New Oral Anticoagulants for VTE, A-fib, and ACS

Transcription

1 New Oral Anticoagulants for VTE, A-fib, and ACS KCUMB Fall CME 2014 September 18, 2014 Schoen W. Kruse, Ph.D. Assistant Dean Associate Professor of Pharmacology KCUMB

2 An 82 y/o male presents to the ED with a 2 hour history of anxiety, heart palpitations, and dizziness. He has experienced similar episodes 3 times over the past week with each resolving after roughly 15 minutes. He has a 26 yr. history of hypertension and hyperlipidemia. Current medications include lisinopril, simvastatin, and HCTZ. A 12-lead EKG is recorded and shown below. This patient is at most risk for which of the following thromboembolic events? A. Deep vein thrombosis B. Disseminated intravascular coagulation C. Pulmonary embolism D. Stroke E. Superficial venous thrombosis

3 An 82 y/o male presents to the ED with a 2 hour history of anxiety, heart palpitations, and dizziness. He has experienced similar episodes 3 times over the past week with each resolving after roughly 15 minutes. He has a 26 yr. history of hypertension and hyperlipidemia. Current medications include lisinopril, simvastatin, and HCTZ. A 12-lead EKG is recorded and shown below. This patient is at most risk for which of the following thromboembolic events? A. Deep vein thrombosis B. Disseminated intravascular coagulation C. Pulmonary embolism D. Stroke 1 E. Superficial venous thrombosis 1 Stroke. 1991;22:

4 Virchow s triad: factors contributing to thrombosis Abnormalities of blood flow Atrial fibrillation Bed rest/immobilization Left ventricular dysfunction (CHF, MI) Venous obstruction (tumor, obesity) Abnormalities of surfaces in contact with blood Acute MI Atherosclerosis Valvular disease Trauma Indwelling catheters Abnormalities of clotting components Antithrombin deficiency Estrogen therapy Factor V Leiden Malignancy Pregnancy Protein C/S deficiency

5 Anticoagulation therapy and cardiovascular disease Most of the common cardiovascular disorders in older adults involve thrombosis Ischemic heart disease Atrial fibrillation (AF) Valvular disease Atherosclerotic vascular disease Oral anticoagulation drugs are commonly indicated for: Venous thromboembolic disease (VTE, including PE and DVT) Atrial fibrillation (AF) Ischemic heart disease Cardioembolic stroke Valvular heart disease and prosthetic heart valves Peripheral artery disease Acute coronary syndromes (ACS)

6 A 76 y/o obese male was admitted to the hospital 3 days ago for management of recurrent angina. He was started on a nitroglycerin drip and confined to bed rest with gradual increases in his oral antianginal medications. On the third day of hospitalization, he notes progressive swelling and soreness of the right calf. He denies shortness of breath, cough, or chest pain. Past medical history includes coronary artery disease, MI at ages 55 and 67, and hypercholesterolemia. Current medications are diltiazem, isosorbide mononitrate, atenolol, aspirin, and simvastatin. A tender, cordlike entity is palpated in the affected area. Given your suspected diagnosis, which parenteral therapy is most likely administered? A. Apixaban B. Dabigatran C. Heparin D. Rivaroxaban E. Warfarin

7 A 76 y/o obese male was admitted to the hospital 3 days ago for management of recurrent angina. He was started on a nitroglycerin drip and confined to bed rest with gradual increases in his oral antianginal medications. On the third day of hospitalization, he notes progressive swelling and soreness of the right calf. He denies shortness of breath, cough, or chest pain. Past medical history includes coronary artery disease, MI at ages 55 and 67, and hypercholesterolemia. Current medications are diltiazem, isosorbide mononitrate, atenolol, aspirin, and simvastatin. A tender, cordlike entity is palpated in the affected area. Given your suspected diagnosis, which parenteral therapy is most likely administered? A. Apixaban B. Dabigatran C. Heparin D. Rivaroxaban E. Warfarin

8 Traditional anticoagulation Short-term: Heparin (subcutaneous) and warfarin (oral) Major limitations Narrow therapeutic window of adequate anticoagulation without bleeding Highly variable dose-response (requiring monitoring) Long-term: Warfarin Difficulties in achieving optimal anticoagulation Slow onset of action (full therapeutic effect 5-7 days) Long half-life (40 hrs) Variable pharmacologic effects (polymorphisms in CYP2C9 and VKORC1) Numerous food and drug interactions

9 Warfarin Approved in 1954 MOA: inhibits vitamin K epoxide reductase complex I (VKORC1) depleting vitamin K reserves Vitamin K is an essential cofactor required for coagulation; decreases in vitamin K results in decreased coagulation Biotransformation by CYP2C9

10 Warfarin dose affected by genetics, food, and drugs Vitamin K epoxide reductase complex I (VKORC1) and CYP2C9 polymorphisms VKORC1 Range 1 of Expected Therapeutic Maintenance Dose Based on CYP2C9 2 and VKORC1 3 Genotypes CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg mg mg AA 3-4 mg 3-4 mg mg mg mg mg Note: Must also take into account other patient related factors when determining initial dose (e.g., age, body weight, concomitant medications, comorbidities). The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt, 2012). 1 Ranges derived from multiple published clinical studies. 2 Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen. 3 VKORC1-1639G>A (rs ) variant is used in this table; other VKORC1 variants may also be important determinants of dose. Foods rich in vitamin K: kale, spinach, brussels sprouts, broccoli, asparagus, prunes Drugs that affect CYP450 enzymes substrates, inhibitors, inducers

11 What are qualities of the ideal oral anticoagulant? Broad therapeutic window Predictable effects without need for monitoring No food and drug interactions Short plasma half-life Safe, with low or no adverse effects Low inter- and intra-patient variability No need for parenteral to oral switch Use as single agent in acute and chronic indications and in both the hospital and home settings Easily reversible with or without an antidote

12 New oral anticoagulants (NOAs) Since October 2010, the US FDA has approved 3 new oral anticoagulants Mechanism Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor Direct Xa inhibitor Brand Name Pradaxa Xarelto Eliquis Approval status in US 10/2010: stroke prevention in nonvalvular AF 7/2011: VTE prophylaxis in ortho surgery Direct Xa inhibitor 12/2012: stroke prevention in nonvalvular AF 4/2014: initial and extended treatment of VTE and PE 11/2012: stroke prevention in nonvalvular AF; initial and extended treatment of VTE 3/2014: VTE prophylaxis in ortho surgery *adapted from A. Wittkowski, University of Washington

13 Summary of clinical trial information of NOAs Phase 3 trials of NOAs compared with warfarin show: Statistically significant reductions in the following primary outcomes Stroke or systemic embolism (18% relative reduction) All-cause mortality (9%) Hemorrhagic stroke (49%) As good as, if not more effective, than warfarin However NOAs should not be considered superior in the absence of additional direct comparisons and treatment decisions must be individualized

14 Since October 2010, the US FDA has approved 3 new oral anticoagulants Mechanism Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor Direct Xa inhibitor Brand Name Pradaxa Xarelto Eliquis Approval status in US New oral anticoagulants (NOAs) 10/2010: stroke prevention in nonvalvular AF 7/2011: VTE prophylaxis in ortho surgery Direct Xa inhibitor 12/2012: stroke prevention in nonvalvular AF 4/2014: initial and extended treatment of VTE and PE 11/2012: stroke prevention in nonvalvular AF; initial and extended treatment of VTE 3/2014: VTE prophylaxis in ortho surgery *adapted from A. Wittkowski, University of Washington

15 Dabigatran and coagulation cascade Prodrug lacking anticoagulant activity that is converted in vivo to the active dabigatran MOA: specific, reversible, direct thrombin inhibitor Inhibits coagulation by preventing thrombin-mediated effects, including cleavage of fibrinogen to fibrin monomers, activation of factors V, VIII, XI, and XIII, and inhibition of thrombin-induced platelet aggregation Henry's Clinical Diagnosis and Management by Laboratory Methods,

16 Dabigatran indications for use Deep venous thrombosis and pulmonary embolism treatment and prevention: Treatment of deep venous thrombosis (DVT) and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days To reduce the risk of recurrence of DVT and pulmonary embolism in patients who have been previously treated Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)

17 Dabigatran pharmacokinetics Peak effect Half-life Metabolism Elimination Bioavailability Available dose 2 hours hours 28 hours in severe renal impairment Hepatic (no CYP450 interaction) 80% renal 20% fecal 3-7% (increases to 75% when taken without capsule shell) 75 mg, 150 mg

18 Renal impairment affects dabigatran dose In response to a single 150 mg dose: Renal Function CrCl (ml/min) Increase in AUC Increase in C max t 1/2 (h) Normal 80 1x 1x 13 Mild x 1.1x 15 Moderate x 1.7x 18 Severe x 2.1x 27 DVT and PE: 150 mg twice daily (after 5-10 days of parenteral anticoagulation) Nonvalvular AF (to prevent stroke and systemic embolism): 150 mg twice daily CrCl > 30 ml/min: CrCl 15 to 30 ml/min: CrCl < 15 ml/min or on dialysis: No dosing adjustments for hepatic impairment 150 mg twice daily 75 mg twice daily not recommended

19 Adverse effects Bleeding/hemorrhage GI Dyspepsia, epigastric discomfort, GERD Dabigatran Drug-drug interactions P-glycoprotein substrate P-gp inhibitors increase serum concentrations (amiodarone, verapamil, clarithromycin, ketoconazole) P-gp inducers decrease serum concentrations (rifampin, carbamazepine, phenytoin) Drugs that affect coagulation Contraindications Patients with mechanical prosthetic heart valves

20 New oral anticoagulants (NOAs) Since October 2010, the US FDA has approved 3 new oral anticoagulants Mechanism Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor Direct Xa inhibitor Brand Name Pradaxa Xarelto Eliquis Approval status in US 10/2010: stroke prevention in nonvalvular AF 7/2011: VTE prophylaxis in ortho surgery Direct Xa inhibitor 12/2012: stroke prevention in nonvalvular AF 4/2014: initial and extended treatment of VTE and PE 11/2012: stroke prevention in nonvalvular AF; initial and extended treatment of VTE 3/2014: VTE prophylaxis in ortho surgery *adapted from A. Wittkowski, University of Washington

21 Rivaroxaban and apixaban MOA: specific, reversible, inhibitor of factor Xa Henry's Clinical Diagnosis and Management by Laboratory Methods,

22 Rivaroxaban and apixaban indications for use Rivaroxaban is indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for the treatment of DVT, PE, and for the reduction in the risk of recurrence of DVT and of PE for the prophylaxis of DVT, which may lead to PE, in patients undergoing knee or hip replacement surgery Apixaban is indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for the prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or knee replacement surgery

23 Rivaroxaban and apixaban pharmacokinetics Rivaroxaban Apixaban Peak effect 2-4 hours 3-4 hours Half-life Metabolism Elimination 5-9 hours 9-13 hours (elderly) Hepatic, mainly via CYP3A4/5 and CYP2J2 66% renal 33% fecal Bioavailability >80% 50% hours Hepatic, mainly via CYP3A4 27% renal 63% fecal Available dose 10 mg, 15 mg, 20 mg 2.5 mg, 5 mg

24 Dosage and administration Rivaroxaban: recommended dose for most patients is 20 mg once daily CrCl > 50 ml/min CrCl ml/min CrCl < 15 ml/min 20 mg once daily 10 mg once daily Do not use Prophylaxis of DVT/PE following surgery - 10 mg once daily No clinical data are available for patients with severe hepatic impairment. Apixaban: recommended dose for most patients is 5 mg taken twice daily Serum creatinine 1.5 mg/dl and either age 80 years or body weight 60 kg: 2.5 mg twice daily Prophylaxis of DVT/PE following surgery mg twice daily No dose adjustment is required in patients with mild hepatic impairment.

25 Adverse effects Bleeding/hemorrhage Rivaroxaban and apixaban Drug-drug interactions P-glycoprotein and CYP3A4 substrate P-gp and CYP3A4 inhibitors increase serum concentrations (erythromycin, ritonavir, clarithromycin, ketoconazole) P-gp and CYP3A4 inducers decrease serum concentrations (rifampin, carbamazepine, phenytoin) Drugs that affect coagulation Contraindications No major

26 Reversal of new oral anticoagulants

27 Reversal of new oral anticoagulants Charcoal or gastric lavage (must be within 2-3 hours of drug administration) Dabigatran is able to be removed by hemodialysis (~57% over 4 hours*); rivaroxaban and apixaban are not due to high protein binding Replace clotting factors (limited literature to support use) 3-factor prothrombin complex concentrate (PCC) (Bebulin ) 4-factor PCC (Kcentra ) Activated PCC (FEIBA ) Recombinant factor VIIa (NovoSeven ) Drug inactivation not commercially available Idarucizumab binds specifically to and inhibits dabigatran (phase 3) *

28 Characteristic Warfarin Dabigatran Rivaroxaban Apixaban Target Vitamin K epoxide reductase Factor IIa (free and clotbound thrombin) Factor Xa Prodrug No Yes No No Bioavailability (%) > >80 50 Metabolism Plasma protein binding (%) Hepatic, mainly via Hepatic (no CYP450) CYP2C9, CYP1A2, CYP3A4 Hepatic, mainly via CYP3A4/5 and CYP2J (primarily albumin) Half-life (h) (elderly) Peak effect (h) Elimination 92% renal 80% renal 20% fecal 66% renal 33% fecal Factor Xa Hepatic, mainly via CYP3A % renal 63% fecal Monitoring INR adjusted Not needed Not needed Not needed Drug interactions CYP2C9, CYP1A2, and CYP3A4 P-gp inducers/inhibitors CYP3A4 and P-gp inducers/inhibitors Antidote Vitamin K None None None Reversal via hemodialysis No Yes No No CYP3A4 and P-gp inducers/inhibitors CYP = cytochrome; INR = international normalized ratio; P-gp = P-glycoprotein; Mayo Clin Proc. 2013

29 Which drug is best for your patient?? Warfarin Candidate INR monitoring not burdensome INR monitoring gives reassurance Unable to accept NOA Agent with antidote Renal impairment Interacting drugs that require INR monitoring NOA Candidate INR monitoring inconvenient Good adherence Accepting of NOA cost Limited bleeding risk Good renal function Vitamin K stability difficult to manage *adapted from A. Wittkowski, University of Washington

30 A 62 y/o male neurosurgeon presents to the ED with a 2 hour history of anxiety, heart palpitations, and dizziness. He has experienced similar episodes 3 times over the past week with each resolving after roughly 15 minutes. He has a 15 yr. history of hypertension and 5 yr. history of hyperlipidemia. Current medications include lisinopril, simvastatin, HCTZ, and OTC St. John s wort. A 12-lead EKG is recorded and supports a diagnosis of atrial fibrillation. Renal function is normal. He is overweight, but not obese, and admits to having difficulty maintaining a stable diet. Which oral anticoagulant is the best choice for this patient? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin

31 A 62 y/o male neurosurgeon presents to the ED with a 2 hour history of anxiety, heart palpitations, and dizziness. He has experienced similar episodes 3 times over the past week with each resolving after roughly 15 minutes. He has a 15 yr. history of hypertension and 5 yr. history of hyperlipidemia. Current medications include lisinopril, simvastatin, HCTZ, and OTC St. John s wort. A 12-lead EKG is recorded and supports a diagnosis of atrial fibrillation. Renal function is normal. He is overweight, but not obese, and admits to having difficulty maintaining a stable diet. Which oral anticoagulant is the best choice for this patient? A. Apixaban B. Dabigatran C. Rivaroxaban D. Warfarin

32 Conclusions Dabigatran, rivaroxaban, and apixaban all appear to be effective and safe for treatment of acute venous thromboembolism (use in older and sicker patients is more limited) NOAs do not require INR monitoring No dietary restrictions Short half-lives increase the risk of thrombosis with missed doses No specific antidote to reverse their anticoagulant effect

33 References 1. Stroke. 1991;22: Hurst s The Heart, 13 th Ed. 4. New England Journal of Medicine. 2011; : Applied Therapeutics, 9 th Ed. 6. Henry's Clinical Diagnosis and Management by Laboratory Methods, Heidbuchel H et al. Euro Heart Journal 2013; 15: Heart. 2014; 100(5): The Medical Letter on Drugs and Therapeutics, January 6, 2014 (Issue 1433)