CHAPTER 23

Direct Thrombin Inhibitors

ERIN E. MANCL, PharmD, BCPS

STACY A. VOILS, PharmD, MS, BCPS

OVERVIEW OF INTRAVENOUS DIRECT THROMBIN INHIBITORS

Intravenous (IV) direct thrombin inhibitors (DTIs), including argatroban, bivalirudin, and lepirudin have been developed and evaluated for the treatment of heparin-induced thrombocytopenia (HIT), acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), and venous thromboembolism (VTE). DTIs exert their anticoagulant effect by binding directly to thrombin, thereby inhibiting both soluble and fibrin-bound thrombin.¹ The direct binding to thrombin produces an anticoagulant effect independent of antithrombin (AT) activity. The ability to bind to fibrin-bound thrombin may be particularly advantageous in the setting of an active clot, such as a coronary thrombosis, because fibrin-bound thrombin can stimulate further clotting activity. In addition, compared to heparin-based regimens, DTIs may offer a more predictable anticoagulant effect due to their lack of binding to other plasma proteins. Furthermore, DTIs are a mainstay therapy in patients with HIT because they are not associated with immune-mediated thrombocytopenia.

DTIs were developed after the discovery of hirudin, a peptide first isolated from the salivary glands of medicinal leeches.^2,3 Currently, three IV DTIs are approved for use in North America: argatroban, bivalirudin, and lepirudin. However, as of May 31, 2012, the manufacturer of lepirudin discontinued production and distribution of lepirudin.⁴ At the time of writing this chapter, no other manufacturers were producing lepirudin; therefore, its current use in practice is limited and will likely cease once supply is exhausted.

PHARMACOKINETICS

ARGATROBAN

Argatroban is a small (molecular weight 500 kDa) synthetic DTI administered as a continuous IV infusion due to its limited bioavailability if administered orally.⁵ Upon initiation of an infusion, anticoagulant effect is seen immediately. The volume of distribution is approximately 174–180 mL/kg, with protein binding observed at 20 percent and 35 percent to albumin and alpha-1-acid glycoprotein, respectively. Argatroban is hepatically cleared primarily via hydroxylation and aromatization of the 3-methyltetrahydroquino-line ring. Minor metabolism to four known metabolites through cytochrome (CYP)-450 3A4/5 has been observed. Plasma concentration of metabolite M1 is 0–20 percent parent drug concentration, and this metabolite has a pharmacodynamics effect three–five times weaker than argatroban. Metabolites M2 to M4 are found in low quantities and are pharmacodynamically inactive. Total clearance ranges from 4.7 to 5.1 mL/kg/min at doses up to 40 mcg/kg/min, but such clearance is reduced to 1.9 mL/kg/min in hepatic impairment. The elimination half-life of argatroban is approximately 39–51 minutes but extends to 181 minutes in patients with hepatic dysfunction (defined as Child-Pugh score >6). Therefore, dose adjustment and close monitoring in patients with hepatic impairment are essential. Approximately 20 percent of argatroban is removed through hemodialysis.

BIVALIRUDIN

Bivalirudin is a 20-amino-acid semisynthetic polypeptide analog of hirudin administered as a continuous IV infusion.⁶ Although not usually administered subcutaneously, the bioavailability of bivalirudin is approximately 40 percent when given in this manner. When administered as an IV infusion, bivalirudin is also relatively rapid acting with anticoagulant effects seen immediately upon therapy initiation. The volume of distribution is approximately 200 mL/kg. Other than thrombin, bivalirudin does not bind to any other proteins in the plasma. Bivalirudin is cleared renally and through plasma esterase. Approximately 20 percent of bivalirudin is eliminated unchanged in the urine. Most of this elimination (70%) is observed within 2 hours after IV administration. The remaining clearance occurs through proteolytic cleavage in the plasma. Overall drug clearance decreases as glomerular filtration rate (GFR) decreases. Observed clearance rates are 3.4 mL/min/kg, 2.7 mL/min/kg, 2.8 mL/min/kg, and 1 mL/min/kg for patients with GFR of >60 mL/min, 30–59 mL/min, 10–29 mL/min, and dialysis-dependent off dialysis, respectively. These clearance rates correlate with an elimination half-life of approximately 25 minutes, 22 minutes, 34 minutes, and 57 minutes. In dialysis-dependent patients, the observed half-life is approximately 3.5 hours as approximately 25 percent of bivalirudin is cleared through hemodialysis.

LEPIRUDIN

Lepirudin is typically administered as a continuous IV infusion, but when given subcutaneously, the bioavailability is near 100 percent.⁷ The exact volume of distribution is not well-quantified, but it is known to distribute into extracellular fluids. Approximately 35 percent of lepirudin is excreted in the urine as unchanged drug. Clearance in healthy patients is approximately 174 mL/min compared to 2.7 mL/min in patients undergoing hemodialysis. Notably, total body clearance is also dependent on gender and age, with clearance reduced by 25 percent in women and 20–25 percent in elderly. The elimination half-life ranges 0.8–2 hours in patients with normal renal function, but can be as prolonged as 107 hours in severe renal insufficiency. Lepirudin is cleared through high-flux dialyzers, and dialysis has been successfully used to reduce concentrations to therapeutic levels in cases of excessive dosing.

DOSING

ARGATROBAN

Argatroban is mainly used in the treatment and prevention of thrombosis in patients with HIT, but it is also less commonly used in PCI and coronary thrombosis.⁵ In the prophylaxis and treatment of HIT with or without thrombosis, the American College of Chest Physicians (ACCP) guidelines recommend an initial infusion rate of 1–2 mcg/kg/min adjusted to maintain a steady-state activated partial prothrombin time (aPTT) of 1.5–3 times the initial baseline value.^5,8 Institution-specific protocols often vary in their titration recommendations but, in general, the aPTT is checked 2 hours after initiation or any rate change. If the aPTT is below goal range, a 20 percent increase in rate is recommended whereas if the aPTT is above range, the infusion is held for 2 hours before resuming at 50 percent lower rate. If the aPTT is significantly elevated (e.g., >150 seconds), it is appropriate to repeat the aPTT to ensure adequate decrease before resuming therapy at a reduced rate. Due to reduced clearance in patients with hepatic disease, the recommended initial dosage is 0.5 mcg/kg/min with titration to an aPTT 1.5–3 times the initial baseline. It has also been observed that critically ill patients, with and without hepatic dysfunction, have an impaired clearance of argatroban. In a study of critically ill patients, an argatroban dosing nomogram was developed and evaluated for ability to achieve and maintain goal therapeutic aPTT ranges.⁹ In this study, the time to stabilization of aPTTs was 27 hours using an initial dose of 0.5 mcg/kg/min and titrating to a goal aPTT range of 45–90 seconds. In the critically ill population, the aPTT was checked at 4 hours after initiation and each dose adjustment, an increase from the usual 2 hours in healthy patients. Therefore, it is reasonable and highly recommended to start at a reduced dose (~25% usual dose for healthy patients) in patients with critical illness and/or hepatic impairment. Empiric dose adjustments are not necessary in noncritically ill patients with isolated renal impairment. Observational data suggest that no dose adjustment is required for obese patients (body mass index up to 51 kg/m²); therefore, argatroban should be dosed using actual body weight.¹⁰

Although less commonly used compared to bivalirudin, argatroban is sometimes used in the treatment of coronary artery thrombosis or in patients undergoing PCI, especially in patients identified to have or be at risk for HIT. In PCI, argatroban is administered with an initial bolus of 350 mcg/kg given over 3–5 minutes, followed by a continuous infusion ranging 15–30 mcg/kg/min, usually titrated to a goal-activated clotting time (ACT).⁵ Infusion rates higher than 40 mcg/kg/min are usually reserved for patients with thrombus formation during procedure, dissection, or impending abrupt closure.

If administered for the medical treatment of an acute myocardial infarction, the recommended dose of argatroban is 100 mcg/kg bolus over 1 minute followed by a continuous infusion of 1–3 mcg/kg/min titrated to a goal aPTT of 50–85 seconds.¹¹

BIVALIRUDIN

Bivalirudin is used in patients undergoing PCI for unstable angina or acute MI and in patients with HIT who require PCI.⁶ When used in PCI, bivalirudin is typically initiated with a 0.75 mg bolus dose followed by a continuous infusion of 1.75 mg/kg/hr.¹² The infusion can be maintained for the duration of the procedure and titrated as needed to a goal ACT. If used as adjunct therapy in patients receiving thrombolytics, an infusion of 0.5 mg/kg/hr with subsequent decrease to 0.1 mg/kg/hr after 12 hours has been used with success.¹³ Dose reduction is recommended for patients with renal insufficiency.⁶ In patients with a creatinine clearance of 30–59 mL/minute, the bolus dose should be omitted and an infusion at 1.75 mg/kg/hr should be given. If the creatinine clearance is less than 30 mL/min, then the bolus dose is omitted and the initial infusion rate is reduced to 1 mg/kg/hr. Finally, in hemodialysis patients, the recommended infusion rate is 0.25 mg/kg/hr.

Although bivalirudin is not FDA-approved for the treatment of HIT, it has been utilized in the setting of HIT with or without thrombosis. ACCP guidelines recommend use of bivalirudin in patients with HIT if they require cardiac surgery intervention.⁸ In addition, due to limitations with argatroban as well as evidence suggesting equal effectiveness,¹⁴ bivalirudin is frequently used in the management of HIT in noncardiac surgery patients as well. In this setting, bivalirudin is initiated as a continuous infusion rate of 0.15–0.2 mg/kg/hr and titrated to a goal aPTT 1.5–2.5 times the baseline.⁸ The aPTT can be checked 2 hours after initiation and any subsequent dose adjustment. Like other IV DTIs, titration of bivalirudin varies by institution-specific protocols and clinical practice, but in general, when the aPTT is less than goal range, the infusion is increased by 20 percent. If the aPTT is elevated, the infusion is held for 2 hours before resuming at 50 percent infusion rate. In addition, several studies have demonstrated a reduced dose requirement in patients with renal insufficiency.^15-17 The average dose required for creatinine clearance of >60 mL/min, 30–60 mL/min, and <30 mL/min was 0.13, 0.08, and 0.05 mg/kg/hr, respectively.¹⁶ In addition, intermittent hemodialysis, sustained low-efficiency daily diafiltration, and continuous renal replacement therapy patients required 0.07, 0.09, and 0.07 mg/kg/hr, respectively. Therefore, empiric dose reduction should be strongly considered in this population. Furthermore, in critically ill patients with and without renal impairment, similar dose reductions are recommended. Observational data suggest bivalirudin can be safely initiated at 0.14 mg/kg/hr in critically ill patients with isolated hepatic impairment, 0.03–0.05 mg/kg/hr in those with renal or combined hepatic and renal impairment, and 0.03–0.04 mg/kg/hr in patients receiving continuous renal replacement therapy.¹⁸ Finally, bivalirudin should be dosed on actual body weight, even in obese individuals. In a retrospective review of 135 patients treated with bivalirudin for HIT, dosing with actual body weight was not associated with reduced effectiveness or increased adverse event rates in an obese population (body mass index >30 kg/m²).¹⁹

Bivalirudin has been administered subcutaneously for the prevention of DVT in orthopedic surgery patients who have undergone major hip or knee surgery.²⁰ In this setting, bivalirudin 1 mg/kg subcutaneously every 8 hours was more effective than lower doses (0.3–1 mg/kg every 12 hours).

LEPIRUDIN

When lepirudin was available, it was primarily used for the treatment of HIT with or without thrombosis. According to the ACCP guidelines, the initial recommended infusion rate is 0.15 mg/kg/hr with an optional initial bolus dose of 0.4 mg/kg in the case of perceived life-threatening thrombosis.²¹ A lepirudin infusion is normally adjusted to achieve a target range of aPTT 1.5–2.5 times higher than baseline.⁸ In patients with renal failure, ACCP guidelines recommend initiating the infusion at a rate based on the serum creatinine value. For a serum creatinine of <1.02 mg/dL, 1.02–1.58 mg/dL, 1.58–4.42 mg/dL, and >4.52 mg/dL, the recommended initial rate is 0.1, 0.05, 0.01, and 0.005 mg/kg/hr, respectively. Furthermore, in a small study of 10 patients receiving lepirudin during hemodialysis, doses ranged from 0.008 to 0.125 mg/kg/hr.²²

In rare clinical scenarios, lepirudin has been administered subcutaneously for the treatment of VTE. When administered in this fashion, a dose of 1.25 mg/kg given subcutaneously twice daily into the abdominal wall was found to be safe and effective.²³

MONITORING

Although IV DTIs affect prothrombin time (PT), the aPTT is used to monitor response to DTI therapy. The aPTT is prolonged during DTI therapy since thrombin inhibition leads to a decrease in platelet activation and other clotting factors activated by thrombin. Infusions of IV DTIs are normally titrated to a goal aPTT range above baseline (usually 1.5–2.5 times). It is important to note that the dose-response relationship is not linear, as a plateau of the aPTT is sometimes observed at higher doses of the DTIs. In addition, the commercially available aPTT reagents will vary in their sensitivities to each DTI. The ecarin clotting time (ECT) yields a more linear dose-response relationship, but this test is not widely available, nor has it been consistently studied in clinical trials. Furthermore, all IV DTIs affect the international normalized ratio (INR) to a variable extent specific to the DTI. At therapeutic doses, argatroban has the greatest effect on the INR. For patients transitioning to vitamin K antagonist therapy, it is recommended to continue overlap until the INR is 4 before discontinuing the argatroban infusion.⁵ Once the infusion is stopped, a repeat INR in 4–6 hours should be checked to assess the INR when therapeutic concentrations of argatroban are no longer present. Alternatively, some centers utilize testing of the factor X levels during anticoagulation bridging. If the factor X level is <45 percent, the INR value is more likely to remain above 2 when argatroban has been fully eliminated.

ADVERSE EFFECTS

The most common adverse effects reported with all IV DTIs are hemorrhagic complications. The risk of any major bleeding complication associated with intravenous DTIs was observed in clinical trials to vary from 1–11 percent.^5-7 These complications include events such as major and minor gastrointestinal bleeding, retroperitoneal bleeding, and intracranial hemorrhage. In a retrospective analysis, bleeding risk factors associated with argatroban therapy included major surgery prior to or during therapy, dosing weight >90 kg, total bilirubin >3 mg/dL, and baseline platelets ≤70,000 per mL.²⁴

In addition to bleeding, lepirudin is also associated with antibody development during therapy.⁷ Formation of antihirudin antibodies occurs in approximately 40–70 percent of patients who receive lepirudin for HIT. The antibody-lepirudin complexes can alter the pharmacokinetics of the drug, usually resulting in prolonged clearance of lepirudin. This impaired elimination may enhance the anticoagulant effect. In a prospective evaluation of patients with HIT treated with lepirudin, the development of antibodies was dependent on duration of treatment and was associated with enhanced anticoagulant effect, although no difference was noted in rates of major bleeds.²⁵

REVERSAL OF ANTICOAGULANT EFFECT OF INTRAVENOUS DTI

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