Newer Anticoagulants

Properties of an ideal anticoagulant:

Oral administration
Rapid onset of action/rapid offset of action
Wide therapeutic range
Predictable therapeutic effect with fixed or weight-based dosing
No food or drug-drug interactions
No monitoring required (but the ability to monitor if desired)
Well defined pharmacokinetics in presence of renal/hepatic disease
Easily reversible
Cost effective

A. Direct thrombin (Factor IIa) inhibitors :

Dabigatran(Pradaxa)

Oral direct thrombin Inhibitor. In October 19, 2010 it was approved by U.S. FDA for the prevention of stroke in patients with nonvalvular AF. In February 2011 it was added by American College of Cardiology Foundation and American Heart Association to their guidelines for management of nonvalvular AF (Class IB recommendation).

Pharmacokinetics: Ingested orally it is a competitive and reversible DTI. The maximum antiticoagulant activity starts 2-3 hours after ingestion. Its half life is 12–17 hours. Dabigatran is 35% protein bound. Metabolism is by conjugation and elimination is mostly renal (80%) and biliary(20%). It is contraindicated in patients with CrCl <30ml/min.

Main side effect is dyspepsia (10%) and the disadvantage with dabigatran is that no antidote is available. Once a bottle of dabigatran is opened, the medication expires after four months because the drug is affected by humidity. Hence the bottle cap contains a desiccant to reduce the humidity

Drug interactions:

PPI’s reduce the absorption by 20-30%
Drug excretion through P-glycoprotein pumps is slowed in patients taking P-gp pump inhibitors such as Quinidine, Verapamil, Clarithromycin, Amiodarone, thus raising plasma levels of dabigatran
P-gp inducers such as Rifampicin, Carbamazepine or Phenytoin lead to decreased dabigatran concentrations
Long term anti-platelet drugs (aspirin/clopidogrel) doubles the incidence of major bleeding events
Long term NSAIDs can cause more bleeding episodes
Antidepressants such as SSRIs and SNRIs also interact with dabigatran.

Indications and dosage:

1.VTE Prophylaxis during Hip/Knee replacement

Dabigatran 110-mg capsule taken one to four hours after end of operation

Continues with 220 mg (two 110-mg capsules) OD for 28-35 days after hip replacement/for 10 days after knee replacement

Lower dose is advised in patients with

Moderate kidney problems
Patients >75 years age
Patients also taking amiodarone, quinidine or verapamil

2. Prevention of stroke in non-valvular atrial fibrillation

Dabigatran 300 mg (as 150 mg capsule BD) and should be taken long term.

Contraindications:

Severe renal impairment (Cr Cl <30 ml/min)
Deranged liver function
Active pathological bleeding /Conditions at significant risk of major bleeding

Moderate kidney problems
Patients >75 years age
Patients also taking amiodarone, quinidine or verapamil

Patients with prosthetic heart valve requiring anticoagulant treatment
Valvular heart disease as mitral stenosis
With other anticoagulants (warfarin/enoxaparin/heparin) except when switching treatment to/from dabigatran
Hypersensitivity reaction to Dabigatran
During pregnancy or lactation (not recommended)

Major trials of Dabigatran:

RE-LY (Sep 2009) – Dabigatran versus Warfarin in Patients with Atrial Fibrillation

showed that Dabigatran 110 mg had rates of stroke and systemic embolism similar to warfarin, but lower rates of major hemorrhage. Dabigatran 150 mg was associated with lower rates of stroke and systemic embolism as compared with warfarin, but similar rates of major hemorrhage.

RECOVER (Dec 2009) – Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism showed that Dabigatran 150 mg BD for the treatment of acute venous thromboembolism is as effective as warfarin with safety profile similar to warfarin and does not require laboratory monitoring.

B. Factor Xa inhibitors

Fondaparinux (Arixtra):

Fondaparinux is a synthetic pentasaccharide Factor Xa inhibitor. It mediates its effects indirectly through antithrombin III and is selective for factor Xa. Route of administration is subcutaneous.

Phrmacokinetics: Bioavailability of fondaparinux is 100% and the peak plasma time is 2-3 hrs. The half life is 17-21 hours. Fondaparinux is 94% protein bound (AT III). Metabolism of Fondapariux is by renal excretion in unchanged form. Hence, renal excretion precludes its use in patients with renal dysfunction.

The advantage of Fondaparinux over LMWH/UFH is that risk for Heparin-induced thrombocytopenia (HIT) is substantially lower.

Indications and dosage:

1. Treatment of DVT/PE:

<50 kg: 5 mg SC /Day
50-100 kg: 7.5 mg SC /Day
>100 kg: 10 mg SC /Day

2.Prophylaxis of DVT/PE:

>50 kg: 2.5 mg SC /Day

3.Heparin-Induced Thrombocytopenia

DVT prophylaxis (2.5 mg SC/Day) in patients with history of HIT

4.Acute Coronary syndrome

5 mg SC/Day

Contraindications

Severe renal impairment (CrCl <30 mL/min)
Body weight <50 kg ( VTE prophylaxis only)
Active major bleeding
Bacterial endocarditis
Thrombocytopenia with antiplatelet antibody in presence of fondaparinux
History of serious hypersensitivity reaction (i.e angioedema / anaphylactic reactions)

Major trials of Fondaparinux:

DVT Prophylaxis: In patients undergoing surgery for hip fracture, fondaparinux was found to be more effective compared to enoxaparin, and was equally safe.
MATISSE (Jun 2004): Fondaparinux vs Enoxaparin for Initial Treatment of Symptomatic DVT showed that once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily enoxaparin.
MATISSE PE (Dec 2003): Fondaparinux vs UFH for treatment of Symptomaic PE showed that once-daily unmonitored subcutaneous administration of fondaparinux is at least as effective as adjusted-dose intravenous administration of UFH. The incidence of major bleeding was similar with fondaparinux and UFH.

Rivaroxaban (Xarelto)

Rivaroxaban is an oral anticoagulant, a direct factor Xa inhibitor, and is marketed as Xarelto. On July 1, 2011, it was U.S.FDA approved for DVT / PE prophylaxis in adults undergoing hip and knee replacement surgery. On November 4, 2011, it got U.S.FDA approval for stroke prophylaxis in patients with non-valvular atrial fibrillation. On November 2, 2012, it got U.S. FDA approval for treatment of DVT and PE, as well as long-term treatment to prevent recurrence.

Pharmacokinetics: The peak plasma concentration of rivaroxaban is achieved 2.5-4 hours after oral administration. Its half life is 7-11 hours and elimination is 2/3 renal and 1/3 fecal. The metabolism is by oxidation (via CYP3A4 and CYP2J2) and hydrolysis.

The disadvantages with Rivaroxaban are that no specific antidote is available and there is no established way to reverse the anticoagulant effect in cases of serious bleeding, which can be expected to persist for 24 hours after last dose.

Prevention of VTE in orthopedic patients undergoing elective hip/knee replacement surgery – 10 mg once daily
Treatment of DVT and secondary prevention of DVT and PE – 15 mg twice daily (for the first 3 weeks) followed by 20 mg once daily (for continued treatment)
Prevention of stroke and systemic embolism in patients with AF – 20 mg once daily.

Drug interactions:

Strong dual Inhibitors of CYP3A4 and P-gp ( Ketoconazole, Itraconazole, Ritonavir, Clarithromycin) increase exposure to Rivaroxaban/risk of bleeding
Strong dual inducers of CYP3A4 and P-gp (Rifampicin, Carbamazepine, Phenytoin) decrease exposure to Rivaroxaban and increase the risk of stroke
Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID increases risk of bleeding.
There are no drug-food interactions

Contraindications :

Active bleeding, Liver disease
Risk of major bleeding, such as peptic ulcers, treatment with other anticoagulants
Pregnant/ Breast feeding women
Patients less than 18 yrs of age
Severe renal impairment (Cr Cl <15 ml/min)
Concomitant systemic treatment azole-antimycotics/ HIV protease inhibitors
Hypersensitivity to Rivaroxaban or any of the other ingredients

Major trials of Rivaroxaban:

RECORD 1,2,3 and 4 (Jun 2008): Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Knee/Hip Arthroplasty showed that a once-daily, Rivaroxaban 10-mg oral dose significantly more effective for extended thromboprophylaxis than once-daily, 40-mg s/c dose of enoxaparin in patients undergoing elective total hip/knee arthroplasty. The trial showed similar safety profiles, except in RECORD 4 where risk of bleeding was higher in patients randomized to Rivaroxaban (10 mg/day) rather than enoxaparin 30 mg twice daily.

EINSTEIN (Dec 2010): Oral Rivaroxaban for Symptomatic Venous Thromboembolism concluded that oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) offered a simple, single-drug approach to the short-term and continued treatment of VTE that may improve the benefit-to-risk profile of anticoagulation
EINSTEIN Extension (2011): Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study proved that Rivaroxaban is an effective anticoagulant agent for long-term secondary prevention of VTE in moderate to high-risk patients, without safety concerns in terms of nonbleeding adverse events
EINSTEIN PE ( Apr 2012): Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism showed that a fixed-dose regimen of rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) is noninferior to standard therapy for initial and long-term treatment of PE and had a potentially improved benefit–risk profile
ROCKET AF (Sep2011): Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation concluded that Rivaroxaban (20 mg once daily) was noninferior to warfarin for the prevention of stroke or systemic embolism. No significant between-group difference was observed in risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the Rivaroxaban group.