VTE Risk Stratification

• Low: Minor surgery, fully ambulatory
  • No therapy recommended
• Moderate: Non-ortho surgery pts, acutely ill
  • Surgical Pts: UFH, LMWH, or Fondaparinux recommended up to 28d after discharge
  • Above are appropriate, but not length recommendation post-discharge
• High Risk: Orthopedic Surgery
  • Above for ≥ 10-14d post-op and up to 35d
• Use mechanical means in high bleed risk pts

Treatment

General Considerations

• Start parenteral and overlap w/ warfarin for at least 5d AND INR > 2 for ≥ 24h
• Rivaroxaban and Apixaban do not need warfarin overlap
• Edoxaban and Dabigatran do not need warfarin overlap, but parenteral should be overlapped for 5-10d

UFH

t_1/2 = 30-90min

Condition	Dose
Initial Dose	80 U/kg then 18 U/kg/hr
aPTT <35s (< 1.2x control)	80 U/kg, increase rate by 4 U/kg/hr
aPTT 35-45s (1.2-1.5x control)	40 U/kg, increase rate by 2 U/kg/hr
aPTT 46-70s (1.5-2.3x control)	No Change
aPTT 71-90s (2.3-3x control)	Decrease rate by 2 U/kg/hr
aPTT > 90s (> 3x control)	Hold infusion x1hr, decrease rate by 3 U/kg/hr

Monitoring

• aPTT at baseline then q6h after dose or w/ dosage change x24h, then QD if in range
• SSx of bleeding
• SSx of HIT
• Osteoporosis
  • Doses > 20k U QD for > 6mo (pregnancy)
• Plt QOD x14d

HIT

If Plts drop > 50% OR to < 100k consider HIT, D/C heparin, DO NOT give Plts, give bivalirudin, argatroban, fondaparinux, etc. Do not give warfarin until Plts > 150k

Heparin Reversal

Protamin Sulfate

Time Elapsed	Protamin Dose (mg) / 100 U UFH
Immediate	1-1.5
30-120 min	0.5-0.75
> 2h	0.25-0.375

Dose is cumulative (i.e. add up dose for each time category)

SEs

• Hypotension / Bradycardia
  • Infuse over 1-3min NTE 50mg/10min
• Anaphylaxis
  • At risk w/ fish allergy, Surg. Hx of vasectomy, or protamine containing insulin use

LMWH

Drug	Prophylactic Dose	Treatment Dose	Note
Enoxaparin Q12H	30mg SubQ	1 mg/kg SubQ	No Q12 dosing in CrCl < 30
Enoxaparin QD	40mg SubQ	1.5 mg/kg SubQ	30mg or 1 mg/kg SubQ in renal failure QD for prophylactic and treatment respectively
Dalteparin QD	2.5k-5k IU SubQ	200 IU/kg SubQ	Monitor anti-Xa level (0.5-1.5 4-6h after injection)
Tinzaparin QD	-	1754 IU/kg SubQ

• Obesity and LMWH
  • NTE 144kg Enoxaparin
  • NTE 190kg Dalteparin
  • NTE 165kg Tinzaparin
• Safe in pregnancy

Monitoring

• CBC w/ Plt
• SCr
• Fecal occult blood
• Anti-Xa Level
  • Consider in children, CKD-5, obesity, long courses, and pregnancy
  • Treatment doses expect 0.6-1 U/mL 4hr post dose in BID, our 0.1-0.3 U/mL as trough in QD dosing
  • Not recommended for routine monitoring
• Use w/ neural anesthesia or spinal puncture can lead to spinal hematoma

SEs

• Bleeding
• Thrombocytopenia
• Delayed hypersensitivity

Reversal Agent

• Protamine Sulfate
  • If w/i 8hr of last dose, 1mg per 100 IU or 1mg enoxaparin
  • If > 8hr since last dose, 0.5mg per 100 IU or 1mg enoxaparin

Fondaparinux

Dosing

• Prophylaxis
  • 2.5mg SubQ QD
• Treatment
  • < 50kg: 5mg SubQ QD
  • 50-100kg: 7.5mg SubQ QD
  • 100kg: 10mg SubQ QD

Notes

• CI in CrCl < 30
• Not for prophylaxis in body wts < 50kg
• Safe in pregnancy

Monitoring

• No routine monitoring, but can monitor Anti-Xa levels
• Bleeding

IV Thrombin Inhibitors

Drug	Dose	Use	Note
Lepirudin	0.15 mg/kg/hr +/- 0.4 mg/kg bolus	HIT	aPTT 1.5-2.5x normal Reduce dose if CrCl < 60
Bivalirudin	0.7 mg/kg then 1.75 mg/kg/hr	HIT UFH alternative in PCI
Argatroban	2 mcg/kg/min Hepatic Impairment: 0.5 mcg/kg/min	HIT	Elevates INR, overlap w/ warfarin until INR ≥ 4 (then D/C argatroban)

Have no antidote

NOACs

Approved Inidications

	Post-Op Prophylaxis	Non-Valvular A-Fib	DVT/PE Treatment	Secondary DVT/PE Prevention	VTE Prophylaxis
Dabigatran	Hip Only	X	X
Rivaroxaban	X	X	X	X
Apixaban	X	X	X	X
Edoxaban		X	X
Betrixaban					X

Dosing

Post-Op Prophylaxis

	Dabigatran	Rivaroxaban	Apixaban
Dose	Day of Surgery: 110mg x1 (1-4hr post-op) Not Day of Surgery: 220mg QD x28-35d	Hip: 10mg QD x35d Knee 10mg QD x12d 6-10hr post-op	Hip: 2.5mg BID x35d Knee 2.5mg BID x12d 12-24hr post-op
Renal Adj.	CrCl ≤ 30, no evidence	CrCl ≤ 30, no evidence	CrCl ≤ 30, no evidence

Non-Valvular A-Fib

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Dose	150mg BID	20mg QD	5mg BID	60mg QD
Renal Adj.	CrCl 15-30: 75mg BID	CrCl 15-30: 15mg QD	2 of the following: SCr ≥ 1.5, Age ≥ 80, or Wt ≤ 60kg get 2.5mg BID HD Pts: 5mg BID unless above criteria are met, then reduce	CrCl 15-50: 30mg QD Not for use if CrCl > 95

DVT / PE Treatment (3mo if provoked, 3-12+mo if unprovoked)

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Dose	150mg BID	15mg BID x3wks then 20mg QD	10mg BID x7d then 5mg BID	60mg QD
Renal Adj.	CrCl < 30: No Data	CrCl < 30: Avoid	CrCl < 25 or SCr > 2.5: No evidence	CrCl 15-50: 30mg QD ≤ 60kg: 30mg QD
Notes	Requires 5-10d parenteral anticoagulation			Requires 5-10d parenteral anticoagulation

Secondary DVT / PE Prophylaxis (May D/C after 6mo)

	Rivaroxaban	Apixaban
Dose	20mg QD	2.5mg BID
Renal Adjustment	CrCl < 30: Avoid	CrCl < 25 or SCr > 2.5: No evidence

VTE Prophylaxis

	Betrixaban
Dose	160mg load then 80mg QD x35-42d
Renal Adjustment	CrCl 15-30: 80mg load then 40mg QD x35-42d
Note	Lasts > 72hr after D/C

DOAC Comparison

• Dabigatran is metabolized by glucuronidation, Betrixaban has minimal CYP, and all others are 3A4 metabolized
• All have P-GP interactions
• All have renal adjustments
• Dabigatran has higher levels of GI upset and bleeding
• Dabigatran must be left in manufacturer bottle, and is only good for 4mo

DOAC Conversions

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
From IV/SC Anticoag	≤ 2hr prior to next dose	UFH at D/C Otherwise ≤ 2hr prior to next dose	UFH at D/C Otherwise at next scheduled doses	4h after UFH D/C Otherwise at next scheduled dose
To IV/SC Anticoag	CrCl ≥ 30: 12hr after last dose CrCl < 30: 24hr after last dose	Next scheduled dose	Next scheduled dose	Next scheduled dose
From PO Anticoag	Warfarin: INR < 2 Otherwise at next scheduled doses	Warfarin: INR < 3 Otherwise at next scheduled doses	Warfarin: INR < 2 Otherwise at next scheduled doses	Warfarin: INR < 2.5 Otherwise at next scheduled doses
To PO Anticoag	CrCl > 50: Start 3d before stopping CrCl 30-50: Start 3d before stopping CrCl 15-30: Start 1d before stopping	Warfarin and IV/SC bridge at next scheduled dose	Warfarin and IV/SC bridge at next scheduled dose	Reduce by 50%, start warfarin, and stop when INR ≥ 2

CIs

• Recent GI bleeding
• Malignancy
• Recent brain, spine, or ophthalmic surgery
• Intracerebral hemorrhage
• Varices
• AV Malformations
• Concurrent use of other anticoagulants

Reversal Agents

• Dabigatran
  • Praxbind (Idarucizumab) 5g IV (2.5g IV q15min x2)
  • Monitor aPTT at baseline, 2hr, and Q12H until normal
• Others
  • Andexanet

Monitoring

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
aPTT	At peak aPTT is 1.5-1.8x higher	At peak aPTT is 1.5-2x higher	At peak aPTT is 1.2x higher	At peak aPTT is 1.3x higher
PT	Insensitive	Insensitive	PT increased by 2.9x at peak	PT increased by 2x at peak
TT	Dose-Dependent	Sensitive but highly variable	Insensitive	Insensitive
Fibrinogen	Affected, but not dose dependent	N/A	N/A	N/A
Anti-Thrombin / Anti-Xa	Insensitive	Anti-Xa	Anti-Xa	Anti-Xa

Thrombolytics

Dosing

Drug	Dose	Consideration
tPA	10mg the 90mg over 2hr	For PE
Reteplase		Only for ACS
Tenecteplase		Only for ACS
Urokinase	4400 U/kg x10min then 4400 U/kg/hr x12hr

Therapy Disruptions for Invasive Procedures

• Stop warfarin 5d before surgery
  • Give UFH or LMWH until procedure, stoping LMWH 24hr pre-op or UFH 4-6hr pre-op
  • Resume 12-24hr after surgery