Oral Anti-coagulants

Presenter: Amarendra Chowdary

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin(II) Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent Factors

Affected by Oral Anticoagulants

VIIIa

Va

Va

VIIIa

Available Anticoagulants

Parenteral anticoagulants:

– Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid

– Direct thrombin inhibitors: Lepirudin, Bivalirudin

Oral anticoagulants:

– Coumarin Derivative: Bishydroxycoumarin (dicumarol), Warfarin sodium, Acenocoumarol

– Inandione derivatives: Phenindione

New oral anti coagulants

• Direct Thrombin inhibitors:

o Ximelagatron

o Dabigatran

• Factor Xa inhibitors:

o Rivaroxaban

o Apixaban

o Edoxaban

New Parenteral Anticoagulants

o Fondaparinux

o Indraparinux

o Lepirudin

o Argatroban

o Bivaluridin

OLD Oral Anti-coagulants

MOA (warfarin)

• The oral anticoagulants are antagonists of vitamin K.

• Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9 to 13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding g-carboxyglutamate(Gla) residues.

Warfarin

Synthesis of Non Functional

Coagulation Factors

Antagonismof

Vitamin K

Warfarin Mechanism of Action

Vitamin K

VII

IX

X

II

Contraindication

Drug interaction

Increased bleeding risk due to increased effect of warfarin: ➞ INR

• Antiarrhythmics - amiodarone , propafenone

• Antibiotics - amoxicillin , cephalosporins , fluoroquinolones, macrolides.

• Anticonvulsants - phenytoin ,sodium valproate

• Antidepressants -duloxetine ,venlafaxine, SSRI.

• Antifungals- fluconazole , itraconazole , ketoconazole.

• Antihyperlipidemics - Ezetimibe , fenofibrate,Atorvastatin, fluvastatin ,rosuvastatin

Decreased effect warfarin:➞INR

• Antibiotics - rifampin

• Antidepressants- trazodone

• Antiepileptics - carbamazepine , phenobarbitone ,phenytoin.

Complications

Hemorrhage- 2.7% (major- 1.1%-8.1%)

Warfarin Embryopathy -5% -30%

Warfarin necrosis- 0.02%

Osteoporosis- 0.1%

Purple toe syndrome-0.01%

Problems with warfarin

• Genotype testing for CYP2C9 and VKORC1 (FDA suggested)

• Slow onset and offset of action (TTI)

• Narrow therapeutic range

• Regular monitoring (TTR)

• Drug interactions

• Resistance

Other Oral Anti-coagulants

Phenprocoumon and Acenocoumarol

• Phenprocoumon (MARCUMAR) has a longer plasma half-life (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7 to 14 days).

• It is administered in daily maintenance doses of 0.75 to 6 mg. By contrast, acenocoumarol(SINTHROME) has a shorter half-life (10 to 24 hours), a more rapid effect on the PT, and a shorter duration of action (2 days). The maintenance dose is 1 to 8 mg daily.

Indandione Derivatives• Anisindione is available for clinical use in some countries. It is similar to warfarin in its kinetics

of action; however, it offers no clear advantages and may have a higher frequency of untoward effects.

• Phenindione still is available in some countries. Serious hypersensitivity reactions, occasionally fatal, can occur within a few weeks of starting therapy with this drug, and its use can no longer be recommended.

Newer oral Anti-coagulants

Mechanism of Action of new oral anti-coagulants

Dabigatran Etexilate

• Onset of action 0.5-2 hours

• Potent and reversible oral Direct Thrombin Inhibitor

• Inhibiting both clot bound and free thrombin

• Anticoagulation monitoring—Not required

• No food–drug interactions reported

• Dosing independent of meals or dietary restrictions

Rivaroxaban

Onset of action 2-4 hours

• No observed effects on agonist-induced platelet aggregation

• No laboratory monitoring required

• No dosage adjustment for gender, age, extreme body weight

• Approved by Europe and Canadian agencies, and FDA

Apixaban

• Peak Plasma Levels = 3 hrs

• Eliminated via multiple pathways

• No laboratory monitoring required

• Approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) and for the reduction in the risk of recurrent DVT and PE

Edoxaban

• Reversible Factor Xa

inhibitor

• Application filed for FDA

Black Box Warning

Dabigatran

Premature discontinuation

• Premature discontinuation of any oral anticoagulant, including dabigatran, increases the risk of thrombotic events

Spinal/epidural hematoma

• Epidural or spinal hematomas may occur in patients who are receiving neuraxial anesthesia or undergoing spinal puncture

• These hematomas may result in long-term or permanent paralysis

RivaroxabanEpidural or spinal hematomas

Discontinuing use for atrial fibrillation

o Premature discontinuation of anticoagulants, including rivaroxaban, places patients at increased risk for thrombotic events

Apixaban

Discontinuing in patients with nonvalvular atrial fibrillation(risk of stroke)

Spinal/epidural hematoma

Dosing and Indications

Stroke Prophylaxis With Atrial Fibrillation

• CrCl >30 mL/min: 150 mg PO BID

• CrCl 15-30 mL/min: 75 mg PO BID

Dosing modifications (atrial fibrillation)

• CrCl >30 mL/min if patient not being treated with a P-glycoprotein (P-gp) inhibitor (eg, dronedarone, ketoconazole): No dosage adjustment required

• CrCl 30-50 mL/min plus P-gp inhibitor (eg, dronedarone, ketoconazole): Decrease dose to 75 mg PO BID

• CrCl 15-30 mL/min if patient not being treated with a Pgp inhibitor: Decrease dose to 75 mg PO BID

• CrCl 15-30 mL/min plus a Pgp inhibitor: Avoid concurrent use

oCrCl <15 mL/min or dialysis: No data available; not recommended

Dabigatran Etexilate

DVT or PE Treatment

• Indicated for treatment of deep vein thrombosis (DVT) and pulmonary embolus (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days

• Also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated

• CrCl >30 mL/min: 150 mg PO BID

• CrCl <30 mL/min or on dialysis: Dosage recommendations cannot be provided

• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration

CLINICAL TRIALS WITH DABIGATRAN

AFIB –FDA approval of 150 mg bid dose, n = 18,111 :

• Re-LY: 150mg or 110mg bid vs warfarin. Event prevention - 150 mg superior p< 0.001; bleeding non-inferior to warfarin (3.1 vs 3.3%)

Acute DVT/PE Treatment – NOT FDA approved – n = 2564

• RE-COVER: 150 mg bid vs warfarin. VTE - warfarin 2.1 vs dabigatran 2.4%, p< 0.001 for non-inferiority; bleeding- warfarin 1.9 vs 1.6% dabigatran, non-inferior

Postop THA – NOT FDA approved

• RE-NOVATE I & II – 150 or 220 mg daily vs Enoxaparin 40 mg daily. Events – 150 mg 8.6%, 220mg 6%, enox 6.7% - non-inferior; bleeding, non- inferior

Postop TKA – NOT FDA approved :

RE-MODEL (non-inferior p<.003) & RE-MOBILIZE ( inferior p=.02; bleeding non- inferior

Dosing and Indications

DVT Prophylaxis (Orthopedic Surgery)Knee replacement: 10 mg PO qDay for 12 days; may take with or without foodHip replacement: 10 mg PO qDay for 35 days; may take with or without food

Nonvalvular Atrial Fibrillation

20 mg/day PO with the evening meal

DVT or PE Treatment

15 mg PO q12hr for 21 days with food, THEN 20 mg PO qDay for 6 months

Reduce risk for recurrent DVT or PE

20 mg PO qDay following initial 6 months of treatment for DVT and/or PE

Renal dosage Adjustment Required incase of renal failure

Rivaroxaban

RIVAROXABAN CLINICAL TRIALS A-fib – ROCKET AF, FDA approved

• 20 mg daily (15 mg CrCl < 30-49) vs warfarin

• Events: warfarin 2.4% vs rivaroxaban 2.1%, p< 0.001

• Bleeding: warfarin 14.5%/y vs rivaroxaban 14.9%, p=.44

THA/TKA – RECORD 1 & 2 & 3 & 4, FDA approved

• 1-3 10 mg daily vs enoxaparin 40 mg qd; 4 enox 30 mg bid

• Events: P< 0.001 for superiority of rivaroxaban in all

• Bleeding: < 1% in all, p<.18, not significant, p< .77

Medical prophylaxis – NOT FDA approved

• 10 mg vs 40 mg enox; event p=.0025 non-inf; bleeding MORE bleeding with rivaroxaban p < .001

RIVAROXABAN VTE TREATMENT TRIALS

Treatment of acute DVT (EINSTEIN DVT study)

• 15mg bid X 3wk, 20 mg daily vs enox-warfarin INR 2-3

• Events: p<.001 for non inferiority of rivaroxaban

• Bleeding: 8.1% for both, p=.77

Treatment of acute PE (EINSTEIN PE Study)

• 15mg bid X 3wk, 20 mg daily vs enox-warfarin INR 2-3

• Events: p<.003 for non inferiority of rivaroxaban

• Bleeding: 11.4% warfarin vs 10.3% warfarin p=.23

Continued treatment DVT / PE (EINSTEIN-EXT)

• 20 mg daily for additional 6-12 months AFTER initial treat

• Events: 7.1% placebo vs 1.3% riva; Bleeding 0.7% p=.11

Dosing and Indications

Stroke Prophylaxis with Atrial Fibrillation

5 mg PO BID

Postoperative Prophylaxis of DVT/PE

Initial: Give 2.5 mg PO 12-24 hr after surgery

Duration of therapy (hip replacement): 2.5 mg PO BID for 35 days

Duration of therapy (knee replacement): 2.5 mg PO BID for 12 days

DVT or PE Treatment

10 mg PO BID x 7 days, then 5 mg BID

Reduce risk for recurrent DVT or PE

2.5 mg PO BID

No Renal and Hepatic Dosage Adjustments Required

Apixaban

APIXABAN CLINICAL TRIALS

A-fib – AVERROES and ARISTOTLE, FDA approved

• ROSES - 5 mg bid vs aspirin – terminated apixaban better

ARISTOTLE – 5 mg bid vs warfarin.

• EVENT: apixaban non- inferiority p < 0.001, superiority p = 0.01

• Bleeding: apixaban 2.1% vs warfarin 3. 1%, p< 0.001

THA/TKA – ADVANCE 1 & 2 & 3 , not FDA approved

• A1- 2.5 mg bid vs enox 30 mg bid; A2&3 - enox 40 mg daily

• Events: A1 P< 0.06 non-inferior, A2 p < 0.001 superior, A3 p< 0.001 for superior. for A-1 for superiority of rivaroxaban in all

• Bleeding: A1 apixaban 2.9%, enox 4.3% p=0.03; A2 apixaban 3.5% , enox 4.8% p=.09; A3 apixaban 4.8%, enox 5% p=.72

Ximelagatran

• Ximelagatran is a novel drug that is readily absorbed after oral administration and is rapidly metabolized to melagatran, a direct thrombin inhibitor. Therefore, its onset of action is much faster than that of warfarin.

• Ximelagatran has been used successfully in clinical trials for prevention of venous thromboembolism (Francis et al., 2003; Schulman et al., 2003).

• Ximelagatran causes elevation of hepatic transaminases in about 6% of patients, but this side effect usually is asymptomatic and often is transient. The drug has not yet been approved for use in the United States

A Meta-analysis Of Randomized Trial

• Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation

Aim

• To assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes

Methods:

• Articles of Medline from Jan 1, 2009, to Nov 19, 2013,

• The main outcomes were stroke and systemic embolic events, ischaemicstroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding.

• Relative risks (RRs) and 95% CIs for each outcome was calculated. Subgroup analyses was done to assess whether differences in patient and trial characteristics affected outcomes.

• A random-effects model was employed to compare pooled outcomes and tested for heterogeneity.

Findings• New oral anticoagulants significantly reduced stroke or systemic embolic events by 19%

compared with warfarin

• New oral anticoagulants also significantly reduced all-cause mortality and intracranial hemorrhage but increased gastrointestinal bleeding.

• Noted that no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the center-based time in therapeutic range was less than 66% than when it was 66% or more.

• Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin and a more favorable bleeding profile but significantly more ischemic strokes.

Interpretation

• New oral anticoagulants had a favorable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding.

• The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients.

Interesting Discussion points

References

1. Christian T Ruff: Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials: Published Online December 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0 Lancet Article

2. GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS -11th Ed.

3. Medscape.com

4. Uptodate 20.2 version