Novel Oral Anticoagulants and Warfarin Comparative evidence and Information for Prescribers

Transcription

1 Novel Oral Anticoagulants and Warfarin Comparative evidence and Information for Prescribers How does it work? Dose and Administration Monitoring Warfarin Dabigatran Rivaroxaban Apixaban Warfarin has an effect Acts as a direct thrombin (factor IIa) on several steps of the inhibitor. It is formulated as clotting cascade using dabigatran etexilate, a pro-drug, compounds made with and converted to dabigatran after vitamin K by the liver. administration 2. Variable dose taken once daily, dose adjustment dependent on INR Needs to be adjusted to the individual needs of the patient and therefore requires regular monitoring using blood tests. Patients under 80 years - 150mg twice daily 2 Patients >80 years - 110mg twice daily 2 (due to the increased risk of bleeding in this population) Consider 110 mg twice daily when the bleeding risk is high and the thromboembolic risk is low, patients weighing <50kg, patients 75-80yrs, CrCl ml/min and patients taking concomitant verapamil 2. Available in two strengths which have predictable effects, meaning that the drug does not need the same level of monitoring as warfarin. Renal function should be assessed in all patients before starting dabigatran and at least once a year in patients >75 years or those with a suspected decline in renal function 5. A number of cases of serious and fatal haemorrhage have been reported in elderly patients with renal impairment who were receiving dabigatran. Acts as a selective direct factor Xa inhibitor. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi mg once daily 10 15mg once daily when CrCl is ml/min 10 Available in two strengths which have predictable effects, meaning that the drug does not need the same level of monitoring as warfarin. Annual renal function assessment is recommended to assess appropriate dose is being prescribed. Acts as a selective direct factor Xa inhibitor which interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting thrombin and the development of thrombi 13 5mg twice daily 2.5mg twice daily in patients with at least two of: age 80 years, body weight 60 kg, or serum creatinine 1.5 mg/dl (133 micromole/l) 2.5mg twice daily for patients with creatinine clearance ml/min 13. Available in two strengths which have predictable effects, so the drug does not need the same level of monitoring as warfarin. Check LFTs before prescribing 13. Annual renal function assessment is recommended to assess appropriate dose is being prescribed.

2 Warfarin Dabigatran Rivaroxaban Apixaban What is the evidence? In a meta-analysis 1 the relative risk reduction (RRR) of stroke with warfarin was highly significant and amounted to 64%, corresponding to an absolute annual risk reduction in all strokes of 2.7%. When only ischaemic strokes were considered, adjusteddose VKA use was associated with a 67% RRR. This reduction was similar for both primary and secondary prevention and for both disabling and non disabling strokes. The RE-LY study 6 enrolled 18,113 patients with AF, who were at increased risk of stroke. 50% of patients were naïve to oral anticoagulants. It was a prospective, open-label, blinded endpoint (PROBE) design. Average CHADS 2 score of 2. Dabigatran 150mg bd reduced the annual absolute risk of stroke or systemic embolism by 0.6% compared with warfarin (35% RRR; NNT = 167; out of a 1000 patients treated with dabigatran 150mg bd instead of warfarin, a further 6 strokes were prevented) and by 0.43% (10% RRR) compared with dabigatran 110mg bd. Both haemorrhagic and ischaemic stroke occurred less often in the dabigatran 150mg bd group than with warfarin. Dabigatran 110mg bd was noninferior to warfarin. Compared with warfarin, dabigatran 110mg bd significantly reduced the incidence of haemorrhagic, but not ischaemic stroke. ROCKET-AF 11 was a double-blind, double dummy randomized trial that enrolled 14,264 patients to either rivaroxaban 20mg od or warfarin with a target INR 2-3. Patients were moderate to high risk of stroke (mean CHADS 2 >3). Patients received r i v a r o x a b a n 20mg od (15mg od if CrCl 30-49mls/min) or warfarin. Rivaroxaban was found to be noninferior to warfarin for the prevention of stroke and systemic embolism in both the per-protocol and intention-to-treat (ITT) analysis. In the ITT analysis 2.1 events were recorded per 100 patientyears in the rivaroxaban group compared to 2.4 events with warfarin (HR 0.88, 95% CI 0.75to 1.03, p<0.001). A superiority test did not reach statistical significance in the ITT population, but did in the safety population. In the ITT population, 30% of outcome events in the rivaroxaban arm occurred after discontinuation of treatment, compared with 22% of events in the warfarin arm. ARISTOTLE 14 was a non inferiority, randomised, double blind, double dummy trial that enrolled 18,201 patients to apixaban or warfarin with a target INR 2-3. Patients had a mean CHADS 2 of 2.1. Apixaban was found to meet the pre-specified endpoint for noninferiority to warfarin, and also demonstrated superiority. After a median follow up of 1.8 years, the annual rates of the composite primary endpoint of stroke or systemic embolism were 1.27% for apixaban and 1.6% for warfarin. Each of the annual rates of intra-cranial bleeding, major or clinically relevant non-major bleeding, and any bleeding were significantly lower with apixaban than warfarin

3 Warfarin Dabigatran Rivaroxaban Apixaban Contraindications Safety Hypersensitivity to the active substance or to any of the excipients. Haemorrhagic stroke Clinically significant bleeding Within 72 hours of major surgery with risk of severe bleeding (for information on other surgery see SPC) 1 st and 3 rd trimester of pregnancy and within 48 hours postpartum Long-term safety based on >50 years use in clinical practice. Hypersensitivity to the active substance or to any of the excipients. 2 Severe renal impairment (CrCL < 30 ml/min) Active clinically significant bleeding Organic lesion at risk of bleeding Spontaneous or pharmacological impairment of haemostasis Hepatic impairment or liver disease expected to have any impact on survival Pregnancy and breastfeeding No information available on longterm safety Cannot be used if CrCl <30mls/min. Hypersensitivity to the active substance or to any of the excipients. Clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. Pregnancy and breast feeding CrCl <15mls/min 10 No information available on longterm safety. If CrCl 15-49mls/min a reduced dose is recommended 10. Cannot be used if CrCl<15ml/min Hypersensitivity to the active substance or to any of the excipients. Clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Lesion or condition at significant risk of major bleeding. Concomitant treatment with any other anticoagulant agent. CrCl <15ml/min Severe hepatic impairment Pregnancy and breast feeding13 No information available on longterm safety. If CrCl ml/min 13, a reduced dose is recommended. Cannot be used if CrCl<15ml/min Reversibility Effective and well known antidote, should a severe bleed occur whilst being treated No antidotes currently known. Patients with bleeding risk factors were excluded from RE-LY. Haemodialysis will clear dabigatran 9. The serious consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding has increased morbidity and may contribute to deaths 4. No antidote currently known although prothrombin complex concentrate (PCC) has been successful in reversing the effects in a small preliminary trial 12. The serious consequences of the lack of an effective reversal agent should not be underestimated. No antidotes currently known. The serious consequences of the lack of an effective reversal agent should not be underestimated. Prolonged bleeding has increased morbidity and may contribute to deaths

4 Bleeding Warfarin Dabigatran Rivaroxaban Apixaban See respective agent for comparison of bleeding risk. RE-LY showed 3 : Major bleeding rates were similar for dabigatran 150mg bd and warfarin, however, major bleeding was lower with dabigatran 110mg BD than with warfarin. The incidence of GI bleeding was significantly higher with dabigatran 150mg bd (p=0.0008), but similar with dabigatran 110mg bd (p=0.52), than in patients treated with warfarin. ROCKET-AF showed 11 : No significant difference in the primary safety endpoint of major or non-major clinically relevant bleeding. GI bleeding was more common with rivaroxaban than warfarin (3.2% vs.2.2%, p=<0.001), as were a decrease in Hb of >2g/dl (4.3% vs. 3.6%, p=0.02), need for transfusion (2.6% vs. 2.1%, p=0.04), epistaxis (10.1% vs. 8.6%, p<0.05), and haematuria (4.2% vs. 3.4%, p<0.05). Intracranial haemorrhage was less Intracranial bleeding was common with rivaroxaban than uncommon but higher with warfarin. Dabigatran 150mg bd warfarin (0.8% vs. 1.2%, p=0.02), reduced the absolute risk of as were critical bleeding (1.3% vs. intracranial bleeding compared 1.9%, p=0.007) and fatal bleeding with warfarin (0.32% vs 0.76% (0.4% vs. 0.8%, p=0.003). respectively) A recent audit of bleeding events with dabigatran highlighted that frail, elderly patients, particularly those with renal impairment and low body weight are at risk of increased bleeds 4. ARISTOTLE showed: Lower risk of major bleeding with apixaban than with warfarin (annual rate 2.13% vs 3.09%). Rates of intracranial haemorrhage (ICH) and all bleeding were also lower with apixaban (ICH annual rate 0.33% vs 0.8%, all bleeding 18.1% vs 25.8%) 14.

5 Warfarin Dabigatran Rivaroxaban Apixaban Nonhaematological side effects Other side effects can include hair loss Dyspepsia occurred at a higher rate with both doses of dabigatran, compared with warfarin. These events may be due in part to the acidic core of the dabigatran etexilate capsule formulation (the tartaric acid core lowers ph and enhances dabigatran etexilate a bsorption). These GI adverse events frequently led to drug discontinuation (7%, 6.5% and 3.9% in the dabigatran 150mg, 110mg and warfarin groups respectively) 3. There was a non-significant increase in the number of myocardial infarctions (MI) in patients taking dabigatran compared to warfarin (0.82% for 110mg and 0.81% for 150mg vs. There were no significant differences in the incidence of any other adverse event other than bleeding in ROCKET-AF 10 (81% with rivaroxaban vs. 82% of warfarin patients). The most frequently reported non-haematological adverse events in the rivaroxaban group were peripheral oedema (6.1%) and dizziness (6.1%), and in the warfarin group were nasopharyngitis (6.4%) and dizziness (6.3%). The rate of MI was numerically, but not statistically significantly lower in the rivaroxaban arm compared with the warfarin group 11. There were no significant differences in the incidence of any other adverse event other than bleeding in ARISTOTLE 14 (81% with apixaban vs. 83% of warfarin patients). The only serious adverse events reported in >1% of patients in either group were atrial fibrillation in 3.3% apixaban and 3.2% warfarin patients, and pneumonia in 2.2% of apixaban and 2.6% of warfarin patients. 0.64% p=0.12) 3,6,7. A meta-analysis 8 combining 7 studies showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group. The control group varied and included enoxaparin, warfarin and placebo 8.

6 Interactions Warfarin Dabigatran Rivaroxaban Apixaban Drug-food interactions Drug-food interactions 2 Cranberry juice and Currently there are no known alcohol interact with food interactions. warfarin. Some foods Drug-drug interactions 2 interact with warfarin (e.g. Not recommended to foods containing high concomitantly administer with amounts of vitamin K). other drugs which increase Drug-drug bleeding risk, e.g. antiplatelets, interactions heparin, other anticoagulants. Many interactions requiring additional INR monitoring. Chronic NSAID use and SSRIs increase risk of bleeding in combination with dabigatran. No effect on cytochrome P450, so the potential for cytochrome P450 drug interactions is low. There is a potential for P-gp interactions. Concomitant treatment with systemic ketoconazole, cyclosporin, itraconazole, dronedarone and tacrolimus is contraindicated. Caution with amiodarone, quinidine, clarithromycin and verapamil (reduce dose to 110mg bd with verapamil). Concomitant administration of a P-gp inducers such as rifampicin, St. John s wort, carbamazepine, phenytoin or protease inhibitors such as ritonavir should be avoided. Consult the SPC for full details. Drug-food interactions 10 Currently there are no known food interactions. It is recommended that the 15mg and 20mg tablets are taken with food to increase absorption. Drug-drug interactions 10 Not recommended with concomitant systemic treatment with azole-antimycotics e.g. ketoconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors e.g. ritonavir and dronedarone. These active substances are strong inhibitors of both CYP3A4 and P-gp. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to reduced rivaroxaban plasma concentrations and should be coadministered with caution Rivaroxaban itself has no inhibiting or inducing effect on any major CYP isoforms like CYP3A4. Due to the increased bleeding risk, care should be taken if treating concomitantly with any other anticoagulant, antiplatelet or NSAID. Consult the SPC for full details. Drug-food interactions 13 Currently there are no known food interactions. Drug-drug interactions 13 Not recommended to concomitantly administer with other drugs which increase bleeding risk, e.g. antiplatelets, heparin, other anticoagulants. Caution is recommended with concomittant use of NSAIDs. Not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azoleantimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). Caution recommended for concomitant use with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort). Consult the SPC for full details

7 When should it be avoided? Warfarin Dabigatran Rivaroxaban Apixaban Intolerance to warfarin including allergy, rash, side effects likely to result in discontinuation of therapy (other than bleeding complications) e.g. severe alopecia (although acenocoumarol may be a suitable alternative in these patients). Unmanageable warfarin control due to long term interacting drug therapy (INR persistently and significantly above or below range that does not respond to dose titration), and/or impossibility of accessing monitoring services AVOID dabigatran in patients with a history of poor medication adherence. Dabigatran is not stable in compliance aids such as blister packs. Dabigatran cannot be pushed out from its packaging. The seal has to be carefully peeled off to access the tablet. AVOID in patients with severe renal impairment and patients with severe hepatic impairment. Dabigatran is not a suitable alternative to warfarin in patients with contraindications to warfarin therapy due to a high bleeding risk or trivial side effects related to warfarin. AVOID rivaroxaban in patients with a history of poor medication adherence. AVOID in patients with severe renal impairment and patients with severe hepatic impairment. Rivaroxaban is not a suitable alternative to warfarin in patients with bleeding complications associated with warfarin treatment, contraindications to warfarin therapy due to a high bleeding risk or trivial side effects related to warfarin. AVOID apixaban in patients with a history of poor medication adherence. AVOID in patients with severe renal impairment and patients with severe hepatic impairment. Apixaban is not a suitable alternative to warfarin in patients with contraindications to warfarin therapy due to a high bleeding risk or trivial side effects related to warfarin. 1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146: SPC Pradaxa. Accessed march Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: Harper P, Young L, Merriman E. Bleeding Risk with Dabigatran in the Frail Elderly. N Engl J Med 2012; 366: Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363: Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial. Circulation 2012; DOI: /?CIRCULATIONAHA Available at: 8. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; DOI: /archinternmed Available at: 9. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single- centre study. Clin Pharmacokinet Apr;49(4): SPC Xarelto 20mg. Accessed march Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365: Eerenberg ES et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. Circulation 2011; 124: SPC Eliquis, accessed March Granger et al, Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation. N Engl J Med 2011;365: MHRA Drug Safety Update, March 2013 (Volume 6, Issue 8)

8 Summary of key NOAC facts The following factors need to be considered in selecting a NOAC for non-valvular AF (Note that the trials compared different rates of INR control) Efficacy in stroke prevention compared to warfarin Reduced risk of bleeding compared to warfarin Dabigatran Rivaroxaban Apixaban Overall no difference Superior (150mg bd dose) Non-inferior (110mg bd dose) Evidence for reduced bleeding risk at lower dose. NB Increased risk of GI bleed compared to warfarin at higher dose which is the usual dose. Overall reduced intra cranial Overall no difference Non inferior (ITT analysis) Equivalent to warfarin (except reduced ICH) haemorrhage (ICH) Reversibility Uncertain. Uncertain (possible data supports use of prothrombin complex concentrate which may reverse the laboratory abnormalities of clotting but this may not translate into stopping the actual bleeding event) Dialysable Yes, but will need to be carried out for at least 6 hours in order to ensure adequate drug clearance treatment. Disclaimer: This summary in itself is not enough to educate prescribers on the comparative information on these new anticoagulants. Pages 1-7 give more comprehensive referenced information and should be used in conjunction with the summary. For full prescribing information refer to Summaries of Product Characteristics (SPCs) available at Produced by Hertfordshire Pharmacy and Medicines Optimisation Team Hertfordshire, Bedfordshire and Luton Commissioning Support NHS Central Eastern Commissioning Support Unit No Superior Evidence for reduced bleeding risk. Uncertain. Currently no experience with the use of recombinant factor VIIa in individuals receiving apixaban Dosing bd od bd Drug interactions P- glycoprotein inducers and inhibitors Simultaneous PGP & CYP- 3A4 inducers/inhibitors Simultaneous PGP & CYP- 3A4 inducers/inhibitors Drug cautions (increased bleeding risk) Antiplatelet agents, NSAIDs, SSRIs or SNRIs Antiplatelet agents, NSAIDs Antiplatelet agents, NSAIDs Use in patients with swallowing difficulties Suitability for storage in monitored dosage system NHS cost /patient/ year (Costs may vary in different settings because of negotiated procurement discounts) Possibility of using in other conditions Cannot be crushed May be crushed and put May be crushed and put through NG tube through NG tube Not suitable Suitable Suitable 804 (cost is significantly reduced in Herts due to primary care rebate scheme) NICE approved for orthopaedic prophylaxis. Phase III data shows efficacy in DVT but no NICE appraisal currently planned 767 (cost is significantly reduced in Herts due to primary care rebate scheme) NICE approved for orthopaedic prophylaxis, treatment of DVT and the prevention of recurrent VTE. Licensed and NICE recommended for prevention of DVT associated with hip and knee surgery, treatment of DVT, and the prevention of recurrent DVT and PE following an acute DVT in adults. Licensed for PE No 804 (no rebate scheme offered by the company) Licensed and NICE recommended for orthopaedic prophylaxis.