intelligent use of anticoagulants.ppt

8/10/2019 Intelligent Use of Anticoagulants.ppt

1/69

Intelligent Use of

Anticoagulants

Murray L. Shames, M.D.

Assistant Professor of Surgery andRadiology

Division of Vascular and Endovascular

Surgery


2/69

Outline

Available anticoagulants Surgical prophylaxis DVT and pulmonary embolus

Atrial fibrillation Perioperative management of patients on

chronic anticoagulation Arterial thromboembolism

Cerebral Visceral Extremity

Anticoagulation in pregnancy


3/69

The Coagulation Cascade

X

Xa+

Va + Ca++

Intrinsic system

XIIXIIaXI IX

Xia

IXa+

VIIa+

Ca++

Extrinsic system

Injury

Tissuethromboplastin

+

VII

Prothrombin Thrombin

Fibrinogen Fibrin


4/69

Available anticoagulants

Unfractionated heparin

Low Molecular Weight Heparins

Oral Anti-coagulants Alternative agents


5/69

Unfractionated Heparin-Mechanism of Action

Binds anti-thrombin III 1:1

Inactivates thrombin and F Xa

Secondary effect on F V

Effects not first order kinetics

Effective after subcutaneousand intravenousadministration

Short half life (90 min)

Reversed with protamine(1mg per 100 U circulatingheparin)


6/69

Unfractionated Heparin-Limitations

Significant protein binding

Response is unpredictable (closemonitoring required)


7/69

Unfractionated Heparin-Dosing

Loading 80-100 U/ kg IV

Then IV infusion at 18 U/kg/hr

Normogram available for mosthospitals

Therapeutic range 1.5-2.5 X control PTT


8/69

Unfractionated Heparin-Complications

Major bleeding complications 0-7%

HIT 1-5%

Osteoporosis Alopecia

Hypoadrenalism

Anaphylaxis


9/69

HeparinInducedThrombocytopenia

Incidence 1-5%

Can occur with all methods ofadministration

No known risk factors

Increased incidence with Bovine

preparations Dx- plt count < 100-150 000/uL


10/69

HeparinInducedThrombocytopenia I

HIT I Heparin induced platelet aggregation

Platelet sequestration and consumption

Mild Thrombocytopenia in first few days of therapy

Plt count usually > 100 000/uL

Asymptomatic

Resolves spontaneously without d/c heparin


11/69

HeparinInducedThrombocytopenia II

HIT II (HITT) Immunologically mediated

Ab to Heparin-PF 4 complex

More severe but less common 5-7 days after initiating Tx

PLT


12/69

HeparinInducedThrombocytopenia II

Thrombotic events arterial and venous

Associated skin necrosis

Global amnesia Prosthetic valve thrombosis

29% mortality and 21% amputation rate

H i I d d


13/69

HeparinInducedThrombocytopenia

Treatment Withdrawal of ALL heparin and heparin

products Plasmapheresis - anecdotal success

Further treatment should await confirmationof Dx Start anti-platelet therapy ? LMWH

Thrombin inhibitors Ancrod Conversion to Warfarin


14/69

Available Anticoagulants





15/69

Characteristics of UFH andLMWH Chains

Molecular weight (daltons)10,000 15,000 20,0005,000

5,400

Anti-Xa Anti-IIa and anti-XaResistant to PF4 Sensitivity to PF4Little non-specific binding Non-specific bindingInhibition of thrombin generation Less inhibition thrombin generation

Hirsh J, Levine MN. Blood. 1992; 79: 1-17.


16/69


Effect through AT IIIInhibits Factor XaMore predictable

anticoagulant responseLonger half-lifeBetter bioavailability atlow dosesRenal clearanceLower incidence of HITNo need to monitor PTT

in most cases


17/69

FDA-Approved Indications (May 2001)for Available LMWHs


18/69

Advantages of LMWH OverUFH

Less platelet activation

Less vascular permeability

Smaller size

Increased release of TFPIfrom vascular endothelium

Less plasma protein binding

Less interaction with PF4

Less osteoclast activation

Less binding to VWF Stimulates megakaryopoiesis

Less thrombin, growth factorproduction

May limit tumor movement intointravascular space

More potent anti-angiogenesis

activity More potent anticoagulant and

anti-cancer activity Predictable PK, safety, once daily

dosing Lower incidence of HIT

Less osteoporosis with long termuse

Less bleeding May attenuate chemotherapy -

induced thrombocytopenia


19/69

Low Molecular Weight Heparins-Dosing

1mg/kg q12H

Can monitor anti-factor Xa levels


20/69






21/69

Oral Anticoagulation-Mechanism of Action

Inhibition of Vitamin K-dependantcoagulation factors II, VII, IX, X

Inhibition of Vitamin K- dependantcarboxylation of Protein C and S


22/69

Oral Anticoagulation-Limitations

May create initial hypercoaguable state

3-5 days for anticoagulant effect

3-5 days to reverse effects Reversed rapidly by FFP

Can reduce time of reversal with

supplemental Vit K (10mg IV or 3-5mg PO)


23/69

Oral Anticoagulation-Complications

Hemorrhage

Skin necrosis

Protein C deficiency

Malignancy

Teratogenic


24/69

Oral Anticoagulation- Dosing

Loading 5mg PO QD

Adjust daily dose to reach goal INR


25/69






26/69

Alternative Anticoagulants

Danaproid

Thrombin Inhibitors

Hirudin

Lepirudin

Argatroban

Ancrod


27/69

Alternative Anticoagulants-Danaproid

Heparinoid

Mixture heparin-like glycosaminoglycans andchondroitins

Anti-factor Xa and anti-factor IIa activity Can be used in patients with HIT

Approved for DVT prophylaxis

Longer duration than UF heparin

Measure by anti-factor Xa levels

Weight based dosing


28/69

Alternative Anticoagulants-Thrombin Inhibitors

Hirudin

Protein isolated from salivary gland ofleech

Irreversible binding to thrombin

High incidence of bleeding complications

Monitor by PTT and ACT

Substitute for heparin in patients with HIT Efective DVT prophylaxis


29/69


Lepirudin

Recombinant Hirudidn derivative

Reduced mortality and morbidity in HIT

patients

Renally excreted

Dosing - 0.4mg/kg IV loading and

0.15mg/kg maintenance Monitor PTT

Therapeutic range: 1.52.5 X normal


30/69


Argatroban

Competitive thrombin inhibitor

Univalent thrombin inhibitor (less

specificity and affinity)

Short plasma life- no adj. for RF

2ug/kg/min IV

Monitor by PTT or ACT (2-3.5 X baseline)


31/69

Alternative Anticoagulants-Ancrod

Venom of Malaysian Pit Viper

Defibrinating agent

Converts fibrinogen to soluble aggregate

removed by plasmin and RES Increases FDPaugments anticagulant

effect

Indirect micro-fibrinolytic by increasing TPArelease

Monitor fibrin levels


32/69

Venous Thromboembolism

Virchows Triad

Stasis

Intimal injury Activation of coagulation

(hypercoaguable state)


33/69

Venous Thrombosis-Epidemiology

Venous thromboembolism is the 3rd mostcommon vascular disease in the UnitedStates

Mortality and morbidity associated with VTEis enormous

Average cost per admission in the US:

PE = $12,595

DVT = $9,337

Additional long-term costs of morbidity > 75% ofinitial therapy costs


34/69

Venous Thrombosis-Rationale for Prophylaxis

Clinically silentdisease High prevalence in hospitalized patients Dire consequences of missed DVT

First manifestation may be fatal PE Most deaths within 30 min of acute event Long term morbidity from post-phlebitic

syndrome

Wide variations in practice of physicians

Only 1/3 of at risk patients receive adequateprophylaxis 58% of fatal PE patients not prophylaxed in spite

of risk factors


35/69

Venous Thrombosis-Risk Factors

Obesity Varicose Veins Cardiac dysfunction Indwelling vascular

catheter IBD Nephrotic syndrome Pregnancy or estrogen

use

Advanced age Prolonged immobility Stroke or Paralysis Previous VTE

Cancer and itstreatment Major Surgery

esp. abdomen,pelvis, and lower

extremities Trauma

esp. fractures ofpelvis, hip, or leg


36/69

Surgical Prophylaxis-Low Risk Patient

Risk Factors

Age under 40 yearsMinor surgeryNo other risk factors

Event rate

Calf DVT 2.0%Proximal DVT 0.4%Clinical PE 0.2%Fatal PE 0.002%

Recommended Regimens

No specific measuresAggressive mobilization


37/69

Surgical Prophylaxis-Moderate Risk Patient

Risk Factors Major surgery in

patients with additional

risk factors Non-major surgery in

patients 40-60 with noadditional risk factors

Major surgery inpatients < 40 with noadditional risk factors

Event Rates

Calf DVT 10-20%

Proximal DVT 2-4%

Clinical PE 1-2% Fatal PE 0.1-0.4%

Recommended RegimensLMWH

Low dose UFHElastic stockings

Intermittent Pneumatic Compression


38/69

Surgical Prophylaxis-High Risk Patient

Risk Factors

Non-major surgeryin patients > 60 or

additional riskfactors

Major surgery inpatient < 40 oradditional riskfactors

Event Rate

Calf DVT 20-40%

Proximal DVT 4-8%

Clinical PE 2-4%

Fatal PE 0.4-1.0%

Recommended Regimen

LMWH

Low dose UFH q8h

IPC


39/69

Surgical Prophylaxis-Highest Risk Patient

Risk Factors Major surgery in

patients > 40 plus

prior VTE, cancer,hypercoaguablestate

Hip or knee

arthroplasty Major trauma

Spinal cord injury

Event Rate Calf DVT 40-80%

Proximal DVT 10-20%

Clinical PE 4-10% Fatal PE 0.2-5.0%

Recommended Regimen

LMWH

Oral Anticoagulants

IPC/ES + LMWH/LDUFH

Adjustable dose UFH


40/69


41/69

LMWH vs. UFH

In Acute Treatment of VTE

In Favor of LMWH In Favor of UFH

0.0 1 20.25 0.5 0.75 1.5 0.751.25

Venous Thromboembolism

Pulmonary Embolism

Major Bleeding

Thrombocytopenia

Total Mortality

Minor Bleeding

Pooled Relative Risk

Dolovich L, et al. Arch Intern Med. 2000:160:181-187.


42/69

LMWH: Fewer Deaths

Meta-Analysis: N=3,566

LMWH UFH PMortality 5.1% 6.7% 0.02

Overall 30% mortality reduction from:Recurrent Thromboembolism, Bleeding,and Cancer

Gould, et al. Ann Intern Med. 1999; 130: 800-9.


43/69

Study DesignEnoxaparin

sodium 1mg/kgq12h SC

Adjusted-doseheparininfusion

Documentedacute, proximalDVT without PE

Warfarin therapyinitiated on 2nd day

Warfarin 90 dayspost randomization

Clinicalendpoints

Clinicalendpoints

Outpatient Treatment of DVTEnoxaparin q12h vs. Heparin


44/69

Embolic Event

Total VTE*DVT onlyProximal DVTPE

13 (5.3)11 (4.5)10 (4.0)2 (0.8)

17 (6.7)14 (5.5)12 (4.7)3(1.2)

Enoxaparin sodiumn=247 (%)

Heparinn=254 (%)

Outpatient Treatment of DVTEnoxaparin q12h vs. HeparinResults: Recurrences of Thromboembolism

* VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/orpulmonary embolism [PE]).

95% CI = -5.6 to 2.7. Two died during the study.


45/69

Treatment Group & Event

Enoxaparin sodium (n=5)Soft-tissue hematoma of hip 6 2.7 27Abdominal-wall hematoma 7 2.7 55Abdominal-wall hematoma 7 3.2 40Subdural hematoma 5 3.4 40Hematemesis

6 2.4 40Heparin (n=3)Hematuria 2 1.3 64Gastrointestinal bleeding 3 3.0 88Hematemesis 1 2.7 64

Study Day INR*

* International Normalized Ratio. P= 0.50. Patient had cancer and associated thrombocytopenia due to chemotherapy and radiation.

Outpatient Treatment of DVTEnoxaparin q12h vs. Heparin

Results: Episodes of Major Bleeding

aPTT(sec)


46/69

Atrial Fibrillation

Most common arrythmia in adults

Responsible for 15% CVA

Better survival with combined ratecontrol and anticoagulation

IV heparin/ LMWH + coumadin

Administer anticoagulation before and3 - 4 weeks after cardioversion


47/69

Atrial Fibrillation

Age

< 65

>65-75

Any

Risk FactorsFor Stroke*

None

None

1 or more

*Mitral stenosis, HTN, previous TIA or stroke, CHF, LV

dysfunction, or age > 75

Therapy

ASA or none

ASA or Warfarin

Warfarin

Perioperative Management Of


48/69

Perioperative Management OfPatients on Chronic

AnticoagulationPatients at low risk

VTE adequatelt treated for > 3 months, no

predisposing factors Nonvalvular A. Fib without embolic events

Most bioprosthetic and mechanical heart

valves without thromboembolism



49/69


AnticoagulationRecommendations

Hold warfarin 4 days before surgery Recheck PT day of surgery

Resume warfarin on post-op day 2



50/69


AnticoagulationPatients at intermediate risk Venous or arterial embolism

In 2nd

to 3rd

month of Tx, no predisposingfactors

Recurrent VTE tx for 12 months

Valvular heart disease, A. Fib,prosthetic heart valve with distant h/oembolism



51/69



Hold warfarin 4 days before surgery Prophylactic SC UFH or LMWH pre-op

Recheck PT day of surgery

Continue prophylaxis in peri-operative period Restart warfarin at pre-operative dose on

post-op day 2

Stop heparin when INR > 2



52/69


AnticoagulationPatients at highest risk Venous thromboembolism with specific

circumstances (consider IVC filter) Onset within last month

Idiopathic, last 6 months

Recurrent VTE, within last 12 months

Documented hypercoaguable state

Recent embolism from A. Fib, prosthetic ordiseased heart valve

Acute arterial embolism within 1 month



53/69



Hold warfarin 4 days prior to surgery

Begin IV heparin or SC LMWH 2 days prior tosurgery

Recheck PT day of surgery

Hold heparin 6-12 hrs before surgery

Resume heparin 12 hours after surgery ifadequate hemostasis

Resume warfarin on post-op day 2

D/C heparin when INR > 2

A t i l Th b b li


54/69

Arterial Thromboembolism-Goals of Therapy

Prevent recurrent thrombosis or embolism

Adequate anticoagulation reduces in-

hospital recurrence from 31% to 9% Decrease mortality from 25% to 4%

Does result in increased woundcomplications (without major bleeding

episodes) UFH first choice in therapy

Increased flexibility in monitoring and control

A t i l Th b b li


55/69

Arterial Thromboembolism-Extremity

Patient with

suspected ALI

History

PEDoppler

HEPARIN

Diagnosis confirmed

Arterial Thromboembolism


56/69

Arterial Thromboembolism-Extremity

IV HEPARIN5000 u bolus

Titrate to PTT 60-80 sec

Protection against clot propagation

Prevent embolus



57/69

Arterial Thromboembolism -Cerebral

No benefit to anticoagulation in completed

stroke

May benefit stroke-in-progress if < 25 hrsand submaximal

Need to eliminate other causes of

neurologic deterioration



58/69

Arterial Thromboembolism -Cerebral

Cardioembolic stroke

Risk of recurrence 10-20% within 2-4 weeks

Evaluate for cardiac source (13-34%)

No clear consensus

Cerebral embolism study group

Anticoagulation in normotensive patients with

small moderate strokes after 24 hrs

Larger strokes after 5-7 days

Recommendations

IV heparin without loading dose

Start Warfarin after 24 hrs

INR 2.0-3.0

Long-term therapy in patients with AtrialFibrillation



59/69

Arterial Thromboembolism-Visceral

Acute mesenteric ischemia

Embolic

Thrombotic

Non-occlusive

Venous thrombosis



60/69


Diagnosis requires high index of suspicion

Angiography diagnostic

Treatment

Initiate IV heparin at time of diagnosis (bolus

and titrate to PTT 60-80 sec)

Thrombolysis if no evidence of peritonitis

Surgical thrombectomy/revascularization withbowel resection



61/69


Non-occlusive mesenteric ischemia

Multi-system organ failure, low-flow states,and visceral vasoconstriction

Rarely exists without severe cardiacdysfunction

Abdominal pain75%



62/69


Arteriography demonstrate mesenteric arterial

spasm

Reversible with intra-arterial papaverine infusion

or other vasodilating agents Adjunctive use of IV heparin recommended



63/69


Venous thrombosis Hypercoaguable state

Intraabdominal infection or inflammation

Asymptomatic state to catastrophic illness Generalized abdominal pain out of proportion to physical

exam

Diagnosis by CT, angiography

Treatment

Rigorous resuscitation IV heparin anticoagulation (PTT 60-80)

Surgical exploration for peritonitis

Long-term therapy with warfarin (life-time if hypercoaguablestate identified)


64/69

Anticoagulation in Pregnancy

Sixfold risk of venous thrombembolism

PE most common cause of maternal

mortality in US

Gravid uterus compressing Vena Cava

Pregnancy related hypercoagulability

(increase II, VII, VIII, X)

Decreased fibrinolytic activity and AT III


65/69


Coumadin during first trimester associated

with specific malformations in > 25% of

births

Fetal Warfarin Syndrome (nasalhypoplasia, stippled epiphyses)

Increase CNS anomalies if used during

other time during pregnancy


66/69


Drugs with molecular weight < 1000

daltons pass through placental

membranes

Fetus has already low levels of Vit-Kdependant factors- further depleted by

warfarin effect



67/69

Anticoagulation in Pregnancy-Recommendations

Initiate anticoagulation with intravenous heparin

Continue Tx with subcutaneous heparin orLMWH

Continue Tx through delivery and post-partumperiod

After delivery coumadin for 6 months

Prophylaxis (LMWH) recommended during

subsequent pregnancy Acute iliofemoral DVT consider thrombectomy

or vena Caval filter placement


68/69


69/69

intelligent use of anticoagulants.ppt

Documents