Capri Cardiovascular Conference 2.0 Capri, marzo 2014

Transcription

1 Capri Cardiovascular Conference 2.0 Capri, marzo 2014 Web Round Table Rivaroxaban nella fibrillazione atriale e oltre 29 marzo ore 9:30-10:45 Rivaroxaban ed il valore della monosomministrazione nella prevenzione dell ictus da FA Raffaele De Caterina Università G. d Annunzio Chieti e Fondazione G. Monasterio Pisa, Italia 29 marzo 2014, 9:30-9:50 + disc.

2 Prof. Raffaele De Caterina Disclosures Co-author ESC Guidelines on Atrial Fibrillation Steering Committee member, National Coordinator for Italy, and Co-author of APPRAISE-2, ARISTOTLE, AVERROES National Coordinator for Italy of ENGAGE-AF Fees, honoraria and research funding from Sanofi- Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi-Sankyo, Lilly

3 Features of novel oral anticoagulants Dabigatran 1 Rivaroxaban 1,2 Apixaban 1,3 Edoxaban 4-6 Target IIa (thrombin) Xa Xa Xa Hours to Cmax CYP metabolism None 32% Minimal <4% Bioavailability 6% 80% 60% 62% Transporters P-gp P-gp/BCRP P-gp/ BCRP P-gp Protein binding 35% 93% 87% 50% Half-life h 7-11 h 8-15 h 8-10 h Renal elimination 80%* 33% # 25% # 35% # BCRP, breast cancer resistance protein CYP, cytochrome P450; P-gp, P-glycoprotein NR, not reported * Of absorbed substance # Of ingested substance 1. Eriksson et al. Clin Pharmacokinet 2009;48:1-22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011; 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics in Cardiology 2009;18:1-32; 5. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 6. Ogata et al. J Clin Pharmacol 2010;50:743-53

4 Pharmacokinetics of rivaroxaban vs other NOACs Relatively similar time-to-peak Relatively similar half-life and yet, once daily administration chosen for several rivaroxaban indications (and for edoxaban), while twice daily administration chosen for the development of dabigatran etexilate and apixaban

5 Established/possible rivaroxaban dosing regimens according to indications Indication Rivaroxaban dose Duration VTE prevention after orthopaedic surgery Stroke prevention in AF 10 mg od 2 weeks (total knee replacement) 20 mg od (15 mg od in patients with moderate renal impairment*) 5 weeks (total hip replacement) As long as risk factors persist VTE treatment 15 mg bid First 3 weeks 20 mg od (15 mg od in patients with moderate renal impairment*) As long as risk factors persist ACS 2.5 mg bid (pending approval) Pending approval # *Creatinine clearance (CrCl) ml/min; to be administered with food ACS, acute coronary syndromes; AF, atrial fibrillation; bid, twice daily; od, once daily # Treatment durations in ATLAS TIMI 51: mean: 13 months, max.: 31 months

6 Once vs twice daily an important choice! The choice of the dose and regimen of administration is crucial in drug development Dose selection has to consider all elements maximizing efficacy while preserving safety It is selected in phase II studies ideally, but not always in the same patient population to whom the drug should be given Everything else being equal, patient s convenience (e.g., once daily dosing) is taken into account, as it increases adherence Adherence to the selected drug dosing is a major factor in the difference between a registration clinical trial and the actual post-marketing use of the drug

7 Influence of PK and PD parameters on dosing regimens The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the new oral anticoagulants provide the opportunity for either od or bid dosing Determination of the optimal dosing regimen must be based on assessment of benefit (reduction in thrombotic events) versus risk (increase in bleeding events) in clinical studies

8 Rivaroxaban C max (μg/l) Rivaroxaban C valle (μg/l) Rivaroxaban dosing: ample overlap between od and bid regimens C max C through Bid study Od study Bid study Od study Dose giornaliera di rivaroxaban (mg) Dose giornaliera di rivaroxaban (mg) Maximum (C max ) and minimum (C valle ) plasma concentrations of rivaroxaban in bid and od studies, with 25 th and 75 th percentiles (horizontal lines) and 5 th and 95 th percentiles (circles) Mueck et al, 2008

9 Rivaroxaban AUC 0 24, µg h/l Concentrazione plasmatica di rivaroxaban (µg/l) Rivaroxaban od vs bid 250 Rivaroxaban 20 mg od 250 Rivaroxaban 10 mg bid C peak C through Tempo (giorni) Mueck et al, mg od 10 mg bid

10 Therefore the minimum concentration achieved at 24 h is always sufficient to maintain a certain degree of inhibition of FXa Rivaroxaban: pharmacodynamics OD regimen Rivaroxaban (MW nm = ng/ml) inhibits: Free FXa activity = IC nm Prothrombinase activity = IC nm C trough (after 24 h) with 10 mg ng/ml [ nm] C trough (after 24 h) with 20 mg ng/ml [ nm]

11 Dosing considerations: Clot type Venous/venous-like versus arterial Indication Prophylaxis versus treatment/secondary prevention Co-medications use e.g. antiplatelet therapy for ACS Timing/intensity High pressure for treatment versus lower pressure for prophylaxis Compliance od versus bid dosing Renal function Dose adjustment for renally impaired patients

12 Why use different doses? Pathophysiology of the clot Arterial Thrombosis Venous Platelet-rich clot (platelets and coagulation) Fibrin-rich clot (coagulation)

13 Arterial vs venous thrombi Venous clots (DVT, PE) AF clots Clot type Venous Venous-like Composition Fibrin rich Fibrin rich Size Large Large Growth Slow Slow Location Large venous vessels Atria (usually left appendage) Potential outcome PE Ischaemic stroke Antiplatelet therapy required No Not recommended *Usually rapid response to plaque rupture

14 CUS and PLS CUS and PLS CUS Follow-up Phase II studies with rivaroxaban in DVT treatment: ODIXa-DVT ed EINSTEIN DVT ODIXa-DVT 1 CUS + PLS Open label 613 patients randomized Double blind R Enoxaparin (1 mg/kg) VKA Rivaroxaban 10 mg bid 20 mg bid 30 mg bid 40 mg od INR EINSTEIN DVT 2 Open label CUS 543 patients + PLS R randomized Double blind Day 1 Days 5 7 Day 21 Day 84 Day 114 LMWH/heparin VKA Rivaroxaban 20 mg od 30 mg od 40 mg od INR Agnelli G et al. Circulation 2007;116: ; 2. Büller HR et al. Blood 2008;112: CUS = compression ultrasound; PLS= perfusion lung scan Day 1 Day 5 Day 84

15 Rate of deterioration (%) Rate of thrombus regression without recurrent VTE (%) Phase II studies in DVT treatment efficacy ODIXa-DVT 1 : rivaroxaban showed similar efficacy to standard therapy 80 bid rivaroxaban doses od rivaroxaban dose Rivaroxaban total daily dose (mg) Enoxaparin/VKA EINSTEIN DVT (phase II) 2 : rivaroxaban showed similar efficacy to standard therapy 20 Recurrent DVT or PE, VTE-related death od rivaroxaban dose 16 and deterioration in CUS or PLS Rivaroxaban total daily dose (mg) 1. Agnelli et al, 2007; 2. Büller et al, 2008 LMWH/VKA CUS, compression ultrasound; LMWH, low molecular weight heparin; PLS, perfusion lung scan; VKA, vitamin K antagonist

16 Phase II studies in DVT treatment safety ODIXa-DVT 1 Results after 12 weeks treatment Rivaroxaban dose Enoxaparin/VKA 10 mg bid 20 mg bid 30 mg bid 40 mg od Any event, %* Major bleeding, % # *Incidence of recurrent DVT, PE (non-fatal) and VTE-related death up to day 84 (+14): ITT population (n=543); # Incidence of bleeding events occurring <2 days after last dose of study drug: safety population (n=604) EINSTEIN DVT 2 LMWH/VKA Rivaroxaban dose 20 mg od 30 mg od 40 mg od Symptomatic events, % Major bleeding, % Incidence of composite of symptomatic recurrent DVT, symptomatic fatal or non-fatal PE and asymptomatic deterioration in thrombotic burden (n=449); Safety population (n=542) ITT, intention to treat 1. Agnelli et al, 2007; 2. Büller et al, 2008

17 Dose finding studies for DVT treatment and stroke prevention in atrial fibrillation Similar pathophysiology (clot-type) for DVT and AF clots Identical long-term treatment approach: Anticoagulation with VKAs target INR Evaluation in DVT treatment phase II studies for rivaroxaban Use of the identified dose in phase III SPAF study* *An additional dose finding trial in SPAF on top of available data would have been redundant and was considered unethical.

18 Dosing considerations: summary Clot type Venous/venous-like versus arterial Indication Prophylaxis versus treatment/secondary prevention Co-medications use e.g. antiplatelet therapy for ACS Timing/intensity High pressure for treatment versus lower pressure for prophylaxis Compliance od versus bid dosing Renal function Dose adjustment for renally impaired patients

19 Compliance to therapy Poor adherence accounts for substantial worsening of Disease Death Increased health care costs In the USA, it has been estimated that 33-69% of all medication related hospital admission are due to poor medication adherence. The resultant cost of non-compliance is approximately $100 billion/yr Osterberg et al. N Engl J Med 2005;353:487-97; Song et al. Am J Cardiovasc Drugs 2012; 12 (4):

20 Factors related to compliance Barriers to adherence (patients survey): Forget Other priorities Decision to quit dose Lack of information Emotional reasons Improve adherence: Emphasizing value of regimen Simple regimen Adapt regimen to patient s lifestyle Osterberg et Osterberg al. N Engl J et Med al. 2005;353:487-97; N Engl J Med 2005;353:487-97; Song et al. Am J Cardiovasc Song et Drugs al. Am 2012; J 12 Cardiovasc (4): Drugs 2012; 12 (4):

21 Compliance with od versus bid regimens is generally better for chronic conditions Number of studies Number of studies that directly assessed compliance od > bid* od = bid # od < bid *Patient compliance (assessed in study) with od regimen is significantly better than with bid regimen # No significant difference in patient compliance (assessed in study) between od and bid regimens Patient compliance (assessed in study) with bid regimen is significantly better than with od regimen Pubmed search; March

22 No doubts that in AF patients compliance to therapy is better with OD than with BID dosing

23 Can there be other reasons for once vs twice daily dosing? Could it be that once daily is also safer than twice daily?

24 Edoxaban phase II dose finding study in atrial fibrillation: design Study design: Randomised, double blind edoxaban dose regimens, open-label warfarin, parallel treatment groups Primary endpoints: Occurrence of major and/or clinically relevant non-major bleeding, elevated hepatic enzymes and/or bilirubin Screening N= days R a n d o m i s a t i o n Day 1 Edoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID* Active control (Warfarin, INR ) 3-month randomised treatment period *Stopped prematurely QD, once daily; BID, twice daily; INR, International Normalised Ratio Follow-up assessment +30 days after last dose Weitz et al. Thromb Haemost 2010;104:633-41

25 Bleeding incidence (%) Edoxaban Phase II dose finding study in atrial fibrillation: major and clinically relevant non-major bleeding Same total daily dose * ** Warfarin Edoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID n/n 8/250 7/235 11/234 19/244 19/180 *p<0.05, **p<0.01, vs warfarin QD, once daily; BID, twice daily Weitz et al. Thromb Haemost 2010;104:633-41

26 Bleeding incidence, % ng/ml Ng*h/mL ng/ml Edoxaban phase II dose finding study in atrial fibrillation: exposure and bleeding C max AUC C min QD 60 QD 30 BID 60 BID 30 QD 60 QD 30 BID 60 BID 0 30 QD 60 QD 30 BID 60 BID AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state; C max, maximum steady-state plasma concentration; C min, minimum steady-state concentration; QD, once daily; BID, twice daily QD Edoxaban 60 QD 30 BID 60 BID Weitz et al. Thromb Haemost 2010;104:633-41

27 Bleeding incidence, % ng/ml Edoxaban phase II dose finding study in atrial fibrillation: exposure and bleeding C min QD 60 QD 30 BID 60 BID AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state; C max, maximum steady-state plasma concentration; C min, minimum steady-state concentration; QD, once daily; BID, twice daily QD Edoxaban 60 QD 30 BID 60 BID Weitz et al. Thromb Haemost 2010;104:633-41

28 Cumulative risk (%) 25 RUBY-1: cumulative risk of major and clinically relevant non-major bleeding and any bleeding events at 6 months (safety analysis set) Major and CRNM bleeding Any bleeding mg 10mg 15mg 30mg 30mg 60mg Placebo 5mg 10mg 15mg 30mg 30mg 60mg Placebo BID QD BID QD BID QD BID QD BID QD BID QD (n=159) (n=159) (n=159) (n=156) (n=153) (n=153) (n=319) (n=159) (n=159) (n=159) (n=156) (n=153) (n=153) (n=319) CRNM, clinically relevant non-major BID, twice daily; QD, once daily Darexaban Steg et al. Eur Heart J 2011;32:2541 4

29 Therefore (conclusions): OD therapy in long-term stroke prevention in atrial fibrillation: Appears to be as effective as BID Appears to be as safe as BID It might actually be safer than BID (indirect evidence from other anticoagulants) It is certainly more appealing for the patient

30 In unselected patients in daily care: treatment adherence was high with 90.7% of patients still taking rivaroxaban at 9 month (follow up by phone visits by the registry office) Rivaroxaban is effective and safe with low rates of cardiovascular or major bleeding events Beyer-Westendorf J. et al. Eur Heart J ESC Congress 2013 Abstracts

31 Renda G. and De Caterina R. Vascul Pharmacol 2013;59:53-62 Renda G. and De Caterina R. Topics/2013/12/New-Oral-Anticoagulants-in-Atrial- Fibrillation.aspx

32 Thank you! Grazie!