Therapeutic Advances for the Management of Thrombosis: Navigating the New Paradigm. Formulary and Contract Manager SelectHealth

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1 Therapeutic Advances for the Management of Thrombosis: Navigating the New Paradigm Jeffrey D Dunn PharmD MBA Jeffrey D. Dunn, PharmD, MBA Formulary and Contract Manager SelectHealth

2 Faculty Disclosure The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Jeffrey D. Dunn, PharmD, MBA Consulting fees: Johnson & Johnson

3 Talking Point Evaluate recent advances in thromboprophylactic Evaluate recent advances in thromboprophylactic therapy including patient risks and benefits of emerging anticoagulants compared with standard treatments

4 Characteristics of an Ideal Anticoagulant High efficacy-tosafety index Predictable dose response (no need for monitoring) Parenteral and oral administration Rapid onset of action Antidote Minimal nonanticoagulant side effects Minimal drug-drug interactions Hirsh J, et al. Blood. 2005;105:

5 Unmet Needs in SPAF in North America Pharmacotherapy Warfarin Numerous food and drug interactions Narrow therapeutic index Burden of monitoring Slow onset of action and bridging g Unpredictable dose response Aspirin Poor alternative in patients who should receive warfarin Ansell J, et al. Chest. 2001;119:22S-38S. Hirsh J, et al. Chest. 2001;119:64S-94S. Waldo AL, et al. J Am Coll Cardiol. 2005;46: Clinical Practice Guidelines Warfarin is recommended for stroke prevention in most patients with AF but it is underused d Many physicians do not adhere to the guidelines Stroke risk stratification has had little effect on warfarin use Patient Management Elderly patients benefit most from an anticoagulant, t but are less likely l to receive it, largely because of their perceived risk of falling or bleeding Only ~50% of patients treated with warfarin are in the therapeutic range SPAF=stroke prevention of atrial fibrillation.

6 Need for New Oral Anticoagulants in the Treatment of AF The Problem (Unmet Clinical Need) 29% of all strokes are due to AF Stroke risk can be reduced by 70% with treatment Warfarin too often not used, although indicated When warfarin used, too often INR not therapeutic The Solution? Use of new, effective, and safe oral agents offers the prospect of: simplified (fixed) dosage rapid onset of action absence of need for monitoring few drug drug and drug food interactions Turpie AG. Eur Heart J. 2008;29: AF=atrial fibrillation. INR=international normalized ratio.

7 Therapies to Prevent Thromboembolism Anticoagulants Antiplatelet Agents Non-antithrombotic Drugs Vitamin K Antagonist New Anticoagulants Aspirin +/- Clopidogrel Statin Antihypertensive Antiarrhythmic Warfarin Non-warfarin Direct Factor Xa vitamin K Thrombin Inhibitors antagonists Inhibitors Apixaban Tecarfarin Ximelagatran Rivaroxaban Dabigatran Idraparinux AZD 0837 Edoxaban YM150 Betrixaban LY Left Atrial Appendage occlusion or excision Umbrella device External clip Surgical excision

8 Coagulation Cascade Initiation IX Propagation Prothrombin II Vlla/TF Xa Va IXa VllIa X Warfarin acts on II, VII, IX, and X Fibrin Formation IIa (Thrombin) TF=tissue factor. Fibrinogen Fibrin

9 Approaches to Preventing Stroke in Atrial Fibrillation 1. Thrombin Inhibitors Direct: Ximelagatran (withdrawn); Dabigatran (RE-LY completed low/high dose not inferior/superior to warfarin); Indirect: Odiparcil (withdrawn) 2. Factor Xa Inhibitors: Idraparinux (withdrawn); Apixaban (ARISTOTLE completed; AVERROES terminated); Rivaroxaban (ROCKET-AF completed); Edoxaban (ENGAGE AF ongoing) 3. Vitamin K Antagonists: Tecarfarin (EmbraceAC) 4. Antiplatelet Agents: Aspirin + Clopidogrel; ACTIVE W terminated warfarin superior; ACTIVE A completed ASA + Clopidogrel superior to ASA; Active I Irbasartan completed negative primary outcome 5. Maintain Sinus Rhythm with y Anti-arrhythmic Drugs: unpredictable efficacy; with Catheter Ablation or Surgical MAZE procedure: improving; long-term follow-up with high recurrence; most pts ineligibe; with Devices: poor efficacy 6. Left Atrial Appendage Occlusion catheter-based: PLAATO; WATCHMAN (PROTECT AF completed noninferior to warfarin; PREVAIL ongoing); surgical: LAAOS; thorascopic: Cosgrove-Gillinov Clip (ongoing) 7. Left Atrial Appendage Excision: at open heart surgery

10 RCTs of the New Anticoagulants RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 ENGAGE AF 4 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose Investigated (mg) 150, (15) 5 (2.5) 60, 30 Dose Frequency Twice daily Once daily Twice daily Once daily Drug Target Factor IIa Factor Xa Factor Xa Factor Xa Subjects (n) 18,113 14,266 ~15,000 ~21,000 Trial Design Open label Double blind Double blind Double blind Blind dose Double dummy Double dummy Double dummy Primary Efficacy Endpoint Stroke/SEE Stroke/SEE Stroke/SEE Stroke/SEE Dose Adjustment for Drug Clearance (mg) Non-inferiority Hazard Ratio Margin No Yes Yes Yes Not published Connolly SJ, et al. NEJM. 2009;361: ROCKET-AF Study Investigators. Am Heart J. 2010;159: Lopes RD, et al. Am Heart J. 2010;159: Clinicaltrials.gov. NCT RCT=randomized controlled trial. SEE=systemic embolic event.

11 Key AF Stroke Risk Factors: CHADS 2 Risk Stratification Scheme Risk Factor Points C Congestive heart failure 1 (recent) H Hypertension 1 A Age 75 years 1 D Diabetes 1 S 2 Prior stroke or TIA 2 Stroke Rate (% %) Based on 1773 NRAF Patients CHADS 2 Score Gage BF, et al. JAMA. 2001;285: NRAF=National Registry of Atrial Fibrillation. TIA=transient ischemic attack.

12 For Anticoagulation, Factor Xa May Be a Better Target Than Thrombin Has fewer functions outside of coagulation (compared with thrombin) thus expect fewer side effects Has wider therapeutic window (efficacy not associated with excessive bleeding) Thrombin inhibitors are associated with rebound thrombin generation no evidence of this with Factor Xa inhibitors Efficacy of heparin-based anticoagulants improves as selectivity for Factor Xa increases (UFH < LMWH < fondaparinux) Turpie AG. Eur Heart J. 2008;29: LMWH=low-molecular-weight heparin. UFH=unfractionated heparin.

13 Apixaban Oral, direct, selective factor Xa inhibitor Produces concentration-dependent anticoagulation No formation of reactive intermediates No organ toxicity or liver function test abnormalities in chronic toxicology studies Low likelihood of drug interactions Good oral bioavailability No food effect Balanced elimination (~25% renal) T 1/2 : ~12 hours O N N O O N N NH 2 O He K, et al. Blood. 2006;108:910. Lassen MR. Blood. 2006;108:574.

14 ARISTOTLE: Apixaban Phase III Trial AF or atrial flutter Warfarin INR, ,206 randomized E R Double-blind Apixaban 5 mg twice daily 2.5 mg twice daily in selected patients* N=5599 patients Is apixaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (stroke, at least 1 risk factor) AF/AFL patients? 1 0 efficacy endpoint: confirmed ischemic or hemorrhagic stroke, or systemic embolism 2 0 efficacy endpoints: composite of confirmed ischemic or hemorrhagic stroke, systemic embolism, and all-cause death 1 0 safety endpoint: time to first occurrence of confirmed major bleeding Treatment period: up to 4 years (until 448 primary outcome events have been observed >90% power to demonstrate non-inferiority) Stratified by warfarin-naïvenaïve status * At least 2 of the following: age 80 years, weight 60 kg, or serum creatinine 0.5 mg/dl. Lopes RD, et al. Am Heart J. 2010;159: AF=atrial fibrillation. AFL=atrial flutter. ARISTOTLE=Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation.

15 AVERROES Trial Unsuitable for warfarin therapy N=5600 E R ASA mg daily up to 36 mo/end of study Double-blind Apixaban 5 mg twice daily 2.5 mg twice daily in selected patients* up to 36 mo/end of study Is apixaban more effective than ASA in preventing stroke and systemic embolism in moderate- to high-risk (stroke, at least 1 risk factor) AF patients? 1 0 efficacy endpoint: confirmed ischemic or hemorrhagic stroke or systemic embolism 2 0 study endpoints: as above, including MI or vascular death 1 0 safety endpoint: major bleeding Study period: until 226 primary outcome events have been observed In June 2010, the study was stopped early because a predefined interim analysis revealed clear evidence of a clinically important reduction in stroke and systemic embolism * At least 2 of: age 80 years, weight 60 kg, or serum creatinine 1.5 mg/dl. Connolly SJ, et al. N Engl J Med. 2011;364: ASA=acetylsalicylic acid. AVERROES=Apixaban Versus ASA to Reduce the Risk of Stroke.

16 AVERROES Baseline Characteristics Characteristic Apixaban ASA Randomized Age (Mean and SD) 70 ±10 yrs 70 ±10 yrs Male 1661 (59%) 1615 (60%) CHADS 2 Score (Mean and SD) ± (36%) 1042 (37%) 2.1± (37%) 959 (34%) (27%) 811 (29%) Prior Stroke/TIA 389 (14%) 375 (14%) Diabetes 537 (19%) 558 (20%) Hypertension 2424 (87%) 2406 (86%) CHF 1113 (40%) 1050 (38%) Baseline ASA 2126 (76%) 2074 (74%) Prior VKA Use and Discontinued 1083 (39%) 1089 (39%) Connolly SJ, et al. N Engl J Med. 2011;364:

17 AVERROES: Stroke or Systemic Embolic Event Cumula ative Ris sk Relative e Risk= % CI, P<0.001 ASA Apixaban Number at Risk Months ASA Apixaban Connolly SJ, et al. N Engl J Med. 2011;364:

18 AVERROES: Primary Outcome Events Outcome Events Apixaban ASA Apixaban vs ASA Annual Rate Events Annual Rate RR 95% CI P- value Stroke or SEE <0.001 Stroke <0.001 Ischemic < Hemorrhagic Type Not Determined SEE Connolly SJ, et al. N Engl J Med. 2011;364: SEE=systemic embolic event.

19 AVERROES: Bleeding Events Outcome Apixaban ASA Apixaban vs ASA Events Annual Rate Events Annual Rate RR 95% CI P- value Major Clinically Relevant Non-major Minor Fatal Intra-cranial Connolly SJ, et al. N Engl J Med. 2011;364:

20 Rivaroxaban Direct specific competitive inhibitor of Factor Xa Well tolerated Half-life 5-13 hrs No direct effect on platelet aggregation Potently inhibits free and clot-associated Factor Xa activity Rapid onset of action (T max 2-4 hrs) Elimination: 1/3 renal (unchanged) 2/3 liver metabolism Low propensity p for clinically relevant drug drug g interactions Oral, once-daily dosing without need for coagulation monitoring Studied in >25,000 patients (post-op, op, deep vein thrombosis, pulmonary embolism, and acute coronary syndrome) Turpie AG. Eur Heart J. 2008;29:

21 ROCKET-AF Trial: Rivaroxaban Treatment period months Rivaroxaban 20 mg once daily Nonvalvular AF, history of stroke, TIA, or embolism, or 2 of the following: HF, HTN, age 75 years, or diabetes mellitus R N=14,264 Rivaroxaban 15 mg once daily (creatinine clearance ml/min at entry) Warfarin target INR, 2.5 (INR range: ) En nd of trea atment ow-up Foll Day 1 In AF, patients with a moderate to high risk of stroke, does rivaroxaban reduce the risk of major vascular events compared with warfarin? 1 0 study endpoint: composite of all-cause stroke and non-cns systemic embolism 2 0 endpoints: composite of TIA, all-cause death, vascular death, and MI 1 0 safety endpoint: composite of major and clinically relevant non-major bleeding events Randomization completed in June 2009; follow-up completed 2010 Follow-up: up to 4 years (until 405 primary outcome events have been observed) Day 30 after last dose ROCKET-AF=Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Nonvalvular Atrial Fibrillation. ROCKET-AF Study Investigators. Am Heart J. 2010;159: e1. HF=heart failure. HTN=hypertension. INR=interantional normalization ratio. TIA=transient ischemic attack.

22 ROCKET-AF: Baseline Demographics CHADS 2 Score (mean) 2 (%) 3 (%) 4(%) 5 (%) 6 (%) Rivaroxaban (N=7081) Warfarin (N=7090) Prior VKA Use (%) Congestive Heart Failure (%) Hypertension (%) Diabetes Mellitus (%) Prior Stroke/TIA/Embolism (%) Prior Myocardial Infarction (%) CHADS 2 =a score that estimates the risk of stroke in patients with AF and includes Congestive heart failure, Hypertension, Age 75, Diabetes mellitus, and prior incidence of Stroke or Transient Ischemic Attack. ROCKET-AF Study Investigators. Am Heart J. 2010;159: e1. AF=atrial fibrillation. TIA=transient ischemic attack. VKA=vitamin K antagonists.

23 Primary Efficacy Outcome Stroke and Non-CNS Embolism Event Rates Are per 100 Patient-Years Based on Protocol Compliant on Treatment Population Cumulati ive Event Rate (%) Event Rate Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-inferiority: < Days From Randomization No. at risk: Rivaroxaban Warfarin Mahaffey KW, et al. Presented at the American Heart Association meeting. 2010; Chicago, IL. 960

24 ROCKET-AF: Major and Non-Major Bleeding Outcome Rivaroxaban (n=7081) Warfarin (n=7090) Hazard Ratio (95% CI) P-value Major and Non-major Bleeding ( ) Major Bleeding ( ) >2 g/dl hemoglobin drop ( ) 1.44) Transfusion ( ) Critical organ bleeding ( ) Bleeding causing death ( ) Intracranial hemorrhage ( ) Califf RM, et al. Presented at the American Heart Association meeting. 2010; Chicago, IL.

25 ROCKET-AF: Summary Efficacy: Rivaroxaban was noninferior to warfarin for prevention of stroke and non-cns embolism Rivaroxaban was superior to warfarin while patients were taking study drug By intention-to-treat, rivaroxaban was noninferior to warfarin but did not achieve superiority Safety: Similar rates of bleeding and adverse events Less ICH and fatal bleeding with rivaroxaban Conclusion: Rivaroxaban is a potential alternative to warfarin for moderateor high-risk patients with AF ICH=intracranial hemorrhage. CNS=central nervous system. Mahaffey KW, et al. Presented at the American Heart Association meeting. 2010; Chicago, IL.

26 Dabigatran Etexilate Competitive inhibitor of thrombin Prodrug converted completely to active dabigatran Orally active; peak plasma concentration at 2 hours post- dose; T ½: hours Extensively metabolized, mainly by CYP3A; proton pump inhibitors reduce absorption; bioavailability is increased by meals Eliminated predominantly by kidneys (80%) Phase 2 data identified 110 mg bid and 150 mg bid as viable doses Liesenfeld KH, et al. Br J Clin Pharmacol. 2006;62: Stangier J, et al. Br J Clin Pharmacol. 2007;64: Stangier J, et al. J Clin Pharmacol. 2005;45: bid=twice daily.

27 RE-LY: A Non-inferiority Trial Atrial fibrillation 1 RiskFactor Absence of contra-indications 951 centers in 44 countries 1 0 efficacy outcome=stroke or systemic embolism 1 0 safety outcome=major bleeding Non-inferiority margin=1.46 R Performed December 2005-March 2009 Median follow-up: 2.0 years Follow-up is 99.9% complete Mean TTR=64% (patients on warfarin) Open Blinded Warfarin (INR ) n=6000 Connolly SJ, et al. N Engl J Med. 2009;361: Dabigatran Etexilate 110 mg bid Dabigatran Etexilate 150 mg bid n=6000 n=6000 n=6000 bid=twice daily. INR=international normalized ratio. RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy.

28 RE-LY: Stroke or Systemic Embolism Non-inferiority P-value Superiority P-value Dabigatran 110 mg vs Warfarin < Dabigatran 150 mg vs Warfarin <0.001 <0.001 Margin=1.46 Connolly SJ, et al. N Engl J Med. 2009;361: Dabigatran better HR (95% CI) Warfarin better

29 RE-LY: 1 0 Outcome Superiority Analysis D 110 mg D 150 mg Warfarin D 110 mg vs Warfarin D 150 mg vs Warfarin Annual Rate Annual Rate Annual Rate RR 95% CI P- value RR 95% CI P- value Stroke or Systemic Embolism 1.5% 1.1% 1.7% <0.001 Stroke 1.4% 1.0% 1.6% <0.001 Connolly SJ, et al. N Engl J Med. 2009;361:

30 RE-LY: Hemorrhagic Stroke Hazard Rates Cum mulative D 110 mg vs Warfarin D 150 mg vs Warfarin RR = % CI = RR = % CI = P <0.001 P <0.001 Warfarin Dabigatran 110 mg Dabigatran 150 mg Connolly SJ, et al. N Engl J Med. 2009;361: Years of Follow-up

31 RE-LY: Bleeding D 110 mg Annual Rate D 150 mg Warfarin D 110 mg vs Warfarin Annual Rate Annual Rate Total 14.6% 16.4% 18.2% Major 27% 2.7% 31% 3.1% 34% 3.4% Life-threatening Major 1.2% 1.5% 1.8% RR P- 95% CI value < <0.001 D 150 mg vs Warfarin RR P- 95% CI value Gastrointestinal t ti % 1.5% 1.0% 0.43 Major <0.001 Major bleeding = HGB >20 g/l, transfusion >2 units, or sympt. bleeding in a critical area or organ Connolly SJ, et al. N Engl J Med. 2009;361:

32 RE-LY: Conclusions Dabigatran 150 mg significantly reduced stroke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cerebral, life- threatening, and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding Connolly SJ, et al. N Engl J Med. 2009;361:

33 Characteristics of Edoxaban Potent and specific inhibitor of factor Xa Bioavailability over 45% Rapidly absorbed Cmax 1-2 hours Half-life of 8-10 hours Multiple l pathways of excretion: 30% renal 65% hepatic Linear PK, providing a predictable and consistent exposure Exposure to edoxaban increases with renal dysfunction & low body weight ( 60 kg) It is a substrate for the efflux transporter p-glycoprotein (P-gp) reduced dosage of edoxaban may be needed when coadministered with strong P-gp inhibitors (eg, verapamil, quinidine) Once-daily regimens associated with less bleeding than twice-daily regimens Weitz JI. Presented at the 50 th meeting of the American Society of Hematology San Francisco, CA. Ruff CT, et al. Am Heart J. 2010;160: ar

34 Edoxaban: Incidence of Bleeding Bleeding n (%) 30 mg 30 mg 60 mg 60 mg qd bid qd bid (n=235) (n=244) (n=234) (n=180) Warfarin (n=250) Major Clinically Relevant (CR) Major + CR * * 3.2 Minor Bleeds All *Statistically significant Weitz JL, et al. Thromb Haemost. 2010;104: qd=once daily. bid=twice daily.

35 ENGAGE AF TIMI 48: Edoxaban AF >20,000 patients E R Warfarin INR, Double-blindblind 3 treatment arms Edoxaban 60 mg vs 30 mg qd Is edoxaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (CHADS 2 score 2) AF patients? 1 0 efficacy endpoint: composite primary endpoint of stroke and systemic embolic events 2 0 efficacy endpoints: composite clinical outcome of stroke, systemic embolic events, and all-cause mortality; also major bleeding events Treatment period: up to 2 years ENGAGE AF-TIMI=Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation. ClinicalTrials.gov identifier NCT

36 Summary Once-daily edoxaban dosing regimens are associated with less bleeding than twice-daily regimens Edoxaban, at 30 or 60 mg qd, appears to have a safety profile similar to that of warfarin (target INR of ) INR=international normalized ratio. qd=once daily. Weitz JI, et al. Presented at the 50 th meeting of the American Society of Hematology San Francisco, CA.

37 Clinical Challenges With New Oral Anticoagulants No validated tests to measure anticoagulation effect No established therapeutic range No antidote for most agents Assessment of compliance more difficult than with vitamin K antagonists Unknown long-term safety (adverse events) Balancing cost against efficacy Lack of head-to-head studies comparing new agents Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:

38 Questions to Consider What are the new anticoagulant therapies and how do we compare them? What are the potential cost offsets and budget impact with new anticoagulant therapies? How will new therapies impact anticoagulation clinics? What is the impact of new therapies on plans operation processes? What is the anticipated impact of future indications on utilization and cost?

39 Formulary Management Considerations and Managed Care Issues Preferred agents Collaborate with providers Guidelines? Contracting opportunities? Limit to data and indications Step edits Prior authorizations PMPM and budgeting with employers Direct current costs vs cost offsets PMPM=per member, per month. Ansell J. Hematology. 2010;

40 Summary Long-term anticoagulation is recommended for AF patients However, only about 50% of patients with AF receive regular anticoagulation placing them at increased risk for stroke Warfarin reduces risk and costs associated with stroke, but only if patients adhere to their regimen Advantages of oral anticoagulants such as the DTIs or factor Xa inhibitors over warfarin include predictable therapeutic effect at fixed doses and limited drug drug interactions Oral anticoagulants may also be more cost-effective in the prevention of ischemic stroke Increasing availability of oral anticoagulants will require plans to restructure clinical and cost management policies and processes