Esteban Gandara

Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis

Objective To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism. Design Systematic review and network meta-analysis. Data sources Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. Review methods Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms. Results 12 articles met our inclusion criteria, with 11 999 patients evaluated for efficacy and 12 167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available. Conclusions All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

Outpatient treatment of symptomatic pulmonary embolism: A systematic review and meta-analysis

BACKGROUND Patients with acute deep vein thrombus (DVT) can safely be treated as outpatients. However the role of outpatient treatment in patients diagnosed with a pulmonary embolism (PE) is controversial. We sought to determine the safety of outpatient management of patients with acute symptomatic PE. MATERIALS AND METHODS A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated. RESULTS A total of 1258 patients were included in the systematic review. The rate of recurrent venous thromboembolism (VTE) in patients with PE managed as outpatients was 1.47% (95% CI: 0.47 to 3.0%; I(2): 65.4%) during the 3 month follow-up period. The rate of fatal PE was 0.47% (95% CI: 0.16 to 1.0%; I(2): 0%). The rates of major bleeding and fatal intracranial hemorrhage were 0.81% (95% CI: 0.37 to 1.42%; I(2): 0%) and 0.29% (95% CI: 0.06 to 0.68%; I(2): 0%), respectively. The overall 3 month mortality rate was 1.58% (95% CI: 0.71 to 2.80%; I(2): 45%). The event rates were similar if employing risk stratification models versus using clinical gestalt to select appropriate patients for outpatient management. CONCLUSIONS Independent of the risk stratification methods used, the rate of adverse events associated with outpatient PE treatment seems low. Based on our systematic review and pooled meta-analysis, low-risk patients with acute PE can safely be treated as outpatients if home circumstances are adequate.

Diagnosis: Use of Clinical Probability Algorithms

Evidence suggests that patients with suspected pulmonary embolism are managed better with a diagnostic strategy that includes clinical pretest probability assessment, D-dimer test, and/or imaging. Several clinical prediction rules have been described in the literature during the last decade. This review focuses on the role of clinical prediction rules in the diagnostic process and their clinical application into diagnostic algorithms.

Long-term risk of venous thrombosis after stopping anticoagulants for a first unprovoked event: A multi-national cohort

BACKGROUND Choosing short-term (3-6 months) or indefinite anticoagulation after a first unprovoked venous thromboembolic event (VTE) is a common and difficult clinical decision. The long-term absolute risk of recurrent VTE after a first unprovoked VTE, in all patients and sub-groups, is not well established, hindering decision making. METHODS We conducted a multi-center multi-national prospective cohort study in first unprovoked VTE patients to establish the long-term risk of recurrent VTE after short-term anticoagulation in first unprovoked VTE patients (and sub-groups).We followed patients for symptomatic suspected VTE off of OAT. Suspected recurrent VTE was investigated with reference to baseline imaging and then independently and blindly adjudicated. FINDINGS We recruited 663 participants between October, 2001 and March 2006 with the last follow-up in April 2014. During a mean 5.0 years of follow-up, 165/663 suspected VTE (in 408 patients) were adjudicated as recurrent VTE resulting in an annualized risk of recurrent VTE of 5.0% (95% CI: 4.2-5.8%) with a cumulative risk of 29.6% at 8 years. Men had a 7.6% (95% CI: 6.3-9.2%) annual risk of recurrent VTE. High risk women (2 or more HERDOO2 points; see text) had an annual risk of recurrent VTE of 5.9% (95% CI: 4.2-8.1%). Low risk women (1 or 0 HERDOO2 points) had 1.1% (95% CI: 0.6-2.0%) annual risk of recurrent VTE with a cumulative risk of 8.7% at 8 years. INTERPRETATION Men and high risk women with unprovoked VTE should be considered for long-term anticoagulant therapy given a high risk of recurrent VTE after long-term follow-up. Women with a low HERDOO2 score may be able to safely discontinue anticoagulants. FUNDING This study was funded by the Canadian Institutes of Health Research (Grant # MOP 64319) and Heart and Stroke Foundation of Ontario (Grant # NA 6771). Registered at www.clinicaltrials.gov identifier: NCT00261014.

The diagnosis of venous thromboembolism.

Venous thromboembolism (VTE) is a serious and potentially fatal medical condition. Correct diagnosis and early treatment of VTE with anticoagulant drugs are critical steps in preventing further complications and recurrence. Evidence suggests that patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) should be managed with a diagnostic strategy that includes clinical pretest probability assessment, D-dimer test, and imaging. Clinical probability scoring, complemented by selective D-dimer testing, has become the recommended strategy for diagnosis. The reason is that overwhelming evidence suggests that patients with suspected VTE are better managed with a diagnostic strategy. If diagnostic algorithms are followed correctly, the chances of adverse events are extremely low (< 1%) in patients in whom VTE has been ruled out, whereas incomplete strategies leads to an increased risk of recurrent VTE or death. This review focuses on the application of diagnostic strategies with suspected DVT or PE into daily clinical practice while discussing the benefits and disadvantages of different approaches.

Will there be a role for genotyping in warfarin therapy

Purpose of reviewIn North America warfarin is the current standard for oral anticoagulation therapy in the treatment and/or prophylaxis of different thrombotic conditions. In daily clinical practice a significant proportion of patients on long-term warfarin therapy fail to stabilize within their target therapeutic range leading to a resultant increased risk of thromboembolism or bleeding. Various authors and agencies advocate the role of genetic testing to guide warfarin dosing. Recent findingsEvidence regarding the clinical efficacy and cost-effectiveness of genotype-based warfarin dosing has been conflicting, although some recent studies have suggested a potential benefit in certain subgroups. SummaryMore evidence is needed before the wide adoption of genotype-based warfarin dosing. Future studies should be designed to address outcomes such as major bleeding or recurrent thrombosis, and allow economic evaluations.

Timing of vitamin K antagonist re-initiation following intracranial hemorrhage in mechanical heart valves: Systematic review and meta-analysis

BACKGROUND While evidence supports resumption of vitamin K antagonists (VKAs) among mechanical heart valve (MHV) patients presenting with anticoagulant-associated intracranial hemorrhage (ICH), ideal timing of resumption is uncertain. OBJECTIVE To determine the optimal timing of VKA re-initiation and its associated clinical outcomes. METHODS We performed a systematic review and a meta-analysis of studies published from January 1950 to August 2015. We extracted data on the location of initial ICH, use of cranial surgery, presence of atrial fibrillation, MHV type and position, number of MHVs, and timing of VKA resumption. Outcomes including valve thrombosis, thromboembolic events or ICH recurrence were recorded. Meta-regression analysis was conducting with controlling for covariates. We calculated absolute risks, and assessed the effect of anticoagulant resumption timing on ICH recurrence. RESULTS 23 case-series and case-reports were identified. Overall ICH recurrence was 13% (95% confidence interval [CI], 7%-25%), while valve thrombosis and ischemic strokes occurred at 7% (95% CI, 3%-17%) and 12% (95% CI, 5%-23%) respectively. A trend towards lower ICH recurrence was observed with delayed VKA resumption (slope estimate -0.2154, p=0.10). Recurrence rate ranged from 50% with VKA resumption at 3days to 0% with resumption at 16days. CONCLUSION Among patients with MHV, there is inadequate data to suggest an optimal timing of VKA re-initiation following an ICH, though delayed restart appears to be protective against recurrence but is associated with higher risk of thrombosis. Our analysis suggests 4-7days might be an ideal time with least risk of thrombosis or ICH recurrence.

Risk of major bleeding in patients receiving vitamin K antagonists or low doses of aspirin. A systematic review and meta-analysis

UNLABELLED Prior meta-analysis and observational studies have suggested that the bleeding risks associated with anticoagulation using vitamin K antagonists (VKA) or aspirin (ASA) are similar. OBJECTIVE The aim of this systematic review was to provide the odds ratios (ORs) of major bleeding, intracranial bleeding or major extra-cranial bleeding of anticoagulation with VKA compared to low doses of ASA. METHODS We conducted a systematic review of Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (RCT). Randomized controlled trials reporting bleeding rates in adult patients randomized to a VKA (INR 2-3) or to ASA alone (<325mg daily). Random effects OR were calculated. RESULTS Fifteen trials reporting the outcome of 2511 participants treated with VKA alone and 2471 treated with ASA alone were included; most common conditions evaluated were non-valvular atrial fibrillation (five trials) and heart failure (three trials). Overall, the use of VKA was associated with an increased risk of major bleeding (OR 1.76 (95% CI 1.33-2.33) when compared to ASA. The OR associated with VKA use for intracranial bleeding and extra-cranial bleeding were 1.74 (95% CI 0.83-3.62) and 1.66 (95% CI 0.94-2.92), respectively. In trials achieving good control of anticoagulation [time in therapeutic range (TTR) >65%], the risk of bleeding with VKA was similar to that of ASA [OR 1.16 (95% CI 0.79-1.71)]. CONCLUSION Contrary to prior reports our results suggest that the risk of major bleeding with the use VKA is higher compared to those of patients treated with ASA alone. However, in patients achieving a good TTR, the risk of major bleeding with VKA or ASA is similar.

Management of pregnancy associated venous-thromboembolism: a survey of practices

IntroductionLow-molecular-weight heparin (LMWH) is frequently recommended for the treatment of pregnancy associated venous thromboembolism (PAVTE). Given that prior reports have suggested a wide variation in dosing of LMWH in pregnancy and the use of anti-Xa monitoring in pregnancy, the principal aim of this survey was to assess current practices for the management of PAVTE.MethodsAn electronic survey was conducted. The target sample was members of the North American Society of Obstetric Medicine and Thrombosis Interest Group of Canada.ResultsThe final sample consisted of 27/69 hematologists (39.1%), 30/69 internists (43.5%), 8/69 obstetricians (11.6%), and 4/69 from other specialties (5.7%). For the acute treatment of patients pregnant patients with deep vein thrombosis 42/69 (60.8%) preferred LMWH given twice a day 42/69 (60.8%), whereas 25/69 (36.2%) preferred once daily. These results were similar for patients with pulmonary embolism (PE). For long-term treatment more than 70% of the respondents favoured treatment with full doses of LMWH given once a day or twice a day and 16/69 (23.2%) intermediate doses for patients diagnosed with DVT. These results were similar for patients with PE. Fourteen physicians out of 69 (20.3%) did not measure anti-Xa monitoring during acute treatment period and 24/69 (34.8%) never used anti-Xa levels during the long term treatment period. Management during the peri-partum period varied widely according to the time of the diagnosis of PAVTE.DiscussionIn conclusion, our survey shows wide variation in practice regarding LMWH dosing and anti-Xa monitoring in pregnancy associated VTE and calls for trials comparing different long term strategies using LMWH in patients with PAVTE.

Haematological problems in obstetrics

Physiologic changes occur during pregnancy, which influence normal haematologic values and impact the diagnosis and management of haematologic disease in pregnancy. Physiologic changes of pregnancy also commonly lead to mimicking symptoms of haematologic disease that may prompt investigations for haematologic disease. The toxicity and radiation associated with the diagnostic imaging and pharmacologic management of both benign and malignant haematological conditions during pregnancy present unique challenges. Strategies for diagnosis and treatment must weigh the benefits and risks to the mother while also taking foetal outcome into consideration. In this review, we highlight the common haematologic diseases encountered by obstetricians and try to provide guidance for the most prevalent diagnostic and therapeutic questions. At the other end of the spectrum, we also comment on less common but very challenging haematologic diseases in pregnancy that require multidisciplinary effort to arrive at difficult individual diagnostic and treatment decisions.