2014ESC急性肺栓塞诊断和管理指南(英文版)

ESC GUIDELINES 2014ESC 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)Endorsed by the European Respiratory Society (ERS)

Authors/Task Force Members:Stavros Konstantinides *(Chairperson)(Germany/Greece),Adam Torbicki *(Co-chairperson)(Poland),Giancarlo Agnelli (Italy),Nicolas Danchin (France),David Fitzmaurice (UK),Nazzareno Galie `(Italy),

J.Simon R.Gibbs (UK),Menno Huisman (The Netherlands),Marc Humbert ?(France),Nils Kucher (Switzerland),Irene Lang (Austria),Mareike Lankeit (Germany),John Lekakis (Greece),Christoph Maack (Germany),Eckhard Mayer (Germany),

Nicolas Meneveau (France),Arnaud Perrier (Switzerland),Piotr Pruszczyk (Poland),Lars H.Rasmussen (Denmark),Thomas H.Schindler (USA),Pavel Svitil (Czech

Republic),Anton Vonk Noordegraaf (The Netherlands),Jose Luis Zamorano (Spain),Maurizio Zompatori (Italy)

ESC Committee for Practice Guidelines (CPG):Jose Luis Zamorano (Chairperson)(Spain),Stephan Achenbach (Germany),Helmut Baumgartner (Germany),Jeroen J.Bax (Netherlands),Hector Bueno (Spain),Veronica Dean (France),Christi Deaton (UK),?etin Erol (Turkey),Robert Fagard (Belgium),Roberto Ferrari (Italy),David Hasdai (Israel),Arno Hoes (Netherlands),Paulus Kirchhof (Germany/UK),Juhani Knuuti (Finland),Philippe Kolh (Belgium),Patrizio Lancellotti (Belgium),Ales Linhart (Czech Republic),Petros Nihoyannopoulos (UK),Massimo F.

Piepoli *Corresponding authors.Stavros Konstantinides,Centre for Thrombosis and Hemostasis,Johannes Gutenberg University of Mainz,University Medical Centre Mainz,Langenbeckstrasse 1,55131Mainz,Germany.Tel:+496131176255,Fax:+496131173456.Email:stavros.konstantinides@unimedizin-mainz.de ,and Department of Cardiology,Democritus University of Thrace,Greece.Email:skonst@med.duth.gr .

Adam Torbicki,Department of Pulmonary Circulation and Thromboembolic Diseases,Medical Centre of Postgraduate Education,ECZ-Otwock,Ul.Borowa 14/18,05-400Otwock,Poland.Tel:+48227103052,Fax:+4822710315.Email:adam.torbicki@ecz-otwock.pl .

?Representing the European Respiratory Society

Other ESC entities having participated in the development of this document:

ESC Associations:Acute Cardiovascular Care Association (ACCA),European Association for Cardiovascular Prevention &Rehabilitation (EACPR),European Association of Cardio-vascular Imaging (EACVI),Heart Failure Association (HFA),ESC Councils:Council on Cardiovascular Nursing and Allied Professions (CCNAP),Council for Cardiology Practice (CCP),Council on Cardiovascular Primary Care (CCPC)

ESC Working Groups:Cardiovascular Pharmacology and Drug Therapy,Nuclear Cardiology and Cardiac Computed Tomography,Peripheral Circulation,Pulmonary Circulation and Right Ventricular Function,Thrombosis.

Disclaimer:The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scienti?c and medical knowledge and the evidence available at the time of their publication.

The ESC is not responsible in the event of any contradiction,discrepancy and/or ambiguity between the ESC Guidelines and any other of?cial recommendations or guidelines issued by the relevant public health authorities,in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment,as well as in the determination and the implementation of preventive,diagnostic or therapeutic medical strategies;however,the ESC Guidelines do not override,in any way whatsoever,the inpidual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and,where appropriate and/or necessary,the patient’s caregiver.Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant of?cial updated recommendations or guidelines issued by the competent public health authorities,in order to manage each patient’s case in light of the scienti?cally accepted data pursuant to their respective ethical and professional obligations.It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

National Cardiac Societies document reviewers:listed in the Appendix.

&The European Society of Cardiology 2014.All rights reserved.For permissions please email:journals.permissions@e43f5da204a1b0717ed5dd2a.European Heart Journal doi:10.1093/eurheartj/ehu283

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(Italy),Piotr Ponikowski(Poland),Per Anton Sirnes(Norway),Juan Luis Tamargo(Spain),Michal Tendera(Poland), Adam Torbicki(Poland),William Wijns(Belgium),Stephan Windecker(Switzerland).

Document Reviewers:?etin Erol(CPG Review Coordinator)(Turkey),David Jimenez(Review Coordinator)(Spain), Walter Ageno(Italy),Stefan Agewall(Norway),Riccardo Asteggiano(Italy),Rupert Bauersachs(Germany),

Cecilia Becattini(Italy),Henri Bounameaux(Switzerland),Harry R.Bu¨ller(Netherlands),Constantinos H.Davos (Greece),Christi Deaton(UK),Geert-Jan Geersing(Netherlands),Miguel Angel Go′mez Sanchez(Spain),

Jeroen Hendriks(Netherlands),Arno Hoes(Netherlands),Mustafa Kilickap(Turkey),Viacheslav Mareev(Russia), Manuel Monreal(Spain),Joao Morais(Portugal),Petros Nihoyannopoulos(UK),Bogdan A.Popescu(Romania), Olivier Sanchez?(France),Alex C.Spyropoulos(USA).

The disclosure forms provided by the experts involved in the development of these guidelines are available on the ESC website e43f5da204a1b0717ed5dd2a/guidelines.

------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Guidelines?Pulmonary embolism?Venous thrombosis?Shock?Hypotension?Chest pain?Dyspnoea ?Heart failure?Diagnosis?Treatment–Anticoagulation?Thrombolysis

Table of Contents

Abbreviations and acronyms (3)

1.Preamble (3)

2.Introduction (4)

2.1Epidemiology (5)

2.2Predisposing factors (5)

2.3Natural history (6)

2.4Pathophysiology (6)

2.5Clinical classi?cation of pulmonary embolism severity (7)

3.Diagnosis (7)

3.1Clinical presentation (7)

3.2Assessment of clinical probability (8)

3.3D-dimer testing (8)

3.4Computed tomographic pulmonary angiography (10)

3.5Lung scintigraphy (11)

3.6Pulmonary angiography (11)

3.7Magnetic resonance angiography (11)

3.8Echocardiography (11)

3.9Compression venous ultrasonography (12)

3.10.Diagnostic strategies (12)

3.10.1Suspected pulmonary embolism with shock

or hypotension (12)

3.10.2Suspected pulmonary embolism without

shock or hypotension (13)

3.11.Areas of uncertainty (14)

4.Prognostic assessment (15)

4.1Clinical parameters (15)

4.2Imaging of the right ventricle by echocardiography

or computed tomographic angiography (16)

4.3Laboratory tests and biomarkers (17)

4.3.1Markers of right ventricular dysfunction (17)

4.3.2Markers of myocardial injury (17)

4.3.3Other(non-cardiac)laboratory biomarkers (18)

4.4Combined modalities and scores (19)

4.5Prognostic assessment strategy (19)

5.Treatment in the acute phase (20)

5.1Haemodynamic and respiratory support (20)

5.2Anticoagulation (20)

5.2.1Parenteral anticoagulation (20)

5.2.2Vitamin K antagonists (21)

5.2.3New oral anticoagulants (22)

5.3Thrombolytic treatment (23)

5.4Surgical embolectomy (24)

5.5Percutaneous catheter-directed treatment (24)

5.6Venous?lters (24)

5.7Early discharge and home treatment (25)

5.8Therapeutic strategies (26)

5.8.1Pulmonary embolism with shock or hypotension

(high-risk pulmonary embolism) (26)

5.8.2Pulmonary embolism without shock or hypotension

(intermediate-or low-risk pulmonary embolism) (26)

5.9Areas of uncertainty (27)

6.Duration of anticoagulation (29)

6.1New oral anticoagulants for extended treatment (30)

7.Chronic thromboembolic pulmonary hypertension (31)

7.1Epidemiology (31)

7.2Pathophysiology (31)

7.3Clinical presentation and diagnosis (31)

7.4Treatment and prognosis (32)

8.Speci?c problems (34)

8.1Pregnancy (34)

8.1.1Diagnosis of pulmonary embolism in pregnancy (34)

8.1.2Treatment of pulmonary embolism in pregnancy (34)

8.2Pulmonary embolism and cancer (35)

8.2.1Diagnosis of pulmonary embolism in patients with

cancer (35)

8.2.2Prognosis for pulmonary embolism in patients with

cancer (35)

8.2.3Management of pulmonary embolism in patients with

cancer (35)

8.2.4Occult cancer presenting as unprovoked pulmonary

embolism (36)

8.3Non-thrombotic pulmonary embolism (36)

8.3.1Septic embolism (36)

8.3.2Foreign-material pulmonary embolism (36)

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8.3.3Fat embolism (36)

8.3.4Air embolism (37)

8.3.5Amniotic?uid embolism (37)

8.3.6Tumour embolism (37)

9.Appendix (37)

References (37)

Abbreviations and acronyms

ACS acute coronary syndrome

AMPLIFY Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-line

Therapy

aPTT activated partial thromboplastin time

b.i.d.bis in diem(twice daily)

b.p.m.beats per minute

BNP brain natriuretic peptide

BP blood pressure

CI con?dence interval

CO cardiac output

COPD chronic obstructive pulmonary disease

CPG Committee for Practice Guidelines

CRNM clinically relevant non-major

CT computed tomographic/tomogram

CTEPH chronic thromboembolic pulmonary hypertension CUS compression venous ultrasonography

DSA digital subtraction angiography

DVT deep vein thrombosis

ELISA enzyme-linked immunosorbent assay

ESC European Society of Cardiology

H-FABP heart-type fatty acid-binding protein

HIT heparin-induced thrombocytopenia

HR hazard ratio

ICOPER International Cooperative Pulmonary Embolism Registry

ICRP International Commission on Radiological Protection INR international normalized ratio

iPAH idiopathic pulmonary arterial hypertension

IVC inferior vena cava

LMWH low molecular weight heparin

LV left ventricle/left ventricular

MDCT multi-detector computed tomographic(angiography) MRA magnetic resonance angiography

NGAL neutrophil gelatinase-associated lipocalin

NOAC(s)Non-vitamin K-dependent new oral anticoagulant(s) NT-proBNP N-terminal pro-brain natriuretic peptide

o.d.omni die(every day)

OR odds ratio

PAH pulmonary arterial hypertension

PE pulmonary embolism

PEA pulmonary endarterectomy

PEITHO Pulmonary EmbolIsm THrOmbolysis trial

PESI pulmonary embolism severity index

PH pulmonary hypertension PIOPED Prospective Investigation On Pulmonary Embolism Diagnosis

PVR pulmonary vascular resistance

RIETE Registro Informatizado de la Enfermedad Throm-boembolica venosa

RR relative risk

rtPA recombinant tissue plasminogen activator

RV right ventricle/ventricular

SPECT single photon emission computed tomography sPESI simpli?ed pulmonary embolism severity index TAPSE tricuspid annulus plane systolic excursion

Tc technetium

TOE transoesophageal echocardiography

TTR time in therapeutic range

TV tricuspid valve

UFH unfractionated heparin

V/Q scan ventilation–perfusion scintigraphy

VKA vitamin K antagonist(s)

VTE venous thromboembolism

1.Preamble

Guidelines summarize and evaluate all available evidence at the time of the writing process,on a particular issue with the aim of assisting health professionals in selecting the best management strategies for an inpidual patient,with a given condition,taking into account the impact on outcome,as well as the risk-bene?t-ratio of particular diag-nostic or therapeutic means.Guidelines and recommendations should help the health professionals to make decisions in their daily practice.However,the?nal decisions concerning an inpidual patient must be made by the responsible health professional(s)in consultation with the patient and caregiver as appropriate.

A great number of Guidelines have been issued in recent years by the European Society of Cardiology(ESC)as well as by other soci-eties and organisations.Because of the impact on clinical practice, quality criteria for the development of guidelines have been estab-lished in order to make all decisions transparent to the user.The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site(e43f5da204a1b0717ed5dd2a/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx).ESC Guide-lines represent the of?cial position of the ESC on a given topic and are regularly updated.

Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology.Selected experts in the?eld undertook a comprehensive review of the published evidence for management(including diagno-sis,treatment,prevention and rehabilitation)of a given condition according to ESC Committee for Practice Guidelines(CPG)policy.

A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk-bene?t-ratio.Estimates of expected health outcomes for larger populations were included, where data exist.The level of evidence and the strength of recom-mendation of particular management options were weighed and graded according to prede?ned scales,as outlined in Tables1and2. The experts of the writing and reviewing panels?lled in declara-tions of interest forms which might be perceived as real or potential

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sources of con?icts of interest.These forms were compiled into one ?le and can be found on the ESC Web Site(e43f5da204a1b0717ed5dd2a/ guidelines).Any changes in declarations of interest that arise during the writing period must be noti?ed to the ESC and updated.The Task Force received its entire?nancial support from the ESC without any involvement from healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines produced by Task Forces,expert groups or consensus panels.The Committee is also responsible for the endorsement process of these Guidelines.The ESC Guidelines undergo extensive review by the CPG and external experts.After appropriate revisions it is approved by all the experts involved in the Task Force.The?na-lized document is approved by the CPG for publication in the Euro-pean Heart Journal.It was developed after careful consideration of

the scienti?c and medical knowledge and the evidence available at the time of their dating.

The task of developing ESC Guidelines covers not only the integra-tion of the most recent research,but also the creation of educational tools and implementation programmes for the recommendations. To implement the guidelines,condensed pocket guidelines versions, summary slides,booklets with essential messages,summary cards for non-specialists,electronic version for digital applications(smart-phones etc)are produced.These versions are abridged and,thus, if needed,one should always refer to the full text version which is freely available on the ESC Website.The National Societies of the ESC are encouraged to endorse,translate and implement the ESC Guidelines.Implementation programmes are needed because it has been shown that the outcome of disease may be favourably in?uenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily prac-tice is in keeping with what is recommended in the guidelines,thus completing the loop between clinical research,writing of guidelines, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive,diag-nostic or therapeutic medical strategies.However,the ESC Guide-lines do not override in any way whatsoever the inpidual responsibility of health professionals to make appropriate and ac-curate decisions in consideration of each patient s health condition and in consultation with that patient and the patient’s caregiver where appropriate and/or necessary.It is also the health professio-nal’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

2.Introduction

This document follows the two previous ESC Guidelines focussing on clinical management of pulmonary embolism,published in2000 and2008.Many recommendations have retained or reinforced their validity;however,new data has extended or modi?ed our knowl-edge in respect of optimal diagnosis,assessment and treatment of patients with PE.The most clinically relevant new aspects of this 2014version as compared with its previous version published in 2008relate to:

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(1)Recently identi?ed predisposing factors for venous thrombo-

embolism

(2)Simpli?cation of clinical prediction rules

(3)Age-adjusted D-dimer cut-offs

(4)Sub-segmental pulmonary embolism

(5)Incidental,clinically unsuspected pulmonary embolism

(6)Advanced risk strati?cation of intermediate-risk pulmonary

embolism

(7)Initiation of treatment with vitamin K antagonists

(8)Treatment and secondary prophylaxis of venous thrombo-

embolism with the new direct oral anticoagulants

(9)Ef?cacyand safety of reperfusion treatment for patients at inter-

mediate risk

(10)Early discharge and home(outpatient)treatment of pulmonary

embolism

(11)Current diagnosis and treatment of chronic thromboembolic

pulmonary hypertension

(12)Formal recommendations for the management of pulmonary

embolism in pregnancy and of pulmonary embolism in patients with cancer.

These new aspects have been integrated into previous knowledge to suggest optimal and—whenever possible—objectively validated management strategies for patients with suspected or con?rmed pul-monary embolism.

In order to limit the length of the printed text,additional informa-tion,tables,?gures and references are available as web addenda at the ESC website(e43f5da204a1b0717ed5dd2a).

2.1Epidemiology

Venous thromboembolism(VTE)encompasses deep vein throm-bosis(DVT)and pulmonary embolism(PE).It is the third most fre-quent cardiovascular disease with an overall annual incidence of 100–200per100000inhabitants.1,2VTE may be lethal in the acute phase or lead to chronic disease and disability,3–6but it is also often preventable.

Acute PE is the most serious clinical presentation of VTE.Since PE is,in most cases,the consequence of DVT,most of the existing data on its epidemiology,risk factors,and natural history are derived from studies that have examined VTE as a whole.

The epidemiology of PE is dif?cult to determine because it may remain asymptomatic,or its diagnosis may be an incidental?nding;2 in some cases,the?rst presentation of PE may be sudden death.7,8 Overall,PE is a major cause of mortality,morbidity,and hospitaliza-tion in Europe.As estimated on the basis of an epidemiological model,over317000deaths were related to VTE in six countries of the European Union(with a total population of454.4million)in 2004.2Of these cases,34%presented with sudden fatal PE and 59%were deaths resulting from PE that remained undiagnosed during life;only7%of the patients who died early were correctly diag-nosed with PE before death.Since patients older than40years are at increased risk compared with younger patients and the risk approxi-mately doubles with each subsequent decade,an ever-larger number of patients are expected to be diagnosed with(and perhaps die of)PE in the future.9

In children,studies reported an annual incidence of VTE between 53and57per100000among hospitalized patients,10,11and between

1.4and4.9per100000in the community at large.12,13

2.2Predisposing factors

A list of predisposing(risk)factors for VTE is shown in Web Addenda Table I.There is an extensive collection of predisposing environmen-tal and genetic factors.VTE is considered to be a consequence of the interaction between patient-related—usually permanent—risk factors and setting-related—usually temporary—risk factors.VTE is considered to be‘provoked’in the presence of a temporary or re-versible risk factor(such as surgery,trauma,immobilization,preg-nancy,oral contraceptive use or hormone replacement therapy) within the last6weeks to3months before diagnosis,14and‘unpro-voked’in the absence thereof.PE may also occur in the absence of any known risk factor.The presence of persistent—as opposed to major,temporary—risk factors may affect the decision on the dur-ation of anticoagulation therapy after a?rst episode of PE.

Major trauma,surgery,lower limb fractures and joint replace-ments,and spinal cord injury,are strong provoking factors for VTE.9,15Cancer is a well-recognized predisposing factor for VTE. The risk of VTE varies with different types of cancer;16,17haemato-logical malignancies,lung cancer,gastrointestinal cancer,pancreatic cancer and brain cancer carry the highest risk.18,19Moreover, cancer is a strong risk factor for all-cause mortality following an episode of VTE.20

In fertile women,oral contraception is the most frequent predis-posing factor for VTE.21,22When occurring during pregnancy,VTE is a major cause of maternal mortality.23The risk is highest in the third trimester of pregnancy and over the6weeks of the postpartum period,being up to60times higher3months after delivery,compared with the risk in non-pregnant women.23In vitro fertilization further increases the risk of pregnancy-associated VTE.In a cross-sectional study derived from a Swedish registry,the overall risk of PE(com-pared with the risk of age-matched women whose?rst child was born without in vitro fertilization)was particularly increased during the?rst trimester of pregnancy[hazard ratio(HR)6.97;95%con?-dence interval(CI)2.21–21.96].The absolute number of women who suffered PE was low in both groups(3vs.0.4cases per10000 pregnancies during the?rst trimester,and8.1vs.6.0per10000preg-nancies overall).24In post-menopausal women who receive hormone replacement therapy,the risk of VTE varies widely depend-ing on the formulation used.25

Infection has been found to be a common trigger for hospitaliza-tion for VTE.15,26,27Blood transfusion and erythropoiesis-stimulating agents are also associated with an increased risk of VTE.15,28

In children,PE is usually associated with DVT and is rarely unpro-voked.Serious chronic medical conditions and central venous lines are considered to be likely triggers of PE.29

VTE may be viewed as part of the cardiovascular disease con-tinuum and common risk factors—such as cigarette smoking, obesity,hypercholesterolaemia,hypertension and diabetes melli-tus30–33—are shared with arterial disease,notably atheroscler-osis.34–37However,at least in part,this may be an indirect association,mediated by the effects of coronary artery disease and,

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in the case of smoking,cancer.38,39Myocardial infarction and heart failure increase the risk of PE;40,41conversely,patients with VTE have an increased risk of subsequent myocardial infarction and stroke.42

2.3Natural history

The?rst studies on the natural history of VTE were carried out in the setting of orthopaedic surgery during the1960s.43Evidence collected since this initial report has shown that DVT develops less frequently in non-orthopaedic surgery.The risk of VTE is highest during the?rst two post-operative weeks but remains elevated for two to three months.Antithrombotic prophylaxis signi?cantly reduces the risk of perioperative VTE.The incidence of VTE is reduced with increas-ing duration of thromboprophylaxis after major orthopaedic surgery and(to a lesser extent)cancer surgery:this association has not been shown for general surgery.44,45The majority of patients with symp-tomatic DVT have proximal clots,complicated by PE in40–50%of cases,often without clinical manifestations.44,45

Registries and hospital discharge datasets of unselected patients with PE or VTE yielded30-day all-cause mortality rates between 9%and11%,and three-month mortality ranging between8.6%and 17%.46–48Following the acute PE episode,resolution of pulmonary thrombi,as evidenced by lung perfusion defects,is frequently incom-plete.In one study,lung perfusion scintigraphy demonstrated abnor-malities in35%of patients a year afteracute PE,although the degree of pulmonary vascular obstruction was,15%in90%of the cases.49 Two relatively recent cohort studies covering173and254patients yielded incidences approaching30%.50,51The incidence of con?rmed chronic thromboembolic pulmonary hypertension(CTEPH)after unprovoked PE is currently estimated at approximately1.5%(with a wide range reported by mostly small-cohort studies),with most cases appearing within24months of the index event.52,53

The risk of recurrence of VTE has been reviewed in detail.54–56 Based on historical data,the cumulative proportion of patients with early recurrence of VTE(on anticoagulant treatment)amounts to 2.0%at2weeks,6.4%at3months and8%at6months;more recent,randomized anticoagulation trials(discussed in the section on acute phase treatment)indicate that recurrence rates may have dropped considerably recently.The rate of recurrence is highest during the?rst two weeks and declines thereafter.During the early period,active cancer and failure to rapidly achieve therapeutic levels of anticoagulation appear to independently predict an increased risk of recurrence.56,57

The cumulative proportion of patients with late recurrence of VTE (after six months,and in most cases after discontinuation of anticoa-gulation)has been reported to reach13%at1year,23%at5years, and30%at10years.56Overall,the frequency of recurrence does not appear to depend on the clinical presentation(DVT or PE)of the?rst event,but recurrent VTE is likely to occur in the same clinical form as the index episode(i.e.if VTE recurs after PE,it will most likely be PE again).Recurrence is more frequent after multiple VTE epi-sodes as opposed to a single event,and after unprovoked VTE as opposed to the presence of temporary risk factors,particularly surgery.58It is also more frequent in women who continue hormone intake after a VTE episode,and in patients who have suffered PE or proximal vein thrombosis compared to distal(calf) vein thrombosis.On the other hand,factors for which an independ-ent association with late recurrence have not been de?nitely estab-lished include age,male sex,59,60a family history of VTE,and an increased body mass index.54,56Elevated D-dimer levels,either during or after discontinuation of anticoagulation,indicate an increased risk of recurrence;61–63on the other hand,single thrombo-philic defects have a low predictive value and anticoagulation manage-ment based on thrombophilia testing has not been found to reduce VTE recurrence.64,65

2.4Pathophysiology

Acute PE interferes with both the circulation and gas exchange.Right ventricular(RV)failure due to pressure overload is considered the primary cause of death in severe PE.

Pulmonary artery pressure increases only if more than30–50% of the total cross-sectional area of the pulmonary arterial bed is occluded by thromboemboli.66PE-induced vasoconstriction, mediated by the release of thromboxane A2and serotonin,contri-butes to the initial increase in pulmonary vascular resistance after PE,67an effect that can be reversed by vasodilators.68,69Anatomical obstruction and vasoconstriction lead to an increase in pulmonary vascular resistance and a proportional decrease in arterial compliance.70

The abrupt increase in pulmonary vascular resistance results in RV dilation,which alters the contractile properties of the RV myocar-dium via the Frank-Starling mechanism.The increase in RV pressure and volume leads to an increase in wall tension and myocyte stretch. RV contraction time is prolonged,while neurohumoral activation leads to inotropic and chronotropic stimulation.Together with sys-temic vasoconstriction,these compensatory mechanisms increase pulmonary artery pressure,improving?ow through the obstructed pulmonary vascular bed,and thus temporarily stabilize systemic blood pressure(BP).71The extent of immediate adaptation is limited,since a non-preconditioned,thin-walled right ventricle (RV)is unable to generate a mean pulmonary artery pressure above40mm Hg.

The prolongation of RV contraction time into early diastole in the left ventricle leads to leftward bowing of the interventricular septum.72The desynchronization of the ventricles may be exacer-bated by the development of right bundle-branch block.As a result,left ventricular(LV)?lling is impeded in early diastole,and this may lead to a reduction of the cardiac output and contribute to systemic hypotension and haemodynamic instability.73

As described above,excessive neurohumoral activation in PE can be the result both of abnormal RV wall tension and of circulatory shock.The?nding of massive in?ltrates in the RV myocardium of patients who died within48hours of acute PE may be explained by high levels of epinephrine released as a result of the PE-induced‘myo-carditis’.74This in?ammatory response might explain the secondary haemodynamic destabilization which sometimes occurs24–48 hours after acute PE,although early recurrence of PE may be an alter-native explanation in some of these cases.75

Finally,the association between elevated circulating levels of bio-markers of myocardial injury and an adverse early outcome indicates

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The detrimental effects of acute PE on the RV myocardium and the

circulation are summarized in Figure1.

Respiratory failure in PE is predominantly a consequence of haemodynamic disturbances.79Low cardiac output results in desat-uration of the mixed venous blood.In addition,zones of reduced ?ow in obstructed vessels,combined with zones of over?ow in the capillary bed served by non-obstructed vessels,result in ventila-tion–perfusion mismatch,which contributes to hypoxaemia.In about one-third of patients,right-to-left shunting through a patent foramen ovale can be detected by echocardiography:this is caused by an inverted pressure gradient between the right atrium and left atrium and may lead to severe hypoxaemia and an increased risk of paradoxical embolization and stroke.80Finally,even if they do not affect haemodynamics,small distal emboli may create areas of alveo-lar haemorrhage resulting in haemoptysis,pleuritis,and pleural effu-sion,which is usually mild.This clinical presentation is known as ‘pulmonary infarction’.Its effect on gas exchange is normally mild, except in patients with pre-existing cardiorespiratory disease. 2.5Clinical classi?cation of pulmonary embolism severity

The clinical classi?cation of the severity of an episode of acute PE is based on the estimated PE-related early mortality risk de?ned by in-hospital or30-day mortality(Figure2).This strati?cation,which has important implications both for the diagnostic and therapeutic strategies proposed in these guidelines,is based on the patient’s clin-ical status at presentation,with high-risk PE being suspected or con-?rmed in the presence of shock or persistent arterial hypotension and not high-risk PE in their absence.3.Diagnosis

Throughout these Guidelines and for the purpose of clinical manage-ment,‘con?rmed PE’is de?ned as a probability of PE high enough to indicate the need for PE-speci?c treatment,and‘excluded PE’as a probability of PE low enough to justify withholding PE-speci?c treat-

ment with an acceptably low risk.

3.1Clinical presentation

PE may escape prompt diagnosis since the clinical signs and symptoms

are non-speci?c(Table3).When the clinical presentation raises the suspicion of PE in an inpidual patient,it should prompt further objective testing.In most patients,PE is suspected on the basis of dys-pnoea,chest pain,pre-syncope or syncope,and/or haemoptysis.81–83 Arterial hypotension and shock are rare but important clinical pre-sentations,since they indicate central PE and/or a severely reduced haemodynamic reserve.Syncope is infrequent,but may occur regard-

less of the presence of haemodynamic instability.84Finally,PE may

be completely asymptomatic and be discovered incidentally during diagnostic work-up for another disease or at autopsy.

Chest pain is a frequent symptom of PE and is usually caused by

pleural irritation due to distal emboli causing pulmonary infarction.85

In central PE,chest pain may have a typical angina character,possibly

re?ecting RV ischaemia and requiring differential diagnosis with acute coronary syndrome(ACS)or aortic dissection.Dyspnoea may be

acute and severe in central PE;in small peripheral PE,it is often

mild and may be transient.In patients with pre-existing heart failure

or pulmonary disease,worsening dyspnoea may be the only symptom indicative of PE.

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is also often present.The chest X-ray is frequently abnormal and,al-though its?ndings are usually non-speci?c in PE,it is useful for exclud-ing other causes of dyspnoea or chest pain.89Electrocardiographic changes indicative of RV strain,such as inversion of T waves in leads V1–V4,a QR pattern in V1,S1Q3T3pattern,and incomplete or complete right bundle-branch block,may be helpful.These elec-trocardiographic changes are usually found in more severe cases of PE;90in milder cases,the only anomaly may be sinus tachycardia, present in40%of patients.Finally,atrial arrhythmias,most frequently atrial?brillation,may be associated with acute PE.

3.2Assessment of clinical probability Despite the limited sensitivity and speci?city of inpidual symptoms, signs,and common tests,the combination of?ndings evaluated by clinical judgement or by the use of prediction rules allows to classify patients with suspected PE into distinct categories of clinical or pre-test probability that correspond to an increasing actual preva-lence of con?rmed PE.As the post-test(e.g.after computed tomog-raphy)probability of PE depends not onlyon the characteristics of the diagnostic test itself but also on pre-test probability,this has become a key step in all diagnostic algorithms for PE.

The value of clinical judgement has been con?rmed in several large series,91–93including the Prospective Investigation On Pulmonary Embolism Diagnosis(PIOPED).94Note that clinical judgement usually includes commonplace tests such as chest X-ray and electro-cardiogram for differential diagnosis.However,clinical judgement lacks standardization;therefore,several explicit clinical prediction rules have been developed.Of these,the most frequently used

A number of D-dimer assays are available.110,111The quantitative enzyme-linked immunosorbent assay(ELISA)or ELISA-derived

assays have a diagnostic sensitivity of95%or better and can therefore

be used to exclude PE in patients with either a low or a moderate

pre-test probability.In the emergency department,a negative ELISA

D-dimer,in combination with clinical probability,can exclude the

disease without further testing in approximately30%of patients

with suspected PE.100,112,113Outcome studies have shown that the

three-month thromboembolic risk was,1%in patients left untreated

on the basis of a negative test result(Table5);99,112–116these?ndings

were con?rmed by a meta-analysis.117

Quantitative latex-derived assays and a whole-blood agglutination

assay have a diagnostic sensitivity,95%and are thus often referred

to as moderately sensitive.In outcome studies,those assays proved

safe in ruling out PE in PE-unlikely patients as well as in patients

with a low clinical probability.99,100,105Their safety in ruling out PE

has not been established in the intermediate clinical probability cat-

egory.Point-of-care tests have moderate sensitivity,and data from outcome studies in PE are lacking,with the exception of a recent

primary care-based study using the Simplify D-dimer assay,118in

which the three-month thromboembolic risk was1.5%in PE-unlikely patients with a negative D-dimer.

The speci?city of D-dimer in suspected PE decreases steadily with

age,to almost10%in patients.80years.119Recent evidence sug-

gests using age-adjusted cut-offs to improve the performance of

D-dimer testing in the elderly.120,121In a recent meta-analysis,

age-adjusted cut-off values(age x10m g/L above50years)allowed increasing speci?city from34–46%while retaining a sensitivity

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above97%.122A multicentre,prospective management study evalu-ated this age-adjusted cut-off in a cohort of3346patients.Patients with a normal age-adjusted D-dimer value did not undergo computed tomographic pulmonary angiography and were left untreated and formally followed up for a three-month period.Among the766 patients who were75years or older,673had a non-high clinical prob-ability.On the basis of D-dimer,using the age-adjusted cut-off (instead of the‘standard’500m g/L cut-off)increased the number of patients in whom PE could be excluded from43(6.4%;95%CI 4.8–8.5%)to200(29.7%;95%CI26.4–33.3%),without any addition-al false-negative?ndings.123D-dimer is also more frequently elevated in patients with cancer,124,125in hospitalized patients,105,126and during pregnancy.127,128Thus,the number of patients in whom D-dimer must be measured to exclude one PE(number needed to

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test)varies between3in the emergency department and≥10in the speci?c situations listed above.The negative predictive value of a (negative)D-dimer test remains high in these situations.

3.4Computed tomographic pulmonary angiography

Since the introduction of multi-detector computed tomographic (MDCT)angiography with high spatial and temporal resolution and quality of arterial opaci?cation,computed tomographic(CT)angiog-raphy has become the method of choice for imaging the pulmonary vasculature in patients with suspected PE.It allowsadequate visualiza-tion of the pulmonary arteries down to at least the segmental level.131–133The PIOPED II trial observed a sensitivity of83%and a speci?city of96%for(mainly four-detector)MDCT.134PIOPED II also highlighted the in?uence of clinical probability on the predictive value of MDCT.In patients with a low or intermediate clinical prob-ability of PE as assessed by the Wells rule,a negative CT had a high negative predictive value for PE(96%and89%,respectively), whereas this was only60%in those with a high pre-test probability. Conversely,the positive predictive value of a positive CT was high (92–96%)in patients with an intermediate or high clinical probability but much lower(58%)in patients with a low pre-test likelihood of PE. Therefore,clinicians should be particularly cautious in case of discor-dancy between clinical judgement and the MDCT result.

Four studies provided evidence in favour of computed tomog-raphy as a stand-alone imaging test for excluding PE.In a prospective management study covering756consecutive patients referred to the emergency department with a clinical suspicion of PE,all patients with either a high clinical probability or a non-high clinical probability and a positive ELISA D-dimer test underwent both lower limb ultrasonog-raphy and MDCT.113The proportion of patients in whom—despite a negative MDCT—a proximal DVT was found on ultrasound was only 0.9%(95%CI0.3–2.7).113In another study,99all patients classi?ed as PE-likely by the dichotomized Wells rule,or those with a positive D-dimer test,underwent a chest MDCT.The three-month thrombo-embolic risk in the patients left untreated because of a negative CT was low(1.1%;95%CI0.6–1.9).99Two randomized,controlled trials reached similar conclusions.In a Canadian trial comparing V/ Q scan and CT(mostly MDCT),only seven of the531patients (1.3%)with a negative CT had a DVT,and one had a thromboembolic event during follow-up.135Hence,the three-month thromboembolic risk would have been1.5%(95%CI0.8–2.9)if only CT had been used.135A European study compared two diagnostic strategies based on D-dimer and MDCT,one with-and the other without lower limb compression venous ultrasonography(CUS).116In the D-dimer–CT arm,the three-month thromboembolic risk was 0.3%(95%CI0.1–1.2)among the627patients left untreated, based on a negative D-dimer or MDCT.

Taken together,these data suggest that a negative MDCT is an ad-equate criterion for excluding PE in patients with a non-high clinical probability of PE.Whether patients with a negative CT and a high clin-ical probability should be further investigated is controversial.MDCT showing PE at the segmental or moreproximal level is adequate proof of PE in patients with a non-low clinical probability;however,the positive predictive value of MDCT is lower in patients with a low clin-ical probability of PE,and further testing may be considered,especial-ly if the clots are limited to segmental or sub-segmental arteries. The clinical signi?cance of isolated sub-segmental PE on CT angiog-raphy is questionable.This?nding was present in4.7%(2.5–7.6%)of patients with PE imaged by single-detector CT angiography and9.4% (5.5–14.2%)of those submitted to MDCT.136The positive predictive value is low and inter-observer agreement is poor at this distal level.137 There may be a role for CUS in this situation,to ensure that the patient does not have DVT that would require treatment.In a patient with iso-lated sub-segmental PE and noproximalDVT,the decisionon whether to treat should be made on an inpidual basis,taking into account the clinical probability and the bleeding risk.

Computed tomographic venography has been advocated as a simple way to diagnose DVT in patients with suspected PE,as it can be combined with chest CT angiography as a single procedure,using onlyone intravenousinjection ofcontrast dye.In PIOPEDII,combining CT venography with CT angiography increased sensitivity for PE from 83%to90%and had a similar speci?city(around95%);134,138however, the corresponding increase in negative predictive value was not clinically signi?cant.CT venography adds a signi?cant amount of irradi-ation,which may be aconcern,especially in younger women.139AsCT venography and CUS yielded similar results in patients with signs or symptoms of DVT in PIOPED II,138ultrasonography should be used instead of CT venography if indicated(see Section3.10).

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The incidental discovery of clinically unsuspected PE on CT is an in-creasingly frequent problem,arising in1–2%of all thoracic CT exam-inations,most often in patients with cancer,but also among those with paroxysmal atrial?brillation or heart failure and history of atrial?bril-lation.140–143There are no robust datato guide the decision onhow to manage unsuspected PE with anticoagulants,but most experts agree that patients with cancer and those with clots at the lobar or more proximal level should be treated with anticoagulants.144

3.5Lung scintigraphy

Ventilation–perfusion scintigraphy(V/Q scan)is an established diag-nostic test for suspected PE.It is safe and few allergic reactions have been described.The test is based on the intravenous injection of technetium(Tc)-99m-labelled macroaggregated albumin particles, which block a small fraction of the pulmonary capillaries and thereby enable scintigraphic assessment of lung perfusion.Perfusion scans are combined with ventilation studies,for which multiple tracers such as xenon-133gas,Tc-99m-labelled aerosols,or Tc-99m-labelled carbon microparticles(Technegas)can be used. The purpose of the ventilation scan is to increase speci?city:in acute PE,ventilation is expected to be normal in hypoperfused seg-ments(mismatch).145,146According to the International Commission on Radiological Protection(ICRP),the radiation exposure from a lung scan with100MBq of Tc-99m macroaggregated albumin parti-cles is1.1mSv for an average sized adult,and thus is signi?cantly lower than that of CT angiography(2–6mSv).147,148

Being a radiation-and contrast medium-sparing procedure,the V/Q scan may preferentially be applied in outpatients with low clinical probability and a normal chest X-ray,in young(particularly female)patients,in pregnancy,in patients with history of contrast medium-induced anaphylaxis and strong allergic history,in severe renal failure,and in patients with myeloma and paraproteinaemia.149 Lung scan results are frequently classi?ed according to the criteria established in the PIOPED study:normal or near-normal,low,inter-mediate(non-diagnostic),and high probability of PE.94These criteria have been the subject of debate,following which they were revised.150,151To facilitate communication with clinicians,a three-tier classi?cation is preferable:normal scan(excluding PE),high-probability scan(considered diagnostic of PE in most patients),and non-diagnostic scan.135,152,153Prospective clinical outcome studies suggested that it is safe to withhold anticoagulant therapy in patients with a normal perfusion scan.This was recently con?rmed by a ran-domized trial comparing the V/Q scan with CT.135An analysis from the recent PIOPED II study con?rmed the effectiveness of the high-probability V/Q scan for diagnosing PE and of the normal perfusion scan for ruling it out.154Performing onlya perfusion scan is acceptable in patients with a normal chest X-ray;any perfusion defect in this situ-ation will be considered to be a mismatch.155The high frequency of non-diagnostic intermediate probability scans has been a cause for criticism,because they indicate the necessity for further diagnostic testing.Various strategies to overcome this problem have been pro-posed,notably the incorporation of clinical probability.91,156,157 Recent studies suggest that data acquisition in the tomographic mode in single photon emission computed tomography(SPECT) imaging,with or without low-dose CT may reduce the frequency of non-diagnostic scans.152,158–161SPECT imaging may even allow the use of automated detection algorithms for PE.162Large-scale pro-spective studies are needed to validate these new approaches.3.6Pulmonary angiography

Pulmonary angiography has for decades remained the‘gold standard’for the diagnosis or exclusion of PE,but is rarely performed now as less-invasive CT angiography offers similar diagnostic accuracy.163Pul-monary angiography is more often used to guide percutaneous catheter-directed treatment of acute PE.Digital subtraction angiog-raphy(DSA)requires less contrast medium than conventional cinean-giography and has excellent imaging quality for peripheral pulmonary vessels in patients who can hold their breath;it is less useful for imaging of the main pulmonaryarteries,due to cardiac motion artefacts. The diagnosis of acute PE is based on direct evidence of a thrombus in two projections,either as a?lling defect or as amputation of a pul-monary arterial branch.94Thrombi as small as1–2mm within the sub-segmental arteries can be visualized by DSA,but there is substan-tial inter-observer variability at this level.164,165Indirect signs of PE, such as slow?ow of contrast,regional hypoperfusion,and delayed or diminished pulmonary venous?ow,are not validated and hence are not diagnostic.The Miller score may be used in quantifying the extent of luminal obstruction.166

Pulmonary angiography is not free of risk.In a study of1111 patients,procedure-related mortality was0.5%,major non-fatal complications occurred in1%,and minor complications in5%.167 The majority of deaths occurred in patients with haemodynamic compromise or respiratory failure.The risk of access-related bleed-ing complications is increased if thrombolysis is attempted in patients with PE diagnosed by pulmonary angiography.168 Haemodynamic measurements should always be recorded during pulmonary angiography for estimation of the severity of PE and because they may suggest alternative cardiopulmonary disorders. In patients with haemodynamic compromise,the amount of contrast agent should be reduced and non-selective injections avoided.169

3.7Magnetic resonance angiography Magnetic resonance angiography(MRA)has been evaluated for several years in suspected PE but large-scale studies were published only recently.170,171Their results show that this technique,although promising,is not yet ready for clinical practice due to its low sensitiv-ity,high proportion of inconclusive MRA scans,and low availability in most emergency settings.The hypothesis—that a negative MRA combined with the absence of proximal DVT on CUS may safely rule out clinically signi?cant PE—is being tested in a multicentre outcome study(e43f5da204a1b0717ed5dd2a NCT02059551).

3.8Echocardiography

Acute PE may lead to RV pressure overload and dysfunction,which can be detected by echocardiography.Given the peculiar geometry of the RV,there is no inpidual echocardiographic parameter that provides fast and reliable information on RV sizeorfunction.This is whyechocar-diographic criteria for the diagnosis of PE have differed between studies. Because of the reported negative predictive value of40–50%,a nega-tive result cannot exclude PE.157,172,173On the other hand,signs of RV overload or dysfunction may also be found in the absence of acute PE and be due to concomitant cardiac or respiratory disease.174 RV dilation is found in at least25%of patients with PE,and its detec-tion,either by echocardiography or CT,is useful for risk strati?cation of the disease.Echocardiographic?ndings—based either on a disturbed RV ejection pattern(so-called‘60–60sign’)or on depressed

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contractility of the RV free wall compared with the RV apex(‘McCon-nell sign’)—were reported to retain a high positive predictive value for PE,even in the presence of pre-existing cardiorespiratory disease.175 Additional echocardiographic signs of pressure overload may be required to avoid a false diagnosis of acute PE in patients with RV free wall hypokinesia or akinesia due to RV infarction,which may mimic the McConnell sign.176Measurement of the tricuspid annulus plane sys-tolic excursion(TAPSE)may also be useful.177New echocardiographic parameters of RV function,derived from Doppler tissue imaging and wall strain assessment,were reported to be affected by the presence of acute PE,but they are non-speci?c and may be normal in haemo-dynamically stable patients,despite the presence of PE.178–181 Echocardiographic examination is not recommended as part of the diagnostic work-up in haemodynamically stable,normotensive patients with suspected(not high-risk)PE.157This is in contrast to sus-pected high-risk PE,in which the absence of echocardiographic signs of RV overload or dysfunction practically excludes PE as the cause of haemodynamic instability.In the latter case,echocardiography may be of further help in the differential diagnosis of the cause of shock, by detecting pericardial tamponade,acute valvular dysfunction, severe global or regional LV dysfunction,aortic dissection,or hypovol-aemia.Conversely,in a haemodynamically compromised patient with suspected PE,unequivocal signs of RV pressure overload and dysfunc-tion justify emergency reperfusion treatment for PE if immediate CT angiography is not feasible.182

Mobile right heart thrombi are detected by transthoracic or trans-oesophageal echocardiography(or by CT angiography)in less than 4%of unselected patients with PE,183–185but their prevalence may reach18%in the intensive care setting.185Mobile right heart thrombi essentially con?rm the diagnosis of PE and their presence is associated with RV dysfunction and high early mortality.184,186,187 Consequently,transoesophageal echocardiography may be consid-ered when searching for emboli in the main pulmonary arteries in speci?c clinical situations,188,189and it can be of diagnostic value in haemodynamically unstable patients due to the high prevalence of bilateral central pulmonary emboli in most of these cases.190

In some patients with suspected acute PE,echocardiography may detect increased RV wall thickness and/or tricuspid insuf?ciency jet velocity beyond values compatible with acute RV pressure overload. In these cases,chronic pulmonary hypertension,and CTEPH in par-ticular,should be included in the differential diagnosis.

3.9Compression venous ultrasonography In the majority of cases,PE originates from DVT in a lower limb.In a study using venography,DVT was found in70%of patients with proven PE.191Nowadays,lower limb CUS has largely replaced venog-raphy for diagnosing DVT.CUS has a sensitivity.90%and a speci?-city of approximately95%for symptomatic DVT.192,193CUS shows a DVT in30–50%of patients with PE,116,192,193and?nding a proximal DVT in patients suspected of having PE is considered suf?cient to warrant anticoagulant treatment without further testing.194

In the setting of suspected PE,CUS can be limited to a simple four-point examination(groin and popliteal fossa).The only validated diag-nostic criterion for DVT is incomplete compressibility of the vein, which indicates the presence of a clot,whereas?ow measurements are unreliable.The diagnostic yield of CUS in suspected PE may be increased further by performing complete ultrasonography,which includes the distal veins.Two recent studies assessed the proportion of patients with suspected PE and a positive D-dimer result,in whom a DVT could be detected by complete CUS.195,196The diagnostic yield of complete CUS was almost twice that of proximal CUS,but a high proportion(26–36%)of patients with distal DVT had no PE on thoracic MDCT.In contrast,a positive proximal CUS result has a high positive predictive value for PE,as con?rmed by data from a large pro-spective outcome study,in which524patients underwent both MDCT and CUS.The sensitivity of CUS for the presence of PE on MDCT was 39%and its speci?city was99%.194The probability of a positive prox-imal CUS in suspected PE is higher in patients with signs and symptoms related to the leg veins than in asymptomatic patients.192,193

3.10Diagnostic strategies

The prevalence of con?rmed PE in patients undergoing diagnostic work-up because of suspicion of disease has been rather low(10–35%)in large series.99,100,113,116,197Hence,the use of diagnostic algo-rithms is warranted,and various combinations of clinical assessment, plasma D-dimer measurement,and imaging tests have been pro-posed and validated.These strategies were tested in patients present-ing with suspected PE in the emergency ward,99,113,114,116,197during the hospital stay and more recently in the primary care setting.118,126 Failure to comply with evidence-based diagnostic strategies when withholding anticoagulation was associated with a signi?cant increase in the number of VTE episodes and sudden cardiac death at three-month follow-up.198The most straightforward diagnostic algorithms for suspected PE—with and without shock or hypotension—are pre-sented in Figures3and4,respectively;however,it is recognized that the diagnostic approach to suspected PE may vary,depending on the availability of—and expertise in—speci?c tests in various hospi-tals and clinical settings.Accordingly,Table6provides the necessary evidence for alternative evidence-based diagnostic algorithms. The diagnostic strategy for suspected acute PE in pregnancy is dis-cussed in Section8.1.

3.10.1Suspected pulmonary embolism with shock

or hypotension

The proposed strategy is shown in Figure3.Suspected high-risk PE is an immediately life-threatening situation,and patients presenting with shock or hypotension present a distinct clinical problem.The clinical probability is usually high,and the differential diagnosis includes acute valvular dysfunction,tamponade,acute coronary syndrome(ACS), and aortic dissection.The most useful initial test in this situation is bedside transthoracic echocardiography,which will yield evidence of acute pulmonary hypertension and RV dysfunction if acute PE is the cause of the patient’s haemodynamic decompensation.In a highly un-stable patient,echocardiographic evidence of RV dysfunction is suf?-cient to prompt immediate reperfusion without further testing.This decision may be strengthened by the(rare)visualization of right heart thrombi.184,199,200Ancillary bedside imaging tests include transoeso-phageal echocardiography which,if available,may allow direct visualiza-tion of thrombi in the pulmonary artery and its main branches,188,190,201 and bedside CUS,which can detect proximal DVT.As soon as the patient can be stabilized by supportive treatment,?nal con?rmation of the diagnosis by CT angiography should be sought.

For unstable patients admitted directly to the catheterization la-boratory with suspected ACS,pulmonary angiography may be con-sidered as a diagnostic procedure after the ACS has been excluded, provided that PE is a probable diagnostic alternative and particularly if percutaneous catheter-directed treatment is a therapeutic option.

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3.10.2Suspected pulmonary embolism without shock

or hypotension

Strategy based on computed tomographic angiography(Figure4) Computed tomographic angiography has become the main thor-acic imaging test for investigating suspected PE but,since most patients with suspected PE do not have the disease,CT should not be the?rst-line test.

In patients admitted to the emergency department,plasma D-dimer measurement,combined with clinical probability assess-ment,is the logical?rst step and allows PE to be ruled out in around30%of patients,with a three-month thromboembolic risk in patients left untreated of,1%.D-dimer should not be measured in patients with a high clinical probability,owing to a low negative pre-dictive value in this population.202It is also less useful in hospitalized patients because the number needed to test to obtain a clinically rele-vant negative result is high.

In most centres,MDCT angiography is the second-line test in patients with an elevated D-dimer level and the?rst-line test in patients with a high clinical probability.CT angiography is considered to be diagnostic of PE when it shows a clot at least at the segmental level of the pulmonary arterial tree.False-negative results of MDCT have been reported in patients with a high clinical probability of PE;134however,this situation is infrequent,and the three-month thromboembolic risk was low in these cases.99Therefore,both the necessity of performing further tests and the nature of these tests in such patients remain controversial.

Value of lower limb compression ultrasonography

Under certain circumstances,CUS can still be useful in the diagnostic work-up of suspected PE.CUS shows a DVT in30–50% of patients with PE,116,192,193and?nding proximal DVT in a patient suspected of PE is suf?cient to warrant anticoagulant treatment without further testing.194Hence,performing CUS before CT may be an option in patients with relative contraindications for CT such as in renal failure,allergy to contrast dye,or pregnancy.195,196 Value of ventilation–perfusion scintigraphy

In centres in which V/Q scintigraphy is readily available,it remains a valid option for patients with an elevated D-dimer and a

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contraindication to CT.Also,V/Q scintigraphy may be preferred over CT to avoid unnecessary radiation,particularly in younger and female patients in whom thoracic CT may raise the lifetime risk of breast cancer.139V/Q lung scintigraphy is diagnostic(with either normal or high-probability?ndings)in approximately30–50%of emergency ward patients with suspected PE.83,94,135,203The proportion of diag-nostic V/Q scans is higher in patients with a normal chest X-ray,and this supports the recommendation to use V/Q scan as the?rst-line imaging test for PE in younger patients.204

The number of patients with inconclusive?ndings may also be reduced by taking into account clinical probability.94Thus,patients with a non-diagnostic lung scan and low clinical probability of PE have a low prevalence of con?rmed PE.94,157,203The negative predict-ive value of this combination is further increased by the absence of a DVT on lower-limb CUS.If a high-probability lung scan is obtained from a patient with low clinical probability of PE,con?rmation by other tests may be considered on a case-by-case basis.

3.11Areas of uncertainty

Despite considerable progress in the diagnosis of PE,several areas of uncertainty persist.The diagnostic value and clinical signi?cance of sub-segmental defects on MDCT are still under debate.136,137A recent retrospective analysis of two patient cohorts with suspected PE showed similar outcomes(in terms of three-month recurrence and mortality rates)between patients with sub-segmental and more proximal PE;outcomes were largely determined by comorbid-ities.205The de?nition of sub-segmental PE has yet to be standardized and a single sub-segmental defect probably does not have the same clinical relevance as multiple,sub-segmental thrombi.

There is also growing evidence suggesting over-diagnosis of PE.206A randomized comparison showed that,although CT detected PE more frequently than V/Q scanning,three-month out-comes were similar,regardless of the diagnostic method used.135 Data from the United States show an80%rise in the apparent in-cidence of PE after the introduction of CT,without a signi?cant impact on mortality.207,208

Some experts believe that patients with incidental(unsuspected) PE on CT should be treated,144especially if they have cancer and a proximal clot,but solid evidence in support of this recommendation is lacking.The value and cost-effectiveness of CUS in suspected PE should be further clari?ed.

Finally,‘triple rule-out’(for coronary artery disease,PE and aortic dissection)CT angiography for patients presenting with non-traumatic chest pain appears to be accurate for the detection of cor-onary artery disease.209However,the bene?ts vs.risks(including increased radiation and contrast exposure)of such a diagnostic ap-proach need thorough evaluation,given the low(,1%)prevalence of PE and aortic dissection in the studies published thus far.

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short-term prognosis.For example,in the International Cooperative Pulmonary Embolism Registry(ICOPER),age.70years,systolic BP ,90mm Hg,respiratory rate.20breaths/min,cancer,chronic heart failure and chronic obstructive pulmonary disease(COPD), were all identi?ed as prognostic factors.48In the Registro Informati-zado de la Enfermedad Thomboembolica venosa(RIETE)study,im-mobilization for neurological disease,age.75years,and cancer were independently associated with an increased risk of death within the?rst three months after acute VTE.47The diagnosis of con-comitant DVT has also been reported to be an independent predict-or of death within the?rst three months following diagnosis.210 Various prediction rules based on clinical parameters have been shown to be helpful in the prognostic assessment of patients with acute PE.Of those,the pulmonary embolism severity index(PESI; Table7)is the most extensively validated score to date.211–214In one study,215the PESI performed better than the older Geneva prog-nostic score216for identi?cation of patients with an adverse30-day outcome.The principal strength of the PESI lies in the reliable identi-?cation of patients at low risk for30-day mortality(PESI Class I and II). One randomized trial employed a low PESI as the inclusion criterion for home treatment of acute PE.217

Owing to the complexity of the original PESI,which includes11dif-ferently weighted variables,a simpli?ed version known as sPESI (Table7)has been developed and validated.218,219In patients with PE,the sPESI was reported to quantify their30-day prognosis better than the shock index(de?ned as heart rate pided by systolic BP),220and a simpli?ed PESI of0was at least as accurate for identi?-cation of low-risk patients as the imaging parameters and laboratory biomarkers proposed by the previous ESC Guidelines.221Combin-ation of the sPESI with troponin testing provided additional prognos-tic information,222especially for identi?cation of low-risk patients.76 4.2Imaging of the right ventricle by echocardiography or computed tomographic angiography

Echocardiographic?ndings indicating RV dysfunction have been reported in≥25%of patients with PE.223They have been identi?ed as independent predictors of an adverse outcome,224but are heterogeneous and have proven dif?cult to standardize.225Still,in haemodynamically stable,normotensive patients with PE,echocardio-graphic assessment of the morphologyand function ofthe RV may help in prognostic strati?cation.

As already mentioned in the previous section on the diagnosis of PE,echocardiographic?ndings used to risk stratify patients with PE include RV dilation,an increased RV–LV diameter ratio,hypokinesia of the free RV wall,increased velocity of the jet of tricuspid regurgi-tation,decreased tricuspid annulus plane systolic excursion,or com-binations of the above.Meta-analyses have shown that RV dysfunction detected by echocardiography is associated with an ele-vated risk of short-term mortality in patients without haemodynamic instability,but its overall positive predictive value is low (Table8).226,227In addition to RV dysfunction,echocardiography can also identify right-to-left shunt through a patent foramen ovale and the presence of right heart thrombi,both of which are associated with increased mortality in patients with acute PE.80,184

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Four-chamber views of the heart by CT angiography may detect RV enlargement(end-diastolic diameter,compared with that of the left ventricle)as an indicator of RV dysfunction.Following a number of early retrospective studies,227the prognostic value of an enlarged RV on CT angiography was con?rmed by a prospective mul-ticentre cohort study of457patients(Table8).228In-hospital death or clinical deterioration occurred in44patients with-and in8patients without RV dysfunction on CT(14.5%vs.5.2%;P,0.004).Right ven-tricular dysfunction was an independent predictor for an adverse in-hospital outcome,both in the overall population(HR3.5;95% CI1.6–7.7;P?0.002)and in haemodynamically stable patients (HR3.8;95%CI1.3–10.9;P?0.007).Additional recent publications have con?rmed these?ndings.229,230

4.3Laboratory tests and biomarkers

4.3.1Markers of right ventricular dysfunction

Right ventricular pressure overload is associated with increased myo-cardial stretch,which leads to the release of brain natriuretic peptide (BNP)or N-terminal(NT)-proBNP.The plasma levels of natriuretic peptides re?ect the severity of haemodynamic compromise and (presumably)RV dysfunction in acute PE.231A meta-analysis found that51%of1132unselected patients with acute PE had elevated BNP or NT-proBNP concentrations on admission.These patients had a10%risk of early death(95%CI8.0–13)and a23%(95%CI 20–26)risk of an adverse clinical outcome.232

In normotensive patients with PE,the positive predictive value of elevated BNP or NT-proBNP concentrations for early mortality is low.233In a prospective,multicentre cohort study that included 688patients,NT-proBNP plasma concentrations of600pg/mL were identi?ed as the optimal cut-off value for the identi?cation of elevated risk(Table8).234On the other hand,low levels of BNP or NT-proBNP can identify patients with a favourable short-term clinic-al outcome based on their high negative predictive value.226,232,235,236 Haemodynamically stable patients with low NT-proBNP levels may be candidates for early discharge and outpatient treatment.237

4.3.2Markers of myocardial injury

Transmural RV infarction despite patent coronary arteries has been found atautopsyofpatientswhodied ofmassivePE.238Elevatedplasmatropo-nin concentrations on admission have been reported in connection with PE and were associated with worse prognosis.A meta-analysis covering a total of1985patients showed elevated cardiac troponin I or-T concentrations in approximately50%of the patients with acute PE(Table8).239Elevated troponin concentrations were associated with high mortality both in unselected patients[odds ratio(OR)9.44; 95%CI 4.14–21.49]and in haemodynamically stable patients [OR5.90;95%CI2.68–12.95],and the results were consistent for troponin I or-T;however,other reports have suggested a limited prog-nostic value of elevated troponins in normotensive patients.240

The reported positive predictive value of troponin elevation for PE-related early mortality ranges from12–44%,while the negative

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predictive value is high,irrespective of the assays and cut-off values used.Recently developed high-sensitivity assays have improved the prognostic performance of this biomarker,particularly with regard to the exclusion of patients with an adverse short-term outcome.241For example,in a prospective,multicentre cohort of 526normotensive patients with acute PE,troponin T concentrations

,14pg/mL,measured by a high-sensitivity assay,had a negative pre-dictive value of 98%with regard to a complicated clinical course,which was similar to that of the sPESI.76Heart-type fatty acid-binding protein (H-FABP),an early marker of myocardial injury,was also found to possess prognostic value in acute PE.242,243In normotensive patients,circulating H-FABP levels ≥6ng/mL had a positive predictive value of 28%and a negative pre-dictive value of 99%for an adverse 30-day outcome (Table 8).244A simple score,based on the presence of tachycardia,syncope,and a positive bedside test for H-FABP,provided prognostic information similar to that of RV dysfunction on echocardiography.245,2464.3.3Other (non-cardiac)laboratory biomarkers Elevated serum creatinine levels and a decreased (calculated)glom-erular ?ltration rate are related to 30-day all-cause mortality in acute PE.247Elevated neutrophil gelatinase-associated lipocalin (NGAL)and cystatin C,both indicating acute kidney injury,have also been found to be of prognostic value.248Elevated D-dimer ESC Guidelines Page 18of 48 at Fujian University of Traditional Chinese Medicine on August 30, 2014e43f5da204a1b0717ed5dd2a/Downloaded from

concentrations were associated with increased short-term mortality in some studies,249,250while levels ,1500ng/mL had a negative pre-dictive value of 99%for excluding three-month all-cause mortality.2514.4Combined modalities and scores In patients with acute PE who appear haemodynamically stable at diagnosis,no inpidual clinical,imaging,or laboratory ?nding has been shown to predict risk of an adverse in-hospital outcome that could be considered high enough to justify primary reperfusion.As a result,various combinations of clinical ?ndings with imaging and laboratory tests have been proposed and tested in registries and cohort studies in an attempt to improve risk strati?ca-tion.222,246,254–259The clinical relevance of most of these modalities and scores,particularly with regard to the therapeutic implications,remains to be determined;however,the combination of RV dysfunc-tion on the echocardiogram (or CT angiogram)with a positive cardiac troponin test 256,260was used as an inclusion criterion in a recently published randomized thrombolysis trial,261which enrolled 1006normotensive patients with acute PE.Patients treated with standard anticoagulation had a 5.6%incidence of death or haemodynamic decompensation within the ?rst 7days following randomization.2534.5Prognostic assessment strategy For prediction of early (in-hospital or 30-day)outcome in patients with acute PE,both the PE-related risk and the patient’s clinical status and comorbidities should be taken into consideration.The def-inition for level of clinical risk is shown in Table 9.The risk-adjusted therapeutic strategies and algorithms recommended on the basis of this classi?cation are discussed in the following section and summar-ized in Figure 5.At the stage of clinical suspicion of PE,haemodynamically unstable patients with shock or hypotension should immediately be identi?ed as high-risk patients (Figure 2).They require an emergency diagnostic

algorithm as outlined in the previous section and,if PE is con?rmed,

primary pharmacological (or,alternatively,surgical or interventional)reperfusion therapy.

Patients without shock or hypotension are not at high risk of an adverse early outcome.Further risk strati?cation should be considered after the diagnosis of PE has been con?rmed,as this may in?uence the therapeutic strategy and the duration of the hospi-talization (see Section 5.8).In these patients,risk assessment should begin with a validated clinical prognostic score,preferably the PESI or sPESI,its simpli?ed version,to distinguish between intermediate and low risk.Around one-third of PE patients are at low risk of an early adverse outcome as indicated by a PESI Class I or II,or a simpli?ed PESI,of 0.On the other hand,in registries and cohort studies,patients in PESI Class III–V had a 30-day mortality rate of up to 24.5%,214and those with a simpli?ed PESI ≥1up to 11%.218Accordingly,normoten-sive patients in PESI Class ≥III ora simpli?ed PESI of ≥1are considered to constitute an intermediate-risk group.Within this category,further risk assessment should be considered,focusing on the status of the RV in response to the PE-induced acute pressure overload.Patients

who display evidence of both RV dysfunction (by echocardiography

or CT angiography)and elevated cardiac biomarker levels in the circu-

lation (particularly a positive cardiac troponin test)should be classi?ed

into an intermediate-high-risk category.As discussed in more detail in the following section,close monitoring is recommended in these cases to permit early detection of haemodynamic decompensation and the need for initiation of rescue reperfusion therapy.253On the other hand,patients in whom the RV is normal on echocardiography or CT angiography,and/or have normal cardiac biomarker levels,belong to an intermediate-low-risk group.

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Data from registries and cohort studies suggest that patients in PESI Class I–II,or with sPESI of0,but with elevated cardiac biomarkers or signs of RV dysfunction on imaging tests,should also be classi?ed into the intermediate-low-risk category.76,222,262Never-theless,routine performance of imaging or laboratory tests in the presence of a low PESI or a simpli?ed PESI of0is not considered necessary at present as,in these cases,it has not been shown to have therapeutic implications.

Recommendations for prognostic assessment

Recommendations Class a Level b Ref c

Initial risk stratification of

suspected or confirmed PE—

based on the presence of shock

or persistent hypotension—is

recommended to identify

patients at high risk of early

mortality.

I B47, 48

In patients not at high risk, use of

a validated clinical risk prediction

score, preferably the PESI or sPESI, should be considered to distinguish between low-and intermediate-risk PE. IIa B

214,

218

In patients at intermediate risk,

assessment of the right ventricle

with echocardiography or CT,

and of myocardial injury using a

laboratory biomarker, should be

considered for further risk

stratification.

IIa B253

CT?computed tomographic(pulmonary angiography);PE?pulmonary embolism;PESI?pulmonary embolism severity index;sPESI?simpli?ed pulmonary embolism severity index.

a Class of recommendation.

b Level of evidence.

c References.

5.Treatment in the acute phase 5.1Haemodynamic and respiratory support

Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE.Therefore,supportive treatment is vital in patients with PE and RV failure.Experimental studies indicate that aggressive volume expansion is of no bene?t and may even worsen RV function by causing mechanical overstretch, or by re?ex mechanisms that depress contractility.263On the other hand,modest(500mL)?uid challenge may help to increase cardiac index in patients with PE,low cardiac index,and normal BP.264 Use of vasopressors is often necessary,in parallel with(or while waiting for)pharmacological,surgical,or interventional reperfusion treatment.Norepinephrine appears to improve RV function via a direct positive inotropic effect,while also improving RV coronary perfusion by peripheral vascular alpha-receptor stimulation and the increase in systemic BP.Its use should probably be limited to hypo-tensive patients.Based on the results of small series,the use of dobu-tamine and/or dopamine may be considered for patients with PE,low cardiac index,and normal BP;however,raising the cardiac index above physiological values may aggravate the ventilation–perfusion mismatch by further redistributing?ow from(partly)obstructed to unobstructed vessels.265Epinephrine combines the bene?cial prop-erties of norepinephrine and dobutamine,without the systemic vaso-dilatory effects of the latter.It may therefore exert bene?cial effects in patients with PE and shock.

Vasodilators decrease pulmonary arterial pressure and pulmonary vascular resistance,but the main concern is the lack of speci?city of these drugs for the pulmonary vasculature after systemic(intraven-ous)administration.According to data from small clinical studies,in-halation of nitric oxide may improve the haemodynamic status and gas exchange of patients with PE.266,267Preliminary data suggest that levosimendan may restore right ventricular–pulmonary arterial coupling in acute PE by combining pulmonary vasodilation with an in-crease in RV contractility.268

Hypoxaemia and hypocapnia are frequently encountered in patients with PE,but they are of moderate severity in most cases.

A patent foramen ovale may aggravate hypoxaemia due to shunting when right atrial-exceeds left atrial pressure.80Hypoxaemia is usually reversed with administration of oxygen.When mechanical ventilation is required,care should be taken to limit its adverse haemodynamic effects.In particular,the positive intrathoracic pres-sure induced by mechanical ventilation may reduce venous return and worsen RV failure in patients with massive PE;therefore,positive end-expiratory pressure should be applied with caution.Low tidal volumes(approximately6mL/kg lean body weight)should be used in an attempt to keep the end-inspiratory plateau pressure ,30cm H2O.

Experimental evidence suggests that extracorporeal cardiopul-monary support can be an effective procedure in massive PE.269 This notion is supported by occasional case reports and patient series.270–272

5.2Anticoagulation

In patients with acute PE,anticoagulation is recommended,with the objective of preventing both early death and recurrent symptomatic or fatal VTE.The standard duration of anticoagulation should cover at least3months(also see Section6).Within this period,acute-phase treatment consists of administering parenteral anticoagulation [unfractionated heparin(UFH),LMWH or fondaparinux]over the ?rst5–10days.Parenteral heparin should overlap with the initiation of a vitamin K antagonist(VKA);alternatively,it can be followed by administration of one of the new oral anticoagulants:dabigatran or edoxaban.If rivaroxaban or apixaban is given instead,oral treatment with one of these agents should be started directly or after a1–2day administration of UFH,LMWH or fondaparinux.In this latter case, acute-phase treatment consists of an increased dose of the oral anti-coagulant over the?rst3weeks(for rivaroxaban),or over the?rst7 days(for apixaban).

In some cases,extended anticoagulation beyond the?rst3 months,or even inde?nitely,may be necessary for secondary preven-tion,after weighing the inpidual patient’s risk of recurrence vs. bleeding risk.

5.2.1Parenteral anticoagulation

In patients with high or intermediate clinical probability for PE(see Section3),parenteral anticoagulation should be initiated whilst awaiting the results of diagnostic tests.Immediate anticoagulation

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can be achieved with parenteral anticoagulants such as intravenous UFH,subcutaneous low-molecular-weight heparin (LMWH),or sub-cutaneous fondaparinux.LMWH or fondaparinux are preferred over UFH for initial anticoagulation in PE,as they carry a lower risk of in-ducing major bleeding and heparin-induced thrombocytopenia (HIT).273–276On the other hand,UFH is recommended for patients in whom primary reperfusion is considered,as well as for those with serious renal impairment (creatinine clearance ,30mL/min),or severe obesity.These recommendations are based on the short half-life of UFH,the ease of monitoring its anticoagulant effects,and its rapid reversal by protamine.The dosing of UFH is adjusted,based on the activated partial thromboplastin time (aPTT;Web Addenda Table II ).277

The LMWHs approved for the treatment of acute PE are listed in Table 10.LMWH needs no routine monitoring,but periodic mea-surement of anti-factor Xa activity (anti-Xa levels)may be considered during pregnancy.279Peak values of anti-factor Xa activity should be measured 4hours after the last injection and trough values just before the next dose of LMWH would be due;the target range is 0.6–1.0IU/mL for twice-daily administration,and 1.0–2.0IU/mL for once-daily administration.280

Fondaparinux is a selective factor Xa inhibitor administered once daily by subcutaneous injection at weight-adjusted doses,without the need for monitoring (Table 10).In patients with acute PE and no indi-cation for thrombolytic therapy,fondaparinux was associated with recurrent VTE and major bleeding rates similar to those obtained with intravenous UFH.281No proven cases of HIT have been

reported with fondaparinux.282Subcutaneous fondaparinux is con-traindicated in patients with severe renal insuf?ciency (creatinine clearance ,30mL/min)because it will accumulate and increase the risk of haemorrhage.Accumulation also occurs in patients with moderate renal insuf?ciency (clearance 30–50mL/min)and,there-fore,the dose should be reduced by 50%in these patients.2835.2.2Vitamin K antagonists

Oral anticoagulants should be initiated as soon as possible,and pref-erably on the same day as the parenteral anticoagulant.VKAs have been the ‘gold standard’in oral anticoagulation for more than 50years and warfarin,acenocoumarol,phenprocoumon,phenindione and ?unidione remain the predominant anticoagulants prescribed for PE.284Anticoagulation with UFH,LMWH,or fondaparinux should be continued for at least 5days and until the international nor-malized ratio (INR)has been 2.0–3.0for two consecutive days.285

Warfarin can be started at a dose of 10mg in younger (e.g.,60years of age),otherwise healthy outpatients,and at a dose of 5mg in older patients and in those who are hospitalized.The daily dose is adjusted according to the INR over the next 5–7days,aiming for an INR level of 2.0–3.0.Rapid-turnaround pharmacogenetic testing may increase the precision of warfarin dosing.286,287In particular,var-iations 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,while the other deter-mines the activity of vitamin K epoxide reductase,the enzyme that produces the active form of vitamin K.288Pharmacogenetic algorithms incorporate genotype and clinical information and recommend warfarin doses according to integration of these data.A trial published in 2012indicated that,compared with standard care,pharmacogenetic guidance of warfarin dosing resulted in a 10%absolute reduction in out-of-range INRs at one month,primarily due to fewer INR values ,1.5;this improvement coincided with a 66%lower rate of DVT.289In 2013,three large randomized trials were published.290–292All used,as the primary endpoint,the per-centage of time in therapeutic range (TTR)(a surrogate for the quality of anticoagulation)for the INR during the ?rst 4–12weeks of therapy.In 455patients,genotype-guided doses of warfarin,with a point-of-care test,resulted in a signi?cant but modest increase in TTR over the ?rst 12weeks,compared with a ?xed 3-day loading-dose regimen (67.4%vs.60.3%;P ,0.001).The median time to reaching a therapeutic INR was reduced from 29to 21days.292Another study in 1015patients compared warfarin loading—based on genotype data in combination with clinical variables—with a loading regimen based on the clinical data alone;no signi?cant im-provement was found in either group in terms of the TTR achieved between days 4and 28of therapy.291Lack of improvement was also shown by a trial involving 548patients,comparing acenocou-marol or phenprocoumon loading—based on point-of-care geno-typing in combination with clinical variables (age,sex,height,weight,amiodarone use)—with a loading regimen based entirely on clinical information.290

In summary,the results of recent trials appear to indicate that pharmacogenetic testing,used on top of clinical parameters,does not improve the quality of anticoagulation.They also suggest that dosing based on the patient’s clinical data is possibly superior to

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