vte-ב לופיטב םינוכדע · risk of recurrent vte after stopping anticoagulant therapy...

VTE-עדכונים בטיפול ב

ר ענת רבינוביץ"ד

מנהלת יחידת קרישת דם

מכון המטולוגי

המרכז הרפואי האוניברסיטאי סורוקה

Epidemiology • Venous thromboembolism (VTE), clinically presenting as DVT

or PE, is globally the third most frequent acute cardiovascular syndrome behind myocardial infarction and stroke.

• Annual incidence rates for PE range from 39-115 per 100000

population; for DVT, incidence rates range from 53-162 per 100 000 population.

• The incidence of VTE is almost X8 higher in individuals aged

>_80 years than in the fifth decade of life. • PE may cause ~ 300 000 deaths per year in the US, ranking

high among the causes of cardiovascular mortality. In six European countries with a total population of 454.4 million, more than 370 000 deaths were related to VTE

1מקרה

מגיע למיון עם נפיחות . בריא בדרך כלל, 50גבר בן • . ברגל שמאל מזה יומיים

ווריד iliac veinמשמאל עם מעורבות DVTבדופלקס • . פמורלי

. יציב המודינמית ונשימתית•

: שאלות•

? שחרור או אשפוז–

?איזה טיפול להתחיל–

? מתי? איזה בירור דרוש–

Pulmonary embolism severity index (PESI) - Full

Clinical feature Points

Age x (eg, 65)

Male gender 10

History of cancer 30

Heart failure 10

Chronic lung disease 10

Pulse ≥110/min 20

Systolic blood pressure <100 mmHg 30

Respiratory rate ≥30/min 20

Temperature <36° Celcius 20

Altered mental status 60

Arterial oxygen saturation <90 percent 20

Class I Low risk <66

Class II 66 to 85

Class III High risk 86 to 105

Class IV 106 to 125

Class V >125

Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;

172:1041.

Simplified pulmonary embolism severity index (sPESI)

Clinical feature Points

Age >80 years 1

History of cancer 1

Chronic cardiopulmonary disease 1

Pulse ≥110/min 1

Systolic blood pressure <100 mmHg 1

Arterial oxygen saturation <90 percent 1

Low risk 0

High risk >1

In a cohort of 995 patients with PE that compared PESI with sPESI, 30-day mortality was reported in patients classified as low risk (1% ) or high risk (11%) Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients

with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383.

A composite model that incorporates sPESI, BNP, cardiac troponin I, and lower limb ultrasound (done within 48 hours of admission)

The combination of a low risk sPESI score and BNP <100 pg/mL identified patients at low risk of death, hemodynamic collapse, and/or recurrent PE at 30 days (negative predictive value 99 – 100%).

Thrombolysis for DVT?????

ACCP Guidelines1, published

January 2016:

Treatment of VTE in patients without cancer –

suggest use of dabigatran, rivaroxaban, apixaban,

or edoxaban over VKA therapy (all Grade 2B)*

ACCP = American College of Chest Physicians; NOAC = non-VKA oral anticoagulant; VKA = vitamin K antagonist; VTE =

venous thromboembolism.

* Order of NOAC presentation is based on the chronology of publication of the phase 3 trials in VTE treatment and does not

reflect the guideline panel’s order of preference for the use of these agents

1. Kearon C et al. CHEST 2016; doi: 10.1016/j.chest.2015.11.026.

Summary of Acute Treatment

The duration of follow-up differed between trials therefore event rates should not be compared or interpreted as an indicator of the risk of the

population.

*Not significant based on 95% CI for hazard ratio.

** Pooled analysis

NR=not reported

Head-to-head studies do not exist, and direct comparisons between agents may not be made.

Recurrent VTE + VTE death

Major Bleeding Major + CRNM

Bleeding

Drug Trial NOAC vs Comparator (%), P-value

Apixaban AMPLIFY

Non-inferiority 2.3 vs 2.7

P<0.001 (NI)

Superiority RRR 69% 0.6 vs 1.8 P<0.001

Superiority RRR 56% 4.3 vs 9. P<0.001

Rivaroxaban

EINSTEIN- DVT


P<0.001 (NI)

Not signif. 0.8 vs 1.2

P=0.21


P=0.77

EINSTEIN-PE


P=0.003 (NI)

Superiority RRR 51% 1.1 vs 2.2 P=0.003


P=0.23

Dabigatran RE-COVER**


NR*


NR*

Superiority RRR 38% 5.3 vs 8.5

NR

????טרומבופיליהבירור

? בימינו" קלאסית" טרומבופיליהמה המשמעות של

( אם בכלל עדיין יש משמעות)

https://www.google.co.il/url?url=https://www.engrade.com/wikis/page-print.php?itemid%3D300000000696920%26pageid%3D1&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwi255vS3IrTAhXFDCwKHUnLCJYQwW4IJzAJ&usg=AFQjCNF2LaTzfFQuuRD3sU-ODg2Ml_LoNQ

VTE Terminology and Risk Factors

Avoid terms such as ‘unprovoked’ or ‘idiopathic’ VTE.

Risk of recurrence is related to the risk factors predisposing to index PE:

Transient/reversible (usually setting-related)

Persistent (usually patient-related)

Risk factors further classified as:

Strong (OR > 10)

Moderate (OR 2-9)

Weak (OR < 2)

Konstantinidis, et al. European Heart Journal 2019; 00: 161

Predisposing Factors for VTE


Strong (major) risk factors (OR > 10)

Fracture of lower limb

Hospitalization for heart failure or atrial fibrillation/flutter (within previous 3 months)

Hip or knee replacement

Major trauma

Myocardial infarction (within previous 3 months)

Previous VTE

Spinal cord injury

OR, odds ratio

Predisposing Factors for

VTE


Moderate risk factors (OR 2-9)

Arthroscopic knee surgery

Autoimmune diseases

Blood transfusion

Central venous lines

Intravenous catheters and leads

Chemotherapy

Congestive heart failure or respiratory failure

Erythropoiesis-stimulating agents

Hormone replacement therapy (depends on formulation)

In vitro fertilization

Oral contraceptive therapy

Post-partum period

Infection (specifically pneumonia, urinary tract infection, HIV)

Inflammatory bowel disease

Cancer (highest risk in metastatic disease)

Paralytic stroke

Superficial vein thrombosis

Thrombophilia

Predisposing Factors for VTE


Weak (minor) risk factors (OR < 2)

Bed rest >3 days

Diabetes mellitus

Arterial hypertension

Immobility due to sitting (e.g. prolonged car or air travel)

Increasing age

Laparoscopic surgery (e.g. cholecystectomy)

Obesity

Pregnancy

Varicose veins

Risk Factors Classified by Risk of VTE Recurrence


Clinical disorders associated with Acquired (Secondary) Hypercoagulable States

• Nephrotic syndrome • Heparin-induced thrombocytopenia • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria

More “genetic” thrombophilias…. • GWAS revealed several additional genetic polymorphisms

with borderline but measurable statistical association with VTE

• The non O-blood group status is the most common mild

predisposition. Two VTE associated loci, TSPAN15 and SLC44A2, increase also slightly the odds ratio for VTE (1.31 for TSPAN15 and 1.21 for SLC44A2, respectively).

• The ThromboGenomics group in the United Kingdom

using next generation sequencing and a high-throughput screening panel for genetic analysis of patients with coagulation, platelet or thrombotic disorders was able to identify a genetic diagnosis in 48.9% of patients with thrombotic disease.

Assessment • Clinical VTE is multifactorial and the sum of gene–gene and/or gene-environment interactions which

lead to overcome a threshold and trigger the event • In this framework of predisposing factors inherited thrombophilia interacts dynamically with

environmental factors, which are partly modifiable • Acquired predisposing factors for VTE—that may be classified in major/minor and

persistent/transient—play a different role in the presence of an inherited thrombophilia. • A minor risk factor may be sufficient to trigger an episode of VTE in a young patient typically in

association with a genetic risk factor. • On the other hand, most patients over 60 years may develop a VTE in the presence of one or more

acquired risk factors, even without an inherited thrombophilia • All patients with first should be evaluated clinically for thrombophilia. This starts with a careful

personal and family history for venous (or arterial) thrombosis, past clinical history, associated diseases and their prognosis, evaluation of acquired risk factors for VTE.

• A basic laboratory test is indicated in all patients . An important issue at this point is to carefully

select the patient who should be screened with supplementary thrombophilia specific laboratory tests.

Thrombophilia screening revisited: an issue of personalized medicine. ColucciG, Tsakiris AD. Journal of Thrombosis and Thrombolysis 2019

Antithrombin Protein C Protein S Neonatal period Neonatal period Neonatal period

Pregnancy pregnancy Pregnancy

Liver disease Liver disease Liver disease

DIC DIC DIC

Nephrotic syndrome Chemotherapy (CMF)

Major surgery Inflammatory states

Acute thrombosis Acute thrombosis Acute thrombosis

Treatment with:

Heparin Warfarin Warfarin

L-Asparaginase L-Asparaginase L-Asparaginase

Estrogens Estrogens

Causes of acquired protein C, S and

antithrombin deficiencies

IVC filterאינדיקציות להכנסת

קונטרה אינדיקציה מוחלטת למתן קיום •

סיכון גבוה , לדוגמא דימום פעיל) אנאטיקואגולציה

(רסנטידימום מוחי , לדימום

טיפול מלא חוזר תחת VTEהתפתחות •

(טובה) באנטיקואגולציה

המשך -1מקרה

אותו מטופל השלים שישה חודשים של טיפול •

. מלאה באנטיקואגולציה

. שלילי טרומבופיליהבירור •

. ללא עדות לממאירות•

מרגיש טוב•

מה ? להמשיך טיפול? להפסיק טיפול? מה עכשיו

? חוזר VTE-הסיכון ל

What do the “old” guidelines say?

• Kearon C et al. Chest 2012:

• 3.1.4. In patients with an unprovoked DVT of the leg (isolated distal or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B) . After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefit ratio of extended therapy.

• 3.1.4.1. In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .

• Kearon C et al. Chest 2016:

• In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B).

Risk of recurrent VTE after stopping anticoagulant therapy

provocation after 1 year % after 5 years %

surgery 1 3

nonsurgical

reversible risk

factor * 5 15

Unprovoked 10 30

Cancer ** 15

* nonsurgical trigger : eg, estrogen therapy, pregnancy, leg injury, flight of > 8 h

** cancer: vary according to whether the cancer is metastatic, being treated

with chemotherapy, or rapidly progressing

CHEST 2012;141 suppl e419S-e494S

Recurrence rate Provoked/unprovoked

Martinez et al. Thromb Haem 2014;112.

28.4%

20.5%

Can we figure out the risk for recurrent

VTE in an individual patient without known

conventional risk factors?

https://www.google.co.il/url?url=https://www.engrade.com/wikis/page-print.php?itemid%3D300000000696920%26pageid%3D1&rct=j&frm=1&q=&esrc=s&sa=U&ved=0ahUKEwi255vS3IrTAhXFDCwKHUnLCJYQwW4IJzAJ&usg=AFQjCNF2LaTzfFQuuRD3sU-ODg2Ml_LoNQ

• “Men continue and HERDOO2” Rule:

Men and women with 2 or more of the following are labeled

as “high risk of recurrent VTE”:

1) Hyperpigmentation, Edema or Redness in either leg (PTS)

2) Vidas Ddimer > 250 ug/ml

3) Obesity with BMI > 30 kg/m2

4) Older than age 65

• During a mean follow-up interval of 5.0 years, annualized

risk of recurrent VTE of 5.0% (95% CI:4.2-5.8%).

• The cumulative risk of recurrent VTE at 8 years was

29.6%

• In total study population, male gender was the strongest

predictor of recurrence. Men had a 7.6% (95% CI: 6.3-

9.2%) annual risk of recurrent VTE in mean follow-up of

4.4 years compared to 2.8% (95% CI: 2.2% to 3.7%) in

women in a mean follow-up of 5.6 years (RR: 2.7; 95% CI

2.0- 3.7).

Vienna Prediction Model for Recurrent VTE

• Eichinger et al, multicenter prospective cohort study of 929 consecutive patients with a first episode of unprovoked VTE.

• Risk factors for recurrence: • Male sex (HR 1.90, 95 % confidence interval 1.31–2.75)

• Proximal DVT (HR 2.08, 95 % confidence interval 1.16–3.74)

• PE (HR 2.60, 95 % confidence interval 1.49–4.53)

• Elevated D-dimer (HR per doubling 1.27, 95 % confidence interval 1.08–1.51).

• Using these factors they have developed a web-based risk prediction calculator (Vienna Prediction Model for Recurrent VTE) that is available on the web (http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/)

Risk Factors Classified by Risk of VTE Recurrence


2.5 mg BD

20 mg OD

150 mg BD

10 mg BD

Day 7 6 months >6 months

Apixaban in DVT & PE (AMPLIFY1) Apixaban (AMPLIFY-EXT2)

5 mg BD

Initial

(0 to 7 days)

Long-term

(at least 3 months)

Extended

(indefinite)

UFH/

LMWH

15 mg BD

Rivaroxaban (EINSTEIN-DVT3) Rivaroxaban (EINSTEIN-Extension3)

20 mg OD

Day 21

15 mg BD 20 mg OD

Rivaroxaban (EINSTEIN-PE4)

Dabigatran (RE-COVER5, RE-COVERII6) Dabigatran (RE-SONATE7)

150 mg BD UFH/

LMWH

1. Agnelli et al. N Engl J Med 2013;369:799-808; 2. Agnelli et al. N Engl J Med 2013;368:699-708; 3. Bauersachs et al. N Engl J Med 2010;363:2499-510; 4.

Büller et al. N Engl J Med 2012;366:1287-97; 5. Schulman et al. N Engl J Med 2009;361:2342-522; 6. Schulman et al. Circulation 2014;129:764-72; 7.

Schulman et al. N Engl J Med 2013;368:709-18; 8. Weitz JI, et al. N Engl J Med. 2017;376(13):1211-1222. 9. Schulman S, et al. Thromb Haemost. 2011

UFH, unfractionated heparin; LMWH, low molecular weight heparin; BD, twice daily; OD, once daily

Vitamin K Antagonist

10 mg OD

Rivaroxaban vs ASA (EINSTEIN-Choice8)

150 mg BD

Dabigatran vs warfarin (RE-MEDY9)

VTE Treatment

47

Apixaban for Extended Treatment of Venous

Thromboembolism (VTE) The AMPLIFY-EXTENSION Study

Agnelli G et al. N Engl J Med 2013; 368: 699-708

48 For medical non-promotional reactive use only

BID, twice daily; DVT, deep vein thrombosis; PE, pulmonary embolism; R, randomization

• Aim: To compare the efficacy and safety of two doses of apixaban

with placebo for the extended treatment of patients with VTE

• Design: Randomized, double blind, placebo-controlled, superiority

study

Placebo BID

Apixaban 2.5 mg BID

Apixaban 5 mg BID

DVT/PE patients

who have

completed

6–12 months of

anticoagulant

treatment

R

En

d o

f Tre

atm

en

t

Sa

fety

Fo

llo

w-u

p

12 Months 30 Days Day 1


Aim and Design

Agnelli G et al. N Engl J Med 2013;368:699-708.

Demographic and Clinical Characteristics of the Patients.

50

Efficacy Outcomes

8.8%

1.7%


51

Safety Outcomes


Clinical Interpretation

Apixaban 2.5 mg

Apixaban 5 mg

NNT to prevent one recurrent VTE

14 14

NNH - one major or

clinically relevant non-major bleed

200 63

NNH, number needed to harm; NNT, number needed to treat; VTE, venous thromboembolism


Weitz JI et al. N Engl J Med 2017

Rivaroxaban or Aspirin for Extended Treatment

of Venous Thromboembolism

NCT02064439

Study Design

Aim: Compare the efficacy and safety of once daily rivaroxaban (20 or 10 mg)

with aspirin (100 mg) in VTE patients who completed 6 to 12 months of

treatment and with equipoise regarding the need for extended anticoagulation

Randomized, double-blind, active-comparator, event-driven, superiority study

1 month

observation

period

Rivaroxaban 20 mg od

Rivaroxaban 10 mg od

N=3396 Patients with confirmed symptomatic DVT/PE

who completed 6–12 months of anticoagulation

R

Aspirin 100 mg od

12-month treatment duration

Weitz JI et al. Thromb Haemost 2015;114:645–50

Weitz JI et al. N Engl J Med 2017;376:1211-1222.

Demographic and Clinical Characteristics of the Patients at Baseline.

Recurrent VTE – Cumulative Incidence

VTE, Venous thromboembolism; HR, hazard ratio

Aspirin 4.4% (50/1131)

Rivaroxaban 20 mg 1.5% (17/1107)

Rivaroxaban 10 mg 1.2% (13/1127)

Days

0

1

2

3

4

5 C

um

ula

tive

in

cid

en

ce

(%

)

1 30 60 90 120 150 180 210 240 270 300 330 367

Number of patients at risk

Rivaroxaban 20

mg 1107 1102 1095 1090 1084 1079 997 876 872 860 794 718 0

Rivaroxaban 10

mg 1126 1124 1119 1118 1111 1109 1029 890 886 867 812 723 0

Aspirin 1131 1121 1111 1103 1094 1088 1010 859 857 839 776 707 0

The EINSTEIN-CHOICE Trial

Weitz JI, et al.. N Engl J Med. 2017.

Recommendations for Chronic Treatment After PE in Patients Without Cancer (1)

1. Konstantinidis, et al. European Heart Journal 2019; 00: 161; 2. Konstantinidis, et al. European Heart Journal 2014; 35: 3033-69

Level Class Recommendations

A I Therapeutic anticoagulation for ≥3 months is recommended for all patients with PE.

Patients in whom discontinuation of anticoagulation after 3 months is recommended

B I

For patients with first PE/VTE secondary to a major transient/reversible risk factor, discontinuation of therapeutic oral anticoagulation is recommended after 3 months.

ESC 20191 ESC 20142


B I

For patients with PE secondary to a transient (reversible) risk factor, oral anticoagulation is recommended for 3 months .



ESC 20191 ESC 20142


Patients in whom extension of anticoagulation beyond 3 months is recommended

B I

Oral anticoagulant treatment of indefinite duration is recommended for patients presenting with recurrent VTE (that is, with at least one previous episode of PE or DVT) not related to a major transient or reversible risk factor.

B I

Oral anticoagulant treatment with a VKA for an indefinite period is recommended for patients with antiphospholipid antibody syndrome.


B I

Anticoagulation treatment of indefinite duration is recommended for patients with a second episode of unprovoked PE.


ESC 20191


Patients in whom extension of anticoagulation beyond 3 months should be considered

A IIa

Extended oral anticoagulation of indefinite duration should be considered for patients with a first episode of PE and no identifiable risk factor.

C IIa

Extended oral anticoagulation of indefinite duration should be considered for patients with a first episode of PE associated with a persistent risk factor other than antiphospholipid antibody syndrome.

C IIa

Extended oral anticoagulation of indefinite duration should be considered for patients with a first episode of PE associated with a minor transient or reversible risk factor.



B IIa

Extended oral anticoagulation should be considered for patients with a first episode of unprovoked PE and low bleeding risk.

ESC 20142


ESC 20191 ESC 20142


NOAC dose in extended anticoagulation

A IIa

If extended oral anticoagulation is decided after PE in a patient without cancer, a reduced dose of the NOACs apixaban (2.5 mg b.i.d.) or rivaroxaban (10 mg o.d.) should be considered after 6 months of therapeutic anticoagulatione.


B IIa

Rivaroxaban (20 mg once daily), dabigatran (150 mg twice daily, or 110 mg twice daily for patients ≥80 years of age or those under concomitant verapamil treatment) or apixaban (2.5 mg twice daily) should be considered as an alternative to VKA (except for patients with severe renal impairment) if extended anticoagulation treatment is necessary.

e If dabigatran or edoxaban is chosen for extended anticoagulation after PE, the dose should remain unchanged, as reduced-dose regimens were not investigated in dedicated extension trials.


Assessment of Bleeding Risk

Risk is higher in the first month of anticoagulant treatment, then declines and stabilizes.

Risk factors include advanced age, previous bleeding or anemia, active cancer, NSAIDs etc.

Bleeding risk should be assessed at the time of anticoagulation initiation, and periodically.

Assessment should be used to identify and treat modifiable bleeding risk factors, and it may

influence decision-making on the duration and regimen/dose of anticoagulant treatment.


To summarize… • Anticoagulation regimens at intensities tailored to the patients' risk profiles

and VTE characteristics, with a shift of the risk-benefit balance in favor of extended treatment.

• A major challenge is to identify patients who would benefit most from

extended treatment. • In the decision-making process, it should be considered that the risk of

recurrence is greatest in the first months after the withdrawal of anticoagulant therapy, with an incidence of approximately 5-7% per year in patients with a first unprovoked event. However, the haemorrhagic risk remains unchanged over time

• Furthermore, the risk of death associated with recurrence of VTE (case-

fatality rate: 5.1%) tends to decrease over time. Conversely, the mortality rate associated with haemorrhagic complications (9.1-11%) remains stable.

• Individual haemorrhagic risk is difficult to predict, and currently, the available

bleeding risk scores have only a modest predictive value for patients with VTE.

..... VTEשתי מילים על סיבוכי

• The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT)

• 20-50% of DVT patients develop PTS despite

optimal anticoagulation

• Mostly diagnosed between 6-24 months post DVT

Kahn SR, Ginsberg JS, Blood Rev 2002; Kahn SR, Br J Haematol 2006

Post thrombotic syndrome

Anat Rabinovich, Susan R. Kahn, How I treat the postthrombotic syndrome, Blood, 2018

Copyright © 2020 American Society of Hematology

Symptoms None

0 point

Mild

1 point

Moderate

2 points

Severe

3 points Pain

Cramps

Heaviness

Paresthesiae

Pruritis

Clinical signs None

0 point

Mild

1 point

Moderate

2 points

Severe

3 points Pretibial edema

Skin induration

Hyperpigmentation

Redness

Venous ectasia

Pain on calf compression

Venous ulcer Absent Present

Villalta PTS score:

0–4: None 5–9: Mild

10-14: Moderate >14/ulcer: Severe

https://www.google.co.il/url?sa=i&url=https://smw.ch/article/doi/smw.2018.14702&psig=AOvVaw3028afJSDcAQT1PlqM-AT7&ust=1589883193190000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCMDlp8-WvekCFQAAAAAdAAAAABAW

2מקרה ראשון של ארועמגיע למרפאת קרישה חודשיים לאחר . ספר במקצועו, 36בן , א.מ•

"unprovoked” proximal DVT

. ללא ביצוע כל בירור קודם לכן בקסרלטובמחלקה פנימית הוחל טיפול •

. יתר קרישיותלצורך ביצוע בירור לקלקסןומעבר קסרלטוהמטופל מסרב להפסקת •

. triple positive APLAמעלה קסרלטובירור שמבוצע תחת •

. קסרלטושלא תחת APLAמסרב שוב לחזור על פאנל •

"(. ר הסביר לי שזה הכי טוב שיש"הד)" בקומדיןמסרב לעבור לטיפול •

מבוצעת התערבות, צ"דועורקי פריפרי ארועחודשיים לאחר מכן אשפוז בכלי דם עם • . לקלקסןמועבר . מוצלחת אנדווסקולרית

. עד להשלמת הבירור בקלקסןהפעם מסכים להמתין תחת טיפול •

triple positive APLAמדגים שוב קלקסןחוזר תחת APLAפאנל •

? במיון DOACהאם בכל מטופל להתחיל העמסת ? APLAבמטופלים עם DOAC-טיפול ב

? DOACיתר קודם להתחלת קרישיותאיך לבצע בירור

• Randomized open-label multicenter noninferiority study with blinded end point adjudication. • Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin

(INR target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome.

• Only high-risk patients triple positive for lupus anticoagulant, anticardiolipin, and anti–b2-glycoprotein I antibodies (triple positivity) were included in the study.

• The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm.

• Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin.

• Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. • The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an

increased rate of events compared with warfarin, thus showing no benefit and excess risk.

• ASTRO-APS (Apixaban for Secondary Prevention of Thrombosis Among Patients with Antiphospholipid Syndrome) is an open-label randomized trial evaluating apixaban vs usual care for prevention of recurrent thrombosis after at least 6 months of initial anticoagulation (www.clinicaltrials.gov identifier NCT02295475).

• After enrolling the first 25 patients, a preplanned DSMB review recommended an increase from apixaban 2.5 mg twice daily to apixaban 5 mg twice daily.

• After a higher than expected rate of stroke in 5 subsequent patients, an unplanned DSMB review recommended changing the enrollment criteria to exclude patients with prior arterial thrombosis and to obtain brain MRI prior to enrollment to exclude stroke or white matter changes disproportionate for age

• Our understanding of this disease is further complicated by our lack of knowledge of its pathophysiology. Although various hypotheses have been proposed for the mechanism by which thrombosis and/or pregnancy loss occur, agreement on its basic biology is far from universal.

• Studies in patients with APS are difficult to perform because the condition is rare, and patients suffer from a spectrum of clinical

disorders, only some of which will qualify them for studies of anticoagulants (eg, patients may present with both new thromboses and profound thrombocytopenia or may have exclusively pregnancy morbidity).

• Patients suspected of having APS should have the diagnosis confirmed by objective testing performed in expert laboratories. A large

proportion of patients, perhaps a majority of them labeled as having APS, do not in fact have the disorder, either because the testing was inadequate (usually only a single test that demonstrated a low-titer anticardiolipin antibody without confirmation) or because they were tested while they were receiving anticoagulants. These patients who do not in fact have the disorder represent a low-risk group for recurrent thrombosis and are probably adequately treated with a DOAC

• Patients with true APS with a more profound prothrombotic state are probably at particularly high risk of thrombosis. • These patients are best treated with warfarin administered to achieve a target INR of 2.0 to 3.0. • Whether aspirin should be added to the treatment for those patients who had prior arterial thrombosis remains unknown. Evidence

suggest that aspirin added to warfarin may be beneficial in some patients. • Dose intensification of DOACs might be considered, and the use of DOACs combined with an antiplatelet agent might also be considered. However, such strategies would require testing in adequately powered clinical trials. • Until such studies are performed, this study reaffirms that warfarin administered with a target INR of 2.0 to 3.0 remains the standard for

the prevention of thrombosis in higher-risk patients with APS.

• The pathogenesis of thromboembolic disease in APS, HIT, and PNH differs from that of the general VTE population and includes cellular- and/or complement-mediated mechanisms. There is a higher incidence of ATE as well as recurrent VTE while on anticoagulation when compared with other thrombotic conditions.

• Unlike warfarin, DOACs have only 1 molecular target so could be less effective in potent

thrombophilic states. • Anticoagulant doses needed to prevent arterial thrombosis are higher, so DOACs may not

be adequate. • Lastly, DOACs’ short half-lives may theoretically lead to additional “breakthrough”

thrombosis and anticoagulation failures.

However….

• Two of the largest studies published in low-risk APS populations have reported reassuring VTE recurrence rates with DOAC use.

• An open-label trial evaluated 116 patients randomized to rivaroxaban or warfarin for secondary VTE prevention with a primary surrogate outcome of percentage change in endogenous thrombin potential. Patients with ATE or recurrent VTE were excluded. The endogenous thrombin potential was higher in the rivaroxaban group than in the warfarin group and did not reach the set non-inferiority threshold of ,20% difference. Although underpowered for clinical events, there were no thrombotic events or major bleeding reported after 210 days in 54 APS patients who received rivaroxaban. (Cohen H, Hunt BJ, Efthymiou M, et al; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):e426-e436.)

• A multicenter prospective cohort of 82 APS patients with a history of VTE were treated with rivaroxaban for secondary VTE prevention. No patients were triple positive, and 5 patients had a history of ATE. There were 4 thromboembolic events (2 cerebrovascular and 2 VTE) in 129.8 patient-years of follow-up, a rate similar to previous studies evaluating warfarin.

• A recent guidance statement from the 14th International Congress on Antiphospholipid Antibodies Task Force recommends that warfarin remain the current standard of care. DOACs may be considered when there is a known VKA allergy/intolerance or poor anticoagulant control.

• There may be a role for DOACs for secondary VTE prevention in a carefully selected subgroup of low-risk APS patients, such as those with a single unprovoked VTE and low-risk antibody profile and no history of arterial thrombotic disease or neurological symptoms possibly related to small-vessel arterial disease. However, given the limited evidence and possible risk of arterial thrombosis, a detailed patient discussion outlining the risks and benefits is warranted.

• Unlike the general VTE population where dose reduction of DOACs may be an option after 6 months of initial anticoagulation, in APS patients, follow the product monographs and not recommend dose reduction of DOACs due to the absence of data and potential for recurrent thrombosis.

3מקרה

מגיעה . בריאה בדרך כלל, חיילת משוחררת 21ה בת .ד•למרפאה חודש לאחר שחרור ממחלקה נוירולוגית באבחנה

פרזנטציה עם . נרחב cerebral vein thrombosisשל , אשפוז בטיפול נמרץ. לאחר יומיים של כאבי ראש, פרכוסים

. אנדווסקולריתהוחלט שלא לבצע התערבות

אין היסטוריה . בעברה נוטלת גלולות מזה כשלש שנים•אין . יתר לקרישיותאישית או משפחתית המתאימה

. היסטוריה של ניתוחים או טיסה שקדמו לאירוע

. קלקסןכעת חודש תחת •

. שנלקח באשפוז בנוירולוגיה תקין APLAפאנל •

? לתת ולכמה זמן פומיאיזה נוגד קרישה

VTE-AL

• About 4% of VTE cases involve other venous territories, sometimes called venous thromboembolism of atypical location (VTE-AL), with sites that include splanchnic, renal, gonadal, and cerebral venous segments.

• VTE-AL cases are commonly associated with malignancy

• As opposed to proximal leg DVT and PE, which have well established therapeutic recommendations based on RCT data, recommendations regarding the method, intensity, and duration of anticoagulation for VTE-AL are less well established.

• All major clinical trials with DOACs have studied only patients with proximal leg DVT, PE, or both. As a result, no RCT data are available for the efficacy and safety for VTE-AL.

Cerebral Vein Thrombosis

• CVT refers to thrombosis occurring in the cerebral veins and the dural venous sinuses (superior sagittal sinus (37–62%) lateral sinuses (31–44%)) . CVT is responsible for around 1% of all strokes.

• Incidence of CVT 13.2–15.7 cases per million persons per year, increase is probably correlated with the progress in radiological investigations.

• CVT is more common in women, with a female/male ratio of about 3:1, and a mean age of 40 y

• The presence of intracranial hemorrhage at the time of CVT diagnosis reported in 20–39% of patients

Risk factors • CVT can be secondary to local or systemic risk factors, and in >40% of cases is a multifactorial

disorder:

– Local risk factors : infections (8–12% of patients), such as infections of the ears, sinuses, mouth, face, neck, or the CNS.

– Mechanical causes (2–5% of patients): head trauma, lumbar puncture, jugular vein

catheterization, and neurosurgical interventions – CNS malignancies (2%) and other CNS disorders (e.g., AVM or dural fistulae) . – Sex-specific risk factors, such as pregnancy/ puerperium and hormonal treatments (such as

OCT or HRT), are reported in 10–17% and 50–53% of women with CVT, respectively. – Thrombophilia is responsible for approximately a third of cases. A recent meta-analysis

reported a strong association, although derived from observational studies only, between the development of CVT and factor V Leiden (OR 2.89, 95% CI 2.10–3.97), prothrombin G20210A mutation (OR 6.05, 95% CI 4.12–8.90), antithrombin deficiency (OR 3.75, 95% CI 1.02–13.82), protein C deficiency (OR 8.35, 95% CI 2.61–26.67), protein S deficiency (OR 6.45, 95% CI 1.89–22.03), and hyperhomocysteinemia (OR 2.99, 95% CI 1.32–6.75). Data on antiphospholipid antibodies in CVT patients are scarce.

– The combined presence of thrombophilic abnormalities and oral contraceptive use can further increase the risk of developing CVT.

– Although the presence of JAK2V617F mutation has been identified in 6.6% of CVT patients,

only 3.8% had a diagnosis of MPN throughout their lives

Treatment • The latest guidelines on the treatment of adult patients with CVT were released by the

European Stroke Organization (ESO), endorsed by the European Academy of Neurology (EAN), and published in 2017

• They recommended anticoagulant treatment with therapeutic heparin during the

acute phase of CVT, despite the presence of intracerebral hemorrhage and LMWH, if no contraindication or planned surgery, then VKA

• DOAC were not recommended for CVT treatment • thrombolysis may be considered as a second line option in CVT causing progressive

clinical deterioration despite anticoagulant treatment • More than 80% of CVT patients achieved recanalization, either complete or partial,

which was associated with a good functional recovery. However, it is still unclear whether the lack of recanalization should influence anticoagulant treatment duration, as the evidence on its correlation with CVT recurrence was scarce

• Approximately 3% of CVT patients had a recurrent CVT, whereas an additional 7% had

a DVT and/or PE, corresponding to an incidence rate of recurrent VTE of 2.03 per 100 person-years. Most of recurrent thrombotic events occurred in the first year after anticoagulant treatment discontinuation. Duration of AC?????

Treatment • Taken together, the results of these studies showed that the rates of recurrent CVT and VTE were

low during anticoagulant treatment.

• The use of the DOACs was associated with extremely variable rates of excellent neurological outcomes (64.1–100% of patients) and major bleeding events (0–8.3% of patients); thus, larger studies are needed to support these findings.

• The 2017 ESO guidelines suggested a variable anticoagulant treatment duration between 3 and 12 months (weak recommendation), which can be prolonged in patients with recurrent VTE or persistent prothrombotic conditions.

• Previous guidelines, released by the European Federation of the Neurological Societies (EFNS) in 2010 and the American Heart Association/American Stroke Association (AHA/ASA) in 2011, suggested 3-6 months of anticoagulant treatment for CVT secondary to transient risk factors, 6-12 months for unprovoked CVT, and indefinite duration for recurrent CVT or VTE or severe thrombophilia.

• These recommendations are supported by the non-negligible risk of recurrent VTE and are partly derived from the treatment of usual site VTE.

Splanchnic Vein Thrombosis

• Splanchnic vein thrombosis (SVT) consists of 5 types: mesenteric vein, splenic vein, portal vein, hepatic vein thrombosis, and Budd–Chiari syndrome

• SVT is the most common form of VTE-AL. PVT has the highest incidence rates (1.73 and 3.78 per 100,000 persons per year in females and males, respectively), BCS showed very low incidence rates (around 1–2 cases per million persons per year).

• MVT more frequently reported in older people in their sixties/seventies, whereas patients with BCS usually in their thirties/forties. PVT more common in males (male/female ratio around 1.5–2:1), whereas a slightly predominance of females has been reported for BCS (male/female ratio around 1:1.3-2)

Risk factors:

• liver cirrhosis (24–27%)

• Solid cancer (22–27% )

• recent abdominal surgery and abdominal infections or inflammation (e.g., pancreatitis, cholecystitis, appendicitis, diverticulitis, liver abscesses, inflammatory bowel diseases).

• MPN represent the most common systemic risk factor, being present in 40.9% of BCS and 31.5% of non-malignant non-cirrhotic PVT. In particular, the JAK2V617F mutation was reported in 37–45% of BCS and 24–34% of PVT.

• PNH is another hematological disorder that can predispose to the development of SVT, particularly BCS. However, the prevalence of PNH among SVT patients is <1%

• Thrombophilic disorders: A strong association between the presence of factor V Leiden and the development of BCS (OR 6.21, 95% CI 3.93–9.79), non-cirrhotic PVT (OR 1.85, 95% CI 1.09–3.13), and cirrhotic PVT (OR 2.55, 95% CI 1.29–5.07), whereas prothrombin G20210A mutation was associated only with non-cirrhotic PVT (OR 5.01, 95% CI 3.03–8.30). A strong association for the development of PVT and antithrombin deficiency (OR 8.89, 95% CI 2.34–33.72), protein C deficiency (OR 17.63, 95% CI 1.97–158.21), and protein S deficiency (OR 8.00, 95% CI 1.61-39.86). The role of antiphospholipid antibodies still needs to be better elucidated.

• oral contraceptives, hormone replacement therapy, pregnancy/puerperium play an important role, especially for BCS.

• in around 15–27% of SVT, no risk factor can be identified, and these cases are classified as “unprovoked” SVT

Worse prognosis than VTE-TL • The mortality rate reported after an episode of SVT is higher than in the general population, both in the

short- (30 days) and long-term (up to 20 years). In a Danish cohort study, the 30-day risk of mortality for SVT patients was 20.6% vs. 0.7% for the comparison cohort, matched for a number of comorbidities. In particular, MVT was associated with the highest short-term mortality rate (63.1% at 30 days), whereas PVT showed the highest mortality rate in the long term(e.g., 23.1% at 1 year, 27.2% at 5 years). This finding can be explained by the fact that MVT can be complicated by acute bowel infarction in around a third of patients.

• The incidence of arterial or venous thrombotic events after SVT in a multicentre international

unselected cohort was 7.3 per 100 patient-years (95% CI 5.8–9.3). The risk of further thrombotic events being the highest in patients with liver cirrhosis (11.3 per 100 patient-years), followed by solid cancer (7.6 per 100 patient-years), unprovoked SVT (6.3 per 100 patient-years), MPN (5.9 per 100 patient-years), and SVT associated with transient risk factors (3.2 per 100 patient-years).

• A recent cohort study of 181 patients with MPN and SVT highlighted that the rate of thrombotic

complications is quite high even during VKA treatment (3.9 per 100 patient-years). • SVT patients are also at higher risk of bleeding compared to patients with usual site VTE, both in the

short- (30 days) and long-term (up to 10 years). The 30-day risk of bleeding for SVT patients was 4.3% vs. 0.5% for usual site VTE. A higher incidence of arterial cardiovascular events was also reported, the 30-day risk was 3.3% for SVT patients vs. 0.9% for usual site VTE

• Management of SVT is difficult. On the one hand, the high incidence of malignancy confers a high prothrombotic risk, and on the other, coexistence of liver cirrhosis with varices (secondary to portal hypertension) and thrombocytopenia (secondary to hypersplenism) increases the risk of bleeding.

Treatment • The latest guidelines on the treatment of patients with SVT were published by the European

Association for the Study of the Liver (EASL) in 2016. • In patients with non-malignant non-cirrhotic PVT, they recommended starting anticoagulation

immediately with LMWH, if no major contraindication, and to continue with VKA (INR target range 2.0–3.0) for at least 6 months. In cirrhotic patients, adequate prophylaxis of gastrointestinal bleeding should be instituted before starting anticoagulation.

• Initial treatment of patients with BCS consists of anticoagulation; however, in non-responsive

patients with progressive liver deterioration, a stepwise approach should be followed: (1) medical treatment, (2) endovascular procedures (e.g., angioplasty, stenting, thrombolysis), (3) transjugular intrahepatic portosystemic shunt (TIPS), and (4) liver transplant.

• MVT - anticoagulation should be the first line treatment of MVT, starting with LMWH or preferably

UFH, because in the early phase a laparotomy for bowel necrosis might be required. About 5% of patients deteriorate despite medical treatment and they are candidates for endovascular procedures (such as thrombolysis, angioplasty, thrombectomy, or TIPS). Switching to oral anticoagulants, either VKA (or DOAC???), is suggested after the acute phase (2–3 weeks).

• Cirrhotic patients are associated with the highest risk of major bleeding and recurrent thrombotic events. However, this increased risk of bleeding should not prevent anticoagulant treatment . A meta-analysis of eight studies reported no significant difference in the rate of any bleeding between treated and untreated cirrhotic patients with PVT (11% in both groups) and a recent study on 182 cirrhotic patients with PVT showed similar rates of major bleeding events among treated and untreated patients (21.8% and 19.7%, respectively)

DOAC & SVT • Although the use of DOACs in patients with SVT is

still limited, it is better documented than in any other group of VTE-AL.

• Taken together, the results of these studies suggest extremely variable rates of recurrent SVT (0–11.1%), major bleeding (0–9.1%), and recanalization (68.8–100%), which can be partly explained by the large heterogeneity among the different cohorts.

• There is an ongoing interventional study evaluating

the use of rivaroxaban in patients with non-cirrhotic SVT (NCT02627053).

In practice… • The 2016 EASL guidelines suggested considering an anticoagulant treatment duration of at least 6 months

• Extend lifelong in patients with BCS, strong prothrombotic conditions (including persistent risk factors, such as MPN), recurrent VTE, intestinal ischemia or involvement of the superior mesenteric vein, and in cirrhotic patients eligible for liver transplant

• After assessing the risk of bleeding, start anticoagulant treatment for SVT in the acute phase with LMWH, together with adequate prophylaxis of variceal bleeding, if needed.

• In patients with thrombocytopenia, a reduced dose of LMWH might be required.

• consider UFH in patients with recent bleeding, severe renal failure, or potential candidate for surgery (such as those with extensive bowel infarct).

• After clinical stability, switch the majority of patients to VKA, with the exception of those with cancer-associated SVT, severe thrombocytopenia, or severe liver disease.

• Pending more evidence on the use of the DOACs and on the basis of the results of RCTs conducted on usual site VTE, consider the use of factor-Xa inhibitors in selected patients without severe liver or renal impairment and at low bleeding risk.

• The majority of SVT patients are candidates for long-term anticoagulation, having either a major persistent risk factor, an unprovoked SVT, or a BCS; however, shorter duration of 3–6 months in those with transient risk factors (such as recent abdominal surgery or abdominal inflammation/infections).

There are two widespread fallacies pertaining to cirrhosis and anticoagulation: the first is that cirrhosis is a contraindication to anticoagulation due to an increased bleeding risk. The second is that those with an elevated INR do not require anticoagulation because they are already “auto-anticoagulated.” Both of these common misconceptions among the medical community have recently been dispelled

Mechanism of Thrombosis and Role of DOACs as antifibrotic Agents

? קומדיןלמי עדיין ניתן

מסתם תותב•

•APLA

•MPN (????ורידיים, עורקיים בטוח) טרומבוטיים ארועיםעם

: DOACעדיין בסימן שאלה אך מתחילות להצטבר עבודות על •

Sinus vein thrombosis, Splanchnic vein thrombosis, rheumatic disease, IBD

vte-ב לופיטב םינוכדע · risk of recurrent vte after stopping anticoagulant therapy...

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