munier nazzal, md, mba, cpe, frcs, facs, faccws, rvt, rpvi
TRANSCRIPT
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
Action of new agents
Warfarin
II,VII
IX,X
Anticoagulation for VTE
Anticoagulation for VTE
Anticoagulation for VTE
Anticoagulation for VTE
Anticoagulation for VTE
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
Special considerations
Special considerations
Length of Anticoagulation
Treatment in VTE
Length of treatment recommendations
for idiopathic (unprovoked) VTE
Action of new agents
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)
≥ 48 hrs (skip 2 doses)
Dabigatran
(Pradaxa)
(85%)
>50
30-50
≥ 24 hrs (skip 2 doses)
≥ 48 hrs (skip 4 doses)
≥ 48 hrs (skip 4 doses)
≥ 96 hrs (skip 8 doses)
Apixaban
(Eliquis)
(27%)
>50
25-50
≥ 24 hrs (skip 2 doses)
≥ 24 hrs (skip 2 doses)
≥ 48 hrs (skip 4 doses)
≥ 48 hrs (skip 4 doses)
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
Reversal of NOAC anticoagulant effect
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
Reversal of NOAC anticoagulant effect
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
Reversal of NOAC anticoagulant effect
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