New therapeutic approaches for the protection of AF patients from stroke: Do aspirin or warfarin have a role anymore?

Transcription

1 New therapeutic approaches for the protection of AF patients from stroke: Do aspirin or warfarin have a role anymore? Dr Tina Biss Consultant Haematologist The Newcastle Hospitals NHS Foundation Trust Newcastle Cardiac Update Course The County Hotel, Newcastle 26 th April 2012

2 Disclosures/Conflicts of interest None to declare

3 Summary Background: The extent of the problem Current approach to anticoagulant therapy for stroke prevention in AF New oral anticoagulant agents Should there be a change in practice?

4 The extent of the problem Prevalence AF in primary care has a prevalence of 1.2% 600,000 people affected by AF in the UK Prevalence of AF doubles with each advancing decade AF is under-recognised Stroke in AF AF is associated with a five-fold increase in stroke risk 12,500 strokes per year due to AF, increasing risk with increasing age 5% of all NHS expenditure is stroke; 15% of stroke is due to AF

5 Hart RG et al, 2007;146:857 Comparison RRR Warfarin vs control 64% Aspirin vs control 22%

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7 Lancet 2007;370:493 Primary endpoints Fatal or non-fatal disabling stroke Other intracranial haemorrhage Arterial embolism Warfarin 1.8 % / year Aspirin 3.8 % / year Relative risk 0.48 No increased risk of major haemorrhage with warfarin

8 Current guidance NICE clinical guideline no.36: The management of AF, 2006 Warfarin more protective than aspirin Stroke risk stratification: CHADS 2 score Low risk (0)- Aspirin Moderate risk (1)- Aspirin or warfarin High risk (>1)- Warfarin Assessment of bleeding risk prior to anticoagulation NICE guidance is due to be updated

9 NHS Improvement: Commissioning for Stroke Prevention in Primary Care- The Role of AF, 2009: AF in Primary Care- Making an Impact on Stroke Prevention, 2009: Anticoagulation for Atrial Fibrillation, 2011: Warfarin superior to aspirin Cost of warfarin per year 383, cost per stroke 11,900 in the first year after stroke occurrence Considerable under-use of warfarin: 46% of those who should be on warfarin are not receiving it GRASP AF toolkit Effective anticoagulation: Warfarin with time in therapeutic range <65% may be suboptimal

10 RCPE Consensus Statement, 2012: Aspirin is ineffective for stroke prevention and patients who take sole aspirin should be reviewed with a view to an alternative more effective anticoagulation Anticoagulants should be well controlled warfarin (currently standard treatment) or one of the newer OACs. Newer OACs are an option for patients who cannot tolerate, have an allergy to, or who cannot achieve satisfactory anticoagulant control on warfarin Attention to improving time in therapeutic range for patients on warfarin

11 Quality Outcomes Framework (QoF) Records AF1. The practice can produce a register of patients with atrial fibrillation Initial diagnosis AF5. The percentage of patients with atrial fibrillation in whom stroke risk has been assessed using the CHADS2 risk stratification scoring system in the preceding 15 months (excluding those whose previous CHADS2 score is greater than 1) On-going management AF6. In those patients with atrial fibrillation in whom there is a record of a CHADS2 score of 1 (latest in the preceding 15 months), the percentage of patients who are currently treated with anticoagulation drug therapy or anti-platelet therapy AF7. In those patients with atrial fibrillation whose latest record of a CHADS2 score is greater than 1, the percentage of patients who are currently treated with anticoagulation therapy

12 Odds ratio Warfarin and its challenging therapeutic window Ischaemic stroke Therapeutic range Requires dose adjustment and regular monitoring 10 Intracranial bleed International normalized ratio (INR) 8 ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257 e354.

13 Cumulative survival Why time in therapeutic range (TTR) matters Warfarin group % 61 70% 51 60% 41 50% 31 40% <30% Non warfarin Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124:37 41.

14 Problems with warfarin Narrow therapeutic window Unpredictable response therefore requires monitoringinconvenience, cost Variable dosing Interactions with medications Influence of diet and alcohol

15 Advantages of warfarin Cheap- 20 per annum ( 300 pa) Familiar: support structure in place Effective Monitored: encourages better compliance can alter range if clinically indicated Long half-life Rapidly reversible/available antidote

16 Characteristics of the ideal anticoagulant Effective Wide therapeutic window No food or drug interactions Predictable response- no monitoring required, standard dose Rapid onset of action Effective antidote available Cheap

17 Targets of New Anticoagulant Agents ORAL TTP889 TF/VIIa PARENTERAL TFPI (tifacogin) X IX Xa Inhibitors: Rivaroxaban Apixaban Edoxaban LY YM150 PRT IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Indirect Xa inhibitors Fondaparinux Idraparinux SSR IIa Inhibitors Ximelagatran Dabigatran IIa Direct Xa Inhibitors DX-9065a Otamixaban Fibrinogen TF=tissue factor Adapted from Weitz JI et al. J Thromb Haemost. 2005;3: Fibrin

18 Targets of New Anticoagulant Agents ORAL TTP889 TF/VIIa PARENTERAL TFPI (tifacogin) X IX Xa Inhibitors: Rivaroxaban Apixaban Edoxaban LY YM150 PRT IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Indirect Xa inhibitors Fondaparinux Idraparinux SSR IIa Inhibitors Ximelagatran Dabigatran IIa Direct Xa Inhibitors DX-9065a Otamixaban Fibrinogen TF=tissue factor Adapted from Weitz JI et al. J Thromb Haemost. 2005;3: Fibrin

19 Evolution of Anticoagulant Therapy 1993 First commercially available LMWH 1998 First commercially available DTI 2001 First commercially available synthetic Xa inhibitor 1940s UFH commercially available Warfarin commercially available ~50 years 2003 FDA rejects ximelagatran 2009 Rivaroxaban AC=anticoagulant; DTI=direct thrombin inhibitor; FDA=Food and Drug Administration; LMWH=low molecular weight heparin; UFH=unfractionated heparin 2008 Dabigatran approved for clinical use NICE approves both

20 Overview of the most important Phase III randomized controlled trials involving the novel anti coagulants

21 Dabigatran (Pradaxa): oral DTI Dabigatran etexilate: a direct thrombin inhibitor Rapid onset of action- 2 hours Twice daily dosing Predictable and consistent anticoagulant effect- No requirement for routine coagulation monitoring No known dietary restrictions Few drug interactions 80% renal excretion- Dose reduced in moderate renal impairment (egfr ml/min), contraindicated in those with severe renal impairment (egfr<30 ml/min) Half-life hours (up to 30 hours in severe renal impairment)

22 RE-LY study design Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6022 Dabigatran etexilate 110 mg bid N=6015 Dabigatran etexilate 150 mg bid N=6076 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up 1 Connolly SJ et al. N Engl J Med 2009; 361: Ezekowitz MD et al. Am Heart J 2009;157:80 10.

23 Cumulative hazard rates How does Pradaxa compare to warfarin? Time to first stroke / SSE RR 0.90 (95% CI: ) p<0.001 (NI) p=0.30 (Sup) RRR 35% ARR 0.60% RR 0.65 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) Years ARR, absolute risk reduction; RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ et al. N Engl J Med 2009;361:

24 % per year Major bleeding risk compared to warfarin RR 0.80 (95% CI: ) 2.87 p=0.003 (sup) RRR 20% ARR 0.70% RR 0.93 (95% CI: ) 3.32 p=0.32 (sup) RRR 7% ARR 0.25% D110 mg BID D150 mg BID Warfarin 342 / 6, / 6, / 6,022 Connolly et al. N Engl J Med 2010;363: supplementary appendix available at: http//

25 Cumulative hazard rates Time to first intra-cranial bleed 0.02 Warfarin Dabigatran 110 mg Dabigatran 150 mg Total events 90/ / / RR 0.41 (95% CI: ) p<0.001 (Sup) RRR 59% ARR 0.44% RRR 70% ARR 0.53% 0.0 RR 0.30 (95% CI: ) p<0.001 (Sup) Years RR, Relative risk; CI, confidence interval; Sup, superior Oral presentation by Connolly and Camm at ESC, August 2009.

26 Major bleeding and components Characteristic D 110 mg D 150 mg Warfarin p-value 110 vs. W p-value 150 vs. W Number of patients (n) Major bleeding Life threatening Non-life threatening Gastrointestinal < Data represents %/year 1 Connolly SJ et al. N Engl J Med 2009;361: Connolly et al. N Engl J Med 2010;363: supplementary appendix available at: http//

27 Most common adverse events Dabigatran 110 mg % Dabigatran 150 mg % Warfarin % Any bleeding 14.74% 16.56% 18.37% Dyspepsia* Dyspnoea Dizziness Peripheral oedema Fatigue Cough Chest pain Arthralgia Back pain Nasopharyngitis Diarrhoea Atrial fibrillation Urinary tract infection Upper respiratory tract infection * Occurred more commonly on dabigatran p< Connolly SJ et al. N Engl J Med 2009;361: SPC Pradaxa 110 mg and 150 mg 2011.

28 Conclusions from the RE-LY study Dabigatran 110mg bd was associated with: Stroke/systemic embolism rate similar to warfarin A lower rate of major bleeding Dabigatran 150mg bd was associated with: A lower stroke/systemic embolism rate than warfarin A similar rate of major bleeding Significantly lower risk of ICH with dabigatran cf. warfarin Significantly higher risk of GI bleeding with dabigatran 150mg bd Dabigatran 110mg bd and 150mg bd showed equivalence in terms of net clinical benefit. Dose could be tailored according to relative risks in the individual

29 Rivaroxaban (Xarelto): Oral Factor Xa Inhibitor Rivaroxaban- direct factor Xa inhibitor Rapid onset of action- 2 hours Once daily dosing Predictable and consistent anticoagulant effect- No requirement for routine coagulation monitoring No known dietary restrictions Few drug interactions Liver (2/3 rd )/Renal (1/3 rd ) excretion- Dose reduced in moderate to severe renal impairment (egfr<50 ml/min) Half-life hours

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34 Conclusions from the ROCKET-AF study When compared to warfarin (target INR 2.5), rivaroxaban 20 mg daily: was non-inferior for the prevention of stroke/systemic embolism showed no difference in risk of major or non-major clinically significant bleeding was significantly less likely to cause ICH was more likely to cause GI bleeding Note: Low TIR 55%, high risk patients (mean CHADS 2 score 3.5)

35 ARISTOTLE Apixaban 5mg bd vs warfarin (INR 2.5) ARISTOTLE Apixaban Warfarin RR 95% CI p End-point <.001 Bleeding <.001 Death (all causes) Haemorrh stroke <.001 Isch stroke When compared to warfarin (target INR 2.5), apixaban 5mg bd: Was superior to warfarin for prevention of stroke/systemic embolism Resulted in fewer bleeding episodes Resulted in fewer haemorrhagic strokes

36 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost

37 Time in therapeutic range RE-LY Dabigatran 64 % ARISTOTLE Apixaban 62 % ROCKET AF Rivaroxaban 55 %

38 Wallentin et al, Lancet 2010:376:975

39 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost

40 PATIENT RECEIVING DABIGATRAN THERAPY: HAEMORRHAGE PROTOCOL STOP: Dabigatran Contact Haematologist Request: 1. Coagulation screen to include APTT (consider thrombin time),+/- Hemoclot TT if available APTT (and TT) normal APTT (and TT) prolonged NO dabigatran anticoagulant effect present Dabigatran anticoagulant effect maybe present (consider oral charcoal if dabigatran ingestion <2 hours) MILD BLEED MAJOR BLEED LIFE THREATENING BLEED Mechanical compression Tranexamic Acid oral 25 mg/kg or i.v. 10 mg/kg Delay next dabigatran dose or discontinue treatment Continues to bleed Major Bleed: Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial or intramuscular with compartment syndrome (Schulman et al J Thromb Haemost 2010; 3: ) Maintain BP and Urine Output (dabigatran 80% renal excretion) Optimise tissue oxygenation Control haemorrhage Mechanical compression Surgical / radiological intervention Tranexamic Acid (1g i.v.) Red cell transfusion Aim Hb > 7 g/dl Platelet transfusion Aim Plt > 50 x 10 9 /l or If CNS bleed aim Plt > 100 x 10 9 /l Identify bleeding source e.g. surgery, endoscopy, interventional radiology FEIBA* Consider Haemodialysis *NB: PCC or rfviia can be considered as options. The choice of haemostatic agent is currently based on limited published evidence and advice DBG2919 from haematologist September 2011

41 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost

42 FDA: July 2011 MHRA: December 2011

43 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost

44 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost

45 Limitations of the new oral anticoagulants Efficacy Reversibility/Lack of an antidote Accumulation in renal failure Potency Short half-life Cost- 800 pa

46 NICE guidance March 2012 Dabigatran is an option for the prevention of stroke and systemic emboli in non-valvular AF with one or more risk factors Recommended dose: 150mg bd for patients <80 years 110mg bd for patients >80 years, with moderate renal impairment, or at risk of bleeding Can consider in those with newly diagnosed AF and consider switching those already on warfarin NICE guidance for rivaroxaban is under review

47 Should there be a change in practice? Anticoagulant therapy in AF is under-prescribed Warfarin is a highly effective drug and reluctance to use it, particularly in the elderly who are perceived to be at a higher risk of bleeding, should be reduced We need to focus on improving the quality of warfarin anticoagulant therapy in patients with AF Improving time in range Service led Patient led

48 Should there be a change in practice? A new oral anticoagulant agent may be appropriate for patients who have failed warfarin Intolerance/allergy Time in range <65% (with good compliance) Difficulties with monitoring Patients pending cardioversion may benefit from a new oral anticoagulant Caution regarding new oral anticoagulants Lack of an antidote/reversibility Renal impairment