Direct thrombin inhibitors

1. Direct Thrombin Inhibitors
By
Bhukya Nom Kumar Naik DAFE, (Pharm.D)

3. • Thromboembolic disorders are the one of the major causes of comorbidities and
mortalities world wide. They result from blood clots that form inside blood vessel with
the potential to obstruct blood flow1.
• Direct thrombin inhibitors(DTIs) are a class of anticoagulants that act by directly
inhibiting thrombin to delay clotting and are typically used during HIT and cute coronary
syndrome2.
• There 3 types of DTIs, dependent on their interactions with the thrombin molecule.
Bivalent DTIs bind both to the active site and exosite – 1, while univalent DTIs bind only
to the active site3.
• The 3rd class of inhibitors, which are gaining importance recently, is the allosteric
inhibitors4.
• The suffix of Bivalents is – Rudin, where univalent DTIs is – Tran, ban.
• Till now there is no allosteric thrombin inhibitors has yet reached the stage of clinical
trails.
• The most clinically used DTIs are Argatroban, Bivalirudin, Dabigatran etexilate,
Desirudin, Lepirudin5.
• Bivalents are less suitable for long term treatment, they are available in forms of injection
(IV,IM).

5. Argatroban

6. ADULT DOSING
• General Dosage Information Conversion to warfarin:
• Initiate warfarin using the expected daily dose (no loading dose) and overlap therapy with
argatroban. Measure INR daily. For argatroban doses up to 2 mcg/kg/min, discontinue when INR is
greater than 4 with combined therapy and repeat INR in 4 to 6 hours.
• if INR is subtherapeutic, restart infusion and repeat procedure until desired range is reached on
warfarin alone. For argatroban doses of greater than 2 mcg/kg/min, temporarily reduce dose to 2
mcg/kg/min then measure INR of the combined therapy 4 to 6 hours later. Then follow the
procedure for doses up to 2 mcg/kg/min.
• Cerebral thrombosis:
• Off-label dosage : 60mg/day by continuous IV infusion for 2 days, followed by 10 mg IV twice a
day for 5 days.

7. • Coronary artery thrombosis :
• In patients with or at risk for heparin induce thrombocytopenia(HIT) : Prophylaxis – PCI
(percutaneous coronary intervention).
• Initial dosage : 25 mcg/kg/min Iv infusion with a bolus of 350 mcg/kg via large bore IV line over
3 to 5 min. And check ACT (Activated Clotting Time) 5-10 min after bolus dose is completed. PCI
procedure may proceed if the ACT is more than 300 seconds.a
• Titration based on ACT : If ACT is less than 300 seconds, an additional IV bolus dose of 150
mcg/kg should be administered, The infusion dose increased to 30 mcg/kg/min, and the ACT is
checked 5-10 min later. If ACT is greater than 450 seconds, the infusion rate should be decreased
to 15 mcg/kg/min, and the ACT checked 5-10 min later, continue titrating the dose until a
Therapeutic ACT (between 300 and 450 seconds) has been achieved: Continue the same infusion
rate for the duration of PCI procedure.

8. • Heparin-induced thrombocytopenia - Thrombosis; Treatment and Prophylaxis
• Prior to initiation, discontinue heparin and obtain a baseline aPTT (Activated partial
thromboplastin time).
• Initial, 2 mcg/kg/min continuous IV infusion, adjust until steady-state aPTT is 1.5 to 3 times the
initial baseline value (not to exceed 100 seconds); MAX 10 mcg/kg/min (FDA dosage)
• Treatment of acute HIT: No bolus dose; administer infusion of 2 mcg/kg/minute and adjust to
aPTT 1.5 to 3 times baseline (guideline dosage)
• Nomogram dosing, aPTT less than or equal to 44 seconds: Increase infusion rate by 0.5
mcg/kg/minute and obtain next aPTT 3 hours later (off-label dosage)
• Nomogram dosing, aPTT between 45 and 90 seconds (target range): Maintain infusion rate; repeat
aPTT 3 hours after last aPTT. Once 2 consecutive aPTTs are within target range, check aPTT every
12 hours (off-label dosage)

9. • Nomogram dosing, aPTT between 91 and 120 seconds: Decrease infusion rate by
0.5 mcg/kg/minute and obtain the next aPTT 3 hours later (off-label dosage)
• Nomogram dosing, aPTT between 121 and 149 seconds: Hold the infusion for 1
hour then resume at one-half of the previous rate. Obtain aPTT 3 hours after rate
change dosage)
• Nomogram dosing, aPTT 150 seconds or greater: Hold the infusion for 1 hour
then resume at one-half the previous rate when aPTT is less than 90 seconds;
repeat aPTT every hour until aPTT less than 90 seconds (off-label dosage).
• Myocardial infarction
• 100 mcg/kg IV bolus followed by 1 to 3 mcg/kg/min continuous IV infusion for 6
to 72 hours; maintain aPTT between 50 to 85 seconds, given in conjunction with
alteplase and aspirin (off-label dosage).

10. USES
• FDAApproved : –
1.Coronary artery thrombosis : In patients with or at risk for heparin induced thrombocytopenia:
Prophylaxis – PCI.
2.Heparin induced thrombocytopenia – thrombosis: treatment and prophylaxis.
• Non – FDA approved : -
1. Cardiovascular surgical procedures.
2. Cardiovascular surgical procedure
3. Cerebral thrombosis
4. Disseminated intravascular coagulation
5. Extracorporeal circulation procedure
6. Hemodialysis - Venous catheter occlusion; Prophylaxis
7. Myocardial infarction
8. Unstable angina

11. Administration
• Intravenous (100 mg/mL solution) dilute in NS, D5W, or LR to a final concentration of 1
mg/mL; mix by repeated inversion of bag for 1 minute; diluted solution stable for 24 hours at
room temperature with ambient indoor light and stable for 96 hours at room temperature or
under refrigeration when protected from light
• (1 mg/mL solution) ready for administration; no dilution necessary
• administer bolus dose over 3 to 5 minutes through a large bore intravenous line.

12. Dose Adjustments
• Renal impairment: No dosage adjustment necessary
• Hepatic impairment (moderate to severe, Child-Pugh class B and C) in heparin-induced
thrombocytopenia (HIT): Avoid use or use a reduced dose. In patients with bilirubin of greater
than 1.5 mg/dL, use a dose of 0.5 to 1.2 mcg/kg/min. Adjust aPTT to 1.5 to 3 times baseline
• Hepatic impairment (moderate to severe) in (HIT): Initial dose 0.5 mcg/kg/min; monitor aPTT
closely and adjust dosage as clinically indicated. Achievement of steady state aPTT levels may take
longer and require more dose adjustments in patients with hepatic impairment compared to patients
with normal hepatic function.
• Hepatic impairment in percutaneous coronary intervention (PCI): Avoid use with clinically
significant hepatic disease or AST/ALT levels 3 or more times the ULN. In other patients, titrate
carefully until the desired level of anticoagulation is achieved.
• Geriatric: No dosage adjustment necessary in geriatric patients.

13. • Critically ill patients without organ failure in HIT: Initial, 1 mcg/kg/min
• Critically ill patients with multiple organ failure or heart failure in HIT: Initial, 0.5 to 0.6
mcg/kg/min .
• Critically ill patients with multiple organ failure in HIT: Initial, 0.2 mcg/kg/min.
• Heart failure, multiple organ system failure, or severe anasarca, or post-cardiac surgery in
HIT: Initial, 0.5 to 1.2 mcg/kg/min.
• Obesity (BMI up to 51 kg/m(2)): No dosing adjustment required when actual body weight based
dosing to target coagulation response is utilized.
• Dissection, impending abrupt closure, or thrombus formation during PCI, or inability to
achieve or maintain an activated clotting time (ACT) over 300 seconds: Give additional IV
boluses of 150 mcg/kg and increase infusion rate to 40 mcg/kg/min; check ACT after each
additional IV bolus or change in infusion rate; if anticoagulation is required after PCI, may
continue therapy at a lower infusion dose.

14. Contraindications
• Hypersensitivity to argatroban or to any component of the product.
• Major bleeding
Precautions
• Hematologic: Intracranial and retroperitoneal hemorrhage have been reported
• Hematologic: Risk of hemorrhage may be increased in severe hypertension, after lumbar puncture, spinal
anesthesia, major surgery (especially involving the brain, spinal cord, or eye), in conditions associated with
increased bleeding (eg, congenital or acquired bleeding disorders), gastrointestinal lesions (eg, ulcerations), or with
concomitant use of antiplatelet agents, thrombolytics, and other anticoagulants
• Hepatic: Decreased clearance in patients with hepatic impairment; monitoring and dosage adjustment
recommended; full reversal of anticoagulant effect may take longer than in patients with normal hepatic function
• Hepatic: Avoid high doses in patients undergoing percutaneous coronary intervention with clinically significant
hepatic disease or AST/ALT levels 3 times the ULN (Upper limits of normal) or greater.

15. Adverse Effects
• Common
• Cardiovascular: Chest pain (15.2%), Hypotension (7.2% to 10.7%)
• Gastrointestinal: Diarrhea (6.2%), Nausea (4.8% to 7.1%), Vomiting (4.2% to 6.3%)
• Neurologic: Headache (5.4% ) Respiratory: Dyspnea (8.1% )
• Other: Backache (8%), Fever (3.6% to 6.9%)
• Serious
• Cardiovascular: Angina pectoris (1.8% ), Aortic valve stenosis (0.9%), Arterial hemorrhage, Coronary
artery (1.8%), Arterial thrombosis (0.9%), Cardiac arrest (5.8%), Coronary artery thrombosis (1.8%),
Coronary occlusion (1.8%), Myocardial infarction (3.6%), Myocardial ischemia (1.8%), Vascular
disorder (0.9%)
• Gastrointestinal: Gastrointestinal hemorrhage, Major (0.9% to 2.3%), Retroperitoneal hemorrhage,
Major (0.9%)
• Hematologic: Decreased hematocrit level, Major, Decreased hemoglobin, Major, Hemorrhage, Major
(0.5% to 5.3%), Hemorrhage, Major, Limb and Below the Knee Stump (0.5%)
• Immunologic: Sepsis (6%).

16. • Neurologic: Intracranial hemorrhage
• Renal: Genitourinary tract hemorrhage, Major, Hematuria, Major
• Respiratory: Pulmonary edema (0.9%)
Mechanism of Action
• By reversibly binding to the thrombin active site, argatroban acts as a direct thrombin inhibitor.
Without need of co-factor antithrombin III, argatroban inhibits thrombin-catalyzed or induced
reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII; protein C;
and platelet aggregation. Argatroban is selective for thrombin and has little to no effect on related
serine proteases (i.e., trypsin, factor Xa, plasmin, kallikrein).

17. Pharmacokinetics
• Distribution :
1. Vd: 174 to 180 mL/kg
2. Protein binding: 54% (Albumin 20%, Alpha 1-acid glycoprotein 34%).
• Metabolism
1. Hepatic : Hydroxylation and Aromatization.
2. Active metabolite: M1 (0 to 20%).
• Excretion:
1. Renal: 22 to 24.5% (16% unchanged).
2. Fecal: 65% (14% unchanged).
3. Bile: excreted primarily via biliary tract.
4. Dialyzable: yes (hemodialysis), 20%.
• Elimination Half Life
1. 30 to 51 min
2. Hepatic impairment: 181 min

18. Bivalirudin

19. Adult Dosing
• Important Note
• Orphan drug designation: Anticoagulant in patients with or at risk of heparin-induced
thrombocytopenia/heparin-induced thrombocytopenia thrombosis syndrome
• General Dosage Information
• Bivalirudin has been studied only in patients receiving concomitant aspirin
• Acute myocardial infarction, Adjunct to Thrombolytic Therapy
• 0.25 mg/kg IV bolus followed by an infusion of 0.5 mg/kg/hr for 12 hours, then 0.25 mg/kg/hr for
36 hours (off-label dosage)
• Concomitant medication: Streptokinase 1.5 million units IV infused over 30 to 60 minutes (off-
label dosage).

20. • Concomitant medication: Streptokinase 1.5 million units IV infused over 30 to 60 minutes (off-
label dosage).
• Adjunct anticoagulant therapy to fibrinolysis should be administered for a minimum of 48 hours
and preferably for the duration of the hospitalization, up to 8 days or until revascularization if
performed (guideline dosage).
• Deep venous thrombosis; Prophylaxis
• Orthopedic surgery (major hip or knee surgery), 1 mg/kg sub Q every 8 hours until completion of
bilateral ascending contrast venography (up to 14 days); this dose was more effective than lower
doses (0.3 to 1 mg/kg every 12 hours) (off-label dosage).
• Heparin-induced thrombocytopenia, Acute, in patients with or without thrombosis
• 0.15 mg/kg/hour continuous IV infusion; adjust to aPTT 1.5x to 2.5x baseline (guideline dosage).

21. • Heparin-induced thrombocytopenia with thrombosis - Operation on heart - Thromboembolic disorder;
Prophylaxis
• 1 mg/kg IV followed by 2.5 mg/kg/hr IV infusion and pump prime of 50 mg; adjust IV infusion to 2.5x
baseline activated clotting time (ACT); some centers achieved the target ACT levels with lower loading dose
and infusion rates (guideline dosage).
• Percutaneous coronary intervention - Thrombosis; Prophylaxis
• 0.75 mg/kg IV bolus, followed immediately with 1.75 mg/kg/hr IV infusion for the duration of the procedure.
Five minutes after bolus dose, perform an activated clotting time test and give an additional bolus of 0.3
mg/kg if needed (FDA dosage)
• Extended duration of infusion following percutaneous coronary intervention (PCI), 1.75 mg/kg/hr for up to 4
hours post-procedure should be considered in patients with ST segment elevation MI (STEMI) (FDA dosage).
• If pretreated with bivalirudin infusion as early invasive strategy in acute coronary syndrome (ACS): Give
additional loading dose of 0.5 mg/kg and infuse at rate of 1.75 mg/kg/hour during PCI (guideline dosage).

22. • If pretreated with unfractionated heparin in ACS or STEMI: Wait 30 minutes then administer 0.75 mg/kg IV
bolus followed by 1.75 mg/kg/hour IV infusion (guideline dosage).
• If pretreated with enoxaparin subQ dose greater than 12 hours ago: Treat with full-dose de novo
anticoagulation using established bivalirudin regimen (guideline dosage).
• Pretreatment with low-molecular-weight heparin (LMWH): Administer bivalirudin for PCI at least 8 hours
after the last dose of the LMWH (off-label dosage); in patients with non ST ACS, switching to full-dose
bivalirudin within 0 to 12 hours after receiving enoxaparin 1 mg/kg subQ did not result in increased risk of
bleeding (off-label dosage)
• Pretreatment with unfractionated heparin: Administer bivalirudin for PCI at least 6 hours after the last dose of
unfractionated heparin or wait until activated partial thromboplastin time is 50 seconds or less or activated
clotting time is 175 seconds or less (off-label dosage)
• Concomitant therapy: Routine adjunctive use of a glycoprotein IIb/IIIa inhibitor is not recommended when
bivalirudin is the primary anticoagulant, but can be considered for adjunct or bail-out use as necessary
(guideline dosage).

23. • Thromboembolic disorder; Prophylaxis - Unstable angina
• Early invasive strategy: Loading, 0.1 mg/kg IV followed by 0.25 mg/kg/hour until diagnostic angiography or
percutaneous intervention (PCI); at time of PCI, switch to PCI dosing of bivalirudin. Patients also treated with
dual antiplatelet therapy may receive provisional use of a glycoprotein IIb/IIIa inhibitor (guideline dosing).
• Switching from pretreatment with unfractionated heparin to bivalirudin prior to angiography: Patients who
had received unfractionated heparin waited 30 minutes before administration of bivalirudin (off-label dosage).
• Switching from pretreatment with enoxaparin to bivalirudin prior to angiography: Patients who had received a
single dose of enoxaparin waited 8 hours prior to administration of bivalirudin (off-label dosage).

24. Pediatric Dosing
• Important Note
• Orphan drug designation: Anticoagulant in patients with or at risk of heparin-induced
thrombocytopenia/heparin-induced thrombocytopenia thrombosis syndrome
• General Dosage Information
• Safety and efficacy in pediatric patients have not been established.
• Thromboembolic disorder
• (6 months to 18 years) 0.125 mg/kg IV bolus followed by 0.125 mg/kg/hr IV infusion; adjust dose based on
target aPTT of 1.5 to 2.5 times patients' baseline (off-label dosage) [14]

25. Uses
• FDA Uses
• Percutaneous coronary intervention - Thrombosis; Prophylaxis
• Non-FDA Uses
• Acute myocardial infarction, Adjunct to Thrombolytic Therapy
• Deep venous thrombosis; Prophylaxis Heparin-induced thrombocytopenia, Acute, in patients with or without
thrombosis
• Heparin-induced thrombocytopenia with thrombosis - Operation on heart - Thromboembolic disorder;
Prophylaxis
• Peripheral arterial bypass – Thromboembolic disorder; Prophylaxis
• Thromboembolic disorder
• Thromboembolic disorder; Prophylaxis - Unstable angina

26. Dose Adjustments
• Renal impairment (any degree): Reduction in bolus dose not necessary
• Renal impairment (CrCl less than 30 mL/min): Reduce infusion rate to 1 mg/kg/hr; monitor the anticoagulant
status more frequently.
• Hepatic impairment: No specific recommendations are available, however continuous IV infusion dose
reduction may be appropriate in patients with liver dysfunction.
• Hemodialysis: Reduce infusion rate to 0.25 mg/kg/hr; no bolus dose reduction is necessary.
• Obesity: The actual measured body weight (total body weight) should be used for dose calculations,
according to a retrospective review in patients with heparin-induced thrombocytopenia (HIT) (n=135); in the
obese group, the mean total body weight was 105 +/- 21.2 kg (range, 78 to 176 kg) and mean BMI 37.7 +/-
6.7 kg/m(2) (range, 30.1 to 56.2 kg/m(2).

27. Administration
• Intravenous
• (Bolus injection and continuous infusion) Reconstitute each 250-mg vial with 5 mL of sterile water for injection and gently
swirl to dissolve; reconstituted solution will be a clear to slightly opalescent, colorless to slightly yellow.
• (Bolus injection and continuous infusion) Withdraw and discard 5 mL from a 50 mL infusion bag of D5W or NS and add
the contents of a reconstituted vial to yield a final concentration of 5 mg/mL (eg, 1 vial in 50 mL; 2 vials in 100 mL, 5 vials
in 250 mL).
• (Low-rate Infusion following initial infusion) Reconstitute each 250-mg vial with 5 mL of sterile water for injection and
gently swirl to dissolve; reconstituted solution will be a clear to slightly opalescent, colorless to slightly yellow.
• (Low-rate Infusion following initial infusion) Withdraw and discard 5 mL from a 500-mL infusion bag of D5W or NS and
add the contents of a reconstituted vial to yield a final concentration of 0.5 mg/mL.
• Storage, reconstituted vials may be stored at 2 to 8 degrees C for up to 24 hours; diluted solution with a concentration of
between 0.5 and 5 mg/mL is stable at room temperature for up to 24 hours; do not freeze reconstituted or diluted solution.
• Administer infusion at 1.75 mg/kg/hr.
Contraindications
• Active major bleeding.
• Hypersensitivity to bivalirudin or its components.

28. Precautions
• Hematologic: Bleeding events have been reported; consider presence of a hemorrhagic event and discontinuation of therapy
for unexplained decrease in hematocrit or blood pressure; monitoring required, especially in patients with disease states
associated with increased bleeding risk.
• Hematologic: Potentially fatal acute stent thrombosis has been reported in patients with ST segment elevation myocardial
infarction undergoing primary percutaneous coronary intervention; careful monitoring recommended.
• Hematologic: Thrombus formation, with possible fatal outcome, has been reported during coronary artery gamma
brachytherapy; minimize conditions of stasis within catheter and vessels.
• Special populations: Increased bleeding events in elderly patients have been reported.
Adverse Effects
• Common
• Cardiovascular: Hypotension (bivalirudin only, 12%; bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, 3.1% )
• Gastrointestinal: Nausea (bivalirudin only, 15%; bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, 3% )
• Musculoskeletal: Backache (bivalirudin only, 42%; bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, 9.2% )
• Neurologic: Headache (bivalirudin only, 12%; bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, 2.6% )
• Other: Pain (bivalirudin only, 15%; bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, 3.4% )

29. • Serious
• Cardiovascular: Coronary artery stent thrombosis (1.2% ), Ventricular fibrillation (bivalirudin only, less than 1% )
• Gastrointestinal: Retroperitoneal hemorrhage (bivalirudin only, 0.2%; bivalirudin plus provisional glycoprotein IIb/IIIa
inhibitor, 0.2% )
• Hematologic: Hemorrhage, major (2.4% to 3.8% ; bivalirudin plus aspirin and streptokinase, 14% to 19% ), Thrombosis
(1.2% )
• Neurologic: Cerebral ischemia (bivalirudin only, less than 1% ), Intracranial hemorrhage (bivalirudin only, less than 0.1%;
bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor, less than 0.1% ), Peripheral facial palsy (bivalirudin only, less
than 1% )
• Renal: Oliguria (bivalirudin only, less than 1% ), Renal failure (bivalirudin only, less than 1% )
• Other: Sepsis (bivalirudin only, less than 1% )

30. Mechanism of Action:
• Bivalirudin is a highly specific inhibitor of the thrombogenic activity of thrombin bivalirudin directly inhibits thrombin by
specifically binding to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin.
Pharmacokinetics
• Absorption
• Tmax, IV route: 2 (bolus) to 4 (infusion) minutes.
• Tmax, subQ route: 1 to 2 hours.
• Bioavailability, subQ route: 40%
• Distribution
• Protein binding: None
• Vd, pediatric: 28 mL/kg
• Metabolism
• Proteolytic cleavage

31. • Excretion
• Renal clearance: Extent unknown
• Renal excretion: Approximately 20% (unchanged)
• Total body clearance: 3.4 mL/min/kg
• Total body clearance, pediatric: 6.6 mL/min/kg
• Total body clearance, renal impairment: Reduced 21% (moderate and severe impairment); reduced by 70% (dialysis).
• Dialyzable: Yes (hemodialysis).
• Elimination
• Half Life 25 minutes.
• Pediatric: 33 minutes.
• Renal impairment: 34 minutes (moderate impairment), 57 minutes (severe impairment), 3.5 hours (dialysis) [7]

32. Reference
1. Newer antithrombotic drugs. Indian journal of critical care medicine
2. Direct thrombin inhibitors: Clinical uses, mechanism of action, and laboratory measurement.
3. Direct thrombin inhibitors by N engl J med
4. Direct thrombin inhibitors Wikipedia.
5. Www.Micromedex.Com