New Prospective for the Management of Low-Risk Pulmonary Embolism: Prognostic Assessment, Early Discharge, and Single-Drug Therapy with New Oral Anticoagulants

Squizzato, Alessandro

doi:https://doi.org/10.6064/2012/502378

Scientifica

On this page

Abstract Introduction Conclusions Abbreviations References Copyright Related Articles

Review Article | Open Access

Volume 2012 | Article ID 502378 | https://doi.org/10.6064/2012/502378

New Prospective for the Management of Low-Risk Pulmonary Embolism: Prognostic Assessment, Early Discharge, and Single-Drug Therapy with New Oral Anticoagulants

Alessandro Squizzato¹

Academic Editor: A. V. Bruschke, A. Ghanem, C. N. Aroney, B. Z. Simkhovich

Received27 Sept 2012

Accepted05 Nov 2012

Published17 Dec 2012

Abstract

Patients with pulmonary embolism (PE) can be stratified into two different prognostic categories, based on the presence or absence of shock or sustained arterial hypotension. Some patients with normotensive PE have a low risk of early mortality, defined as <1% at 30 days or during hospital stay. In this paper, we will discuss the new prospective for the optimal management of low-risk PE: prognostic assessment, early discharge, and single-drug therapy with new oral anticoagulants. Several parameters have been proposed and investigated to identify low-risk PE: clinical prediction rules, imaging tests, and laboratory markers of right ventricular dysfunction or injury. Moreover, outpatient management has been suggested for low-risk PE: it may lead to a decrease in unnecessary hospitalizations, acquired infections, death, and costs and to an improvement in health-related quality of life. Finally, the main characteristics of new oral anticoagulant drugs and the most recent published data on phase III trials on PE suggest that the single-drug therapy is a possible suitable option. Oral administration, predictable anticoagulant responses, and few drug-drug interactions of direct thrombin and factor Xa inhibitors may further simplify PE home therapy avoiding administration of low-molecular-weight heparin.

1. Introduction

Prognostic assessment is central in the initial management of patients with acute pulmonary embolism (PE) [1–3]. The latest guidelines of the European Society of Cardiology (ESC), and of the American College of Chest Physicians (ACCP), American Heart Association (AHA) scientific statement on PE strongly suggest to stratify PE patients into two categories, which are patients at high risk of early mortality, that is, massive PE, and patients who are not at high risk of early mortality, that is, submassive and low-risk PE, based on the presence or absence of shock or sustained arterial hypotension, respectively, [1–3]. Early prognostic stratification is therefore required to identify those patients who may be theoretically eligible for outpatient treatment or early discharge [4–6] and those patients who may require more aggressive therapeutic strategies [1–3].

Aim of this paper is to summarize current evidence on the best management of PE patients at low risk of adverse outcomes. In particular, available prognostic tools, home-treatment and early discharge, and new drug options will be discussed.

2. Prognostic Assessment

Risk stratification of PE patients may assist clinicians in determining the best treatment and the appropriate setting for the initial therapy [3]. PE patients are commonly admitted to hospital for their initial treatment, though some of them may be suitable for a short-hospital stay or a complete home treatment [4, 5]. The availability of simple tools that accurately predict short-term adverse outcomes after the diagnosis of PE would be extremely valuable for the practicing clinicians.

Patients with acute massive PE, that is, presenting with sustained hypotension or requiring inotropic support, pulselessness, or persistent profound bradycardia, have the highest risk of short-term mortality (>50%) [7]. These patients require hospital admission and administration of pharmacological thrombolysis or, in case of contraindication, cardiac surgery [1–3].

Patients not at high risk of early mortality are highly heterogeneous and are >90% of patients with PE [1]. Among them, a group can be identified with associated low risk of early mortality (defined as ~1%, at 30 day or inhospital), whereas the group at intermediate risk can have an early mortality rate up to about 15% [7]. Several parameters have been proposed and investigated for PE prognostic stratification: demographical, anamnestic, and objective findings (often combined in clinical prediction rules (CPRs)) and imaging tests and laboratory markers of right ventricular (RV) dysfunction or injury [1–3]. The AHA has defined low-risk PE as follows: acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE [2]. However, clinical markers show different prognostic accuracy to stratify PE patients.

2.1. Clinical Prediction Rules

CPRs are based on clinical data that are collected routinely, therefore being easy to obtain and widely applicable. Nine clinical CPRs were developed in recent years [8]. The pulmonary embolism severity index (PESI) and the easier version, the simplified PESI [9–26] and the Geneva prognostic CPR [27–31] are the most rigorously derived and validated CPRs (Tables 1 and 2). In particular, PESI takes into account age, gender, presence of cancer, heart failure, chronic lung disease, tachycardia, hypotension, tachypnea, low body temperature, altered mental status, and hypoxia. In particular, PESI identifies about 40% of PE patients (PESI class I and II) with an inhospital mortality of less than 1% (0.2%, 95% confidence interval (CI) 0–0.7%) [8], that is, both the ESC and the AHA threshold for defining PE patients at low-risk.

2.2. Right Ventricular Dysfunction or Injury

Systematic reviews of the literature have shown that patients with right ventricular dysfunction on echocardiography, elevated levels of brain natriuretic peptide (BNP), NT-pro-BNP, or troponins had an increased risk of adverse inhospital outcomes as compared with patients with normal levels [32–34]. When used to identify low-risk patients, normal levels of BNP or NT-pro-BNP were associated with an early mortality rate of 2.2% (95% CI, 0.45–6.2) and 1.3% (95% CI, 0.15–4.4), respectively, with an overall rate of adverse outcomes of 13% (95% CI, 9.1%–19.0) and 5.3% (95% CI, 2.8–9.1) [32, 35–48]. In patients with normal troponin levels, early mortality rate was 3.7% (95% CI, 2.7–4.7), and the adverse outcome rate was 14.7% (95% CI, 10.8–18.6) [33, 48–54]. Echocardiographic signs of right ventricular dysfunction had a 60% negative predictive value (95% CI, 55–65) for mortality [34, 55–58]. Finally, RV dysfunction is assessed by computerised tomography pulmonary angiography (CTPA), and has been proposed as a possible prognostic tool [1, 2, 59–61]. Recently, right-to-left ventricular dimensional ratio ≥0.9 at CTPA has been suggested to be an independent predictor of early mortality, with a 100% (95% CI 98–100%) negative predictive value for inhospital death [61]. Although it is a promising prognostic test, these findings must be confirmed in other studies.

3. Home Treatment and Early Discharge

Worldwide, complete and partial (i.e., early discharge) outpatient treatment is commonly used for patients at low risk of adverse events. Community-acquired pneumonia is a classical example: patients can be treated completely at home, in a clinical ward or, at the opposite site, in an intensive care unit based on the severity of the disease. Among thrombotic disorders, deep vein thrombosis (DVT) is frequently treated completely at home [3]. However, the choice of the best therapeutic setting is not based only on disease-related criteria. Several social circumstances should be concomitantly present: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to hospital if there is deterioration. Moreover, patient should feel well enough to be treated at home [3].

3.1. Pulmonary Embolism

Emergency physicians are often reluctant to discharge patients with PE for outpatient treatment due to insufficient data supporting the effectiveness and safety of the outpatient management of PE [62, 63]. Indeed, safe outpatient management of patients with PE may lead to a decrease in unnecessary hospitalizations, reducing the risk of acquired infections and death and to an improvement in health-related quality of life and a reduction in health care costs [4, 5]. Moreover, new oral anticoagulant agents may further simplify PE home therapy avoiding administration of low-molecular-weight heparin (LMWH): many patients are not familiar with subcutaneous injections, and a home-care nurse is often needed.

Several published studies have already provided valuable data supporting a safe home treatment for low-risk PE patients [4, 5]. Most of these promising data are derived from cohorts of PE patients that were prospectively selected for home treatment based on a list of inclusion/exclusion criteria and were recently described in a systematic review [4]. Until 2009, a total of 25 studies on PE outpatient treatment and early discharge have been published [64–88]. From 2009, four additional cohort studies and two randomized clinical trials (RCTs) have been published [89–94].

Overall, however, in only 15 manuscripts a complete quality assessment and data extraction were possible [65, 69, 70, 72, 77, 79–82, 85, 87, 89–92]. A total of 1952 patients were analysed in these 15 observational studies. Nine observational studies had a prospective cohort design.

All studies used a classical list of PE-related (e.g., arterial oxygen saturation, clot extension on imaging test), drug-related (e.g., high-risk of major bleeding, creatinine clearance < 30 mL/min), and patient-related (e.g., concomitant medical condition, likelihood of poor compliance) inclusion/exclusion criteria. In the study by Agterof and colleagues a blood test, NT-proBNP level < 500 pg/mL, was used as main criterion for home treatment [91].

In 11 studies patients were discharged from the emergency room within a maximum of 24 h after admission. In the remaining 4 studies, early discharge (1–5 days) was adopted as disposition strategy [70, 72, 77, 79]. An outpatient treatment programme was available in participating centres. This was usually coordinated by a nurse and included the assessment of a physician, if required, an educational session, a daily phone call to each patient, and the availability of a 24 h emergency phone number. Home-care nurses, the patient himself, or a family member administered LMWH. No patient died of pulmonary embolism in the first 7–10 days.

In both RCTs a prognostic CPR, the Uresandi CPR and PESI, was already formally applied to select patients’ disposition for the initial treatment of PE [93, 94]. The two studies randomized patients with acute PE to receive LMWH either in the hospital for only 3 days versus entirely in the hospital [93] or entirely out of the hospital (discharged within 24 h) versus at least partly in hospital [94]. The former study was prematurely stopped due to an unexpected high rate of adverse outcomes in included patients at low risk according to Uresandi CPR, even if results were in favour of short hospital stay: in the 132 enrolled patients, overall mortality was 4.2% (95% CI, 0.5–8.9) in the early discharge group and 8.3% (95% CI, 1.1–15) in the standard hospitalization group [93]. In the latter, the so-called OPTE study, 344 patients with PESI I or II class were discharged from the emergency department within 24 hours after randomization or admitted to the hospital and discharged based on the decision of the treating physician [94]. One (0.6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit (UCL) 2.7%). Only one (0.6%) patient in each treatment group died within 90 days (95% UCL 2.1%), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3.6%). By 90 days, three (1.8%) outpatients but no inpatients had developed major bleeding (95% UCL 4.5%) [94].

The current edition of the ACCP guidelines does not recommend complete home therapy but only suggests “early discharge over standard discharge (e.g., after first 5 days of treatment), in patients with low-risk PE and whose home circumstances are adequate (Grade 2B)”, remarking that “patients who prefer the security of the hospital to the convenience and comfort of home are likely to choose hospitalization over home treatment”. Moreover, the panelists underlie 4 compulsory criteria for out-of-hospital treatment: (1) clinically stable patient with good cardiopulmonary reserve; (2) good social support with ready access to medical care; (3) patient expected to be compliant with followup; (4) absence of severe symptoms or comorbidity.

4. New Oral Anticoagulants

Parenteral unfractionated heparin (UFH), LMWH, and fondaparinux are the current options for acute treatment of non-high-risk PE [1–3]. All three options are efficacious but not optimal for home treatment. UFH requires continuous intravenous infusion with frequent laboratory monitoring of activated partial thromboplastin time and dose titration. LMWH and fondaparinux have a more predictable response after administration that allows fixed weight-adjusted doses without the need for laboratory monitoring, but several patients require daily nurse assistance for subcutaneous injections. Moreover, they are retained in patients with renal impairment. Finally, LMWH required platelet monitoring for heparin-induced thrombocytopenia risk [1, 3]. In the last decade, several new oral anticoagulants have been developed and evaluated in RCTs: the direct thrombin inhibitors (e.g., dabigatran) and the factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) [95, 96]. The oral route of administration is a major advantage over unfractionated heparin, LMWH, or fondaparinux. Moreover, the possibility to administer these drugs without the need for coagulation test monitoring, thanks to their predictable pharmacokinetic and pharmacodynamic actions and to the limited food-drug and drug-drug interactions, is a major advantage over heparins and, also, over oral vitamin K antagonists (VKAs). Finally, the onset of the anticoagulant activity is rapid, with plasma peak levels of all new anticoagulants that range from 2 to 4 hours after administration. This is undoubtedly a clear advantage in comparison to VKA and may permit a “single-drug” approach for the treatment of acute PE, avoiding initial therapy with parenteral drugs (see Tables 3 and 4).

4.1. Direct Thrombin Inhibitors

4.1.1. Dabigatran

Dabigatran etexilate is the prodrug of dabigatran, an univalent, reversible direct thrombin inhibitor that binds exclusively to the active site of thrombin and that dissociates relatively quickly from thrombin [96]. The onset of the anticoagulant activity is rapid, with plasma levels of dabigatran peak at 2 hours. Half-life ranges between 12 and 17 hours. At least 80% of dabigatran is excreted unchanged via the kidneys; therefore, use of dabigatran in patients with severe renal failure, with a creatinine clearance less than 30 mL/min, requires dose reduction and extreme caution [96–100]. Reduced dosages of drug that are substrates for P-glycoprotein (P-gp), such as dabigatran, may be needed when coadministered with strong P-gp inhibitors (e.g., amiodarone, verapamil, and quinidine).

At present, dabigatran is the oral only direct thrombin inhibitors with published phase III trials [101–117]. It is currently licensed in many countries for the prevention of venous thromboembolism (VTE) in patients undergoing hip- and knee-replacement surgery and for the prevention of cardioembolism in patients with nonvalvular atrial fibrillation (AF).

Dabigatran has been evaluated also in two large RCTs focusing on the treatment of acute VTE, the RECOVER and the RECOVER-II studies [118, 119]. In both studies, investigators enrolled patients with acute VTE, DVT, and/or PE, who were initially given parenteral anticoagulation therapy, in a randomized, double-blind, noninferiority trial, aiming to compare dabigatran etexilate, administered at a dose of 150 mg twice daily, with dose-adjusted warfarin (international normalized ratio of 2.0 to 3.0). The choice of the initial parenteral treatment was made in order to ensure the immediate anticoagulant effect and to avoid the high rate of early recurrence, which occurred with the precursor ximelagatran alone [120]. The primary outcome of the studies was the 6-month incidence of recurrent symptomatic, objectively confirmed VTE and related deaths. Safety outcomes included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. In the RECOVER study, 30 of the 1274 (2.4%) dabigatran patients, as compared with 27 of the 1265 (2.1%) warfarin patients, had recurrent VTE [118]. The hazard ratio (HR) with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 (1.6%) dabigatran patients and in 24 (1.9%) warfarin patients (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48). The numbers of deaths and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin, mainly due to dyspepsia (almost 3% with dabigatran). These results were confirmed in the RECOVER II trial, published only in an abstract form [119]. The only reported side effect of dabigatran in the abstract was dyspepsia, in 3% of patients [119].

An increased risk of myocardial infarction has been noted with the use of dabigatran. Two recent meta-analyses have reported an estimated 30% relative risk increase for acute coronary events with the use of dabigatran in patients with VTE and AF [121, 122]. This effect has not been reported with factor Xa inhibitors: it is not clear whether this can be due to an intrinsic property of dabigatran or to a protective effect of the comparator antithrombotic drugs. Before definite data will be provided, it seems wise to prefer other drug options instead of dabigatran in AF patients with known cardiac ischemic disease or at high risk of acute coronary events.

4.2. Factor Xa Inhibitors

4.2.1. Rivaroxaban

Rivaroxaban is a potent, selective, and reversible oxazolidinone-based, active-site-directed factor Xa inhibitor. Plasma levels of the drug peak after 3-4 h. Half-life ranges from 5 to 9 h in young individuals and from 11 to 13 h in the elderly. Coadministration of rivaroxaban with food increases the from 2.75 to 4 hours, with an increase in the and overall exposure of 30–40%. Almost 33% of rivaroxaban is excreted as active metabolites via the kidney [96, 97]. No dose adjustment is required for the elderly, but caution is required for severe renal insufficiency, creatinine clearance 15–30 mL/min [123]. Rivaroxaban is contraindicated in patients with creatinine clearance less than 15 mL/min [123]. Rivaroxaban is also contraindicated in patients receiving concomitant treatment with strong inhibitors of both P-glycoprotein and cytocrome CYP3A4, such as azole compounds and ritonavir.

Rivaroxaban has been extensively investigated in patients undergoing hip- and knee-replacement surgery, for the treatment of VTE and for the prevention of cardioembolism in patients with nonvalvular AF [124–135]. In particular, rivaroxaban has been specifically evaluated for the treatment of PE in the EINSTEIN-PE trial [136]. Overall, 4832 patients with acute symptomatic PE, with or without DVT, were randomized to rivaroxaban alone (15 mg twice a day for 3 weeks, then 20 mg daily) or standard treatment with therapeutic dose of enoxaparin followed within 48 hours by adjusted-dose VKA for 3, 6, or 12 months. Rivaroxaban results were noninferior to enoxaparin plus VKA in terms of symptomatic recurrent VTE (2.1% versus 1.8%, HR 1.12, 95% CI 0.75–1.68). In particular, the efficacy of rivaroxaban was confirmed also in the early phase, with a similar rate of recurrent events after 3 weeks. Fewer episodes of major bleeding were reported with rivaroxaban compared to standard therapy (1.1% versus 2.2%, HR 0.49, 95% CI 0.31–0.79) [136].

4.2.2. Other Xa Inhibitors

Two other molecules, apixaban and edoxaban, are in a advance stage of development and are currently under investigation for the acute treatment of patients with PE [137–156]. Apixaban is a small molecule that inhibits in a selective and reversible manner the active site of both free and prothrombinase-bound factor Xa [96]. Apixaban has high oral bioavailability (50% to 85%) and a half-life of 12 hours [96, 157, 158]. It is absorbed in the gastrointestinal tract, and its plasma peak is achieved in about 3 h [158]. Food does not interfere with its absorption [96]. Apixaban is metabolized in the liver by cytochrome-dependent and -independent mechanisms, and approximately 25% is cleared through the renal route [96].

Edoxaban tosylate is an oral direct factor Xa inhibitor. The drug is rapidly absorbed, reaching a in 1 to 2 hours with a mean plasma half-life of 8 to 10 hours and is mainly eliminated via renal excretion [159].

The AMLIFY and the HOKUSAI-VTE studies are the phase III RCTs specifically designed for assessing the benefit-risk profile of apixaban and edoxaban, respectively, for treating VTE. The AMPLIFY study is a phase III trial comparing apixaban 10 mg bid for 7 days then 5 mg, twice daily or to enoxaparin 1 mg/kg bid until INR >2 then warfarin for 6 months for the treatment of patients with acute symptomatic VTE [160]. The HOKUSAI-VTE study is a phase III trial comparing edoxaban tosylate 60 mg once daily or to dose-adjusted warfarin to maintain INR between 2.0 and 3.0, after the initial treatment with parenteral LMWH/unfractionated heparin (minimum 5 days) of patients with acute symptomatic VTE [160].

4.3. Other New Drug Option

4.3.1. Idrabiotaparinux

Idraparinux is a long-acting synthetic pentasaccharide highly specific for factor Xa inhibition. It requires only a single weekly subcutaneous injection to obtain its antithrombotic effect [161–163].

In the van Gogh trial, 2904 DVT patients and 2215 PE patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months [164]. The incidence of recurrence VTE at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% CI, 0.63 to 1.50) for DVT patients but was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78) for PE patients [164]. In addition to this partially negative results, its prolonged anticoagulant effect raised questions about the potential hazard of bleeding from invasive procedures and the appropriate management of patients with major bleeding.

Therefore, a derivative compound was created. A biotin moiety was added to idraparinux to create idrabiotaparinux, a molecule with the possibility to rapidly reverse its anticoagulant activity by infusing avidin [161, 165, 166].

In the CASSIOPEA study, a noninferiority trial, 3202 PE patients have been randomised to subcutaneous enoxaparin, 1.0 mg/kg twice daily for 5 to 10 days, followed by subcutaneous idrabiotaparinux, 3.0 mg once weekly, and placebo tablets () [167] or enoxaparin plus adjusted-dose warfarin (target international normalized ratio 2.0 to 3.0) plus weekly placebo injections after enoxaparin [167]. Primary end point, that is, symptomatic recurrent VTE, occurred in 2.1% of the idrabiotaparinux group and 2.7% of the standard treatment group (relative risk reduction 21%, 95% CI −24 to 49).

5. Conclusions

A correct prognostic stratification is the first step for early discharge or a complete home treatment, but a dedicated well-organised 24-h outpatient programme should be provided to each patient, similarly to those already existing for DVT patients all over the world. As acute PE is associated with much higher short-term mortality than acute DVT, outpatient-dedicated programme is crucial to rapidly assess and manage any complication and to correctly investigate PE patient for not missing any possible manifest or occult underlying risk factor, such as cancer.

The availability of new oral anticoagulants may actually simplify the management of PE. These new molecules have remarkable pharmacologic properties (rapid onset of action, short half-life- and predictable anticoagulant effect), which make routine laboratory monitoring of anticoagulation effect unnecessary and may reduce overdosage or bleeding events [91]. Moreover, molecules such as rivaroxaban and apixaban have been tested as “single-drug” for the acute phase, thus making possible the outpatients management of selected patients with PE.

Abbreviations

ACCP:	American College of Chest Physicians
AF:	Atrial fibrillation
AHA:	American Heart Association
BNP:	Brain natriuretic peptide
CI:	Confidence interval
CPR:	Clinical prediction rule
CTPA:	Computed tomography pulmonary angiography
DVT:	Deep vein thrombosis
ESC:	European Society of Cardiology
HR:	Hazard ratio
LMWH:	Low molecular weight heparin
PE:	Pulmonary embolism
PESI:	Pulmonary embolism severity index
P-gp:	P-glycoprotein
RCT:	Randomised controlled trial
RV:	Right ventricular
VKA:	Vitamin K antagonists
VTE:	Venous thromboembolism
UCL:	Upper confidence limit
UFH:	Unfractionated heparin.

References

A. Torbicki, A. Perrier, S. Konstantinides et al., “Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC),” European Heart Journal, vol. 29, pp. 2276–2315, 2008.
View at: Google Scholar
M. R. Jaff, M. S. McMurtry, S. L. Archer et al., “Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the american heart association,” Circulation, vol. 123, no. 16, pp. 1788–1830, 2011.
View at: Publisher Site | Google Scholar
C. Kearon, E. A. Akl, A. J. Comerota et al., “Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians evidence-based clinical practice guidelines,” Chest, vol. 141, supplement 2, pp. e419S–e494S, 2012.
View at: Google Scholar
A. Squizzato, M. Galli, F. Dentali, and W. Ageno, “Outpatient treatment and early discharge of symptomatic pulmonary embolism: a systematic review,” European Respiratory Journal, vol. 33, no. 5, pp. 1148–1155, 2009.
View at: Publisher Site | Google Scholar
M. Janjua, A. Badshah, F. Matta, L. G. Danescu, A. Y. Yaekoub, and P. D. Stein, “Treatment of acute pulmonary embolism as outpatients or following early discharge—a systematic review,” Thrombosis and Haemostasis, vol. 100, no. 5, pp. 756–761, 2008.
View at: Publisher Site | Google Scholar
T. Baglin, “Fifty per cent of patients with pulmonary embolism can be treated as outpatients,” Journal of Thrombosis and Haemostasis, vol. 8, no. 11, pp. 2404–2405, 2010.
View at: Publisher Site | Google Scholar
S. Z. Goldhaber, L. Visani, and M. de Rosa, “Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER),” The Lancet, vol. 353, no. 9162, pp. 1386–1389, 1999.
View at: Publisher Site | Google Scholar
A. Squizzato, M. P. Donadini, L. Galli, F. Dentali, D. Aujesky, and W. Ageno, “Prognostic clinical prediction rules to identify a low-risk pulmonary embolism: a systematic review and meta-analysis,” Journal of Thrombosis and Haemostasis, vol. 10, no. 7, pp. 1276–1290, 2012.
View at: Publisher Site | Google Scholar
D. Jiménez, D. Aujesky, L. Moores et al., “Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism,” Archives of Internal Medicine, vol. 170, no. 15, pp. 1383–1389, 2010.
View at: Publisher Site | Google Scholar
D. Jiménez, R. D. Yusen, R. Otero et al., “Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy,” Chest, vol. 132, no. 1, pp. 24–30, 2007.
View at: Publisher Site | Google Scholar
D. Aujesky, D. S. Obrosky, R. A. Stone et al., “Derivation and validation of a prognostic model for pulmonary embolism,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 8, pp. 1041–1046, 2005.
View at: Publisher Site | Google Scholar
D. Aujesky, P. M. Roy, C. P. le Manach et al., “Validation of a model to predict adverse outcomes in patients with pulmonary embolism,” European Heart Journal, vol. 27, no. 4, pp. 476–481, 2006.
View at: Publisher Site | Google Scholar
D. Aujesky, A. Perrier, P. M. Roy et al., “Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism,” Journal of Internal Medicine, vol. 261, no. 6, pp. 597–604, 2007.
View at: Publisher Site | Google Scholar
D. Jiménez Castro, G. Díaz, J. Molina et al., “Troponin I and risk stratification of patients with acute nonmassive pulmonary embolism,” European Respiratory Journal, vol. 31, no. 4, pp. 847–853, 2008.
View at: Publisher Site | Google Scholar
J. Donzé, G. le Gal, M. J. Fine et al., “Prospective validation of the Pulmonary Embolism Severity Index: a clinical prognostic model for pulmonary embolism,” Thrombosis and Haemostasis, vol. 100, no. 5, pp. 943–948, 2008.
View at: Publisher Site | Google Scholar
V. Palmieri, G. Gallotta, D. Rendina et al., “Troponin I and right ventricular dysfunction for risk assessment in patients with nonmassive pulmonary embolism in the Emergency Department in combination with clinically based risk score,” Internal and Emergency Medicine, vol. 3, no. 2, pp. 131–138, 2008.
View at: Publisher Site | Google Scholar
K. Nordenholz, J. Ryan, B. Atwood, and K. Heard, “Pulmonary embolism risk stratification: Pulse oximetry and pulmonary embolism severity index,” Journal of Emergency Medicine, vol. 40, no. 1, pp. 95–102, 2011.
View at: Publisher Site | Google Scholar
W. H. Choi, S. U. Kwon, Y. J. Jwa et al., “The pulmonary embolism severity index in predicting the prognosis of patients with pulmonary embolism,” Korean Journal of Internal Medicine, vol. 24, no. 2, pp. 123–127, 2009.
View at: Publisher Site | Google Scholar
L. Moores, D. Aujesky, D. Jiménez et al., “Pulmonary Embolism Severity Index and troponin testing for the selection of low-risk patients with acute symptomatic pulmonary embolism,” Journal of Thrombosis and Haemostasis, vol. 8, no. 3, pp. 517–522, 2010.
View at: Publisher Site | Google Scholar
C. M. Chan, C. Woods, and A. F. Shorr, “The validation and reproducibility of the pulmonary embolism severity index,” Journal of Thrombosis and Haemostasis, vol. 8, no. 7, pp. 1509–1514, 2010.
View at: Publisher Site | Google Scholar
S. Vanni, S. Gori, Viviani G et al., “Comparison of two prognostic models for acute pulmonary embolism,” European Heart Journal, vol. 31, supplement 1, pp. 915–916, 2010.
View at: Google Scholar
D. Jiménez, D. Aujesky, L. Moores et al., “Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism,” Thorax, vol. 66, no. 1, pp. 75–81, 2011.
View at: Publisher Site | Google Scholar
A. Singanayagam, C. Scally, M. Z. Al-Khairalla et al., “Are biomarkers additive to pulmonary embolism severity index for severity assessment in normotensive patients with acute pulmonary embolism?” QJM, vol. 104, no. 2, Article ID hcq168, pp. 125–131, 2011.
View at: Publisher Site | Google Scholar
P. Hariharan, J. K. Takayesu, and C. Kabrhel, “Association between the pulmonary embolism severity index (PESI) and short-term clinical deterioration,” Thrombosis and Haemostasis, vol. 105, no. 4, pp. 706–711, 2011.
View at: Publisher Site | Google Scholar
C. V. Pollack, D. Schreiber, S. Z. Goldhaber et al., “Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (multicenter emergency medicine pulmonary embolism in the real world registry),” Journal of the American College of Cardiology, vol. 57, no. 6, pp. 700–706, 2011.
View at: Publisher Site | Google Scholar
A. Sam, D. Sánchez, V. Gómez et al., “The shock index and the simplified PESI for identification of low-risk patients with acute pulmonary embolism,” European Respiratory Journal, vol. 37, no. 4, pp. 762–766, 2011.
View at: Publisher Site | Google Scholar
J. Wicki, A. Perrier, T. V. Perneger, H. Bounameaux, and A. F. Junod, “Predicting adverse outcome in patients with acute pulmonary embolism: a risk score,” Thrombosis and Haemostasis, vol. 84, no. 4, pp. 548–552, 2000.
View at: Google Scholar
M. R. Nendaz, P. Bandelier, D. Aujesky et al., “Validation of a risk score identifying patients with acute pulmonary embolism, who are at low risk of clinical adverse outcome,” Thrombosis and Haemostasis, vol. 91, no. 6, pp. 1232–1236, 2004.
View at: Google Scholar
R. M. Subramaniam, J. Mandrekar, D. Blair, P. J. Peller, and N. Karalus, “The Geneva prognostic score and mortality in patients diagnosed with pulmonary embolism by CT pulmonary angiogram,” Journal of Medical Imaging and Radiation Oncology, vol. 53, no. 4, pp. 361–365, 2009.
View at: Publisher Site | Google Scholar
C. Bova, R. Pesavento, A. Marchiori et al., “Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up,” Journal of Thrombosis and Haemostasis, vol. 7, no. 6, pp. 938–944, 2009.
View at: Publisher Site | Google Scholar
N. Vuilleumier, G. Le Gal, J. C. Cornily et al., “Is N-terminal pro-brain natriuretic peptide superior to clinical scores for risk stratification in non-massive pulmonary embolism?” Journal of Thrombosis and Haemostasis, vol. 8, no. 6, pp. 1433–1435, 2010.
View at: Publisher Site | Google Scholar
F. A. Klok, I. C. M. Mos, and M. V. Huisman, “Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis,” American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 4, pp. 425–430, 2008.
View at: Publisher Site | Google Scholar
C. Becattini, M. C. Vedovati, and G. Agnelli, “Prognostic value of troponins in acute pulmonary embolism: a meta-analysis,” Circulation, vol. 116, no. 4, pp. 427–433, 2007.
View at: Publisher Site | Google Scholar
O. Sanchez, L. Trinquart, I. Colombet et al., “Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review,” European Heart Journal, vol. 29, no. 12, pp. 1569–1577, 2008.
View at: Publisher Site | Google Scholar
F. Maziere, S. Birolleau, S. Medimagh et al., “Comparison of troponin I and N-terminal-pro B-type natriuretic peptide for risk stratification in patients with pulmonary embolism,” European Journal of Emergency Medicine, vol. 14, no. 4, pp. 207–211, 2007.
View at: Publisher Site | Google Scholar
D. Logeart, L. Lecuyer, G. Thabut et al., “Biomarker-based strategy for screening right ventricular dysfunction in patients with non-massive pulmonary embolism,” Intensive Care Medicine, vol. 33, no. 2, pp. 286–292, 2007.
View at: Publisher Site | Google Scholar
M. Puls, C. Dellas, M. Lankeit et al., “Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism,” European Heart Journal, vol. 28, no. 2, pp. 224–229, 2007.
View at: Publisher Site | Google Scholar
J. A. Kline, J. Hernandez-Nino, G. A. Rose, H. J. Norton, and C. A. Camargo Jr., “Surrogate markers for adverse outcomes in normotensive patients with pulmonary embolism,” Critical Care Medicine, vol. 34, no. 11, pp. 2773–2780, 2006.
View at: Publisher Site | Google Scholar
P. Ray, F. Maziere, S. Medimagh et al., “Evaluation of B-type natriuretic peptide to predict complicated pulmonary embolism in patients aged 65 years and older: brief report,” American Journal of Emergency Medicine, vol. 24, no. 5, pp. 603–607, 2006.
View at: Publisher Site | Google Scholar
L. Binder, B. Pieske, M. Olschewski et al., “N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism,” Circulation, vol. 112, no. 11, pp. 1573–1579, 2005.
View at: Publisher Site | Google Scholar
M. Kostrubiec, P. Pruszczyk, A. Bochowicz et al., “Biomarker-based risk assessment model in acute pulmonary embolism,” European Heart Journal, vol. 26, no. 20, pp. 2166–2172, 2005.
View at: Publisher Site | Google Scholar
S. Krüger, J. Graf, M. W. Merx et al., “Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism,” American Heart Journal, vol. 147, no. 1, pp. 60–65, 2004.
View at: Publisher Site | Google Scholar
P. Pruszczyk, M. Kostrubiec, A. Bochowicz et al., “N-terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism,” European Respiratory Journal, vol. 22, no. 4, pp. 649–653, 2003.
View at: Google Scholar
N. Kucher, G. Printzen, and S. Z. Goldhaber, “Prognostic role of brain natriuretic peptide in acute pulmonary embolism,” Circulation, vol. 107, no. 20, pp. 2545–2547, 2003.
View at: Publisher Site | Google Scholar
M. Ten Wolde, I. I. Tulevski, J. W. M. Mulder et al., “Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism,” Circulation, vol. 107, no. 16, pp. 2082–2084, 2003.
View at: Publisher Site | Google Scholar
N. Kucher, G. Printzen, T. Doernhoefer, S. Windecker, B. Meier, and O. M. Hess, “Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism,” Circulation, vol. 107, no. 12, pp. 1576–1578, 2003.
View at: Publisher Site | Google Scholar
I. I. Tulevski, A. Hirsch, B. J. Sanson et al., “Increased brain natriuretic peptide as a marker for right ventricular dysfunction in acute pulmonary embolism,” Thrombosis and Haemostasis, vol. 86, no. 5, pp. 1193–1196, 2001.
View at: Google Scholar
I. I. Tulevski, M. T. Wolde, D. J. van Veldhuisen et al., “Combined utility of brain natriuretic peptide and cardiac troponine T may improve rapid triage and risk stratification in normotensive patients with pulmonary embolism,” International Journal of Cardiology, vol. 116, no. 2, pp. 161–166, 2007.
View at: Publisher Site | Google Scholar
K. Yalamanchili, R. Sukhija, W. S. Aronow, N. Sinha, A. G. Fleisher, and S. G. Lehrman, “Prevalence of increased cardiac troponin I levels in patients with and without acute pulmonary embolism and relation of increased cardiac troponin I levels with in-hospital mortality in patients with acute pulmonary embolism,” American Journal of Cardiology, vol. 93, no. 2, pp. 263–264, 2004.
View at: Publisher Site | Google Scholar
E. Giannitsis, M. Müller-Bardorff, V. Kurowski et al., “Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism,” Circulation, vol. 102, no. 2, pp. 211–217, 2000.
View at: Google Scholar
P. Pruszczyk, A. Bochowicz, A. Torbicki et al., “Cardiac troponin T monitoring identifies high-risk group of normotensive patients with acute pulmonary embolism,” Chest, vol. 123, no. 6, pp. 1947–1952, 2003.
View at: Publisher Site | Google Scholar
J. D. Douketis, M. A. Crowther, E. B. Stanton, and J. S. Ginsberg, “Elevated cardiac troponin levels in patients with submassive pulmonary embolism,” Archives of Internal Medicine, vol. 162, no. 1, pp. 79–81, 2002.
View at: Google Scholar
N. Kucher, D. Wallmann, A. Carone, S. Windecker, B. Meier, and O. M. Hess, “Incremental prognostic value of troponin I and echocardiography in patients with acute pulmonary embolism,” European Heart Journal, vol. 24, no. 18, pp. 1651–1656, 2003.
View at: Publisher Site | Google Scholar
K. Janata, M. Holzer, A. N. Laggner, and M. Müllner, “Cardiac troponin T in the severity assessment of patients with pulmonary embolism: cohort study,” British Medical Journal, vol. 326, no. 7384, pp. 312–313, 2003.
View at: Google Scholar
S. Grifoni, I. Olivotto, P. Cecchini et al., “Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction,” Circulation, vol. 101, no. 24, pp. 2817–2822, 2000.
View at: Google Scholar
F. Pieralli, I. Olivotto, S. Vanni et al., “Usefulness of bedside testing for brain natriuretic peptide to identify right ventricular dysfunction and outcome in normotensive patients with acute pulmonary embolism,” American Journal of Cardiology, vol. 97, no. 9, pp. 1386–1390, 2006.
View at: Publisher Site | Google Scholar
A. Vieillard-Baron, B. Page, R. Augarde et al., “Acute cor pulmonale in massive pulmonary embolism: incidence, echocardiographic pattern, clinical implications and recovery rate,” Intensive Care Medicine, vol. 27, no. 9, pp. 1481–1486, 2001.
View at: Publisher Site | Google Scholar
E. Hamel, G. Pacouret, D. Vincentelli et al., “Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation: results from a 128-patient monocenter registry,” Chest, vol. 120, no. 1, pp. 120–125, 2001.
View at: Publisher Site | Google Scholar
A. Ghuysen, B. Ghaye, V. Willems et al., “Computed tomographic pulmonary angiography and prognostic significance in patients with acute pulmonary embolism,” Thorax, vol. 60, no. 11, pp. 956–961, 2005.
View at: Publisher Site | Google Scholar
R. W. van der Meer, P. M. T. Pattynama, M. J. L. Van Strijen et al., “Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism,” Radiology, vol. 235, no. 3, pp. 798–803, 2005.
View at: Publisher Site | Google Scholar
C. Becattini, G. Agnelli, M. C. Vedovati et al., “Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test,” European Heart Journal, vol. 32, no. 13, pp. 1657–1663, 2011.
View at: Publisher Site | Google Scholar
D. Aujesky, L. Mazzolai, O. Hugli, and A. Perrier, “Outpatient treatment of pulmonary embolism,” Swiss Medical Weekly, vol. 139, no. 47-48, pp. 685–690, 2009.
View at: Google Scholar
A. Squizzato, E. Micieli, M. Galli et al., “Diagnosis and management of venous thromboembolism: results of a survey on current clinical practice,” Thrombosis Research, vol. 125, no. 2, pp. 134–136, 2010.
View at: Publisher Site | Google Scholar
W. Ageno, L. Steidl, C. Marchesi et al., “Selecting patients for home treatment of deep vein thrombosis: the problem of cancer,” Haematologica, vol. 87, no. 3, pp. 286–291, 2002.
View at: Google Scholar
W. Ageno, R. Grimwood, S. Limbiati, F. Dentali, L. Steidl, and P. S. Wells, “Home-treatment of deep vein thrombosis in patients with cancer,” Haematologica, vol. 90, no. 2, pp. 220–224, 2005.
View at: Google Scholar
G. Agnelli, M. Verso, W. Ageno et al., “The MASTER registry on venous thromboembolism: description of the study cohort,” Thrombosis Research, vol. 121, no. 5, pp. 605–610, 2008.
View at: Publisher Site | Google Scholar
J. I. Arcelus, J. A. Caprini, M. Monreal, C. Suárez, and J. González-Fajardo, “The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients,” Journal of Vascular Surgery, vol. 38, no. 5, pp. 916–922, 2003.
View at: Publisher Site | Google Scholar
R. M. Bauersachs, E. Lindhoff-Last, and A. M. Ehrly, “Out-patient treatment of acute pulmonary embolism and fresh proximal deep vein thrombosis with low molecular weight heparin,” Deutsche Medizinische Wochenschrift, vol. 124, no. 49, pp. 1485–1488, 1999.
View at: Google Scholar
J. H. Beer, M. Burger, S. Gretener, S. Bernard-Bagattini, and H. Bounameaux, “Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients,” J Thromb Haemost, vol. 1, no. 1, pp. 186–187, 2003.
View at: Google Scholar
H. R. Büller, B. L. Davidson, H. Decousus et al., “Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism,” The New England Journal of Medicine, vol. 349, no. 18, pp. 1695–1702, 2003.
View at: Publisher Site | Google Scholar
W. E. Dager, J. H. King, J. M. Branch et al., “Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis,” Annals of Pharmacotherapy, vol. 39, no. 7-8, pp. 1182–1187, 2005.
View at: Publisher Site | Google Scholar
C. W. H. Davies, J. Wimperis, E. S. Green et al., “Early discharge of patients with pulmonary embolism: a two-phase observational study,” European Respiratory Journal, vol. 30, no. 4, pp. 708–714, 2007.
View at: Publisher Site | Google Scholar
L. Harrison, J. McGinnis, M. Crowther, J. Ginsberg, and J. Hirsh, “Assessment of outpatient treatment of deep-vein thrombosis with low- molecular-weight heparin,” Archives of Internal Medicine, vol. 158, no. 18, pp. 2001–2003, 1998.
View at: Publisher Site | Google Scholar
D. Heaton, D. Y. Han, and A. Inder, “Outpatient treatment of community acquired venous thromboembolism—the Christchurch experience,” New Zealand Medical Journal, vol. 115, no. 1158, p. U105, 2002.
View at: Google Scholar
T. M. Hyers and A. C. Spyropoulos, “Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin,” Journal of Thrombosis and Thrombolysis, vol. 24, no. 3, pp. 225–232, 2007.
View at: Publisher Site | Google Scholar
C. Kearon, J. S. Ginsberg, J. A. Julian et al., “Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism,” Journal of the American Medical Association, vol. 296, no. 8, pp. 935–942, 2006.
View at: Publisher Site | Google Scholar
M. J. Kovacs, D. Anderson, B. Morrow, L. Gray, D. Touchie, and P. S. Wells, “Outpatient treatment of pulmonary embolism with dalteparin,” Thrombosis and Haemostasis, vol. 83, no. 2, pp. 209–211, 2000.
View at: Google Scholar
P. Labas, B. Ohradka, and M. Cambal, “Could deep vein thrombosis be safely treated at home?” Bratislavske Lekarske Listy, vol. 102, no. 10, pp. 458–461, 2001.
View at: Google Scholar
A. Y. H. Lim, D. G. Parr, D. E. Stableforth, M. Fellows, R. Fontaine, and C. D. Fegan, “Early discharge and home supervision of patients with pulmonary embolism treated with low-molecular weight heparin,” European Journal of Internal Medicine, vol. 14, no. 2, pp. 89–93, 2003.
View at: Publisher Site | Google Scholar
B. Lui, A. Tran, and M. Montalto, “Treatment of patients with pulmonary embolism entirely in Hospital in the Home,” Australian Family Physician, vol. 36, no. 5, pp. 381–384, 2007.
View at: Google Scholar
C. G. Olsson, U. Bitzén, B. Olsson et al., “Outpatient tinzaparin therapy in pulmonary embolism quantified with ventilation/perfusion scintigraphy,” Medical Science Monitor, vol. 12, no. 2, pp. PI9–PI13, 2006.
View at: Google Scholar
B. S. Ong, M. A. Karr, D. K. Y. Chan, A. Frankel, and Q. Shen, “Management of pulmonary embolism in the home,” Medical Journal of Australia, vol. 183, no. 5, pp. 239–242, 2005.
View at: Google Scholar
A. Santamaría, S. Juárez, A. Reche et al., “Low-molecular-weight herapin, bemiparin, in the outpatient treatment and secondary prohylaxis of venous thromboembolism in standard clinical practice: the ESFERA study,” International Journal of Clinical Practice, vol. 60, no. 5, pp. 518–525, 2006.
View at: Publisher Site | Google Scholar
K. J. Savage, P. S. Wells, V. Schulz et al., “Outpatient use of low molecular weight heparin (dalteparin) for the treatment of deep vein thrombosis of the upper extremity,” Thrombosis and Haemostasis, vol. 82, no. 3, pp. 1008–1010, 1999.
View at: Google Scholar
S. Siragusa, C. Arcara, A. Malato et al., “Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients,” Annals of Oncology, vol. 16, no. 4, pp. iv136–iv139, 2005.
View at: Publisher Site | Google Scholar
P. S. Wells, M. J. Kovacs, J. Bormanis et al., “Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection,” Archives of Internal Medicine, vol. 158, no. 16, pp. 1809–1812, 1998.
View at: Publisher Site | Google Scholar
P. S. Wells, D. R. Anderson, M. A. Rodger et al., “A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism,” Archives of Internal Medicine, vol. 165, no. 7, pp. 733–738, 2005.
View at: Publisher Site | Google Scholar
S. J. A. Wilson, L. Gray, and D. R. Anderson, “Outpatient treatment of deep vein thrombosis and pulmonary embolism: a hospital-based program,” Canadian Journal of Hospital Pharmacy, vol. 52, no. 5, pp. 282–288, 1999.
View at: Google Scholar
P. M. G. Erkens, E. Gandara, P. Wells et al., “Safety of outpatient treatment in acute pulmonary embolism,” Journal of Thrombosis and Haemostasis, vol. 8, no. 11, pp. 2412–2417, 2010.
View at: Publisher Site | Google Scholar
M. J. Kovacs, J. D. Hawel, J. F. Rekman, and A. Lazo-Langner, “Ambulatory management of pulmonary embolism: a pragmatic evaluation,” Journal of Thrombosis and Haemostasis, vol. 8, no. 11, pp. 2406–2411, 2010.
View at: Publisher Site | Google Scholar
M. J. Agterof, R. E. G. Schutgens, R. J. Snijder et al., “Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level,” Journal of Thrombosis and Haemostasis, vol. 8, no. 6, pp. 1235–1241, 2010.
View at: Publisher Site | Google Scholar
W. Zondag, I. C. Mos, D. Creemers-Schild et al., “Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study,” Journal of Thrombosis and Haemostasis, vol. 9, pp. 1500–1507, 2011.
View at: Publisher Site | Google Scholar
R. Otero, F. Uresandi, D. Jiménez et al., “Home treatment in pulmonary embolism,” Thrombosis Research, vol. 126, no. 1, pp. e1–e5, 2010.
View at: Publisher Site | Google Scholar
D. Aujesky, P. M. Roy, F. Verschuren et al., “Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial,” The Lancet, vol. 378, no. 9785, pp. 41–48, 2011.
View at: Publisher Site | Google Scholar
I. Ahrens, G. Y. H. Lip, and K. Peter, “New oral anticoagulant drugs in cardiovascular disease,” Thrombosis and Haemostasis, vol. 104, no. 1, pp. 49–60, 2010.
View at: Publisher Site | Google Scholar
W. Ageno, A. S. Gallus, A. Wittkowsky, M. Crowther, E. M. Hylek, and G. Palareti, “Oral anticoagulant therapy: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, vol. 141, supplement 2, pp. e44S–e88S, 2012.
View at: Publisher Site | Google Scholar
B. I. Eriksson, D. J. Quinlan, and J. I. Weitz, “Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development,” Clinical Pharmacokinetics, vol. 48, no. 1, pp. 1–22, 2009.
View at: Publisher Site | Google Scholar
S. Blech, T. Ebner, E. Ludwig-Schwellinger, J. Stangier, and W. Roth, “The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans,” Drug Metabolism and Disposition, vol. 36, no. 2, pp. 386–399, 2008.
View at: Publisher Site | Google Scholar
J. Stangier, K. Rathgen, H. Stähle, D. Gansser, and W. Roth, “The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects,” British Journal of Clinical Pharmacology, vol. 64, no. 3, pp. 292–303, 2007.
View at: Publisher Site | Google Scholar
European Medicines Agency (EMA), “European public assessment report: Pradaxa,” http://www.emea.europa.eu.
View at: Google Scholar
B. I. Eriksson, O. E. Dahl, H. R. Büller et al., “A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial,” Journal of Thrombosis and Haemostasis, vol. 3, no. 1, pp. 103–111, 2005.
View at: Publisher Site | Google Scholar
B. I. Eriksson, O. E. Dahl, N. Rosencher et al., “Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial,” The Lancet, vol. 370, no. 9591, pp. 949–956, 2007, Erratum in: The Lancet, vol. 370, no. 9604, p. 2004, 2007.
View at: Publisher Site | Google Scholar
B. I. Eriksson, O. E. Dahl, N. Rosencher et al., “Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial,” Journal of Thrombosis and Haemostasis, vol. 5, no. 11, pp. 2178–2185, 2007.
View at: Publisher Site | Google Scholar
J. S. Ginsberg, B. L. Davidson, P. C. Comp et al., “Oral thrombin inhibitor dabigatran etexilate versus North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery,” Journal of Arthroplasty, vol. 24, no. 1, pp. 1–9, 2009.
View at: Publisher Site | Google Scholar
T. Fuji, S. Fuijita, T. Ujihira, and T. Sato, “Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo,” Journal of Arthroplasty, vol. 25, no. 8, pp. 1267–1274, 2010.
View at: Publisher Site | Google Scholar
B. I. Eriksson, O. E. Dahl, M. H. Huo et al., “Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II): a randomised, double-blind, non-inferiority trial,” Thrombosis and Haemostasis, vol. 105, no. 4, pp. 721–729, 2011.
View at: Publisher Site | Google Scholar
M. V. Huisman, D. J. Quinlan, O. E. Dahl, and S. Schulman, “Enoxaparin versus Dabigatran or rivaroxaban for thromboprophylaxis after hip or knee arthroplasty: results of separate pooled analyses of phase III multicenter randomized trials,” Circulation, vol. 3, no. 6, pp. 652–660, 2010.
View at: Publisher Site | Google Scholar
C. Pechlaner and P. Marschang, “Dabigatran versus enoxaparin after total hip replacement,” The Lancet, vol. 370, no. 9604, p. 2002, 2007.
View at: Publisher Site | Google Scholar
M. D. Ezekowitz, P. A. Reilly, G. Nehmiz et al., “Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study),” American Journal of Cardiology, vol. 100, no. 9, pp. 1419–1426, 2007.
View at: Publisher Site | Google Scholar
M. D. Ezekowitz, S. Connolly, A. Parekh et al., “Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran,” American Heart Journal, vol. 157, no. 5, pp. 805.e2–810.e2, 2009.
View at: Publisher Site | Google Scholar
S. J. Connolly, M. D. Ezekowitz, S. Yusuf et al., “Dabigatran versus warfarin in patients with atrial fibrillation,” The New England Journal of Medicine, vol. 361, no. 12, pp. 1139–1151, 2009, Erratum in: The New England Journal of Medicine, vol. 363, p. 1877, 2010.
View at: Publisher Site | Google Scholar
R. G. Hart, H. C. Diener, S. Yang et al., “Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial,” Stroke, vol. 43, pp. 1511–1517, 2012.
View at: Publisher Site | Google Scholar
L. Wallentin, S. Yusuf, M. D. Ezekowitz et al., “Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial,” The Lancet, vol. 376, no. 9745, pp. 975–983, 2010.
View at: Publisher Site | Google Scholar
S. H. Hohnloser, J. Oldgren, S. Yang et al., “Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial,” Circulation, vol. 125, pp. 669–676, 2012.
View at: Publisher Site | Google Scholar
J. Oldgren, M. Alings, H. Darius et al., “Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS₂ score: a subgroup analysis of the Re-Ly trial,” Annals of Internal Medicine, vol. 155, no. 10, pp. 660–667, 2011.
View at: Google Scholar
J. Oldgren, A. Budaj, C. B. Granger et al., “Dabigatran versus placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial,” European Heart Journal, vol. 32, no. 22, pp. 2781–2789, 2011.
View at: Publisher Site | Google Scholar
H. C. Diener, S. J. Connolly, M. D. Ezekowitz et al., “Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial,” The Lancet Neurology, vol. 9, no. 12, pp. 1157–1163, 2010.
View at: Publisher Site | Google Scholar
S. Schulman, C. Kearon, A. K. Kakkar et al., “Dabigatran versus warfarin in the treatment of acute venous thromboembolism,” The New England Journal of Medicine, vol. 361, no. 24, pp. 2342–2352, 2009.
View at: Publisher Site | Google Scholar
S. Schulman, A. K. Kakkar, S. M. Schellong et al., “A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RECOVER II),” Blood, vol. 118, no. 21, 2011, abstract 205.
View at: Google Scholar
J. N. Fiessinger, M. V. Huisman, B. L. Davidson et al., “Ximelagatran versus low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial,” Journal of the American Medical Association, vol. 293, no. 6, pp. 681–689, 2005.
View at: Publisher Site | Google Scholar
K. Uchino and A. V. Hernandez, “Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials,” Archives of Internal Medicine, vol. 172, no. 5, pp. 397–402, 2012.
View at: Publisher Site | Google Scholar
S. S. Adam, J. R. McDuffie, T. L. Ortel, and J. W. Williams Jr., “Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review,” Annals of Internal Medicine. In press.
View at: Publisher Site | Google Scholar
European Medicines Agency (EMA), “European public assessment report: Xarelto,” http://www.emea.europa.eu.
View at: Google Scholar
B. I. Eriksson, L. Borris, O. E. Dahl et al., “Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement,” Journal of Thrombosis and Haemostasis, vol. 4, pp. 121–128, 2006.
View at: Google Scholar
B. I. Eriksson, L. C. Borris, O. E. Dahl et al., “Dose-escalation study of rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—for the prevention of venous thromboembolism in patients undergoing total hip replacement,” Thrombosis Research, vol. 120, no. 5, pp. 685–693, 2007.
View at: Publisher Site | Google Scholar
W. Mueck, B. I. Eriksson, K. A. Bauer et al., “Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery,” Clinical Pharmacokinetics, vol. 47, no. 3, pp. 203–216, 2008.
View at: Publisher Site | Google Scholar
B. I. Eriksson, L. C. Borris, R. J. Friedman et al., “Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty,” The New England Journal of Medicine, vol. 358, no. 26, pp. 2765–2775, 2008.
View at: Publisher Site | Google Scholar
A. K. Kakkar, B. Brenner, O. E. Dahl et al., “Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial,” The Lancet, vol. 372, no. 9632, pp. 31–39, 2008.
View at: Publisher Site | Google Scholar
M. R. Lassen, W. Ageno, L. C. Borris et al., “Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty,” The New England Journal of Medicine, vol. 358, no. 26, pp. 2776–2786, 2008.
View at: Publisher Site | Google Scholar
A. G. Turpie, M. R. Lassen, B. L. Davidson et al., “Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial,” The Lancet, vol. 373, no. 9676, pp. 1673–1680, 2009.
View at: Publisher Site | Google Scholar
B. I. Eriksson, A. K. Kakkar, A. G. G. Turpie et al., “Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement,” Journal of Bone and Joint Surgery B, vol. 91, no. 5, pp. 636–644, 2009, Erratum in: Journal of Bone and Joint Surgery, vol. 91, p. 1120, 2009.
View at: Publisher Site | Google Scholar
M. R. Patel, K. W. Mahaffey, J. Garg et al., “Rivaroxaban versus warfarin in non-valvular atrial fibrillation,” The New England Journal of Medicine, vol. 365, pp. 883–891, 2011.
View at: Publisher Site | Google Scholar
W. Mueck, A. W. A. Lensing, G. Agnelli, H. Decousus, P. Prandoni, and F. Misselwitz, “Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention,” Clinical Pharmacokinetics, vol. 50, no. 10, pp. 675–686, 2011, Erratum in: Clinical Pharmacokinetics, vol. 51, p. 136, 2012.
View at: Publisher Site | Google Scholar
K. A. A. Fox, J. P. Piccini, D. Wojdyla et al., “Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment,” European Heart Journal, vol. 32, no. 19, pp. 2387–2394, 2011.
View at: Publisher Site | Google Scholar
G. J. Hankey, M. R. Patel, S. R. Stevens et al., “Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF,” The Lancet Neurology, vol. 11, no. 4, pp. 315–322, 2012.
View at: Publisher Site | Google Scholar
H. R. Büller, M. H. Prins, A. W. A. Lensing et al., “Oral rivaroxaban for the treatment of symptomatic pulmonary embolism,” The New England Journal of Medicine, vol. 366, no. 14, pp. 1287–1297, 2012.
View at: Publisher Site | Google Scholar
C. B. Granger, J. H. Alexander, J. J. McMurray et al., “Apixaban versus warfarin in patients with atrial fibrillation,” The New England Journal of Medicine, vol. 365, pp. 981–992, 2011.
View at: Publisher Site | Google Scholar
S. Ogawa, Y. Shinohara, and K. Kanmuri, “Safety and efficacy of the oral direct factor Xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation,” Circulation Journal, vol. 75, no. 8, pp. 1852–1859, 2011.
View at: Publisher Site | Google Scholar
S. J. Connolly, J. Eikelboom, C. Joyner et al., “Apixaban in patients with atrial fibrillation,” The New England Journal of Medicine, vol. 364, no. 9, pp. 806–817, 2011.
View at: Publisher Site | Google Scholar
J. D. Easton, R. D. Lopes, M. C. Bahit et al., “Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial,” The Lancet Neurology, vol. 11, no. 6, pp. 503–511, 2012.
View at: Publisher Site | Google Scholar
H.-C. Diener, J. Eikelboom, S. J. Connolly et al., “Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial,” The Lancet Neurology, vol. 11, no. 3, pp. 225–231, 2012.
View at: Publisher Site | Google Scholar
M. N. Levine, C. Gu, H. A. Liebman et al., “A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer,” Journal of Thrombosis and Haemostasis, vol. 10, no. 5, pp. 807–814, 2012.
View at: Publisher Site | Google Scholar
S. Z. Goldhaber, A. Leizorovicz, A. K. Kakkar et al., “Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2167–2177, 2011.
View at: Google Scholar
J. H. Alexander, R. C. Becker, D. L. Bhatt et al., “Apixaban, an oral, direct, selective factor xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the apixaban for prevention of acute ischemic and safety events (APPRAISE) trial,” Circulation, vol. 119, no. 22, pp. 2877–2885, 2009.
View at: Publisher Site | Google Scholar
J. H. Alexander, R. D. Lopes, S. James et al., “Apixaban with antiplatelet therapy after acute coronary syndrome,” The New England Journal of Medicine, vol. 365, no. 8, pp. 699–708, 2011.
View at: Publisher Site | Google Scholar
M. R. Lassen, B. L. Davidson, A. Gallus, G. Pineo, J. Ansell, and D. Deitchman, “The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement,” Journal of Thrombosis and Haemostasis, vol. 5, no. 12, pp. 2368–2375, 2007.
View at: Publisher Site | Google Scholar
H. Buller, D. Deitchman, M. Prins, and A. Segers, “Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study,” Journal of Thrombosis and Haemostasis, vol. 6, no. 8, pp. 1313–1318, 2008.
View at: Publisher Site | Google Scholar
M. R. Lassen, G. E. Raskob, A. Gallus, G. Pineo, D. Chen, and R. J. Portman, “Apixaban or enoxaparin for thromboprophylaxis after knee replacement,” The New England Journal of Medicine, vol. 361, no. 6, pp. 594–604, 2009.
View at: Publisher Site | Google Scholar
M. R. Lassen, G. E. Raskob, A. Gallus, G. Pineo, D. Chen, and P. Hornick, “Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial,” The Lancet, vol. 375, no. 9717, pp. 807–815, 2010.
View at: Publisher Site | Google Scholar
M. R. Lassen, A. Gallus, G. E. Raskob, G. Pineo, D. Chen, and L. M. Ramirez, “Apixaban versus enoxaparin for thromboprophylaxis after hip replacement,” The New England Journal of Medicine, vol. 363, no. 26, pp. 2487–2498, 2010.
View at: Publisher Site | Google Scholar
C. T. Ruff, R. P. Giugliano, E. M. Antman et al., “Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis in Myocardial Infarction study 48 (ENGAGE AF-TIMI 48),” American Heart Journal, vol. 160, no. 4, pp. 635.e2–641.e2, 2010.
View at: Publisher Site | Google Scholar
N. Chung, H. K. Jeon, L. M. Lien et al., “Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation,” Thrombosis and Haemostasis, vol. 105, no. 3, pp. 535–545, 2011.
View at: Publisher Site | Google Scholar
M. M. Samama, S. Kunitada, A. Oursin, F. Depasse, and S. Heptinstall, “Comparison of a direct Factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: a randomised controlled trial in healthy elderly adults,” Thrombosis Research, vol. 126, no. 4, pp. e286–e293, 2010.
View at: Publisher Site | Google Scholar
T. Fuji, S. Fujita, S. Tachibana, and Y. Kawai, “A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty,” Journal of Thrombosis and Haemostasis, vol. 8, no. 11, pp. 2458–2468, 2010.
View at: Publisher Site | Google Scholar
J. I. Weitz, S. J. Connolly, I. Patel et al., “Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation,” Thrombosis and Haemostasis, vol. 104, no. 3, pp. 633–641, 2010.
View at: Publisher Site | Google Scholar
G. Raskob, A. T. Cohen, B. I. Eriksson et al., “Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement: a randomised double-blind dose-response study,” Thrombosis and Haemostasis, vol. 104, no. 3, pp. 642–649, 2010.
View at: Publisher Site | Google Scholar
European Medicines Agency (EMA), “European public assessment report: eliquis,” http://www.emea.europa.eu.
View at: Google Scholar
P. C. Wong, E. J. Crain, B. Xin et al., “Apixaban, an oral, direct and highly selective factor Xa inhibitor: In vitro, antithrombotic and antihemostatic studies,” Journal of Thrombosis and Haemostasis, vol. 6, no. 5, pp. 820–829, 2008.
View at: Publisher Site | Google Scholar
K. Ogata, J. Mendell-Harary, M. Tachibana et al., “Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers,” Journal of Clinical Pharmacology, vol. 50, no. 7, pp. 743–753, 2010.
View at: Publisher Site | Google Scholar
http://clinicaltrials.gov/.
C. Veyrat-Follet, N. Vivier, M. Trellu, C. Dubruc, and G. J. Sanderink, “The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials,” Journal of Thrombosis and Haemostasis, vol. 7, no. 4, pp. 559–565, 2009.
View at: Publisher Site | Google Scholar
M. G. Bousser, J. Bouthier, H. R. Büller et al., “Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial,” The Lancet, vol. 371, no. 9609, pp. 315–321, 2008, Erratum in: The Lancet, vol. 372, no. 9655, p. 2022, 2008.
View at: Publisher Site | Google Scholar
H. R. Buller, A. T. Cohen, B. Davidson et al., “Extended prophylaxis of venous thromboembolism with idraparinux,” The New England Journal of Medicine, vol. 357, no. 11, pp. 1105–1112, 2007.
View at: Publisher Site | Google Scholar
H. R. Buller, A. T. Cohen, B. Davidson et al., “Idraparinux versus standard therapy for venous thromboembolic disease,” The New England Journal of Medicine, vol. 357, no. 11, pp. 1094–1104, 2007.
View at: Publisher Site | Google Scholar
The Equinox Investigators, “Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis,” Journal of Thrombosis and Haemostasis, vol. 9, no. 1, pp. 92–99, 2011.
View at: Publisher Site | Google Scholar
I. Paty, M. Trellu, J. M. Destors, P. Cortez, E. Boëlle, and G. Sanderink, “Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion,” Journal of Thrombosis and Haemostasis, vol. 8, no. 4, pp. 722–729, 2010.
View at: Publisher Site | Google Scholar
H. R. Büller, A. S. Gallus, G. Pillion, M. H. Prins, and G. E. Raskob, “Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial,” The Lancet, vol. 379, no. 9811, pp. 123–129, 2012.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2012 Alessandro Squizzato. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3670

Downloads

1289

Citations