Milosz Jankowski

Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic Review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Development of clinical practice guidelines involves making trade-offs between desirable and undesirable consequences of alternative management strategies. Although the relative value of health states to patients should provide the basis for these trade-offs, few guidelines have systematically summarized the relevant evidence. We conducted a systematic review relating to values and preferences of patients considering antithrombotic therapy. METHODS We included studies examining patient preferences for alternative approaches to antithrombotic prophylaxis and studies that examined, in the context of antithrombotic prophylaxis or treatment, how patients value alternative health states and experiences with treatment. We conducted a systematic search and compiled structured summaries of the results. Steps in the process that involved judgment were conducted in duplicate. RESULTS We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four with stroke or myocardial infarction prophylaxis, six with thrombolysis in acute stroke or myocardial infarction, and 17 with burden of antithrombotic treatment. CONCLUSION Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.

Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects

Objective—Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. Methods and Results—We studied healthy men not taking any medication (n=76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n=33), men with diabetes mellitus diagnosed recently (median hemoglobin A1c 7.65%; n=16), and patients with isolated hypercholesterolemia (>7.0 mmol/L; n=15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R2=0.88, P<0.0001 and R2=0.54, P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R2=0.84; P<0.0001) than was fibrinogen alone (R2=0.66; P<0.0001), whereas tHcy was the only predictor of lysis time (R2=0.69; P<0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P=0.0002) and shorter lysis time (P<0.0001). Conclusions—Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy–thiolactone.

Risk prediction models for mortality in ambulatory patients with heart failure: a systematic review

Background—Optimal management of heart failure requires accurate assessment of prognosis. Many prognostic models are available. Our objective was to identify studies that evaluate the use of risk prediction models for mortality in ambulatory patients with heart failure and describe their performance and clinical applicability. Methods and Results—We searched for studies in Medline, Embase, and CINAHL in May 2012. Two reviewers selected citations including patients with heart failure and reporting on model performance in derivation or validation cohorts. We abstracted data related to population, outcomes, study quality, model discrimination, and calibration. Of the 9952 studies reviewed, we included 34 studies testing 20 models. Only 5 models were validated in independent cohorts: the Heart Failure Survival Score, the Seattle Heart Failure Model, the PACE (incorporating peripheral vascular disease, age, creatinine, and ejection fraction) risk score, a model by Frankenstein et al, and the SHOCKED predictors. The Heart Failure Survival Score was validated in 8 cohorts (2240 patients), showing poor-to-modest discrimination (c-statistic, 0.56–0.79), being lower in more recent cohorts. The Seattle Heart Failure Model was validated in 14 cohorts (16 057 patients), describing poor-to-acceptable discrimination (0.63–0.81), remaining relatively stable over time. Both models reported adequate calibration, although overestimating survival in specific populations. The other 3 models were validated in a cohort each, reporting poor-to-modest discrimination (0.66–0.74). Among the remaining 15 models, 6 were validated by bootstrapping (c-statistic, 0.74–0.85); the rest were not validated. Conclusions—Externally validated heart failure models showed inconsistent performance. The Heart Failure Survival Score and Seattle Heart Failure Model demonstrated modest discrimination and questionable calibration. A new model derived from contemporary patient cohorts may be required for improved prognostic performance.

Antibodies to N -homocysteinylated albumin as a marker for earlyonset coronary artery disease in men

N-homocysteinylated (Nepsilon-Hcy) proteins and corresponding antibodies have recently been discovered in humans and animals. Increased autoimmune response to Nepsilon-Hcy-proteins has been reported in stroke patients. The aim of the present study was to investigate whether antibodies against N-homocysteinylated albumin are associated with coronary artery disease (CAD). We studied 88 male patients aged 50 years or under with angiographically documented CAD and 100 age-matched apparently healthy men as controls. Serum levels of IgG antibodies against Nepsilon-Hcy-albumin were determined using an enzymelinked immunosorbent assay. Seropositivity to anti-Nepsilon-Hcy-albumin antibodies was 5-fold more frequent in CAD patients than in controls (52.3% vs 10.0%; p<0.0001). Plasma Hcy levels in CAD patients were also significantly higher in the former than in the latter group (medians, 13.0 microM vs 12.1 microM; p=0.026). Importantly, 41.2% of subjects with plasma total Hcy >14.5 mM were seropositive compared with 25.5% of normohomocysteinemic individuals (p=0.048). There was a weak correlation between anti-Nepsilon-Hcy-albumin antibodies and Hcy levels (r=0.16; p=0.03). By multivariate logistic regression analysis, seropositivity to anti-Nepsilon-Hcy-albumin antibodies was an independent predictor of early CAD (OR, 14.82; 95% CI, 4.47 to 49.19; p=0.00002). Interestingly, anti-Nepsilon-Hcy-albumin antibodies were associated with C-reactive protein levels (r=0.24; p=0.002). Seropositivity to anti-Nepsilon-Hcy-albumin antibodies showed no association with the MTHFR C677T polymorphism. Our results suggest that seropositivity to antibodies against Nepsilon-homocysteinylated albumin is associated with early-onset CAD. An autoimmune response to Nepsilon-Hcy-albumin may represent a novel mechanism involved in the early development of CAD.

Treatment of Hyperhomocysteinemia with Folic Acid and Vitamins B12 and B6 Attenuates Thrombin Generation

The effect of homocysteine-lowering treatment on thrombin generation was investigated in 17 subjects with hyperhomocysteinemia (aged 22-60 years), 11 of whom had symptomatic atherosclerotic vascular disease. All subjects had fasting total homocysteine levels above 16 micromol/L. The formation of thrombin was assessed by measuring thrombin-antithrombin III complexes and prothrombin fragment 1+2 in peripheral venous blood and in the bleeding time blood collected at 30-second intervals from skin incisions on a forearm. All the tests were performed before and after an 8-week treatment with folic acid p.o. 5 mg/day, vitamin B6 p.o. 300 mg/day, and vitamin B12 i.m. 1000 microg given on a weekly basis. Following the 8-week therapy, the median plasma homocysteine concentration became significantly reduced from 20 to 10 micromol/L, while plasma levels of fibrinogen, prothrombin, and antithrombin III as well as activity of protein C, S, and factor VII showed no changes. Vitamin treatment was associated with a significant fall in thrombin-antithrombin III complexes and prothrombin fragment 1+2 concentrations in peripheral venous blood. Bleeding time became prolonged by about 60 seconds. At sites of hemostatic plug formation, plasma concentrations of both thrombin markers significantly decreased. Compared with pretreatment values, significantly less thrombin was produced during the first 3 minutes of bleeding after homocysteine-lowering therapy. In subjects with hyperhomocysteinemia a reduction of plasma fasting homocysteine concentration by folic acid and vitamins B12 and B6 administration is associated with attenuation of thrombin generation both in peripheral blood and at sites of hemostatic plug formation.

Risk Prediction Models for Mortality in Ambulatory Patients With Heart Failure

Background—Optimal management of heart failure requires accurate assessment of prognosis. Many prognostic models are available. Our objective was to identify studies that evaluate the use of risk prediction models for mortality in ambulatory patients with heart failure and describe their performance and clinical applicability. Methods and Results—We searched for studies in Medline, Embase, and CINAHL in May 2012. Two reviewers selected citations including patients with heart failure and reporting on model performance in derivation or validation cohorts. We abstracted data related to population, outcomes, study quality, model discrimination, and calibration. Of the 9952 studies reviewed, we included 34 studies testing 20 models. Only 5 models were validated in independent cohorts: the Heart Failure Survival Score, the Seattle Heart Failure Model, the PACE (incorporating peripheral vascular disease, age, creatinine, and ejection fraction) risk score, a model by Frankenstein et al, and the SHOCKED predictors. The Heart Failure Survival Score was validated in 8 cohorts (2240 patients), showing poor-to-modest discrimination (c-statistic, 0.56–0.79), being lower in more recent cohorts. The Seattle Heart Failure Model was validated in 14 cohorts (16 057 patients), describing poor-to-acceptable discrimination (0.63–0.81), remaining relatively stable over time. Both models reported adequate calibration, although overestimating survival in specific populations. The other 3 models were validated in a cohort each, reporting poor-to-modest discrimination (0.66–0.74). Among the remaining 15 models, 6 were validated by bootstrapping (c-statistic, 0.74–0.85); the rest were not validated. Conclusions—Externally validated heart failure models showed inconsistent performance. The Heart Failure Survival Score and Seattle Heart Failure Model demonstrated modest discrimination and questionable calibration. A new model derived from contemporary patient cohorts may be required for improved prognostic performance.

Thrombin generation in chronic obstructive pulmonary disease: Dependence on plasma factor composition

BACKGROUND Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for thromboembolic events. We investigated thrombin generation profiles in COPD patients and their dependence on plasma factor/inhibitor composition. METHODS Factors (f) (fII, fV, fVII, fVIII, fIX, fX), antithrombin, protein C (PC) and free tissue factor pathway inhibitor (fTFPI) from 60 COPD patients (aged 64.2 ± 10.1 years; a mean forced expiratory volume in 1 second [FEV(1)], 55.6 ± 15.8% of predicted values) were compared with those for 43 controls matched for age, sex, weight and smoking. Patients receiving anticoagulation were excluded. Using each individuals plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed computationally. RESULTS COPD patients had higher fII (115 ± 16 vs 102 ± 10%, p < 0.0001), fV (114 ± 19 vs 102 ± 12%, p = 0.0002), fVII (111 ± 15 vs 102 ± 17%, p = 0.002), fVIII (170 ± 34 vs 115 ± 27%, p < 0.0001), and fIX (119 ± 21 vs 107 ± 17%, p = 0.003), and lower fTFPI (17.7 ± 3.2 vs 18.9 ± 3.2 ng/ml, p = 0.047) compared with controls, while fX, antithrombin, and PC were similar in both groups. Computational thrombin generation profiles showed that compared with controls, COPD patients had higher maximum thrombin levels (+28.3%, p < 0.0001), rates of thrombin generation (+46.1%, p < 0.0001) and total thrombin formation (+14.4%, p < 0.001), together with shorter initiation phase of thrombin generation (p < 0.0001) and the time to maximum thrombin levels (p < 0.0001). Thrombin generation profiles in COPD patients can be normalized via correction of fII, fVIII , fIX and TFPI. The severity of COPD and inflammatory markers were not associated with thrombin generation profiles. CONCLUSIONS Prothrombotic phenotype in COPD patients is largely driven by increased prothrombin, fVIII, fIX, and lower fTFPI.

Continuous renal replacement therapy during extracorporeal membrane oxygenation in patients treated in medical intensive care unit: technical considerations.

Extracorporeal membrane oxygenation (ECMO) is used as a salvage therapy in refractory acute respiratory distress syndrome (ARDS). Although technological progress in the ECMO systems improved the survival rate, prognosis is still significantly worsened by acute kidney injury (AKI), particularly if renal replacement therapy (RRT) is required. There are no exact guidelines recommending which techniques of ECMO and continuous RRT (CRRT) should be used for management of AKI coexisting with respiratory or circulatory failure, and how to combine them. The aim of this review is to describe methods of CRRT and ECMO simultaneous application, and to present advantages of various technical approaches versus possible complications.

Systematic review and network meta-analysis of interventions for fibromyalgia: a protocol

BackgroundFibromyalgia is associated with substantial socioeconomic loss and, despite considerable research including numerous randomized controlled trials (RCTs) and systematic reviews, there exists uncertainty regarding what treatments are effective. No review has evaluated all interventional studies for fibromyalgia, which limits attempts to make inferences regarding the relative effectiveness of treatments.Methods/designWe will conduct a network meta-analysis of all RCTs evaluating therapies for fibromyalgia to determine which therapies show evidence of effectiveness, and the relative effectiveness of these treatments. We will acquire eligible studies through a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, PsychINFO, PapersFirst, ProceedingsFirst, and the Cochrane Central Registry of Controlled Trials. Eligible studies will randomly allocate patients presenting with fibromyalgia or a related condition to an intervention or a control. Teams of reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-important outcomes when possible. To assess relative effects of treatments, we will construct a random effects model within the Bayesian framework using Markov chain Monte Carlo methods.DiscussionOur review will be the first to evaluate all treatments for fibromyalgia, provide relative effectiveness of treatments, and prioritize patient-important outcomes with a focus on functional gains. Our review will facilitate evidence-based management of patients with fibromyalgia, identify key areas for future research, and provide a framework for conducting large systematic reviews involving indirect comparisons.

International Diabetes Federation document concerning postmeal glycemic control: assessment of quality of clinical practice guidelines using AGREE instrument.

Clinical practice guidelines constitute one of the most important sources of information and education for physicians. Therefore, establishing rules to develop and appraise such guidelines properly is of increasing importance. This task is served by the AGREE (Appraisal of Guidelines Research and Evaluation) instrument, a questionnaire, which, according to its authors, allows reproducible assessment of guideline quality. The aim of this paper is to allow readers familiarize themselves with such rules of guidelines appraisal. In order to achieve this purpose, we present the actual application of the AGREE instrument using as an example recently published document on postmeal hyperglycemia issued by the International Diabetes Federation.