Are the days of Warfarin numbered?

Transcription

1 2 nd SAVTE Symposium Are the days of Warfarin numbered? YES Dr. Mohamed A. Abdelaal, MD, FRCPath, FRCPI Consultant Haematologist King Abdulaziz Medical City - Jeddah, Saudi Arabia 1 3 May 2012, Casablanca, Morocco

2 Disclosure: Nothing to Disclose

3 Overview Why do we need alternatives to our old friend warfarin? Review of the 3 new oral anticoagulants Approvals Cost effectiveness Monitoring/effects on anticoagulation tests Review advantages/disadvantages Retirement of Warfarin?

4 What s wrong with warfarin? 1. Narrow therapeutic range 2. Slow onset of action 3. Slow offset of action (long duration of action, long elimination half life) 4. Multiple drug and dietary interactions 5. Monitoring required Thromb Haemost 2010;103:34-39

5 What s wrong with warfarin? 6. Difficult to manage for invasive procedures 7. Impaired quality of life for the patient 8. Labor intensive for health care provider 9. Under-use of therapy due to fear of adverse events and complexity of management Thromb Haemost 2010;103:34-39

6 What s wrong with warfarin? 10. Efficacy is dependent upon infrastructure Time in therapeutic range TTR is improved with AC management programs TTR is greater in countries with more sophisticated health care infrastructure

7 What are the attributes of the 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 Warfarin is NOT an ideal OAC Thromb Haemost 2010;103:34-39

8 What are the attributes of the ideal anticoagulant? No monitoring required with ability to monitor if desired Well defined pharmacokinetics in presence of renal or hepatic disease Easily reversible Cost effective Warfarin is NOT an ideal OAC Thromb Haemost 2010;103:34-39

9 New oral anticoagulants oral anticoagulants Direct thrombin (IIa) inhibitor Dabigatran (Pradaxa) Factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban

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11 Dabigatran--basics Direct thrombin (factor IIa) inhibitor Max anticoag activity 2-3 hours after ingestion Half life hours Metabolism--conjugation Elimination--renal (80%), remainder excreted in bile Contraindicated in patients with CrCl <30ml/min Main side effect--dyspepsia (10%) Significant and sometimes fatal bleeding (FDA July 2011)

12 Dabigatran--basics Drug-drug interactions --least likely No P450 interactions P glycoprotein substrate Amiodarone (increases level by 60%), verapamil, rifampin, clarithromycin, quinidine (contraindicated) Proton pump inhibitors Reduce absorption by 20-30% No drug-food interactions Food delays absorption, not clinically significant No antidote Dialyzable

13 Dabigatran--approvals FDA indication: Non-valvular atrial fibrillation October 2010 Canada/EU Approved for post-operative thromboprophylaxis

14 Rivaroxaban--the basics Direct factor Xa inhibitor Peak plasma concentration hours after administration Half life hours Metabolism: oxidation (via CYP3A4 and CYP2J2) and hydrolysis Elimination--2/3 renal, 1/3 fecal

15 Rivaroxaban--the basics Drug interactions--most likely to have interactions CYP 3A4 and P glycoprotein substrate Drugs that are substrates for both may cause more significant interaction Ketoconazole, ritonavir, clarithromycin, erythromycin (increase levels %) Rifampicin (decrease levels 50%) Drug-food interactions Recommended to be taken with food H2blockers, antacids no effect; no info on PPIs

16 Rivaroxaban--approvals EU Approval for VTE prophylaxis after Orthopedic surgeries (THR & TKR) Canadian Approval for VTE prophylaxis after Orthopedic surgeries (THR & TKR) FDA Approval for VTE prophylaxis after Orthopedic surgeries (THR & TKR) SFDA Approval for VTE prophylaxis after Orthopedic surgeries (THR & TKR) FDA Approval for stroke prevention in AF patients EU Approval for both stroke prevention in AF patients as well as the treatment of DVT and prevention of recurrent DVT and PE.

17 Apixaban--the basics Direct factor Xa inhibitor Time to peak AC effect hours Half life hours Metabolism--oxidation (via CYP3A4) and conjugation Elimination--25% renal, 75% fecal Drug-drug interactions Likely CYP3A4 interactions, but no data available Drug-food interactions No information

18 Apixaban--approvals Not yet approved for clinical use or commercially available in the US or other countries Apixaban approval for A. Fib FDA answer delayed to 28 June 2012.

19 Monitoring of New Oral Anticoagulants Clinical signs, symptoms of bleeding, CBC The ECT (Ecarin clotting test ) is usually a better measure of anticoagulant response (higher sensitivity and accuracy in comparison to low precision and sensitivity with aptt) but ECT is not recommended a routine clinical monitoring

20 Need for monitoring Patients with low body weights or obese patients Pediatric patients Renal or hepatic impairment Accidental or deliberate overdose To measure adherence To evaluate patients with hemorrhagic or thrombotic complications? Reliable test Ther Drug Monit 2010;32:

21 Ecarin Clotting Time The Ecarin Clotting Time (ECT) is a meizothrombin generation test that can be sued to measure the activity of the direct thrombin inhibitors such as r- hirudin (lepirudin) but is likely to be useful with the introduction of new oral direct thrombin inhibitors.

22 Cost Effectiveness Perspective Society, patient, provider, payer What are the costs? Cost of the drug Cost of monitoring Cost of events Quantifiable Unquantifiable Cost of Clinic/ER visits Cost of additional Clinical Services

23 Raw Cost Comparison in SR

24 New oral anticoagulants--will they be cost effective? Cost of the new OAC is to be compared with overall cost of Warfarin therapy: Cost of drug raw Cost of the diagnostic service Cost of support service Cost of clinical services Cost of management of serious events

25 Advantages of new oral anticoagulants over VKAs Oral administration Rapid onset of action Predictable therapeutic effect with therapeutic effect with fixed dosing No routine monitoring Thromb Haemost 2010;103:34-39

26 Advantages of new oral anticoagulants over VKAs Limited or no food or drug interactions Short half-life No need for bridging for invasive procedures More convenient for the patient More convenient for physician Thromb Haemost 2010;103:34-39

27 Advantages of new oral anticoagulants over VKAs Potential for greater use Barriers are coming down with widespread use and more experience with new medications Potentially more cost effective Possible superior efficacy/safety Thromb Haemost 2010;103:34-39

28 Long term treatment with new oral anticoagulant drugs Non valvular atrial fibrillation Treatment of acute VTE Secondary prevention in patients with VTE Acute coronary syndrome (treatment during and post)

29 New anticoagulants ready to challenge WARFARIN

30 Conclusions Given the superiority in one or more aspects (efficacy, safety, ease-of-use) of novel OAC, warfarin should not remain first choice therapy for anticoagulation in patients with non-valvular atrial fibrillation and at least moderate thromboembolic risk.

31 Dear Warfarin, Time to step aside is in the horizon

32 Thank you for your attention For any correspondence:

33 Use in Special Population Pregnancy :Category C, (the drug has not been studied in pregnant woman) Lactation : unknown ( Not recommended ) Pediatrics: unknown Elderly: average age of 71 yrs old has been studied in RE-LY Renal : Renal dosage reduction is required in renal patients: patients with CrCL of ml/min : Dabigatran75 mg PO BID Patients with CrCL of less than 15 ml/min or dialysis there : NO dosage recommendation (not to be given) Hepatic impairment: unknown, patients with severe hepatic were excluded from the studies