Munier Nazzal, MD, MBA, CPE, FRCS, FACS, FACCWS, RVT, RPVI

Munier Nazzal, MD, MBA, CPE, FRCS, FACS, FACCWS, RVT, RPVI.

Professor, Vice Chair, Research and Education

University of Toledo

CHIEF, DIVISON OF VASCULAR SURGERY.

Chief, Division of Surgery Education

DIRECTOR OF VASCULAR L ABORATORY

Disclosure

None

Outline

Introduction with definitions.

Assessment.

Outpatient Vs Inpatient.

Anticoagulation medications.

Advanced treatment.

DVT: Definitions

Acute DVT:

Uncomplicated DVT:

New thrombosis in iliac, common femoral, femoral, deep

femoral, popliteal, anterior/posterior tibial or peroneal

vein(s).

Implies absence of: iliofemoral thrombosis, extensive

thrombosis (i.e., entire extremity or bilateral above-knee

DVT), pulmonary embolus, hemodynamic instability,

pregnancy, active cancer (receiving cancer treatment within

past 6 months or current palliative treatment).

Suspecting DVT: Initial Assessment

Hx and Exam not adequate for diagnosis.

Diagnostic tools with or without D dimer might be

helpful.

Must confirm by an imaging study: Duplex US,

or CT venogram

Clinical scoring system: Wells

DVT treatment:

Outpatient vs Inpatient

Outpatient to be considered in certain cases.

Patient history

Presence of contraindications

Compliance of patient

Medication coverage.

Low bleeding risk

No anticoagulation contraindication

Physician in charge of treatment

Assess for anticoagulation

contraindication

Absolute contraindication Relative contraindication

Fresh surgical wound Severe hypertension (SBP>220,

DBP>110)

Active GI bleeding Platelet count (50k-100K)

Hx of intracranial hemorrhage GI bleeding within 6 months

Multiple/ Major trauma CKD stage IV (Cre>2.5)

Recent Neuro or spine surgery Morbid obesity (BMI > 40)

Compliance concerns Medical co morbidities

Concurrent symptomatic PE Recent major surgery

Renal failure Recent eye surgery

Nonambulatory due to DVT

Platelet less than 50,000

Hx of HIT is planning heparin

Initial VTE Treatment Setting (Hospital vs

Home)

HESTIA Study:

Outpatient vs Inpatient

How to start therapy

Start as soon as possible after confirming Dx

After hours treatment: start on Lovenox if no

contraindication and do US during hours then

decide on treatment.

Action of new agents

Warfarin

II,VII

IX,X

Options for outpatient treatment

Direct Oral anticoagulants (DOACs)

Warfarin

LMWH as monotherapy

DOACS

Rivaroxaban, apixaban (direct Factor Xa inhibitors): does not require

LMWH bridging or lab test. Do not use if GFR < 30 ml/min.

Edoxaban (direct Factor Xa inhibitor): requires concurrent LMWH

bridging for initial 5-10 days; lab tests for monitoring unnecessary, no

reversal agent. Reduce dose if GFR 15-30 ml/min; do not use if GFR <

15 ml/min.

Dabigatran (direct thrombin inhibitor): requires concurrent LMWH bridging

for initial 5-10 days; lab tests for monitoring unnecessary, reversal agent

(idarucizumab) available. Do not use if GFR < 30 ml/min.

Coumadin

LMWH bridging for 5 days

Requires initial and periodic INR monitoring to maintain

therapeutic range of 2.0-3.0.

Anti-clotting action can be reversed with IV or oral vitamin

K, fresh frozen plasma or prothrombin complex concentrate

(PCC).

Low Molecular Weight Heparin

Recommended in patients with cancer or

pregnancy.

Low risk patients for HITS.

Fondaparinux can be an alternative

Evaluation for the risk of bleeding

Warfarin Vs DOACS

Safety, Efficacy, Pharmacology

Safety, Efficacy, Pharmacology

Choice of anticoagulants in VTE

Best practices in anticoagulation


Warfarin

II,VII

IX,X

Anticoagulation for VTE






Half life of anticoagulants and

metabolism

drug Half life (hrs) metabolism

Unfractionated heparin 1-5 Reticulendothelial S

Daltaparin (Fragmin) 3-5 Renal *

Enoxaparin (lovenox) 4.5-7 Renal *

Rivaroxoban (Xarelto) 5-9 66% renal * GP, P450

34A inhibitor

Apixaban (Eliquis) 12 27% renal *???

Edoxaban (Savaysa) 10-14 50% renal *

Dabigatran (Pradaxa) 12-17 80% renal *, B-gp inhib.

Fondaparinux (Arixtra) 17-21 100 renal *

Warfarin 21-89 92% renal

Special considerations



Length of Anticoagulation

Treatment in VTE

Length of treatment recommendations

for idiopathic (unprovoked) VTE


Warfarin

II,VII

IX,X

Is Warfarin becoming obsolete?

NO

Still preferred agent for:

- Mechanical valves

- Rheumatic mitral valve disease

- Advanced renal failure

- Antiphospholipid antibody

syndrome(APAS)

- Cancer patients (if LMWH not used)

Cost

Factors Increasing or Decreasing

Warfarin Sensitivity

NOACs

Pharmacological Properties

Characteristic

Rivaroxaban

(Xarelto)

Dabigatran

(Pradaxa)

Apixaban

(Eliquis)

Warfarin

Target Factor Xa Factor IIa Factor Xa II,VII,IX,X

Dosing OD BID BID OD

Bioavailability 80-100%* 6% 50% 100%

Time to peak

effect 2-4 h 1-2 h 3-4 h 4-5 d

Half-life 5-13h 12-14 h 8-15 h 40 h

Renal

clearance ~33% 85% ~27% None

Rivaroxaban

(Xarelto)

Dabigatran

(Pradaxa)

Apixaban

(Eliquis)

aPTT ↑ or ↔ ↑ ↑ or ↔

PT/INR ↑ or ↔ ↑ or ↔ ↑ or ↔

Thrombin Time Minimal effect ↑ Minimal effect

Hemoclot thombin

inhibitor assay No effect ↑ No effect

Anti Factor Xa ↑ Minimal effect ↑

1. Xarelto® PM, July 18, 2012 ; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. Goette Trends Cardiovasc Med. 2013 [Epub ahead of print]

NOACs

Effect on Coagulation Tests

Approved Indications

Drug

Rivaroxaban

Dabigatran

Apixaban

Approved

Indication

Prophylaxis of

DVT/PE in

Orthopedic

surgery

Prevention of

stroke in atrial

fibrillation

Treatment of DVT

and PE

Prophylaxis of

DVT/PE in

Orthopedic

surgery

Prevention of

stroke in atrial

fibrillation

Treatment of DVT

and PE

Prophylaxis of

DVT/PE in

Orthopedic

surgery

Prevention of

stroke in atrial

fibrillation

Treatment of DVT

and PE

Perioperative

Management of the

NOACs

Goals of Perioperative Management

1) Minimize window of

“subtherapeutic” anticoagulation

preoperatively, Bridging ?

2) Normal hemostasis during surgery

3) Balance bleeding and

thromboembolic risk post-

operatively, when to restart NOACs

postoperatively

Preoperative Management of Patients

Taking NOACs

Influenced by different factors:

- pharmacokinetics of the drug

- renal function

- elective vs urgent surgery

- bleeding risk of the procedure

Bleeding Risks

Procedures not requiring discontinuation of anticoagulation:

- dental

- cataract surgery

- superficial surgeries (skin biopsy)

Procedures at low bleeding risk:

- prostate/bladder biopsies

- pacemaker implantation

Procedures at high bleeding risk:

- major surgery

- spinal/epidural anesthesia

- Lumbar puncture

- TURP

- kidney biopsy

NOACS CrCl

(ml/min)

LOW BLEEDING

RISK

HIGH BLEEDING

RISK

Rivaroxaban

(Xarelto)

(33%)

>50

30-50

≥ 24 hrs (skip 1 dose)

≥ 24 hrs (skip 1 dose)

≥ 48 hrs (skip 2 doses)


Dabigatran

(Pradaxa)

(85%)

>50

30-50





Apixaban

(Eliquis)

(27%)

>50

25-50





Bridging Anticoagulation

In most circumstances bridging

anticoagulation not required with NOACs

Interruption of anticoagulation is

associated with an increased risk of

thromboembolic events such as stroke,

mechanical valve thrombosis, stent

thrombosis, and venous thromboembolism

(VTE).

Risk of Thromboembolism

Mechanical Heart

Valve

Atrial

Fibrillation

VTE

High Risk

(>10%)

Any mitral valve prosthesis

Older aortic valve prosthesis

Recent stroke or TIA (within 6 months)

CHADS 5-6

Recent stroke or TIA (within 3 months)

Rheumatic valve disease

Recent VTE (within 3 months)

Severe thrombophilia

Bileaflet aortic valve prosthesis

+

≥1 additional risk factor (CHADS)

CHADS 3-4

VTE within 3-12 months

Nonsevere thrombophilia

Low Risk

(<5%)

Bileaflet aortic valve prosthesis with no additional risk factors or atrial fibrillation

CHADS 0-2 with no previous TIA or stroke

Single VTE >12 months and no other risk factors

Moderate

Risk

(5-10%)

CHADS : C(ongestive) heart failure; H(ypertension), A(ge) over 75 years, D(iabetes) mellitus, S(troke)

Coagulation Testing

Role of coagulation testing for elective procedures has not been determined and is not recommended

Managing patients that require emergency surgery is a challenge

- timing of last dose

- can test for non-specific tests of coagulation (PT, aPTT, thrombin time)

- specific tests (Hemoclot, specific anti-Xa assays)

Need to weigh the benefits of emergency surgery against the risk of major hemorrhage.

Reversal of NOAC anticoagulant effect

Prothrombin Complex Concentrate (PCC)

- 3 factor PCC (factors II, IX, X)

- 4 factor PCC (factors II, VII, IX, X)

Octaplex, Beriplex

No high-quality evidence efficacy and safety of

PCC in the bleeding patient

PCC associated with 1.4% risk of thrombosis

when administered to bleeding patients on

warfarin


Activated Prothrombin Complex Concentrate (FEIBA)

- contains activated factors II, VII, IX, X

- in vitro data suggests it corrects some abnormal coagulation parameters for all 3 NOACs but no clinical data

- risk of thrombosis 4-8 events/100,000

infusions in hemophilia


Recombinant factor VIIa

- also developed for hemophilia

- in animal models, rfVIIa failed to improve bleeding following treatment with Dabigatran or Rivaroxaban

- twice the risk of thrombotic complications


Plasma (FFP):

- not shown to reverse abnormal coagulation tests

- risks include volume overload,Transfusion-related acute lung injury (TRALI), allergic reactions, infection

Adjunctive Therapies

Desmopressin (DDAVP):

- used for bleeding in context of platelet dysfunction (uremia, VWD)

- no clinical data

- watch serum Na

- no increased risk of thrombosis

Tranexamic Acid:

- antifibrinolytic

- can be used as adjunctive therapy for severe bleeding in a variety of circumstances

- effect in NOAC bleeding unknown

- no increased risk of thrombosis in perioperative setting

Hemodialysis

Given that only 35% of Dabigatran is

bound to plasma proteins, hemodialysis

typically removes 60% of Dabigatran after

4 hours and should be considered,

especially in patients with impaired renal

function

Rivaroxaban and Apixaban are highly

protein bound which limits removal with

hemodialysis

Suggested strategy for management of TSOAC-associated bleeding.

Siegal D M et al. Blood 2014;123:1152-1158 ©2014 by American Society of Hematology

Specific Antidotes on the Horizon

Specific antidotes may provide an additional option for bleed management

Reversal of Dabigatran :

Idarucizumab (Praxbind)

”approved by FDA in October 2015”

Reversal of FXa inhibitors(Rivaroxaban & Apixaban) :

Andexanet alpha (Andexxa)

"approved by FDA in May 2018”

RE-INITIATION

This process depends on the nature of the

surgery, the urgency for restarting

thromboprophylaxis therapy, and the hemostatic

state of the patient.

Given the rapid clearance of the NOAs from the

circulation and the rapid onset of action when

reintroduced, no bridging therapy with LMWH or

unfractionated heparin is necessary.

Post-procedure NOAC resumption

NOAC LOW BLEEDING RISK HIGH BLEEDING RISK

Dabigatran

(Pradaxa)

Resume AM post-op day

+1

(24 hrs)

Resume AM post-op day +2 to

+3

(48-72 hrs)

Rivaroxaban

(Xarelto)

As above

As above

Apixaban

(Eliquis)

As above

As above

Option to use low doses of NOACs or bridging with LMWH if felt full dose

NOAC to be delayed

Pros and Cons of DOACS

Pros and Cons of DOACS

Advanced DVT Treatment

DVT Treatment

Anticoagulation

Heparins

coumadin

DOACS

Clot Removal

CDL

PMT

Surgery

Clot Removal

Systemic lysis.

CDL

Mechanical thrombectomy

Mechanico pharmacological thrombectomy

Surgery

Why Clot Removal

Reduce the risk of postthrombotic

syndrome (PTS) in patients with

proximal, iliofemoral deep venous

thrombosis (IFDVT)

Procedures Basic Principle

Benefits Risks

Minor bleeding

Major bleeding

cost

Dye Complications

symptoms

PTS

QOL

Benefits of Clot removal

QOL

PTS

Symptoms

Attract investigators, circulation 2019

Attract investigators, circulation 2019

Conclusion

The field of thrombosis and anticoagulation is

rapidly evolving

Patients taking anticoagulants frequently require

surgery

Perioperative management of patients treated

with NOACs is an ongoing challenge

Outcomes of major bleeding after NOACs are

similar or better compared with warfarin

Until specific antidotes are widely available, bleed

management protocols may improve outcomes

Thank you

Documents

Munier Nazzal, MD, MBA, CPE, FRCS, FACS, FACCWS, RVT, RPVI