Current and emerging drug strategies for the prevention of venous thromboembolism in acutely ill medical inpatients.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in patients hospitalized for acute medical illnesses. Therefore, medical inpatients require a careful VTE and bleeding risk assessment to drive optimal strategies for VTE prevention. Low molecular weight heparin and fondaparinux have long been used for inhospital prophylaxis for patients at increased risk of VTE. The selection of patients who require post-discharge prophylaxis, and the role of direct oral anticoagulants remain debated. New molecules currently under development may contribute to improve the risk benefit of VTE prevention in this setting. AREAS COVERED: This text summarizes the evidence on approved treatments and on other drugs for the prevention of VTE in acutely ill medical patients. The main focus is on their pharmacological properties, clinical efficacy and safety, and the current license approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency). The trials presented consider both inhospital and extended prophylaxis. EXPERT OPINION: Thanks to the potentially favorable safety profile, factor XI inhibitors may play a role in the prevention of VTE in this setting. The expert opinion section discusses pharmacological properties, prophylaxis trials, and potential clinical applications of this novel class of drugs.

Post-operative arterial thrombosis with non-vitamin K antagonist oral anticoagulants after total hip or knee arthroplasty.

The incidence of post-operative arterial thrombosis (AT) (acute myocardial infarction [AMI] and ischaemic stroke) is increased in patients undergoing total hip replacement (THR) or total knee replacement (TKR). We compared the incidence of post-operative AT in non-vitamin K antagonist oral anticoagulants (NOACs)-treated and enoxaparin-treated patients, performing a systematic review of phase III randomised controlled trials (RCTs) of venous thromboembolism (VTE) prophylaxis in THR and TKR. Studies were identified by electronic search of MEDLINE and EMBASE database until July 2014. Differences between NOACs and enoxaparin groups in the efficacy and safety outcomes were expressed as odds ratios (ORs) with pertinent 95 % confidence intervals (95 % CI). Statistical heterogeneity was assessed with the I² statistic. Eleven phase III RCTs for a total of 31,319 patients were included. Patients underwent TKR in six studies and THR in five studies. The NOACs under study were dabigatran (four studies), apixaban (three studies) and rivaroxaban (four studies). AT occurred in 0.23 % of patients on NOACs and in 0.27 % of patients on enoxaparin: the OR at fixed-effect model was 0.86 (95 % CI 0.53-1.40; I² 11 %). No differences in AT incidence among the three NOACs were observed. The incidence of major and clinically relevant bleeding was similar in NOACs and enoxaparin groups (OR 1.03, 95 % CI 0.92-1.15; I² 38 %). In conclusion, in RCTs of pharmacological VTE prophylaxis in patients undergoing THR or TKR, there was no difference in the incidence of post-operative AT among patients treated with NOACs, compared to those treated with enoxaparin.

Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study.

Numerous case reports have been published on acquired von Willebrand syndrome (aVWS) in patients with hypothyroidism, but no prospective studies have been published. The aim of this study was to investigate laboratory and clinical characteristics of aVWS in patients with newly diagnosed overt hypothyroidism. An observational cohort study was performed between May 2007 and February 2012. Consecutive hypothyroid patients before or within the first 48 h of replacement therapy were enrolled. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat samples were obtained after restoration of euthyroidism. The prevalence of aVWS, defined as von Willebrand factor antigen (VWF:Ag) ≤50% and/or VWF ristocetin activity (VWF:RCo) ≤50%, was calculated. Patients with aVWS were subsequently divided into severe (VWF:Ag and/or VWF:RCo ≤10%), moderate (VWF:Ag and/or VWF:RCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RCo between 30 and 50%). A total of 90 patients were included among whom a prevalence of aVWS of 33% was found. There were no patients with severe aVWS. Eight patients (9%) had moderate aVWS and 21 (23%) had mild aVWS. Bleeding score was negatively correlated with both VWF:Ag (ß -0.32, P = 0.03) and VWF:RCo (ß -0.32, P = 0.02). After restoration of euthyroidism, VWF:Ag had significantly increased by 44%, VWF:RCo by 36%, factor VIII by 39%, and endogenous thrombin potential by 10%. aVWS has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance.

Pulmonary embolism severity index accurately predicts long-term mortality rate in patients hospitalized for acute pulmonary embolism.

BACKGROUND: The Pulmonary Embolism (PE) Severity Index (PESI) is a clinical prognostic rule that accurately classifies PE patients into five risk classes with increasing mortality. PESI score has been validated in studies with a relatively short-term follow-up and its accuracy in predicting long-term prognosis has never been established. METHODS: Consecutive patients admitted to the tertiary care hospital of Varese (Italy) with an objectively diagnosed PE between January 2005 and December 2009 were retrospectively included. Information on clinical presentation, diagnostic work-up, risk factors, treatment and mortality during a 1-year follow-up was collected. RESULTS: Five hundred and thirty-eight patients were enrolled in this study. The mean age was 70.6 years (± SD 15.2), 44.4% of patients were male, and 27.9% had known cancer. One-year follow-up was available for 96.1% of patients. The overall mortality rate was 23.2% at 3 months, 30.2% at 6 months and 37.1% at 12 months. The discriminatory power of the PESI score to predict long-term mortality, expressed as the area under the ROC curve, was 0.77 (95%CI, 0.72-0.81) at 3 months, 0.77 (95%CI, 0.73-0.81) at 6 months and 0.79 (95%CI, 0.75-0.82) at 12 months. The PESI score confirmed its accurate prediction in patients without cancer. Simplified PESI had a similar overall accuracy to the original PESI at 3 and 6 months, but this was significantly lower at 1 year. CONCLUSIONS: The results of this study suggest that PESI score may also be an accurate tool to define the 6-month and 1-year mortality rates in PE patients.

Optimal treatment duration of venous thrombosis.

Randomized controlled trials have shown that patients with venous thromboembolism benefit from a minimum of three months of anticoagulant therapy. After this period, it was suggested that patients with an expected annual recurrence rate of < 5% could safely discontinue treatment. Using a population-based approach for stratification, these patients are those with major transient risk factors, and represent the minority. For all other patients, including those with previous episodes of venous thromboembolism, cancer, or unprovoked events, this treatment duration may not be sufficiently protective. Because extending anticoagulation for additional three to nine months does not result in further, long-term reduction of recurrences, indefinite treatment duration should be considered. However, case-fatality rate for major bleeding in patients taking warfarin for more than three months is higher than case-fatality rate of recurrent venous thromboembolism. Thus, an individual patient approach to improve and increase the identification of those who can safely discontinue treatment at three months becomes necessary. Clinical prediction rules or management strategies based on D-dimer levels or residual vein thrombosis have been proposed and need further refinement and validation. Specific bleeding scores are lacking. Meanwhile, the oral direct inhibitors have been proposed as potential alternatives to the vitamin K antagonists, and aspirin may provide some benefit in selected patients who discontinue anticoagulation. Deep vein thrombosis in unusual sites is associated with less, but potentially more severe recurrences, in particular in patients with splanchnic vein thrombosis who also face an increased risk of bleeding complications while on treatment.

Risk of recurrence of unusual site venous thromboembolism.

The term unusual site venous thrombosis defines uncommon clinical manifestations of venous thromboembolism occurring in sites different from the lower limbs or the lungs, with peculiar pathophysiological features and clinical history. Information on long-term outcomes of unusual site thrombosis is generally scant, because most studies are small and usually retrospective. Recurrence rate of cerebral vein thrombosis is about 2/100 patient-years; the only identified predisposing factors have been male gender and personal history of thrombosis. Retinal vein occlusion showed a recurrence in the same eye of 2.5% and in the fellow eye of 11.9% within four years. Hypercholesterolemia, hypertriglyceridaemia and hyperhomocysteinaemia were significantly associated with recurrent events. Recurrence rates of splanchnic vein thrombosis are difficult to estimate given the heterogeneity of patient populations; higher recurrence rates are reported in the cirrhotic population (from 27% to 38.5%). Hormone therapy, myeloproliferative neoplasm or other prothrombotic states, and absence of anticoagulant therapy emerged as independent prognostic factors. Future studies should aim at better assessing the risk of recurrence in different patients subgroups and at identifying more accurate prognostic markers.

Diagnostic accuracy of lung ultrasound for pulmonary embolism: a systematic review and meta-analysis.

BACKGROUND: Computed tomographic pulmonary angiography (CTPA) has simplified the diagnostic approach to patients with suspected pulmonary embolism (PE). However, PE diagnosis is still probabilistic and CTPA should be used with caution in some patient groups, such as patients with severe renal insufficiency and pregnant women. Among alternative imaging tests, lung ultrasound is the most promising technique. We aimed to systematically assess the diagnostic accuracy of lung ultrasound for PE diagnosis. METHODS: Studies evaluating the diagnostic accuracy of lung ultrasound for the diagnosis of PE were systematically searched for in the MEDLINE and EMBASE databases (up to June 2012). The QUADAS-2 tool was used for the quality assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity. RESULTS: Ten studies, for a total of 887 patients, were included. A composite reference test was used in six studies, with single-row detector CTPA as the principal imaging test in four studies. Overall, seven studies used a proper reference test. Lung ultrasound bivariate weighted mean sensitivity was 87.0% (95% confidence interval [CI] 79.5, 92.0%), whereas bivariate weighted mean specificity was 81.8% (95% CI 71.0, 89.3%). CONCLUSIONS: Our findings suggest that lung ultrasound may be a useful diagnostic tool in the management of patients with suspected PE. However, several methodological drawbacks of the primary studies limit any definite conclusion. Further well-designed accuracy studies are necessary before planning diagnostic management studies, in particular in those with a contraindication for CTPA.

Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature.

Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta-analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60-2.41%; I) antenatally and 1.90% (95% CI 0.80-3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88-3.49%; I(2) 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy-related VTE, but the optimal dosing regimens remain uncertain.

Low-dose aspirin for in vitro fertilization or intracytoplasmic sperm injection: a systematic review and a meta-analysis of the literature.

BACKGROUND: It was hypothesized that low-dose aspirin could improve implantation rates in subsequent pregnancies in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Previous studies have shown inconclusive results or focused on surrogate endpoints. We therefore conducted a systematic review and meta-analysis of the literature investigating the effect of low-dose aspirin on hard outcomes, including live birth rate, pregnancy rate and miscarriage. METHODS: MEDLINE and EMBASE databases were searched up to November 2011. Randomized controlled trials comparing low-dose aspirin with placebo/no treatment in IVF/ICSI women were included. Pooled odds ratios (ORs) and 95%confidence intervals (CIs) were calculated. RESULTS: Seventeen studies with 6403 patients were included. The use of aspirin did not improve live birth pregnancy rate compared with placebo or no treatment (1.08; 95% CI, 0.90, 1.29). Pregnancy rates were significantly increased in patients randomized to low-dose aspirin (OR, 1.19; 95% CI, 1.01, 1.39), but miscarriage rates were not (OR, 1.18; 95% CI, 0.82, 1.68). Results of sensitivity analyses including high-quality studies did not show statistically significant differences in all considered endpoints. CONCLUSIONS: The results of this study do not show a substantial efficacy of aspirin inwomen undergoing IVF/ICSI and do not support the use of low-dose aspirin to improve the success of IVF/ICSI in terms of pregnancy outcomes. Further high-quality studies evaluating the possible efficacy of aspirin in selected groups of patients are warranted.

Prognostic clinical prediction rules to identify a low-risk pulmonary embolism: a systematic review and meta-analysis.

BACKGROUND: Prognostic assessment is important for the management of patients with a pulmonary embolism (PE). A number of clinical prediction rules (CPRs) have been proposed for stratifying PE mortality risk. The aim of this systematic review was to assess the performance of prognostic CPRs in identifying a low-risk PE. METHODS: MEDLINE and EMBASE databases were systematically searched until August 2011. Derivation and validation studies that assessed the performance of prognostic CPRs in predicting adverse events-risk in PE patients were included. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I(2) statistics. RESULTS: Of 1125 references in the original search, 33 relevant articles were included. Nine CPRs were assessed in 37 cohorts, for a total of 35,518 patients. Pulmonary Embolism Severity Index and prognostic Geneva CPR were investigated in 22 and 6 cohorts, respectively. Eleven (29.7%) cohorts were of high quality. The median follow-up was 30 days. In low-risk PE patients, pooled short-term mortality (within 14 days or less) was 0.7% (95% CI 0.3-1.1%, random-effects model; I(2) = 49.6%), 30-day mortality was 1.7% (95% CI 1.1-2.3%, random-effects model; I(2) = 82.4%) and 90-day mortality was 2.2% (95% CI 1.2-3.4%, random-effects model; I(2) = 59.8%). CONCLUSIONS: Prognostic CPRs efficiently identify PE patients at a low risk of mortality. Before implementing prognostic CPRs in the routine care of PE patients, well-designed management studies are warranted.

D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature.

BACKGROUND: Quantitative measurement of circulating D-dimer, a product of fibrin degradation, has been shown to be a very useful diagnostic tool in the management of patients with suspected deep vein thrombosis and/or pulmonary embolism. Whether D-dimer can play a similar role in the diagnostic approach to patients with suspected cerebral vein thrombosis (CVT) remains controversial. METHODS: Studies evaluating the diagnostic accuracy of the D-dimer test in the diagnosis of CVT were systematically searched for in the MEDLINE and EMBASE databases (up to July 2011). Weighted mean sensitivity and specificity with 95% confidence intervals (CIs) were calculated with a bivariate random-effects regression approach. RESULTS: Fourteen studies, for a total of 1134 patients, were included. D-dimer accuracy was good, with a resulting weighted mean sensitivity of 93.9% (95% CI 87.5-97.1) and weighted mean specificity of 89.7% (95% CI 86.5-92.2), calculated with a bivariate approach. Potential risk factors for false-negative D-dimer results included isolated headache, longer duration of symptoms, and limited sinus involvement. CONCLUSIONS: Our findings suggest that D-dimer may be a useful diagnostic tool in the management of patients with suspected CVT. Future prospective studies are warranted to confirm our preliminary findings.

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study.

BACKGROUND: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. OBJECTIVE: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. PATIENTS AND METHODS: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. RESULTS: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor-1 (PAI-1) and clot-lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI-1 by 116% and clot-lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. CONCLUSIONS: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose-dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.