Treatment of Venous Thromboembolism With New Anticoagulant Agents …news.medlive.cn/uploadfile/20160419/14610471879554.pdf · 2016. 4. 19. · III trials, rivaroxaban, apixaban,

Listen to this manuscript’s

audio summary by

JACC Editor-in-Chief

Dr. Valentin Fuster.

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 7 , N O . 1 6 , 2 0 1 6

ª 2 0 1 6 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0

P U B L I S H E D B Y E L S E V I E R h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 6 . 0 1 . 0 7 2

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Treatment of Venous ThromboembolismWith New Anticoagulant Agents
Cecilia Becattini, MD, PHD, Giancarlo Agnelli, MD
ABSTRACT

Fro

pe

Ing

Ma

Venous thromboembolism (VTE) is a common disease associated with high risk for recurrences, death, and late sequelae,

accounting for substantial health care costs. Anticoagulant agents are the mainstay of treatment for deep vein

thrombosis and pulmonary embolism. The recent availability of oral anticoagulant agents that can be administered in

fixed doses, without laboratory monitoring and dose adjustment, is a landmark change in the treatment of VTE. In Phase

III trials, rivaroxaban, apixaban, edoxaban (antifactor Xa agents), and dabigatran (an antithrombin agent) were

noninferior and probably safer than conventional anticoagulation therapy (low-molecular-weight heparin followed by

vitamin K antagonists). These favorable results were confirmed in specific patient subgroups, such as the elderly and

fragile. However, some patients, such as those with cancer or with intermediate- to high-risk pulmonary embolism, were

underrepresented in the Phase III trials. Further clinical research is required before new oral anticoagulant agents can be

considered standard of care for the full spectrum of patients with VTE. (J Am Coll Cardiol 2016;67:1941–55)

© 2016 by the American College of Cardiology Foundation.

EPIDEMIOLOGY AND CLINICAL COURSE OF

VENOUS THROMBOEMBOLISM

Venous thromboembolism (VTE), which includes deepvein thrombosis (DVT) and pulmonary embolism, isone of the most common cardiovascular diseases (1–3).A systematic review on the disease burden of VTEreported annual incidences ranging from 0.75 to 2.69per 1,000 subjects, which increased to between 2.0 and7.0 per 1,000 among subjects $70 years of age (4).

VTE is a main cause of health care expenditure (5),and hospitalization accounts for the majority of thehealth care costs (6,7). In the United States, the rateof hospitalization for VTE per 100,000 subjectsage $60 years increased from 581 in 2001 to 739 in2010 (6), with an average length of stay in 2011 of4.7 days for patients with DVT and 5.1 days forpatients with pulmonary embolism (8).

The 30-day and 1-year case-fatality rates after VTEwere found to be 10.6% (95% confidence interval

m the Internal and Cardiovascular Medicine–Stroke Unit, University of

rsonal fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Bayer. D

elheim, Daiichi-Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer.

nuscript received October 26, 2015; revised manuscript received January

[CI]: 10.4 to 10.8) and 23.0% (95% CI: 22.8 to 23.3),respectively (2). The 30-day mortality rates forpatients with first-time DVT or pulmonary embolismwere 3.0% and 31%, respectively (9).

After a first episode, VTE tends to recur, with anexpected 10-year cumulative incidence rate of recur-rence of approximately 25% (1). Recurrence rate peaksin the first 6 months (11% patient-years), thendecreases slowly to stabilize after 3 years, remainingat about 2% per patient-year up to 10 years after theacute event. The risk for recurrence is similar afterDVT or pulmonary embolism (hazard ratio [HR]: 1.19;95% CI: 0.87 to 1.63) (10). However, pulmonaryembolism tends to recur as pulmonary embolism andDVT as DVT (10,11).

The long-term sequelae of VTE are post-thromboticsyndrome, which occurs in 20% to 50% of patientsafter DVT, and chronic thromboembolic pulmonaryhypertension, which occurs in 0.1% to 3.8% ofpatients after pulmonary embolism (12,13). These

Perugia, Perugia, Italy. Dr. Becattini has received

r. Agnelli has received personal fees from Boehringer

19, 2016, accepted January 26, 2016.

https://s3.amazonaws.com/ADFJACC/JACC6716/JACC6716_fustersummary_07




http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2016.01.072&domain=pdf

http://dx.doi.org/10.1016/j.jacc.2016.01.072

ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

DVT = deep vein thrombosis

HR = hazard ratio

LMWH = low-molecular-

weight heparin

NOACs = new oral

anticoagulant agents

NSAID = nonsteroidal

anti-inflammatory drug

OR = odds ratio

PESI = pulmonary embolism

severity index

RR = relative risk

VTE = venous

thromboembolism

Becattini and Agnelli J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

New Anticoagulant Agents for Venous Thromboembolism A P R I L 2 6 , 2 0 1 6 : 1 9 4 1 – 5 5

1942

conditions adversely affect quality of life andreduce productivity, causing a substantialburden to patients and to the health caresystem (14–19).

THE CONVENTIONAL

TREATMENT OF VTE

Anticoagulant treatment of VTE includes3 phases: an initial phase; a long-term orchronic phase; and an extended phase(20,21). Traditionally, in the initial treatmentof VTE, rapid-onset parenteral anticoagulantagents are used to quickly achieve thera-peutic anticoagulation and reduce earlyrecurrences and mortality (22–24). Forseveral decades, long-term and extendedtreatments were performed with oral vitamin

K antagonists. In patients with cancer-associatedthrombosis, low-molecular-weight heparin (LMWH)is recommended over vitamin K antagonists (20).

The rate of recurrent VTE during well-conductedanticoagulation is estimated to be about 2% (20) andthat of major bleeding 2.2% (95% CI: 2.05 to 2.42) at90 days (25,26). After anticoagulant treatment isstopped, the recurrence rate is low (about 3% per yearor lower) in patients with VTE associated with majortrauma or surgery, and it is particularly high inpatients with cancer-associated VTE (about 10% peryear) (27–29). Patients treated for unprovoked VTE(no identifiable risk factors) have a recurrence rate of15% in the 2 years after treatment discontinuation(30). Although the rate of major bleeding during long-term anticoagulant treatment seems to decrease overtime, the related case fatality rate remains stable andhigher than the case fatality rate associated withrecurrent VTE after anticoagulant treatment isstopped (26).

Anticoagulant treatment is usually withdrawnafter 3 months in patients with VTE associated withmajor temporary risk factors (e.g., surgery, trauma)and is continued indefinitely in the case of recurrenceof VTE or in patients with cancer-associated throm-boembolism. The optimal duration of anticoagulanttreatment after the first unprovoked VTE remainsunclear (20). In these patients, prolonging anti-coagulation for a definite time frame beyond theinitial 3 months simply delays recurrences, withoutreducing the risk for this event once anticoagulationis withdrawn (11,30). After an unprovoked VTE, thenature of the initial thromboembolism (DVT or pul-monary embolism), clinical risk scores, the persis-tence of thrombosis in the lower limbs, or rightventricular dilation and elevated D-dimer have been

proposed as methods for identifying patients at highrisk for recurrence (20,31); how these results translateto the duration of treatment was not fully evaluated,however.

Parenteral anticoagulation during the initial treat-ment and the need for laboratory monitoring anddose adjustment during long-term treatment are themain limitations of conventional anticoagulation, inaddition to a high number of drug–drug interactions.

THE NEW ORAL ANTICOAGULANT AGENTS

Two classes of oral direct anticoagulant agents wereintroduced in clinical practice to overcome the limitsof conventional anticoagulation. These agents aresynthetic, selective, and reversible inhibitors of factorXa (rivaroxaban, apixaban, and edoxaban) orthrombin (dabigatran) (32–35). The predictable anti-coagulant effect allows these agents to be adminis-tered in fixed doses, with no need for laboratorymonitoring or dose adjustment. The short half-life ofthe new anticoagulant agents (NOACs) may makeclinical management of situations requiring reversalof anticoagulation (needed for invasive proceduresand bleeding complications) easier. Rivaroxabanand edoxaban offer the possibility of once-dailyadministration.

Dabigatran is a prodrug with a bioavailability ofapproximately 6.5%; circulating esterases rapidlyconvert the prodrug to the active form, 80% of whichis eliminated by the kidneys (32). None of the factorXa inhibitors is a prodrug, and all have oral bioavail-ability >50% (33–35). The kidneys excrete one-third ofrivaroxaban as active drug; the liver metabolizes two-thirds of the drug to an inactive form, one-half ofwhich is eliminated in the urine and one-half via thehepatobiliary route (33). Apixaban is eliminated viathe intestinal (about 75%) and renal (about 25%)routes (34). Approximately one-half of edobaxan iseliminated via the renal route (35). Time to peakconcentration is similar for all of these agents,ranging from 1 to 4 h, with half-lives ranging from 6 to17 h. Half-lives can be influenced by renal clearance,and this scenario is particularly true for dabigatran.Care should be taken when using all NOACs inpatients with impaired renal function (36). Reduceddoses of rivaroxaban, apixaban, and edoxaban havebeen tested in patients with atrial fibrillation andimpaired renal function; reduced doses of NOACswere not tested in patients with VTE, with theexception of edoxaban.

No data are currently available on the use of NOACsin pregnancy, breastfeeding women, and children.Clinical studies (mainly dose-finding trials) have

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Becattini and AgnelliA P R I L 2 6 , 2 0 1 6 : 1 9 4 1 – 5 5 New Anticoagulant Agents for Venous Thromboembolism

1943

started or are about to start on the use of dabigatran(NCT01895777, NCT02197416, NCT02223260, andNCT01083732), rivaroxaban (NCT02497716, NCT02309411,and NCT02234843), apixaban (NCT01707394,NCT02464969 and NCT02369653), and edoxaban(NCT02303431) in children.

NOACs FOR THE INITIAL AND

LONG-TERM TREATMENT OF VTE

DESIGN OF THE CLINICAL TRIALS. Overall, in theinitial and long-term treatment of patients with VTE,6 randomized trials have been performed: 2 studieswith dabigatran, 2 studies with rivaroxaban, and1 study each with apixaban and edoxaban (Table 1)(37–42). The study designs of these trials reveal sim-ilarities and differences. All the trials were designedto demonstrate noninferior efficacy compared withconventional anticoagulant treatment (LMWH fol-lowed by vitamin K antagonists). Noninferiority wasdeemed to be a satisfactory achievement, as the mainadvantage of these agents over conventional treat-ment is oral administration in fixed doses withoutlaboratory monitoring. The lack of superiority couldcause some clinicians to refrain from consideringtreatment with NOACs as a real breakthrough tobe transferred to clinical practice. However, the

TABLE 1 Efficacy and Safety of NOACs for the Treatment of VTE: Res

Trial Name (Ref. #) Design TreatmentsDuration(months)

RE-COVER,2009 (37)

DB Enoxa/dabigatran(150 mg bid)

Enoxa/warfarin

6

RE-COVER II,2011 (38)

DB Enoxa/dabigatran(150 mg bid)

Enoxa/warfarin

6

EINSTEIN-DVT,2010 (39)

Open-label Rivaroxaban (15 mg bidfor 3 weeks, then20 mg od)

Enoxaparin/VKA

3, 6, or 12

EINSTEIN-PE,2012 (40)

Open-label Rivaroxaban (15 mg bidfor 3 weeks, then20 mg od)

Enoxa/VKA

3, 6, or 12

AMPLIFY,2013 (41)

DB Apixaban (10 mg bid for7 days, then 5 mg bid)

Enoxa/warfarin

6

Hokusai,2013 (42)

DB LMWH/edoxaban (60 mgod or 30 mg od)

UFH or LMWH/warfarin

#12

AMPLIFY¼ Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein ThrombEINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute SymSymptomatic Pulmonary Embolism; HOKUSAI ¼ Comparative Investigation of Low MoSymptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; LMWH ¼ low-molecular-Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acutvitamin K antagonist; VTE ¼ venous thromboembolism.

advantages observed in terms of bleeding complica-tions, as well as the drugs’ improved practicality,confer clinical value to these noninferiority results.Different criteria for definitions of noninferioritywere used across the studies (upper 95% CI: 2.75 fordabigatran, 2.0 for rivaroxaban, 1.8 for apixaban, and1.5 for edoxaban). These criteria contributed todifferent sample size estimations (2,550 patients ineach study with dabigatran, 3,000 patients withrivaroxaban in the pulmonary embolism and DVTstudies, 5,400 patients with apixaban, and 7,500 pa-tients with edoxaban).

All the studies used recurrence and VTE-relateddeath as the primary efficacy outcome. The rivarox-aban and edoxaban studies followed an event-drivendesign on the basis of efficacy outcomes. Majorbleeding was the primary safety outcome in theapixaban trial, whereas the composite of major andclinically relevant nonmajor bleeding (clinically rele-vant bleeding) was the primary safety outcome in theremaining trials. Four trials enrolled patients witheither DVT or pulmonary embolism, whereas therivaroxaban program comprised 2 separate studies(1 for patients with DVT and 1 for patients with pul-monary embolism). The trials were double-blind,except for those with rivaroxaban (39,40). In theHokusai trial, edoxaban was given as a 60-mg daily

ults From Clinical Trials

Patients TTR (%) Efficacy Outcome Safety Outcome

2,539 acute VTE 60 Recurrent VTE or VTE-related death:2.4% enoxa/dabigatran,2.1% enoxa/warfarin

Major/clinically relevantnonmajor bleeding:5.6% dabigatran,8.8% warfarin

2,539 acute VTE 57 Recurrent VTE or fatal PE:2.3% dabigatran,2.2% warfarin

Major/clinically relevantnonmajor bleeding:5.0% dabigatran,7.9% warfarin

3,449 acute DVT 58 Recurrent VTE:2.1% rivaroxaban,3.0% enoxa/warfarin

Major/clinically relevantnonmajor bleeding:8.1% rivaroxaban,8.1% enoxa/warfarin

4832 acute PE 63 Recurrent VTE:2.1% rivaroxaban,1.8% enoxa/VKA

Major/clinically relevantnonmajor bleeding:10.3% rivaroxaban,11.4% enoxa/VKA

5,395 acute VTE 61 Recurrent VTE or VTE-related death:2.3% apixaban,2.7% enoxa/VKA

Major bleeding:0.6% apixaban,1.8% enoxa/warfarin

8,292 acute VTE 63 Recurrent VTE:3.2% enoxa/edoxaban,3.5% enoxa/warfarin

Major/clinically relevantnonmajor bleeding:8.5% enoxa/edoxaban,10.3% enoxa/warfarin

osis or Pulmonary Embolism; bid ¼ once daily; DB¼ double-blind; DVT ¼ deep vein thrombosis; enoxa¼ enoxaparin;ptomatic deep vein thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acutelecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment ofweight heparin; NOAC ¼ new oral anticoagulant agent; od ¼ once daily; PE ¼ pulmonary embolism; RE-COVER ¼e Symptomatic Venous Thromboembolism; TTR ¼ time in therapeutic range; UFH ¼ unfractionated heparin; VKA ¼

https://clinicaltrials.gov/ct2/show/NCT01895777?term=NCT01895777&rank=1








https://clinicaltrials.gov/ct2/show/NCT02464969?term=NCT02464969%26rank=1





1944

dose or at the reduced dose of 30 mg in patients withimpaired renal function or low body weight (42).Dabigatran and apixaban were given twice daily,whereas rivaroxaban and edoxaban were given oncedaily (37,38,41). Rivaroxaban and apixaban wereevaluated according to the “single-drug approach,”which means that the initial heparin treatment isused for no longer than 48 h (39–41). When the single-drug approach was followed, increased doses ofrivaroxaban (50% of the maintenance dose for3 weeks) and apixaban (100% of the maintenancedose for 1 week) were used because of the increasedrisk for early recurrences. This increase was observedin previous trials evaluating NOACs withoutinitial heparin treatment (22–24). Initial heparin pre-treatment (5 to 9 days) was used with dabigatranand edoxaban (37,38,42).

MAIN RESULTS OF THE STUDIES. Concerning theprimary efficacy outcomes, dabigatran (hazard ratio[HR]: 1.09; 95% CI: 0.76 to 1.57) (38), rivaroxaban (HR:0.89; 95% CI: 0.66 to 1.19) (43), apixaban (relative risk[RR]: 0.84; 95% CI: 0.60 to 1.18) (41), and edoxaban(HR: 0.89; 95% CI: 0.70 to 1.13) (42) were all non-inferior to conventional treatment. Apixaban wasassociated with a significant reduction in majorbleeding compared with conventional treatment (RR:0.31; 95% CI: 0.17 to 0.55) (41). This outcome was alsothe case for rivaroxaban in the pulmonary embolismstudy but not in the DVT trial (40). Edoxaban wassafer than conventional treatment in terms of clini-cally relevant bleeding (HR: 0.81; 95% CI: 0.71 to 0.94)(42), and this scenario was also the case for dabiga-tran (HR: 0.62; 95% CI: 0.50 to 0.76) (38). Similar ratesof clinically relevant bleeding compared with con-ventional treatment were observed with rivaroxaban(HR: 0.93; 95% CI: 0.81 to 1.06) (43). A statisticallynonsignificant reduction in intracranial hemorrhagewas reported with all NOACs, but the studies were notsized to show a definitive effect on this safetyoutcome. Fatal bleeding was significantly reduced inthe Hokusai study with edoxaban compared withwarfarin (2 events vs. 10 events; odds ratio [OR]: 0.20;95% CI: 0.04 to 0.91) (42). No definitive data areavailable concerning the incidence of gastrointestinalor mucosal bleeding with NOACs in patients withVTE. Twice-daily apixaban could be preferred for itssafety profile, as shown by the 69% reduction inmajor bleeding (41).

No direct head-to-head comparisons are availablefor NOACs in VTE treatment. Dabigatran or edoxabancould be preferred in patients requiring heparintreatment in the acute phase (pretreatment withheparin was formally tested in Phase III clinical trials

with these agents). Indeed, the use of heparin andNOACs in regimens different from those evaluated inclinical trials and approved for clinical use couldexpose patients to overtreatment or undertreatment.Whether the efficacy and safety profile of rivaroxabanand apixaban is preserved if the duration of the initialincreased dose is shortened or skipped is unclear. It isconceivable that if pre-NOAC administration ofLMWH lasted <7 days, the initial increased doses ofapixaban and rivaroxaban should be given for 7 or21 days, respectively. In case of LMWH treatmentlasting >7 days, it may be reasonable to start apixabanwith the maintenance dose (5 mg twice daily) or tocontinue LMWH up to 3 weeks, and then start withthe maintenance dose of rivaroxaban (20 mg oncedaily). Edoxaban is the only agent for which efficacyresults are provided in patients with pulmonaryembolism with and without right ventriculardysfunction (42). Edoxaban is also the only agent forwhich dose reduction was tested in patients withcreatinine clearance between 30 and 50 ml/min,weighing <60 kg, or receiving concomitant treatmentwith potent P-glycoprotein inhibitors.

Concerning patients with renal failure, those withcreatinine clearance <30 ml/min (<25 ml/min forapixaban) were excluded from all Phase III trials. Forpatients with fluctuations in renal function (e.g.,concomitant diuretic agents) or borderline stage IIIkidney disease (creatinine clearance near 30 ml/min),reduced doses of edoxaban could be considered. Theefficacy and safety of reduced doses of rivaroxaban orapixaban in patients with VTE and moderate renalfailure have not been evaluated in clinical trials(Table 2). When NOACs are used in these patients,renal function should be checked at least twice a year(Table 3) (36).

Several meta-analyses have been performed onstudies with NOACs for the treatment of VTE. A meta-analysis including 10 trials and 35,029 patients foundthat the rates of recurrent VTE (4.1% patient-years vs.4.4% patient-years) and the related case fatality rates(16% vs. 13%) were similar in patients receivingNOACs or conventional therapy (44). Major bleeding(1.8% per patient-year vs. 3.1% per patient-year), fatalbleeding (0.1% per patient-year vs. 0.3% per patient-year), and the related case fatality rates (6% vs.10%; p ¼ 0.18) were lower with NOACs than withconventional therapy. In a subsequent meta-analysis,NOACs were associated with a reduction in all-causemortality (risk ratio: 0.51; 95% CI: 0.26 to 1.01) (45).

In a meta-analysis, the results in patients withpulmonary embolism were evaluated independentlyfrom those in patients with DVT (46). In patients withacute pulmonary embolism, recurrence of VTE

TABLE 2 Treatment of VTE in Particular Clinical Situations

Suggested Anticoagulant Regimen*

Stage IV renal failure Prefer conventional treatment*

Concomitant treatment with verapamil ordronedarone

Prefer conventional treatment or rivaroxaban

Concomitant treatment with carbamazepine,phenobarbital, phenytoin

Prefer conventional treatment

Active cancer LMWH or conventional treatment or NOACs†

Isolated distal DVT If to be treated,‡ prefer conventional treatmentor LMWH or NOACs†

Unsuspected VTE If to be treated, treat as symptomatic VTE§

Upper arm Treat as lower-limb VTE

Splanchnic or cerebral vein thrombosis Prefer conventional treatment

APLA Prefer conventional treatment

Patients with vena cava filter Prefer conventional treatment

*Indications reported here are on the basis of the available evidence. A conservative approach is suggested inclinical situations in which NOAC data are limited. This scenario does not mean that the choice of NOACs cannotbe made on the basis of clinical judgment. †Patients should be informed about the lack of evidence for thisparticular indication. ‡Positive D-dimer thrombosis that is extensive or close to the proximal veins (e.g., >5 cm inlength, involves multiple veins, >7 mm maximum diameter), no reversible provoking factor for DVT, activecancer, history of VTE, and inpatient status are risk factors for proximal extension of distal DVT and could be usedto identify patients to be treated with anticoagulant agents (20). Similarly, the presence of symptoms that aredeemed to be due to distal DVT should lead to consideration of the patient for anticoagulant treatment. In thiscase, the accuracy of the diagnosis of distal DVT was indeed higher. §VTE is unsuspected or incidental if detectedon results of imaging tests performed for other purposes. The need for anticoagulation for unsuspected VTE hasnever been assessed in clinical trials. In current clinical practice, anticoagulant treatment is given for unsuspectedproximal DVT and at least segmental PE (20).

APLA ¼ antiphospholipid antibodies; other abbreviations as in Table 1.

TABLE 3 Practical Aspects of VTE Treatment With NOACs

How to:

Follow-up patients on NOACs Normal renal function: first visit þ renal function andblood cell count at 1 mo, then every 6 mo

Abnormal renal function: first visit þ renal functionand blood cell count at 1 mo, then at least twicea year

Switch from VKAs INR <2: NOACs can be initiated immediatelyINR 2.0–2.5: better to start NOACs the next dayINR >2.5: take into account the actual INR value and

the half-life of the VKA. A new INR can bescheduled before starting the NOAC

How to manage:

Recurrent VTE on NOAC treatment Verify compliance to NOAC treatmentReassess concomitant medicationsConsider change to a different NOAC or to

conventional treatment

Overdosing With active bleeding:Manage as patients with bleeding complications

In the absence of bleeding:Consider activated charcoal if <2 hWithhold the next dose

Missing dose In bid regimens: take if <6 h from scheduled intake

In od regimens: take if <12 h from scheduled intake

INR ¼ international normalized ratio; other abbreviations as in Table 1.


1945

occurred in similar proportions in patients random-ized to receive NOACs or conventional treatment(2.4% vs. 2.6%; OR: 0.89; 95% CI: 0.70 to 1.12).Treatment with NOACs was associated with a reducedrate of major bleeding by approximately 50%(RR: 0.49; 95% CI: 0.26 to 0.95) (47). Similar rates ofclinically relevant bleeding were observed withNOACs or conventional treatment (10.2% vs. 11.3%;OR: 0.89; 95% CI: 0.77 to 1.03) (46).

A network meta-analysis, on the basis of indirectcomparison of NOACs for the treatment of VTE,revealed a relative risk for a major bleeding event of0.42 (95% CI: 0.21 to 0.87; p¼0.02) for apixaban versusdabigatran; 0.57 (95% CI: 0.29 to 1.15; p ¼ 0.12) forapixaban versus rivaroxaban; 0.37 (95% CI; 0.19 to0.73; p < 0.001) for apixaban vs. edoxaban; 0.74(95% CI: 0.42 to 1.30; p ¼ 0.30) for rivaroxaban versusdabigatran; 0.64 (95% CI: 0.38 to 1.08; p ¼ 0.10) forrivaroxaban versus edoxaban; and 1.15 (95% CI: 0.66 to2.00; p ¼ 0.62) for edoxaban versus dabigatran (48).

RESULTS IN PARTICULAR PATIENTS

In all of the studies, subgroup analyses were per-formed on the efficacy and safety of NOACs in specificpopulations of patients.

ELDERLY PATIENTS. A recent analysis of the dabi-gatran trials showed that the efficacy of dabigatrancompared with warfarin was to some extent higher inelderly patients (p ¼ 0.099 for interaction), with equalefficacy at approximately 60 years of age (38). Thedifference in efficacy was not statistically significantat any age. Concerning clinically relevant bleeding,the risk reduction in favor of dabigatran was influ-enced by age (p ¼ 0.010 for interaction) and wasgreater in younger patients.

No age effect in efficacy and safety was observed insubgroup analyses in the rivaroxaban, apixaban, andedoxaban studies (Table 4) (41–43). However, only aminority of the patients included in Phase III studies(about 5%) were aged >80 years.

In a meta-analysis of Phase III studies, a signifi-cantly lower rate of recurrent VTE was observed withNOACs compared with conventional treatment inpatients aged $75 years (RR: 0.56; 95% CI: 0.38 to0.82) (49). In these patients, a significant reduction inmajor bleeding was associated with NOACs (RR: 0.49;95% CI: 0.25 to 0.96).

PATIENTS WITH RENAL INSUFFICIENCY. In arecently published subgroup analysis of the rivarox-aban studies, increasing rates of recurrent VTE wereobserved in patients with deteriorated renal function(50). Similar HRs for recurrent VTE were observedacross renal function categories in the rivaroxaban and

conventional treatment groups (Table 4). Concerningmajor bleeding, in patients with deteriorating renalfunction, a trend in favor of rivaroxaban was observedcompared with conventional treatment. No effect wasobserved with respect to efficacy and safety across therenal function impairment categories in subgroup

TABLE 4 Efficacy and Safety of NOACs in Particular Populations: Results on Efficacy and Safety of NOACs as Reported in Papers or Substudies Published

After the Main Publications of Phase III Studies

Trial Name (Ref. #) Context Treatment Definition Recurrent VTE Safety Outcome

RE-COVERstudies (53)

Renal function Dabigatran (150 mg bid)Warfarin

Creatinine clearance$80 ml/min

3.1% vs. 2.6% CRB: 3.3% vs. 6.2%

Creatinine clearance 50 to<80 ml/min

1.9% vs. 1.6% CRB: 7.1% vs. 12.3%


0% vs. 4.1% CRB: 11.3% vs. 10.5%

NSAIDs Use of NSAIDs 2.8% dabigatran,2.0% warfarin

MB: 1.1 dabigatran,1.0% warfarin

Nonuse of NSAIDs 2.6% dabigatran,2.5% warfarin

MB: 0.9% dabigatran,1.8% warfarin

Aspirin Use of aspirin 3.1% dabigatran,2.3% warfarin


Nonuse of aspirin 2.6% dabigatran,2.4% warfarin


RE-MEDYstudy (54)

Thrombophilia Dabigatran (150 mg bid)Warfarin

Thrombophilia present 1.5% dabigatran,2.3% warfarin


Thrombophilia absent 2.3% dabigatran,0.7% warfarin


Thrombophilia not tested 1.8% dabigatran,1.3% warfarin


EINSTEIN-DVTand PE(43,50-52)

Fragile patients Rivaroxaban (15 mg bid for3 weeks, then 20 mg od)

Enoxa/VKA

Age >75 yrs (n¼ 1,279), orcreatinine clearance<50 ml/min, or bodyweight #50 kg

2.7% rivaroxaban,3.8% enoxa/warfarin

MB: 1.3% rivaroxaban,4.5% enoxa/warfarin

Nonfragile 1.9% rivaroxaban,1.9% enoxa/warfarin


Renal function Creatinine clearance$80 ml/min






MB 0.8% rivaroxaban,1.0% enoxa/warfarin



Body weight #50 kg 6.7% rivaroxaban,2.2% enoxa/warfarin


>50 kg and <100 kg 1.9% rivaroxaban,2.4% enoxa/warfarin


$100 kg 2.3% rivaroxaban,2.0% enoxa/warfarin


NSAIDs* Use of NSAIDs NR MB: 4.7% rivaroxaban,8.4% enoxa/warfarin

Nonuse of NSAIDs MB: 1.4% rivaroxaban,2.7% enoxa/warfarin

Aspirin* Use of aspirin NR MB: 3.3% rivaroxaban,6.9% enoxa/warfarin

Nonuse of aspirin MB: 1.6% rivaroxaban,2.9% enoxa/warfarin

EINSTEINPE (65)

PESI score Rivaroxaban (15 mg bid for3 weeks, then 20 mg od)

Simplified PESI scores of 0, 0.8% rivaroxaban,0.7% enoxa/VKA


Enoxa/VKA Simplified PESI scores of 1, or 1.0% rivaroxaban,1.1% enoxa/warfarin


Simplified PESI scores $2 1.6% rivaroxaban,3.6% enoxa/warfarin


*Percentages per patient-year.

CRB ¼ clinically relevant bleeding; MB ¼ major bleeding; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; NR ¼ not reported; PESI ¼ pulmonary embolism severity index; other abbreviations as in Table 1.



1946

analyses in the dabigatran, apixaban, and edoxabanstudies (38,41,42).Pat ients wi th extreme body weight . An analysiswas performed to determine the association betweenbody weight and clinical outcomes in patients treatedwith rivaroxaban compared with conventional

therapy (51). There was no association between bodyweight (#50 kg, >50 to <100 kg, and $100 kg) and riskof recurrent VTE for patients taking rivaroxaban orreceiving conventional therapy (Table 4). Majorbleeding was not associated with body weight forpatients taking rivaroxaban, whereas in patients


1947

undergoing conventional treatment, major bleedingwas more common in patients with low body weight.

No effects on efficacy and safety were observed insubgroup analyses for body weight categories in thedabigatran, apixaban, and edoxaban studies. How-ever, patients with body weight <50 kg weremarginally represented in all trials.

In a meta-analysis of Phase III trials comparingNOACs with conventional treatment for acute symp-tomatic VTE, the efficacy of NOACs in patients with abody weight $100 kg was consistent with that of thegeneral population (49).

The efficacy and safety of apixaban and dabigatranin the treatment of VTE were confirmed acrossdifferent classes of body mass index. Caution is rec-ommended with the use of NOACs in patients withbody weight <50 kg and >150 kg.Frag i le pat ients . Among patients included instudies with rivaroxaban, 1,573 were categorized asfragile because of age >75 years (n¼ 1,279), moderateor severe renal impairment according to a creatinineclearance level <50 ml/min (n¼649), or bodyweight #50 kg (n¼ 107) (43). Recurrent VTE was morecommon in fragile than in nonfragile patients(Table 4), with no difference between treatmentgroups. In fragile patients, major bleeding wassignificantly lower with rivaroxaban compared withconventional therapy (HR: 0.27; 95% CI: 0.13 to 0.54).This difference was not seen in nonfragile patients.

A favorable efficacy profile was shown with edox-aban compared with warfarin in the subgroup anal-ysis in fragile patients, without any safety concern.Patients receiving nonsteroidal anti-inflammatoryagents. An analysis was performed in the rivarox-aban trials on the efficacy and safety of concomitanttreatment with nonsteroidal anti-inflammatory drugs(NSAIDs) (52). According to this analysis, the inci-dence of clinically relevant bleeding (37.5% perpatient-year vs. 16.6% per patient-year; HR: 1.77;95% CI: 1.46 to 2.14) and that of major bleeding (6.5%per patient-year vs. 2.0% per patient-year; HR: 2.37;95% CI: 1.51 to 3.75) were higher in patients concom-itantly treated with NSAIDs and anticoagulant agents.Clinically relevant bleeding was more common inaspirin users than in nonusers (36.6% vs. 16.9% perpatient-year; HR: 1.70; 95% CI: 1.38 to 2.11). Majorbleeding occurred in 4.8% per patient-year in aspirinusers compared with 2.2% per patient-year in non-users (HR: 1.50; 95% CI: 0.86 to 2.62). Increases in riskfor clinically relevant and major bleeding were similarfor rivaroxaban and conventional treatment.

A similar analysis was reported on the efficacy andsafety of concomitant treatment with NSAIDs anddabigatran (53). About 10% of patients included in the

dabigatran studies received aspirin and about 20%received NSAIDs. No apparent difference in recurrentVTE was observed in patients with concomitantNSAIDs or low-dose aspirin versus those without(Table 4). Incidence of bleeding was similar ornumerically lower for dabigatran versus warfarin.Treatment with concomitant NSAIDs/low-doseaspirin resulted in no statistically significant in-teractions for efficacy or safety.Pat ients with molecu lar thrombophi l i a . In thedabigatran studies, thrombophilia did not affect theefficacy or safety profiles of dabigatran comparedwith warfarin (54). Dabigatran was noninferior towarfarin in preventing recurrent VTE or pulmonaryembolism, with a similar or lower risk of bleedingevents, regardless of thrombophilia status. There isno reason to hypothesize that there would be adifferent efficacy to safety profile of NOACs inpatients with thrombophilia. The only exceptioncould be for antiphospholipid syndrome or lupusanticoagulant agent (Table 2). Ad hoc studies arecurrently ongoing with rivaroxaban (NCT02116036and NCT02157272) and apixaban (NCT02295475) inpatients with these abnormalities.

LIMITS OF THE AVAILABLE TRIALS

LIMITED NUMBER OF PATIENTS WITH CANCER.

A proportion ranging between 2.5% and 9.4% ofpatients included in the Phase III trials with NOACshad cancer (37–42). This finding contrasts sharplywith data from clinical practice reporting that about20% of patients with VTE have cancer. In addition, ithas been claimed that patients with cancer includedin the NOAC Phase III trials were not completelyrepresentative of the full spectrum of patients withcancer. Indeed, it is possible that patients with moreextensive disease were not included in the studies.Furthermore, in these studies, the comparator waswarfarin and not LMWH, which is considered thetreatment of choice for cancer patients with VTE.Thus, there are some concerns about whether theresults of these studies are applicable to patients withcancer-associated VTE.

The results of 6 studies comparing NOACs withconventional anticoagulation for treatment of VTE,including patients with cancer, were pooled in ameta-analysis (55). VTE recurred in 3.9% and 6.0% ofpatients with cancer treated with NOACs or withconventional treatment, respectively (OR: 0.63;95% CI: 0.37 to 1.10). Major bleeding occurred in 3.2%and 4.2% of patients receiving NOACs and conven-tional treatment (OR: 0.77; 95% CI: 0.41 to 1.44).Several studies aimed at assessing the efficacy and






1948

safety of NOACs in patients with cancer-associatedVTE have started or are about to start. Until moredata become available, caution is advised regardingthe use of NOACs in patients with cancer, particularlyin the case of cancer patients receiving chemo-therapy. Patients should be informed of the advan-tages, in terms of practicality of these agents, but alsoon the lack of data in the cancer setting.

OPTIMAL RISK-TAILORED STRATEGIES FOR INITIAL

TREATMENT OF PATIENTS WITH PULMONARY

EMBOLISM. In-hospital mortality in hemodynami-cally unstable patients with acute pulmonary embo-lism may be as high as 58.3% (56). At the otherextreme, clinical risk assessment models, includingpulmonary embolism severity index (PESI) (orsimplified PESI) scores, can identify patients withacute pulmonary embolism at risk of 1% or lower30-day death (57). In hemodynamically stable pa-tients with acute pulmonary embolism, right ven-tricular dilation, as seen with echocardiography(OR: 2.36; 95% CI: 1.3 to 4.3) or computed tomographyangiography (OR: 1.64; 95% CI: 1.06 to 2.52), andincreased serum troponin level (OR: 5.90; 95% CI: 2.68to 12.95) were associated with increased short-termrisk of death (58–60). Thrombolytic therapy isreserved for selected patients with pulmonary embo-lism and hemodynamic compromise (61,62) or for pa-tients with DVT-associated phlegmasia of the lowerlimbs (20,31). Patients with acute pulmonary embo-lism requiring thrombolytic treatment in the acutephase were excluded from clinical trials. A case serieson treatment with thrombolysis and rivaroxaban in 98patients with acute pulmonary embolism reported noexcess bleeding complications (63).

Whether the results obtained with NOACs in thetreatment of acute pulmonary embolism apply tohemodynamically stable patients with right ventric-ular dysfunction and increased serum troponin levelsis unclear. The combination of LMWH followed byedoxaban was more effective than conventionaltreatment in the prevention of recurrent VTE inpatients with acute pulmonary embolism andincreased B-type natriuretic peptide levels includedin the Hokusai study (42). In this study, the combi-nation of LMWH followed by edoxaban was non-inferior to conventional treatment in patients withacute pulmonary embolism and right ventriculardysfunction according to computed tomographyscanning. Data on right ventricular dysfunction and/or injury were not available for patients included inthe remaining Phase III trials.

Studies with antifactor Xa agents reported data onthe anatomic extent of pulmonary embolism, as

assessed by the thrombotic burden at computedtomography scan (40–42). About one-fourth of thepatients included in the rivaroxaban pulmonaryembolism study had extensive pulmonary embolism(involvement of >25% of the entire pulmonary vas-culature), about 58% had intermediate pulmonaryembolism, and about 12% had limited pulmonaryembolism (#25% of a single lobe) (40). In the apix-aban study, about one-third of patients with pulmo-nary embolism had extensive pulmonary arteryinvolvement (41). Efficacy and safety profiles ofrivaroxaban and apixaban were confirmed in patientswith different magnitudes of vascular involvement.However, a poor association has been shown betweenthe burden of emboli at computed tomography scanand the clinical outcome in several studies, and riskstratification based on embolic burden has beendiscontinued (31,64).

In a post hoc analysis of the rivaroxaban for pul-monary embolism study, a simplified PESI score wascalculated in almost all patients; 54%, 36%, and 10%had PESI scores of 0, 1, and $2, respectively (65). Thesimplified PESI score was significantly associatedwith fatal pulmonary embolism and all-cause mor-tality at 7 days (p ¼ 0.014 and p < 0.0001, respec-tively), at 14 days (p ¼ 0.035 and p < 0.0001), and atthe end of the intended treatment period (p ¼ 0.0001and p < 0.0001). No treatment effect was observedwith rivaroxaban or conventional treatment accord-ing to the simplified PESI score (Table 4). Adverseoutcomes occurred more frequently in patients withsimplified PESI scores $2.

SAFETY AND FEASIBILITY OF HOME TREATMENT OR

SHORT HOSPITAL STAY. Home treatment is nowcommon in clinical practice for patients with DVT,except those with severe renal failure or highbleeding risk; the evidence regarding the safety ofhome treatment for patients with acute pulmonaryembolism is encouraging but still limited (66,67).Patients with acute pulmonary embolism at low riskof short-term mortality according to the simplifiedPESI score and the absence of right ventriculardysfunction are candidates for short hospitalizationor even home treatment if adequate support forinitiation of anticoagulation is available in theoutpatient setting (31). In clinical practice, regardlessof the anticoagulant agent, home treatment is madechallenging by difficulties in the identification oflow-risk patients and in the assessment of bleedingrisk in patients starting anticoagulation. Indeed, theaccuracy of available risk scores for bleeding riskassessment in patients with VTE (Outpatient BleedingRisk Index and the Kuijer, RIETE, and Kearon scores)


1949

was shown to be poor to moderate (68). Positivepredictive values and positive likelihood ratios seemto be low and vary from 3.1% to 6.6% and from 0.72 to1.59, respectively. The HAS-BLED score (hypertension[uncontrolled systolic blood pressure >160 mm Hg],abnormal renal and/or liver function, previous stroke,bleeding history or predisposition, labile interna-tional normalized ratios, elderly, and concomitantdrugs and/or alcohol excess) seems to have the bestpredictive value for bleeding complications duringthe first 3 months of treatment (area under the curve:0.68; 95% CI: 0.59 to 0.78) (69). None of the existingbleeding scores seemed to predict major bleedingbetter than chance (70). If the reduction in bleedingrisk observed with NOACs in Phase III trials isconfirmed in real-world studies, the issue of bleedingrisk scores could become less important.

NOACs have the potential to facilitate the hometreatment of VTE. However, limited data arecurrently available on the use of NOACs for outpa-tient treatment. About 52% of patients included in therivaroxaban DVT study and 90% of those included inthe rivaroxaban pulmonary embolism study wereadmitted to the hospital (71). The proportion ofpatients with a length of hospital stay #5 days was54% and 31% in those receiving rivaroxaban or con-ventional treatment, respectively. For patients withpulmonary embolism, the corresponding values were45% and 33%.

MANAGEMENT OF ISOLATED DISTAL DVT. DVT isdefined as distal when it is limited to below thepopliteal vein. Moderate diagnostic accuracy hasbeen shown with lower-limb ultrasonography for thediagnosis of distal DVT, and there is no definitiveevidence that the clinical course of patients withdistal DVT is influenced by anticoagulant treatment(72,73). Thus, international guidelines currentlyaccept 2 approaches: to treat distal DVT as proximalDVT or to observe the patients by using serial ultra-sound imaging and initiate therapy with anticoagu-lant agents only in the case of extension to theproximal veins (Table 2) (20). A randomized trial hasrecently been presented in which patients with distalDVT were randomized to receive the LMWH nadro-parin or placebo for 42 days (74). At day 42, symp-tomatic proximal extension of DVT or pulmonaryembolism occurred in 7 patients in the placebo armand in 4 patients in the nadroparin arm: 5.4% versus3.3% (p ¼ 0.54). Five major or clinically relevantepisodes of nonmajor bleeding occurred, all in thenadroparin arm. Although this study reported nosignificant advantage of anticoagulant treatmentcompared with placebo in patients with distal DVT, it

also found that distal DVT extends to the proximalveins or causes pulmonary embolism in a non-negligible proportion of patients.

Patients with isolated distal DVT were excludedfrom clinical trials with NOACs, and further evidence isneeded to apply the results obtained in major VTE tothese patients. It is implausible that patients with calfDVT would not benefit from NOACs and should bedenied the advantage of NOACs (over conventionaltherapy). However, patients should be informed aboutthe lack of evidence in this particular indication.

MANAGEMENT OF BLEEDING COMPLICATIONS. Inpatients experiencing major bleeding while under-going treatment with vitamin K antagonists, currentguidelines recommend the use of prothrombincomplex concentrates to resupply coagulation factors(75,76). These concentrates rapidly normalize clottingtimes, although a clear benefit in terms of clinicaloutcome remains to be demonstrated (77). Theadministration of prothrombin complex concentratesin healthy volunteers treated with rivaroxaban wasassociated with a complete and rapid normalizationof clotting times that was not observed in healthyvolunteers treated with dabigatran (78). On the basisof this evidence, the use of prothrombin complexconcentrates is recommended in patients experi-encing major bleeding while undergoing treatmentwith antifactor Xa agents (Figure 1) (36).

Clinical data are available regarding the useof specific target antibodies created to reverse theanticoagulant effect of NOACs. Idarucizumab, anantibody fragment developed to reverse the antico-agulant effects of dabigatran, completely reversed theanticoagulant effect of this agent within minuteswhen given as a single intravenous bolus in 90dabigatran-treated patients who had serious bleedingor required an urgent procedure (79–81). Idar-ucizumab is now licensed in the United States andEurope for dabigatran reversal. Andexanet alfa, amodified recombinant human factor Xa molecule thatis catalytically inactive but retains the ability to binddirect and indirect factor Xa inhibitors, was able tocorrect the anticoagulant effect of apixaban in 34volunteers (82,83). In a recent study, andexanetreversed the anticoagulant activity of therapeuticdoses of apixaban and rivaroxaban in healthy elderlyvolunteers within minutes after its administrationand for the duration of infusion, with no evidence ofclinical toxic effects (84).

The clinical development of small molecules ableto antagonize the effect of several parenteral and oralantifactor Xa agents has also started (85). However,given the short half-life of the NOACs, the clinical

FIGURE 1 VTE and the NOACs

NOACs non inferior toLMWH followed by VKAsin the treatment of VTEand prevention ofrecurrences

NOACs associated withless bleeding* comparedwith LMWH followed byVKAs

VENOUS THROMBOEMBOLISM AND THE NOACs

Elderly:

Intermediate-high risk PE:

Renal failure:

Extreme body weight:

Pregnancy-breast feeding:

No specific dose adjustmenttested in clinical trials

limited evidence available;patients excluded fromclinical trials if thrombolysisindicated

dose reduction indicated foredoxaban; no dosereduction tested for VTEwith other NOACs. NOACsnot recommended if creatinineclearance < 30ml/min (25 ml/min for apixaban)

Dose reduction tested foredoxaban. Caution for bodyweight <50 or >120 kg

Limited evidence available

Main results of trials with new oral anticoagulant agents (NOACs) for the treatment of venous thromboembolism (VTE) and prevention of

recurrences (left side) and specific issues associated with the use of NOACs for the treatment of VTE (right side). *Different results in terms of

major bleeding or clinically relevant bleeding obtained with different NOACs. LMWH ¼ low-molecular-weight heparin; PE ¼ pulmonary

embolism; VKA ¼ vitamin K antagonist.



1950

value in real life of these antidotes remains to bedefined. Administration of activated charcoal shouldbe considered when the last dose of NOACs occurredwithin 2 h (36).

A proposal regarding the management of surgery orinvasive procedures while undergoing treatment withNOACs for VTE is reported in Figure 1 and in theCentral Illustration.

NOACs FOR EXTENDED TREATMENT OF VTE

DESIGN OF THE CLINICAL TRIALS. In the extendedtreatment of VTE, clinical trials were conducted withdabigatran, rivaroxaban, and apixaban (Table 5).Dabigatran, rivaroxaban, and 2 doses of apixabanwere compared with placebo in patients with uncer-tainty about the clinical benefit of continued anti-coagulation (39,86,87). Dabigatran was also comparedwith warfarin in patients with indications forextended treatment of VTE (86). All of the trials ofNOACs versus placebo were superiority studies,

whereas the trial of dabigatran versus warfarin was anoninferiority study. The primary outcome wasrecurrent VTE and VTE-related death; the exceptionwas the study with apixaban, which had recurrentVTE and overall mortality as the primary outcome.The primary safety outcome in all of the studies wasmajor bleeding. Treatment duration was 12 months inthe dabigatran and apixaban studies versus placebo,and 6 or 12 months in the rivaroxaban study. In thestudy of dabigatran versus warfarin, treatment wasgiven for up to 36 months.

MAIN RESULTS OF THE STUDIES. Dabigatran (HR:0.08; 95% CI: 0.02 to 0.25) (80), rivaroxaban (HR: 0.18;95% CI: 0.09 to 0.39) (39), and both doses of apixaban(RR: 0.36; 95% CI: 0.25 to 0.53 for the 5-mg twice-dailydose; RR: 0.33; 95% CI: 0.22 to 0.48 for the 2.5-mgtwice-daily dose) (87) were more effective than pla-cebo for the extended treatment of VTE. The rate ofmajor bleeding was low in all of the placebo-controlledstudies. Dabigatran, rivaroxaban, and the higher dose

CENTRAL ILLUSTRATION New Anticoagulants for Venous Thromboembolism: Mechanisms of Actionof Anticoagulant Agents and of Antidotes for New Oral Anticoagulant Agents

Becattini, C. et al. J Am Coll Cardiol. 2016;67(16):1941–55.

The coagulation cascade and anticoagulant agents. Targets of anticoagulation and targets of the antidotes idarucizumab and andexanet. AT ¼ antithrombin;

LMWH ¼ low-molecular-weight heparin; TF ¼ tissue factor; TFPI ¼ tissue factor pathway inhibitor; VKAs ¼ vitamin K antagonists.


1951

of apixaban were associated with an increased rate ofclinically relevant bleeding, whereas this outcome didnot occur with the lower dose of apixaban. Dabigatranwas noninferior to warfarin for the extended treat-ment of VTE, with an improved safety profile (86). Thelower dose of apixaban was as effective as and saferthan the higher dose for the extended treatment ofVTE in patients with clinical equipoise regarding thecontinuation or cessation of anticoagulation therapy(87). An ongoing clinical trial is aimed at assessing the

clinical value of full-dose rivaroxaban compared withthe prophylactic dose and aspirin in the extendedtreatment of VTE (88).

In a meta-analysis of Phase III placebo-controlledstudies on extended treatment, both all-cause mor-tality and recurrent VTE were lower with NOACsthan with placebo (0.6% per year vs. 1.1% per year[p ¼ 0.01] and 1.9% per year vs. 10.9% per year[p < 0.0001], respectively) (45). No significant dif-ference between treatments was observed in case

TABLE 5 Main Results of Phase III Studies With NOACs for Extended Treatment of VTE

NOAC (Ref. #) Study N TreatmentDuration(months) Efficacy Outcome Safety Outcome

Dabigatran(85)

RE-MEDY 2,856 Dabigatran 150 mg bid vs.warfarin (INR 2–3)

18–36 Recurrent VTE: 1.8% withdabigatran, 1.3% withwarfarin

Major bleeding: 0.9% withdabigatran, 1.8% withwarfarin

RESONATE 1,343 Dabigatran 150 mg bid vs.placebo

6 Recurrent VTE: 0.4% withdabigatran, 5.6% withwarfarin

Major bleeding: 0.3% withdabigatran, 0 withplacebo

Rivaroxaban(39)

EINSTEIN-extension 602 Rivaroxaban 20 mg dailyvs. placebo

6 or 12 Recurrent VTE: 1.3% withrivaroxaban, 7.1% withplacebo

Major bleeding: 0.7% withrivaroxaban, 0 withplacebo

Apixaban (86) AMPLIFY-extension 2,486 Apixaban 2.5 mg bid vs.placebo

12 Recurrent VTE and death:1.7% with apixaban,8.8% with placebo

Major bleeding: 0.2% withapixaban, 0.5% withplacebo

Apixaban 5 mg twice dailyvs. placebo

Recurrent VTE and death:1.7% with apixaban,8.8% with placebo

Major bleeding: 0.1% withapixaban, 0.5 % withplacebo

RESONATE ¼ Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; other abbreviations as in Tables 1 and 3.



1952

fatality rates of VTE recurrence (p ¼ 0.17). No fatalbleeding events were reported with NOACs duringextended treatment. A nonsignificant increase inmajor bleeding was reported in patients receivingNOACs (risk ratio: 1.41; 95% CI: 0.53 to 3.76).

The enhanced benefit-to-risk profile of the NOACsrelative to the vitamin K antagonists could lead toa change in practice concerning extended treatment inpatients with unprovoked VTE or in those withpersistent risk factors. Indeed, the benefit of extend-ing treatment with low doses could increase the pro-portion of patients prescribed extended treatment.However, when making decisions regarding extendedtreatment, the poor predictive value of commonlyused bleeding risk scores should be taken into account.The extension studies also open the way for shiftingpatients from conventional treatment to NOACs.

NOACs IN CLINICAL PRACTICE

The real-world safety profile of NOACs remains to bedefined. If the efficacy to safety profile reported inPhase III trials is confirmed, the reduction in medicalcosts estimated in economic analyses could also betranslated to the real world (89).

The PREFER (PREvention oF thromboembolicevents) registry showed that in clinical practice,NOACs were more frequently used for treatment ofVTE in younger patients (age <65 years, 26.8%; age 65to 74 years, 19.8%; and age $75 years, 14.3%). NOACswere used less frequently in those with lower weight(#60 kg vs.>60 kg 13.4% vs. 23.3%), renal insufficiency(22.7% vs. 11.1% in patients with creatinine clearancelevels #60 ml/min), diabetes (22.9% vs. 13.5% in pa-tients without and with diabetes), and those at risk ofbleeding (according to HAS-BLED score [low 27.1%;

medium 17.8%; and high 12.5%]) (90). Use in pulmo-nary embolism was as frequent as use in DVT.

Disease-based registry studies aimed at eval-uating NOACs in real-life patients are underway(NCT02210819, NCT02155491, NCT02295475, andNCT02345343).

NOACs FOR VTE TREATMENT IN THE

CURRENT GUIDELINES

Because the results of clinical trials with NOACs werepublished in the past few years, these agents havebeen considered only in the most recent guidelines.In the 2014 European Society of Cardiology guidelinesfor the management of pulmonary embolism, dabi-gatran, rivaroxaban, apixaban, and edoxaban were allrecommended as alternatives to conventional anti-coagulation agents for the treatment of pulmonaryembolism (31). Rivaroxaban and apixaban are indi-cated according to the single-drug approach, whereasdabigatran and edoxaban should be used after initialheparin treatment. Dabigatran, rivaroxaban, andapixaban are also indicated as alternatives to warfarinfor extended treatment.

THE RESPONSIBLE USE OF NOACs FOR THE

TREATMENT OF VTE

Although >30,000 patients have been included instudies with NOACs for the treatment of VTE, thesepatients may not be completely representative of thereal-life population of patients with this disease. Asan example, the mean age of patients included inthe trials is significantly lower than the mean age ofpatients with VTE included in disease registries;mortality rates reported in clinical trials were also






1953

lower than that seen in registries. Thus, cautionshould be used whenever a NOAC is to be given incompromised patients or in complex clinical settings.Although the treatment is apparently easier, itrequires a high level of clinical judgment to identifythe patients to be treated and exclude those morelikely to have complications.

Although associated with a reduced rate ofbleeding complications, NOACs may still causebleeding. To reduce these complications, emphasisshould be given to clinical history and patient edu-cation. A follow-up program should also formed withthe purpose of providing the patients with clinicalsurveillance and optimizing treatment adherence.

A document has been released on how to manageNOACs in specific clinical situations in patients withatrial fibrillation (36). Although patients with VTEdiffer from those with atrial fibrillation, and althoughtransfer of evidence from 1 clinical setting to anotheris not always appropriate, it is conceivable that thesame indications can be applied to patients with VTEuntil specific data become available.

CONCLUSIONS

In the treatment of VTE, NOACs are at least as effec-tive as warfarin but produce less bleeding and aremore convenient to administer. The availability ofNOACs for the treatment of VTE has the potential tobe a landmark achievement and, likely, the mostsignificant accomplishment in antithrombotic ther-apy since the introduction of LMWH approximately30 years ago. The results obtained with these agentsallow effective and simplified treatment in a largeproportion of patients with VTE. Better definitions ofefficacy and safety of NOACs in specific patient sub-groups (including those with cancer or intermediate-to high-risk pulmonary embolism), as well as in thoseaffected by thrombosis at unusual sites, will be tasksfor clinical research in the coming years.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Cecilia Becattini, Internal and CardiovascularMedicine–Stroke Unit, University of Perugia, Italy.E-mail: [email protected].

RE F E RENCE S

1. Martinez C, Cohen AT, Bamber L, et al. Epide-miology of first and recurrent venous thrombo-embolism: a population-based cohort study inpatients without active cancer. Thromb Haemost2014;112:255–63.

2. Tagalakis V, Patenaude V, Kahn SR, et al. Inci-dence of and mortality from venous thromboem-bolism in a real-world population: the Q-VTEStudy Cohort. Am J Med 2013;126:832.e13–21.

3. Wiener RS, Schwartz LM, Woloshin S. Timetrends in pulmonary embolism in the UnitedStates: evidence of overdiagnosis. Arch Intern Med2011;171:831–7.

4. ISTH Steering Committee for World ThrombosisDay. Thrombosis: a major contributor to globaldisease burden. Thromb Res 2014;134:931–8.

5. Cohen AT, Agnelli G, Anderson FA, et al., VTEImpact Assessment Group in Europe (VITAE).Venous thromboembolism (VTE) in Europe. Thenumber of VTE events and associated morbidityand mortality. Thromb Haemost 2007;98:756–64.

6. Yusuf HR, Reyes N, Zhang QC, et al. Hospitali-zations of adults $60 years of age with venousthromboembolism. Clin Appl Thromb Hemost2014;20:136–42.

7. Kröger K, Küpper-Nybelen J, Moerchel C, et al.Prevalence and economic burden of pulmonaryembolism in Germany. Vasc Med 2012;17:303–9.

8. LaMori JC, Shoheiber O, Mody SH, et al. Inpa-tient resource use and cost burden of deep veinthrombosis and pulmonary embolism in the UnitedStates. Clin Ther 2015;37:62–70.

9. Søgaard KK, Schmidt M, Pedersen L, et al.30-Year mortality after venous thromboembolism:

a population-based cohort study. Circulation2014;130:829–36.

10. Boutitie F, Pinede L, Schulman S, et al. Influ-ence of preceding length of anticoagulant treat-ment and initial presentation of venousthromboembolism on risk of recurrence afterstopping treatment: analysis of individual partici-pants’ data from seven trials. BMJ 2011;342:d3036.

11. Agnelli G, Prandoni P, Becattini C, et al.,Warfarin Optimal Duration Italian Trial In-vestigators. Extended oral anticoagulant therapyafter a first episode of pulmonary embolism. AnnIntern Med 2003;139:19–25.

12. Lang IM, Madani M. Update on chronicthromboembolic pulmonary hypertension. Circu-lation 2014;130:508–18.

13. Pengo V, Lensing AW, Prins MH, et al.,Thromboembolic Pulmonary Hypertension StudyGroup. Incidence of chronic thromboembolic pul-monary hypertension after pulmonary embolism.N Engl J Med 2004;350:2257–64.

14. Kahn SR, Shrier I, Julian JA, et al. Determinantsand time course of the post-thrombotic syndromeafter acute deep venous thrombosis. Ann InternMed 2008;149:698–707.

15. Ginsberg JS, Hirsh J, Julian J, et al. Preventionand treatment of postphlebitic syndrome: resultsof a 3-part study. Arch Intern Med 2001;161:2105–9.

16. Aschwanden M, Jeanneret C, Koller MT, et al.Effect of prolonged treatment with compressionstockings to prevent post-thrombotic sequelae: arandomized controlled trial. J Vasc Surg 2008;47:1015–21.

17. Kahn SR, Comerota AJ, Cushman M, et al.,American Heart Association Council on PeripheralVascular Disease, Council on Clinical Cardiology,and Council on Cardiovascular and Stroke Nursing.The postthrombotic syndrome: evidence-basedprevention, diagnosis, and treatment strategies:a scientific statement from the American HeartAssociation. Circulation 2014;130:1636–61.

18. MacDougall DA, Feliu AL, Boccuzzi SJ, et al.Economic burden of deep vein thrombosis, pul-monary embolism, and post-thrombotic syn-drome. Am J Health Syst Pharm 2006;63 20 Suppl6:S5–15.

19. Schweikert B, Pittrow D, Vizza CD, et al.Demographics, clinical characteristics, healthresource utilization and cost of chronic thrombo-embolic pulmonary hypertension patients: retro-spective results from six European countries. BMCHealth Serv Res 2014;14:246.

20. Kearon C, Akl EA, Comerota AJ, et al.Antithrombotic therapy for VTE disease: antith-rombotic therapy and prevention of thrombosis,9th ed: American College of Chest PhysiciansEvidence-based Clinical Practice Guidelines. Chest2012;141:e419S–94S.

21. Agnelli G, Becattini C. Anticoagulant treatmentfor acute pulmonary embolism: a pathophysiology-based clinical approach. Eur Respir J 2015;45:1142–9.

22. Anand SS, Bates S, Ginsberg JS, et al. Recur-rent venous thrombosis and heparin therapy: anevaluation of the importance of early activatedpartial thromboplastin times. Arch Intern Med1999;159:2029–32.

23. Fiessinger JN, Huisman MV, Davidson BL,THRIVE Treatment Study Investigators.

mailto:[email protected]

http://refhub.elsevier.com/S0735-1097(16)00818-4/sref1












































































































1954

Ximelagatran vs low-molecular-weight heparinand warfarin for the treatment of deep veinthrombosis: a randomized trial. JAMA 2005;293:681–9.

24. van Gogh Investigators. Idraparinux versusstandard therapy for venous thromboembolicdisease. N Engl J Med 2007;357:1094–104.

25. Nieto JA, Solano R, Ruiz-Ribó MD, et al., RIETEInvestigators. Fatal bleeding in patients receivinganticoagulant therapy for venous thromboembo-lism: findings from the RIETE registry. J ThrombHaemost 2010;8:1216–22.

26. Lecumberri R, Alfonso A, Jiménez D, et al.,RIETE Investigators. Dynamics of case-fatalityrates of recurrent thromboembolism and majorbleeding in patients treated for venous thrombo-embolism. Thromb Haemost 2013;110:834–43.

27. Prandoni P, Lensing AW, Cogo A, et al. Thelong-term clinical course of acute deep venousthrombosis. Ann Intern Med 1996;125:1–7.

28. Baglin T, Luddington R, Brown K, et al. Inci-dence of recurrent venous thromboembolism inrelation to clinical and thrombophilic risk factors:prospective cohort study. Lancet 2003;362:523–6.

29. Iorio A, Kearon C, Filippucci E, et al. Risk ofrecurrence after a first episode of symptomaticvenous thromboembolism provoked by a transientrisk factor: a systematic review. Arch Intern Med2010;170:1710–6.

30. Agnelli G, Prandoni P, Santamaria MG, et al.,Warfarin Optimal Duration Italian Trial Investi-gators. Three months versus one year of oralanticoagulant therapy for idiopathic deep venousthrombosis. N Engl J Med 2001;345:165–9.

31. Konstantinides SV, Torbicki A, Agnelli G, et al.2014 ESC Guidelines on the diagnosis and manage-ment of acute pulmonary embolism. Eur Heart J2014;35:3033–69.

32. Baetz BE, Spinler SA. Dabigatran etexilate: anoral direct thrombin inhibitor for prophylaxis andtreatment of thromboembolic diseases. Pharma-cotherapy 2008;28:1354–73.

33. Kubitza D, Becka M, Voith B, et al. Safety,pharmacodynamics, and pharmacokinetics of sin-gle doses of BAY 59-7939, an oral, direct factor Xainhibitor. Clin Pharmacol Ther 2005;78:412–21.

34. Raghavan N, Frost CE, Yu Z, et al. Apixabanmetabolism and pharmacokinetics after oraladministration to humans. Drug Metab Dispos2009;37:74–81.

35. Ahrens I, Bode C. Oral anticoagulation withedoxaban. Focus on current phase III clinicaldevelopment. Hämostaseologie 2012;32:212–5.

36. Heidbuchel H, Verhamme P, Alings M, et al.Updated European Heart Rhythm Associationpractical guide on the use of non-vitamin Kantagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467–507.

37. Schulman S, Kearon C, Kakkar AK, et al., RE-COVER Study Group. Dabigatran versus warfarin inthe treatment of acute venous thromboembolism.N Engl J Med 2009;361:2342–52.

38. Schulman S, Kakkar AK, Goldhaber SZ, et al.,RE-COVER II Trial Investigators. Treatment of

acute venous thromboembolism with dabigatranor warfarin and pooled analysis. Circulation 2014;129:764–72.

39. EINSTEIN Investigators. Oral rivaroxaban forsymptomatic venous thromboembolism. N Engl JMed 2010;363:2499–510.

40. EINSTEIN–PE Investigators. Oral rivaroxabanfor the treatment of symptomatic pulmonaryembolism. N Engl J Med 2012;366:1287–97.

41. Agnelli G, Buller HR, Cohen A, et al., AMPLIFYInvestigators. Oral apixaban for the treatment ofacute venous thromboembolism. N Engl J Med2013;369:799–808.

42. Hokusai-VTE Investigators. Edoxaban versuswarfarin for the treatment of symptomatic venousthromboembolism. N Engl J Med 2013;369:1406–15.

43. Prins MH, Lensing AW, Bauersachs R, et al.Oral rivaroxaban versus standard therapy for thetreatment of symptomatic venous thromboem-bolism: a pooled analysis of the EINSTEIN-DVTand PE randomized studies. Thromb J 2013;11:21.

44. Gómez-Outes A, Lecumberri R, Suárez-Gea ML, et al. Case fatality rates of recurrentthromboembolism and bleeding in patientsreceiving direct oral anticoagulants for the initialand extended treatment of venous thromboem-bolism: a systematic review. J Cardiovasc Phar-macol Ther 2015;20:490–500.

45. Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor’schoice—efficacy and safety of the new oral anti-coagulants dabigatran, rivaroxaban, apixaban, andedoxaban in the treatment and secondary pre-vention of venous thromboembolism: a systematicreview and meta-analysis of phase III trials. Eur JVasc Endovasc Surg 2014;48:565–75.

46. Vedovati MC, Becattini C, Germini F, et al.Efficacy and safety of direct oral anticoagulantsafter pulmonary embolism: a meta-analysis. Int JCardiol 2014;177:601–3.

47. Dentali F, Di Minno MN, Gianni M, et al.Non-vitamin K oral anticoagulants in patients withpulmonary embolism: a systematic review andmeta-analysis of the literature. Intern Emerg Med2015;10:507–14.

48. Mantha S, Ansell J. Indirect comparison ofdabigatran, rivaroxaban, apixaban and edoxabanfor the treatment of acute venous thrombo-embolism. J Thromb Thrombolysis 2015;39:155–65.

49. van Es N, Coppens M, Schulman S, et al. Directoral anticoagulants compared with vitamin Kantagonists for acute venous thromboembolism:evidence from phase 3 trials. Blood 2014;124:1968–75.

50. Bauersachs RM, Lensing AW, Prins MH, et al.Rivaroxaban versus enoxaparin/vitamin K antago-nist therapy in patients with venous thromboem-bolism and renal impairment. Thromb J 2014;12:25.

51. Prins MH, Nisio MD, Vedovati MC, et al.AS099: fixed-dose rivaroxaban is not associatedwith increased recurrent venous thromboembo-lism or major bleeding in patients with a high orlow body weight. J Thromb Haemost 2015;13:35.Abstract.

52. Davidson BL, Verheijen S, Lensing AW, et al.Bleeding risk of patients with acute venousthromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med2014;174:947–53.

53. Schulman S, Eriksson H, Goldhaber SZ, et al.Influence of concomitant NSAID or ASA on theefficacy and safety of dabigatran versus warfarinfor the treatment of acute venous thromboem-bolism: a pooled analysis from RE-COVER andRE-COVER II. Blood 2013;122:1136. Abstract.

54. Schulman S, Eriksson H, Goldhaber SZ, et al.Influence of thrombophilia on the efficacy ofdabigatran versus warfarin for the extendedtreatment of acute venous thromboembolism inRE-MEDY. Blood 2014;124:1544. Abstract.

55. Vedovati MC, Germini F, Agnelli G, et al. Directoral anticoagulants in patients with VTE and can-cer: a systematic review and meta-analysis. Chest2015;147:475–83.

56. Goldhaber SZ, Visani L, De Rosa M. Acutepulmonary embolism: clinical outcomes in theInternational Cooperative Pulmonary EmbolismRegistry (ICOPER). Lancet 1999;353:1386–9.

57. Jiménez D, Aujesky D, Moores L, et al., RIETEInvestigators. Simplification of the pulmonaryembolism severity index for prognostication inpatients with acute symptomatic pulmonaryembolism. Arch Intern Med 2010;170:1383–9.

58. Coutance G, Cauderlier E, Ehtisham J, et al.The prognostic value of markers of right ventric-ular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011;15:R103.

59. Becattini C, Agnelli G, Germini F, et al.Computed tomography to assess risk of death inacute pulmonary embolism: a meta-analysis. EurRespir J 2014;43:1678–90.

60. Becattini C, Vedovati MC, Agnelli G. Prog-nostic value of troponins in acute pulmonaryembolism: a meta-analysis. Circulation 2007;116:427–33.

61. Chatterjee S, Chakraborty A, Weinberg I, et al.Thrombolysis for pulmonary embolism and risk ofall-cause mortality, major bleeding, and intracra-nial hemorrhage: a meta-analysis. JAMA 2014;311:2414–21.

62. Meyer G, Vicaut E, Danays T, et al., PEITHOInvestigators. Fibrinolysis for patients withintermediate-risk pulmonary embolism. N Engl JMed 2014;370:1402–11.

63. Sharifi M, Bay C, Schwartz F, et al. Safe-dosethrombolysis plus rivaroxaban for moderate andsevere pulmonary embolism: drip, drug, anddischarge. Clin Cardiol 2014;37:78–82.

64. Vedovati MC, Germini F, Agnelli G, et al.Prognostic role of embolic burden assessed atcomputed tomography angiography in patientswith acute pulmonary embolism: systematicreview and meta-analysis. J Thromb Haemost2013;11:2092–102.

65. Fermann GJ, Erkens PM, Prins MH, et al.Treatment of pulmonary embolism with rivarox-aban: outcomes by simplified pulmonary embolismseverity index score from a post hoc analysis ofthe EINSTEIN PE study. Acad Emerg Med 2015;22:299–307.








































































































































































































1955

66. Aujesky D, Roy PM, Verschuren F, et al.Outpatient versus inpatient treatment for patientswith acute pulmonary embolism: an international,open-label, randomised, non-inferiority trial.Lancet 2011;378:41–8.

67. den Exter PL, Zondag W, Klok FA, et al. OR257:Efficacy and safety of outpatient treatment basedon the Hestia clinical decision rule with or withoutNT-proBNP testing in patients with acute pulmo-nary embolism: a randomized trial. J ThrombHaemost 2015;13:193. Abstract.

68. Scherz N, Méan M, Limacher A, et al. Pro-spective, multicenter validation of predictionscores for major bleeding in elderly patients withvenous thromboembolism. J Thromb Haemost2013;11:435–43.

69. Riva N, Bellesini M, Di Minno MN, et al. Poorpredictive value of contemporary bleeding riskscores during long-term treatment of venousthromboembolism. A multicentre retrospectivecohort study. Thromb Haemost 2014;112:511–21.

70. Dentali F, Ageno W, Becattini C, et al. Preva-lence and clinical history of incidental, asymp-tomatic pulmonary embolism: a meta-analysis.Thromb Res 2010;125:518–22.

71. van Bellen B, Bamber L, Correa de Carvalho F,et al. Reduction in the length of stay with rivar-oxaban as a single-drug regimen for the treatmentof deep vein thrombosis and pulmonary embolism.Curr Med Res Opin 2014;30:829–37.

72. Horner D, Hogg K, Body R, et al. The anti-coagulation of calf thrombosis (ACT) project: re-sults from the randomized controlled externalpilot trial. Chest 2014;146:1468–77.

73. Pinede L, Ninet J, Duhaut P, et al., In-vestigators of the “Durée Optimale du TraitementAntiVitamines K” (DOTAVK) Study. Comparison of3 and 6 months of oral anticoagulant therapy aftera first episode of proximal deep vein thrombosis orpulmonary embolism and comparison of 6 and 12weeks of therapy after isolated calf deep veinthrombosis. Circulation 2001;103:2453–60.

74. Righini M, Galanaud JP, Guenneguez H, et al.AS137: anticoagulant therapy for symptomaticdistal deep vein thrombosis: the CACTUS ran-domized placebo controlled trial (abstr). J ThrombHaemost 2015;13:50.

75. Levi M, Eerenberg E, Kamphuisen PW.Bleeding risk and reversal strategies for old andnew anticoagulants and antiplatelet agents.J Thromb Haemost 2011;9:1705–12.

76. Baker RI, Coughlin PB, Gallus AS, et al.,Warfarin Reversal Consensus Group. Warfarinreversal: consensus guidelines, on behalf of theAustralasian Society of Thrombosis and Haemo-stasis. Med J Aust 2004;181:492–7.

77. Voils SA, Baird B. Systematic review: 3-factorversus 4-factor prothrombin complex concen-trate for warfarin reversal: does it matter? ThrombRes 2012;130:833–40.

78. Eerenberg ES, Kamphuisen PW, Sijpkens MK,et al. Reversal of rivaroxaban and dabigatran byprothrombin complex concentrate: a randomized,placebo-controlled, crossover study in healthysubjects. Circulation 2011;124:1573–9.

79. Glund S, Stangier J, Schmohl M, et al. Idar-ucizumab, a specific antidote for dabigatran:immediate, complete and sustained reversal ofdabigatran induced anticoagulation in elderlyand renally impaired subjects (abstr). Blood 2014;124:344.

80. Glund S, Stangier J, Schmohl M, et al. Safety,tolerability, and efficacy of idarucizumab for thereversal of the anticoagulant effect of dabigatranin healthy male volunteers: a randomised,placebo-controlled, double-blind phase 1 trial.Lancet 2015;386:680–90.

81. Pollack CV Jr., Reilly PA, Eikelboom J, et al.Idarucizumab for dabigatran reversal. N Engl JMed 2015;373:511–20.

82. Crowther M, Kitt M, Lorenz T, et al. AS20.1: aphase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal

antidote for direct and indirect factor Xainhibitors. J Thromb Haemost 2013;11:30.

83. Crowther M, Lu G, Conley P, et al. P738: sus-tained reversal of apixaban anticoagulation withandexanet alfa using a bolus plus infusion regimenin a phase 2 placebo controlled trial (abstr). EurHeart J 2014;35:137.

84. Siegal DM, Curnutte JT, Connolly SJ, et al.Andexanet alfa for the reversal of factor Xainhibitor activity. N Engl J Med 2015;373:2413–24.

85. Ansell JE, Bakhru SH, Laulicht BE, et al. Use ofPER977 to reverse the anticoagulant effect ofedoxaban. N Engl J Med 2014;371:2141–2.

86. Schulman S, Kearon C, Kakkar AK, et al.,RE-MEDY and the RE-SONATE Trials Investigators.Extended use of dabigatran, warfarin, or placeboin venous thromboembolism. N Engl J Med 2013;368:709–18.

87. Agnelli G, Buller HR, Cohen A, et al., AMPLIFY-EXT Investigators. Apixaban for extended treat-ment of venous thromboembolism. N Engl J Med2012;368:699–708.

88. Weitz JI, Bauersachs R, Beyer-Westendorf J,et al., EINSTEIN CHOICE Investigators. Two dosesof rivaroxaban versus aspirin for prevention ofrecurrent venous thromboembolism. Rationale forand design of the EINSTEIN CHOICE study.Thromb Haemost 2015;114:645–50.

89. Amin A, Jing Y, Trocio J, et al. Evaluation ofmedical costs associated with use of new oralanticoagulants compared with standard therapyamong venous thromboembolism patients. J MedEcon 2014;17:763–70.

90. Agnelli G, Bauersachs R, Gitt AK, et al. P5559:the current use of direct oral anticoagulants(DOACs) for the treatment of VTE in Europe-PREFER in VTE (abstr). Eur Heart J 2014;35:1002.

KEY WORDS anticoagulant agents,pulmonary embolism, venous thrombosis

























































































































Documents

Treatment of Venous Thromboembolism With New Anticoagulant Agents …news.medlive.cn/uploadfile/20160419/14610471879554.pdf · 2016. 4. 19. · III trials, rivaroxaban, apixaban,