The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients.

PURPOSE: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. METHODS: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. RESULTS: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. CONCLUSION: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation.

Anti Xa activity after high dose LMWH thrombosis prophylaxis in covid 19 patients at the intensive care unit.

INTRODUCTION: Coagulopathy in Coronavirus disease 2019 (covid-19) has been demonstrated by an increase in D-dimer, prothrombin time (PT), fibrinogen and factor VIII. Venous thromboembolic events are a common abnormality in patients with covid-19. We evaluate the results of intensive care unit (ICU) thrombosis prophylaxis of 5700 international unit (IU) nadroparin low molecular weight heparin (LMWH) twice daily. METHODS: After introduction of this high-dose pharmacological thrombosis prophylaxis twice weekly anti-factor Xa (anti Xa) concentrations and results from routine laboratory and viscoelastic hemostatic tests in 16 ICU covid-19 patients were evaluated. RESULTS: During one week, median peak anti Xa activities were 0.38 [0.16-0.45] and 0.38 [0.20-0.58] at time point 1 and 2 respectively. Laboratory coagulation tests showed PT, AT and platelet count (PltC) values within normal range and markedly increased D-dimer and fibrinogen levels. Viscoelastic tests showed a maximum clot strength just above normal reference value, while fibrin clot strength was strongly increased. The overall contribution of fibrin to clot strength was high with 71 [56-85]%. CONCLUSION: Anti Xa activity was within the target range of pharmacodynamic endpoint for covid-19 patients but viscoelastic tests still demonstrated a procoagulant pattern.

The relevance of geriatric assessment for older patients receiving palliative chemotherapy.

OBJECTIVES: No tools accurately discriminate between older patients who are fit and those who are frail to tolerate systemic palliative treatment. This study evaluates whether domains of geriatric assessment (GA) are associated with increased risk of chemotherapy intolerance in patients who were considered fit to start palliative chemotherapy after clinical evaluation by their treating clinician. MATERIALS AND METHODS: This prospective multicenter study included patients ≥70 years who started first line palliative systemic treatment. Before treatment initiation, patients completed GA including Activities of Daily Life (ADL), Instrumental Activities of Daily Life (IADL), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS-15) and the Timed Up and Go Test (TUGT). Primary endpoint was treatment modification, defined as inability to complete the first three sessions of systemic treatment as planned. Secondary endpoint was treatment related toxicity ≥ grade 3 (CTCAE Version 4). The association between GA and endpoints were assessed using univariable and multivariable logistic regression analysis. RESULTS: Ninety-nine patients with median age of 77 (+/- 8) years underwent GA. 48% of the patients required treatment modification and grade 3 toxicity occurred in 53% of patients. One or more geriatric impairments were present in 71% of patients and 32% of patients were frail in two or more domains. Only TUGT was associated with treatment modifications (OR 2.9 [95% CI 1.3-6.5]) and grade 3 toxicities (OR 2.8 [95% CI 1.2-6.3]). CONCLUSION: Frailty was common in older patients who were considered fit to receive palliative chemotherapy. Treatment modification was necessary in half of the patients. Only TUGT was significantly associated with treatment modifications and grade 3 chemotherapy toxicities.

Hairy cell leukemia presenting with Ecthyma Gangrenosum- a case report.

BACKGROUND: Ecthyma gangrenosum is a cutaneous infectious usually associated with P. aeruginosa. It usually develops In patients with an underlying immunodeficiency. CASE PRESENTATION: A 50-year old mentally disabled white male with a history of epilepsy presented with fever and a painless red macule on his right arm which rapidly progressed to a painful ulcer. Blood and lesion cultures revealed P.aeruginosa, confirming our clinical diagnosis of ecthyma gangrenosum. Subsequently an underlying immune deficit was found, namely patient was diagnosed with hairy-cell leukemia. Despite adequate antibiotics no infection control could be achieved. After treating the underlying immune deficit as well, the infection and hairy-cell leukemia resolved completely. CONCLUSION: Ecthyma gangrenosum is an important cutaneous infection to recognize, because it is it is typically associated with P.aeruginosa bacteremia. Recognizing this skin leasion should prompt empiric antimicrobial therapy including an agent with antipseudomonal activity. Furthermore, just like in our case, the presence of ecthyma gangrenosum can signal the presence of an occult immune deficit, warranting further investigation.

Ciprofloxacin strongly inhibits clozapine metabolism: two case reports.

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient's clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin.

A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism.

OBJECTIVES: Diagnostic strategies in patients with suspected pulmonary embolism have been extensively studied in outpatients; their value in hospitalized patients has not been well established. Our aim was to determine the safety and clinical utility of a simple diagnostic strategy in hospitalized patients with suspected pulmonary embolism. DESIGN: Prospective management study. SETTING: Twelve teaching hospitals (five academic, seven general hospitals). SUBJECT: A total of 605 hospitalized patients with clinically suspected pulmonary embolism. All patients completed the study. INTERVENTIONS: First the clinical decision rule (CDR)-score was calculated. An unlikely CDR-score in combination with a normal D-dimer excluded pulmonary embolism. All other patients underwent helical computed tomography (CT). CT either diagnosed or excluded pulmonary embolism, in which case anticoagulants were started or withheld. All patients were instructed to report symptoms of venous thrombosis. Objective tests were performed to confirm venous thromboembolism. The primary outcome was the incidence of symptomatic venous thrombosis during 3-month follow-up. RESULTS: The combination of an unlikely CDR-score and a normal D-dimer excluded pulmonary embolism in 60 patients (10% of all patients); no venous thromboembolic event occurred during follow-up (0%; 95% CI 0-6.7%). CT excluded pulmonary embolism in 380 patients; during follow-up venous thromboembolism occurred in five patients (1.4%; 95% CI 0.4-3.1%). CONCLUSIONS: An unlikely CDR-score in combination with a normal D-dimer appears to exclude pulmonary embolism safely in hospitalized patients. Before clinical implementation it is important this safety is confirmed by others. CT testing was obviated in only 10% of patients. CT can safely exclude pulmonary embolism in hospitalized patients.

Family history and inherited thrombophilia.

BACKGROUND: It is a common belief that patients with venous thrombosis and a positive family history for venous thromboembolism (VTE) have an increased likelihood of having an inherited thrombophilic defect. METHODS: We analyzed the relation between family history, qualified with three different methods, and thrombophilic status in 314 patients with proven VTE. A positive family history (one or more first-degree relatives with VTE) and a strongly positive family history (two or more first-degree relatives with VTE). In 118 of the patients a third, more precise method was analyzed: the family history score, which compares the observed and the expected number of first-degree family members with VTE. RESULTS: Patients with a positive or strongly positive family history had a slightly increased chance of having inherited thrombophilia compared to those without a positive family history. For positive family history this was 42% vs. negative 32%, likelihood ratio 1.3 (95% confidence interval; CI 0.9-2.1) and for strongly positive family history this was 46% vs. negative 34%, likelihood ratio 1.6 (95% CI 0.7-3.3). The family history score correlated with the chance of having inherited thrombophilia [OR 1.23 per score point (95% CI 1.01-1.48)]. However, even with this method the chance of having inherited thrombophilia is lower than 50% in 97% of the cases. CONCLUSIONS: Family history of VTE is not a precise tool in clinical practice to identify patients with inherited thrombophilia among patients with VTE. The family history score is more precise, but probably only useful for research purposes and not for daily practice.

Accuracy of clinical decision rule, D-dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism.

BACKGROUND: The diagnostic work-up of patients with suspected pulmonary embolism (PE) has been optimized and simplified by the use of clinical decision rules (CDR), D-dimer (DD) testing and spiral computed tomography (s-CT). Whether this strategy is equally safe and efficient in specific subgroups of patients is evaluated in this study. METHODS: A diagnostic strategy including a CDR, DD test and s-CT was evaluated in patients with malignancy, previous venous thromboembolism (VTE), chronic obstructive pulmonary disease or heart failure and in older patients. PE was ruled out by either an unlikely CDR and a normal DD or a s-CT negative for PE. The safety of these tests was assessed by the 3-month incidence rate of symptomatic VTE in those without PE at baseline. The efficiency was evaluated by calculating the numbers needed to test for the different subgroups. RESULTS: The venous thromboembolic incidence rate after the combination of an unlikely CDR and a normal DD varied from 0% (95% CI: 0-7.9%) in the 482 patients older than 75 years of age to 2% (95% CI: 0.05-10.9%) in the 474 patients with a malignancy. For s-CT these incidences varied from 0.3% to 1.8%. The number needed to test in order to rule out one patient from PE with the studied strategy was highest in cancer patients and in the elderly patients (approximately 10). CONCLUSION: It appears to be safe to rule out PE by either the combination of an unlikely CDR and a normal DD or by a negative s-CT in various subgroups of patients with suspected PE. However, the clinical usefulness of the CDR in combination with the DD as the initial step in the diagnostic process varied among these patient groups.

Brain natriuretic peptide in hemodynamically stable acute pulmonary embolism.

BACKGROUND: Controversy exists about the indication of thrombolytic therapy in the subgroup of hemodynamically stable patients with acute pulmonary embolism (PE) and right ventricular dysfunction. Brain natriuretic peptide (BNP) is excreted from the cardiac ventricles in response to cardiomyocyte stretch and can be measured with an easy-to-perform blood test. OBJECTIVE: The objective of this study was to determine the predictive value of elevated BNP levels for early recurrent venous thromboembolism with or without fatal outcome in hemodynamically stable patients with acute PE. In addition, we assessed the potential clinical consequences of initiating thrombolytic therapy based on the BNP levels alone. METHODS: A nested case-control study was performed within the framework of a large randomized-controlled trial totalling 2213 hemodynamically stable patients with confirmed acute, symptomatic PE. Ninety patients experienced a fatal or non-fatal recurrent venous thromboembolism during the first 3 months of follow-up (cases); Two hundred and ninety-seven patients with uneventful follow-up served as controls. Blood for BNP levels was obtained at referral and assayed in a central laboratory. RESULTS: Cases had significantly higher mean baseline BNP levels (P = 0.0002). The odds ratio (OR) for every logarithmic (log) unit increase in BNP concentration was 2.4 (95% CI: 1.5-3.7). A BNP cut-off level of 1.25 pmol L(-1) [the optimal point on the receiver-operating characteristic (ROC) curve] was associated with a sensitivity and specificity of 60% and 62%, respectively. In theory, for every patient correctly receiving thrombolytic therapy at this cut-off, 16 patients will receive this therapy unnecessarily. CONCLUSIONS: Brain natriuretic peptide level at presentation is significantly associated with early (fatal) recurrent venous thromboembolism in hemodynamically stable patients with acute PE. However, this relationship appears clinically insufficient to guide the initiation of thrombolytic therapy.

Treatment of venous thromboembolism.

This review on the treatment of patients with venous thromboembolic disease consists of three sections. The first section describes the epidemiology, natural history and reasons for treatment of venous thromboembolism (VTE), as well as a short overview on the evaluation of the use of antithrombotic agents and the spectrum of treatment options. In the second section, the evidence from clinical studies available to us in 2005 with the various treatment modalities is summarized. This section describes the current recommendations about how to treat patients with VTE initially and long term. Finally, in the third section the challenges for the treatment of patients beyond 2005 are discussed.

D-Dimer test in cancer patients with suspected acute pulmonary embolism.

BACKGROUND: The safety of a D-dimer (DD) measurement in cancer patients with clinically suspected pulmonary embolism (PE) is unclear. OBJECTIVES: The aim of this study was to assess the accuracy of the DD test in consecutive patients with clinically suspected PE with and without cancer. METHODS: The diagnostic accuracy of DD (Tinaquant D-dimer) was first retrospectively assessed in an unselected group of patients referred for suspected PE (n = 350). Subsequently, the predictive value of the DD was validated in a group of consecutive inpatients and outpatients with clinically suspected PE prospectively enrolled in a management study (n = 519). The results of the DD test in cancer patients were assessed according to the final diagnosis of PE and the 3-month clinical follow-up. RESULTS: In the first study group, DD showed a sensitivity and a negative predictive value (NPV) of 100% and 100% in patients with cancer and 97% and 98% in those without malignancy, respectively. In the validation cohort, the sensitivity and NPV of DD were both 100% (95% CI 82%-100% and 72%-100%, respectively), whereas in patients without malignancy, the corresponding estimates were 93% (95% CI 87%-98%) and 97% (95% CI, 95%-99%), respectively. The specificity of DD was low in patients with (21%) and without cancer (53%). CONCLUSIONS: A negative DD result safely excludes the diagnosis of PE in patients with cancer. Because of the low specificity, when testing 100 patients with suspected PE, a normal DD concentration safely excludes PE in 15 patients with cancer and in 43 patients without cancer.

The incidence and prognostic significance of elevated cardiac troponins in patients with submassive pulmonary embolism.

Although the incidence and prognostic significance of elevated cardiac troponins are known in patients with massive pulmonary embolism (PE), few studies have addressed this issue in patients with hemodynamically stable, submassive PE, who comprise the majority of patients presenting with PE. This prospective cohort study was, therefore, designed to determine the incidence and prognostic significance of elevated cardiac troponins in patients with submassive PE. Consecutive patients with acute, symptomatic, submassive PE that was confirmed by objective diagnostic testing were studied. All patients received treatment with either unfractionated heparin or fondaparinux followed by a coumarin derivative and underwent clinical follow-up for 3 months. Cardiac troponin I (cTnI) levels were measured within 24 h of clinical presentation. An elevated cTnI was defined as > 0.5 microg L(-1) and indicated myocardial injury. Major myocardial injury, that is associated with myocardial infarction, was defined by a cTnI > 2.3 microg L(-1). The clinical outcomes were recurrent venous thromboembolism and all-cause death. In 458 patients with submassive PE, the incidence of cTnI > 0.5 microg L(-1) was 13.5%[95% confidence interval (CI): 10.4-16.7], and the incidence of cTnI > 2.3 microg L(-1) was 3.5% (95% CI: 2.0-5.6). An elevated cTnI > 0.5 microg L(-1) was associated with an increased risk of all-cause death [odds ratio (OR) = 3.5; 95% CI: 1.0-11.9], but did not appear to confer an increased risk of recurrent venous thromboembolism (OR = 1.1; 95% CI: 0.2-4.9). In patients who present with submassive PE, an elevated cTnI occurs in about one in seven patients and is associated with a 3.5-fold increased risk of all-cause death.

Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism.

BACKGROUND: Despite effective treatment with anticoagulants, 2% to 7% of patients with pulmonary embolism will die as a result of their disease. METHODS AND RESULTS: We examined in 110 consecutive patients with pulmonary embolism whether plasma brain natriuretic peptide (BNP), a novel marker of (right) ventricular dysfunction, is a predictor of fatal pulmonary embolism. The relationship between BNP concentration measured at presentation and clinical outcome was assessed by comparing the proportion of outcome events among tertiles. Positive and negative predictive values of BNP levels in the highest and lowest tertiles were calculated. The risk of death related to pulmonary embolism if the BNP level is >21.7 pmol/L is 17% (95% CI, 6% to 33%). The negative predictive value for uneventful outcome of a BNP value <21.7 pmol/L is 99% (95% CI, 93% to 100%). CONCLUSIONS: This is the first study to show that plasma BNP levels seem to predict adverse outcome in patients with acute pulmonary embolism.