European Heart Journal Advance Access published September 13, 2012

European Heart Journal doi:10.1093/eurheartj/ehs258

REVIEW

Clinical update

Pulmonary embolism: risk assessment and management

Stavros Konstantinides 1,2* and Samuel Z. Goldhaber 3
1 Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Building 403, Langenbeckstrasse 1, 55131 Mainz, Germany; 2Department of Cardiology, University General Hospital, Democritus University of Thrace, Alexandroupolis, Greece; and 3Cardiovascular Division, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA

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Received 20 May 2012; revised 24 July 2012; accepted 27 July 2012

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Pulmonary embolism Prognosis Risk assessment Imaging Biomarkers Prediction rules Anticoagulants Thrombolysis Embolectomy Intervention

Acute pulmonary embolism (PE) poses a signicant burden on health and survival. Its severity ranges from asymptomatic, incidentally discovered subsegmental thrombi to massive, pressor-dependent PE complicated by cardiogenic shock and multisystem organ failure. Rapid and accurate risk stratication is therefore of paramount importance to ensure the highest quality of care. This article critically reviews currently available and emerging tools for risk-stratifying acute PE, and particularly for distinguishing between elevated (intermediate) and low risk among normotensive patients. We focus on the potential value of risk assessment strategies for optimizing severity-adjusted management. Apart from reviewing the current evidence on advanced early therapy of acute PE (thrombolysis, surgery, catheter interventions, vena cava lters), we discuss recent advances in oral anticoagulation with vitamin K antagonists, and with new direct inhibitors of factor Xa and thrombin, which may contribute to profound changes in the treatment and secondary prophylaxis of venous thrombo-embolism in the near future.

Clinical cases in pulmonary embolism

Case 1
A 75-year-old man who underwent left nephrectomy for renal cell carcinoma 6 months ago is admitted to the emergency department with acute severe dyspnoea and cyanosis. His blood pressure is 100 over 60 mmHg; his heart rate, 120 b.p.m. Arterial oxygen saturation is 75% while breathing room air and fails to rise under supplemental oxygen. The patient undergoes endotracheal intubation and is mechanically ventilated with 100% oxygen, which results in further drop of the arterial saturation to 65% despite correct positioning of the tube. Chest X-ray shows clear lungs without inltrates. Transthoracic echocardiography reveals a large right ventricle with a hypokinetic free wall. What are the next diagnostic and therapeutic steps?

pathological ndings. Acute pulmonary embolism (PE) and deep vein thrombosis are conrmed by computed tomography (CT) and ultrasonography, respectively. The patient strongly desires to be discharged immediately and receive treatment at home. Is this acceptable?

Case 3
A 60-year-old woman presents for clinical follow-up 6 months after acute PE. The event was unprovoked, i.e. no reversible predisposing factors were found, but thrombophilia screening revealed heterozygous factor V Leiden mutation; the patient is obese (body mass index, 34 kg/m2). She had an uneventful in-hospital course and was treated with vitamin K antagonists over the past 6 months without recurrence; there were a few minor bleeding episodes under warfarin. Can anticoagulation be safely discontinued now, or is the patient a candidate for indenite secondary prophylaxis? Is regular echocardiographic follow-up necessary for early detection of chronic thrombo-embolic pulmonary hypertension (CTEPH)?

Case 2
A 50-year-old woman is re-admitted to the hospital with mild-to-moderate dyspnoea 10 days after surgical cholecystectomy. Physical examination reveals a swollen right calf and no further

Introduction
Pulmonary embolism spans a broad spectrum of illness, ranging from asymptomatic, incidentally discovered subsegmental

* Corresponding author. Tel: + 49 6131 176255, Fax: + 49 6131 173456, Email: stavros.konstantinides@unimedizin-mainz.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com

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thrombus detected on chest CT scan1 to pressor-dependent PE complicated by cardiogenic shock and multisystem organ failure.2,3 Between these two extremes are patients with symptomatic low-risk or intermediate-risk disease.4,5 As clinicians specializing in cardiovascular medicine, we are likely to be consulted on patients at the sicker end of the risk continuum. Our toolbox of options is rapidly expanding. For the patient without haemodynamic compromise, we can offer conventional unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux as a bridge to vitamin K antagonists. More recently, oral monotherapy anticoagulation (without any injectable or intravenous anticoagulant) was reported to be safe and effective.6 On the other hand, some normotensive and most unstable patients will require specic advanced therapy, in addition to parenteral anticoagulation. Options for advanced therapy include placement of an inferior vena cava lter, systemic thrombolysis, open surgical embolectomy, or pharmacomechanical therapy.5,7 This article critically reviews currently available and emerging tools for risk-stratifying acute PE as well as severity-adjusted management strategies. We also discuss the recent advances in oral anticoagulation with vitamin K antagonists, and with new direct inhibitors of factor Xa and thrombin which are being introduced into the market and may contribute to profound changes in the treatment strategy for acute venous thrombo-embolism in the near future.

S. Konstantinides and S.Z. Goldhaber

event and the patients comorbidity. The Pulmonary Embolism Severity Index (PESI) is the most extensively validated prognostic clinical score to date.17 20 Its major strength lies in excluding (ruling out) an adverse outcome as indicated by the high negative predictive value (NPV) of the lowest PESI classes I and II.21,22 In fact, a recently published randomized trial successfully employed a low PESI score as the main inclusion criterion for home treatment of acute PE.23 The main limitation of the index is that it requires numerous variables and is relatively complex to calculate, which may reduce its practicability in high-volume centres. Reliable prognostic information can also be obtained with a simplied version of the score (sPESI) which focuses on six equally weighted variables: age . 80 years; history of cancer; history of heart failure or chronic lung disease; systolic blood pressure , 100 mmHg; pulse rate . 110 b.p.m.; and arterial oxyhaemoglobin saturation , 90%.24 In an external validation study, the sPESI was at least as accurate as imaging and biomarker criteria for excluding an elevated risk.25 The implications of this latter score for patient management remain to be shown.26

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Advanced risk stratication: imaging ndings

Imaging of the right ventricle with echocardiography detects the changes occurring in the morphology and function of the right ventricle as a result of acute pressure overload in PE.9,27 Registries and cohort studies demonstrate an association between echocardiographic parameters of RV dysfunction and a poor in-hospital outcome.3,15,28,29 Nevertheless, the prognostic value of cardiac ultrasound in haemodynamically stable patients appears moderate at best,30 mostly due to the poor standardization of echocardiographic criteria.30,31 In a prospective randomized trial, normotensive patients with intermediate-risk PE (mostly) dened by echocardiography appeared to have a low early mortality risk, regardless of whether they received thrombolysis plus heparin or heparin alone.32 It thus appears that an abnormal echocardiogram needs to be accompanied by clinical signs indicating severe PE, or by a positive biomarker test indicating the presence of heart failure or myocardial injury (as explained below), to justify advanced therapy in normotensive patients with acute PE. Four-chamber views of the heart on multidetector-row CT may, besides visualizing the thrombi in the pulmonary vasculature (Figure 1A and B), also detect RV enlargement and (indirectly) dysfunction (Figure 1C).30 The prognostic value of an enlarged right ventricle on CT was recently conrmed by an international prospective cohort study,33 but data from therapeutic trials are needed before it can be safely concluded that this modality can replace the echocardiogram in guiding risk-adjusted management of acute PE.

Risk assessment in pulmonary embolism

Initial risk stratication
The key to an effective treatment of PE in the acute phase lies in the assessment of the patients early death risk. A crucial determinant is the presence and severity of right ventricular (RV) dysfunction resulting from acute pressure overload.8,9 The denition of high-risk (European classsication5) or massive (North American classication7) PE is usually straightforward and relies on the presence of clinically overt RV failure which results in haemodynamic compromise. This condition, which is encountered in , 5% of all patients presenting with acute PE,10,11 constitutes a medical emergency, since it is associated with at least a 15% risk of in-hospital death, particularly during the rst hours after admission.12 14

Advanced risk stratication: clinical scores

The absence of haemodynamic collapse or persistent hypotension at presentation is generally thought to predict a favourable early outcome, provided that the disease is diagnosed correctly and anticoagulation is started without delay.3,12,15 However, some of the (initially) normotensive patients with acute PE may have an elevated risk of death or major complications (intermediate-risk PE in Europe; submassive PE in North America) which warrants further risk stratication and possibly specic advanced therapy. Prediction rules based on clinical ndings at diagnosis can help with the prognostic assessment of patients with acute PE.16,17 These scores account both for the clinical severity of the acute

Advanced risk stratication: laboratory markers

Circulating biochemical markers have been proposed as an alternative (or additional) tool for risk stratication of normotensive patients with PE. Among these, circulating natriuretic peptides are highly sensitive indicators of neurohormonal activation due to acute and chronic heart failure. A meta-analysis of 13 studies found

Management of PE

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Figure 1 The extent of thrombotic load on computed tomography does not always correlate with the clinical severity of acute pulmonary embolism or its impact on right ventricular function. (A) A straightforward case in which massive thrombi are present in both the right and the left pulmonary artery of a patient presenting with haemodynamic instability (persistent tachycardia, systolic blood pressure between 90 and 100 mmHg). (B) However, a patient presenting with similar clinical ndings had an apparently much smaller thrombotic load on computed tomography; in this latter patient, the size of thrombi was also in discordance with the impressive enlargement (as a surrogate for dysfunction) of the right ventricle (C ).

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that 51% of 1132 patients with acute PE had elevated brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP concentrations; these were associated with an increased risk of early death and a complicated in-hospital course.34 Nevertheless, their positive predictive value for an elevated risk has been consistently low.35 Elevated cardiac troponin I or T levels are also found in up to 50% of the patients with acute PE.36 A meta-analysis of studies published between 1998 and 2007, with a total of 1985 patients, showed that cardiac troponin elevation was associated with an increased risk of death and major adverse events in the acute phase.37 However, another meta-analysis which excluded hypotensive patients did not conrm the prognostic value of circulating troponin levels.38 Recently developed high-sensitivity assays may improve the prognostic performance of this biomarker, at least at the low-risk end of the severity spectrum. More specically, a derivation study showed that high-sensitivity troponin T (hsTnT) was useful for excluding an adverse outcome in the acute phase of PE.39 In a multicentre, multinational cohort of 526 normotensive patients with acute PE, hsTnT exhibited a high NPV (98%) which was comparable with that of the sPESI (99%).40 Heart-type fatty acid-binding protein (H-FABP) is a small cytoplasmic protein which diffuses rapidly into the circulation following myocardial cell damage.41 It may provide relevant prognostic information in non-high-risk PE.42 Cardiac expression of growthdifferentiation factor-15 (GDF-15), a distant member of the transforming growth factor-b cytokine family, also increases sharply after pressure overload or myocardial ischaemia.43,44 Growth-differentiation factor-15 might be capable of integrating information on RV dysfunction, myocardial injury, and possibly comorbidity in patients with acute PE.45 Both biomarkers appear promising and deserve further evaluation in external patient cohorts.

being, no individual laboratory marker or imaging parameter has been shown to justify advanced therapy in haemodynamically stable patients with PE. Therefore, attention is shifting to prognostic models combining clinical, imaging, and biochemical parameters. Some registries and cohort studies did suggest that biomarkers may possess prognostic value additive to that of clinical parameters and echocardiography,45 49 and various combinations of the three modalities were reported to possess satisfactory predictive performance.50,51 An external validation of these scores has not yet been undertaken. At present, one large randomized trial is testing the possible implications of a combination prognostic model for the management of intermediate-risk or submassive PE. The Pulmonary Embolism Thrombolysis Study (PEITHO) is randomizing 1000 normotensive patients with acute PE, an echocardiogram (or CT scan) indicating RV dysfunction, and a positive cardiac troponin test, to receive thrombolysis with tenecteplase as opposed to heparin alone.52 Recruitment is completed, and the results will be available in 2013.

Initial treatment of pulmonary embolism

Heparin anticoagulation
Anticoagulant treatment should be administered to all patients with high or intermediate clinical probability of acute PE, without awaiting denitive conrmation by imaging procedures.5,53 Intravenous unfractionated heparin is the preferred mode of initial anticoagulation for patients with severe renal impairment (creatinine clearance , 2030 mL/min); for those at high risk of bleeding; for high-risk, hypotensive patients; and, as a rule, for extremely overweight, underweight, or old patients. With the exception of these circumstances, LMWH or fondaparinux is given subcutaneously at weight-adjusted doses53 (Figure 2); routine anticoagulation monitoring, i.e. measurement of anti-factor Xa levels, is not necessary. Though controversial, obtaining these levels may be

Emerging concepts: combined parameters and scores

A critical overview of currently available and emerging prognostic tools for patients with acute PE is shown in Table 1. For the time

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S. Konstantinides and S.Z. Goldhaber

Table 1

Risk assessment tools in acute pulmonary embolism

Strengths Weaknesses

...............................................................................................................................................................................
Clinical prediction rules PESI Geneva risk score Assessment of clinical severity, comorbidity PESI strong for dening low-risk PE, successfully employed in a randomized trial Prognostic value for intermediate-risk PE unknown Clinical scores do not account for RV function, a key prognostic determinant in the early phase

...............................................................................................................................................................................
Imaging tests Echocardiography Real-time, bedside assessment of RV size and function, PA systolic pressure Moderate positive and NPV Poorly standardized parameters and criteria Ultrasound failed to identify candidates for thrombolysis in a randomized trial Implications of an enlarged RV on CT for the management of intermediate-risk PE unclear

CT

...............................................................................................................................................................................
Laboratory markers Cardiac troponin I, T Troponin elevation correlated with PE prognosis Sensitive test, high NPV Widely used test BNP/NT-proBNP elevation correlated with PE prognosis High NPV Widely used test H-FABP GDF-15 Early marker of adverse outcome Global marker of myocardial injury, heart failure, comorbidity Non-specic test, positive predictive value low (positive test does not justify advanced therapy)

Diagnosis of PE and assessment of RV size in one test Findings correlated with PE prognosis

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Natriuretic peptides (BNP, NT-proBNP)

Non-specic test, positive predictive value very low (positive test does not justify advanced therapy) Appropriate cut-off value(s) unclear

Not available for routine use at present Not available for routine use at present

PESI, Pulmonary Embolism Severity Index; CT, computed tomography; PE, pulmonary embolism; BNP, brain natriuretic peptide; GDF-15, growth differentiation factor-15; H-FABP, heart-type fatty acid-binding protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; PA, pulmonary artery; RV, right ventricular; NPV, negative predictive value.

Figure 2 Current and evolving anticoagulation regimens for acute pulmonary embolism. b.i.d., twice daily; Fonda, fondaparinux; LMWH, low-molecular-weight heparin; o.d., once daily; s.c., subcutaneously; VKA, vitamin K antagonist. *Unfractionated heparin (continuous intravenous infusion) can be given as an alternative to LMWH; see text and reference 90 for details of dosing regimen; see text and references 6 and 85 for details of dosing regimen.

Management of PE

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by echocardiography.29 In the only randomized thrombolysis trial with clinical endpoints, early thrombolytic treatment given to normotensive patients with evidence of RV dysfunction signicantly reduced the need for emergency escalation of therapy during the hospital stay.32 Currently approved thrombolytic regimens for PE, and the contraindications to thrombolysis, are shown in Table 2. Overall, . 90% of patients with PE appear to respond favourably to thrombolysis as indicated by clinical and echocardiographic improvement within the rst 36 h.55 The greatest benet is observed when treatment is initiated within 48 h of symptom onset, but thrombolysis can still be useful in patients who have had symptoms for 614 days.56 Two recent epidemiological reports, derived from the Nationwide Inpatient Sample (representing 20% of non-federal, shortterm hospitals in the USA) and including more than 2 000 000 patients discharged between 1998 and 2008 with the diagnosis of PE, support the efcacy and safety of thrombolysis in haemodynamically unstable patients with acute PE. In the rst report,10 case fatality rates attributable to PE were drastically lower among unstable patients who received (compared with those

considered in patients with (moderate) impairment of renal function, and intermittently during pregnancy. In these cases, anti-Xa levels should be determined 4 h after the morning injection; the proposed target range is 0.6 1.0 IU/mL for twice-daily and 1.0 2.0 IU/mL once-daily administration. The anti-Xa assay must be calibrated separately by the laboratory for each anticoagulant that is assayed. Anticoagulation with unfractionated heparin or LMWH/fondaparinux should be continued for at least 5 days. Oral anticoagulants (vitamin K antagonists) should be initiated as soon as possible in haemodynamically stable patients, preferably on the same day as heparin (Figure 2). Parenteral anticoagulation can be stopped as soon as the international normalized ratio (INR) has been in the therapeutic range (between 2.0 and 3.0) on 2 consecutive days.

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Thrombolysis
Randomized trials have consistently shown that thrombolytic therapy of PE effectively resolves thrombo-embolic obstruction and promptly reduces pulmonary artery pressure and resistance with a concomitant increase in cardiac output.54 One trial also demonstrated a signicant improvement in RV function as assessed Table 2 Thrombolysis for pulmonary embolism

Agents and regimens

...............................................................................................................................................................................
Streptokinasea 250 000 U as a loading dose over 30 min, followed by 100 000 U/h over 12 24 h Accelerated regimen: 1.5 million IU over 2 hb Absolute History of haemorrhagic stroke or stroke of unknown origin Ischaemic stroke in previous 6 months Central nervous system neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major trauma, surgery, or head injury in previous 3 weeks Urokinasea,c Relative 4400 U per kg of body weight as a loading dose over Transient ischaemic attack in previous 6 months 10 min, followed by 4400 U/kg/h over 12 24 h Oral anticoagulation Accelerated regimen: 3 million U over 2 hb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy or rst postpartum week Non-compressible puncture sites Alteplasea Traumatic resuscitation d 100 mg over 2 h Refractory hypertension (systolic blood pressure . 180 mmHg) Accelerated regimen: 0.6 mg/kg for 15 min Advanced liver disease .................................................................................................. Infective endocarditis Reteplasea,e Active peptic ulcer Two bolus injections of 10 U 30 min apart

Contraindications

..................................................................................................
Tenecteplasef 30 50 mg bolus for 5 10 s adjusted for body weight , 60 kg 60 to , 70 kg 70 to , 80 kg 80 to , 90 kg 90 kg 30 mg 35 mg 40 mg 45 mg 50 mg

Adapted and modied from references 5 and 111. a Unfractionated heparin should not be infused together with streptokinase or urokinase; it can be given during alteplase or reteplase administration. Low-molecular-weight heparins have not been tested in combination with thrombolysis in patients with pulmonary embolism. b Short (2 h) infusion periods are generally recommended.53 c Urokinase is not available in the USA. d FDA-approved regimen. e Off-label use of reteplase. f Off-label use of tenecteplase; this is the regimen recommended for acute myocardial infarction. A randomized pilot trial112 found it to be safe and effective in non-high-risk pulmonary embolism.

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who did not receive) thrombolytic treatment [relative risk, 0.20; 95% condence interval (CI), 0.19 0.22]. Unfortunately, only 21 390 out of 72 230 unstable (30%) patients received thrombolytic agents as recommended. In the second report,57 the overall prevalence of intracerebral haemorrhage after thrombolytic therapy was low (0.9%), although it did appear to increase in the elderly and in patients with kidney disease.

S. Konstantinides and S.Z. Goldhaber

Surgical or interventional treatment

Pulmonary embolectomy is a recommended therapeutic option in patients with high-risk PE in whom there are absolute contraindications to thrombolysis, or if thrombolysis has failed.5,53 Recent technical advances in transportable extracorporeal assist systems, and particularly the timely early involvement of the cardiac surgeon as part of an interdisciplinary approach to high-risk PE before haemodynamic collapse, have contributed to improved postoperative outcomes and case fatality rates as low as 23%.58 As an alternative to surgical procedures, catheter-based reperfusion is an option for patients with high-risk PE, and possibly also for selected patients with intermediate-risk PE. In case of absolute contraindications to thrombolysis, thrombus fragmentation, rheolytic thrombectomy, suction thrombectomy, or rotational thrombectomy have been performed. If no absolute contraindications are present, conventional catheter-directed thrombolysis and, more recently, pharmacomechanical thrombolysis have become available. The methods and techniques of catheter-based interventions were reviewed recently.59 Although the evidence is thus far mostly based on uncontrolled data and single-centre experience, a review of 29 retrospective and 6 prospective series yielded promising success rates.60 Two multicentre clinical trials, a randomized study in Europe and a single-arm study in the USA (NCT01166997 and NCT01513759, respectively), are currently underway to determine the efcacy and safety of ultrasound-enhanced low-dose catheter-delivered thrombolysis in intermediate-risk PE.

Inferior vena cava lters

Caval lters may be used as a means of primary or secondary PE prevention. However, the data on their safety and efcacy remain inconclusive. Moreover, therapeutic anticoagulation is generally very effective in preventing recurrent thrombo-embolism.61 In a meta-analysis, fatal PE occurred in 0.3 1.3% of patients during the rst 3 months of treatment with heparin or warfarin.62 On the other hand, recent epidemiological data suggest that the combination of thrombolytic therapy with the placement of a vena cava lter may be particularly effective in lowering case fatality rates in unstable patients.10,63 At present, retrievable inferior vena cava lters have a place mostly when anticoagulation is absolutely contraindicated, or in cases of recurrence despite therapeutic dosing of anticoagulants.53 Their widespread use in clinical practice, as recently recorded in the USA,64 may not be justied.

arteries.5,7,53 Patients with suspected high-risk PE should immediately receive a weight-adjusted bolus of unfractionated heparin; if PE is conrmed, thrombolysis should be administered without delay. If thrombolysis is contraindicated or has failed, surgical embolectomy or catheter-based reperfusion treatment are valuable alternatives. Low-molecular-weight heparin or fondaparinux is considered adequate initial treatment for most normotensive patients. Thrombolysis may be considered in selected cases,5 such as in patients with evidence of RV dysfunction or myocardial injury, particularly if they also present with acute respiratory failure and/or are at high risk of death (due, for example, to diminished cardiopulmonary reserves and severe comorbidity), provided they have no contraindications to thrombolytic agents. A recently presented small pilot study in patients with moderate PE suggested that a lower dose of a thrombolytic (half the standard dose of alteplase) might reduce the rate of PE recurrence and persistent pulmonary hypertension without causing excess bleeding (ACC 2012 Late-Breaking Trials; session 308). These results may be hypothesis-generating, but do not justify a change in our practice regarding the management of the intermediate-risk group or the dosing of alteplase. A large multinational randomized trial has set out to determine whether normotensive patients with RV dysfunction, detected by echocardiography or CT, plus evidence of myocardial injury indicated by a positive troponin test, may benet from early thrombolytic treatment.52 The primary efcacy endpoint is a clinical composite endpoint of all-cause mortality or haemodynamic collapse within the rst 7 days. Six-month and 2-year follow-up is also being conducted. Normotensive patients without serious comorbidity or signs of (right) heart failure belong to a low-risk group which could be treated out of hospital.65 67 Recently, a randomized study reported that low-risk patients as dened by the PE severity index can safely be discharged within 24 h and treated as outpatients.23 Early discharge of patients with low-risk PE is mentioned as an option in updated guidelines,53 but the appropriate criteria for identifying the patients to benet from such treatment remain to be dened.

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Established and new oral anticoagulants in treatment and secondary prophylaxis

Vitamin K antagonists
Worldwide, vitamin K antagonists such as warfarin, acenocoumarol, or phenprocoumon remain the predominant anticoagulant prescribed for PE. In 2010, for example, more than 25 million prescriptions were written for warfarin in the USA.68 Nevertheless, this is a difcult medication to utilize properly, being responsible for one-third of emergency hospitalizations due to adverse drug events in patients 65 years of age or older.69 Not surprisingly, in view of its actual and perceived bleeding risks, warfarin continues to be largely underused in clinical practice.70 Although warfarin is an old drug, several developments have improved its prole and the quality of anticoagulation. Centralized

Risk-adjusted management strategy

In view of the high early mortality and complication risk associated with high-risk PE, patients who present with persistent arterial hypotension or shock are in need of immediate pharmacological or mechanical recanalization of the occluded pulmonary

Management of PE

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dialysis appears to be an option for dabigatran84 but not for rivaroxaban, which is 95% protein bound. The Oral Rivaroxaban for Symptomatic Venous Thromboembolism (EINSTEIN) programme tested the efcacy and safety of oral monotherapy (replacing both parenteral anticoagulation and warfarin) with rivaroxaban to treat venous thromboembolism. EINSTEIN comprised three trials: (i) the Acute Deep Vein Thrombosis (DVT) Study85; (ii) the Continued Treatment Study of DVT85; and (iii) the Acute PE Study.6 In both the acute DVT and PE studies, the dosing regimen of rivaroxaban was 15 mg twice daily for the rst 3 weeks, followed by 20 mg once daily thereafter. A higher dose was administered for 3 weeks because PE and DVT patients are considered especially hypercoagulable during this period, when the highest rate of treatment failures occur.86 88 Patients with a creatinine clearance , 30 mL/min were excluded from the EINSTEIN programme. This approach differed from the dosing regimen of rivaroxaban in the atrial brillation trial, in which patients with a creatinine clearance between 30 and 49 mL/min received a reduced dose (15 mg rather than 20 mg once daily).89 In the EINSTEIN-PE study,6 4832 patients were enrolled. Recurrent venous thrombo-embolism occurred in 2.1% of patients receiving rivaroxaban compared with 1.8% of those on standard enoxaparin/warfarin therapy. Rivaroxaban was non-inferior to standard therapy (P 0.003). Major or clinically relevant nonmajor bleeding occurred in 10.3% of rivaroxaban patients compared with 11.4% standard therapy patients (P 0.32); however, major bleeding was observed in only 1.1% of patients taking rivaroxaban compared with 2.2% of those on enoxaparin/warfarin (P 0.003). In particular, intracranial bleeding occurred in one rivaroxaban patient compared with 10 patients receiving standard therapy. Thus, the results of the EINSTEIN trial support the use of rivaroxaban as monotherapy for the management of acute PE. The single oral drug approach is also being evaluated in an ongoing trial testing the factor Xa inhibitor, apixaban (AMPLIFY; NCT00643201). In this latter trial, the dosing regimen of apixaban is 10 mg twice daily for the rst week, followed by 5 mg twice daily thereafter (Figure 2). Dabigatran also showed non-inferiority for the prevention of recurrent venous thrombo-embolism in patients presenting with acute PE or DVT. In the RE-COVER trial, dabigatran 150 mg twice daily was compared with warfarin for the treatment of acute venous thrombo-embolism.90 Patients with a creatinine clearance , 30 mL/min were excluded. All patients, regardless of randomization assignment, received at least 5 days of parenteral anticoagulation, usually enoxaparin. The primary outcome was the 6-month incidence of recurrent symptomatic and objectively conrmed venous thrombo-embolism. Overall, 2564 patients were enrolled, 21% with PE only and the rest with DVT with/ without PE. Parenteral anticoagulation was administered for a mean of 10 days in both groups. For the efcacy endpoint, dabigatran was non-inferior to warfarin (2.4 vs. 2.1%, respectively). The rates of major bleeding in the two groups were similar: 1.6% for dabigatran and 1.9% for warfarin. There were no intracranial bleeds with dabigatran compared with three intracranial bleeds with warfarin. There were also fewer episodes of any bleeding with dabigatran (16%) compared with warfarin (22%). The RE-COVER trial supports the use of dabigatran as a xed dose

anticoagulation services appear to reduce the risks of warfarin compared with usual care.71 Certain tricks of the trade have emerged. If the INR is out of range, it is preferable to make small and subtle changes in warfarin dosing rather than large dosing adjustments. And, counterintuitively, vitamin K supplementation can improve the stability of anticoagulation for patients with unexplained variability in response to warfarin.72 Some patients may have stable INRs from month to month, and thus their INR testing can be reduced in frequency to once every 12 weeks.73 Trials of self-testing INR at home with point of care devices have generally been favourable, but the results are not conclusive. A recent meta-analysis of 11 trials with 6417 participants and 12 800 person-years of follow-up demonstrated a halving of thrombo-embolic events in the self-monitoring group, but no difference in major bleeding.74 Rapid turnaround pharmacogenetic testing may increase the precision of warfarin dosing.75,76 In particular, variations in two genes may account for more than one-third of the dosing variability of warfarin. One gene determines the activity of cytochrome CYP2C9, the hepatic isoenzyme that metabolizes the S-enantiomer of warfarin into its inactive form, whereas the other determines the activity of vitamin K epoxide reductase (VKORC1), the enzyme that produces the active form of vitamin K.77 Pharmacogenetic algorithms, such as the one available at www.warfarindosing.org, incorporate genotype and clinical information and recommend warfarin doses according to the integration of these data. A randomized trial undertook a clinical effectiveness comparison of pharmacogenetic vs. standard care warfarin dosing in 1866 patients who were starting warfarin therapy.78 The pharmacogenetic cohort had a 10% absolute reduction in out-of-range INRs at 1 month, primarily due to fewer INR values , 1.5, which coincided with a 66% lower rate of deep vein thrombosis. The pharmacogenetic cohort also had higher times in therapeutic ranges than the usual care group: 69 vs. 58% at 1 month, and 71 vs. 59% at 3 months. There are at least four ongoing large randomized, controlled trials testing pharmacogenetic testing to guide warfarin dosing: two in the USA, one in Europe, and one in Asia.68

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New oral anticoagulants

New oral anticoagulants are characterized by a rapid onset of action, a predictable anticoagulant effect, a specic coagulation enzyme target, and a low potential for drug or food interactions. They can be prescribed in xed doses because of predictable pharmacokinetics, and routine laboratory coagulation monitoring is not required.79 82 Of the drugs that have completed phase 3 trials in venous thrombo-embolism, rivaroxaban competitively binds activated factor X, whereas dabigatran is a direct inhibitor of thrombin. To date, neither drug has a specic antidote. In a randomized crossover study performed in 12 male healthy volunteers, prothrombin complex concentrate rapidly reversed the effect of rivaroxaban on the prothrombin time, although it could not reverse the prolongation of coagulation parameters (activated partial thromboplastin time, ecarin clotting time, and thrombin time) caused by dabigatran.83 Of note, however, this study did not address clinical endpoints such as the reversibility of drug-related bleeding. If emergent bleeding must be reversed,

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oral treatment for acute DVT and PE, after an initial period of parenteral anticoagulation. The switch to a new oral anticoagulant (compared with warfarin) following at least 5 days of parenteral anticoagulation is also being evaluated in an ongoing trial testing the factor Xa inhibitor edoxaban (Hokusai, NCT00986154) (Figure 2).

S. Konstantinides and S.Z. Goldhaber

Risk of recurrence and optimal duration of anticoagulation

One of the most common dilemmas when managing patients with PE is to decide upon the optimal duration of anticoagulation. The recurrence rate of venous thrombo-embolism after discontinuing anticoagulation is surprisingly high. For example, in a cohort of 1626 patients with proximal DVT or PE, the cumulative incidence of recurrence was 11% after 1 year, 20% after 3 years, 29% after 5 years, and 40% after 10 years; the strongest risk factor predisposing to recurrent thrombosis was an initial idiopathic, unprovoked event.91 Another study evaluated the long-term clinical benet of extending a 3-month course of oral anticoagulant therapy to 6 months (PE associated with temporary risk factors) or to 1 year (idiopathic PE); patients with PE had a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration.92 It thus appears that physicians should try to identify patients who are at high risk for recurrence and therefore potential candidates for indenite oral anticoagulant therapy. This recommendation is supported by data showing that patients who receive extended anticoagulation are effectively protected from recurrent thrombo-embolism while on therapy.85,93 What determines recurrence risk after acute PE? In a cohort of 929 patients, 19% of whom had recurrent venous thromboembolism after a median of 43 months following discontinuation of anticoagulation, the most important risk factors for recurrence were idiopathic, rather than provoked, PE; male gender; location of the thrombotic event (proximal DVT . calf DVT and PE . proximal DVT); and elevated D-dimer levels.94 Other reported risk factors include excess body weight95 and persistent RV dysfunction at hospital discharge after acute PE.96 An association has also been reported with immobilization, cancer, chronic obstructive pulmonary disease, low high-density lipoprotein cholesterol, and a positive family history.97 A literature review found that . 50% of patients with PE had residual thrombi on CT imaging 11 months after the initial event98; this rate was lower, 30%, when lung scan was used for followup.99 However, the clinical relevance of these ndings remains unclear and certainly does not support basing the duration of anticoagulation therapy on serial imaging tests. Moreover, and perhaps counterintuitively, most thrombophilias do not appear to be associated with an elevated risk of recurrent venous thrombo-embolism.100 Current guidelines recommend 3 months of anticoagulation in patients with PE provoked by surgery or by a non-surgical transient risk factor.5,53 Patients with an unprovoked PE will need evaluation for the riskbenet ratio of extended anticoagulation therapy after the rst 3 months of treatment. Nevertheless, many patients reside in a grey zone where personalized assessment is required to decide on the optimal duration of anticoagulation.97

In a recent investigator-initiated, double-blind study, patients who had completed 6 18 months of oral anticoagulation after a rst episode of unprovoked venous thrombo-embolism were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years.101 Recurrence occurred in 28 of the 205 patients (6.6% per year) on aspirin vs. 43 of 197 (11.2% per year) on placebo (hazards ratio, 0.58; 95% CI, 0.360.93). Although the relative proportion of platelets in venous thrombi is low, they participate by releasing polyphosphates, microparticles, and proinammatory mediators, and by interacting with neutrophils to generate DNA histone granule constituent complexes.102 Clearly, any protection offered by aspirin is inferior to that provided by vitamin K antagonists and new oral anticoagulants; however, if these results are conrmed by larger trials, aspirin might nd a place in long-term secondary prophylaxis for selected patients with high bleeding risk.

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Early discharge and outpatient treatment

The traditional approach to venous thrombo-embolism management has been to treat most DVT patients as outpatients and to treat virtually all PE patients initially in the hospital. With the development of more precise tools for accurate and rapid risk stratication, and with the availability of new oral anticoagulants and simplied regimens, the decisions about whether to hospitalize and the optimal duration of hospital stay may soon warrant re-examination. It is usually straightforward to identify the patients who are not candidates for outpatient treatment. Clearly, patients with severe comorbidity and a predicted high potential for adverse outcomes should be hospitalized. These patients have consistently been excluded from prospective management (cohort) studies focusing on home treatment66,67 (exclusion criteria reviewed in Lankeit and Konstantinides26). Many will require supplemental oxygen, parenteral analgesics or antibiotics, or specic treatment for concomitant disease, and they may be considered for advanced therapy such as systemic thrombolysis, pharmacomechanical catheterdirected therapy, surgical embolectomy, or a vena cava lter. Another crucial factor besides the patients medical prognosis is the presence of an adequate social safety net to ensure strict adherence to the prescribed anticoagulation regimen. A randomized trial of 344 patients with low-risk PE (PESI risk class I or II) was undertaken to determine the safety and effectiveness of outpatient treatment.23 After randomization to outpatient treatment, patients were contacted by the study staff daily for 7 days, and then on days 14, 30, 60, and 90. Outcomes were excellent in both groups. Only one patient in the outpatient group and none in the inpatient group had recurrent venous thromboembolism within 90 days. Only two outpatients and no inpatients had major bleeding. With this model of assiduous outpatient care, which may be feasible in the Netherlands66,67 and a few other European countries, it appears that low-risk patients with PE can be safely and effectively treated without (or with very short) hospitalization. Whether the home treatment concept is likely to carry over to other, larger parts of the real world in the future remains to be determined.

Management of PE

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these conditions increase the risk of recurrence moderately94,106 and may not mandate lifelong treatment according to current guidelines.5,53 As the patient also reported repeated episodes of minor bleeding during the past 6 months, we would recommend optimization of anticoagulation, perhaps at a lower than standard intensity such as targeting an INR range of 2.0 to 2.5. We would also strongly encourage lifestyle modication and physical activity with weight loss. An alternative approach would be to interrupt treatment for 1 month and then resume anticoagulation (only) if the D-dimer test is positive.107 Finally, although one study indicated that CTEPH may develop in as many as 3.8% of patients 2 years after acute PE,108 the true incidence of the disease is probably lower,109 and the recent data from a large population with idiopathic PE did not provide support for routine echocardiographic follow-up in search of developing CTEPH.110 We would recommend 6-month echocardiographic follow-up of a patient with elevated pulmonary artery pressure at discharge, but acknowledge that the issue remains unsettled. The randomized PEITHO trial52 will include a 2-year prospective follow-up to determine whether thrombolysis of intermediate-risk PE may, among others, prevent the development of CTEPH over the long term. Conict of interest: S. K. received research grants from Bayer HealthCare, Boehringer Ingelheim and Consultancy and lecture fees from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, LEO Pharma. S. Z. G received research grants from Daiichi Sankyo, Eisai, EKOS, Johnson and Johnson, and Sano Aventis. Consultancy fees from Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Merck, Pzer, Portola, and Sano Aventis.

Conclusions and outlook

Although case fatality rates appear to have dropped over the past two decades,11,103 acute PE continues to pose a serious burden on health and survival.104 Rapid and accurate risk stratication is of paramount importance to ensure the highest quality of care. We must rst classify patients as stable or unstable, i.e. distinguish between high-risk and non-high-risk PE. This dichotomy will help us to optimize patient management. High-risk PE clearly warrants immediate thrombolytic, surgical, or interventional reperfusion therapy. However, the intensive search continues for an intermediate-risk group among normotensive patients who will benet from advanced therapy in addition to anticoagulation. The large European randomized trial, PEITHO, may yield some answers shortly. Signicant progress has been made in the eld of anticoagulation with the optimization of treatment with vitamin K antagonists and the encouraging results of trials using new oral anticoagulants. Emerging management strategies may simplify secondary prevention in the future and help to resolve the persistent controversy over the optimal duration of anticoagulation after acute PE.

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Resolution of cases
In Case 1, we are dealing with a patient who most likely has highrisk (massive) PE, even if he does not full all formal criteria of haemodynamic instability or cardiogenic shock. This is an emergency situation. The patients persistent respiratory insufciency and paradoxical further aggravation of hypoxaemia after endotracheal intubation is a particular reason for concern. We strongly recommend bedside contrast echocardiography, as the most probable explanation is the presence of a patent foramen ovale, which is now wide open due to the increased right atrial pressure and leads to severe right-to-left shunting.105 In view of the patients persistent tachycardia, marginally low blood pressure, and intractable hypoxaemia, we would not demand further conrmation of the diagnosis by CT; instead, we would immediately proceed to systemic thrombolysis with 100 mg of alteplase administered over 2 h. In Case 2, we need to make clear to the patient that immediate discharge and out-of-hospital anticoagulation is not (yet) a widely accepted treatment option for PE. Even if the calculation of the (simplied) PESI yields a low risk, the patient may still have a residual risk for early complications which needs to be further claried by future management trials; besides, most studies on home treatment have thus far excluded obese patients.26 New oral anticoagulants may facilitate home treatment of PE in the future, but they are not yet approved for this indication. Therefore, we would recommend a brief (4 6 days) hospitalization to ensure that parenteral anticoagulants are administered properly and that overlapping administration of a vitamin K antagonist results in a therapeutic INR (2.0 3.0) for 2 consecutive days. In Case 3, the patient has completed the minimal duration of anticoagulation after a rst episode of unprovoked PE. Unequivocal indications for indenite anticoagulation, such as active cancer or the antiphospholipid antibody syndrome, are not present in this case. The patient is obese and has heterozygous thrombophilia;

References
1. Carrier M, Righini M, Wells PS, Perrier A, Anderson DR, Rodger MA, Pleasance S, Le GG. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010;8: 1716 1722. 2. Kucher N, Goldhaber SZ. Management of massive pulmonary embolism. Circulation 2005;112:e28e32. 3. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H. Prognostic signicance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart 1997;77:346 349. 4. Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010;122:1124 1129. 5. Torbicki A, Perrier A, Konstantinides SV, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP. 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). Eur Heart J 2008;29:2276 2315. 6. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287 1297. 7. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientic statement from the American Heart Association. Circulation 2011;123:1788 1830. 8. Lualdi JC, Goldhaber SZ. Right ventricular dysfunction after acute pulmonary embolism: pathophysiologic factors, detection, and therapeutic implications. Am Heart J 1995;130:1276 1282.

Page 10 of 12
9. Konstantinides S. Pulmonary embolism: impact of right ventricular dysfunction. Curr Opin Cardiol 2005;20:496501. 10. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med 2012;125:465 470. 11. Laporte S, Mismetti P, Decousus H, Uresandi F, Otero R, Lobo JL, Monreal M. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: ndings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008;117:1711 1716. 12. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation 2006;113:577 582. 13. Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995;108:978 981. 14. Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30:1165 1171. 15. Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, Conti A, Agnelli G, Berni G. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817 2822. 16. Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 2000;84:548 552. 17. Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy PM, Fine MJ. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041 1046. 18. Donze J, Le Gal G, Fine MJ, Roy PM, Sanchez O, Verschuren F, Cornuz J, Meyer G, Perrier A, Righini M, Aujesky D. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost 2008;100:943 948. 19. Aujesky D, Roy PM, Le Manach CP, Verschuren F, Meyer G, Obrosky DS, Stone RA, Cornuz J, Fine MJ. Validation of a model to predict adverse outcomes in patients with pulmonary embolism. Eur Heart J 2006;27:476 481. 20. Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy PM, Fine MJ. A prediction rule to identify low-risk patients with pulmonary embolism. Arch Intern Med 2006;166:169175. 21. Jimenez D, Yusen RD, Otero R, Uresandi F, Nauffal D, Laserna E, Conget F, Oribe M, Cabezudo MA, Diaz G. Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy. Chest 2007;132: 24 30. 22. Vanni S, Nazerian P, Pepe G, Baioni M, Risso M, Grifoni G, Viviani G, Grifoni S. Comparison of two prognostic models for acute pulmonary embolism: clinical vs. right ventricular dysfunction-guided approach. J Thromb Haemost 2011;9: 1916 1923. 23. Aujesky D, Roy PM, Verschuren F, Righini M, Osterwalder J, Egloff M, Renaud B, Verhamme P, Stone RA, Legall C, Sanchez O, Pugh NA, Ngako A, Cornuz J, Hugli O, Beer HJ, Perrier A, Fine MJ, Yealy DM. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, openlabel, randomised, non-inferiority trial. Lancet 2011;378:41 48. 24. Jimenez D, Aujesky D, Moores L, Gomez V, Lobo JL, Uresandi F, Otero R, Monreal M, Muriel A, Yusen RD. Simplication of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383 1389. 25. Lankeit M, Gomez V, Wagner C, Aujesky D, Recio M, Briongos S, Moores CL, Yusen RD, Konstantinides S, Jimenez D. A strategy combining imaging and laboratory biomarkers in comparison with a simplied clinical score for risk stratication of patients with acute pulmonary embolism. Chest 2012;141:916 922. 26. Lankeit M, Konstantinides S. Is it time for home treatment of pulmonary embolism ? Eur Respir J 2012. Advance Access published 10 April 2012. 27. Goldhaber SZ. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002;136:691 700. 28. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997;134:479487. 29. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507 511. 30. Sanchez O, Trinquart L, Colombet I, Durieux P, Huisman MV, Chatellier G, Meyer G. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008;29:1569 1577. 31. ten Wolde M, Sohne M, Quak E, Mac Gillavry MR, Buller HR. Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism. Arch Intern Med 2004;164:1685 1689.

S. Konstantinides and S.Z. Goldhaber

32. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143 1150. 33. Becattini C, Agnelli G, Vedovati MC, Pruszczyk P, Casazza F, Grifoni S, Salvi A, Bianchi M, Douma R, Konstantinides S, Lankeit M, Duranti M. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratication in a single test. Eur Heart J 2011;32:1657 1663. 34. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:425 430. 35. Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratication of patients with acute pulmonary embolism. Circulation 2003;108:2191 2194. 36. Korff S, Katus HA, Giannitsis E. Differential diagnosis of elevated troponins. Heart 2006;92:987993. 37. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007;116:427 433. 38. Jimenez D, Uresandi F, Otero R, Lobo JL, Monreal M, Marti D, Zamora J, Muriel A, Aujesky D, Yusen RD. Troponin-based risk stratication of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis. Chest 2009;136:974 982. 39. Lankeit M, Friesen D, Aschoff J, Dellas C, Hasenfuss G, Katus H, Konstantinides S, Giannitsis E. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J 2010;31:1836 1844. 40. Lankeit M, Jimenez D, Kostrubiec M, Dellas C, Hasenfuss G, Pruszczyk P, Konstantinides S. Predictive value of the highly sensitive troponin T assay and the simplied Pulmonary Embolism Severity Index in hemodynamically stable patients with acute pulmonary embolism: a prospective validation study. Circulation 2011;124:2716 2724. 41. Alhadi HA, Fox KA. Do we need additional markers of myocyte necrosis: the potential value of heart fatty-acid-binding protein. QJM 2004;97:187 198. 42. Dellas C, Puls M, Lankeit M, Schafer K, Cuny M, Berner M, Hasenfuss G, Konstantinides S. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol 2010;55:2150 2157. 43. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006; 98:351 360. 44. Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 2006;98:342 350. 45. Lankeit M, Kempf T, Dellas C, Cuny M, Tapken H, Peter T, Olschewski M, Konstantinides S, Wollert KC. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 2008;177:1018 1025. 46. Spirk D, Aujesky D, Husmann M, Hayoz D, Baldi T, Frauchiger B, Banyai M, Baumgartner I, Kucher N. Cardiac troponin testing and the simplied Pulmonary Embolism Severity Index. The SWIss Venous ThromboEmbolism Registry (SWIVTER). Thromb Haemost 2011;106:978 984. 47. Dellas C, Puls M, Lankeit M, Schafer K, Cuny M, Berner M, Hasenfuss G, Konstantinides S. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol 2010;55:2150 2157. 48. Binder L, Pieske B, Olschewski M, Geibel A, Klostermann B, Reiner C, Konstantinides S. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratication of acute pulmonary embolism. Circulation 2005;112:1573 1579. 49. Scridon T, Scridon C, Skali H, Alvarez A, Goldhaber SZ, Solomon SD. Prognostic signicance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. Am J Cardiol 2005;96:303 305. 50. Jimenez D, Aujesky D, Moores L, Gomez V, Marti D, Briongos S, Monreal M, Barrios V, Konstantinides S, Yusen RD. Combinations of prognostic tools for identication of high-risk normotensive patients with acute symptomatic pulmonary embolism. Thorax 2011;66:75 81. 51. Sanchez O, Trinquart L, Caille V, Couturaud F, Pacouret G, Meneveau N, Verschuren F, Roy PM, Parent F, Righini M, Perrier A, Lorut C, Tardy B, Benoit MO, Chatellier G, Meyer G. Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study. Am J Respir Crit Care Med 2010;181:168 173. 52. The PEITHO Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury:

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Zittermann A. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012;379:322334. Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 2011;124:2554 2559. Epstein RS, Moyer TP, Aubert RE, OKane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010;55:2804 2812. Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009;30:375 386. Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Manseld JW, Robinson M, Barton S, Brunisholz K, Mower CP, Huntinghouse JA, Rollo JS, Siler D, Bair TL, Knight S, Muhlestein JB, Carlquist JF. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012;125: 1997 2005. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116 1127. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 2011;10:61 75. Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011;31:478 492. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor Xa inhibitor. Drugs 2011;71:1503 1526. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573 1579. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012;119:2172 2174. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499 2510. Buller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, Pillion G, Piovella F, Prins MH, Raskob GE. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007;357:1094 1104. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, Lundstrom T, Berkowitz SD, Nystrom P, Thorsen M, Ginsberg JS. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005;293:681 689. Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, Kakkar AK, Misselwitz F, Schellong S. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59 7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007;116:180 187. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial brillation. N Engl J Med 2011;365:883 891. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342 2352. Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1626 patients. Haematologica 2007;92:199205. Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, Imberti D, Poggio R, Ageno W, Pogliani E, Porro F, Zonzin P. Extended oral anticoagulant therapy after a rst episode of pulmonary embolism. Ann Intern Med 2003;139: 19 25. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a rst episode of idiopathic venous thromboembolism. [Comments]. N Engl J Med 1999;340:901 907 [published erratum appears in N Engl J Med 1999 Jul 22;341(4):298].

53.

54.

55.

56.

57.

58. 59. 60.

61.

62.

63.

64. 65.

66.

67.

68. 69. 70.

71.

72.

73.

74.

rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J 2012;163:3338. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl.):e419S e494S. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004;110:744 749. Meneveau N, Seronde MF, Blonde MC, Legalery P, Didier-Petit K, Briand F, Cauleld F, Schiele F, Bernard Y, Bassand JP. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006;129: 10431050. Daniels LB, Parker JA, Patel SR, Grodstein F, Goldhaber SZ. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Am J Cardiol 1997;80:184188. Stein PD, Matta F, Steinberger DS, Keyes DC. Intracerebral hemorrhage with thrombolytic therapy for acute pulmonary embolism. Am J Med 2012;125: 50 56. Stein PD, Matta F. Case fatality rate with pulmonary embolectomy for acute pulmonary embolism. Am J Med 2012;125:471 477. Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation 2011;124:2139 2144. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheterdirected therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20: 14311440. Pacouret G, Alison D, Pottier JM, Bertrand P, Charbonnier B. Free-oating thrombus and embolic risk in patients with angiographically conrmed proximal deep venous thrombosis. A prospective study. [Comments]. Arch Intern Med 1997;157:305308. Carrier M, Le GG, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152:578589. Stein PD, Matta F, Keyes DC, Willyerd GL. Impact of vena cava lters on in-hospital case fatality rate from pulmonary embolism. Am J Med 2012;125: 478 484. Stein PD, Matta F, Hull RD. Increasing use of vena cava lters for prevention of pulmonary embolism. Am J Med 2011;124:655 661. Davies CW, Wimperis J, Green ES, Pendry K, Killen J, Mehdi I, Tiplady C, Kesteven P, Rose P, Oldeld W. Early discharge of patients with pulmonary embolism: a two-phase observational study. Eur Respir J 2007;30:708 714. Zondag W, Mos IC, Creemers-Schild D, Hoogerbrugge AD, Dekkers OM, Dolsma J, Eijsvogel M, Faber LM, Hofstee HM, Hovens MM, Jonkers GJ, van Kralingen KW, Kruip MJ, Vlasveld T, DE Vreede MJ, Huisman MV. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost 2011;9:1500 1507. Agterof MJ, Schutgens RE, Snijder RJ, Epping G, Peltenburg HG, Posthuma EF, Hardeman JA, van der Griend R, Koster T, Prins MH, Biesma DH. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level. J Thromb Haemost 2010;8:1235 1241. Johnson JA. Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 2012;125:19641966. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002 2012. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the rst year of therapy among elderly patients with atrial brillation. Circulation 2007;115:2689 2696. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest 2005;127:1515 1522. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007;109:2419 2423. Schulman S, Parpia S, Stewart C, Rudd-Scott L, Julian JA, Levine M. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med 2011;155:653. Heneghan C, Ward A, Perera R, Bankhead C, Fuller A, Stevens R, Bradford K, Tyndel S, Alonso-Coello P, Ansell J, Beyth R, Bernardo A, Christensen TD, Cromheecke ME, Edson RG, Fitzmaurice D, Gadisseur AP, Garcia-Alamino JM, Gardiner C, Hasenkam JM, Jacobson A, Kaatz S, Kamali F, Khan TI, Knight E, Kortke H, Levi M, Matchar D, Menendez-Jandula B, Rakovac I, Schaefer C, Siebenhofer A, Souto JC, Sunderji R, Gin K, Shalansky K, Voller H, Wagner O,

75. 76.

77. 78.

79.

Downloaded from http://eurheartj.oxfordjournals.org/ at University of Athens on September 18, 2012

80.

81. 82. 83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

Page 12 of 12
94. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010;121:1630 1636. 95. Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O, Heinze G, Kyrle PA. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med 2008;168:1678 1683. 96. Grifoni S, Vanni S, Magazzini S, Olivotto I, Conti A, Zanobetti M, Polidori G, Pieralli F, Peiman N, Becattini C, Agnelli G. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Arch Intern Med 2006;166:2151 2156. 97. Goldhaber SZ, Piazza G. Optimal duration of anticoagulation after venous thromboembolism. Circulation 2011;123:664 667. 98. Nijkeuter M, Hovens MM, Davidson BL, Huisman MV. Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review. Chest 2006;129:192 197. 99. Sanchez O, Helley D, Couchon S, Roux A, Delaval A, Trinquart L, Collignon MA, Fischer AM, Meyer G. Perfusion defects after pulmonary embolism: risk factors and clinical signicance. J Thromb Haemost 2010;8:1248 1255. 100. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005;293:2352 2361. 101. Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959 1967. 102. Becker RC. Aspirin and the prevention of venous thromboembolism. N Engl J Med 2012;366:2028 2030. 103. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386 1389.

S. Konstantinides and S.Z. Goldhaber

104. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98:756 764. 105. Konstantinides S, Geibel A, Kasper W, Olschewski M, Blumel L, Just H. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. [Comments]. Circulation 1998;97: 1946 1951. 106. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009;29:298 310. 107. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AW, Tripodi A. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355: 1780 1789. 108. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257 2264. 109. Becattini C, Agnelli G, Pesavento R, Silingardi M, Poggio R, Taliani MR, Ageno W. Incidence of chronic thromboembolic pulmonary hypertension after a rst episode of pulmonary embolism. Chest 2006;130:172175. 110. Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Huisman MV. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica 2010;95:970 975. 111. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008;359:2804 2813. 112. Becattini C, Agnelli G, Salvi A, Grifoni S, Pancaldi LG, Enea I, Balsemin F, Campanini M, Ghirarduzzi A, Casazza F. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010;125:e82 e86.

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