Adverse Effects
- Bleeding, caution in renal impairment
PMCH’s Dosing & Monitoring Parameters (may differ slightly across children’s hospitals)
Purpose
To provide details about bivalirudin use during the hospital admission
Background
Specific and reversible DTI irrespective of antithrombin. Binds to both circulating and clot-bound thrombin via catalytic and anionic exosite. Catalytic exosite inhibits coagulant effects by preventing thrombin-mediated cleavage of fibrinogen to fibrin monomers and activation of factors V, VIII and XIII. Demonstrates linear dose- and concentration-dependent prolongation of the ACT, aPTT, PT and TT.
Indication
Heparin-induced thrombocytopenia, anticoagulation for patients with ventricular-assist device, and in select cases, anticoagulation for patients with venous thromboembolism in consultation with IHTC.
USE
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
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.
Pharmacokinetics
| Onset of action | 2 min. |
| Half-life |
Adults = 25 min. Pediatrics = 20 min. Neonatal = 15 min. Doubles in severe renal failure (can be prolonged up to 4 h for severe renal failure/dysfunction) Cleared with CRRT and HD |
| Steady state reached | in 4 h |
| Metabolism | 20% renal clearance and 80% proteolytic destruction. *Thus it is contraindicated in patients with physiology leading to static blood flow (e.g., non-ejecting LV or RV) |
| Protein/albumin binding? | No |
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
*Per Dr. Christina VanderPluym from ACTION: “We have yet to identify a max total dose and/or a max mg/kg dose that has been associated with adverse events. For obese patients, we generally use their “dry weight” if we feel that some part of their weight is actually fluid from heart failure, etc. That said, I have found that in larger patients the overall mg/kg dose is generally much smaller than we see in younger patients (e.g., starting 0.5 mg/kg for younger/smaller child, but only 0.1 mg/kg for larger adolescent).”
Centers have reported using bolus of 0.25-0.5 mg/kg to achieve therapeutic aPTT.
Monitoring Therapy on ECMO
- ACT or aPTT levels are used to monitor bivalirudin activity at PMCH.
- 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 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.
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.
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 |
Goal aPTT of 1.5-4x may also be need to be utilized over exact seconds when titrating bivalirudin.
For non-ECMO patients receiving bivalirudin for anticoagulation
Follow the below titration protocol, with the expectation that monitoring aPTT on bivalirudin can be challenging. Use Monitoring Therapy for aPTT as above.
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 titration 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
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
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
Perioperative Management
- Decision making regarding whether anticoagulation needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. If it is indicated, bivalirudin should be held for 2 hours prior to procedure for complete reversal. Alternatively, can decrease infusion rate to 0.1 mg/kg/hr for 30 minutes prior to procedure.
- Restart bivalirudin infusion after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionist.
Bleeding Precautions & Warnings
- While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
- Try to avoid IM injections, lumbar punctures, arterial punctures. Apply pressure after venipuncture until bleeding has ceased.
Reversal Information
- There is no reversal agent. Turn off infusion when reversal is indicated.
- For intractable/refractory bleeding, recombinant Factor VII at 10 mcg/kg boluses in increments up to 90 mcg/kg for life-threatening bleed may be given (consider lower doses for cardiac patients).
Transition Information
- The patient should be on a bridge anticoagulant (i.e. heparin or enoxaparin) at the same time to avoid warfarin induced skin necrosis or other thrombotic complications. See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to warfarin.
- Continue the bridge anticoagulant until INR is within therapeutic range.
- See table for switching from warfarin to another anticoagulant:
| From | To | Action |
| Bivalirudin | Argatroban/ Dalteparin/ Enoxaparin/ Fondaparinux/ Heparin | Initiate parenteral anticoagulant within 2 hours after discontinuation of bivalirudin |
| Apixaban/ Betrixaban Dabigatran/ Edoxaban/ Ravaroxaban | Initiate apixaban, betrixaban, dabigatran, edoxaban, or rivaroxaban within 2 hours after discontinuation of bivalirudin infusion | |
| Warfarin |
Bivalirudin must be continued when warfarin is initiated and co-administration should continue for at least 5 days. There is potential for combined effects on INR with the co-administration of bivalirudin and warfarin. A loading dose of warfarin shouldn’t be used. Obtain daily INR with co-administration of bivalirudin and warfarin. After 5 days of co-therapy with warfarin and when INR is *4-5 on combined therapy for at least 1-2 consecutive INR, temporarily suspend the bivalirudin for 4 hours, then check the INR:
*Note, the above target INR when on combined therapy may vary from patient to patient, but in general need to typically target a higher INR during the switch. Can also consider obtaining factor X activity (~13-23%) or chromogenic factor X (~20-40%) that correlates with INR of 2-3. |
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, AT3s, 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.
Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women.
References
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