AF, Stroke Risk and New Anticoagulants

Transcription

1 Carmarthen Cardiac Update Course AF, Stroke Risk and New Anticoagulants Dr Hamsaraj Shetty, B.Sc, FRCP (London & Edinburgh) Consultant Physician & Honorary Senior Lecturer University Hospital of Wales,Cardiff & Cardiff University

2 AF& Stroke Risk Most common cardiac arrhythmia, affects 1 2% of the population Lifetime risk of developing AF is approx. 25% in those who have reached the age of 40 Prevalence with age (5% at 65 yrs & 10% at 80 yrs) European Heart Journal 2010;1:1 61

3 AF& Stroke Risk A F increases the overall risk of ischemic stroke by five fold Accounts for up to 15% of strokes in persons of all ages & 30% in persons over the age of 80 years Associated with severe strokes & significant risk for stroke recurrence Lin et al Stroke1996;27: ; Penado et al Am J Med 2003; 114:

4 AF& Stroke Risk Rate of stroke 5% per yr with no previous TIA or Stroke 12% per yr with prior TIA or Stroke

5 Independent risk factors for stroke in AF Feature Relative risk (95%CI) Prior stroke or TIA 2.5 ( ) Increasing age per decade 1.4 ( ) History of hypertension 1.9 ( ) Systolic BP 160 mm Hg 1.4 ( ) Diabetes 1.7 ( ) Hart et al Stroke 2009; 40:

6 NRAF adjusted stroke rate per 100 patient years, without aspirin How do I risk-assess AF patients simply? Stroke risk assessment with CHADS 2 CHADS 2 criteria Congestive heart failure Score Adjusted stroke risk Hypertension 1 Age >75 yrs 1 Diabetes mellitus 1 Stroke / transient ischaemic attack 1 Gage BF et al. JAMA 2001;285: Based on data from Gage BF et al. JAMA 2001;285: CHADS 2 score DBG2919 September 2011

7 Stroke risk assessment with CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc criteria Congestive heart failure/ left ventricular dysfunction Score Hypertension 1 Age 75 yrs 2 Diabetes mellitus 1 Stroke/transient ischaemic attack/te Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque) Age yrs 1 Sex category (i.e. female gender) CHA 2 DS 2 -VASc total score Rate of stroke/other TE (%/year)* * Theoretical rates without therapy: assuming that warfarin provides a 64% relative reduction in TE risk (2.7% ARR), based on Hart et al. TE = thromboembolism 1 Lip GYH et al. Stroke 2010;41: Hart RG et al. Ann Intern Med 2007;146: DBG2919 September 2011

8 Embolism in AF: mechanisms Most are thrombi form in LA appendage Stagnation in LA contributory Associated cvs disease & age risk Embolic events are intermittent : temporal variation in thrombotic factors?

9 What are the options for stroke prevention?

10 Approach to thromboprophylaxis in patients with AF Risk category One major risk factor or 2 clinically relevant non-major risk factors One clinically relevant non-major risk factor CHA 2 DS 2 -VASc score 2 1 Recommended antithrombotic therapy Oral anticoagulant (OAC) Either OAC or aspirin mg daily. Preferred: OAC rather than aspirin No risk factors 0 Either aspirin mg daily or no antithrombotic therapy. Preferred: no antithrombotic therapy rather than aspirin European Heart Journal 2010;1:1 61. DBG2919 September 2011

11 Why are OACs preferred to aspirin? Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% *, ARR 2.7% (95% CI: 49 74%) RRR (%) Random effects model; Error bars = 95% CI; * p>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) 100 Compared to a 19% RRR, 0.7% ARR for aspirin Hart RG et al. Ann Intern Med 2007;146: DBG2919 September 2011

12 Warfarin vs Aspirin Per 1000 pts treated with warfarin / yr: 23 ischaemic stroke prevented 9 additional major bleeding

13 Warfarin versus aspirin plus clopidogrel Warfarin Aspirin plus Clopidogrel Primary events 3.93% / yr 5.6% / yr (RR 1.44, , P=0.0003) Trial stopped early: Oral anticoagulation therapy is superior to clopidogrel plus aspirin Connolly et al, Lancet 2006; 367:

14 Aspirin vs aspirin plus clopidogrel Aspirin plus Clopidogrel Aspirin plus placebo Relative risk Major vascular 6.8%/ yr 7.6% / yr 0.89 ( p=0.01) Events Stroke 2.4% / yr 3.3% / yr 0.72 ( ,p=0.001) Major bleeding 2% / yr 1.3% / yr 1.57 ( , p=0.001) ACTIVE Investigators. NEJM 2009; 360:

15 Disadvantages of warfarin Narrow therapeutic index Need for regular monitoring Poor anticoagulation control in up to 45% Potentially dangerous interactions Poor compliance

16 How are AF patients at risk of stroke currently being managed? Preadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597) Sub- therapeutic warfarin, 29% No antithrombotic 29% Therapeutic warfarin, 10% Dual antiplatelet therapy, 2% Single antiplatelet agent, 29% Gladstone DJ et al. Stroke 2009;40: DBG2919 September 2011

17 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. DBG2919 September 2011

18 Ideal anticoagulant Orally effective Safe Predictable effect No routine laboratory monitoring Once daily dosing No significant interactions

19 New Drugs

20 Dabigatran etexilate Orally active inhibitor of both free and clot-bound thrombin Rapid onset of action & does not require laboratory monitoring. Dabigatran etexilate is a pro-drug which is hydrolysed to active dabigatran in the liver. 80% of activated dabigatran is excreted unchanged through the kidneys. It should be avoided in patients with severe renal impairment (creatinine clearance < 30ml/minute) & dose should be reduced in moderate renal impairment (creatinine clearance ml/minute) Wittkowsky AK 2010

21 Dabigatran etexilate Is a substrate for the transport protein p-glycoprotein (p- GP), which facilitates renal elimination of certain drugs. Amiodarone, an inhibitor of p-gp, reduces the clearance of dabigatran (doses should be reduced) In patients on strong p-gp inhibitors such as verapamil and clarithomycin, dabigatran should be used with caution and it should not be used together with quinidine. Potent p-gp inducers eg; rifampicin & St John s Wort, may potentially reduce its efficacy. Wittkowsky AK 2010

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: DBG2919 September 2011

23 Cumulative hazard rates How does Pradaxa compare to warfarin? Time to first stroke / Systemic embolism 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: DBG2919 September 2011

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// DBG2919 September 2011

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 DBG2919 September 2011

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// DBG2919 September 2011

27 Conclusions Both doses of dabigatran provide different and complementary advantages over warfarin 150 mg BID has superior efficacy with similar bleeding 1,2 110 mg BID has significantly less bleeding with similar efficacy 1,2 Both doses show a significant reduction in intra-cranial bleeding 1,2 1 Connolly SJ et al. N Engl J Med 2009;361: Connolly et al. N Engl J Med 2010;363: DBG2919 September 2011

28 Rivaroxaban Rivaroxaban is an orally active inhibitor of both the free and prothombinase complex-bound forms of activated factor X (Xa) 2/3 of the dose is metabolized, principally by CYP450 enzymes & 1/3 is excreted unchanged in the urine. Rivaroxaban also appears to be a p-gp substrate and it should be used with caution when prescribed concomitantly with p-gp inhibitors and potent p-gp inducers. It should also be used with caution in patients with creatinine clearance less than 30 ml/min (severe renal impairment) and is contraindicated in those with creatinine clearance less than 15 ml/min. ( Wittkowsky AK 2010

29 Rivaroxaban Several CYP3A4 inhibitors and inducers have been shown to affect its metabolism. Some CYP3A4 inhibitors significantly increase the AUC of rivaroxaban, (particularly ketoconazole and other azole-antimycotics such as itraconazole, voriconazole and posaconazole and also HIV protease inhibitors such as ritonavir The CYP3A4 inducer rifampicin (and possibly other inducers of this cytochrome) reduces the AUC for rivaroxaban. Wittkowsky AK 2010

30 Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Double-blind randomized trial 14,264 patients with NVAF & risk for stroke (CHADS2 score of 2 or more) Received either rivaroxaban, a direct factor Xa inhibitor, (20 mg od) or dose-adjusted warfarin. As-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin Primary end point of stroke or systemic embolism. Patel M et al for the ROCKET AF Investigators, NEJM, 2011; 365:883 89

31 Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. (1.7% per yr vs 2.2% per yr; hazard ratio 0.79; 95% CI, 0.66 to 0.96; P<0.001 for noninferiority) There was no significant difference in the risk of major bleeding But intracranial and fatal bleeding occurred less frequently with rivaroxaban (ICH 0.5% vs. 0.7%, P=0.02; & fatal bleeding 0.2% vs. 0.5%, P=0.003) Patel M et al, for the ROCKET AF Investigators NEJM, 2011; 365:

32 Patel M et al, for the ROCKET AF Investigators NEJM, 2011; 365:883 89

33 Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation In warfarin group, INR was in the therapeutic range in 55% (mean); lower than in previous studies of other new anticoagulants in patients with AF (range, 64 to 68%). Bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group, as did bleeding that led to a drop in the haemoglobin level or bleeding that required transfusion. An intention-to-treat analysis, did not show superiority for rivaroxaban over warfarin. Patel M et al, for the ROCKET AF Investigators NEJM, 2011; 365:883 89

34 Apixaban Apixaban is a direct oral factor Xa inhibitor Absorbed rapidly Half life12-hours 25% renal excretion Granger et al for the ARISTOTLE Committees and Investigators, N Engl J Med 2011

35 Apixaban Apixaban is eliminated by hepatic metabolism via CYP3A4, renal and intestinal excretion. Concomitant treatment with potent inhibitors of CYP3A4 is contraindicated in apixaban-treated patients Eikelboom et al. Circulation. 2010;121:

36 Apixaban vs Warfarin in patients with Atrial Fibrillation Apixaban (5 mg bd) was superior to warfarin in preventing stroke or systemic embolism (1.27% per yr vs 1.60% per yr; hazard ratio 0.79; 95% CI, 0.66 to 0.95; P<0.001 for noninferiority; P = 0.01 for superiority) Caused less bleeding (rate of major bleeding 2.13% per yr vs 3.09% per yr; hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001) Granger et al for the ARISTOTLE Committees and Investigators, N Engl J Med 2011

37 Apixaban vs Warfarin in patients with Atrial Fibrillation Rate of ICH was lower (0.33% per yr vs 0.80% per yr; hazard ratio, 0.42; 95% CI, 0.30 to 0.58; P<0.001) Resulted in lower mortality (the rates of death from any cause: 3.52% vs 3.94%; hazard ratio, 0.89; 95% CI,0.80 to 0.99; P = 0.047). Granger et al for the ARISTOTLE Committees and Investigators, N Engl J Med 2011

38 Apixaban vs Warfarin in patients with Atrial Fibrillation Granger et al for the ARISTOTLE Committees and Investigators, N Engl J Med 2011

39 Apixaban vs Warfarin in patients with Atrial Fibrillation Granger et al for the ARISTOTLE Committees and Investigators, N Engl J Med 2011

40 Percutaneous closure of the left atrial appendage versus warfarin PCLAA Warfarin Relative risk (95% Credible Int) Primary efficacy event rate 3 ( ) 4.9 ( ) 0.62 ( ) (per 100pt yrs) Primary safety event rate 7.4 ( ) 4.4 ( ) 1.69 ( ) (per 100 pt yrs) Probability of non-inferiority: > 99.9% Holmes et al The Lancet 2009; 374:

41 Bleeding risk stratification

42 A score of 3 indicates high risk, and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy. Pisters et al Chest 2010

43 Management of bleeding Newer drugs are associated with lower risk of ICH Warfarin effect can be effectively reversed with Beriplex, factor VIIa High INR can be reduced with vitamin K

44 Reversing high INR with vitamin K Shetty et al Thrombosis & Haemostasis 1992

45

46 Management of bleeding with dabigatran Beriplex stops bleeding with Dabigatran Factor VIIa & activated prothrombinase complex (FEIBA) have also been used Monoclonal antibody to Dabigatran safely reverses anticoagulation. Haemodialysis/haemofiltration, oral charcoal (if dabigatran is ingested within 24 hrs) in O/D or to stop bleeding Maintain good diuresis

47 Who should receive the new oral anticoagulants? Allergic to warfarin Extreme sensitivity to warfarin / difficult to control INR Poor venous access Poor access to INR monitoring. Personal choice

48 Conclusion AF is an important risk factor for stroke In high risk patients, anticoagulation is highly effective in reducing stroke incidence Newer antithrombotic agents/interventions are effective & may replace warfarin in carefully selected patients.