Initiating Therapy

• Prior to initiation of therapy, but no longer than 48 hours before, the following laboratory values are checked: CBC, coagulation panel (PT, PTT, fibrinogen activity), creatine, hepatic function panel, pregnancy test for females if applicable
• Bivalirudin should be ordered using dosing weight regardless of BMI.
• A brain ultrasound is suggested for patients less than 1 year old. If possible to be completed, a brain ultrasound is STRONGLY recommended for neonates less than 44 weeks corrected gestational age.
• When possible, patients should have a dedicated IV line for bivalirudin. The bivalirudin infusion must not be stopped or interrupted for other medications except in cases of emergency.

Bivalirudin protocol for Non-ECMO indications

For non-ECMO patients receiving bivalirudin for anticoagulation

Follow the below dosing and titration protocol, with the expectation that monitoring aPTT on bivalirudin can be challenging. See below for aPTT considerations.

Dosing

Start – 0.3 mg/kg/hr 

• In patient with usual bleeding risk and 
• Normal renal function (GFR >60 mL/min/1.73 m2)

Start – 0.1 mg/kg/hr  

• If bleeding patient 
• At risk neonate (post-arrest, prematurity or severely acidotic)
• If performing procedure or surgery
• Renal failure with GFR < 30  ml/min/1.73 m2

Start – 0.2 mg/kg/hr 

• Mild-to-Moderate renal impairment GFR 30-60 ml/min/1.73 m2
• CRRT in patient with renal failure

Can also consider the following dosing protocol:

• Heparin-induced thrombocytopenia (HIT):
  • CrCl >60 mL/min/1.73m2: 0.15 mg/kg/hour
  • CrCl 30-59 mL/min/1.73m2: 0.075 mg/kg/hour
  • CrCl <30 mL/min/1.73m2: 0.0375 mg/kg/hour
• Thromboembolic disorder: 0.125 mg/kg IV bolus (administered over 3-5 minutes), followed by 0.125 mg/kg/hour IV continuous infusion

Titration protocol for patients receiving bivalirudin for non-ECMO indications:

1. Adjust bivalirudin to maintain aPTT of 1.5 – 2.5x initial baseline aPTT a.
2. Heparin-induced thrombocytopenia (HIT):

Dose adjustments based on initial post-infusion

<1.2x baseline aPTT	Increase rate by 40%
1.2-1.5x baseline aPTT	Increase rate by 20%
1.5-2.5x baseline aPTT	No change
2.5-4x baseline aPTT (upper limit 80 seconds)	Decrease rate by 20%
>4x baseline aPTT or aPTT>100 seconds	-Hold infusion x 1 hour, reassess aPTT -Decrease rate by 50% once aPTT<100 seconds

3. Thromboembolic disorder:

Dose adjustments based on initial post-bolus aPTT (15 minutes post-bolus)

<2.5x baseline aPTT	-Continue infusion at same rate -Reassess aPTT 3-4 hours after continuing infusion
>2.5x baseline aPTT	-Hold infusion x 1 hour, reassess aPTT

Dose adjustments following subsequent aPTT measurements

>4x baseline aPTT	-Hold infusion x 1 hour -Decrease rate by 20% and restart -Reassess aPTT 3-4 hours after continuing infusion
>2.5-4x baseline aPTT	-Hold infusion x 1 hour -Decrease rate by 10% lower rate and restart -Reassess aPTT 3-4 hours after continuing infusion
1.5-2.5x baseline aPTT	-Continue infusion at same rate -Reassess aPTT at next scheduled time
<1.5x baseline aPTT	-Increase rate by 10% -Reassess aPTT 3-4 hours

Monitoring Therapy (non-ECMO/VAD)

• For HIT, the aPTT is monitored.
• Ensure age-based aPTT values for preterm infants and term infants are used.
• ACT or aPTT Monitoring
  • When initiating therapy check the ACT or aPTT level 4 hours. Refer to table above for adjustments in bivalirudin. aPTT is checked every 2-4 hours after initiation of bivalirudin until therapeutic.
  • Once aPTT therapeutic, additional ACT or aPTT level monitoring are checked every 4 hours after each rate change until the patient has reached their targeted anticoagulation level, and every 6 hours if no rate change during the first 24-48 hours.
  • Once the patient is at the targeted anticoagulation level on a stable dose for at least 24-48 hours, the ACT or aPTT level is monitored every 12-24 hours.
• Check PT/INR every am. Goal INR < 2.5.
• Check TEGs every am or as needed (e.g., with bleeding, plateau effect of aPTT). Goal TEG-R 10-24 minutes. If MA < 50, consider using lower aPTT goal.
• Check fibrinogen every am
• CBC monitoring every am
• Serum Cr every am

Bivalirudin protocol for ECMO circuit

Usual Reference Range for Therapeutic Dosing

• ACT: Goal is > 2.5 x baseline or specific time depending on indication
• aPTT: Goal is 1.5-4x baseline
  • Low range is 50-70 seconds
  • Default is 60-80 seconds
  • High range is 80- 95 seconds

Plateau effect on aPTT may be seen at higher concentrations of bivalirudin (>1mg/L). If concern, follow PT/INR and TEG closely to assess for inhibition of clotting factors. 

Cannulation

PMCH will continue to prime the circuit with heparin and give heparin for cannulation to the patient. After the ACT falls to less than 300 then start the bivalirudin infusion
 
Initial starting Bivalirudin infusion for ECMO circuit

Start – 0.3 mg/kg/hr 

• In patient with usual bleeding risk and 
• Normal renal function 

Start – 0.1 mg/kg/hr  

• If bleeding patient 
• At risk neonate (post-arrest, prematurity or severely acidotic)
• If performing procedure or surgery
• Renal failure with GFR < 30  ml/min/1.73 m2

Start – 0.2 mg/kg/hr 

• Moderate renal impairment GFR 30-60 ml/min/1.73 m2
• CRRT in patient with renal failure

PMCH’s titration protocol for patients receiving bivalirudin for anticoagulation during ECMO

To increase PTT by 1-5 seconds	Increase infusion rate by 10%
To increase PTT by 6-10 seconds	Increase infusion rate by 15%
To increase PTT by 11-15 seconds	Increase infusion rate by 20%
To increase PTT by > 15 seconds	Increase infusion rate by 25%
To decrease PTT by 1-5 seconds	Decrease infusion rate by 10%
To decrease PTT by 6-10 seconds	Decrease infusion rate by 15%
To decrease PTT by 11-20 seconds	Decrease infusion rate by 20%
To decrease PTT by 20-30	Decrease infusion rate by 25%
To decrease PTT by >30 seconds

• ACT or aPTT levels are used to monitor bivalirudin activity at PMCH.
  • Ensure age-based aPTT values for preterm infants and term infants are used.
• ACT or aPTT Monitoring
  • When initiating therapy check the ACT or aPTT level 2 hours after the initiation of the bivalirudin infusion. This first aPTT reflects heparin bolus. If aPTT less than 80 seconds, increase bivalirudin by 0.03 mg/kg/hour. Recheck aPTT 2 hours later. This aPTT reflects bivalirudin. Refer to table below for adjustments in bivalirudin. aPTT is checked every 2 hours after initiation of bivalirudin until therapeutic.
  • Once aPTT therapeutic, additional ACT or aPTT level monitoring are checked every 4 hours after each rate change until the patient has reached their targeted anticoagulation level, and every 6 hours with no rate change during the first 24-48 hours.
  • Once the patient is at the targeted anticoagulation level on a stable dose for at least 24-48 hours, the ACT or aPTT level is monitored every 12-24 hours.
• Check PT/INR every 12-24 hours. Goal INR < 2.5.
• Check TEGs every am or as needed (e.g., with bleeding, plateau effect of aPTT). Goal TEG-R 10-24 minutes. If MA < 50, consider using lower aPTT goal.
• Check fibrinogen every am
• CBC monitoring every 12-24 hours
• Serum Cr every am

Other assays which have therapeutic ranges available not currently available at PMCH: “dilute” TT also used (test plasma pre-diluted 1:4 or 1:10 to dilute out the DTIs so that the clot time when thrombin is added will clot at reasonable seconds); chromogenic dTT is the escarin chromogenic assay for DTI concentrations; anti-factor IIa chromogenic assay.
dTT may be impacted by heparin contamination from line (prolonged dTT), fibrinogen levels.
dTT not impacted by lupus inhibitors or elevated d-dimer.

Safety Precautions

• Renal Impairment: Dose adjustment recommended in adults and pediatrics with CrCl less than 60mL/min
• Hepatic Impairment: No dosage adjustment necessary
• Drug-Drug Interactions
  • Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants
• Drug-Food Interactions
  • None 

 aPTT Considerations
aPTT may not always be representative of bivalirudin concentration.

Can see Increased PTT with:

• Heparin contamination (from line)
  • Kathy in special coag lab can run hepzyme assay. But for more rapid TAT, can get PT/INR or anti-Xa to identify contamination, since PT/INR won’t increase with heparin contamination alone, but will increase with bival concentration
• Traumatic phlebotomy
• Low fibrinogen, low Factor XII or VIII (> 30-40% depletion)
• Hemolysis – with elevated plasma free hemoglobin
• Impaired renal function with resultant increased bivalirudin concentration
• Lupus anticoagulant
• Vitamin K deficiency
• Disseminated intravascular coagulopathy or other coagulopathy 
• Hyperbilirubinemia

Can see Decreased PTT with: 

• High factor VIII
• Systemic Inflammation
• Activation of the contact pathway 
• Elevated fibrinogen or D-dimer
• Hypertriglyceridemia
• Hemolysis- elevated plasma free hemoglobin 
• Delay in sample analysis

Additional Information

• Follow PT/INR and when INR is greater than 2, consider need for FFP. Bivalirudin will increase PT/INR. It is not recommended to give products for the sole purpose of correcting INR/fibrinogen unless clinically indicated.
• Bivalirudin can decrease fibrinogen in vitro by knocking off added thrombin in the fibrinogen assay causing prolonged clot time which is then translated into lower fibrinogen. It is not recommended to give products for the sole purpose of correcting INR/fibrinogen unless clinically indicated.
• Bivalirudin not affected by platelet administration.
• Low flow trials – give heparin bolus of 25-50 units/kg due to risk of stasis and repeat bolus after 15 minutes
• Circuit changes consider giving heparin bolus of 50 units/kg at time of change 
• CRRT or HD consult pharmacy for dosing.
• Any interruption of ECMO flow for greater than 10 minutes give patient 50 units/kg of heparin to protect the cannulas

Miscellaneous

• Do NOT need to increase when platelets are given to patient.
• Always keep a backup syringe at the bedside.
• Bivalirudin is good for 24 hours from when it was hung even if expiration is before that time. 
• Do NOT check ACTs, ATIII, or Heparin Levels
• If using a hemofilter in circuit, must hook up the pull side to a pigtail that is before the bivalirudin infusion. You will still return to above the pump head. 
• Document PTTs and rate changes on the spreadsheet made specific for Bivalirudin.