Heterozygosity for bisphosphoglycerate mutase deficiency expressing clinically as congenital erythrocytosis: A case series and literature review.

Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically.

Impact of a Patient's Baseline Risk on the Relative Benefit and Harm of a Preventive Treatment Strategy: Applying Trial Results in Clinical Decision Making.

Background For translating an overall trial result into an individual patient's expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field-Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (P=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE-LY trial (P=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE-LY trial (P<0.001) for major bleeding. Quartile-specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26-0.61) to 1.04 (95% CI, 0.83-1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42-0.88) to 1.20 (95% CI, 0.97-1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Individual Treatment Effect Estimation of 2 Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.

BACKGROUND: We aimed to estimate absolute benefit and harm from treatment with dabigatran in individual patients with atrial fibrillation, and to select the optimal dose for each individual. METHODS: We derived and validated a prediction model for ischemic stroke/systemic embolism and major bleeding in patients with atrial fibrillation from the 3 treatment arms of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy With Dabigatran Etexilate) (n=11 955 in derivation cohort, n=6158 in validation cohort). Readily available patient characteristics were included in Fine and Gray competing risk models (sex, age, smoking, antiplatelet drugs, previous vascular disease, diabetes mellitus, blood pressure, estimated glomerular filtration rate, and hemoglobin). Five-year risks for ischemic stroke/systemic embolism and major bleeding were estimated without anticoagulation therapy, and compared with high- and low-dose dabigatran. RESULTS: Model calibration was good, and discrimination was adequate with a c-statistic of 0.65 (95% CI, 0.62-0.70) for ischemic stroke/systemic embolism and 0.69 (95% CI, 0.66-0.71) for major bleeding. The 5-year absolute risk reduction for ischemic stroke/systemic embolism with dabigatran 150 mg twice daily ranged from <10% in 20% of patients to >25% in 14% of patients, and the 5-year absolute risk increase for major bleeding ranged from <5% in 53% of patients to 15% to 20% in 1% of patients. Comparing high-dose to low-dose dabigatran, the net benefit (absolute risk reduction minus absolute risk increase) was positive for 46% of patients. CONCLUSIONS: The absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics. Such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine the optimal dose. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Cost-effectiveness of PCSK9 inhibition in addition to standard lipid-lowering therapy in patients at high risk for vascular disease.

BACKGROUND: As proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibodies are entering the market, we assessed the cost-effectiveness of PCSK9 inhibition added to standard lipid-lowering therapy in patient groups at high risk for major adverse cardiovascular events (MACE). METHODS: A lifetime Markov Model was designed to estimate healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for PCSK9 inhibition added to standard therapy in patients with Familial Hypercholesterolemia (FH), patients with vascular disease at high MACE recurrence risk, and patients with vascular disease with diabetes mellitus. The balance between costs and health outcomes was established for a broad range of potential relative risk reductions and drug costs. RESULTS: The expected QALY gain per patient and ICER in the main scenario were 1.4 QALYs for €78,485/QALY gained in patients with FH, 0.22 QALYs for €176,735/QALY gained in those with vascular disease and a predicted risk of MACE ≥30% in 10years, and 0.22 QALYs for €295,543/QALY gained in those with vascular disease and diabetes. Results were sensitive to assumptions on PCSK9 inhibitor treatment efficacy, and vascular event risks. CONCLUSION: The costs and effects of PCSK9 inhibition added to standard lipid-lowering treatment in patient groups at high risk for MACE can be estimated and adapted to a specific clinical setting. PCSK9 inhibition could be cost-effective in patients with FH. In patients with vascular disease PCSK9 inhibition is less cost-effective, however, a price development may change clinical practice. This model may aid treatment and reimbursement decisions regarding PCSK9 inhibitors.

Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes.

OBJECTIVE: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity and mortality. The vascular burden in terms of incidence of cardiovascular events (CVE) and vascular interventions is however poorly quantified. In this study we evaluated the incidence rates of CVE and vascular interventions in patients with type 2 diabetes (T2DM) with and without cardiovascular disease (CVD) in comparison to patients without type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 9.808 high-risk patients with and without cardiovascular disease and type 2 diabetes originated from the ongoing, single-center prospective SMART (Second Manifestations of ARTerial disease) cohort, the number and incidence rates of CVE and interventions were calculated. The incidence rates were adjusted for confounders using Poisson regression models. CVE were defined as vascular death, stroke and myocardial infarction (MI). Interventions were defined as percutaneous coronary intervention, coronary artery bypass grafting, percutaneous transluminal angioplasty or stenting of the peripheral arteries and amputation. RESULTS: Patients with T2DM and CVD had a 4-fold higher incidence rate of CVE and a 8-fold higher incidence rate of vascular interventions compared to high-risk patients without T2DM and CVD after adjusting for confounders. The incidence rate for the composite of non-fatal MI, non-fatal stroke and vascular death was 5.8 per 1000person-years in patients without T2DM or CVD at baseline, 15.2 per 1000person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000person-years in patients without T2DM but with CVD and 40.7 per 1000person-years in patients with both T2DM and CVD at baseline. A similar increasing incidence rate was seen for all vascular interventions from patients without T2DM or CVD to patients with both T2DM and CVD. CONCLUSIONS: Patients with type 2 diabetes or CVD are subject to an increased incidence of cardiovascular events and interventions compared to high-risk patients without type 2 diabetes or vascular disease. Patients with type 2 diabetes and CVD have the highest incidence of new cardiovascular diseases and vascular interventions when compared to patients without type 2 diabetes and CVD. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very high risk population.

Cost-Effectiveness of Intensifying Lipid-Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients.

BACKGROUND: A validated prediction model estimates the absolute benefit of intensive versus standard lipid-lowering therapy (LLT) with statins on next major cardiovascular events for individual patients with coronary artery disease. We aimed to assess whether targeting intensive LLT therapy to coronary artery disease patients with the highest predicted absolute benefit is cost-effective compared to treating all with standard or all with intensive LLT. METHODS AND RESULTS: A lifetime Markov model was constructed for coronary artery disease patients (n=10 000) with mean age 61 years. Number of major cardiovascular events, (non) vascular death, costs, and quality-adjusted life years (QALYs) were estimated for the following strategies: (1) standard LLT for all (reference strategy); (2) intensive LLT for those with 5-year absolute major cardiovascular events risk reduction (ARR) ≥3%, ≥2.3%, or ≥1.5% (corresponding to ≥20%, ≥15%, or ≥10% 5-year major cardiovascular events risk); and (3) intensive LLT for all. With intensive LLT for those with ≥3% 5-year ARR (13% of patients), 380 QALYs were gained for €2423/QALY. Using a threshold of ≥2.3% ARR (26% of patients), 630 QALYs were gained for €5653/QALY. Using a threshold of ≥1.5% ARR (56% of patients), 1020 QALYs were gained for €10 960/QALY. By treating all intensively, 1410 QALYs were gained (0.14 QALY per patient) for €17 223/QALY. With benefit-based treatment, 0.16 to 0.17 QALY was gained per treated patient. CONCLUSIONS: Intensive LLT with statins for all coronary artery disease patients results in the highest overall QALY gain against acceptable costs. However, the number of QALYs gained with intensive LLT by statins in individual patients can be increased with selective benefit-based treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00327691 and NCT00159835.

Personalized absolute benefit of statin treatment for primary or secondary prevention of vascular disease in individual elderly patients.

OBJECTIVE: To estimate the absolute treatment effect of statin therapy on major adverse cardiovascular events (MACE; myocardial infarction, stroke and vascular death) for the individual patient aged ≥70 years. METHODS: Prediction models for MACE were derived in patients aged ≥70 years with (n = 2550) and without (n = 3253) vascular disease from the "PROspective Study of Pravastatin in Elderly at Risk" (PROSPER) trial and validated in the "Secondary Manifestations of ARTerial disease" (SMART) cohort study (n = 1442) and the "Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm" (ASCOT-LLA) trial (n = 1893), respectively, using competing risk analysis. Prespecified predictors were various clinical characteristics including statin treatment. Individual absolute risk reductions (ARRs) for MACE in 5 and 10 years were estimated by subtracting on-treatment from off-treatment risk. RESULTS: Individual ARRs were higher in elderly patients with vascular disease [5-year ARRs: median 5.1 %, interquartile range (IQR) 4.0-6.2 %, 10-year ARRs: median 7.8 %, IQR 6.8-8.6 %] than in patients without vascular disease (5-year ARRs: median 1.7 %, IQR 1.3-2.1 %, 10-year ARRs: 2.9 %, IQR 2.3-3.6 %). Ninety-eight percent of patients with vascular disease had a 5-year ARR ≥2.0 %, compared to 31 % of patients without vascular disease. CONCLUSIONS: With a multivariable prediction model the absolute treatment effect of a statin on MACE for individual elderly patients with and without vascular disease can be quantified. Because of high ARRs, treating all patients is more beneficial than prediction-based treatment for secondary prevention of MACE. For primary prevention of MACE, the prediction model can be used to identify those patients who benefit meaningfully from statin therapy.

Effect of Type 2 Diabetes on Recurrent Major Cardiovascular Events for Patients With Symptomatic Vascular Disease at Different Locations.

OBJECTIVE: Our aim is to compare the effect of type 2 diabetes on recurrent major cardiovascular events (MCVE) for patients with symptomatic vascular disease at different locations. RESEARCH DESIGN AND METHODS: A total of 6,841 patients from the single-center, prospective Second Manifestations of ARTerial disease (SMART) cohort study from Utrecht, the Netherlands, with clinically manifest vascular disease with (n = 1,155) and without (n = 5,686) type 2 diabetes were monitored between 1996 and 2013. The effect of type 2 diabetes on recurrent MCVE was analyzed with Cox proportional hazards models, stratified for disease location (cerebrovascular disease, peripheral artery disease, abdominal aortic aneurysm, coronary artery disease, or polyvascular disease, defined as ≥2 vascular locations). RESULTS: Five-year risks for recurrent MCVE were 9% in cerebrovascular disease, 9% in peripheral artery disease, 20% in those with an abdominal aortic aneurysm, 7% in coronary artery disease, and 21% in polyvascular disease. Type 2 diabetes increased the risk of recurrent MCVE in coronary artery disease (hazard ratio [HR] 1.67; 95% CI 1.25-2.21) and seemed to increase the risk in cerebrovascular disease (HR 1.36; 95% CI 0.90-2.07), while being no risk factor in polyvascular disease (HR 1.12; 95% CI 0.83-1.50). Results for patients with peripheral artery disease (HR 1.42; 95% CI 0.79-2.56) or an abdominal aortic aneurysm (HR 0.93; 95% CI 0.23-3.68) were inconclusive. CONCLUSIONS: Type 2 diabetes increased the risk of recurrent MCVE in patients with coronary artery disease, but there is no convincing evidence that it is a major risk factor for subsequent MCVE in all patients with symptomatic vascular disease.

No evidence for distinguishing bacterial from viral acute rhinosinusitis using symptom duration and purulent rhinorrhea: a systematic review of the evidence base.

OBJECTIVE: To evaluate the diagnostic value of symptom duration and purulent rhinorrhea in adults suspected of having acute bacterial rhinosinusitis. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library. REVIEW METHODS: We performed a comprehensive systematic search on March 28, 2013. We included studies on the diagnostic value of duration of symptoms and purulent rhinorrhea in patients suspected of having acute bacterial rhinosinusitis. We assessed study design of included articles for directness of evidence and risk of bias. We extracted prevalence and positive and negative predictive values. RESULTS: Of 4173 unique publications, we included 1 study with high directness of evidence and moderate risk of bias. The prior probability of bacterial rhinosinusitis was 0.29 (95% confidence interval [CI], 0.24-0.35); we could not extract posterior probabilities. Odds ratios (95% CI) from univariate analysis were 1.03 (0.78-1.36) for duration of symptoms and 2.69 (1.39-5.18) for colored discharge on the floor of the nasal cavity. CONCLUSION AND RECOMMENDATION: We included 1 study with moderate risk of bias, reporting data in such a manner that we could not assess the value of symptom duration and purulent rhinorrhea in adults suspected of having acute bacterial rhinosinusitis. Recommendations to distinguish between a viral and a bacterial source based on purulent rhinorrhea are not supported by evidence, and the decision to prescribe antibiotic treatment should not depend on its presence. Based on judgment driven by theory and subsidiary evidence of a greater likelihood of bacterial rhinosinusitis after 10 days, antibiotic therapy may seem a reasonable empirical option.