Séverine Henrard

Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study

CONTEXT The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. OBJECTIVE To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden. DESIGN Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). PATIENTS All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. MAIN OUTCOME MEASURE Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. RESULTS Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. CONCLUSIONS In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.

Coronary artery calcification: a strong predictor of cardiovascular events in renal transplant recipients

BACKGROUND Coronary artery calcification (CAC) independently predicts cardiovascular events (CVE) in the general population. Whether this applies to renal transplant recipients (RTR) is unknown. This prospective study assessed the prognostic impact of CAC on CVE in RTR. METHODS We followed up a published cohort of 281 prevalent RTR. At baseline, 16-slice chest spiral computerized tomography scan was performed and classical as well as CKD-related risk factors were recorded. Major CVE (MCVE) was defined as cardiovascular death, myocardial infarction, stroke or transient ischaemic attack. All CVE (ACVE) included MCVE and revascularizations. Prognostic factors were assessed by univariate and multivariate Cox regression. RESULTS During 2.3 ± 0.5 years of follow-up, 16 patients died from CV (n = 8) or non-CV causes (n = 8). Thirty-one RTR developed at least one CVE (first CVE cardiac in 15, peripheral in 12 and cerebrovascular in 4) for a total of 36 CVE. Thirty-month CV survival, MCVE-free survival and ACVE-free survival was 96.4, 93.9 and 87.9%, respectively. By multivariate analysis, the independent predictors of ACVE were CAC score (hazards ratios [HR] = 1.40 [1.12; 1.75] for a 2.72-fold increase in CAC, P < 0.003) and history of CVE (HR = 2.76 [1.21; 6.39], P < 0.02). CONCLUSION Our study shows for the first time that CAC is a strong independent predictor of CVE in RTR.

A prognostic index for progression-free survival in malignant mesothelioma with application to the design of phase II trials: A combined analysis of 10 EORTC trials.

PURPOSE For cytostatic agents or when the response assessment is difficult, adaptations to phase II designs may allow a better assessment of therapeutic activity: first by using the progression-free survival rate (PFSR) as primary end-point instead of the response rate, and second by considering progression-free survival (PFS) risk groups based on a prognostic index (PI). In mesothelioma, current treatments yield disappointingly poor results and there is a need to investigate new regimens. The purpose of this report is to provide a PI for PFS in mesothelioma and reference values for the PFSR. MATERIALS AND METHODS Data on 523 patients included in 10 European Organisation for Research and Treatment of Cancer (EORTC) mesothelioma studies were analysed to identify prognostic factors using a multivariate Cox regression model. Subsequently, a PI and a nomogram for PFS were developed. The PFSRs at 3, 4, 5 and 6 months were estimated. RESULTS A performance status>0, stage IV disease and mixed or sarcomatous histological type were indicators of a poor prognosis for PFS. From the PI, based on these three variables, four risk groups were defined. The median progression-free survival ranged from 5.3 to 2.1 months in these risk categories. The PFSRs at 3 months were 70.6%, 62.4%, 54.2% and 42.1% in the four categories, respectively. CONCLUSION The PI allows dividing patients into homogeneous risk categories in which PFSRs can be calculated and used to design future phase II mesothelioma trials. Defining homogeneous categories of patients avoids dilution of results between groups and improves the assessment of therapeutic activity.

Classification and regression tree analysis vs. multivariable linear and logistic regression methods as statistical tools for studying haemophilia

Haemophilia is a rare genetic haemorrhagic disease characterized by partial or complete deficiency of coagulation factor VIII, for haemophilia A, or IX, for haemophilia B. As in any other medical research domain, the field of haemophilia research is increasingly concerned with finding factors associated with binary or continuous outcomes through multivariable models. Traditional models include multiple logistic regressions, for binary outcomes, and multiple linear regressions for continuous outcomes. Yet these regression models are at times difficult to implement, especially for non‐statisticians, and can be difficult to interpret.

Risk scores and geriatric profile: can they really help us in anticoagulation decision making among older patients suffering from atrial fibrillation?

Objectives Anticoagulation for the prevention of cardio-embolism is most frequently indicated but largely underused in frail older patients with atrial fibrillation (AF). This study aimed at identifying characteristics associated with anticoagulation underuse. Methods A cross-sectional study of consecutive geriatric patients aged ≥75 years, with AF and clear anticoagulation indication (CHADS2 [Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack] ≥2) upon hospital admission. All patients benefited from a comprehensive geriatric assessment. Their risks of stroke and bleeding were predicted using CHADS2 and HEMORR2HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age >75 years), Reduced platelet count or function, Rebleed risk, Hypertension (uncontrolled), Anemia, Genetic factors, Excessive fall risk, and Stroke) scores, respectively. Results Anticoagulation underuse was observed in 384 (50%) of 773 geriatric patients with AF (median age 85 years; female 57%, cognitive disorder 33%, nursing home 20%). No geriatric characteristic was found to be associated with anticoagulation underuse. Conversely, anticoagulation underuse was markedly increased in the patients treated with aspirin (odds ratio [OR] [95% confidence interval]: 5.3 [3.8; 7.5]). Other independent predictors of anticoagulation underuse were ethanol abuse (OR: 4.0 [1.4; 13.3]) and age ≥90 years (OR: 2.0 [1.2; 3.4]). Anticoagulation underuse was not inferior in patients with a lower bleeding risk and/or a higher stroke risk and underuse was surprisingly not inferior either in the AF patients who had previously had a stroke. Conclusion Half of this geriatric population did not receive any anticoagulation despite a clear indication, regardless of their individual bleeding or stroke risks. Aspirin use is the main characteristic associated with anticoagulation underuse.

The health and economic burden of haemophilia in Belgium: a rare, expensive and challenging disease

BackgroundHaemophilia is a rare hereditary haemorrhagic disease that requires regular intravenous injections of clotting factor (CF) concentrates. This study sought to estimate the health and economic burden of haemophilia in Belgium. This is the first study of its type to be conducted, and reflects the Belgian authorities’ growing interest for haemophilia as part of their priority planning for rare and chronic diseases.MethodsA probabilistic model was developed in order to estimate the lifetime haemophilia burden for the 2011 birth-year Belgian cohort. The health burden was initially expressed in terms of disability-adjusted life years (DALYs), the number of healthy life years lost due to living with disability and dying prematurely. An incidence perspective was used in line with World Health Organization recommendations. The economic burden calculated from direct and indirect haemophilia-related costs was expressed in euros. Data were drawn from the literature if none were available from federal institutions or health insurance. Disability weights for DALY calculation were derived using generic quality-of-life tools such as SF-6D from the SF-36 (36-item Short-Form Health Survey; for adults) and KINDL (generic quality-of-life instrument; for children) compared to population norms. Analyses were stratified according to haemophilia type and severity.ResultsIn Belgium, haemophilia resulted in 145 undiscounted and unweighted DALYs in total (95% credible interval [CrI] = 90-222), which represents an average of 11 DALYs per incident case with haemophilia (95% CrI = 8-15) during his life, varying according to haemophilia severity (17 DALYs for severe haemophilia, 12 DALYs for moderate, and 4 DALYs for mild). Mean total lifetime costs reached €7.8 million per people with haemophilia, 94.3% being direct costs and 5.7% indirect costs. Clotting factors accounted for 82.5% of direct costs.ConclusionsHaemophilia represents both an economic and health burden, especially regarding individual health on an individual patient level. Initiatives to counteract this burden should be clearly identified and given full support, as this burden is likely to increase in the future, especially from an economic perspective. Our study may also contribute towards a better global evaluation of haemophilia in the future.

Impact of being underweight or overweight on factor VIII dosing in hemophilia A patients

Since 1981, the number of factor VIII units to infuse into patients with hemophilia A in order to achieve adequate circulating factor VIII levels has been calculated using the formula: [body weight(kg)×desired factor VIII increase(%)]/2, assuming a factor VIII recovery value of 2 for all patients. This study’s aim was to evaluate the impact of several morphometric parameters and various coagulation factor concentrates on factor VIII recovery. The analysis included 201 hemophilia A adults (>18 years of age) who were carefully selected from eight pharmacokinetic clinical trials using three recombinant factor VIII concentrates (Advate®, Kogenate® FS, or ReFacto AF®/Xyntha®). Regression tree analysis was used to identify factor VIII recovery predictors. The median factor VIII recovery was 2.16 for all patients. Using regression tree analysis, patients were separated into three groups on the basis of body mass index: below 20.3 kg/m2, between 20.3 and 29.5 kg/m2, and 29.6 kg/m2 or more. Each group had a significantly different median factor VIII recovery (P<0.001): 1.60, 2.14, and 2.70, respectively. The type of coagulation factor concentrate had no influence on recovery in the regression tree. In conclusion, factor VIII dosing should be adapted to underweight and overweight patients, as a factor VIII recovery of 2 does not apply to these patients. Ideal body weight should be considered instead of actual body weight in the dose calculations.

Body weight and fat mass index as strong predictors of factor VIII in vivo recovery in adults with hemophilia A

Summary.  Background: The treatment of hemophilia A requires infusions of factor VIII (FVIII) concentrates. The number of units to be given in order to obtain the target level is calculated using the formula: [body weight (BW) × desired FVIII increase]/2, which assumes that each unit infused per kg of BW increases the FVIII level by 2%. Objectives: The present observational study evaluated the dependence of FVIII recovery on different morphometrical variables: BW, fat mass index (FMI), body mass index, and the difference between actual and ideal BW. Patients and methods: FVIII recovery was measured in 46 non‐actively bleeding hemophilia A patients, being treated with a recombinant FVIII concentrate. Regression trees were used to identify morphometrical predictors of recovery. Results: The median recovery was 2.08 for all patients, 2.63 for those with a BW ≥ 81.0 kg and 1.87 for others (P < 0.001). The recovery was significantly higher when FMI was ≥ 20% compared with FMI < 15% (median recovery: 2.35 vs. 1.74; P = 0.007). Using regression trees, three groups were created: BW < 80.5 kg and FMI < 22.3%, BW < 80.5 kg and FMI ≥ 22.3% and BW ≥ 80.5 kg. Median recovery in these groups was 1.80, 2.16 and 2.63, respectively (P < 0.001). Conclusions: The dose calculation of FVIII should take into account both BW and FMI, and be adapted to underweight or overweight patients. Comparison of the average recovery after different FVIII concentrates should keep in mind morphometrical patient characteristics.

Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

Impact of being overweight on factor VIII dosing in children with haemophilia A.

Treatment of haemophilia A (HA) requires infusions of factor VIII (FVIII) concentrates. The number of FVIII units infused to obtain a specific circulating FVIII level is calculated with the formula: [body weight (BW) (kg) × desired FVIII increase (%)]/2, with the assumption that each unit of FVIII infused per kg of BW increases the circulating FVIII level by 2%.