anmcopositionpaper:long-term follow-upofpatients ... filerevised by: marino scherillo, federico...

ANMCO Position Paper long-term follow-up of patientswith pulmonary thromboembolism

Carlo DrsquoAgostino (Coordinator)1 Pietro Zonzin (Coordinator)2 Iolanda Enea(Coordinator)3 Michele Massimo Gulizia FACC FESC (Coordinator)4 WalterAgeno5 Piergiuseppe Agostoni6 Michele Azzarito7 Cecilia Becattini8 AmedeoBongarzoni9 Francesca Bux10 Franco Casazza11 Nicoletta Corrieri12 MicheleDrsquoAlto13 Nicola DrsquoAmato10 Andrea Maria DrsquoArmini14 Maria Grazia De Natale8Giovanni Di Minno15 Giuseppe Favretto16 Lucia Filippi17 Valentina Grazioli14Gualtiero Palareti18 Raffaele Pesavento17 Loris Roncon19 Laura Scelsi20Antonella Tufano15

1Department of Cardiology Cardiologia Ospedaliera University General Hospital Azienda Ospedaliero-UniversitariaConsorziale Policlinico di Bari Piazza G Cesare 11 70124 Bari Italy2Department of Cardiology Presidio Ospedaliero Rovigo Italy3Emergency Care Department Anna e S Sebastiano Hospital Caserta Italy4Cardiology Department Garibaldi Nesima Hospital Azienda di Rilievo Nazionale e Alta SpecializzazioneldquoGaribaldirdquo Catania Italy5Department of Clinical and Experimental Medicine University of Insubria Varese Italy6Monzino Cardiology Center IRCCS Milan Italy7Cardiolgy Unit Hospital San Carlo di Nancy Rome Italy8Department of Internal and Vascular Medicine Perugia General Hospital Perugia Italy9Cardiology Department San Carlo Borromeo Hospital Milan Italy10 Coronary Care Unit Department of Cardiology Di Venere ASL Hospital Bari Italy11Moscati Foundation Buccinasco Milan Italy12Department of Clinical Sciences and Community University of Milan Milan Italy13Cardiology SUN Department Colli and Monaldi Hospital Naples Italy14Cardio-Thoracic Surgery Department University of Pavia IRCCS Foundation San Matteo General Hospital Pavia Italy15Coagulopathies Center lsquoFederico IIrsquo University Naples Italy16Cardiac Rehabilitation and Preventive Unit High Specialization Rehabilitation Hospital Motta di LivenzaTreviso Italy17Thoracic and Vascular Department University of Padova Cardiological Sciences Padova Italy18Angiology and Blood Coagulation Unit S Orsola-Malpighi General Hospital University of Bologna Bologna Italy19Cardiology Department S Maria della Misericordia Hospital Rovigo Italy and20Department of Cardiology University of Pavia IRCCS Foundation San Matteo General Hospital Pavia Italy

Revised by Marino Scherillo Federico Nardi Antonio Francesco Amico FurioColivicchi

Consensus Document Approval Faculty in Appendix

Corresponding author Tel thorn39 080 5015272 Fax thorn39 080 5219894Email carlodagostinopoliclinicobait

VC The Author 2017 Published on behalf of the European Society of CardiologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorglicensesby-nc40) which permits non-commercial re-use distribution and reproduction in any mediumprovided the original work is properly cited For commercial re-use please contact journalspermissionsoupcom

European Heart Journal Supplements (2017) 19 (Supplement D) D309ndashD332The Heart of the Matterdoi101093eurheartjsux030

KEYWORDSPulmonary embolism

Venous thromboembolism

Deep vein thrombosis

Prognosis

Treatment

Consensus document

Venous thromboembolism (VTE) including pulmonary embolism and deep venousthrombosis is the third most common cause of cardiovascular death The manage-ment of the acute phase of VTE has already been described in several guidelinesHowever the management of the follow-up (FU) of these patients has been poorlydefined This consensus document created by the Italian cardiologists wants toclarify this issue using the currently available evidence in VTE Clinical and instru-mental data acquired during the acute phase of the disease are the cornerstone forplanning the FU Acquired or congenital thrombophilic disorders could be identifiedin apparently unprovoked VTE during the FU In other cases an occult cancer couldbe discovered after a VTE The main targets of the post-acute management are toprevent recurrence of VTE and to identify the patients who can develop a chronicthromboembolic pulmonary hypertension Knowledge of pathophysiology and thera-peutic approaches is fundamental to decide the most appropriate long-term treat-ment Moreover prognostic stratification during the FU should be constantlyupdated on the basis of the new evidence acquired Currently the cornerstone ofVTE treatment is represented by both the oral and the parenteral anticoagulationNovel oral anticoagulants should be an interesting alternative in the long-termtreatment

Table of contents

AbstractEpidemiology and pathophysiologyResults of recordsType and timing of follow-up

Biochemical markers and thrombophiliaBiochemical markersThrombophilia

EchocardiographyLung scan computed tomography scan and magneticresonanceRight heart catheterization and haemodynamicevaluationFunctional test The 6-min walking test and cardiopulmonary exercise testingEvaluation of post-thrombotic syndromeResidual venous thrombosis of the lower limbsResidual thrombosis of the pulmonary arteries

Co-morbidity cancer and autoimmune diseasesCancerAutoimmune disease

Overview of medical and surgical therapyAnticoagulants and antiplatelet drugs (traditionaltherapy)AnticoagulantsParenteral anticoagulation low-molecular-weightheparinAntiplatelet agentsNew oral anticoagulants for extended treatmentDuration of the treatment

Venous filters (inferior vena cava)Elastic compression stockingsSurgical treatment of chronic thromboembolicpulmonary hypertensionPharmacological treatment of chronic thromboembolicpulmonary hypertension

Special issues clinical and outpatients managementFuture developments and conclusionsAppendix algorithms

Epidemiology and pathophysiology

Venous thromboembolism (VTE) including pulmonaryembolism (PE) and deep venous thrombosis (DVT) is thethird most common cause of cardiovascular death par-ticularly PE is often difficult to define because it can bepresent with a wide spectrum of symptoms indeed itmay remain asymptomatic or sometimes its diagnosismay be incidental Moreover in over 30 of cases sud-den death may be the first presentation of PE and morethan half of the deaths caused by PE remain undiag-nosed during life

Currently medical decision-making is increasingly sup-ported by International Guidelines1 which are often peri-odically updated and nationwide contextualized23

However these recommendations are in most of the casesprimarily addressed to the treatment of the acute phase ofthe disease lacking a scientific contribution dedicated tothe post-acute phase Also the 2014 European Guidelineson PE1 as pointed out by Rugolotto and Favretto4 in arecent editorial lsquodoes not offer specific guidance on followup and long termmanagement of PErsquo

The relevance of long-term follow-up (FU) could bededuced by a recent Danish survey which enrolled a pop-ulation of 120 000 cases of confirmed VTE between 1980and 2011 The authors reported that these patients wereat increased risk of death during the first year after diag-nosis and the elevated risk persisted during the 30 yearsof FU While 30 day mortality after DVT remained con-stant over that period it markedly improved for PE5

According to the authors individual counselling aimedat tailoring the therapy and intervening on the risk

D310 C DrsquoAgostino et al

factors reduces the recurrence of VTE thereby prevent-ing related deaths

It has been reported that about half of the patientsbetween 6months and 3 years following the acute PE epi-sode referred subjective dyspnoea andor reduced exer-cise tolerance these symptoms have been objectivelyconfirmed by the 6-min walk test (6MWT) and are fre-quently related to higher pulmonary arterial pressure (PAP)and right ventricle (RV) dysfunction6 Exertional dyspnoeais a frequent symptom in the long-term clinical course ofacute PE However in several cases this symptom is likelyto be unrelated to the past thromboembolic event becausethese patients often suffer from several cardiopulmonaryco-morbidities and risk factors such as older age obesityand smoking habits which could also be considered asindependent predictors of VTE7

Actually the role of the lsquodiagnostic delayrsquo which is theperiod between the onset of symptoms and PE diagnosistreatment remains unknown8 At discharge the prognos-tic stratification performed in the acute phase should bereformulated considering both the gravity and the PEextension besides the associated co-morbiditiesFurthermore it is essential to obtain definitive informationabout the presence or persistence of deep vein thrombosis(DVT) haemodynamic instability right ventricular dilata-tion and inherited thrombophilia

These data are useful to plan a lsquopersonalized man-agementrsquo of the patients choosing the more appropriatetreatment9 The aim is to avoid recurrent PE and bleedingevents Moreover this approach allows the early recogni-tion of pulmonary arterial hypertension (PAH) and post-thrombotic syndrome (PTS) With this background ourclinical group has decided to fill the gap regarding theman-agement of VTE FU proposing the possible therapeutic anddiagnostic approaches Indeed to our best knowledge thisissue has been neglected to date

Results of records

In medical practice the VTE FU generally ends with the dis-continuation of anticoagulant therapy however it isknown that after the acute phase the patientrsquos clinicalcourse could be complicated by several and serious adverseevents Moreover in some cases these complications mayalso occur during anticoagulant treatment Recurrent VTEchronic thromboembolic pulmonary hypertension (CTPEH)and arterial thrombotic events are some of the possiblecomplications which are all related with a higher risk ofdeath1011

To clarify the management of VTE FU last internationalregistry on PE andor DVT may be useful to understand theproblem giving also some suggestions about the mostappropriate clinical management

To date only four prospective registries have consideredthe FU of VTE

bull International Cooperative Pulmonary EmbolismRegistry (ICOPER)12

bull Italian Pulmonary Embolism Registry (IPER)13 whichincluded only patients with PE

bull Registro de Informatizado Enfermedad thromboem-bolic (RIETE)14 and

bull MASTER15

ICOPER is an international registry that included 2454consecutive PE patients enrolled in 52 hospitals in 6 differ-ent countries between January 1995 and November 1996Inclusion criteria were

bull PE (asymptomatic or symptomatic) diagnosed within31 days from symptoms onset and

bull PE diagnosed at autopsy

PE diagnosis was done by the physicians of the recruitercentres without an independent revaluation At admission2182 patients (889) were symptomatic and haemody-namically stable 103 (42) were haemodynamicallyunstable and 169 (69) asymptomatic The mean age ofthe population was 623years 63 of the patients wereolder than 60years of ageThe aim of the registry was to evaluate the 3months

mortality rate FU was completed by 98 of patientsThree months mortality was 175 Note that 451 ofdeaths were attributable to PE 176 to cancer 118 tosudden death 118 from respiratory distress 25 to ableeding event 25 to a stroke 13 to acute coronarysyndrome and 73 to other causes PE recurrence after3months was 79 Mortality rates were 337 and 468after 14 days and 3months respectivelyStatistical analysis revealed that age gt70years cancer

chronic obstructive pulmonary disease heart failure (HF)systolic blood pressure lt90mmHg respiratory rate gt20min and a hypokinesia of the RVat presentation were inde-pendent predictors of deathIPER is a multicentric web-based prospective Italian

registry including patients with confirmed PE enrolled in49 Italian centres (58 cardiology departments and 42internal medicine department) The aim of the registrywas to

bull describe the demographic and clinical characteristicsof patients with PE

bull describe the strategies used for the diagnosis progno-sis and therapy and

bull prospectively collect data on clinical course duringboth the hospital phase and the FU

Patients were enrolled between August 2006 andAugust 2010 The 4-year FU ended in August 2014 In par-ticular the registry enrolled 1716 patients (mean age706 15 years 43 men) In-hospital mortality rate was68 The mortality rate between discharge and12months FU was 128 Of the 1600 patients who sur-vived hospital admission FU data after 12months wereobtained for 656 patients (41 of survivors mean age of696 15 years 42 men) Risk factors statistically associ-ated with higher risk of death were age cancer cancerdiagnosed during hospitalization and underweightMortality in patients with provoked and unprovoked PEwas statistically significant (161 vs 3 Plt0001) Inpatients with provoked PE death was generally due to

Long-term follow-up of patients with pulmonary thromboembolism D311

cancer while in unprovoked PE death was due to athero-sclerotic events

In conclusion short-term outcome was related to thehaemodynamic stability at admission Furthermore theshort- and long-term survival were related to the pres-enceabsence of co-morbidities

Riete is a prospective web-based multicentre interna-tional registry Enrolment is still ongoing Riete registryincludes patients with VTE (DVT PE or DVTthorn PE) with theaim of recording data during both the acute phase and theFU In particular it has enrolled patients with symptomaticand objectively confirmed VTE Diagnosis of DVTwas per-formed by venography ultrasound or venous impedanceplethysmography PE was confirmed with pulmonaryangiography lung scan and computed tomography (CT)angiography The patients were treated according to thebest practice of each recruiter centre FU was planned forat least 3months after the acute event but no limit on theduration was recommended in the protocol Among the14391 patients enrolled in 2006 2945 (20) had an activecancer these patients had in the first 3months a higherrate of fatal PE and fatal bleeding in comparison with thepatients without cancer (26 vs 1 and 14 vs 03respectively) Chronic kidney disease metastases recentmajor bleeding and immobilization were the independentrisk factors for fatal PE or bleeding events A lower mortal-ity rate for obese patients was observed although not astatistical difference in PE recurrence Renal insufficiencywas related to a higher level of fatal EP and bleeding butaccording to the authors the higher risk of PE justifies theanticoagulation therapy

Riete registry analyse also the VTE in pregnant womenIn particular 40 of VTE occurred during the first trimestersuggesting that when indicated prophylaxis should be ini-tiated as soon as possible No bleeding events werereported before childbirth however after that the risk ofmajor bleeding was greater than the risk of recurrent PE(56 vs 14)

The authors of the Riete registry have compared the roleof Pulmonary Embolism Severity Index (PESI) with theSimplified Pulmonary Embolism Severity Index (sPESI)reporting no differences between the two scores

MASTER is a web-based prospective multicentre Italianregistry that included 2119 patients with confirmed VTE(1541 DVT 206 PE and 372 DVTthornPE) with a 24month FUThe aim of the study was to collect data on the patientrsquosclinical management Almost all enrolled subjects receivedanticoagulation for at least 6months

Mortality data obtained in 2021 (954) patients showeda mortality rate of 45 143 in unprovoked VTE 203 incancer patients and 17 in patients with transient riskfactors Cancer [hazard ratio (HR) 72]medical treatmentwith heparin (HR 25) in-hospital treatment of VTE (HR20) ileo-caval thrombosis (HR 17) were independentpredictors of death Conversely the use of compressionstockings was associated with a low risk of death (HR 06)Note that there were no differences regardingmortality inpatients with PE and DVT In the 1988 (938) patients fol-lowed for recurrence 124 (363) patients had at least onerecurrent VTE 101 (815) DVT and 23 (185) PEFrequency of recurrent VTE in patients with previous

unprovoked or provoked PE were 45 and 26 respec-tively Rates of recurrent VTE in cancer patients was 26Patients with a first episode of DVT had a recurrent DVT in60 and a PE in 06 Male gender and cancer were inde-pendent predictors of recurrent VTE (HR 17 and 16respectively) Conversely the presence of transient throm-boembolic risk factors was associated with a lower inci-dence of events (HR 04) Statistically significant was themortality rates of patients with recurrent VTE comparedwith those without recurrence (165 vs 42 Plt0001)Data regarding bleeding events PTS cancer and arterialthrombosis were obtained in 1883 patients with bleedingoccurring in 17 of patients treated with heparin and 27using vitamin K antagonists (VKAs) [odds ratio (OR) 06]The incidence ofmajor bleeding events was 25 in partic-ular 55 in patients with known or occult cancer and 18in patients without cancer The incidence of PTS was 97(182 of 1883) in this case patients with and without can-cer were 25 and 59 respectively Cancer was found in13 of patients during the FU while atherothromboticcomplications occurred in 11 (20 of 1883)

Type and timing of follow-up

Previous results and daily clinical experience suggest thatthe main objectives to be pursued during the VTE FU couldbe summarized as follows

bull assess the global cardiovascular riskbull define the anticoagulation therapy and its durationbull assess the risk of bleedingbull early recognition of complications (recurrent VTE)bull identify patients with CTPEH [WHO Group 4 of pulmo-

nary hypertension (PH)]bull evaluate the possibility of PTS of the lower limbs and

or DVT andbull identify as soon as possible the presence of an

unknown cancer or a prothrombotic condition

To perform a correct FU it is necessary to identify theuseful tools and the correct timing

Biochemical markers and thrombophiliaBiochemical markersThe duration of anticoagulation as described in followingparts of this document must be planned on the basis of sev-eral factors mainly for the risk of recurrence of VTE andthe risk of bleeding

D-dimer test assessment may be useful because it isable to discriminate patients at low risk (lt5 per year) inwhich the anticoagulation could be suspended Two recentmeta-analyses1617 have confirmed that elevated D-dimerlevels after 1month from anticoagulation withdrawal areassociated with a significantly increased risk of recurrentVTE Two scores have been proposed to assess the individ-ual risk of VTE recurrence and both include the result ofthe assessment of D-dimer after 1month of treatment dis-continuation18ndash20 More recently another study has shownthat the serial D-dimer assessment performed during the3months after the withdrawal of anticoagulant therapycould be useful to identify those subjects with very low risk


of VTE recurrence It is recommended to assess theD-dimer serially in the first 3months after withdrawal ofanticoagulation a normal persistent result could allow tofinally stop anticoagulation that on the contrary must becontinued in patients with persistent elevation

ThrombophiliaVenous thromboembolism is considered to be a conse-quence of the interaction between patient-related usuallypermanent risk factors and setting-related usually tem-porary risk factors Generally VTE is considered to be lsquopro-vokedrsquo in the presence of a reversible risk factor (surgerytrauma immobilization pregnancy oral contraceptiveuse or hormone replacement therapy) within the last6weeks to 3months before the acute event The presenceof persistent as opposed to major temporary risk factorsis fundamental for the choice of the duration of anticoagu-lation therapy after a first episode Moreover the distinc-tion based on the aetiology influences also the risk ofrecurrent VTE Indeed recurrent rate is generally lower inprovoked compared with unprovoked VTE

Congenital thrombophilic abnormalities are labelled aspersistent factors It has been estimated that thrombo-philic abnormalities range from 5 to 10 in the generalpopulation A prevalence of 40 in patients with VTE hasbeen reported in literature However some thrombophilicabnormalities may be acquired during life (lupus anticoa-gulant and hyperhomocysteinaemia) Several evidenceconfirmed that thrombophilic mutations have a differentclinical penetrance In fact a higher thrombotic risk hasbeen reported in subjects with congenital deficit of proteinC or S or in the presence of one of the following defectshomozygous mutation of the factor V Leiden G 20210Amutation of the prothrombin or in case of double hetero-zygous or multiple defects The aforementioned mutationsare quite rare A higher prevalence has been reported forheterozygosity of factor V Leiden or prothrombin muta-tions However these subjects seems to be at lower risk21

In general the presence or absence of thrombophiliadoes not modify the therapeutic management during theacute phase of VTE Currently the influence of thrombo-philia on the duration of anticoagulant treatment is stilldebated At the samemanner whether it is useful or not toinvestigate thrombophilia in patients with VTE after theacute phase especially for VTE recurrence has not yetbeen clarified Some authors believe that there are no sig-nificant benefits in carrying out such investigations22ndash24

while others support them especially stressing that theincreased risk of recurrent VTE could be associated withthrombophilic defects2526 In general thrombophilicscreening must be recommended to those patients with apositive familiar history of VTE or recurrent disease

The tests to be performed are presented in Table 1The recommendation of the appropriate timing to carry

out the investigation are shown in Tables 1 and 2

EchocardiographyDuring the VTE FU is essential to identify those patientswith PAH Transthoracic echocardiography (TTE) maydetect RV pressure overload In these cases chronic

thromboembolic pulmonary hypertension (CTEPH) must beevaluated because this condition could be treatable withsurgery However it should be noted that there is a lack ofindication regarding

bull which patients must be submitted to echocardio-graphic FU

bull timing of TTEbull which echocardiographic parameters (and respective

cut-off) must be considered andbull further diagnostic tests in case of CTEPH

With regard to the first issue several prospective studiesaffirmed that is not reasonable to refer all survived PEpatients indiscriminately to serial echocardiographicexaminations2728 According to these authors it would behelpful to select the patients on the basis of clinical dataand symptomsIt seems reasonable that every patient with a diagnosis

of PE at intermediate risk receive an echocardiographicexamination In this way it is possible to obtain the correctprognostic assessment especially for those patients classi-fied as no high risk2

TTE should also be performed at discharge especially ifa right ventricular dysfunction (RVD) andor PAH have beenobserved during the acute phase Moreover in the pres-ence of the aforementioned abnormalities at discharge anechocardiographic FUmust be consideredSome considerations must be said about the timing for

TTE during the FU If echocardiographic abnormalities areassociated with moderate exertional dyspnoea the patientshould be re-evaluated clinically and by TTE within3months after discharge In the absence of symptoms TTEmay be performed between the 3rd and the 6th month(when also anticoagulant therapy could be discontinued)The persistence of echocardiographic signs suggestive ofPAH after 3months from the acute event must raise thesuspicion of a chronic condition In this case serial TTEevaluation must be performed on the basis of clinicalsymptoms29

Even though the gold standard for the evaluation of PAPis the right heart catheterization (RHC) an echocardio-graphic evaluations could give important information andremains the methodmost widely usedThe European Society of Cardiology in 2015 in the

lsquoguidelines for the diagnosis and treatment of pulmonaryhypertensionrsquo30 has suggested some echocardiographiccriteria for the estimation of the PAP based on tricuspidregurgitation velocity and the presence of other echo lsquoPHsignsrsquo to identify the probability of PH as low intermedi-ate or high31

In a 12month echocardiographic FU 286 patientsenrolled in the Italian IPER registry32 and evaluated with anechocardiogram within 24h have showed that an RVndashrightatrium (RA) gradient gt45mmHg during the FU (PAH likely)was present only in a small percentage of cases (2 of thetotal) and all these patients had an RVndashRA gradientgt45mmHg at baseline TTE In this group only 6 ofpatients maintained a gradient gt45mmHg during the FUNo patients without tricuspid insufficiency or an RVndashAD gra-dient 45mmHg at baseline TTE were classified as


probable PAH during the FU33 Moreover only 8 of casesduring the FU had TTE findings compatible with PAH allthese patients had been already identified at baseline Inthis study it has not been possible to obtain the confirma-tion of PAPs with cardiac catheterization in the majority ofsuspected cases However patients most severely compro-mised were stratified as PAH likely during the FU twopatients underwent pulmonary endarterectomy (PEA) andonewas treated with oxygen home therapy

Finally there is a unanimous consensus that a perfusionlung scan should always be performed if echocardiographicassessment is suggestive of intermediate or high probabil-ity of hypertension following a PE patient

Table 3 summarizes the recommendations for the execu-tion of TTE

Lung scan computed tomography scan andmagnetic resonanceMagnetic resonance imaging (MRI) has been rarely used inthe diagnosis of PE and has no use in the FU

Computed tomography especially for the high radiationburden is not feasible as a routine test for the FU in VTEdespite its predominant role in the diagnosis of the acutephase

Of greater importance in the FU of PE patients could bethe lung scintigraphy (LS) because it is able to evaluatelung perfusion and indirectly the overall pulmonaryembolic burden

The LS in clinical trials was generally performed by eval-uating both the lungs ventilation (V) and perfusion (Q)either by planar technique (VQ scan) or by tomographictechnique (VQ SPECT)

VQ SPECT seems to have a superior diagnostic perform-ance compared with planar VQ scintigraphy however nodirect comparisons between the techniques have been per-formed during PE FU

Meneveau et al34 demonstrated that residual pulmonaryvascular obstruction (RPVO) evaluated before hospital dis-charge in patients with intermediate- to high-risk PE was apowerful prognostic factor for a 6month outcomeMoreover RPVO 35 was associated with an increasedrisk of adverse events at 6months In fact at 6months 32patients (77) had at least one adverse event 12 deaths(29) 12 recurrent PE (29) and 14 (34) HFIndependent predictors of combined endpoint were cancer[OR 307 (122ndash785)] renal insufficiency at admission[OR 253 (117ndash58)] persistent signs of RVD at 48h echog-raphy [OR 399 (136ndash113)] The severity of RPVO at dis-charge was significantly associated with an unfavourableoutcome [OR 266 (158ndash393)] Note that patients withRPVO greater than threshold at discharge had a signifi-cantly higher risk of death at 6months (Pfrac14 001)

Begic et al35 evaluate through serial VQ SPECTexamina-tions over a 6month period The treating pulmonologistdecided to terminate therapy in 35 (73) patients and tocontinue anticoagulant (AC) in 13 patients because of persis-tent risk factors Six months later at the second controlstage 53 (82) patients had complete recovery of pulmo-nary perfusion Eleven patients still had perfusion defects at6months No recurrence was identified at 6months in the 35patients whose therapy was terminated after 3months Nobleeding effects were observed in any of the patients duringthe 6month FU The authors assessed that anticoagulanttherapy can be tailored by using VQ SPECT Normalizationof perfusion at 3months of initial PE diagnosis was a reliableindicator that the treatment could be safely withdrawn inpatients whowerewithout hypercoagulability risk

Stein et al36 retrospectively assessed the rate of resolu-tion of pulmonary emboli in individual vessels and the rateof complete resolution of PE on CTangiography In particu-lar complete CTangiographic resolution of PE was seen in 6of 15 patients (40) 2ndash7 days after diagnostic imagingAfter Day 28 complete resolution occurred in 17 of 21patients (81) On the contrary Miniati et al37 prospec-tively evaluated 834 consecutive patients with a scinti-graphic FU in order to evaluate the restoration ofpulmonary perfusion over a 1-year period Complete reso-lution of PE by lung scanning was observed in 65 ofpatients after 1 year A lower rate of normalization wasobserved by Wartski et al38 (34) In a prospective seriesof 254 patients with confirmed PE Sanchez et al39

Table 2 When thrombophilic tests must be performed

bull Evaluation of hypercoagulable state may be performed atany time independently from the anticoagulationtreatment

bull Evaluation of protein C and S which are vitamin K-dependent factors should not be performed during thetreatment with vitamin K antagonists

bull Evaluation of thrombophilic defects should not be per-formed during the treatment with the new oralanticoagulants

bull Pregnancy modifies the levels of protein C and protein S(higher and lower levels respectively)

The tests should NOT be routinely performedbull During the acute phase of venous thromboembolism (possi-

ble consumption of physiological anticoagulants factors)bull During anticoagulant therapybull During pregnancyTests are usually performedbull After 3months form the acute eventbull After permanent or temporary suspension of anticoagulant

treatments (after 15 days and 48 h for vitamin K antago-nists and new oral anticoagulantsheparin respectively)

Partial screening should be avoided

Table 1 Thrombophilic tests

Dosing Searching

Antithrombin Factor V LeidenProtein C G20210A mutationProtein S Lupus anticoagulantHomocysteinaemiaAntiphospholipids antibodies(anti-cardiolipine and anti-beta-2 glycoprotein-1)


highlighted with VQ scan that 29 of subjects had perfu-sion defects during FU (median 12months) and were morelikely to have dyspnoea higher systolic PAP and walked ashorter distance during the 6MWT Nijkeuter et al40

described that the percentage of patients with residualpulmonary thrombi was 87 at 8 days after diagnosis 68after 6weeks 65 after 3months 57 after 6months and52 after 11months

Alhadad et al41 identified that patients with persistentperfusion defects at the FU SPECT have a high risk of PErecurrence In particular 16 had recurrent PE and ofthese 34 (92) showed residual perfusion defects at thesecond VP SPECT

Den Exter et al42 in their prospective multicentre studyanalysed 157 patients with acute PE and evaluated the rou-tine use of FU CT pulmonary angiography (CTPA) imagingAfter 6months of treatment complete PE resolutionoccurred in 841 of the patients [95 confidence interval(CI) 774ndash894] During FU 16 (102) patients experi-enced recurrent VTE However the presence of residualthromboembolic obstruction resulted not associated withrecurrent VTE (adjusted HR 092 95 CI 02ndash41) Thesefindings confirmed that the routine use of FU CTPA imagingin patients treated for acute PE is not useful in clinicalpractice Interesting results will come from the Italianstudy SCOPE 2 (Study on the clinical Course Of PulmonaryEmbolism) realized by Raffaele Pesavento and PaoloPrandoni These researchers are searching for a possiblecorrelation between embolic residual (evaluated with per-fusion scans after six months from the acute event) and thedevelopment of symptomatic recurrent PE andor CTPEH

Table 4 summarizes the recommendations for MRI CTand LS

Right heart catheterization and haemodynamicevaluationDespite recent progress in imaging techniques RHC43ndash45 isrequired to confirm the diagnosis of PAH and CTEPH toassess the severity of haemodynamic impairment toundertake vasoreactivity testing of the pulmonary circula-tion in selected patients and to support treatmentdecisions46 Despite clinical symptoms and signs are non-specific or absent in early CTEPH those patients that

during FU developed clinical symptoms compatible withPAH must be evaluated Diagnosis of CTEPH is based on thefindings obtained after at least 3months of effective anti-coagulation in order to discriminate this condition fromlsquosubacutersquo PEFor the diagnosis of CTEPH mean pulmonary arterial

pressure (mPAP) must be 25mmHg with pulmonaryartery wedge pressure (PAWP) 15mmHg and the pulmo-nary vascular resistance (PVR)3Wood units (WU) in addi-tion at least one (segmental) perfusion defect detected byperfusion lung scan or pulmonary artery (PA) obstructionseen by CTangiographymust be present (Table 5)30

Digital subtraction pulmonary angiography is used todefine the extension and distribution of the thromboem-bolic disease highlighting the features of angiographicsigns47

Contrast volume used during angiography should be tail-ored on the basis of the patientrsquos weight and cardiac out-put in order to obtain excellent images minimizing the riskof contrast-induced nephropathy It must be consideredthat poor subpleural perfusion in the capillary phase of pul-monary angiography might be related to small vessel dis-ease and a poor surgical outcome of CTEPH48 Theoperability of patients with CTEPH is determined by multi-ple factors that cannot easily be standardized these arerelated to the suitability of the patient the expertise ofthe surgical team and available resources Coronaryangiography may be required in the presence of anginarisk factors for coronary artery disease and listing forPEA43

Both the extent of proximal occlusion of PAs and secon-dary small-vessel arteriopathy contribute to the elevatedpulmonary vascular resistance High pressure high shearstress inflammation and an imbalance of vasoactivemediators result in vascular remodelling including the for-mation of plexiform lesions49 Finally the presence of highpulmonary vascular resistance compared with the degreeof vascular obstruction is an indirect sign of high operativerisk and in some cases of inoperability (small vessel dis-ease)50 Indeed postoperative pulmonary vascular resist-ance predicted in-hospital and 1-year mortality The lastESC guidelines31 on PAH recommended that pulmonary vas-oreactivity testing for identification of patients suitablefor high-dose calcium channel blocker treatment is recom-mended only for patients with idiopathic PAH heritablePAH or drug-induced PAH It should be performed at thetime of RHC On the contrary some authors verified that

Table 3 Recommendations for TTE

Transthoracic echocardiography (TTE) is useful to assess thepresence of pulmonary arterial hypertension (PAH)However the gold standard technique remains the cardiaccatheterization

TTE should always be performed at discharge to evaluatePAH and if present FU at 3 and 6months must beconsidered

TTE follow-up should be considered only for those patientswith a right ventriclendashright atrium (RVndashRA) gradientgt45mmHg or in the presence of both dyspnoea and a RVndashRA gradient ranging between 32 and 45mmHg atdischarge

Table 4 Recommendations for magnetic resonance imagingcomputed tomography and lung scintigraphy

Lung perfusion scan must be performed 3months after theacute event in those patients with persisting symptomsandor in the presence of right ventricular dysfunction orpulmonary artery hypertension

Computed tomography is not useful to redefine therapeuticstrategies during the follow-up

Pulmonary RMI is not useful during venous thromboembolismfollow-up

MRI magnetic resonance imaging


acute vasoreactivity identifies CTEPH patients prone todevelop persistentrecurrent PH after PEA51

Functional test the 6-minute walking test andcardiopulmonary exercise testingAfter the acute phase of PE patients can be divided intothree different groups patients with complete resolutionof the thrombus with chronic thromboembolism withoutPAH and with chronic thromboembolism associated withCTPEH (Group IV of OMS classification of PH) The lattergroup represents the 38 of all acute PE5253 Diagnosis inthese patients must be performed as soon as possibleHowever the assessment of this condition with non-invasive tests nowadays remains a challenging issueMoreover most part of scientific evidences have posedtheir attention on the role of different functional tests inthe prognosis stratification but not during the FU of PE

The common pathophysiological basis as well as themicrovascular inflammatory remodelling as stated in theEuropean guidelines could allow to transfer the interpreta-tion of the test utilized in the PAH also in the CTEPH3154

Pulmonary hypertension is likely to persist as well afterPEA in patients with significant small-vessel arteriopathyresulting in poor clinical outcome and increased periopera-tive mortality The 6MWT remains the most widely usedexercise test in PH centres Indeed it is easy to performinexpensive and familiar to patients and centres

The assessment of functional capacity by cardiopulmo-nary exercise testing (CPET) seems to be more completebecause CPET allows a discrimination between the meta-bolic cardiovascular and pulmonary components of exer-cise limitation Moreover CPET estimates the severity ofdisease and assesses patientsrsquo prognosis and response totherapy55

Despite there are no definitive data on the use of func-tional tests in the PE FU we suggest that both tests can beused in CTEPH as in PAH patients symptoms and the patientrsquosfunctional status must be the main determinant in the clini-cal decision-making regarding both the most appropriatetherapeutic timing and instrumental strategy Table 656ndash60

Evaluation of post-thrombotic syndromePost-thrombotic syndrome is a problem that can develop innearly half of all patients who experience a DVT in the legMost common symptoms are oedema (typically pronouncedat the end of the day or after prolonged standing andorwalking) pain hyper-pigmentation and skin ulcersAlthough recommended by guidelines appropriate DVTprophylaxis remains considerably underused Increasingthe awareness of PTS and the methods to prevent this com-plication may help reduce its incidence improve long-termoutcomes in patients and decrease resulting costs associ-ated with treatment61ndash64 It is estimated that the quality oflife is worse compared with patients with other chronic dis-eases65 In a prospective study of 387 patients whoreceived an objective diagnosis of acute symptomatic DVTabout half of the cases have developed PTS Severe PTSwas registered in only 2 of patients66 Some studies reportthat the cumulative incidence of PTS continues to increasealso after 2 years up to 10 to 20 years from the acuteepisode6768

Pathogenesis and risk factors In the pathogenesis of PTSa central role is played by the increase in pressure in thelower limb venous system determined by two factors

(1) Venous valvular damage and persistent luminalobstruction

(2) after DVT recanalization of the thrombosed veinsis often incomplete6465 Indeed as demonstratedby Prandoni et al6768 the lack of recanalizationwithin the first 6months after the thrombotic epi-sode is an important predictor of PTS while thedevelopment of trans-popliteal venous reflux isnot

It must also be considered that a significant associationbetweenmarkers of inflammation such as IL-6 and ICAM-1and the development of PTS exists6970

A number of clinical tools or scales have been used tohelp diagnose and define PTS Of these three were devel-oped specifically to diagnose PTS after objectively diag-nosed DVT the Villalta scale Ginsberg measure andBrandjes scale The others developed for chronic venousdisease in general include the CEAP (clinical aetiologicalanatomic pathophysiological) classification VenousClinical Severity Score (VCSS) and Widmer scale TheVillalta scale has beenwidely and successfully used to diag-nose PTS to classify its severity and to evaluate treat-ment including in randomized controlled trials (RCTs)CEAP is not an ideal scoring system to diagnose and FU thecourse of PTS7172

Risk factors for developing PTS are older age elevatedbody mass index and obesity6263666769 Recurrent ipsilat-eral DVT has been shown in numerous studies to be animportant risk factor for PTS The variability in the magni-tude of effect across studies (ORs 16ndash10) is probablyattributable to differences in study populations and defini-tions of PTS However all are consistent in showing ipsilat-eral recurrence to be predictive of future PTS73

Prevention and treatment of PTS Because PTS is a con-sequence of DVT and thromboprophylaxis is an effectivemeans of preventing DVT it is clear that use of pharmaco-logical or mechanical thromboprophylaxis in high-risk

Table 5 Right heart catheterization in chronic thromboem-bolic pulmonary hypertension

Haemodynamic parametersmPAP 25mmHgPAWP 15mmHgPVR gt 3 WU

Pulmonary angiographyPulmonary arteries dilatationVascular obstructionVascular websPost-obstructive dilatationPulmonary areas of reduced perfusion

mPAP mean pulmonary arterial pressure PAWP pulmonary arterywedge pressure PVR pulmonary vascular resistance WU Woodsunits


patients and settings as recommended in evidence-basedconsensus guidelines will prevent cases of PTS Recently aScientific Statement from the American Heart Association(AHA) on PTS has evidenced that the use of thrombopro-phylaxis in patients at significant risk for DVT is recom-mended as a means of preventing PTS (Class I Level ofEvidence C)63 Moreover anticoagulation of appropriateintensity and duration for treatment of the initial DVT isrecommended as a means of reducing the risk of recurrentipsilateral DVT and consequent PTS (Class I Level ofEvidence B) Surgical thrombectomy might be consideredin selected patients with extensive acute proximal DVTwho are not candidates for anticoagulation because ofbleeding risk657475

Graduated stockings (GS) intermittent compressionand medical treatment are the cornerstone in the treat-ment of PTS65

Two small randomized trials comprising a total of 115patients have evaluated the ability of 30ndash40mmHg GS toreduce symptoms in patients with PTS7677 AmericanCollege of Chest Physicians (ACCP) recommended (Grade2B recommendation) GS in acute symptomatic DVT9 whilealthough more recently the SOX study has demonstratedthat GS did not prevent PTS after a first proximal DVT78

The aforementioned AHA Scientific Statement AHA recom-mends the use of GS (Grade IIB) despite the methodologi-cal limitations and statistical imprecision that precludeconfident conclusions about their effectiveness in patientswith PTS6578

Objective risk stratification of PTS using colour Dopplerultrasound for evaluating recanalization and reflux and D-dimer testing must be an integral part in routine clinicalpractice to assess the optimal duration of wearing medicalelastic stockings and anticoagulation for the preventionDVT recurrence as the best option to reduce the incidenceand costs of suffering from irreversible PTS Palaretiet al79 have evaluated the predictive value of D-dimer forthe risk of VTE recurrence after oral anticoagulant therapy(OAT) withdrawal The main result of the study was thatD-dimer has a high negative prognostic value for VTE recur-rence when performed after OAT discontinuation79ndash82

Conversely Latella et al83 showed that D-dimer levelsmeasured 4months after DVT in patients not on warfarinare associated with subsequent development of PTSDifferent results were presented in the PROLONG studywhich concluded that patients with an abnormal D-dimerlevel 1month after the discontinuation of anticoagulationhave a significant incidence of recurrent VTE which is

reduced by the resumption of anticoagulation82 Otherimportant suggestions have been provided by the CFCAguidelines20 Indeed authors recommended a prolongedanticoagulation in patients with idiopathic venous throm-boembolic especially in the case of recurrent episodes oractive malignancy Based on persistently normal D-dimertests anticoagulation could be stopped in gt50 of thepatients included after a single idiopathic VTE or associ-ated with sodiumwarfarins (Table 7)84

Residual venous thrombosis of the lower limbsDifferent Italian studies have demonstrated that residualvenous thrombosis is an important risk factor for recurrentthromboembolism Ultrasonographic assessment of resid-ual venous thrombosis may help clinicians to modify theduration of anticoagulation in patients with DVT8586 Thehazard ratio for recurrent thromboembolism was 24 (95CI 13ndash44 Pfrac14 0004) for patients with persistent residualthrombosis vs those with early vein recanalizationSubsequent randomized studies have suggested that tailor-ing the duration of anticoagulation on the basis of ultraso-nography findings reduces the rate of recurrent VTE inadults with proximal DVT8788 However a recent meta-analysis has evidenced that residual venous obstruction(RVO) was independently associated with recurrent VTE(HRfrac14 132 95 CI 106ndash165) The association was stron-ger if RVO was detected early ie at 3months after DVT(HRfrac14 217 95 CI 111ndash425) but non-significant ifdetected later ie gt6months (HRfrac14 119 95 CI 087ndash161)89 The studies reviewed were heterogeneous not onlyin the timing of the ultrasound evaluation but also in thedefinition of residual thrombusThe measurement of residual vein diameter as the main

characteristic for diagnosing an ipsilateral recurrent DVTin a previously abnormal segment must be performed Wesuggest evaluation of the increase in residual vein diameterin popliteal and femoral veins If the vein diameter isgt4mm the patient should be treated for a recurrent ipsi-lateral proximal DVT if 2ndash4mm we recommend that ultra-sonography with simplified compression be repeated after7 days and that treatment be initiated if the diameter isgt4mm at this time if lt2mm we suggest further imagingtest at 7 days only in patients with a high clinical probabil-ity of recurrence90

Residual thrombosis of the pulmonary arteriesAs previously mentioned we suggest that CTPA or lung scanshould not be routinely performed in all patients with a

Table 6 Timing of clinical evaluation and functional test in patients with chronic thromboembolic pulmonary hypertension

At baseline Every 3ndash6months In case of change intherapy or after PEA

In case of clinicalworsening

Clinical assessment and functional class

6MWT

CPET

6MWT 6-min walking test CPET cardiopulmonary exercise testing PEA pulmonary endarterectomy


previous episode of PE for the research of residual throm-bosis of the PAs because of its lack of prognostic and thera-peutic information However it may be considered in thosethought to be at high risk for recurrence91

Co-morbidity cancer and autoimmunediseases

CancerAn association between VTE and cancer has been previ-ously suggested the overall risk of VTE in cancer patients isfour times as great as in the general populationSometimes malignancy could be the first and only clinicalpresentation of VTE Tumour cells can express everythingrequired for regulation of the fibrinolytic pathway on theircell surface The expression of tissue factor on tumour cellsand the prothrombotic properties of mucins contribute tothe thrombosis risk in malignancy In addition there is evi-dence that tissue factor expression which may result fromproto-oncogene expression and tumour suppressor geneinhibition confers a pro-angiogenic state which mayenhance the aggressiveness and invasiveness of cancer100

Indeed tumour cells are known to carry the specific PAreceptors (u-PAR) on their membranes which can facilitatethe activation of the fibrinolytic system The prevalence ofpreviously undiagnosed cancer in patients with unprovokedVTE has been estimated in previous studies 61 (95 CI50ndash71) at baseline and 100 (95 CI 86ndash113) frombaseline to 12months Moreover cancer is more prevalentin patients with bilateral DVT early VTE recurrence orvery high D-dimer92ndash97 After the first year the number ofdiagnoses is close to that of the general populationalthough some population studies show the persistence ofan increased risk of developing cancer

A systematic review of 15 studies published in 2008affirmed that previously undiagnosed cancer was frequentin patients with unprovoked VTE For this reason an exten-sive cancer screening strategy could be able to detectmore malignant conditions than a limited screening strat-egy does92 This strategy is fundamental to choose the cor-rect anticoagulant treatment in these patientsConversely the utility of screening for cancer in VTEpatients is controversial Routine screening with CT of theabdomen and pelvis did not provide a clinically significant

benefit in these patients Studies published until 2014designed to evaluate the efficacy of an extensive cancerscreening were characterized by methodological hetero-geneity and a relatively small number of subjects enrolledIn fact the largest study enrolled only 396 patients98ndash101

Previous studies have several limitations in particular thereal incidence between asymptomatic cancer at earlystages is very difficult to assess due to the retrospectivedesign of the studies

Further investigations for cancer have been suggested inthe 2012 NICE guidelines abdomino-pelvic CT scan (and amammogram for women) should be performed in allpatients aged over 40years with a first unprovoked DVT orPE who do not have signs or symptoms of cancer based oninitial investigation102 In the last Italian guidelines of ItalianAssociation of Medical Oncology published in 2015103

authors recommend to suspect an occult malignancy in allpatients with first idiopathic VTE and to perform in thesesubjects a routine screening on the basis of current clinicalpractice (Level of evidence D recommendation Positivelow) British Committee for Standards in Haematology(BCSH) affirmed that in patients aged above 40years withunprovoked VTE screening for cancer with CT scan (andmammography for women) should be considered but notroutinely performed (levels of recommendation 2C)100

Recently interesting data have been presented in TheScreening for Occult Malignancy in Patients with IdiopathicVenous Thromboembolism (SOME)104 This trial was amulti-centre open-label RCT comparing an extensive screeningcomprehensive CTof the abdomen and pelvis in addition tolimited occult-cancer screening vs limited occult-cancerscreening alone in patients with unprovoked VTE Patientsassigned to the limited screening strategy underwent acomplete history taking and physical examination meas-urement of complete blood counts and serum electrolyteand creatinine levels liver function testing and chestradiography Sex-specific screening was conducted if it hadnot been performed in the previous year A breast examina-tion mammography or both were performed in womenolder than 50years of age and Papanicolaou (Pap) testingand a pelvic examination were performed in women aged18ndash70 years who had ever been sexually active A prostateexamination prostate-specific antigen test or both wereperformed in men older than 40 years of age Patientsassigned to limited screening plus CT also underwent

Table 7 Recommendation for preventing post-thrombotic syndrome

It is mandatory to assess patient with deep vein thrombosis with both Villalta and CEAP scoring system after 1 3 6 and 12monthsAn accurate diagnosis of post-thrombotic syndrome can be made only after 3ndash6months after the acute eventAll patients who developed symptoms which not disappear at rest suggestive of venous thromboembolism during follow-up mustbe evaluated to exclude a deep vein thrombosis

Physician during venous thromboembolism follow-up must recommend to patientsbull Weight lossbull Compliance with anticoagulation treatmentbull International normalized ratio assessment during vitamin K antagonists treatmentbull Attention to new symptoms and eventually evaluate the presence of lung andor peripheral thrombotic residual


comprehensive CT of the abdomen and pelvis MoreoverCT included a virtual colonoscopy and gastroscopy biphasicenhanced CT of the liver parenchymal pancreatographyand uniphasic enhanced CT of the distended bladder Ofthe 854 patients in the intention-to-test population 33(39 95 CI 28ndash54) received a new diagnosis of cancerin the interval between randomization and the 1-year FUThe diagnosis of occult cancer between limited screeninggroup and limited screening plus CT was not statisticallydifferent Furthermore after the completion of the initialscreening the absolute rates of occult-cancer detectionwere 093 (95 CI 036ndash236) with the limited screeningstrategy and 118 (95 CI 051ndash274) with the strategy oflimited screening plus CT (absolute difference 025 per-centage points 95 CI112 to 163) Then after the com-pletion of the initial screening the absolute rates ofoccult-cancer detection were 093 (95 CI 036ndash236)with the limited screening strategy and 118 (95 CI051ndash274) with the strategy of limited screening plus CT(absolute difference 025 percentage points 95 CI112 to 163) These results confirmed that routinescreening with CT of the abdomen and pelvis did not pro-vide a clinically significant benefit in patients with a firstepisode of idiopathic VTE

Considering nuclear medicine techniques some studiesconfirmed that a diagnosis strategy based on positronemission tomographyndashCT screening for malignancy inpatients with unprovoked VTE had limited diagnosis valueand may lead to unnecessary alarming and money- andtime-consuming investigations105106

We suggest that screening strategy for occult-cancerwhich included clinical evaluation laboratory tests chestX-ray and comprehensive CTof the abdomen and pelvis inpatients who had a first unprovoked VTE should be consid-ered The decision to proceed with an extensive screeningshould be evaluated case by case

Autoimmune diseasesAutoimmune disorders such as systemic lupus erythematosus(SLE) inflammatory bowel disease (IBD) and Behcetrsquos syn-drome have been linked to an increased risk of VTE107ndash112

Moreover in recent years also patients with rheumatoidarthritis celiac disease hyperthyroidism and Wegenerrsquosgranulomatosis had an elevated risk for VTE113ndash116 The linkbetween autoimmune disorders and VTE have not been com-pletely clarified

However many studies have established the associationbetween inflammation and the hypercoagulable state orbetween inflammation and endothelial dysfunction inVTE117

It has been hypothesized that anti-protein S (anti-PS)antibodies independently of antiphospholipid antibodies(aPL) may play a role in the occurrence of PS deficiency insome patients with SLE with possible effects on the func-tion of PS that do not change the levels of PSantigens118119

Antiphospholipid antibodies in fact are commonlyfound in patients with autoimmune diseases It has beenestimated that immunoglobulin G anticardiolipin antibod-ies (aCLs) could be found in 33 of patients with SLE 17 in

systemic vasculitis 25 in thrombotic thrombocytopenicpurpura 24 in thyroid disease in haemolytic autoimmuneanemia and in 16 of patients with rheumatoidarthritis120ndash125 Thrombosis has been reported in about 10ndash26 of patients with SLE moreover these subjects had aVTE risk of three-fold higher respect than the normal pop-ulation126ndash132 On the contrary patients with other autoim-mune diseases such as trombocytopenic thromboticpurpura polyarteritis nodosa polymyositis and dermato-myositis had six-fold higher risk for VTE133 Currently thereis no conclusive evidence about routine screening of auto-immune disease during VTE Once again the InternationalSociety on Thrombosis and Haemostasis (ISTH) the BritishCommittee for Standards in Haematology (BCSH) and theClinical and Laboratory Standards Instituite (CLSI) haverecommended testing for aPL in patients with unprovokedproximal DVT or PE after stopping anticoagulation (for atleast 7 days) as the presence of aPL will influence the bal-ance of risks and benefits and support long-term anticoagu-lant therapy134ndash136

Overview of medical and surgical therapy

Anticoagulants and antiplatelet drugs (traditionaltherapy)AnticoagulantsAnticoagulation is themainstay of treatment for VTEConventionally anticoagulation therapy could be divided

into three phases

(1) An acute phase (conventionally the first 7 days)with the objective of limiting the extension ofthromboembolism and preventing early death andrecurrent symptomatic or fatal VTE

(2) A long-term phase in which prevention of new epi-sodes of VTE predominates

(3) An extended period (indefinite) in which anticoa-gulation is continued for over 3months without ascheduled stop date The indefinite anticoagulationshould be reserved to those patients with high riskof recurrence

At the end of the active phase of treatment therapeuticdecisions are based on patientrsquos risk factors (presence ofcancer obesity male and idiopathic VTE) previous clini-cal history (thrombotic or haemorrhagic disease in thepast provoked or unprovoked VTE) diagnostic assessment(thrombotic burden and persistence of RVD or PH) labora-tory markers (D-dimer or thrombophilic mutations)1189

and the balance between the risk of bleeding and theadvantage of preventing the recurrence of the VTE

Oral anticoagulation vitamin K antagonistsOral anticoagulation with VKAs requires an individual iden-tification of optimal dosage monitoring the internationalnormalized ratio (INR) levels aiming for an INR level of20ndash30 A lower intensity of anticoagulation (INRlt 2) isassociated with a greater likelihood of recurrent throm-boembolic events while a more intense anticoagulation isassociated with the occurrence of bleeding events139


The long-term treatment with warfarin is effective inpreventing recurrent VTE

Recurrency despite VKA therapy occurs in about 2 ofpatients

Parenteral anticoagulation low-molecular-weightheparinPrevious studies in patients with cancer and acute VTEhave demonstrated that dalteparin was more effectivethan oral anticoagulant in reducing the risk of recurrentVTE without increasing the risk of bleeding137138140 Inpatients with cancer and acute PE low-molecular-weightheparin administered in the acute phase (except for high-risk PE) and continued over the first 3ndash6months should beconsidered as first-line therapy For patients with PEand cancer extended anticoagulation (beyond the first3ndash6months) should be considered for an indefinite periodor until the cancer is cured Incidence of recurrent pro-voked VTE (due to surgery trauma immobilization preg-nancy and hormonal replacement therapy) is estimated atalmost 5 per year However among those patients theincidence of recurrence seems to be lower in the case ofprevious surgery In the unprovoked forms the incidence ofrecurrent VTE is approximately 15141142

Antiplatelet agentsIn patients who refuse to take or are unable to tolerate anyform of oral anticoagulants aspirin could be considered forextended secondary VTE prophylaxis In two recent trialsASPIRE142 and WARFASA143 extended therapy with aspirin(after termination of standard oral anticoagulation) wasassociatedwith a 30ndash35 reduction in the risk of recurrenceafter unprovoked without increasing the risk of bleedingevents

New oral anticoagulants for extended treatmentNowadays new oral anticoagulants (NOACs) have beenevaluated both in first phases and in the extended treat-ment of patients with VTE

Four NOACs have been evaluated for VTE treatmentdabigatran (an oral thrombin inhibitor) and rivaroxabanapixaban and edoxaban which are oral factor Xa inhibi-tors All four agents have been compared with conven-tional anticoagulant therapy for the treatment of acutesymptomatic VTE and all but edoxaban have been com-paredwith placebo for extended treatment144ndash149

These studies have some common characteristics

bull Inclusion criteria (age gt18 years a confirmed and pre-viously treated VTE)

bull Exclusion criteria (anticoagulant treatment for otherdiseases dual antiplatelet therapy thrombocytope-nia anaemia renal function-estimated withglomerular filtration rate lt25mLmin or serum crea-tinine gt25mgdL hypertransaminasaemia andhigher bilirubin levels)

bull The endpoint recurrent VTE mortality for all causesand PE related)

Safety of treatment was labelled as a haemoglobin drop2 gdL requiring blood transfusion and minor bleeding

events To notice the concept of lsquoclinically relevantbleedingrsquo this one was defined as the need for medicalintervention (unlike the previous definitions of major orminor bleeding events) Two-thirds of patients enrolledhad a VTE while a third had only PE Except for theREMEDY trial in which Dabigatran was compared withwarfarin184 others studies compared NOACs with placeboThe characteristics of the enrolled populations were simi-lar to those represented in the VTE registry but younger inage with less co-morbidities and a low prevalence ofactive cancer however a greater number of idiopathic PEwas recorded

The results of the aforementioned studies could besummarized as follows

bull Patients treated with placebo despite less seriousVTE respect to patients commonly treated in dailyclinical practice had a higher rates of recurrent VTE(up to 88)

bull Treatment reduced the rates of recurrent VTE how-ever a higher prevalence of bleeding events wasrecorded

bull A single study demonstrated that dabigatran waseffective in the extended treatment of VTE and car-ried a lower risk of major or clinically relevant bleed-ing than warfarin but a higher risk than placebo150

bull The rates of bleeding have not been widely investi-gated in previous studies during the extended phaseof treatment

However daily clinical practice demonstrated thatbleeding events are more frequent than the estimationperformed in clinical trials RESONATE trial shows thattreatment efficacy continues even after treatment with-drawal151 These evidences indicate that NOACs are usefulin the extended phase of treatment especially in patientsat higher risk of recurrent VTE with a relative low risk ofbleeding

Clinical trials have been performed with a view to mak-ing significant changes to the acute long-term andextended treatment of VTE152 ESC guidelines recommendthat the administration of one of the new oral anticoagu-lants such as dabigatran apixaban or rivaroxaban shouldbe considered as an alternative treatment in VTEHowever NOACS are not recommended in patients withsevere renal impairment (evidence level IIa B)2 duringpregnancy breastfeeding and severe liver disease associ-atedwith significant bleeding risk (CHILD PUGH B and C)

Duration of the treatmentWhatever the choice of anticoagulant the standard dura-tion of therapy should cover at least 3months After with-drawal of anticoagulant treatment the risk of recurrenceif anticoagulants are stopped after 6 or 12months can beexpected to be similar to that after 3months On the con-trary an indefinite treatment reduces the risk for recur-rent VTE by about 90 but this benefit is partially offset bya 1 or higher annual risk of major bleeding153

There are no properly evaluated bleeding risk scores forpatients receiving anticoagulant treatment for VTE Basedon currently available evidence risk factors include age


gt75years previous gastrointestinal bleeding previousstroke (either haemorrhagic or ischaemic) chronic renal orhepatic disease concomitant antiplatelet therapy (mustbe avoided if possible) other serious acute or chronic ill-ness poor anticoagulation control and suboptimal moni-toring of anticoagulant therapy

The indefinite duration of anticoagulation should be con-sidered in all the patients in which an unprovoked VTE hasbeen diagnosed or in high-risk provoked cases in thesepatients the option to withdraw anticoagulant treatmentshould periodically be reassessed considering the dynamicbalance between the risks of recurrence and bleeding

Whenever the anticoagulation is abandoned the patientshould be followed for a time sufficient to redefine hisherrisk of recurrence (6ndash12months)

Venous filters (inferior vena cava)Venous filters are indicated in patients with acute PE whohave absolute contraindications to anticoagulant drugs andin patients with objectively confirmed recurrent PE despiteadequate anticoagulation treatment29154 The frequencyof inferior vena cava (IVC) filter placement has doubledover the past decades155156 especially after the introduc-tion of retrievable filters and more complex and smallerdevices generatingmore indications for their use

Nevertheless current clinical evidence supporting the useof the venous filters are limited In fact categories ofpatients with PE in whom vena cava filters reduce in-hospitalcase fatality rate have not been definitively assessed156

Stein et al157 in 2012 observed that patients who receiveda vena cava filter had a lower case fatality rate than thosewho did not moreover unstable patients who receivedthrombolytic therapy had a lower in-hospital case fatalityratewith vena cava filters than thosewho did not

The latest European guidelines on PE published in 2014have stated that IVC filters in patients with PE is not recom-mended2 Indeed IVC should be considered only in thosepatients who have an absolute contraindication to anticoa-gulation therapy or in case of recurrent VTE despite ther-apeutic levels of anticoagulation

Previous evidence has already demonstrated the utilityof placement of an IVC filter for recurrent thromboembo-lism that occurs despite adequate anticoagulation forchronic recurrent embolism with PH and with the concur-rent performance of surgical pulmonary embolectomy orpulmonary thromboendarterectomy (Grade 1C)158159

Broader indications have also been provided by single stud-ies on other clinical conditions such asmalignancies recenttrauma acetabular fractures and after orthopaedic sur-gery placement of joint and hip or knee prosthesis Thelack of definitive recommendations on IVC filters could bedue to the fact that most of the survival data derived fromobservational studies performed in small cohorts Only fewrandomized trials have been performed with the aim toclarify the role of IVC in clinical practice The PREPIC studywas the first randomized trial that studied both the effi-cacy and the safety of vena cava filters in the prevention ofPE in patients with proximal DVT Using a two-by-two facto-rial design 400 patients with proximal deep-vein thrombo-sis who were at risk for PE received a vena cava filter (200

patients) or no filter (200 patients) At 2 years 37 patientsassigned to the filter group (208) when compared with21 patients assigned to the no-filter group (116) hadrecurrent DVT (OR 187 95 CI 110ndash320) No significantdifferences in mortality were recorded160 At 8 years venacava filters reduced the risk of pulmonary embolism butincreased that of deep-vein thrombosis and had no effecton survival161 Instead the PREPIC-2 FU among hospitalizedpatients with severe acute PE the use of a retrievable IVCfilter plus anticoagulation compared with anticoagulationalone did not reduce the risk of symptomatic recurrent pul-monary embolism at 3months162 Schuun et al163 haveshown a higher survival in those patients who had placedan IVC filter compared with subjects who received anticoa-gulation (185 vs 128) Ihnat et al164 showed no signifi-cant differences after 1 year for patients treated withfilter and anticoagulation therapy (35 vs 38 Pfrac14 ns)Kucher et al165 among 2392 patients with PE describedthat none of the patients who received an IVC filter devel-oped recurrent PE within 90 days and 909 survived atleast 90 days On the contrary 90 day survival rates were791 in patients with an IVC filter and 860 in those with-out an IVC filter (HR 150 95 CI 110ndash204 Pfrac14 0009)The main indications for implantation of a vena cava fil-

ter in the presence of VTE are

a proven VTE with contraindications foranticoagulation

b proven VTE complications of anticoagulation treat-ments and

c recurrent VTE despite anticoagulation treatment

Actually there are no definitive data about the use of IVCfilters in the prophylaxis of VTE in patients at high risk (iepatients with multiple trauma) moreover their use is notrecommended in patients who may be treated withanticoagulationImberti et al166 in a recent consensus paper provide evi-

dence and clinical judgements describing the managementof patients with IVC filters (Table 8)

Complications arising from the placement of vena cavafiltersComplications may occur during IVC placement afterinterventional procedure but also in the long-term periodafter many years Intra-procedural complications are rela-tively rare and may result from malposition of the device(13) air embolism (02) pneumothorax (002) andinadvertent carotid puncture (1204)167168 A relativelyfrequent complication in the post-interventional period isrepresented by the thrombosis at the insertion site(108)169170 Delayed complications including filter frac-ture migration IVC thrombosis and recurrent PE andcomplications of filter retrieval after implantation of tem-porary IVC filters have also been described

Vena cava filters in cancer patientsPatients with cancer had twice the incidence of VTE PEand DVT as patients without cancer Many recent studiesquestioned the need to insert IVC filters in advanced-stagecancer patients particularly those whose anticipated


survival is short and prevention of PE may be of little clini-cal benefit and could be a poor utilization of resourcesConflicts have been reported about the indication andappropriate timing to place IVC filters in cancer patientsHowever these data cannot be considered in current medi-cal practice because patients were not stratified accord-ing to the current PE classifications indeed PE wasdefined through both anatomical and angiographic criteria(Miller index or lung scan) Despite that some useful rec-ommendations have been proposed in recent studies Infact haemodynamically stable patients with PE and solidmalignant tumours who were aged gt30years appeared tobe a subset of patients with PE who would benefit fromvena cava filters171

Elastic compression stockingsGraduated elastic compression stockings (GECS) help pre-vent DVT and more in general VTE by applying varyingamounts of pressure to different parts of the leg The PTSis a chronic condition that develops in 20ndash50 of patientswith DVT9172ndash173 The main risk factors for PTS are persis-tent leg symptoms 1month after acute DVT anatomicallyextensive DVT recurrent ipsilateral DVT obesity and olderage

Previous studies on GECS have enrolled surgical patientsin most cases We can divide these studies respect to theirendpoints

bull studies about clinical efficacy andbull studies about haemodynamic effectiveness

Graduated compression stockings or elastic-compressivebandage (GCES) reduce the overall cross-sectional area ofthe limb increase the linear velocity of venous flow tillfive times reduce venous wall distension and improvevalvular function Arterial disease may contraindicate theuse of compression therapy The Italian Society ofPhlebology174 recommends to use of GECS with caution ifthere is an arterial anklendashbrachial index (Winsor index)lt08

The use of Class 3 stockings during the 15ndash20 days afterthe acute event is able to reduce the incidence of PTS of50977172173

The cumulative incidence of the post-thrombotic syn-drome in the control group vs the elastic stockings groupwas 491 vs 245 (CI 156ndash334) after 2 yearsHowever there are some areas of uncertainty about theuse of GECS Partsch et al175 demonstrated in their studythat immediate mobilization with compression in the acutestage of DVTreduces the incidence and the severity of PTSHowever one important limitation was that the bandageprocedures required skilled personnel The same authorshave also demonstrated that the use of Class 2 stockingsmodified over time according to the clinical evolution ofthe disease was related to a rapid reduction of thrombussize measured at venous Duplex

Actually there are no definitive data regarding the roleof GCES in the dissolution of the residual thrombus

The recommendations for the use of GCES are summar-ized in Table 9

Surgical treatment of chronic thromboembolicpulmonary hypertensionChronic thromboembolic pulmonary hypertension has beenclassified in Group 4 of PH30 The incidence of CTEPH afteracute PE is in the range of 05ndash2 Prevalence of CTEPH inPE patients is 38 as reported in the 2013 NICE guide-lines175 Lifelong anticoagulation is recommended in allpatients with CTEPH Pulmonary endarterectomy is thetreatment of choice for the disease The operability ofpatients with CTEPH is determined by multiple factors thatcannot easily be standardized these are related to thesuitability of the patient the expertise of the surgicalteam and available resources Apart from major pulmo-nary vascular obstruction the pathophysiology of CTEPHincludes a pulmonary microvascular disease which may beresponsible for the poor outcome in some cases of PEAMoreover hypercoagulation lsquostickyrsquo red blood cells highplatelet counts and lsquouncleavablersquo fibrinogen may furthercontribute to obliteration of the PAs in CTEPH In situ PAthrombosis in patients who have CTEPH may also occurClinical symptoms and signs are non-specific or absent inearly CTEPH with signs of right HF only becoming evidentin advanced disease These subjects are the most difficultto treat

Table 8 Management of patients with vena cava (inferior vena cava) filters

There is no evidence to support the hypothesis that inferior vena cava (IVC) filters reduce death from acute VTEAvailable evidence shows no short-term or long-term mortality benefit from IVC filter placement plus anticoagulation (comparedwith anticoagulation therapy alone)

It is not known whether IVC filters would reduce death in patients with acute VTE compared with no treatmentIVC filters when used in patients with acute DVT are associated with an increased risk of PTSPatients with IVC filters should remain on anticoagulant therapy as long asa the filter remains in placeb the therapy is well tolerated andc the proportion of time in the therapeutic range is highFilters should be removed at the earliest possible time ideally within weeks and not later than 120 days from their insertionDelaying removal probably reduces the likelihood of removal and the duration of lsquosafe removalrsquo is probably also a function of thetype of filter


The indications for PEA in CTEPH patients is based on thefollowing items

bull Clinical patients with New York Heart AssociationClass II III and IV independently from age

bull Haemodynamic Precapillary PH defined as amPAP 25mmHg with a PAWP 15mmHg and a PVR3 WU

bull Anatomical surgical accessibility of thrombi in themain lobar or segmental PAs176 The expertise of thesurgeon and of the Centre allows to treat lesionslocated not only in the main lobar and segmental butalso in the subsegmental branches of PAs177

Presence of severe pulmonary disease is an absolute con-traindication to PEA

Surgical techniqueSurgical treatment has drastically changed in the lastyears

From the beginning of the transplant programme forCTEPH the attitude has changed from the lungndashhearttransplantation to the bipulmonar transplantation due tothe RV inverse remodelling observed in the first patientsThe extensive applicability of PEA in expert centres hasallowed to reserve the potential lung donors to the treat-ment of pathology different from CTEPH Many patients inprevious observations who were judged inoperable for theclinical and anatomic conditions were successively treatedwith PEAwith satisfactory long-term survival rates177ndash179

The rationale of interventional treatment is the removalof all the chronic thromboembolic material from the pul-monary circulation eliminating the cause for elevation ofresistance An important aspect of surgery is representedby the correct identification of the cleavage plane in thePA wall or in the thickness of the tunica media allowingthe excision of the entire intima in which the chronicthromboembolic are adherent The myocardial protectionis obtained as well as with moderate hypothermia andintermittent reperfusion During the entire procedure cer-ebral oximetry is monitored using a near-infraredspectroscopy

The modification of the San Diego Procedure allows alonger period of cardioplegia with amore accurate removalof thromboembolic material also in distal sites Note thatdistal thrombi have a significant role in the haemodynamicfunction of the lung However in elderly subjects longperiods of cardioplegia in deep hypothermia are notrecommended179

Successful PEA is able to reduce pulmonary arterial hae-modynamic with recovery of both cardiac and respiratoryfunction and clinical benefit on exercise capacity andimproving quality of life180181

Postoperative complications are rare the most frequentare persistence of PH right HF airways bleeding and pul-monary oedema after PEA reperfusion In the long-termhowever recurrent PAHmay occur This event could be dueto the onset of new embolic events (caused for exampleby poormanagement of anticoagulant therapy) or evidenceof small vessel disease (Eisenmenger similar) especially inlong-lasting CTEPH This latter event is the reason why PEAis preferredwhen the patient is defined as NYHA Class IIA pharmacological approach is recommended in sympto-

matic patients who have been classified as having inoper-able CTEPH by a CTEPH team or in patients with very highsurgical risk for severe co-morbidities

Pharmacological treatment of chronicthromboembolic pulmonary hypertensionAlthough PEA is the treatment of choice for CTEPH30

20ndash35 of patients have inoperable CTEPH (for anatomicalreason sites of thromboembolic material andor severeco-morbidities)182 Despite the OAT the mortality rate ofthese patients is 32 at 18months while long-term survival(5 years) is around 30 This percentage dramaticallydecreases to 10 in patients with a PAPgt 50mmHg183184

Because not all patients are deemed operable and up toone-third have persistent or recurrent CTEPH after the pro-cedure several small uncontrolled trials have investi-gated the response to drugs approved for PAH endothelinreceptor antagonists prostacyclin analogues and phos-phodiesterase type 5 inhibitors in CTEPH185 The histopa-thologic pattern in these patients is analogous to the one ofidiopathic PH186

It seems that preoperative high levels of endothelin 1correlate with the haemodynamic alterations observed inPEA and may be used to predict haemodynamic outcomeafter the interventional procedure187 These results aresupported by other evidences that links PAH and CTEPHfor example the nitric oxide (NO)ndashsoluble guanylatecyclase (sGC)ndashcyclic guanosine monophosphate (cGMP)pathway in regulating pulmonary vascular tone is demon-strated by the dysregulation of NO production sGC activ-ity and cGMP degradation in both PAH and CTEPH188

Due to the lack of evidence in the treatment of CTEPHin the past years many drugs in association with anticoa-gulant treatment have been used off-label30

Unfortunately this aspect has delayed the admission of

Table 9 Recommendation for the use of graduated compression stockings

Graduated compression stockings (GCS) are effective in diminishing the risk of deep vein thrombosis (DVT) in hospitalized patientsIn patients with proximal thrombosis GCS (30mmHg at the ankle) should be performed for at least 2 years after the acute eventAnti-embolism stockings cannot replace GCS during the day but must be applied during the nightDVT is associated with significant long-term complications such as the post-thrombotic syndrome Preventive and therapeutic strat-egies (clinical scores andor ultrasound evaluation) are needed for these patients


patients to CTEPH centres in order to evaluate the role ofPEA San Diego Center performed a retrospective analysisof CTEPH patients referred for PAE during 2005ndash07 Theauthors observed that the number of patients alreadytreated medically (off-label) was rising without a post-operative advantage189

In 2008 the Bosentan Effects in iNonopErable Forms ofchronIc Thromboembolic pulmonary hypertension(BENEFiT) study a double-blind randomized placebo-controlled study in CTEPH included patients with eitherinoperable CTEPH or persistentrecurrent PH after PEA(gt6months after PEA) This study demonstrated a positivetreatment effect of bosentan on haemodynamics in thispatient population (Plt 00001) However no improvementwas observed in exercise capacity and functional class190

As demonstrated by different authors after PEA long-term survival and cardiopulmonary function recovery isexcellent in most patients but may needmore than 2 yearsrsquotime191 After the BENEFIT trial Bosentan has not obtainedthe indication for medical treatment in inoperable or per-sistent CTEPH after PEA

Riociguat is a member of a new class of therapeuticagents called sGC stimulators evaluated for its potentialadvantage over the other PAH treatments In particularRiociguat has a dual mode of action directly stimulatingsGC independently of NO and increasing the sensitivity ofsGC to NO Riociguat increases the level of cGMP resultingin vasorelaxation and anti-proliferative and anti-fibroticeffects as shown in experimental models of PH The resultshould be an increase in the availability of NO regardlessof the endogenous initial levels with consequent vasodila-tation anti-fibrotic anti-inflammatory and anti-proliferative effect rather than a decrease in pulmonaryvascular resistance192ndash194

The PATENT PLUS trial evaluated the safety and efficacyof Riociguat in combination with Sildenafil in PAH patientsPatients receiving sildenafil (20mg three times daily) wererandomized to placebo or riociguat (up to 25mg three timesdaily) for 12weeks This trial was stopped for the potentiallyunfavourable safety signals with sildenafil plus riociguatpossibly due to an important systemic vasodilation andsymptomatic hypotension and no evidence of a positive ben-efitrisk ratio Concomitant use of riociguat with phospho-diesterase 5 inhibitors is hence contraindicated189195

Riociguat was evaluated in the Chronic ThromboembolicPulmonary Hypertension Soluble Guanylate CyclasendashStimulator Trial 1 (CHEST-1)192 A total of 261 patientsunderwent randomization and received at least one doseof study medication (173 patients in the riociguat groupand 88 in the placebo group)

Riociguat improved primary and secondary endpoints inboth inoperable patients and patients with persistentrecurrent CTEPH vs baseline with a more marked effectin inoperable patients196 The drug has been well toleratedwhile most common side effects were related to vasodila-tion (headache and fatigue) The CHEST-2 open-labelextension evaluated 237 patients (98 of patients enrolledin CHEST-1) in the long-term safety and efficacy ofriociguat The study showed that long-term riociguat had afavourable benefitndashrisk profile and apparently showed sus-tained benefits in exercise and functional capacity for up

to 2 years Side effects such as haemoptysis remains to beclarified

Currently a Phase II study with Macitentan (MERIT-1) isongoing This trial will evaluate the drug in both inoperableand recurrent CTEPH patients after PEA (main outcomewill be a decrease in PVR)

In conclusion the only drug therapy currently indicatedin patients with inoperable recurrent or permanentCTEPH after PEA is riociguat In particular riociguat is rec-ommended in symptomatic patients who have been classi-fied as having inoperable CTEPH by a CTEPH team includingat least one experienced PEA surgeon or have persistentrecurrent CTEPH after surgery However medical treat-ment before surgery in CTEPH patients is not able tomodifythe surgical outcome of these patients that should bereferred to the expert centre for PEA as soon as possiblealready in an NYHA functional Class II not postponing apossible surgical correction

Future trials must clarify some aspects such as the roleof riociguat in long-term survival and in combination ther-apy and also the role of NOAs in CTEPH

Special issues clinical and outpatientsmanagement

The FU of the patient with VTE requires an appropriatemedical service able to manage both the diagnostic andthe therapeutic strategies of this complex disease Indeedit is essential that management of an outpatient VTE isbased on a clinical care pathway that uses an integratedmultidisciplinary approach able to provide a similar degreeof effectiveness and safety as customary inpatienttherapy197ndash199

One of themain problems discussed in the last ESC guide-lines on PE is the early discharge of low-risk patients2

However these subjects have to be followed with the sameattention and quality of cares that are offered to thehospitalized patients200

Generally after acute VTE the patient is managed byhis or her general practitioner (GP) This lsquorelationshiprsquo isbased especially on the periodical anticoagulation man-agement (VKA) andor on the patientrsquos revaluation thatmust be performed to assess the duration of anticoagu-lant treatment Other specialists could be involved inthis long-term management such as cardiologists orinternal medicine physicians according to the patientrsquosneeds

After analysing our manuscript and the current guide-lines there is a need to revise the current medical strategyin the FU of VTE considering other models of care used inother cardiologic diseases

Given the high incidence of VTE high recurrent ratesseveral co-morbidities associated with the disease themost appropriate health care system seems to be the crea-tion of multidisciplinary teams that work in the same place

Experienced physician and nurses must work together toobtain a higher standard of care

This clinic must represent a simpler way to facilitate thepatientndashGP relationship

Clinicrsquos role should be


bull Monitoring of anticoagulation therapy For this servicea connection to the nearest laboratory is essential

bull Periodical patient evaluationbull Routine laboratory evaluationbull Periodic clinical evaluation that must include

bull electrocardiographybull TTEbull Vascular USbull 6MWTbull CPET

bull Planning and interpretation of imaging testsbull CTAbull LP scan

bull Planning and evaluation of other tests that involve dif-ferent aspects of medicine cardiology pulmonologyhaematology and internal medicine

bull Planning and evaluation of additional tests (if not per-formed during the acute phase)bull thrombophiliabull unknown malignancies

bull Planning change in anticoagulant therapybull Planning anticoagulant withdrawal

The appropriate management for patients with compli-cations must be also guarantee

bull Recurrent VTE that requires hospitalizations andortherapeutic revaluation

bull Decisions regarding other treatment strategies in sub-jects with CTEPH should be made by a multidiscipli-nary team of experts and in collaboration with asurgical referee centre able to perform PEA

bull Bleeding events must be managed also with otherspecialists

If surgical treatment could be performed in a hospitalthis department must also realize protocols and audits withthe aim of reducing VTE risk during hospitalization andmanaging new cases effectively

Nurses must be an integral component of a CTEPH clinicThey should be able to record independently and followvarious stages of the disease In particular

bull examination planningbull planning and first interpretation of laboratory testsbull perform ultrasound vascular examination if trainedbull counselling for patients and their familiesbull home monitoring and home nursing andbull education and prevention of VTE

The VTE clinic must create local lsquodiagnostic protocolsrsquoand therapeutic programmes in accordance with the lastscientific guidelines and the best clinical practice

Medical staff should participate in the training andresearch projects in collaboration with other similar struc-tures in order to increase their knowledge

Future developments and conclusions

There is currently a lack of evidence regarding someaspects of VTE long-term management as optimal durationof anticoagulation in unprovoked VTE There is a need fornew markers able to indicate the treatment withdrawal

when patients are at low risk for recurrent eventsMoreover it must be considered that also provoked VTEcould be associated with other co-morbidities that couldjustify a longer anticoagulant treatmentCTEPH patients must be followed in the long-term and

also in this field other markers for the early detection ofdisease should be useful Despite different studies havealready assessed the role of NOACs in VTE further investi-gation is needed especially on the safety and efficacy inthe long run Furthermore NOACS must also be investi-gatedwidely in cancerWe hope that through the present manuscript an

increased attention will be given to the FU of VTE

Appendix algorithms

To perform an efficacious FU in patients with acute VTE it isfundamental to perform a complete prognostic stratificationduring hospitalization because the short-termmorbidity andmortality depends on this preliminary assessmentAssessment of haemodynamic stability at admission is funda-mental for the early prognostic stratification Indeed thelatter is the main discriminatory factor between high- andnon-high-risk patients PESI Spesi CTA RVD and clinicalbiomarkers allow to complete the prognostic assessment2

Co-morbidities such as cancer or previous cerebrovasculardisease have an important role both in the short-term prog-nosis and in the treatment Residual thrombosis in any sites(lung RV or peripheral veins) andor RVDDespite in the past it was thought that the only problem

after discharge was the duration of anticoagulation webelieve that nowadays FU must have the followingobjectives

bull assess the risk of recurrent VTEbull assess the bleeding riskbull define the duration and the type of anticoagulant

therapybull assess the global cardiovascular risk andbull identify patients with CTEPH

To establish the risk of bleeding events during the3months we recommend the use of the score adopted inRIETE registry14 Conversely to assess the long-term bleed-ing risk the CFCA should be applied9 Actually no scoreshave been proposed for NOACs Bleeding risk is a funda-mental part of the decision-making processAnticoagulant treatment after VTE is recommended for

at least 3months (active phase of treatment) followed bya second period (secondary prevention) which can varywith respect to the recurrence riskIn general morbidity and mortality in patients with VTE

especially in the mid-long-term period is usually due tocancer and cardiovascular diseases Special attention isrequestedwith regard to these aspectsCTEPH is a disease of obstructive PA remodelling as a

consequence of major vessel thromboembolism Thesepatients must perform a TTE FU after 3 and 6months if inthe acute phase they had RVD PAP gt50mmHg residualthrombosis or dyspnoeaFigure 1 is the suggested algorithm for FU in PEVTE


Consensus Document Approval Faculty

Abrignani Maurizio Giuseppe Alunni Gianfranco AmodeoVincenzo Angeli Fabio Aspromonte Nadia Audo AndreaBattistoni Ilaria Bianca Innocenzo Bisceglia Irma BonviciniMarco Cacciavillani Luisa Calculli Giacinto Caldarola

Pasquale Capecchi Alessandro Caporale Roberto CarettaGiorgio Carmina Maria Gabriella Casolo Giancarlo CassinMatteo Casu Gavino Cemin Roberto Chiaranda GiacomoChiarella Francesco Chiatto Mario Cibinel Gian AlfonsoCiccone Marco Matteo Cicini Maria Paola Clerico Aldo DeLuca Giovanni De Maria Renata Del Sindaco Donatella Di

Figure 1 Decision algorithm for follow-up of venous thromboembolic patients VTE venous thromboembolism PH pulmonary hypertension lab labo-ratory FU follow up RV right ventricle VQ Scan ventilationperfusion scintigraphy RHC right heart catheterization Angio angiopneumographyPAH pulmonary artery hypertension MAP pulmonary mean arterial pressure PR pulmonary resistance GP general practitioner PEA pulmonaryendoarterectomy Angio CT computed angio tomography


Fusco Stefania Angela Di Lenarda Andrea Di Tano GiuseppeEgidy Assenza Gabriele Egman Sabrina Enea IolandaFattirolli Francesco Favilli Silvia Ferraiuolo GiuseppeFrancese Giuseppina Maura Gabrielli Domenico GeraciGiovanna Giardina Achille Greco Cesare Gregorio GiovanniIacoviello Massimo Khoury Georgette Ledda AntoniettaLuca Fabiana Lukic Vjerica Macera Francesca Marini MarcoMasson Serge Maurea Nicola Mazzanti Marco MennuniMauro Menotti Alberto Menozzi Alberto Mininni NicolaMoreo Antonella Moretti Luciano Mortara Andrea MuredduGian Francesco Murrone Adriano Musumeci GiuseppeNavazio Alessandro Nicolosi Gian Luigi Oliva Fabrizio ParatoVito Maurizio Parrini Iris Patane Leonardo Pini Daniela PinoPaolo Giuseppe Pirelli Salvatore Procaccini VincenzaPugliese Francesco Rocco Pulignano Giovanni RadiniDonatella Rao Carmelo Massimiliano Riccio Carmine RossiniRoberta Ruggieri Maria Pia Rugolotto Matteo Sanna FabiolaSauro Rosario Severi Silva Sicuro Marco Silvestri Paolo SistoFrancesco Tarantini Luigi Uguccioni Massimo UrbinatiStefano Valente Serafina Vatrano Marco Vianello GabrieleVinci Eugenio and Zuin Guerrino

Conflict of interest none declared

References

1 Authors Task Force Members Konstantinides SV et al The TaskForce for the diagnosis and management of acute pulmonary em-bolism of the European Society of Cardiology 2014 ESC guidelineson the diagnosis and management of acute pulmonary embolismEur Heart J 2014353033ndash3080

2 Zonzin P Agnelli G Casazza F Favretto G Giuntini C MorpurgoM Vizza CD Commento alle linee guida della Task ForcesullrsquoEmbolia Polmonare della Societa Europea di Cardiologia ItalHeart J Suppl 200121342ndash1356

3 DrsquoAgostino C Vizza CD Le linee guida europee 2008 su diagnosie trattamento dellrsquoembolia polmonare una nuova classificazioneper una piu organica valutazione clinica Commento EditorialeGiornale Italiano Di Cardiologia 200910348ndash349

4 Rugolotto M Favretto G European 2014 guidelines on the diag-nosis and treatment of acute pulmonary embolism underlyingthe importance of patient-centered clinical assessment as wellas of new management and therapeutic approaches G ItalCardiol (Rome) 201516203ndash205

5 Soggard KK Scmidt M Pedersen L Horvath-Puho E Sorensen HT30 year mortality following venous thromboembolism apopulation-based cohort study Circulation 2014130829ndash836

6 Klok FA Van de Hulle T denExter PL Lankeit M Huisman MVKonstantinides S The post-PE syndrome a new concept forchronic complications of pulmonary embolism Blood Reviews291428221ndash226

7 Klok FA van Kralingen KW van Dijk AP et al Prevalence and po-tential determinants of exertional dyspnea after acute pulmo-nary embolism Respir Med 20101041744ndash1749

8 Stevison BG Hernandez-Nino J Rose G Kline JAEchocardiographic and functional cardiopulmonary problems6months after first-time pulmonary embolism in previouslyhealthy patients Eur Heart J 2007282517ndash2524

9 Kearon C Akl EA Comerota AJ Prandoni P Bounameaux HGoldhaber SZ Nelson ME Wells PS Gould MK Dentali FCrowther M Kahn SR American College of Chest PhysiciansAntithrombotic therapy for VTE disease antithrombotic therapyand prevention of thrombosis 9th ed American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines Chest2012141e419Sndashe494S

10 den Exter P van der Hulle LT Lankeit M Huisman MV Klok FALong term clinical course of acute pulmonary embolism Blood Rev201327185ndash192

11 Uresandi F Monreal M Bragado FG Domenech P Lecumberri REscribano P Zamorano JL Jimenez S Ruiz-Artacho P Lozano FRomera A Jimenezl D on behalf of the National Consensus onDiagnosis Risk Stratification and Treatment of Patients WithPulmonary Thromboembolism National consensus on the diagno-sis risk stratification and treatment of patients with pulmonaryembolism Arch Bronconeumol 201349534ndash547

12 Goldhaber SZ Visani L De Rosa M Acute pulmonary embolismclinical outcomes in the International Cooperative PulmonaryEmbolism Registry (ICOPER) Lancet 19993531386ndash1389

13 Bongarzoni A Rossi A Tassinario G Porro F Enea I Casazza FPrognosi a breve e a lungo termine dellrsquoEmbolia Polmonare acutadati dallrsquoItalian Pulmonary Embolism Registry (IPER) InComunicazione orale 46 CONGRESSO NAZIONALE DICARDIOLOGIA ANMCO Milano 4-6 giugno 2015

14 Tzoran I Brenner B Papadakis M Di Micco P Monreal M VTE reg-istry what can be learned from RIETE Rambam Maimonides MedJ 20145e0037

15 Verso M Agnelli G Ageno W Imberti D Moia M Palareti GPistelli R Cantone V Cantone and for the MASTERInvestigators Long-term death and recurrence in patients withacute venous thromboembolism The MASTER registry ThrombRes 2012130369ndash373

16 Douketis J Tosetto A Marcucci M et al Patient-level meta-analysis effect of measurement timing threshold and patientage on ability of D-dimer testing to assess recurrence risk afterunprovoked venous thromboembolism Ann Intern Med2010153523ndash531

17 Marcucci M Smith CT Douketis JD et al Patient-level comparedwith study-level meta-analyses demonstrate consistency of D-di-mer as predictor of venous thromboembolic recurrences J ClinEpidemiol 201366415ndash425

18 Eichinger S Heinze G Jandeck LM Kyrle PA Risk assessment ofrecurrence in patients with unprovoked deep vein thrombosis orpulmonary embolism the Vienna prediction model Circulation20101211630ndash1636

19 Tosetto A Iorio A Marcucci M et al Predicting disease recurrencein patients with previous unprovoked venous thromboembolism aproposed prediction score (DASH) J Thromb Haemost2012101019ndash1025

20 Palareti G Cosmi B Legnani C et al D-dimer to guide the dura-tion of anticoagulation in patients with venous thromboembolisma management study Blood 2014124196ndash203

21 De Stefano V Rossi E Testing for inherited thrombophilia and con-sequences for antithrombotic prophylaxis in patients with venousthromboembolism and their relatives A review of the Guidelinesfrom Scientific Societies and Working Groups Thromb Haemost2013110697ndash705

22 Coppens M Reijnders JH Middeldorp S Doggen CJ Rosendaal FRTesting for inherited thrombophilia does not reduce the recur-rence of venous thrombosis J Thromb Haemost200861474ndash1477

23 Reitter-Pfoertner S Waldhoer T Mayerhofer M et al The influ-ence of thrombophilia on the long-term survival of patients with ahistory of venous thromboembolism Thromb Haemost201310979ndash84

24 Kearon C Influence of hereditary or acquired thrombophilias onthe treatment of venous thromboembolism Curr Opin Hematol201219363ndash370

25 Vossen CY Walker ID Svensson P et al Recurrence rate after afirst venous thrombosis in patients with familial thrombophiliaArterioscler Thromb Vasc Biol 2005251992ndash1997

26 Brouwer JL Lijfering WM Ten Kate MK Kluin-Nelemans HCVeeger NJ van der Meer J High long-term absolute risk of recur-rent venous thromboembolism in patients with hereditary defi-ciencies of protein S protein C or antithrombin Thromb Haemost200910193ndash99

27 Surie S Gibson NS Gerdes VEA Bouma BJ van Eck-Smit BLFBuller HR Bresser P Active search for thromboembolic pulmonaryhypertension does not appear indicated after acute pulmonaryembolism Thromb Res 2010125e202ndashe205

28 Klok FA Van Kralingen KW van DijK APJ Heining FH Vliegen HWHuisman MV Prospective cardiopulmonary screening to de-tect chronic thromboembolic pulmonary hypertension in patients


after acute pulmonary embolism Haematologica 201095970ndash975

29 Guerin L Couturaud F Parent F Revel MP Gillaizeau F PlanquetteB Pontal D Guegan M Simonneau G Meyer G Sanchez OPrevalence of chronic thromboembolic pulmonary hypertension af-ter acute pulmonary embolism Thomb Haemost2014112598ndash605

30 Nazzareno G et al 2015 ESCERS Guidelines for the diagnosis andtreatment of pulmonary hypertension The Joint Task Force for theDiagnosis and Treatment of Pulmonary Hypertension of theEuropean Society of Cardiology (ESC) and the EuropeanRespiratory Society (ERS) Endorsed by Association for EuropeanPaediatric and Congenital Cardiology (AEPC) International Societyfor Heart and Lung Transplantation (ISHLT) Eur Heart J20163767ndash119

31 Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande LFlachskamps FA Foster E Goldstein SA Kuznetsova T LancellottiP Muraru D Picard MH Rietzschel ER Rudski L Spencer KT TsangW Voigt JU Reccomendations for cardiac chamber quantificationby echocardiography in adultsan update of the American Societyof Echocardiography anf European Association of CardiovascularImaging Eur Heart J Cardiovasc Imaging 201516233ndash271

32 Casazza F Bongarzoni A Forgione C Cuccia C Imperadore FArrigo G Floriani I Pignataro L Echocardiographic evolution ofpulmonary artery pressure after acute pulmonary embolismResults from IPER Registry Thromb Res 20141341224ndash1228

33 Galie N Hoeper MM Humbert M et al Guidelines for the diagno-sis and treatment of pulmonary hypertension the Task Force forthe Diagnosis and Treatment of Pulmonary Hypertension of theEuropean Society of Cardiology (ESC) and the EuropeanRespiratory Society (ERS) endorsed by the International Society ofHeart and Lung Transplantation (ISHLT) Eur Heart J2009302493ndash2537

34 Meneveau N et al Long-term prognostic value of residual pulmo-nary vascular obstruction at discharge in patients withintermediate-to high-risk pulmonary embolism Eur Heart J201334693ndash701

35 Begic A et al Impact of ventilationperfusion single-photon emis-sion computed tomography on treatment duration of pulmonaryembolism Nucl Med Com 201536162ndash167

36 Stein PD et al Resolution of pulmonary embolism on CT pulmo-nary angiography AJR Am J Roentgenol 20101941263ndash1268

37 Miniati M et al Survival and restoration of pulmonary perfusion ina long-term follow-up of patients after acute pulmonary embo-lism Medicine 200685253ndash262

38 Wartski M et al Incomplete recovery of lung perfusion after3months in patients with acute pulmonary embolism treated withantithrombotic agents THESEE Study Group Tinzaparin ouHeparin Standard Evaluation dans lrsquoEmbolie Pulmonaire StudyJ Nucl Med 2000411043ndash1048

39 Sanchez O et al Perfusion defects after pulmonary embolismrisk factors and clinical significance J Thromb Haemost201081248ndash1255

40 Nijkeuter M et al Resolution of thromboemboli in patients withacute pulmonary embolism a systematic review Chest2006129192ndash197

41 Alhadad A et al The value of tomographic ventilationperfu-sion scintigraphy (VPSPECT) for follow-up and prediction ofrecurrence in pulmonary embolism Thromb Res 2012130877ndash881

42 Den Exter PL et al Thromboembolic resolution assessed by CTpulmonary angiography after treatment for acute pulmonary em-bolism Thromb Haemost 201511426ndash34

43 Hoeper MM Bogaard HJ Condliffe R et al Chronic thromboem-bolic pulmonary hypertension J Am Coll Cardiol 201362(25Suppl)D92ndashD99

44 Reichelt A Hoeper MM Galanski M Keberle M Chronic thrombo-embolic pulmonary hypertension evaluation with 64-detector rowCT versus digital subtraction angiography Eur J Radiol20097149ndash54

45 He J Fang W Lv B et al Diagnosis of chronic thromboembolicpulmonary hypertension comparison of ventilationperfusionscanning and multidetector computed tomography pulmonary

angiography with pulmonary angiography Nucl Med Commun201233459ndash463

46 Auger WR Kim NH Trow TK Chronic thromboembolic pulmonaryhypertension Clin Chest Med 201031741ndash758

47 Jenkins D Mayer E Screaton N Madani M State-of-the-artchronic thromboembolic pulmonary hypertension diagnosis andmanagement Eur Respir Rev 201212132ndash39

48 Tanabe N Sugiura T Jujo T et al Subpleural perfusion as a pre-dictor for a poor surgical outcome in chronic thromboembolic pul-monaryhypertension Chest 2012141929ndash934

49 Hoeper MM Mayer E Simonneau G Rubin LJ Chronic thromboem-bolic pulmonary hypertension Circulation 20061132011ndash2020

50 Mayer E Jenkins D Lindner J et al Surgical management andoutcome of patients with chronic thromboembolic pulmonary hy-pertension results from an international prospective registryJ Thorac Cardiovasc Surg 2011141702ndash710

51 Skoro-Sajer N Hack N Sadushi-Kolici R et al Pulmonary vascularreactivity and prognosis in patients with chronic thromboembolicpulmonary hypertension a pilot study Circulation2009119298ndash305

52 Pengo V Lensing AW Prins MH Marchiori A Davidson BL Tiozzo Fet al Incidence of chronic thromboembolic pulmonary hyperten-sion after pulmonary embolism N Engl J Med20043502257ndash2264

53 Becattini C Agnelli G Pesavento R Silingardi M Poggio R TalianiMR et al Incidence ofchronic thromboembolic pulmonary hyper-tension after a first episode of pulmonary embolism Chest2006130172ndash175

54 Paolillo S Farina S Agostoni P et al Exercise testing in the clini-cal management of patients affected by pulmonary arterial hyper-tension Eur J Prev Cardiol 201219960ndash971

55 Sun XG Hansen JE Oudiz RJ Wasserman K Exercise pathophysiol-ogy in patients with primary pulmonary hypertension Circulation2001104429ndash435

56 Agostoni P Smith DD Schoene RB Robertson HT Butler JEvaluation of breathlessness in asbestos workers Results of exer-cise testing Am Rev Respir Dis 1987135812ndash816

57 Sue DY Oren A Hansen JE Wasserman K Lung function and exer-cise performance in smoking and nonsmoking asbestos-exposedworkers Am Rev Respir Dis 1985132612ndash618

58 Hansen JE Sue DY Wasserman K Predicted values for clinical ex-ercise testing Am Rev Respir Dis 1984129S49ndashS55

59 Yasunobu Y Oudiz RJ Sun XG Hansen JE Wasserman K End-tidalPCO2 abnormality and exercise limitation in patients with primarypulmonary hypertension Chest 20051271637ndash1646

60 Agostoni P Butler J Cardiac evaluation In JFE Murray JA Nadeleds Textbook of Respiratory Medicine Boston WB SaundersCompany 1994 p943ndash962

61 Prandoni P Lensing AWA Cogo A et al The long-term clinicalcourse of acute deep venous thrombosis Ann Intern Med19961251ndash7

62 Kahn SR The post-thrombotic syndrome Thromb Res 2011127(suppl 3)S89ndashS92

63 Keeling D Alikhan R Management of venous thromboembolism-controversies and the future Br J Haematol 2013161755ndash763

64 Michiels JJ Moosdorff W Maasland H et al Duplex ultrasoundclinical score thrombotic risk and D-dimer testing for evidencebased diagnosis and management of deep vein thrombosis and al-ternative diagnoses in the primary care setting and outpatientward Int Angiol 2014331ndash19

65 Kahn SR Comerota AJ Cushman M et al The postthrombotic syn-drome evidence-based prevention diagnosis and treatmentstrategies a scientific statement from the American HeartAssociation Circulation 20141301636ndash1661

66 Kahn RS Shier I Julian JA et al Determinants and time course ofthe post thrombotic syndrome after acute deep venous thrombo-sis Ann Intern Med 2008149698ndash707

67 Prandoni P Frulla M Sartor D Concolato A Girolami A Vein ab-normalities and the post-thrombotic syndrome J ThrombHaemost 20053401ndash402

68 Vedovetto V Dalla Valle F Milan M Pesavento R Prandoni PResidual vein thrombosis and trans-popliteal reflux in patientswith and without thepost-thrombotic syndrome Thromb Haemost2013110854ndash855


69 Roumen-Klappe EM Janssen MC van Rossum J et alInflammation in deep vein thrombosis and the development ofpost-thrombotic syndrome a prospective study J ThrombHaemost 20097582ndash587

70 Shbaklo H Holcroft CA Kahn SR Levels of inflammatory markersand the development of the post thrombotic syndrome ThrombHaemost 2009101505ndash512

71 Henke PK Comerota AJ An update on etiology prevention andtherapy of postthrombotic syndrome J Vasc Surg201153500ndash509

72 Kahn SR Partsch H Verdantham S et al Definition of post-thrombotic syndrome of the leg for use in clinical investigations arecommendation for standardization J Thromb Haemost20097879ndash883

73 Chitsike RS Rodger MA Kovacs MJ Kahn SR et al Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagula-tion for a first unprovoked deep vein thrombosis results from theREVERSE study J Thromb Haemost 2012102039ndash2044

74 Enden T Haig Y Kloslashw N-E et al Long-term outcome after addi-tional catheterdirectedthrombolysis versus standard treatment foracute iliofemoraldeep vein thrombosis (the CaVenT study) a rand-omised controlled trial Lancet 201237931ndash38

75 Sharifi M Bay C Mehdipour M Sharifi J TORPEDO InvestigatorsThrombus obliteration by rapid percutaneous endovenous inter-ventionin deep venous occlusion (TORPEDO) trial midterm resultsJ Endovasc Ther 201219273ndash280

76 Brandjes DPM Buller HR Heijboer H et al Randomised trial ofeffect of compression stockings in patients with symptomaticproximal-vein thrombosis Lancet 1997349759ndash762

77 Prandoni P Lensing AW Prins MH et al Below-knee elastic com-pression stockings to prevent the post-thrombotic syndrome a ran-domized controlled trial Ann Intern Med 2004141249ndash256

78 Kahn SR Shapiro S Wells PS et al Compression stockings to pre-vent post-thrombotic syndrome a randomized placebo-controlledtrial Lancet 2014383880ndash888

79 Palareti G Legnani C Cosmi B et al Risk of venous thromboem-bolism recurrence high negative predictive value of D-dimer per-formed after oral anticoagulation is stopped Thromb Haemost2002877ndash12

80 Palareti G Legnani C Cosmi B et al Predictive value of D-dimertest for recurrent venous thromboembolism afteranticoagulation withdrawal in subjects with a previous idiopathicevent and in carriers of congenital thrombophilia Circulation2003108313ndash318

81 Eichinger S Minar E Bialonczyk C et al D-dimer levels and risk ofrecurrent venous thromboembolism JAMA 20032901071ndash1074

82 Palareti G Cosmi B Legnani C et al D-dimer testing to deter-mine the duration of anticoagulation therapy N Engl J Med20063551780ndash1789

83 Latella J Desmarais S Miron MJ et al Relation between D-dimerlevel venous valvular reflux and the development of post-thrombotic syndrome after deep vein thrombosis J ThrombHaemost 201082169ndash2175

84 Vazquez SR Kahn SR Advances in the diagnosis and managementof postthrombotic syndrome Best Pract Res Clin Haematol201225391ndash402

85 Prandoni P Lensing AWA Prins MH et al Residual thrombosis as apredictive factor of recurrent venous thromboembolism AnnIntern Med 2002137955ndash960

86 Piovella F Crippa L Barone M et al Normalization rates of com-pression ultrasonography in patients with a first episode of deepvein thrombosis of the lower limbs association with recurrenceand new thrombosis Haematologica 200287515ndash522

87 Siragusa S Malato A Anastasio R et al Residual vein thrombosis toestablish duration of anticoagulation after a first episode of deep veinthrombosis the Duration of Anticoagulation based on CompressionUltraSonography (DACUS) study Blood 2008112511ndash515

88 Prandoni P Prins MH Lensing AWA et al Residual thrombosis onultrasonography to guide the duration of anticoagulation in pa-tients with deep venous thrombosis Ann Intern Med2009150577ndash585

89 Donadini MP Ageno W Antonucci E et al Prognostic significanceof residual venous obstruction in patients with treated unprovoked

deep vein thrombosis A patient-level meta-analysis ThrombHaemost 2014111172ndash179

90 Ageno W Squizzato A Wells PS et al The diagnosis of symptom-atic recurrent pulmonary embolism and deep vein thrombosisguidance from the SSC of the ISTH J Thromb Haemost2013111597ndash1602

91 Monreal M Lafoz E Casals A et al Occult cancer in patients withdeep venous thrombosis A systematic approach Cancer199167541ndash545

92 Carrier M Le Gal G Wells PS et al Systematic review theTrousseau syndrome revisited should we screen extensively forcancer in patients with venous thromboembolism Ann Intern Med2008149323ndash333

93 Jodice S Venous thromboembolic events and organ specific occultcancer a review and meta-analysis J Thromb Haemost20086781ndash788

94 Watson HG Keeling DM Laffan M et al British Committee forStandards in Haematology Guideline on aspects of cancer-relatedvenous thrombosis Br J Haematol 2015170640ndash648

95 Prins MH Hettiarachchi RJ Lensing AW et al Newly diagnosedmalignancy in patients with venous thromboembolism Search orwait and see Thromb Haemost 199778121ndash125

96 White RH Chew HK Zhou H et al Incidence of venous thrombo-embolism in the year before the diagnosis of cancer in 528693adults Arch Intern Med 20051651782ndash1787

97 Prandoni P Casiglia E Piccioli A et al The risk of cancer in pa-tients with venous thromboembolism does not exceed that ex-pected in the general population after the first 6months JThromb Haemost 201081126ndash1127

98 Piccioli A Lensing AWA Prins MH et al Extensive screening foroccult malignant disease in idiopathic venous thromboembolism aprospective randomized clinical trial J Thromb Haemost20042884ndash889

99 Piccioli A Bernardi E Dalla Valle F et al The value of thoraco-abdominal CT scanning for the detection of occult cancer in pa-tients with unprovoked venous thromboembolism A randomizedstudy Thromb Res 2012129 Suppl 1S155ndashS194

100 Van Doormaal FF Terpstra W Van Der Griend R et al Is extensivescreening for cancer in idiopathic venous thromboembolism war-ranted J Thromb Haemost 2011979ndash84

101 Robertson L Yeoh SE Stansby G et al Effect of testing for canceron cancer- and venous thromboembolism (VTE)- related mortalityand morbidity in patients with unprovoked VTE Cochrane DatabaseSyst Rev 20153CD010837

102 NICE Venous Thromboembolic Diseases the Management ofVenous Thromboembolic Diseases and the Role of ThrombophiliaTesting Clinical Guideline 144 London National Institute forHealth and Clinical Excellence 2012

103 httpwwwaiomitprofessionistidocumenti-scientificilinee-guida14131 (20 April 2017)

104 Carrier M Lazo-Langner A Shivakumar S et al SOME InvestigatorsScreening for occult cancer in unprovoked venous thromboembo-lism N Engl J Med 2015373697ndash704

105 Chauchard M Benali K Papo T et al Positron emission tomogra-phy combined with computed tomography as a screening tool foroccult malignancy in patients with unprovoked venous thrombo-embolism an observational study Medicine (Baltimore)201493e110

106 Alfonso A Redondo M Rubio T et al Screening for occult malig-nancy with FDG-PETCT in patients with unprovoked venous throm-boembolism Int J Cancer 20131332157ndash2164

107 Peck B Hoffman GS Franck WA Thrombophlebitis in systemic lupuserythematosus JAMA 19782401728ndash1730

108 Cervera R Khamashta MA Font J et al European Working Party onSystemic Lupus Erythematosus Morbidity and mortality in systemiclupus erythematosus during a 10-year period a comparison of earlyand late manifestations in a cohort of 1000 patients Medicine(Baltimore) 200382299ndash308

109 Palatinus A Adams M Thrombosis in systemic lupus erythematosusSemin Thromb Hemost 200935621ndash629

110 Di Fabio F Lykoudis P Gordon PH Thromboembolism in inflamma-tory bowel disease an insidious association requiring a high degreeof vigilance Semin Thromb Hemost 201137220ndash225


111 Murthy SK Nguyen GC Venous thromboembolism in inflammatorybowel disease an epidemiological review Am J Gastroenterol2011106713ndash718

112 Yazici H Fresko I Yurdakul S Behcetrsquos syndrome disease manifes-tations management and advances in treatment Nat Clin PractRheumatol 20073148ndash155

113 Matta F Singala R Yaekoub AY et al Risk of venous thromboembo-lism with rheumatoid arthritis Thromb Haemost2009101134ndash138

114 Ludvigsson JF Welander A Lassila R et al Risk of thromboembo-lism in 14000 individuals with coeliac disease Br J Haematol2007139121ndash127

115 Lin HC Yang LY Kang JH Increased risk of pulmonary embolismamong patients with hyperthyroidis m a 5-year follow-up studyJ Thromb Haemost 201082176ndash2178

116 Merkel PA Lo GH Holbrook JT et al Wegenerrsquos GranulomatosisEtanercept Trial Research Group Brief communication high inci-dence of venous thrombotic events among patients with Wegenergranulomatosis the Wegenerrsquos Clinical Occurrence of Thrombosis(WeCLOT) Study Ann Intern Med 2005142620ndash626

117 Rahman P Inman RD El-Gabalawy H et al Pathophysiology andpathogenesis of immune-mediated inflammatory diseases com-monalities and differences J Rheumatol Suppl 20108511ndash26

118 Song KS Park YS Kim HK Prevalence of anti-protein S antibodies inpatients with systemic lupus erythematosus Arthritis Rheum200043557ndash560

119 DrsquoAngelo A Della Valle P Crippa L et al Brief report autoimmuneprotein S deficiency in a boy with severe thromboembolic diseaseN Engl J Med 19933281753ndash1757

120 Bengtsson A Zoller B de Frutos PG et al Factor VQ506 mutationand anticardiolipin antibodies in systemic lupus erythematosusLupus 19965598ndash601

121 Rees JD Lanca S Marques PV et al Prevalence of the antiphospho-lipid syndrome in primary systemic vasculitis Ann Rheum Dis200665109ndash111

122 Pierrot-Deseilligny Despujol C Michel M et al Antiphospholipidantibodies in adults with immune thrombocytopenic purpura Br JHaematol 2008142638ndash643

123 de Carvalho JF Caleiro MT Primary antiphospholipid syndrome andthyroid involvement J Clin Rheumatol 201016164ndash167

124 Rottem M Krause I Fraser A et al Autoimmune hemolytic anae-mia in the antiphospholipid syndrome Lupus 200615473ndash477

125 Pahor A Hojs R Holc I et al Antiphospholipid antibodies as a pos-sible risk factor for atherosclerosis in patients with rheumatoid ar-thritis Immunobiology 2006211689ndash694

126 Burgos PI Alarcon GS Thrombosis in systemic lupus erythe-matosus risk and protection Expert Rev Cardiovasc Ther200971541ndash1549

127 Somers E Magder LS Petri M Antiphospholipid antibodies and inci-dence of venous thrombosis in a cohort of patients with systemiclupus erythematosus J Rheumatol 2002292531ndash2536

128 Brouwer JL Bijl M Veeger NJ et al The contribution of inheritedand acquired thrombophilic defects alone or combined with anti-phospholipid antibodies to venous and arterial thromboembolismin patients with systemic lupus erythematosus Blood2004104143ndash148

129 Sarabi ZS Chang E Bobba R et al Incidence rates of arterial andvenous thrombosis after diagnosis of systemic lupus erythematosusArthritis Rheum 200553609ndash612

130 Calvo-Alen J Toloza SM Fernandez M et al LUMINA Study GroupSystemic lupus erythematosus in a multiethnic US cohort (LUMINA)XXV Smoking older age disease activity lupus anticoagulant andglucocorticoid dose as risk factors for the occurrence of venousthrombosis in lupus patients Arthritis Rheum 2005522060ndash2068

131 Chang ER Pineau CA Bernatsky S et al Risk for incident arterialor venous vascular events varies over the course of systemic lupuserythematosus J Rheumatol 2006331780ndash1784

132 Romero-Dıaz J Garcıa-Sosa I Sanchez-Guerrero J Thrombosis insystemic lupus erythematosus and other autoimmune diseases ofrecent onset J Rheumatol 20093668ndash75

133 Zoller B Li X Sundquist J Sundquist K Risk of subsequent coronaryheart disease in patients hospitalized for immune-mediated dis-eases a nationwide follow-up study from Sweden PLoS One20127e33442

134 Pengo V Tripodi A Reber G et al Subcommittee on LupusAnticoagulantAntiphospholipid Antibody of the Scientific andStandardisation Committee of the International Society onThrombosis and Haemostasis 200971737ndash1740 Update of theguidelines for lupus anticoagulant detection J Thromb Haemost

135 Keeling D Mackie I Moore GW et al British Committee forStandards in Haematology Guidelines on the investigation andmanagement of antiphospholipid syndrome Br J Haematol201215747ndash58

136 Clinical and Laboratory Standards Institute Laboratory testing forthe lupus anticoagulant approved guideline CLSI document H60-AWayne PA CLSI 2014

137 Lee AY Rickles FR Julian JA Gent M Baker RI Bowden C KakkarAK Prins M Levine MN Randomized comparison of low molecularweight heparin and coumarin derivatives on the survival of patientswith cancer and venous thromboembolism J Clin Oncol2005232123ndash2129

138 Kakkar AK Levine MN Kadziola Z Lemoine NR Low V Patel HKRustin G Thomas M Quigley M Williamson RC Low molecularweight heparin therapy with dalteparin and survival in advancedcancer the Fragmin advanced malignancy outcome study(FAMOUS) J Clin Oncol 2004221944ndash1948

139 Ageno W Gallus AS Wittkowsky A et al Oral anticoagulant ther-apy antithrombotic therapy and prevention of thrombosis 9th edAmerican College of Chest Physicians Evidence-Based ClinicalPractice Guidelines Chest 2012141e44S

140 Lee AY Levine MN Baker RI Bowden C Kakkar AK Prins M RicklesFR Julian JA Haley S Kovacs MJ Gent M Low-molecular-weightheparin vs a coumarin for theprevention of recurrent venousthromboembolism in patients with cancer N Engl J Med2003349146ndash153

141 Agnelli G Prandoni P Becattini C Silingardi M Taliani MR MiccioM Imberti D Poggio R Ageno W Pogliani E Porro F Zonzin PExtended oral anticoagulant therapy after a first episode of pulmo-nary embolism Ann Intern Med 200313919ndash25

142 Anthony R Stephen M Rory C Colin P Prevention of pulmonaryembolism and deep vein thrombosis with low dose aspirin pulmo-nary Embolism Prevention (PEP) trial Lancet 20003551295ndash1302

143 Becattini C et al WARFASA Investigators Aspirin for preventingthe recurrence of venous thromboembolism N Engl J Med20123661959ndash1967

144 Mueck W et al Rivaroxaban and other novel oral anticoagulantspharmacokinetics in healthy subjectsspecific patient populationsand relevance of clinical monitoring Thromb J 20131110

145 Cohen AT Dobromirski M Gurwith MP Managing pulmonary embo-lism from presentation to extended treatment Thromb Res2014133 139ndash148

146 Agnelli G et al New oral anticoagulants for the treatment of ve-nous thromboembolism Best Pract Res Clin Haematol201326151ndash161

147 Schulman S et al Extended use of dabigatran warfarin or placeboin venous thromboembolism N Engl J Med 2013368 709ndash718

148 Bauersachs R et al Oral rivaroxaban for symptomatic venousthromboembolism N Engl J Med 20103632499ndash2510

149 Agnelli G et al Apixaban for extended treatment of venous throm-boembolism N Engl J Med 2013368 699ndash708

150 Prandoni P The treatment of venous thromboembolism with noveloral anticoagulants warnings and limitations Blood Transfus201513178ndash180

151 Schulman S et al Benefit of extended maintenance therapy for ve-nous thromboembolism with dabigatran etexilate is maintainedover 1 year of post-treatment follow-up Poster 21 from Session332 Antithrombotic Therapy 1 In Presented on 8 December at theAmerican Society of Hematology (ASH) Annual Meeting 2012 Blood201212021

152 Cohen A Phase III trials of new oral anticoagulants in the acutetreatment and secondary prevention of VTE comparison and cri-tique of study methodology and results Adv Ther 201431473ndash493

153 Levine MN Hirsh J Gent M et al Optimal duration of oral antico-agulant therapy a randomized trial comparing four weeks withthree months of warfarin in patients with proximal deep veinthrombosis Thromb Haemost 199574606

154 Caplin D Nikolic N Kalure S et al Quality Improvement guidelinesfor the performance of inferior vena cava filter placement for the


prevention of pulmonary embolism J Vasc Interv Radiol2011221499ndash1506

155 Duszak R Jr Parker L Levin DC Rao VM Placement and removal ofinferior vena cava filters national trends in the medicare popula-tion J Am Coll Radiol 20118483ndash489

156 Stein PD Matta F Hull RD Increasing use if vena cave filters forprevention if pulmonary embolism Am J Med 2011124655ndash661

157 Stein PD Matta F et al Impact of vena cava filters on in-hospitalcase fatality rate from pulmoanry embolism Am J Med2012125478ndash484

158 Hyers TM Agnelli G Hull RD et al Antithrombotic theraphy for ve-nous thromboembolic disease Chest 2001119176Sndash193S

159 Spencer FA Bates SM et al A population-based study of inferiorvena cava filters in aptients with acute venous ThromboembolismArch Inter Med 20101701456ndash1462

160 Decousus H Leizorovicz A Parent F et al A clinical trial of venacaval filters in the prevention of pulmonary embolism in patientswith proximal deep-vein thrombosis Prevention du RisquedrsquoEmbolie Pulmonaire par Interruption Cave Study Group N Engl JMed 1998338409ndash415

161 PREPIC Study Group Eight-year follow-up of patients with perma-nent vena cava filters in the prevention of pulmonary embolismthe PREPIC (Prevention du Risque drsquoEmbolie Pulmonaire parInterruption Cave) randomized study Circulation2005112416ndash422

162 Mismetti P Laporte S Pellerin O et al Effect of a retrievable infe-rior vena cava filter plus anticoagulation vs anticoagulation aloneon risk of recurrent pulmonary embolism a randomized clinicaltrial JAMA 20153131627ndash1635

163 Schuun C Shuun GB et al Inferior vena cava filter placment inlate-stage cancer Vasc Endovasc Surg 200640287ndash294

164 Ihnat DM Mills JL et al Treatment of patients with fvenous throm-boembolism and malignant diseaseshould vena cava filter plac-ment be routine J Vasc Surg 199828800ndash807

165 Kucher N Rossi E De Rosa M Goldhaber SZ Massive pulmonary em-bolism Circulation 2006113577ndash582

166 Imberti D Dentali F Ageno W Crowther M Garcia D Huisman MRodeghiero F Drsquoangelo A Palareti G Evidence and clinical judge-ment vena cava filters Thromb Haemost 2014111618ndash624

167 Ray CE Kaufman JA Jr Complications of inferior vena cavafiltersAbdom Imaging 199621368ndash374

168 Dorfman GS Percutaneous inferior vena cava filters Radiology1990174987ndash992

169 Blebea J Wilson R Waybill P et al Depp venous thrombosisafterpercutaneous insertion of vena caval filters J Vasc Surg199930821ndash829

170 Aswad MA Sandager GP Pais SO et al Early duplex scan evaluationof four vena caval interruption devices J Vasc Surg199624809ndash818

171 Stein PD Matta F Sabra MJ Case fatality rate with vena cava fil-ters in hospitalized stable patients with cancer and pulmonqry em-bolism Am J Med 2013126819ndash824

172 Jaff MR McMurtry MS Archer SL Cushman M Goldenberg NGoldhaber SZ Jenkins JS Kline JA Michaels AD Thistlethwaite PVedantham S White RJ ZierlerBK American Heart AssociationCouncil on Cardiopulmonary Critical Care Perioperative andResuscitation American Heart Association Council on PeripheralVascular Disease American Heart Association Council onArteriosclerosis Thrombosis and Vascular Biology Management ofmassive and submassive pulmonary embolism iliofemoral deepvein thrombosis and chronic thromboembolic pulmonary hyperten-sion a scientific statement from the American Heart AssociationCirculation 20111231788ndash1830

173 Lyman GH Bohlke K Khorana AA Kuderer NM Lee AY ArcelusJI Balaban EP Clarke JM Flowers CR Francis CW Gates LEKakkar AK Key NS Levine MN Liebman HA Tempero MA WongSL Somerfield MR FalangaA American Society of ClinicalOncology Venous thromboembolism prophylaxis and treatmentin patients with cancer American Society of Clinical Oncologyclinical practice guideline update 2014 J Clin Oncol201533654ndash656

174 LINEE GUIDA Collegio Italiano di Flebologia Revisione 2013 ActaPhlebol 201314(Suppl 1 al N 2)1ndash160

175 Partsch H Kaulich M Mayer W Immediate mobilisation in acutevein thrombosis reduces post-thrombotic syndrome Int Angiol200423206ndash212

176 Morsolini M Nicolardi S Milanesi E Sarchi E Mattiucci G Klersy CDrsquoarmini AM Evolving surgical techiniques for pulmonaryendoarterectomy according to the changing features of chronic throm-boembolic pulmonary hypertension patients during 17-years single-center experience J Thorac Cardiovasc Surg 2012144100ndash107

177 DrsquoArmini AM Morsolini M Mattiucci G Grazioli V Pin M ValentiniA Silvaggio G Klersy C Dore R Pulmonary endoarterectomy fordistal chronic thromboembolic pulmonary hypertension J ThoracCardiovasc Surg 20141481005ndash1011

178 DrsquoArmini AM Morsolini M Mattiucci G Grazioli V Pin M SciortinoA Arbustini E Goggi C Vigano M Chronic thromboembolic pulmo-nary hypertension from transplantation to distal pulmonary endar-terectomy J Heart Lung Transplant 201635827ndash831

179 Vistarini N Morsolini M Klersy C Mattiucci G Grazioli V Pin MGhio S Drsquoarmini AM Pulmonary endarterectomy in the elderlysafety efficacy and risk factors J Cardiovasc Med (Hagerstown)201617144ndash151

180 Ghio S Morsolini M Corsico A Klersy C Mattiucci G Raineri CScelsi L Vistarini N Oltrona Visconti L Drsquoarmini AM Pulmonary ar-terial compliance and exercise capacity after pulmonary endarter-ectomy Eur Respir J 2014431403ndash1409

181 Petrucci L Carlisi E Ricotti S Zanellato S Klersy C Drsquoarmini AMNicolardi S Morsolini M Vigano M Dalla Toffola E Functional as-sessment and quality of life before and after pulmonary endarter-ectomy G Ital Med Lav Ergon 201537170ndash175

182 Pepke-Zaba J et al Chronic thromboembolic pulmonary hyperten-sion (CTEPH) results from an international prospective registryCirculation 20111241973ndash1981

183 Lewczuch J et al Prognostic factors in medically treated patientswith chronic pulmonary embolism Chest 2001119818ndash823

184 Wilkens H et al Chronic thromboembolic pulmonary hypertension(CTEPH) Updated recommendations of the Cologne ConsensusConference 2011 Int J of Cardiol 2011154S54ndashS60

185 Hoeper M Pharmacological therapy for patients with chronicthromboembolic pulmonary hypertension Eur Respir Rev201524272ndash282

186 Moser MK et al Pulmonary vascular lesions occurring in patientswith chronic major vessel thromboembolic pulmonary hyperten-sion Chest 1993103685ndash692

187 Langer F et al Circulating big endothelin-A an active role in pul-monary thromboendarterectomy J Thorac Cardiovasc Surg20051301342ndash1347

188 Reesink HJ et al Hemodynamic and clinical correlates ofendothelin-1 in chronic thromboembolic pulmonary hypertensionCirculation 2006701058ndash1063

189 Stasch JP et al soluble guanylate cyclase stimulators in pulmonaryhypertension Handp Exp Pharmacol 2013218279ndash313

190 Jensen KW et al Pulmonary hypertensive medical therapyin chronic thromboembolic pulmonary hypertension before pulmo-nary thromboendarterectomy Circulation 20091201248ndash1254

191 Jais X et al Bosentan for treatment of inoperable chronic throm-boembolic pulmonary hypertension J Am Coll Cardiol2008522127ndash2134

192 Corsico A et al Long-term outcome after pulmonary endarterec-tomy Am J Respir Crit Care Med 2008178419ndash424

193 Ghofrani HA et al Riociguat for the treatment of chronic thrombo-embolic pulmonary hypertension N Engl J Med 2013369319ndash329

194 Nossaman B Stimulators and activators of soluble guanylate cy-clase review and potential therapeutic indications Crit Care ResPract 201220290ndash298

195 Mullershausen F et al Direct activation of PDE5 by cGMP long-termeffects within NOcGMP signaling J Cell Biol 2003160719ndash727

196 Galie N et al A placebo-controlled double-blind phase II interac-tion study to evaluate blood pressure following addition of riociguatto patients with symptomatic pulmonary arterial hypertension(PAH) receiving sildenafil (PATENT PLUS) Am J Respir Crit CareMed 2013187 abstract A3530

197 Vinson DR Berman DR Patel PB Hickey DO Outpatient manage-ment of deep venous thrombosis 2 models of integrated care AmJ Manag Care 200612405ndash410


198 Vali Y Ladwa R Bailie E Bennett J Free C Investigating and man-aging suspected pulmonary embolism in an outpatient setting theLeicester experience Thorax 201570291ndash293

199 Vinson DR Berman DA Outpatient treatment of deep venousthrombosis a clinical care pathway managed by the emergency de-partment Ann Emerg Med 200137251ndash258

200 Al-Hameed FM Al-Dorzi HM Al-Momen AM Algahtani FH Al-Zahrani HA Al-Saleh KA Al-Sheef MA Owaidah TM Alhazzani WNeumann I Wiercioch W Brozek J SchuNemann H Akl EA TheSaudi clinical practice guideline for the treatment of venous throm-boembolism Outpatient versus inpatient management Saudi MedJ 2015361004ndash1010


sux030-TF4

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KEYWORDSPulmonary embolism

Venous thromboembolism

Deep vein thrombosis

Prognosis

Treatment

Consensus document

Venous thromboembolism (VTE) including pulmonary embolism and deep venousthrombosis is the third most common cause of cardiovascular death The manage-ment of the acute phase of VTE has already been described in several guidelinesHowever the management of the follow-up (FU) of these patients has been poorlydefined This consensus document created by the Italian cardiologists wants toclarify this issue using the currently available evidence in VTE Clinical and instru-mental data acquired during the acute phase of the disease are the cornerstone forplanning the FU Acquired or congenital thrombophilic disorders could be identifiedin apparently unprovoked VTE during the FU In other cases an occult cancer couldbe discovered after a VTE The main targets of the post-acute management are toprevent recurrence of VTE and to identify the patients who can develop a chronicthromboembolic pulmonary hypertension Knowledge of pathophysiology and thera-peutic approaches is fundamental to decide the most appropriate long-term treat-ment Moreover prognostic stratification during the FU should be constantlyupdated on the basis of the new evidence acquired Currently the cornerstone ofVTE treatment is represented by both the oral and the parenteral anticoagulationNovel oral anticoagulants should be an interesting alternative in the long-termtreatment

Table of contents

AbstractEpidemiology and pathophysiologyResults of recordsType and timing of follow-up

Biochemical markers and thrombophiliaBiochemical markersThrombophilia

EchocardiographyLung scan computed tomography scan and magneticresonanceRight heart catheterization and haemodynamicevaluationFunctional test The 6-min walking test and cardiopulmonary exercise testingEvaluation of post-thrombotic syndromeResidual venous thrombosis of the lower limbsResidual thrombosis of the pulmonary arteries

Co-morbidity cancer and autoimmune diseasesCancerAutoimmune disease

Overview of medical and surgical therapyAnticoagulants and antiplatelet drugs (traditionaltherapy)AnticoagulantsParenteral anticoagulation low-molecular-weightheparinAntiplatelet agentsNew oral anticoagulants for extended treatmentDuration of the treatment

Venous filters (inferior vena cava)Elastic compression stockingsSurgical treatment of chronic thromboembolicpulmonary hypertensionPharmacological treatment of chronic thromboembolicpulmonary hypertension

Special issues clinical and outpatients managementFuture developments and conclusionsAppendix algorithms

Epidemiology and pathophysiology

Venous thromboembolism (VTE) including pulmonaryembolism (PE) and deep venous thrombosis (DVT) is thethird most common cause of cardiovascular death par-ticularly PE is often difficult to define because it can bepresent with a wide spectrum of symptoms indeed itmay remain asymptomatic or sometimes its diagnosismay be incidental Moreover in over 30 of cases sud-den death may be the first presentation of PE and morethan half of the deaths caused by PE remain undiag-nosed during life

Currently medical decision-making is increasingly sup-ported by International Guidelines1 which are often peri-odically updated and nationwide contextualized23

However these recommendations are in most of the casesprimarily addressed to the treatment of the acute phase ofthe disease lacking a scientific contribution dedicated tothe post-acute phase Also the 2014 European Guidelineson PE1 as pointed out by Rugolotto and Favretto4 in arecent editorial lsquodoes not offer specific guidance on followup and long termmanagement of PErsquo

The relevance of long-term follow-up (FU) could bededuced by a recent Danish survey which enrolled a pop-ulation of 120 000 cases of confirmed VTE between 1980and 2011 The authors reported that these patients wereat increased risk of death during the first year after diag-nosis and the elevated risk persisted during the 30 yearsof FU While 30 day mortality after DVT remained con-stant over that period it markedly improved for PE5

According to the authors individual counselling aimedat tailoring the therapy and intervening on the risk






Results of records







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Results of records







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Dosing Searching

























































6MWT

CPET




























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Appendix algorithms


















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Appendix algorithms


















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6MWT

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Appendix algorithms


















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References



















































































































































































































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sux030-TF1

sux030-TF2

anmcopositionpaper:long-term follow-upofpatients ... filerevised by: marino scherillo, federico...

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