Initial Treatment
Prognostic Stratification
PE may display many different clinical characteristics at presentation, including
chest pain, dyspnoea, haemoptysis, cough, tachycardia, fever and syncope. Less commonly,
the clinical presentation can be either very mild or even silent (unsuspected PE)
or very severe, with haemodynamic collapse. This latter clinical scenario is associated
with the highest mortality rates (early mortality > 15%) and warrants immediate reperfusion
therapies, including pharmacological and/or mechanical thrombolysis. In all other
cases (i.e., PE without shock or persistent hypotension), it is crucial to stratify
the short-term risk of adverse outcomes, to choose the optimal management strategy.
Indeed, not only the clinical presentation may inform physicians about the risk of
early mortality, but several additional variables should be taken into consideration,
including age and sex, personal history of reduced cardiovascular reserve, active
cancer, right ventricular dysfunction (RVD) or injury and site and extension of thrombosis.
As suggested by current clinical guidelines,[1]
[2] when PE patients are haemodynamically stable, a primary distinction should be done
to identify those patients at very low risk of adverse outcome (30 days mortality < 1%).
For this purpose, the European Society of Cardiology (ESC) guidelines suggest the
use of the Pulmonary Embolism Severity Index (PESI) or its simplified version (sPESI),[3]
[4] a clinical prediction model (CPM) that includes 11 (or 6 in the simplified version)
easily available variables. Even if PESI has yet to be supported by the results of
an impact analysis, it represents the most widely validated CPM in this setting.[5]
[6] As demonstrated by several studies, PESI has a high negative predictive value, being
able to adequately identify PE patients at low risk of short-term adverse outcome.[5]
Other variables have been shown to be associated with PE prognosis, including right-to-left
ventricle diameter ratio at computed tomography (CT) scan, RVD at echocardiography,
brain natriuretic peptide (BNP) and troponin levels. These parameters have shown high
negative predictive values, although none has the same performance of PESI to discriminate
patients at low risk.[1] On the other hand, all these variables are associated with the risk of early mortality
with odds ratios that vary between ∼2 and 6.[2] Therefore, these markers have been proposed to identify haemodynamically stable
patients at intermediate risk of early mortality.
Therapeutic Approach
The treatment of PE traditionally consists of three subsequent phases, initial (0–7
days), long-term (from 7 days to 3 months) and extended (from 3 months to indefinite).
The initial treatment requires anticoagulant drugs with a rapid onset of action, such
as the parenteral heparins/fondaparinux or the direct oral anticoagulants (DOACs).
Low-molecular weight heparin (LMWH), unfractionated heparin (UFH) or fondaparinux
are administered for at least 5 days, either in association with the vitamin K antagonists
(VKAs) or preceding the administration of the DOACs dabigatran or edoxaban. In contrast,
the DOACs apixaban and rivaroxaban can be administered without lead-in parenteral
treatment from the beginning, with a loading dose given for 7 or 21 days, respectively
([Table 1]).
Table 1
Therapeutic options for initial and early maintenance therapy
|
Apixaban
|
Edoxaban
|
Rivaroxaban
|
Dabigatran
|
VKA
|
LMWH
(cancer patients)
|
|
Initial treatment
|
10 mg bid for 7 d
|
Parenteral anticoagulation for at least 5 d, then 60 mg od[a]
|
15 mg bid for 21 d
|
Parenteral anticoagulation for at least 5 d, then 150 mg bid[b]
|
Parenteral anticoagulation for at least 5 d associated with VKA AND until INR ≥2,
then VKA only (INR range, 2–3)
|
Full dose for 1 mo
|
|
Early maintenance therapy
|
5 mg bid
|
60 mg od[a]
|
20 mg od
|
150 mg bid[b]
|
INR, 2–3
|
50–75% of full dose after 1st mo
|
Abbreviations: INR, international normalized ratio; LMWH, low-molecular weight heparin;
VKA, vitamin K antagonists.
a Doses should be reduced, as tested in the Hokusai trial and according the Summary
of Product Characteristics, to 30 mg od for patients with one or more of the following
factors: creatinine clearance 15–50 mL/min; body weight ≤ 60 kg; concomitant treatment
with potent P-gp inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole).
b Doses should be reduced, according the Summary of Product Characteristics (not directly
tested in the RE-COVERY I and II trials), to 110 mg bid for patients aged ≥ 80 years
and/or receiving concomitant verapamil and should be considered for the following
groups, based on an individual assessment of the thromboembolic risk and the risk
of bleeding:
• Patients between 75 and 80 years.
• Patients with moderate renal impairment.
• Patients with gastritis, oesophagitis or gastro-oesophageal reflux.
• Other patients at increased risk of bleeding.
The choice of the treatment strategy depends on patient characteristics and on the
clinical setting. DOACs were shown to be non-inferior to warfarin in terms of efficacy[7]
[8]
[9]
[10]
[11]
[12] and to significantly reduce the risk of major bleeding and intracranial bleeding,
this latter by ∼50%.[13] The efficacy and safety of the DOACs in patients with VTE has been confirmed by
the results of post-marketing studies.[14]
[15]
[16]
[17] Thus, evidence-based guidelines now suggest DOACs as the first treatment option
for patients with PE.[18]
VKAs remain a valid option in particular when contraindications to DOACs exist, such
as severe renal or liver failure or concomitant use of interfering drugs such as strong
inducers/inhibitors of CYP3A4 and competitors/inducers of P-glycoprotein (e.g., human
immunodeficiency virus [HIV] protease inhibitors, azole antimycotics, carbamazepine,
phenytoin, phenobarbital).[19]
Patients with cancer-associated PE carry the highest risk of recurrence (∼20–25% per
year)[20]
[21] and benefit from LMWH, that is recommended for both the acute and the long-term
phase of treatment for up to 3 to 6 months.[18]
[22]
[23]
[24] LMWH was shown to be superior to warfarin at reducing the risk of VTE recurrence
(hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.32–0.71) with a similar
risk of bleeding events[25] ([Table 1]).
Cancer patients in phase III trials of DOACs are underrepresented. Although sub-group
analyses suggest DOACs are effective in reducing the risk of recurrent VTE as compared
with VKAs,[26] no head-to-head comparison with LMWH is currently available. Randomized controlled
trials directly comparing DOACs with LMWH in the acute treatment of VTE have recently
completed enrolment (Hokusai-Cancer trial)[27] or are on-going (Caravaggio trial, NCT03045406).
Setting of Care
Patients identified to be at low risk of short-term adverse outcomes represent at
least 40% of PE patients and may benefit from a short hospital stay (48 hours) or
home treatment.[5]
[28] This option is currently suggested for patients who have also adequate home circumstances.[1]
[18]
Several approaches have been proposed to identify and manage this group of PE patients.
In a randomized controlled trial comparing discharge after PE diagnosis at the emergency
department with hospitalization in low-risk patients defined by PESI class I–II or
simplified PESI 0, no increase in adverse events was documented.[28] In two prospective cohort management studies, patients suitable for outpatient treatment
defined by the Hestia criteria (a list of exclusion criteria for home treatment),
were safely managed with very low rates of adverse events.[29]
[30]
This approach may be appealing in several countries, since the mean length of hospital
stay (LOS) for PE remains high both in Europe and in the United States.[31]
[32]
[33] It should be also mentioned that the use of the DOACs has already resulted in a
reduction of LOS in patients with venous thrombosis.[14] In addition, a trend towards a reduction of LOS was already observed in recent years,
even before the availability of DOACs, probably due to the improved prognostic stratification.[32]
[33]
For patients with PESI risk class III-IV-V or simplified PESI ≥ 1, the risk of early
mortality is not negligible and hospitalization is recommended. Because this group
defined at intermediate risk is heterogeneous, with mortality rates ranging from 2
to 10 to 15%, a further stratification into intermediate-low and intermediate-high
risk was proposed.[2] This latter group benefits from a more intensive monitoring to early detect signs
of haemodynamic decompensation. The simultaneous presence of imaging signs of RVD
and the positivity of cardiac laboratory biomarkers, as suggested by the ESC guidelines
to identify intermediate-high risk patients, was adopted in the PEITHO trial, a randomized
controlled trial comparing systemic fibrinolysis with placebo on top of anticoagulant
therapy.[34] This approach was effective to identify patients who could benefit from treatment
with tenecteplase, with a significant reduction in the combined primary outcome of
mortality and haemodynamic decompensation (but no significant reduction in mortality
alone), although this benefit was offset by a significant increase in major bleeding
rates.
The DOACs have not been tested in specifically designed trials on PE patients at intermediate-high
risk of mortality. A sub-group analysis of the HOKUSAI VTE trial found a statistically
significant reduction with LMWH/edoxaban, as compared with LMWH/warfarin in VTE recurrence
(HR, 0.52; 95% CI, 0.28–0.98) in PE patients with RVD defined by increased N-terminal
pro-BNP levels.[35] In the EINSTEN-PE trial, patients with anatomically extensive PE treated with rivaroxaban
showed a similar incidence of VTE recurrence as compared with patients treated with
LMWH/warfarin (2.5% vs. 2.2%).[10] However, the question on whether lead-in parenteral treatment in PE patients at
intermediate-high risk is warranted remains open.
Finally, in case of shock or sustained hypotension at presentation, reperfusion therapy
should be performed by using systemic fibrinolysis, unless contraindicated. Alternative
strategies in case of high bleeding risk or fibrinolysis failure include the use of
endovascular or surgical thromboembolectomy. This issue is specifically discussed
in another article included in this issue by Kucher et al.
Long-Term and Extended Treatment
Who Should Continue on Anticoagulation
After the initial acute phase, patients should continue on anticoagulant therapy for
at least 3 months.[18] Beyond this period, there is adequate evidence to suggest that continuing anticoagulation
for a definite time only postpones the risk of VTE recurrence, without substantially
reducing it (so-called ‘catch-up’ phenomenon).[36]
[37] It should be noted, however, that clinicians tend to prolong the duration of treatment
up to 6 to 12 months, in case of both provoked and unprovoked event.[38]
When deciding the optimal duration of anticoagulation, the individual risk of recurrent
VTE must be balanced against the risk of bleeding, taking into consideration several
clinical variables and also patients values and preferences. The major determinant
of the recurrence risk is represented by the presence and type of provoking factors
identified at the time of the index event. In the presence of major transient risk
factors, such as major surgery, pregnancy/puerperium, immobilization due to trauma
or related to an acute medical illness, the risk of recurrence is low (< 5%/year)[39]
[40]
[41] and continuation of anticoagulation beyond 3 months is not warranted. On the other
end of the spectrum, permanent provoking factors such as active cancer or chronic
inflammatory diseases are associated with a high risk of recurrence and, thus, indefinite
anticoagulation is warranted.[41]
However, in up to 50% of patients with PE a major provoking factor cannot be identified.
In these patients, recurrence rates have been reported to be as high as 50% after
8 to 10 years,[42] and indefinite duration of anticoagulation is suggested by evidence-based guidelines
when bleeding risk is sufficiently low. However, this group of PE patients is quite
heterogeneous and this approach may not be necessary for all patients. Some baseline
characteristics have been consistently associated with a higher risk of recurrence,
with a mild to moderate strength of association: male sex, age > 65 years and obesity.
Moreover, thrombus location was also found to be associated with the risk of recurrent
VTE, with an increasing risk going from distal deep vein thrombosis (DVT) to proximal
DVT to PE. Also, it has been shown that patients presenting with PE are more likely
to recur with PE. Finally, some variables measured at the end of anticoagulant therapy
may also assist clinicians to determine the optimal duration of treatment, including
the presence of residual venous occlusion (RVO) or residual perfusion defects, post-thrombotic
syndrome (PTS) or elevated D-dimer.
RVO, that is measured by means of compression ultrasound of the veins involved in
DVT, has been shown to be independently associated with recurrent VTE, with variable
strength across several studies.[43]
[44]
[45]
[46]
[47] An individual patient data meta-analysis found that RVO is meaningful when measured
at 3 months after the index event, with a HR of 2.17 (95% CI, 1.11–4.25).[48] Recently, also residual pulmonary obstruction was shown to be independently associated
with recurrent VTE in two cohort studies conducted in Italy and in France, with HR
of 2.26 (95% CI 1,.23–4.16) and 1.94 (95% CI, 1.11–3.39), respectively.[49]
[50]
In several studies enrolling patients with unprovoked or ‘weakly-provoked’ VTE who
completed at least 3 months of anticoagulation, D-dimer was measured just before withholding
anticoagulation or within the subsequent month to evaluate its ability to predict
recurrent VTE. The results of these studies invariably show that D-dimer is significantly
associated with the risk of recurrent VTE.[51]
[52] Subsequently, D-dimer was used in combination with RVO in a management study that
demonstrated that anticoagulation can be safely withdrawn in ∼40% of patients with
unprovoked VTE who have negative D-dimer associated with the absence of RVO (in case
of DVT) or normal pulmonary artery pressure (in case of PE).[53] Moreover, D-dimer is included in all the three available CPMs on the risk of recurrent
VTE.
Even if the abovementioned variables are independent predictors of recurrent VTE,
their association is not strong enough to rely on their value when deciding to prolong
or discontinue anticoagulation. To improve the prediction of VTE recurrence, CPMs
have been proposed, derived and validated to select a group of patients with unprovoked
VTE who can safely discontinue anticoagulant treatment at the end of the initially
planned period (at least 3 months) ([Table 2]).[54] The Canadian ‘men continue and HERDOO2’ rule was first derived and internally validated
in 2008, showing that men are at high risk of recurrence, as well as women with at
least two characteristics among ‘HER’ (hyperpigmentation, oedema, redness in either
leg), positive ‘D’-dimer (≥ 250 µg/L, measured during anticoagulant treatment), older
age (≥ 65 years) and obesity (body mass index ≥ 30).[55] This rule was recently validated in a multinational prospective cohort management
study, that showed that ∼50% of women were classified as low risk and therefore discontinued
anticoagulant treatment, with an incidence of recurrent VTE of 3.0% per patient year
(95% CI, 1.8–4.8%).[56]
Table 2
Clinical prediction models for recurrent VTE after first unprovoked VTE
|
DASH[57]
|
MEN CONTINUE and
HER-DOO2[55]
|
VIENNA model[59]
|
|
D2
|
D-dimer (qualitative or ≥ 500 ng/mL at 3–5 wk)
|
Men
|
Male sex
|
Sex
|
Male/Female
|
|
A1
|
Age ≤ 50 y
|
HER1
|
Hyperpigmentation, oedema
or redness in either leg
|
Extension
|
Pulmonary embolism, proximal DVT,
distal DVT
|
|
S1
|
Male sex
|
D1
|
D-dimer ≥ 250 ng/mL on warfarin
|
D-dimer
|
Quantitative scale (µg/L)
|
|
H-2
|
Hormone use in women
|
01
|
Body mass index ≥ 30
|
|
|
|
|
01
|
Age ≥ 65 y
|
|
|
Abbreviations: DVT, deep vein thrombosis; VTE, venous thromboembolism.
The DASH score was originally derived and internally validated in 2012 within an individual
patient data meta-analysis and is based on positive post-anticoagulation D-dimer (2
points), age ≤ 50 years (1 point), male sex (1 point) and hormone use at time of initial
VTE in women only (–2 points). The annual incidence of recurrent VTE was 3.1% (95%
CI, 2.4–3.9) in patients with a DASH score of ≤ 1 and 9.3% (95% CI, 8.1–10.8) in patients
with a DASH score of > 1.[57] This model has been recently externally validated in a prospective cohort study.[58]
Finally, the Vienna model was published in 2010 and includes sex, site of index event
and D-dimer. A nomogram based on the model was designed to easily calculate patients'
cumulative recurrence rate at 12 and 60 months after cessation of therapy.[59] More recently, the original model was updated, by recalculating the risk of recurrence
using new measurements of D-dimer levels at 3, 9 and 15 months after cessation of
therapy.[60] The Vienna prediction model is currently being tested in a randomized trial, in
comparison to usual care, to decide on treatment duration (the VISTA study).[61]
All these CPMs can support clinicians when deciding on the duration of anticoagulant
treatment. Indeed, they may represent a useful tool to identify some sub-groups of
patients who are at low risk of recurrence. However, it should be noted that none
of these CPM has been extensively validated and only the HERDOO2 model has been tested
in a single management study.[56] Moreover, for patients not identified at low risk of recurrence, the decision should
still be taken on an individual basis, taking into account also the bleeding risk
and patients' values and preferences. Therefore, these CPMs can support clinicians
when deciding on anticoagulant treatment continuation after a first episode of unprovoked
VTE, but, at the moment, they should not be considered as single tools to rely on.
In addition to the abovementioned CPMs, several scores have also been proposed to
stratify the risk of bleeding in patients receiving anticoagulant treatment for VTE.
These scores may be of some help when balancing the recurrence and bleeding risks,
even if the predictive value of most of them needs to be better confirmed.[62] Ideally, some recently validated bleeding scores, which showed good predictive performances,[63]
[64] should be tested in management studies before being implemented in clinical practice.
Therapeutic Options for Extended Treatment
Several treatment options have been assessed in the extended treatment phase of VTE.
These include oral anticoagulants (DOACs or VKA), acetylsalicylic acid (ASA) and sulodexide.
Oral anticoagulants represent the first choice in terms of efficacy, because they
are associated with a 90% reduction of the risk of recurrent VTE as compared with
placebo.
The use VKAs is associated with a 1 to 2% yearly risk of major bleeding.[65] To improve their safety, lower intensity strategies were tested (international normalized
ratio [INR] range, 1.5–2), but failed to show a clinical benefit.[66]
[67]
The DOACs have been extensively assessed in the extended treatment of VTE, but only
in one study dabigatran was compared with warfarin, showing similar efficacy and safety
(although a non-statistically significant 50% reduction of major bleeding events was
observed with the use of dabigatran).[68] In all other studies, the DOACs were compared with placebo or ASA ([Table 3]).
Table 3
Therapeutic options for extended treatment
|
Apixaban
|
Edoxaban
|
Rivaroxaban
|
Dabigatran
|
VKA
|
ASA
|
Sulodexide
|
|
Dosage
|
2.5 or 5 mg bid
|
60 mg od[a]
|
10 or 20 mg od
|
150 mg bid[b]
|
INR range: 2–3
|
100 mg od
|
500 lipasemic units bid
|
|
VTE recurrence risk reduction compared with placebo (95% CI)
|
RR, 0.19
(0.11–0.33) for 2.5 mg bid[66]
RR, 0.20
(0.11–0.34) for
5 mg bid[66]
|
n/a
|
HR, 0.26
(0.14–0.47) for 10 mg od[c]
[67]
HR, 0.18
(0.09–0.39) for 20 mg od[9]
|
HR, 0.08
(0.02–0.25)[65]
|
RR, 0.12
(0.09–0.38)[75]
|
HR, 0.68
(0.51–0.90)[70]
|
HR, 0.49
(0.27–0.92)[71]
|
Abbreviations: ASA, acetylsalicylic acid; CI, confidence interval; HR, hazard ratio;
INR, international normalized ratio; RR, relative risk; VKA, vitamin K antagonists;
VTE, venous thromboembolism.
a Doses should be reduced, as tested in the Hokusai trial and according the Summary
of Product Characteristics, to 30 mg od for patients with one or more of the following
factors: creatinine clearance 15–50 mL/min; body weight ≤ 60 kg; concomitant treatment
with potent P-gp inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole).
b Doses should be reduced, according the Summary of Product Characteristics (not directly
tested in the RE-MEDY and RE-SONATE trials), to 110 mg bid for patients aged ≥ 80
years and/or receiving concomitant verapamil and should be considered for the following
groups, based on an individual assessment of the thromboembolic risk and the risk
of bleeding:
• Patients between 75 and 80 years.
• Patients with moderate renal impairment.
• Patients with gastritis, oesophagitis or gastro-oesophageal reflux.
• Other patients at increased risk of bleeding.
c As compared with ASA 100 mg.
In the RE-SONATE trial, dabigatran was associated with a significant reduction of
the risk of VTE recurrence, as compared with placebo (HR, 0.08, 95% CI, 0.02–0.25).[68]
The AMPLIFY-Extension trial showed that apixaban given at reduced-dose (2.5 twice
daily) significantly lowers the incidence of recurrent VTE as compared with placebo
(relative risk [RR], 0.19, 95% CI, 0.11–0.33), at a similar extent as the full-dose
(RR, 0.20, 95% CI, 0.11–0.34).[69]
In the EINSTEIN-Extension trial, rivaroxaban was also found to significantly reduce
the risk of recurrent VTE, as compared with placebo (HR, 0.18, 95% CI, 0.09–0.39).[9]
Very recently, the EINSTEIN-Choice trial was published, comparing rivaroxaban 20 mg
and rivaroxaban 10 mg to ASA 100 mg.[70] The results demonstrated superiority of both doses of rivaroxaban as compared with
ASA (HR, 0.34, 95% CI, 0.20–0.59 and HR, 0.26, 95% CI, 0.14–0.47, respectively), with
a non-statistically different risk of major bleeding.
The rationale for including ASA in the EINSTEIN-Choice trial relies on the results
of two studies (WARFASA and ASPIRE)[71]
[72] that demonstrated efficacy of low-dose ASA in reducing the risk of VTE recurrence
(HR, 0.68, 95% CI, 0.51–0.90), as well as arterial thrombosis (HR, 0.66, 95% CI, 0.51–0.86),
after an unprovoked VTE event, with a non-significant increased risk of major bleeding
(HR, 1.47, 95% CI, 0.70–3.08).[73] Based on these results, evidence-based guidelines suggest aspirin over no aspirin
to prevent recurrent VTE (Grade 2B), in patients with an unprovoked proximal DVT or
PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin.[18] However, this recommendation is now questionable after the results of the EINSTEIN-Choice
study.
Finally, sulodexide, a natural glycosaminoglycan with antithrombotic and profibrinolytic
activities, was recently compared with placebo in patients with a first unprovoked
VTE after completion of VKA therapy for 3 to 12 months (SURVET).[74] Sulodexide was effective in reducing the risk of recurrent VTE by 51% without increasing
the risk of bleeding.
Future Perspectives
The role of the DOACs in the treatment of PE in different risk sub-groups is currently
explored in several on-going studies. The HoT-PE Trial (home treatment of patients
with low-risk PE with the oral factor Xa inhibitor rivaroxaban) is a prospective cohort
study enrolling low risk PE patients (defined by the absence of RVD by means of CT
or echocardiography parameters) who receive rivaroxaban and are discharged within
48 hours from PE diagnosis (EudraCT Nr. 2013–001657–28).[75] The MERCURY PE (Multicenter Trial of Rivaroxaban for Early Discharge of Pulmonary
Embolism From the Emergency Department) study is also assessing rivaroxaban in low-risk
PE patients using the Hestia criteria.[76]
Dabigatran is currently tested in a trial enrolling patients at intermediate risk
of adverse outcomes, defined by either imaging or laboratory evidence of RVD (Safety
and Efficacy of Low Molecular Weight Heparin for 72 Hours Followed by Dabigatran for
the Treatment of Acute Intermediate-Risk Pulmonary Embolism–PEITHO-2, ClinicalTrials.gov:
NCT02596555). In this study, dabigatran is administered 72 hours after heparin initial
treatment, instead of the 5 days used in the registration trials.
Moreover, besides PE, several trials are testing DOACs on additional VTE-related indications
and/or in special populations ([Table 4]).
Table 4
On-going trials on VTE-related indications for direct oral anticoagulants
|
Study
|
Population
|
Intervention
|
Comparison
|
Primary Outcome
|
|
Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
(VERDICT) NCT02664155
|
Acute VTE patients with moderate or severe renal insufficiency
|
Rivaroxaban (15 mg od after standard 3 wk loading dose), apixaban (2.5 bid after standard
1 wk loading dose)
|
LMWH/UFH
Warfarin
|
Recurrent VTE and major bleeding
|
|
Treatment of Splanchnic Vein Thrombosis With Rivaroxaban. A Pilot, Prospective Cohort
Study (RivaSVT100) NCT02627053
|
Acute portal, mesenteric or splenic vein thrombosis
|
Rivaroxaban (standard dosing)
|
Not applicable
|
Major bleeding
|
|
Xarelto Versus no Treatment for the Prevention of Recurrent Thrombosis in Patients
With Chronic Portal Vein Thrombosis (RIPORT) NCT02555111
|
Chronic portal vein thrombosis
|
Rivaroxaban 15 mg od
|
No anticoagulation
|
Thromboembolic events (arterial or venous) or death
|
|
Apixaban for the Secondary Prevention of Thromboembolism Among Patients With the AntiphosPholipid
Syndrome (ASTRO-APS)
NCT02295475
|
Antiphospholipid syndrome
|
Apixaban 5 mg bid
|
Warfarin
(INR, 2–3)
|
Arterial and/or venous thrombosis
|
|
Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS) NCT02157272
|
Triple-positive antiphospholipid syndrome
|
Rivaroxaban 20 mg od (15 mg if creatinine clearance between 30 and 49 mL/min)
|
Warfarin
(INR, 2–3)
|
Arterial and/or venous thrombosis,
major bleeding or death
|
|
Apixaban for the Acute Treatment of Venous Thromboembolism in Children NCT02464969
|
Acute VTE
|
Apixaban (10 mg bid for 7 d, then 5 mg bid for weight ≥ 35 kg; 0.28 mg/kg bid for
7 d then 0.14 mg/kg twice daily for weight < 35 kg)
|
Standard of care
|
Major and clinically relevant non-major bleeding
|
|
Oral Rivaroxaban in Children With Venous Thrombosis (EINSTEIN Jr) NCT02234843
|
Acute VTE
|
Rivaroxaban (age and body weight-adjusted dosing equivalent to 20 mg in adults, once
daily, twice or three times daily)
|
Standard of care
|
Recurrent VTE
|
|
Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard
of Care in Pediatric Patients With Venous Thromboembolism NCT01895777
|
Acute VTE, initially treated with parenteral anticoagulation therapy
|
Dabigatran (age and weight appropriate dose)
|
Standard of care
|
Co-primary:
-Complete thrombus resolution, recurrent VTE, VTE related mortality
-Major bleeding
|
|
A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin
in Patients With Cerebral Venous and Dural Sinus Thrombosis (RE-SPECT CVT) NCT02913326
|
Cerebral venous or dural sinus thrombosis initially treated with parenteral anticoagulation
therapy
|
Dabigatran (standard dosing)
|
Warfarin
|
Major bleeding and VTE events
|
Abbreviations: INR, international normalized ratio; LMWH, low-molecular weight heparin;
UFH, unfractionated heparin; VTE, venous thromboembolism.
Finally, a new compound, acting on the endogenous fibrinolytic system, has been recently
tested in a phase I trial[77] and is currently used in a phase Ib trial on top of standard therapy for haemodynamically
stable PE patients. This drug (DS1040) acts as an inhibitor of the activated form
of thrombin-activatable fibrinolysis inhibitor (TAFIa), thus enhancing the endogenous
fibrinolysis.
