2017ANMCO立场文件：非维生素K依赖的新型口服抗凝剂在肺栓塞治疗和预防中的应用

ANMCO Position Paper:the use of non-vitamin K dependent new oral anticoagulant(s)in pulmonary embolism therapy and prevention

Iolanda Enea (Coordinator)1*,Loris Roncon (Coordinator)2,

Michele Massimo Gulizia,FACC,FESC (Coordinator)3*,Michele Azzarito (Coordinator)4,Cecilia Becattini 5,Amedeo Bongarzoni 6,Franco Casazza 7,Claudio Cuccia 8,Carlo D’Agostino 9,Matteo Rugolotto 10,Marco Vatrano 11,Eugenio Vinci 12,Paride Fenaroli 13,Dario Formigli 14,Paolo Silvestri 14,

Federico Nardi,FACC,FESC 15,Maria Cristina Vedovati 16,and Marino Scherillo 14

1

Emergency Care Department,S.Anna e S.Sebastiano Hospital,Via G.Tescione,1.81100Casert,Italy 2Cardiology Department,S.Maria della Misericordia Hospital,Rovigo,Italy 3

Cardiology Department,Garibaldi-Nesima Hospital,Azienda di Rilievo Nazionale e Alta Specializazione “Garibaldi”,Catania,Italy 4

Cardiology Unit,San Carlo di Nancy Hospital,Rome,Italy 5

Department of Internal and Vascular Medicine,Perugia General Hospital,Perugia,Italy 6

Cardiology Department,San Carlo Borromeo Hospital,Milano,Italy 7

Moscati Foundation,Buccinasco,Milan,Italy 8

Cardiology Unit,Poliambulanza Foundation Hospital,Brescia,Italy 9

Cardiology Department,University General Hospital,Bari,Italy 10

Cardiology Department,Ca’Foncello Hospital,Treviso,Italy 11

CCU-Hemodynamics and Interventional Cardiology Department,Civil Pugliese Hospital,Catanzaro,Italy 12

Cardiology-CCU Department,Umberto I Hospital,Siracusa,Italy 13

Nephrology and Dialysis Unit,Salvatore Maugeri Foundation,University of Pavia,Pavia,Italy 14

Interventional Cardiology-CCU Department,G.Rummo Hospital,Benevento,Italy 15

Cardiology Department,Castelli Hospital,Verbania,Italy 16

Department of Internale and Vascular Medicine,S.Maria della Misericordia Hospital,University of Perugia,Perugia,Italy

Revised by :Maria Gabriella Carmina,Maria Paola Cicini,Anna Maria Costante,Giuseppe Favretto,Adriano Murrone,and Pietro Zonzin.Consensus Document Approval Faculty in appendix

*Corresponding author.Tel:+393402369289,Email:

i_enea@https://www.wendangku.net/doc/db9229476.html,

V

C The Author 2017.Published on behalf of the European Society of Cardiology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://www.wendangku.net/doc/db9229476.html,/licenses/by-nc/4.0/),which permits non-commercial re-use,distribution,and reproduction in any medium,provided the original work is properly cited.For commercial re-use,please contact journals.permissions@https://www.wendangku.net/doc/db9229476.html,

European Heart Journal Supplements (2017)19(Supplement D),D293–D308The Heart of the Matter

doi:10.1093/eurheartj/sux026

KEYWORDS Pulmonary embolism; Venous thromboembolism; New oral anticoagulants (NOACs); Prevention;

Therapy.The new oral anticoagulants(NOACs)have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism.The authors of this position paper face,in succession,issues concerning NOACs,including(i)their mechanism of action,pharmacodynamics,and pharmacokinetics;(ii)the use in the acute phase with the‘double drug single dose’approach or with‘single drug double dose’;(iii)the use in the extended phase with demonstrated ef?cacy and with low incidence of bleeding events;(iv)the encouraging use of NOACs in particular sub-groups of patients such as those with cancer,the ones under-or overweight,with renal insuf?ciency(creatinine clearance>30mL/min),the elderly(>75years);(v) they propose a possible laboratory clinical pathway for follow-up;and(vi)carry out an examination on the main drug interactions,their potential bleeding risk,and the way to deal with some bleeding complications.The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to con-ventional therapy and associated with fewer major bleeding events,which make their use in patients at higher risk of recurrences safer.

Introduction

Pulmonary embolism(PE)remains the third leading cause of cardiovascular death after myocardial infarction(MI) and stroke.1The introduction of new oral anticoagulants, or‘Non vitamin K Oral Anticoagulants’(NOACs)have changed the way we treat PE patients during and after hos-pital stay as well as throughout long-term period.2–10The purpose of this document is to provide cardiologists with the opinion of experts on emerging topics related to the use of NOACs for PE.The authors will describe:(i)the role of the NOACs in the treatment of acute PE,according to the latest European Society of Cardiology(ESC)Guidelines (GL);(ii)the meaning of innovation of the NOACs compared with the traditional therapy;(iii)an update on their use in ‘frail patient’,in cancer patients and obesity;(iv)a practi-cal follow-up(FU)scheme for PE patients treated with the NOACs;and(v)drug–drug interactions,management of bleeding risk and relative complications.

Pulmonary embolism after the European Society of Cardiology guidelines2014: diagnostic flow-charts,prognostic stratifica-tion,and treatment options

Over the years the‘anatomic’definition of massive or non-massive PE has been replaced by the‘functional’one of the ‘high-risk’PE or‘not-high-risk’PE.11In order to identify patients at higher risk of death in not-high-risk group,2008 ESC GL12underlined the importance of the measurement of the right ventricular to left ventricular diastolic diameter ratio(RVDD/L VDD)on echocardiography or computed tomo-graphic angiography(CTA)and the assessment of markers of myocardial injury,like troponins,or of right heart overload, like brain natriuretic peptide(BNP)or N-terminal pro-BNP (NT-pro-BNP).According to the current ESC GL,a further risk stratification has to be considered for stable patients, using some validated clinical scores as PE severity index (PESI)or its simplified version(sPESI),to decide whether or not to perform echocardiography and troponin assessment.1

At presentation,a simple cardiovascular evaluation is enough to plan the most appropriate diagnostic and thera-peutic works-up for patients with suspected PE.1According to systolic blood pressure,two different paths are pro-posed to obtain the final diagnosis:rapid times and simpli-fied procedure in‘high-risk patients’,longer time and well-constructed procedure in‘not-high-risk patients’. The high-risk group constitutes about5–10%of all patients with PE and includes patients with a wide range of mortality risk,from17%in patients with blood pressure90–63%in patients with early cardiac arrest.13,14European Society of Cardiology guidelines emphasize the role of echocardiogra-phy as a rapid bed-side examination in this setting,because high-risk PE is a life-threatening event and echocardio-graphic features of right ventricular dysfunction(RVD)are believed to be sufficient to perform an immediate reperfu-sion therapy,without further testing.13,15

In not-high-risk patients,ESC GL suggest a stepwise approach based on the pre-test clinical probability and D-dimer determination,to avoid the early performance of CTA or scintigraphy.16T oday,to the original Wells’score of 3levels of probability(low,intermediate,and high),we prefer the simplified one involving only two levels of proba-bility,namely‘PE unlikely’and‘PE likely’.17–20If the score is compatible with a‘PE unlikely’,a D-dimer test should be performed,due to its high negative predictive value:if normal,it excludes a current thrombotic process,if abnor-mally high a CTA should be performed.T o give D-Dimer a greater specificity and to reduce the high number of false positives,a cut-off value adjusted for the age(age?10l g/L for age>50years)was introduced.21If PE is‘likely’the D-dimer dosage can be omitted since a normal value does not exclude PE.Regarding the sub-segmental defects at CTA,single defects should be interpreted with caution.22 As for the prognostic stratification,the ESC GL2014pro-posed the PESI score23and its simplified version sPESI.24 The aim of these scores is to better stratify not-high-risk category.We believe that sPESI is a simpler and friendly tool for the prognostic stratification of PE patients, because it takes into account only6variables,instead of 11,commonly assessed at admission.

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The sPESI score stratifies not-high-risk patients into two groups:

(1)Low-risk patients,with sPESI?0,who do not

require further testing and are candidates for early discharge;

(2)Intermediate-risk patients,with a sPESI greater

than or equal to1point.This group requires a fur-ther stratification into two sub-groups by means of imaging and laboratory tests:‘intermediate-high’are those patients in whom both RVD and troponin increase are present and a monitoring appears needed;‘intermediate-low’are those patients in whom only one test,either imaging or laboratory,is abnormal:they do not seem to require special attention,when anticoagulant therapy is started.

In conclusion,PESI and sPESI may be considered useful tools for the initial evaluation of PE patients,although we believe in agreement with other authors,25that further studies are probably required to improve the risk profile of patients at intermediate risk.It is possible that the wide-spread use of high-sensitivity troponin will increase the number of positive results at presentation26and improve its prognostic value.

Patients who can benefit from non-vitamin K dependent new oral anticoagulant(s) treatment

Anticoagulation theraphy is the cornerstone in the treat-ment of venous thromboembolism(VTE)because it can reduce mortality in the acute phase and recurrence in both the short and long periods.Accoriding to the current clini-cal practice,the treatment of VTE generally consists of three phases:an acute phase of5–7days,a short-term phase,up to3months after the acute event and a long-term phase with undefined duration which must be reserved for those patients at higher risk for recurrence.27 High-risk patients must be treated with a drug able to reperfuse the lung and reduce the right ventricle overload as soon as possible.28For this purpose,the systemic thromboly-sis with Actilyse is reccomeded,T enecteplase,tested in Peitho study in intermediate-risk patients,is not approved.29 Surgical embolectomy(Grade I recommendation and evi-dence C)or a percutaneous embolectomy(recommendation IIa degree and evidence C)are currently recommend in case of absolute and/or relative contraindications to thrombolysis or if thrombolytic treatment has failed.13,15

In not-high-risk patients,anticoagulation is the therapy of choice and often the only therapy to practice.The tradi-tional anticoagulation therapy consists of low molecular weight heparins(LMWHs)or fondaparinux.30The indication to start parenteral anticoagulation therapy in patients with PE likely,without waiting for the definitive diagnostic confir-mation,appears clinically relevant;equally the early initia-tion of therapy with vitamin K inhibitors(VKAs)to achieve adequate interantional normalized ratio(INR)within a rea-sonable time,for the purpose of early discharge is useful.31 The use of NOACs should be reserved for patients at low or intermediate-low risk,both in the form of‘single drug approach’or,instead of Warfarin,as‘double drug single dose approach’after few days of parenterally anticoagula-tion with heparin.

For intermediate-risk patients,the GL suggest hospital-ization in wards with monitoring just to observe the hae-modynamic evolution according to the‘wait and watch’strategy,reserving‘rescue’thrombolysis to the ones who evolve towards hypotension or shock.In these cases,when thrombolysis is contraindicated,alternative procedures, such as surgery(IIb-C recommendation)or percutaneous embolectomy(IIb-B),should be considered.32–34

In intermediate-high risk patients with PESI class III–V or sPESI!1,in the presence of positive troponin and of RVD, the possibility of using thrombolysis precludes NOACs ther-apy;even if after the acute phase,if there is right ventricu-lar function improvement,we envisage the therapy with NOACs,waiting for definitive clinical evidence in this popula-tion and using,if necessary,a‘safe dose’of thrombolysis.35 In not-high-risk patients the use of NOACs cannot be administrated in the presence of severe renal failure(RF);in the presence of a systolic blood pressure>180mmHg or dia-stolic>100mmHg;in pregnancy or breastfeeding;in cancer patients requiring anticoagulant treatment by LMWHs; inpatients with liver failure associated with coagulopathy and increased risk of bleeding;inpatients with moderate or severe chronic liver cirrhosis(Child Pugh B or C)in the case of Rivaroxaban and Edoxaban,and severe chronic liver cirrhosis (Child Pugh C)in the case of Apixaban and Dabigatran.36 From the traditional therapy to non-vitamin K dependent new oral anticoagulant(s):the meaning of innovation compared with traditional therapy

The availability of NOACs represents a significant achieve-ment for the treatment of VTE in terms of feasibility. Conventional anticoagulation for VTE includes initial parenteral anticoagulant treatment with:(i)unfractio-nated heparin(UFH)by intravenous bolus followed by con-tinuous infusion based on the coagulation response,got by monitoring the activated partial thromboplastin time (aPTT)(the use of calcic heparin is no more used in clinical practice);(ii)LMWHs;(iii)fondaparinux,a synthetic penta-saccharide factor X activated(FXa)inhibitor;the initial therapy has to be overlapped with Warfarin from3to5 days,until therapeutic INR is obtained.Thanks to their rapid onset of action(T max1–4h),NOACs do not require to be overlapped with heparin,so it is a helpful treatment in reducing the duration of hospitalization and it seems to be associated with a lower risk of bleeding.Furthermore, while Warfarin requires laboratory monitoring for dose adjustment,NOACs are administered orally in fixed doses without the need for periodical laboratory monitoring, reducing medical examinations and long-term costs.37 Therapeutic scheme’s innovation

The clinical development of NOACs in two different regimes allows the choice of the most adequate regimen for differ-ent clinical settings.In the Dabigatran vs.Warfarin in the treatment of acute venous thromboembolism(RE-COVER)

The use of non-vitamin K dependent new oral anticoagulant(s)in pulmonary embolism D295

studies2,3and in the HOKUSAI study,10Dabigatran and Edoxaban were used for the acute and long-term treatment of VTE after initial treatment with heparin or fondaparinux. In the Apixaban for Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First Line Therapy. In oral Apixaban for the treatment of acute venous thromboembolism study(AMPLIFY),7in oral Rivaroxaban for the treatment of acute deep vein thrombosis study (EINSTEIN DVT)5and in oral Rivaroxaban for the treatment of acute pulmonary embolism(EINSTEIN PE)6studies, Apixaban and Rivaroxaban were used according to the ‘single drug’approach and no parenteral pre-treatment was required.The single-drug approach consists of an ini-tial higher dosage of the drug,lasting1week for Apixaban and3weeks for Rivaroxaban,followed by a maintenance dose of the same drug to be continued for the long-term treatment of VTE.The rationale for the increased initial doses of oral anticoagulants are the high risk of recurrence in the early period after diagnosis of VTE and the results of previous studies showing potential lower efficacy of idra-parinux and ximelagatran at maintenance doses as com-pared with conventional treatment in the acute phase.38,39 These different regimens facilitate the management of anticoagulant therapy in different clinical scenarios of acute PE.The safety of NAOCs in the prolonged treatment can induce a further innovation of the therapeutic approach in intermediate-risk patients where the exten-sion of a potentially dangerous therapy often induces an inopportune withdrawal of anticoagulant treatment. Home treatment

The NOACs can facilitate home treatment of VTE. Approximately52and90%of patients included in the EINSTEIN DVT and EINSTEIN PE studies were hospitalized, respectively.Specifically the proportion of patients with PE hospitalized for five days or less was45%in those who received Rivaroxaban and33%in those who received con-ventional anticoagulation.The use of the NOACs with the ‘single drug’approach is of particular interest in patients with PE at low risk of death(sPESI?0).One hundred and six patients with low risk VTE,including35with PE,were treated as outpatients with Rivaroxaban according to the ‘single drug’approach.No recurrence of VTE or major bleeding or clinically relevant non-major bleeding was observed during anticoagulant treatment(0%,95%CI0–3.4%).40,41A final remark on the health facilities is dedicated to patients on anticoagulant therapy.T o date,the patients taking anticoagulant treatment need to be followed by the centres dedicated to monitor the activity of the drug.Now it becomes necessary to implement outpatients’clinics dedi-cated to the clinical disorder where the patient is followed globally.Here anticoagulant treatment is simply one aspect of the management of the disease,rather than the only one. Acute phase therapy:are the NOACs all the same?

Six randomized phase III studies on the treatment of VTE showed the non-inferiority of NOACs as compared with conventional therapy in terms of efficacy,with potential advantage in terms of safety(T able1).

A meta-analysis,including11539patients with PE,con-firmed the improved safety profile of NOACs compared with conventional treatment:OR0.3095%CI0.10–0.95for major bleeding and OR0.89,95%CI0.77–1.03for clinically relevant bleeding.42?Concerning the type of bleeding, pooled data from phase III studies on the treatment of VTE have shown a significant reduction of intracranial bleeding [risk ratio(RR)0.3795%CI0.21–0.68]and fatal bleeding (RR0.3695%CI0.15–0.84).A trend toward reduction in major gastrointestinal bleeding was observed with NOACs as compared with conventional treatment,but further evi-dence is needed on this issue(RR0.78,95%CI0.47–1.31). The net clinical benefit defined as a first episode of a patient-relevant outcome(recurrence of VTE,VTE related mortality or major bleeding),was in favour of NOACs as compared with conventional treatment(3.2%vs.4.0%,RR 0.79,95%CI0.70–0.90),while similar rates of all-cause death were observed in the two treatment groups(RR 0.98,95%CI0.84–1.14).43It is hard to give an indication of the preference of one over the other new oral anticoagu-lants in the acute phase of PE because the primary outcome of non-inferiority for the efficacy and the safety were bril-liantly achieved by all the NOACs.44,45If we analyse the profiles of the patients enrolled in the different trials,we discover that the degree of PE haemodynamic commit-ment,the definition of its anatomic extent,the degree of RVD,its own genesis(provoked or unprovoked),the pres-ence of co-morbidities and the applied therapeutic approach are different;not to mention the type of the study(open-label vs.double-blind).These are the reasons preventing us from the choice of the suitable NOAC.The practical use might make the difference:Rivaroxaban and Apixaban have the advantage of not requiring a preliminary parenteral therapy,even if their dosage has to be adjusted after one(Apixaban)or3weeks’(Rivaroxaban)initial ‘intensive’anticoagulation phase that is useful for the pre-vention of embolic recurrence,observed in previous stud-ies.38,39,46It is difficult to think that the definition of the patient’s risk profile takes place in a single transit in an emergency room.Who has analysed the predictive good-ness of PESI and sPESI scores in post hoc analyses in the NOACs trials says that low-risk patients so identified will nevertheless be treated‘in a clinical decision unit or by a closely monitored outpatient strategy’.47European Society of Cardiology guidelines suggest the possibility of treating these patients as outpatients and always by a close moni-toring strategy.1,48It is necessary to have the time to reflect on the certainty of the diagnosis of embolic disease, during the screening of other diseases.Finally,in situations where it is not immediately certain to be faced with a patient with PE at low risk,we have to make a prudent observation,perhaps to avoid the risk of a thrombolytic therapy or an invasive strategy when the patient has assumed a NOAC.Just for this reason,we suggest a period of48h hospitalization also for the lowest risk patient.We have to consider also the fact that the patients enrolled in the trials are younger(average56years)2,10than the ones we meet in the common clinical practice(average70 years).13The NOACs are more than just an alternative to

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T a b l e 1T h e n o n -v i t a m i n k d e p e n d e n t n e w o r a l a n t i c o a g u l a n t (s )i n t h e a c u t e p h a s e o f v e n o u s t h r o m b o e m b o l i s m

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R e s u l t s i n t e r m s o f e f ?c a c y a n d s a f e t y o f t h e p h a s e I I I c l i n i c a l t r i a l s f o r t h e t r e a t m e n t i n t h e a c u t e p h a s e o f p u l m o n a r y e m b o l i s m o r d e e p v e i n t h r o m b o s i s .C R N M ,c l i n i c a l l y r e l e v a n t n o n -m a j o r b l e e d i n g ;N O A C s ,n o n -v i t a m i n k d e p e n d e n t n e w o r a l a n t i c o a g u l a n t (s );V T E ,v e n o u s t h r o m b o e m b o l i s m ;P E p u l m o n a r y e m b o l i s m ;V K A ,v i t a m i n K a n t a g o n i s t ;D V T ,d e e p v e i n t h r o m b o s i s s t u d y ;U F H ,u n f r a c t i o n a t e d h e p a r i n .

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the standard in the treatment of patients with PE.49We have to prescribe them after understanding the risk of the disease,the origin of the acute embolic event and the vul-nerability of our patient.So we can draw a tailored ther-apy,wise,not hasty.

Disputes about using non-vitamin K dependent new oral anticoagulant(s):the cancer patient,the fragile patient,the patient with renal failure,the obese patient Despite a cost-effectiveness ratio more favourable than traditional therapy,NOACs still have some areas of uncer-tain use,which mainly refers to those categories of patients who are normally under represented in clinical tri-als:cancer,RF,obesity and the so-called‘frail’patient. The‘frailty’refers to elderly patients,generally>75 years old,with co-morbidities,an increased risk of adverse events and/or poor prognosis.50It is not‘static’condition but often‘dynamic’.In clinical trials about VTE,patients>75years are defined‘frail’if they have RF and reduced body weight.In fact,the risk of VTE in patients>85years is100times higher than in patient-s<45years,while the risk of recurrent VTE increases of 15–20%for each decade of age.About25%of patients hospitalized for VTE present RF from moderate to severe.51Unfortunately,in clinical trials the percentage of the elderly>75years is only10–17%with exclusion of patients with creatinine clearance(Cr Cl)<30and 25mL/min(Table2).It is difficult to extend the results of the trials to the‘real’frail patients.In any case,the results of some analyses in the frail patients,showed equivalent effectiveness of Dabigatran,Rivaroxaban and Apixaban and statistically significant superiority of Edoxaban(P?0.0408).Regarding the major bleeding events,no significant difference was observed for Apixaban and Edoxaban,a tendency to higher risk of bleeding in patients>85years treated with Dabigatran vs.placebo and a good safety profile was documented for Rivaroxaban(1.3%vs.4.5%of major bleeding events; HR0.27;95%CI0.13to0.54).However,the inclusion cri-teria showed some differences among trials.3,7,10,52 Regarding chronic RF,due to the different pharmacoki-netics of the molecules,that have a specific elimination, an increased incidence of VTE events and bleeding com-plications during anticoagulant therapy has been docu-mented.53Patients with chronic RF have been excluded from the recruitment in the clinical trials evaluating the NOACs.As a result,the current recommendation about the use of NOACs in these groups of patients comes from the analysis of subgroups and from previous pharmacoki-netic studies.53In short,while in patients with severe RF (Cr Cl<25–30mL/min)the NOACs are contraindicated, in patients with moderate RF(Cr Cl30–50mL/min)they can be used.54It would be prudent to use a FXa inhibitor with a subsequent dose adjustment.For Apixaban,dose reduction is recommended when at least two of the fol-lowing factors are present:age>80years,weight <60kg,and serum creatinine>1.5mg/dL,co-exist; Rivaroxaban does not require a dosage reduction in mod-erate renal impairment and it is not recommended in severe RF;Dabigatran should not be used with a Cr Cl<50mL/min;finally,the recommended dose of Edoxaban in moderate RF is30mg/day.A close follow-up of renal function in these patients is mandatory. Obesity,body mass index(BMI)>30kg/m2,is a known risk factor for VTE events.55In the major trials,it was not an exclusion criterion and it did not provide dose modifica-tions.The percentage of obese patients enrolled was small.In the subgroup studies,the efficacy and the safety of the NOACs in obese patients53were good,although the RE-COVER study showed a non-significant trend towards a higher incidence of VTE events in patients with

Table2The subgroups of fragile patients in the great trials

EINSTEIN DVT/PE(pooled)RECOVER I–II(pooled)AMPLIFY Hokusai-VTE Drug Rivaroxaban Dabigatran Apixaban Edoxaban Number of patients8281510752448240 Average age55575755

Cr Cl<30mL/min22(0.4%)15(0.4%)6(0.1%)29(0.5%) Renal excretion33%80%27%50% Cancer%5.2%%5%%3%%9%

Recommended dose in the presence of moderate Cr Cl30–50mL/min kidney failure()15mg/b.i.d.for3weeks

followed by20mg/day

150mg/b.i.d. 2.5mg/b.i.d.30mg/day

Pre-speci?ed subgroups

Age>75aa1283(15.5%)529(10.4%)749(14.3%)1104(13.4%) Kidney Failure

Cr Cl30–49mL/min654(7.9%)–541(6.6%) Cr Cl<80mL/min1373(26.9%)1388(26.5%)

Weight

Weight<50Kg108(1.3%)57(1.1%)n.a.

Weight<60Kg457(8.7%)1043(12.7%) Main epidemiological data on frail patients in the trials with the NOACs.

n.a.,not applicable;DVT,deep vein thrombosis study;PE,pulmonary embolism;VTE,venous thromboembolism;Cr Cl,Creatinine Clearance.

D298I.Enea et al.

BMI>30kg/m2,2these data seem to be in contrast with the results of the Randomized Evaluation of Long-term antico-agulant TherapY study(RE-L Y).56

Cancer and VTE are closely associated.From‘Registro Informatizado de la Enfermedad Thromboembolica Venosa’(RIETE)observations,VTE event occurs in20%of patients with cancer and in patients with VTE cancer was present in20%of cases.57Moreover,VTE is a negative prog-nostic factor in patients with cancer.58Currently,the LMWHs are the first-line therapy in patients with cancer and VTE due to their better efficacy and safety profile com-pared to Warfarin with respect to the reduction of VTE recurrences.The potential benefits of the NOACs can also be extended to patients with cancer,especially in the medium to long-term therapies.Unfortunately,there is no a randomized trial specifically designed for cancer patients.The scientific data available derived from the analysis of subgroups in which the NOACs were compared with the combination therapy of LMWHs/VKAs showed for all the NOACs a safety and efficacy comparable to non-cancer patients.58These observations were confirmed by three recent meta-analyses and systematic reviews.59–61In each observation,the risk of VTE and/or VTE-related death was comparable with the traditional therapy as well as the safety profile.These data,however,should be carefully interpreted because of the small number of very selected cancer patients randomized and the lack of direct confron-tation with LMWHs,first-line therapy.

Briefly,the profile of efficacy and safety of the NOACs and their favourable pharmacokinetic and pharmacody-namic characteristics together with the preliminary results of the subgroups support the use of the NOACs even in eld-erly and frail patients,obesity,or moderate renal impair-ment.The absence of trials built on these patients and the ‘nuanced’differences in the criteria of analysis among sub-groups makes it difficult to do a direct comparison among NOACs.

On the other hand,the complexity of the patients that occurs in clinical practice,where multiple co-morbidity rather than‘isolated factors of frialty’often co-exist,does not allow to provide simple formulas to guide medical ther-apy.It will be the correct assessment of the patients’com-plexity and their risk benefit ratio that will lead us to choice the best treatment for each patient.As far as the cancer patients are concerned,on the contrary,the poten-tial benefit of the NOACs will be supported by dedicated clinical trials.T oday it is not possible to recommend their widespread use in this setting.

The use and the duration of the non-vitamin K dependent new oral anticoagulant(s)in

the extended phase

After the first episode of PE the existing guidelines recom-mend at least3months’anticoagulant therapy in all patients.1,48They give no precise details concerning on how to conduct FU and anticoagulant therapy duration. Follow-up generally ceases with the suspension of anticoa-gulant therapy even though,after a PE episode,the patients have a higher overall mortality than the control population and may experience MI,stroke,PE recurrence, and seldom develop a chronic pulmonary hypertension.62 Stages and duration of treatment

The extended phase(>3months)of anticoagulant therapy is aimed at reducing the risk of PE recurrence if not related to acute episode.48The duration of treatment depends on the risk of PE recurrence,on the bleeding risk,on the pref-erence of the individual patient.In cases of unprovoked PE,various predictive models for identifying patients at low risk of recurrence have been proposed63–65but none of them has been validated in prospective studies.

The annual incidence of major bleeding during anticoa-gulant therapy varies from0.8to over6%,and the annual incidence of fatal bleeding is between0.1and0.5%66–68 while,the rate of major bleeding during the first3months’anticoagulant therapy is about3%.The American College of Chest Physicians GL proposed a score of bleeding risk based on a number of variables derived from the literature.48

Extended therapy:traditional anticoagulant therapy limits

With regard to LMWHs,the limits are represented by the route of administration,the risk of thrombocytopenia,the reduced excretion in RF,and the possible risk of osteoporo-sis in prolonged use.The use of Fondaparinux is limited by parenteral administration,moderate RF or severe RF and there are also poor security data in the event of extended use.Vitamin K inhibitors have several limitations such as a narrow therapeutic window,an unpredictable response,an action to slow onset and cessation,the need for monitor-ing,and the interactions with food and drugs.

Extended therapy:the non-vitamin K dependent new oral anticoagulant(s)

They present some substantial advantages:a rapid onset of action,a short half-life,the absence of an important inter-actions with food or other drugs,less risk of brain bleeding and they don’t require a routine monitoring.The disadvan-tages include:the unavailability of a laboratory test stand-ard for a quantitative evaluation of the effect of drugs in case of major bleeding,emergency surgical procedure; they are also contraindicated if Cl Cr<30mL/min,69,70 lastly,for their use,a good reliability in the regular drug assumption by patients is necessary.

Clinical trials and the extended phase

The studies so far published on the NOACs have dealt with the extended phase but not the indefinite one;in just one study,secondary prevention of venous thromboembolism twice-daily oral direct thrombin inhibitor Dabigatran etexi-late in the long-term prevention of recurrent symptomatic VTE(RE-MEDY)4there was a direct comparison with Warfarin while in others the comparison was placebo.

In the RE-MEDY study4Dabigatran was found to be not inferior to Warfarin in secondary prevention of VTE,the study showed less major haemorrhagic or clinically rele-vant events in the Dabigatran group compared to Warfarin; an increased incidence of acute coronary events in the

The use of non-vitamin K dependent new oral anticoagulant(s)in pulmonary embolism D299

Dabigatran group was also observed,as already shown in RE-L Y study .56This increase was not detected in the placebo-control study ,Secondary Prevention of venous thromboembolism twice-daily oral direct thrombin inhibi-tor Dabigatran etexilate in the long-term prevention of recurrent symptomatic VTE,RE-SONATE and this suggested that the Dabigatran does not increase acute coronary events but it prevents them less than Warfarin.71,72

In the EINSTEIN-Extension study the Rivaroxaban group had a significant recurrence reduction of VTE compared to placebo;similar to the findings with Dabigatran,major and clinically relevant bleedings were more frequent in the Rivaroxaban group than in the placebo group;Rivaroxaban has not been compared in the extended phase with the VKAs.4,5

Venous thromboembolism recurrence and death were found significantly reduced by both dosages of Apixaban vs.placebo in the AMPLIFY -Extension study .8Both 2.5and 5mg Apixaban dosages showed no major or clinically rele-vant bleeding increase compared to placebo.These latest dosages make the use of Apixaban in the extended phase of VTE therapy attractive.Apixaban was also not compared with the VKAs in the extended phase (T able 3).

When to prefer non-vitamin K dependent new oral anticoagulant(s)and when vitamin K inhibitors

In randomized clinical trials younger patients,with low risk of bleeding,no strong indication to continue the anticoagu-lant therapy and with less comorbidity compared with real life,were enrolled;underweight patients,obese people were poorly represented.The data coming from the use of the NOACs in the real world are of some concern as they appear to highlight major bleeding fourfold more than the ones reported from clinical studies.73Possible clarifications regarding the current limitations on the use of the NOACs may come from ad hoc trials.74,75As for efficacy ,NOACs have given excellent results in the extended phase of the VTE https://www.wendangku.net/doc/db9229476.html,pared with traditional therapy ,they showed less bleeding events.70It is likely that,as it was said,their use can be particularly advantageous,compared with traditional therapy in patients at higher risk of recur-rence of VTE who require protracted prophylactic therapy .Non-vitamin K dependent new oral anticoagulant(s)are to be preferred:in presence of logistical problems for VKAs monitoring;if time in the therapeutic range (TTR)is <60%;in patients with a history of cerebral haemorrhage;at the express request of patients,if they are proved to be reliable.

On the contrary the preference falls on VKAs if the TTR is >60%,in the presence of low risk of bleeding or severe RF ,Cl Cr <30mL/min and finally in likely poor compliance in regular intake of NOACs.

Clinical and laboratory follow-up in the non-vitamin K dependent new oral anticoagulant(s)patient

The NOACs are drugs that,for their pharmacological and pharmacodynamic profile,guarantee a rapid mechanism of

T a b l e 3

T h e m a i n t r i a l s i n l o n g -t e r m t r e a t m e n t o f p u l m o n a r y e m b o l i s m

D r u g

T r i a l

C o m p a r i s o n

D e s i g n

E x p e c t e d r e d u c t i o n

T r e a t m e n t t i m e P a t i e n t s n

V T E i n t h e c h e c k

R e d u c e d r i s k o f V T E r e c u r r e n c e

M a j o r b l e e d i n g o r C R N M i n t h e a c t i v e g r o u p

D a b i g a t r a n 150b .i .d .R

E S O N A T E

P l a c e b o

S u p e r i o r i t y

70%

6m o n t h s

1343

5.6%

92%

5.3%v s .1.8%(tC R N M ;P ?0.001)D a b i g a t r a n 150b .i .d .

R E -M E D Y

W a r f a r i n

N o n -i n f e r i o r i t y

A b s o l u t e i n c r e a s e <2.818–36m o n t h s

2856

1.3%

R i s k r e d u c t i o n 0.38%v s .a V K

5.6%v s .10.2%(W a r f a r i n )(tC R N M ;P <0.001)A p i x a b a n 5m g b .i .d .A M P L I F Y E x t

P l a c e b o

S u p e r i o r i t y

41%

12m o n t h s

2486

8.8%

80%

4.2%v s .2.7%(tC R N M ;P ?n s )A p i x a b a n 2.5m g b i d 81%

3.0%v s .2.7%(tC R N M ;P ?n s )R i v a r o x a b a n 20m g

E I N S T E I N -E x t

P l a c e b o S u p e r i o r i t y 50%6–12m o n t h s

11977.1%82%

6.0%v s .1.2%(tC R N M ;P <0.001)

R e s u l t s i n t e r m s o f r e d u c e d r i s k o f V T E r e c u r r e n c e a n d m a j o r b l e e d i n g o r C R N M .P E ,p u l m o n a r y e m b o l i s m ;V T E ,v e n o u s t h r o m b o e m b o l i s m ;C R N M ,c l i n i c a l l y r e l e v a n t n o n -m a j o r b l e e d i n g .

D300I.Enea et al.

action,efficacy stable in time and a short half-life useful in the case of preparation of such surgery(T able4).The administration of fixed doses of the drugs is useful to avoid oscillations of the effectiveness in terms of anticoagulant effect and to avoid the need of periodic blood sampling; finally,the minimal interaction with foods and/or with other drugs makes more favourable their pharmacokinetic characteristics and pharmaco-dynamics.76

As regards the principal pharmacological features,the direct thrombin inhibitors are small synthetic molecules that bind to the active sites of the thrombin inhibiting both free thrombin and the bound one.77,78

Direct FXa inhibitors work by blocking both free FXa,and the one that is incorporated into the prothrombin complex. The FXa block has several theoretical advantages:the pro-duction of thrombin is inhibited both by the intrinsic and extrinsic pathway.76

As known,current guidelines recommend evaluating Cr Cl before starting NOACs.Inpatients with normal renal function or mildly impaired,the reassessment will be per-formed annually,while inpatients with moderate renal impairment(30

?the degree of adherence to treatment;

?the occurrence of adverse reactions(thrombotic and/ or haemorrhagic events);

?the concomitant risk of drug interactions;

?some laboratory parameters(T able5),when necessary; Recently,the results of the study reverse effect of idaru-cizumab on active Dabigatran(RE-VERSE AD)87have led to the approval of the first specific reversal agent,the idaru-cizumab,which specifically binds the molecules of Dabigatran.Other antidotes,PER977,88andexanet-alpha89 are currently under investigation.

Non-vitamin K dependent new oral anticoagulant(s)in everyday clinical practice:drug-drug interactions,protocol for the treatment of bleeding and periopera-tive management

Drug-drug interactions

Despite the lower number of drug–drug interactions com-pared with VKAs,a careful assessment of patients’comorbid-ities and of concomitant therapies is required when prescribing NOACs.The characteristics of the individual NOACs in terms of absorption,metabolism,elimination,and known interactions should be considered.An important mechanism of interaction common to all the NOACs is the significant re-secretion over a P-glycoprotein transporter after absorption in the intestines.Therefore,competitive inhibition of this pathway will result in increased plasma lev-els of NOACs.90Many commonly used drugs,especially in

Table4Mechanism of action and main pharmacological characteristics of the non-vitamin K dependent new oral anticoagulant(s)

Dabigatran Rivaroxaban Apixaban Edoxaban

Target Factor IIa(thrombin)Factor Xa Factor Xa Factor Xa

Reaching peak dose 1.25–3h2–4h3–4h1–2h

Prodrug Yes No No No

Metabolism via CYP No32%15%<4%

Transport P-gp P-gp P-gp P-gp

Bioavailability6%80%60%62%

Absorption with food No Effectt39%No Effectt6–22%

Taking with food With or without food With or without food,

preferably with meals

With or without food With or without food

Protein binding35%93%87%50%

Half-life14–17h(BID)7–11h(QD/BID)8–15h(BID)10–14h(QD)

Renal excretion80%33%25%35%

Absorption H2B/PPIà12–30%No No No

Gastrointestinal tolerability Dyspepsia(5–10%)No Effect No Effect No Effect

The use of non-vitamin K dependent new oral anticoagulant(s)in pulmonary embolism D301

patients with atrial fibrillation as verapamil,dronedarone and amiodarone are inhibitors of P-glycoprotein and their concomitant use can increase plasma levels of NOACs.91The inducers of the P-glycoprotein can significantly reduce plasma levels of NOACs.Whether the change in plasma levels is clinically significant in terms of increased bleeding or thrombotic risk depends on the degree of interaction. Rivaroxaban and Apixaban have hepatic metabolism by CYP3A4(P450).The induction or inhibition of this cyto-chrome may influence the plasma levels of these drugs sub-stantially and therefore their use is not recommended concomitantly with strong inducers/inhibitors such as rifam-picin92or carbamazepine.Only a small proportion of Edoxaban is metabolized by CYP3A4,while this type of metabolism is not described for Dabigatran.NOACs are also contraindicated in patients receiving antiretroviral therapy; no clinical data are currently available on potential interac-tions with other drugs such as anticancer therapies(T able6). Management of bleeding complications

Current GL recommend the use of prothrombin complex concentrates(PCC)to restore the levels of clotting factors in patients who experience major bleeding during treat-ment with VKAs.93A rapid normalization or otherwise a sig-nificant reduction of the clotting times is observed early after infusion of PCC.However,no definitive data are cur-rently available on the clinical benefit associated with the use of these agents.With regard to the NOACs,the admin-istration of PCC led to the complete and rapid normaliza-tion of coagulation time in healthy volunteers treated with Rivaroxaban,but no effect was observed in healthy volun-teers treated with Dabigatran.94Therefore,the use of the PCC is recommended in patients experiencing major bleed-ing during treatment with anti-Xa agents but not with Dabigatran.Promising results are currently available on the role of specific agents,antidotes,designed to reverse the anticoagulant effect of NOACs.Idarucizumab,an anti-body fragment developed to block the anticoagulant effect of Dabigatran,obtained a complete normalization of coag-ulation within minutes when given as a single intravenous bolus in90patients with severe bleeding or need for inva-sive procedures in emergency.95,96Andexanet alfa,a recombinant molecule of human FXa modified to be cata-lytically inactive but to retain high binding affinity for

Table5Non-vitamin K dependent new oral anticoagulant(s)patient follow-up management

Follow-up Check Parameter Drug

Dabigatran Rivaroxaban Apixaban Edoxaban Baseline lab test Haemoglobin

Creatininemia

ALT,AST

First month and each visit Events Thrombosis and/or bleeding

Adherence Remaining drug

Interaction P-gp e CYP3A4

Third month(Only if creatinine clearance 30–60mL/min)Events Thrombosis and/or bleeding Adherence Remaining drug Interaction P-gp e CYP3A4

lab test Haemoglobin

Creatininemia

ALT,AST

Sixth month(Only if creatinine clearance 30–60mL/min)Events Thrombosis and/or bleeding Adherence Remaining drug Interaction P-gp e CYP3A4

lab test Haemoglobin

Creatininemia

ALT,AST

Every12th month (long-term therapy)Events Thrombosis and/or bleeding Adherence Remaining drug Interaction P-gp e CYP3A4

lab test Haemoglobin

Creatininemia

ALT,AST

Speci?c indication (Thromboembolic events,acute bleeding, surgery,etc.)Lab test INR

PT

aPTT

Diluted TT

Chromogenic anti-FXa

ECT

ALT,alanine aminotransferase;AST,aspartate aminotransferase;P-gp,P-glycoprotein;CYP3A4,CytochromeP4503A4;QD,once a day;BID,twice a day;PPI,Proton Pomp Inhibitors;INR,international normalized ratio;PT,prothrombin time;aPTT,activated partial thromboplastin time;TT,throm-bin time;aFX,Activated Factor X;ECT,ecarin aggregation time;ULN,above the upper limit.Green,in favour literature data;Red,negative litera-ture data;Yellow,inconclusive literature data.

D302I.Enea et al.

indirect FXa inhibitors,reversed the anticoagulant effect of Apixaban in34volunteers.97The clinical development of small molecules capable of antagonizing the effect of several parenteral and oral anti Xa agents has started. However,given the short half-life of the NOACs,the clini-cal value of antidotes in real life remains to be determined. Activated charcoal should be used in all patients who had last dose of NOACs in the previous2h(Figure1). Perioperative management

The perioperative management of patients on NOACs for the treatment of VTE should take into account the time since the acute thromboembolic event(T able7).Invasive proce-dures should be delayed beyond3months from acute throm-boembolism whenever it is possible.non-vitamin K dependent new oral anticoagulant(s)should be discontinued at least48h before surgery(a longer time is needed in patients with concomitant kidney failure).98Antithrombotic prophylaxis of VTE should be started as soon as possible after surgery and anticoagulant therapy resumed as soon as adequate haemostasis is obtained.If surgery is required in the first3months from acute VTE,the insertion of a vena cava filter should be considered and the interruption of anti-coagulant treatment should be as short as possible.

Table6Main drug-drug interactions

Apixaban Dabigatran Rivaroxaban Edoxaban

Contraindicated or not recommended

HIV Protease Inhibitors

Rifampicin

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Carbamazepine

Phenobarbital

Phenitoine

St.John’s wort

Rifampicin

Carbamazepine

Phenobarbital

Phenitoine

St.John’s wort

Dronedarone Cyclosporin

Tacrolimus

Dronedarone

Dronedarone

Reduced dose

of NOACssuggested —Verapamil—Clarithromycine

Erythromycine

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Cyclosporin

Tacrolimus

Dronedarone

Interaction with no requirement for dose adjustment a Diltiazem Clarithromycine

Erythromycine

Amiodarone

Quinidine

Clarithromycine

Erythromycine

Fluconazole

Amiodarone

Verapamil

Amiodarone

Quinidine

No effect or minor interaction PPI PPI

Atorvastatin

Digoxin

Diltiazem

PPI

Atorvastatin

Digoxin

Diltiazem

Verapamil

PPI

Atorvastatin

Digoxin

No data available Atorvastatin

Clarithromycine

Erythromycine

Fluconazole

Cyclosporin

Tacrolimus

Amiodarone

Digoxin

Quinidine

Verapamil Fluconazole Cyclosporin

Tacrolimus

Quinidine

Fluconazole

Diltiazem

Table derived from EHRA2015recommendation.

NOACs,non-vitamin K dependent new oral anticoagulant(s).

aIf!2drugs in this category,or if1drug and one among age!75years or body weight60kg or Creatinine clearance50mL/min consider con-ventional therapy(no data available on the ef?cacy and safety of NOACs in the treatment of venous thromboembolism except for Apixaban2.5mg twice daily during extended treatment and Edoxaban30mg once daily).

The use of non-vitamin K dependent new oral anticoagulant(s)in pulmonary embolism D303

Practical suggestions

(1)In suspected PE,a blood pressure measurement

allows us to define the haemodynamic stability,and thus ‘high risk “or”not-high risk’PE.

(2)Prognostic stratification of PE patients based on

clinical,through PESI or sPESI score that is added to the assessment of bio-markers of myocardial damage and the function of the right ventricle at echocardiography allow us to distinguish

intermediate mortality risk patients in intermediate-high risk and intermediate-low risk.(3)

The NOACs can be used as an alternative to tradi-tional therapy both in low-intermediate and in low risk patients.

(4)

The NOACs envisage the evenience of short hospi-talizations for the lowest risk patients for whom we suggest a 48h observation.

(5)

In intermediate-high risk patients with PESI class III–V or sPESI !1,in the presence of positive tropo-nin and of right ventricular dysfunction,we rec-ommend a ‘wait and watch’strategy and the possibility of using thrombolysis precludes,at the time,NOACs therapy;even if after the acute phase,if there is right ventricular function improvement,we envisage the therapy with NOACs,waiting for definitive clinical evidence in this population.

(6)

Therapeutic innovation of the NOACs consists in the way of the therapy administration,with ‘double drug single dose therapy’,for Dabigatran (150mg twice daily)and Edoxaban (60mg daily mono-administration),or a ‘single drug therapy’with Rivaroxaban (15mg ?2x daily for 21days,then 20mg daily)or Apixaban (10mg ?2twice daily for 7days,then x2.5mg twice daily).

(7)

In step ‘extended’the use of the NOACs exceeds the limits of traditional therapy but all the studies with NOACs have not dealt with the indefinite phase and,also,in only one study,they were com-pared with Warfarin.So,to date,patients,who we feel may benefit from treatment with the NOACs in the extended phase,are all na?¨

ve

Figure 1Management of patients with bleeding while on treatment with non-vitamin k dependent new oral anticoagulant(s).

Table 7Periprocedural management in patients on treatment with non-vitamin K dependent new oral anticoagulant(s)Elective major surgery

3months since last acute venous thromboembolism

Delay surgery !3months since acute venous thromboembolism,if possible Stop NOACs !48h before surgery

Consider pre-operative vena cava ?lter insertion (post-operative insertion if contraindications for resumption of anticoagulation 5days from surgery)Start antithrombotic prophylaxis as soon as possible as in non-NOACs patients In the absence of vena cava ?lter resume anticoagulant treatment <5days from Surgery

!3months since last acute venous thromboembolism Stop NOACs !48h before surgery

Start antithrombotic prophylaxis as soon as possible as in non-NOACs patients If indicated,resume anticoagulant treatment !5days from surgery Urgent surgery/invasive procedure

Stop NOACs and assess time of last intake and regimen

Assess blood cells count and renal function.Consider coagulation tests activated charcoal (30–50g)if last NOAC intake <2h

consider pre-operative vena cava ?lter insertion if <3months since last acute venous thromboembolism,

Administer plasma if intra-or peri-operative unexpected bleeding Give red blood cells if needed

Delay surgery !12h since last NOAC intake,if possible surgery required <12h since last NOAC intake:

(a)use antidote,if available,or PCC 30–50UI/Kg (repeat 25UI/Kg if intraoperative unexpected bleeding)

NOACs,non-vitamin K dependent new oral anticoagulant(s).

D304I.Enea et al.

patients with idiopathic VTE intermediate-low,

low risk,and among patients already on treatment

with VKAs,those with logistical problems for the

monitoring of VKAs,if the TTR is<60%;in patients

with a history of cerebral haemorrhage.Patients,

being treated with VKAs,continue this therapy if

the TTR is>60%;preference instead fall back on

VKAs if patients with severe RF,Cr Cl<30mL/min

or likely poor compliance in the regular intake of

NOACs.

(8)With regard to efficacy and safety in special popu-

lations of patients:there are no dosage adjust-

ments up to BMI30;severe RF(Cr Cl<25–30mL/

h)contraindicates the use of the NOACs;in regard

to cancer patients,missing a dedicated clinical

trial and a study by comparison with LMWHs,it is

not yet possible to advise,based on available

data,their widespread use in this area and LMWHs

remain the therapy of choice in patients with

cancer;

(9)We point out the need for clinical-laboratory mon-

itoring,in elderly patients with renal and/or hep-

atic insufficiency according to criteria specified in

the text.

(10)As regards the bleeding risk the FDA has approved

the use of idarucizumab monoclonal antibody for

Dabigatran;the andexanet alpha is being tested;

the PCC have proved effective in the case of

Rivaroxaban;for all the NOACs we recommend the

use of activated carbon two hours after intake.

Lastly we indicate a practical‘table’for the peri-

operative management of patients on NOACs. Consensus Document Approval Faculty Abrignani Maurizio Giuseppe,Alunni Gianfranco,Amico Antonio Francesco,Amodeo Vincenzo,Angeli Fabio, Aspromonte Nadia,Audo Andrea,Battistoni Ilaria,Bianca Innocenzo,Bisceglia Irma,Bonvicini Marco,Cacciavillani Luisa,Calculli Giacinto,Caldarola Pasquale,Capecchi Alessandro,Caporale Roberto,Caretta Giorgio,Casolo Giancarlo,Cassin Matteo,Casu Gavino,Cemin Roberto, Chiaranda Giacomo,Chiarella Francesco,Chiatto Mario, Cibinel Gian Alfonso,Ciccone Marco Matteo,Clerico Aldo, Colivicchi Furio,De Luca Giovanni,De Maria Renata,Del Sindaco Donatella,Di Fusco Stefania Angela,Di Lenarda Andrea,Di T ano Giuseppe,Egidy Assenza Gabriele,Egman Sabrina,Fattirolli Francesco,Favilli Silvia,Ferraiuolo Giuseppe,Francese GiuseppinaMaura,Gabrielli Domenico, Geraci Giovanna,Giardina Achille,Greco Cesare,Gregorio Giovanni,Iacoviello Massimo,Khoury Georgette,Ledda Antonietta,Luca Fabiana,Lukic Vjerica,Macera Francesca,Marini Marco,Masson Serge,Maurea Nicola, Mazzanti Marco,Mennuni Mauro,Menotti Alberto,Menozzi Alberto,Mininni Nicola,Moreo Antonella,Moretti Luciano, Mortara Andrea,Mureddu Gian Francesco,Musumeci Giuseppe,Navazio Alessandro,Nicolosi Pier Luigi,Oliva Fabrizio,Parato Vito Maurizio,Parrini Iris,Patane Leonardo,Pini Daniela,Pino Paolo Giuseppe,Pirelli Salvatore,Procaccini Vincenza,Pugliese Francesco Rocco,Pulignano Giovanni,Radini Donatella,Rao Carmelo Massimiliano,Riccio Carmine,Rossini Roberta,Ruggieri Maria Pia,Sanna Fabiola,Sauro Rosario,Severi Silva,Sicuro Marco,Sisto Francesco,T arantini Luigi,Uguccioni Massimo, Urbinati Stefano,Valente Serafina,Vianello Gabriele,Zuin Guerrino.

Conflict of interest:none declared.

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2021年急性肺栓塞诊断和治疗(全文)

2021年急性肺栓塞诊断和治疗（全文） 摘要 急性肺栓塞发病率高，症状的不典型性容易引起误诊。诊断和危险分层决定了急性肺栓塞的治疗策略。抗凝和系统性溶栓是几十年来的主要的治疗选择，腔内介入技术越来越多地应用于急性肺栓塞的治疗中。尤其对于存在出血风险的病人，可能可以达到降低病人的总体风险，改善预后的作用。仍需要大规模高质量研究数据提供更多临床证据完善相关诊疗方案。 急性肺栓塞（pulmonary embolism，PE）是全球第三大心血管病死亡原因。以往常常认为静脉血栓栓塞症（venous thromboembolism，VTE）的发病率在亚洲人群中低于西方国家。近年来随着临床医师对该疾病的重视程度日益增长、影像学技术的广泛应用，对于VTE的诊治率得到大大提高［1－2］。由于大多数急性PE病人的死亡发生在最初的数小时或数天，＜70％的死亡发生在第一个小时，因此，早期识别和诊断PE，并进行适当的干预至关重要。 1 急性PE的诊断和危险分层

1.1 急性PE的诊断急性PE的症状表现多种多样，由于缺少特异性症状，临床上容易误诊漏诊。临床表现与血管栓塞栓子的多少、发生的速度和心肺的基础状态有关，包括呼吸困难、心动过速、氧饱和度下降、胸痛、晕厥、低血压等，胸背部或胁肋部压痛可能是肺梗死的表现。轻者可以无症状，严重者发生猝死。在临床上如果有以下情况，应注意警惕PE 的发生：与肺部体征不相称、难以用基础肺部疾病解释的呼吸困难；呼吸困难但病人可以平卧；突发昏厥或休克；急性右心室负荷增加的临床表现，特别对于长期卧床、手术史等有下肢深静脉血栓形成危险因素的病人。通过整体病史和临床表现预测PE的可能性常用的量表有修正的Geneva评分和Wells评分。笔者中心常采用Wells评分进行评估。在辅助检查方面，常规胸部X线检查和心电图很难发现特异性改变。D－二聚体已是公认的PE首选的筛选检查。它具有很高的敏感度，但特异度低，肿瘤、创伤、感染、心脑血管疾病和年龄因素都可能使D－二聚体升高。其阴性结果可基本排除PE。但由于阳性预测值低，阳性结果不能确诊PE。经食管超声心动图（transesophageal echocardiography，TEE）可以发现心内或肺动脉主干的栓子，并能观察到右心室负荷过重的征象。肺动脉CT血管成像（CTA）是诊断PE的金标准，其敏感度和特异度高。在肺动脉CTA中可以观察到肺动脉腔内充盈缺损或完全阻断。肺通气灌注核素扫描（V/Q）可用于不适合行CTA的病人，或当病人无法进行CTA使用便携式V/Q扫描。当怀疑有PE且无法进行肺血管检查时，双下肢静脉超声检查可能是一种辅助方法。诊断流程和检查方法的选择主要基于病人的PE临床可能性预测，见图1。

中国急性肺栓塞诊断与治疗指南(2020年)

中国急性肺栓塞诊断与治疗指南（2020年） 急性肺栓塞（pulmonary embolism，PE）是我国常见的心血管系统疾病[1]，在美国等西方国家也是常见的三大致死性心血管疾病之一[2]。PE是内源性或外源性栓子阻塞肺动脉引起肺循环障碍的临床和病理生理综合征，包括肺血栓栓塞症、脂肪栓塞综合征、羊水栓塞、空气栓塞、肿瘤栓塞等。其中肺血栓栓塞症(pulmonary thromboembolism，PTE)是最常见的PE 类型，指来自静脉系统或右心的血栓阻塞肺动脉或其分支所致疾病，以肺循环和呼吸功能障碍为主要临床表现和病理生理特征，占PE的绝大多数，通常所称的PE即指PTE。深静脉血栓形成(deep venous thrombosis，DVT)是引起PTE的主要血栓来源，DVT多发于下肢或者骨盆深静脉，脱落后随血流循环进入肺动脉及其分支，PTE常为DVT的合并症。由于PTE与DVT在发病机制上存在相互关联，是同一种疾病病程中两个不同阶段的临床表现，因此统称为静脉血栓栓塞症(venous thromboembolism，VTE)。本指南相关推荐主要针对血栓性PE，非血栓性PE发病率低，临床证据很有限，暂不做相关推荐。 近年来，对PE的认识不断提高，但临床实践中仍存在误诊、漏诊或诊断不及时，以及溶栓和抗凝治疗等不规范问题。2010年中华医学会心血管病学分会肺血管病学组、中国医师协会心血管内科医师分会专家组编写了“急性肺血栓栓塞症诊断治疗中国专家共识”[3]，对规范我国急性PE的诊断流程和治疗策略，提高我国急性PE的诊治水平起到了极大了推动作用。在此后的5年中，肺血管疾病领域发展迅速,尤其在PE患者诊断、评估和治疗等方面，大量临床试验结果的发表，提供了新的循证医学证据，过去的指南已不能满足临床医师的需要。为此，中华医学会心血管病学分会肺血管病学组专家组在2010年专家共识的基础上，对新近出现的临床证据系统研判，并参考国际最新急性PE诊断和治疗指南[4]，经认真研究讨论，达成共识，制订了本指南。与我国2010年专家共识相比，本指南在易患因素、危险分层、诊断治疗策略、新型口服抗凝剂、慢性血栓栓塞性肺高压等方面进行了更新，并对妊娠期和肿瘤患者PE的治疗给出正式推荐，旨在为PE的诊治提供依据和原则，帮助临床医师作出医疗决策，但在临床实践中面对每一个具体患者时，应该根据个体化原则制定诊疗措施。 为了便于读者了解诊疗措施的价值或意义，多因素权衡利弊，本指南对推荐类别的表述仍沿用国际上通常采用的方式： I类：指那些已证实和(或)一致公认有益、有用和有效的操作或治疗，推荐使用。 Ⅱ类：指那些有用／有效的证据尚有矛盾或存在不同观点的操作或治疗。 Ⅱa类：有关证据／观点倾向于有用／有效，应用这些操作或治疗是合理的。 Ⅱb类：有关证据／观点尚不能充分证明有用／有效，可以考虑应用。 Ⅲ类：指那些已证实和(或)一致公认无用和(或)无效，并对一些病例可能有害的操作或治疗，不推荐使用。 对证据来源的水平表达如下： 证据水平A：资料来源于多项随机临床试验或荟萃分析。 证据水平B：资料来源于单项随机临床试验或多项非随机对照研究。 证据水平C：仅为专家共识意见和(或)小规模研究、回顾性研究、注册研究。 一、流行病学 急性PE是VTE最严重的临床表现，多数情况下PE继发于DVT，现有的流行病学多将VTE作为一个整体进行危险因素、自然病程等研究，其年发病率100-200/10万人[5,6]。 PE可以没有症状，有时偶然发现才得以确诊，甚至某些PE患者的首发表现就是猝死，因而很难获得准确的PE流行病学资料。根据流行病学模型估计[6]，2004年总人口为4.544亿的欧盟6国，与PE有关的死亡超过317,000例。其中，突发致命性PE占34％，其中死前未能确诊的占59％，仅有7％的早期死亡病例在死亡前得以确诊。PE的发生风险与年龄增加相

肺栓塞的快速识别和治疗技术

肺栓塞的快速识别和治疗技术 肺栓塞（PE）是一种常见的临床急症，具有高发病率、高漏诊率、高死亡率、低检出率的“三高一低”特点，必须引起临床医师的重视。 一、肺栓塞的定义 肺栓塞是一种因内源性或外源性栓子阻塞肺动脉引起肺循环障碍的临床和病理生理综合征。包括肺血栓栓塞征、脂肪栓塞综合征、羊水栓塞、空气栓塞、肿瘤栓塞等。 1.大面积肺栓塞（高危） 急性肺栓塞伴有持续性低血压（收缩压<90mmHg至少15分钟，排除非肺栓塞所致的心律失常、血容量不足、败血症或左室功能障碍）、症状性心动过缓（有休克症状或体征，且心率<40次/分）。 2.次大面积肺栓塞（中危） 急性肺栓塞不伴低血压（收缩压≧90mmHg），但有右心室功能障碍或心肌缺血证据。 3.低危肺栓塞 存在急性肺栓塞但缺乏大面积及次大面积肺栓塞的临床指标。 二、肺栓塞的临床表现 肺栓塞的临床表现多样，缺乏特异性，可以无症状，也可以表现为血流动力学不稳定，甚至发生猝死。主要取决于栓子的大小、多少、栓塞部位和范围、发病速度、发病前的心肺功能状态。临床上所谓的“肺栓塞三联征”（呼吸困难、胸痛及咯血）不足30%。表1为肺栓塞的常见症状及其发生概率。

表1肺栓塞常见症状及其发生概率 三、肺栓塞临床预测评分 2014年欧洲心脏病学会（ESC）发布了第3版急性肺栓塞诊断和治疗指南，对肺栓塞的临床判断评分进行了修订，如表2。 表2肺栓塞临床预测评分 四、发现可疑肺栓塞患者 1.有静脉血栓栓塞症的易发因素，如骨折、骨科手术史、久坐不动（如乘坐长途车或飞机）、卧床>3天、静脉曲张等。

2.突发“原因不明”的气短、胸痛、咯血、晕厥、低血压、紫绀，低氧血症、慢性阻塞性肺病（COPD）恶化、手术后肺炎等。 3.注意排除急性心肌梗死、主动脉夹层、肺炎、胸膜炎等。 4.常规行D-二聚体检测，做出排除诊断。 5.超声检查。 五、辅助检查 1.动脉血气分析 2.血浆D-二聚体 血浆D-二聚体对急性肺栓塞具有较大的排除诊断价值，若其含量低于500μg/L，可基本除外急性肺栓塞。但手术、外伤、肿瘤、感染及组织坏死等情况D-二聚体也可增高。因此，其阴性预测价值较大，主要用于排除诊断。 3.心电图 图1肺栓塞心电图表现1

急性肺栓塞的诊断与治疗

急性肺栓塞的诊断与治疗 南昌大学第三附属医院 南昌市第一医院心内科 郑春华 肺栓塞(PE)是指各种栓子阻塞肺动脉系统为其发病原因的一组疾病或临床综合征的总称，包括肺血栓栓塞、脂肪栓塞综合征，羊水栓塞、空气栓塞等。 肺血栓栓塞(PTE)是指来自静脉系统或右心的血栓阻塞肺动脉或其分支所致的疾病，以肺循环和呼吸功能障碍为其主要临床病理生理特征。 PTE是最常见PE。 15%发生肺梗死 深静脉血栓形成(DVT) 症状 典型肺梗死三联症状（呼吸困难、胸痛及咯血）仅占所有肺栓塞患者的1/3 常见症状顺序依次为：呼吸困难，胸痛，心悸，咳嗽，咯血，焦虑，晕厥 特别强调 “不能解释”的呼吸困难：仔细询问病史，明确呼吸困难的诱因、加重、缓解方式及对治疗的反应。误诊为心功能不全的患者，经强心利尿，扩血管治疗仍无好转迹象时，应进一步行血气分析及其他各项检查。 胸痛：常有持续性胸痛，患者经硝酸甘油等不能缓解疼痛。 晕厥：大面积肺栓塞导致脑供血不足时，可引起晕厥，晕厥也常常是慢性栓塞性肺动脉高压最早的症状之一。一些肺栓塞以晕厥为首发症状，常被误诊为心源性及血管源性晕厥。如果能排除其它因素引起的晕厥，因该警惕是否存在肺栓塞。 咯血 体征 低热，紫绀，呼吸次数增加，窦性心动过速，P2 亢进，胸骨左缘第二肋间收缩期杂音，三尖瓣返流性杂音，胸膜摩擦音等。 血气分析 严重的低氧血症 心电图 目前则认为，几乎所有有症状的急性PE患者，心电图都会有不同程度的改变，因此心电图对肺栓塞的诊断具有比较重要的价值。 肺栓塞最为常见的心电图表现为SI加深，QⅢ出现及TⅢ倒置，胸前导联V1-4T波倒置，或完全性及不完全性右束支传导阻滞。 既往无慢性肺病疾患病史的患者，还有一些心电图异常也应警惕肺栓塞的可能 avL导联S波>1.5mm； 胸前导联过渡区左移至V5导联 肢体导联QRS波群低电压（<5mm）等。 还要留心观察一些心电图不典型或轻微的改变 TV1-2倒置，SV1 （或V3R-V5R）粗钝挫折，也可能提示PE。 这些异常的心电图尤其注意与冠心病不稳定性心绞痛，急性及陈旧性心肌梗塞鉴别。 年龄较大的急性肺栓塞患者，如果有胸痛，同时心电图一些导联出现T波改变，易首先考虑为“冠心病、心绞痛”，但是肺栓塞多伴有不同程度的呼吸困难，血气分析及放射性核素肺

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肺栓塞的预防 肺栓塞的预防方法1、识别危险因素和积极预防是防止肺栓塞发生的关键。 加强一般人群的健康教育和高危人群的预防观念至关重要。 2、对危险人群来说，改变生活方式很重要，如戒烟、适当运动、控制体重、保持心情舒畅。 饮食方面应注意减少胆固醇的摄入，多吃蔬菜水果，适量饮茶。 3、乘飞机、车船长途旅行时，要多饮水，一方面可稀释血液，另一方面还可借上厕所之机多活动下肢，有条件时还可做旅行休闲操。 4、下肢外伤或长期卧床时，要注意按摩下肢，防止血栓形成。 肺栓塞的初期症状1、久坐呼吸困难卧床或者久坐后突然发生的呼吸困难，静息后可以缓解，日常活动或者轻微活动后明显加重。 2、单侧腿变粗不明原因的双下肢或者单侧肢体明显粗于另一侧下肢并且出现呼吸困难等症状。 3、短时间的失去记忆不明原因出现一时性意识丧失，持续数秒钟后自行缓解，并且对方才发生的事情没有任何记忆。 4、莫名的心慌不明原因的心慌，尤其是与活动有关系。 5、肺动脉高压心脏超声心动图检查提示有肺动脉高压，尤其是新近出现的肺动脉高压。 肺栓塞的治疗1、抗凝治疗。 抗凝治疗可防止肺栓塞发展和复发，常用的抗凝药物(1)普通肝素

(2)低分子肝素。 低分子肝素半衰期长,注射简单且不用监测,但其价格较普通肝素偏贵。 (3)华法林。 应在最初应用肝素3天内同时使用华法林,华法林的剂量应根据INR调整,合并肝素治疗4～5天使INR达治疗水平至少2天。 INR达治疗水平前,应每天监测INR，长期治疗每4周监测一次。 2、溶栓治疗溶栓治疗与单独应用肝素治疗比较有以下优点：(1)可迅速溶解血栓，恢复肺组织再灌注，使血流动力学参数迅速改善;(2)有利于静脉栓子的溶解，有可能降低肺栓塞的复发率;可阻止慢性肺血管阻塞的发生、发展，从而降低肺动脉高压的发生率。 但由于溶栓引起的出血风险相对较大，使用时须严格遵守适应症和禁忌症。 3、下腔静脉滤网IVC滤网预防PE而不是预防DVT,因此当滤网置入时,应使用肝素抗凝,以防止进一步血栓形成。 4、外科取栓及导管取栓对一些大的肺动脉栓子且具有溶栓禁忌证及经过充分的内科治疗病情迅速恶化的患者,可考虑外科取栓。 另外对于一些较大的、致命的栓子,也可考虑在局部溶栓的同时经导管去栓。

第三课 肺栓塞考试题目

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（3）深静脉血栓的体征：患肢肿胀、周径增粗、疼痛和压痛、皮肤色素沉着、行走后患肢易疲劳或肿胀 加重。但半数或以上病人无自觉症状或无明显体征。 目前确定肺栓塞诊断的检查方法技术要求高，操作难度较大，在一般医院难于开 展；而且敏感性、特异性不高、有一定局限性、需要多项检查互补。让我们看一 下哪些是可以确诊PTE 的检查方法？ （二）辅助检查 1. 有创检查 有创检查主要是肺动脉造影，主要有普通肺动脉造影（CPA ） 和数字减影肺动脉造影（DSA ）两类，该项技术60年代末被广泛 接受，至今被公认为诊断PTE 的“金标准”。 诊断PTE 的“金标准”是以下哪种方法？ A. 肺动脉造影 B. 血气分析 C. 心电图 D. X 线 正确答案：A 解析：CPA 可显示肺动脉及分支全貌，可直接显示动脉内充盈缺损、充盈排空延迟或肺内无血流灌注的截断征象，敏感性与特异性都达到95%以上，因而是当之无愧的PTE 诊断金标准。 （1）肺动脉造影（CPA ）临床应用评价 CPA 可显示肺动脉及分支全貌，可直接显示动脉内充盈缺损、充盈排空延迟或肺内无血流灌注的截断征象，敏感性为98%，特异性为95～98%。CPA 缺憾为：此项检查致残率1%，死亡率0.01%～0.5%；病人病情危急状态时，CPA 检查几乎不能实施；亚肺段以下的肺栓塞则很难以作出判断。 （2）CPA 的禁忌证 碘过敏、肾功能衰竭、左束枝传导阻滞、严重充血性心力衰竭、严重血小板减少症、严重肺动脉高压者。