was significant (P = .0001). Anterior capsule opacification was more predominant in the hydrophobic IOL groups. Posterior capsule opacification of the central 3.0 mm area was lowest in the groups with a sharp‐edged optic (CeeOn 911A, AcrySof) followed by the round‐edged silicone (CeeOn 920), hydrophobic acrylic (AR40), and hydrophilic acrylic IOLs (P = .0001). There was a significant difference in flare between the AR40 lens and the Hydroview, MemoryLens, CeeOn 911A, and CeeOn 920 (P < .004). There was no statistically significant difference in the postoperative cell count at 1 year. The power calculation showed that the sample size was sufficient. Conclusions: The differences in cellular reaction, although clinically mild in normal eyes, indicate that there were more giant cells with hydrophobic acrylic IOLs and an increased tendency toward LEC outgrowth with hydrophilic lenses. The incidence of PCO was lowest in the hydrophobic IOL groups, especially in groups with a sharp‐edged optic. Second‐generation silicone IOLs with a sharp edge had good uveal and capsular biocompatibility 1 year after surgery.

The Short- and Long-Term Benefit in Chronic Low Back Pain Through Adjuvant Electrical Versus Manual Auricular Acupuncture

Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain. Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia. In this prospective, randomized, double-blind, controlled study we tested the hypothesis that auricular electroacupuncture (EA) relieves pain more effectively than conventional manual auricular acupuncture (CO) in chronic low back pain patients with insufficient pain relief (visual analogue scale [VAS] ≥5) treated with standardized analgesic therapy. Disposable acupuncture needles were inserted in the auricular acupuncture points 29, 40, and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear. Patients were randomized into group EA (n = 31) with continuous low-frequency auricular EA (1 Hz biphasic constant current of 2 mA) and group CO (n = 30) without electrical stimulation (sham-electroacupuncture). Treatment was performed once weekly for 6 wk, and in each group needles were withdrawn 48 h after insertion. During the study period and a 3-mo follow-up, patients were asked to complete the McGill questionnaire. Psychological well being, activity level, quality of sleep, and pain intensity were assessed by means of VAS; moreover, analgesic drug consumption was documented. Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO. Similarly, psychological well-being, activity, and sleep were significantly improved in group EA versus group CO, the consumption of analgesic rescue medication was less, and more patients returned to full-time employment. Neuropathic pain in particular improved in patients treated with EA. There were no adverse side effects. These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population.

Prospective Comparison of Flecainide Versus Sotalol for Immediate Cardioversion of Atrial Fibrillation

This study sought to compare the efficacy and safety of intravenous flecainide and sotalol for immediate cardioversion of atrial fibrillation. We performed a prospective, randomized, single-blind, multicenter trial, including 106 hemodynamically stable patients with atrial fibrillation, stratified according to duration of the arrhythmia. Exclusion criteria included severely reduced left ventricular systolic function, recent antiarrhythmic therapy, and hypokalemia. Patients were randomly assigned to receive either intravenous flecainide or intravenous sotalol. Trial medication was given at a dose of 1.5 mg/kg body weight (maximum 150 mg). Overall, 28 of 54 patients (52%) given flecainide and 12 of 52 patients (23%) given sotalol converted to sinus rhythm during the first 2 hours after start of the infusion (p = 0.003). Multivariate analysis confirmed that treatment allocation to flecainide, an arrhythmia duration of < or = 24 hours, higher plasma magnesium level at baseline, higher age for men, and lower age for women independently increases the probability of conversion. The frequency of adverse effects was not significantly different in the 2 treatment groups.

The estimation of average hazard ratios by weighted Cox regression

Often the effect of at least one of the prognostic factors in a Cox regression model changes over time, which violates the proportional hazards assumption of this model. As a consequence, the average hazard ratio for such a prognostic factor is under- or overestimated. While there are several methods to appropriately cope with non-proportional hazards, in particular by including parameters for time-dependent effects, weighted estimation in Cox regression is a parsimonious alternative without additional parameters. The methodology, which extends the weighted k-sample logrank tests of the Tarone-Ware scheme to models with multiple, binary and continuous covariates, has been introduced in the nineties of the last century and is further developed and re-evaluated in this contribution. The notion of an average hazard ratio is defined and its connection to the effect size measure P(X<Y) is emphasized. The suggested approach accomplishes estimation of intuitively interpretable average hazard ratios and provides tools for inference. A Monte Carlo study confirms the satisfactory performance. Advantages of the approach are exemplified by comparing standard and weighted analyses of an international lung cancer study. SAS and R programs facilitate application.

Vitamin D Status and Its Relation to Age and Body Mass Index

Background/Aims: While numerous studies have examined 25(OH)-vitamin D3 (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)2-vitamin D3 (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). Methods: This cross-sectional study comprised a convenience sample of 483 adults which attended the endocrinology outpatient service of a university hospital in the years 2002–2004. Results: The mean concentrations of 25-D, 1,25-D, calcium and PTH were 21.0 ± 10.6 ng/ml, 47.9 ± 21.7 pg/ml, 9.48 ± 0.48 mg/dl and 51.0 ± 27.2 pg/ml, respectively. 25-D was related (p < 0.01) to BMI, age, PTH and 1,25-D. After correction for 25-D, we found no relation between BMI and 1,25-D. PTH was related (p < 0.01) to serum calcium, BMI, age and 1,25-D (p = 0015). There was a seasonal variation in both, 25-D and 1,25-D serum concentrations: 25-D levels were lowest in January and increased until July while the nadir and zenith of 1,25-D were found in April and October, respectively. Conclusion: Since BMI was negatively related to 25-D the prevalence of 25-D deficiency (<8.8 ng/ml) increased from 8.8% in subjects with BMI <30 kg/m2 to 15.0% in subjects with BMI >30 kg/m2. BMI, age and season should be taken into account when assessing a patients vitamin D status and more aggressive vitamin D supplementation should be considered for obese subjects.