Atriumfibrilleren en het ischemisch CVA. Hands on!!! Dr Robert G Tieleman Martini Ziekenhuis Groningen

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1 Atriumfibrilleren en het ischemisch CVA Hands on!!! Dr Robert G Tieleman Martini Ziekenhuis Groningen

2 CVA en Atriumfibrilleren: de feiten CVA is de belangrijkste complicatie van AF AF is geassocieerd met een 5x verhoogde kans op CVA AF verdubbeld het risico op CVA wanneer gecorrigeerd voor andere risico factoren Zonder behandeling is de incidentie van CVA in AF 5% (incl TIAs en stille CVAs > 7%) AF is verantwoordelijk voor 1/4 van alle CVAs AF geassocieerd CVA is 2x vaker dodelijk en meer invaliderend NL telt ptn met niet gediagnosticeerd AF

3 Evaluation of AF associated Stroke 50% of pts had undiagnosed AF; stoke first sign 25% known with AF but inappropriate Rx Pisters,Tieleman Europace 2010;12:761-3

4 AF geassocieerde CVA n 75% van de patienten die opgenomen worden met een CVA en AF gebruikten (ten onrechte) geen antistolling n Screening op AF en behandeling volgens de richtlijnen kan CVAs per jaar voorkomen (in NL)

5 Screenen op AF n ECG noodzakelijk voor diagnose n Mn at risk u Leeftijd > 65 jaar u Hypertensie u DM u Eerdere CVA/TIA u CAD u Hartfalen

6 MyDiagnostick Een nieuw diagnosticum speciaal ontwikkeld voor het opsporen van atriumfibrilleren

7 MyDiagnostick Onderscheidt atriumfibrilleren van sinus ritme MyDiagnostick heeft 2 metalen uiteinden (electrodes) die vastgehouden dienen te worden Automatische start van 1 minuut durende ECG opname MyDiagnostick analyseert het ritme en diagnosticeert atriumfibrilleren (rood( licht) ) of afwezigheid van AF (groen( licht)

8 MyDiagnostick Diagnose is zeer sensitief (100%) and specifiek (97%) MyDiagnostick kan 120 ECG s s opnemen en opslaan De ECG strook kan via een USB connectie worden uitgelezen en eventueel ter verificatie worden voorgelegd

9 MyDiagnostick Screenen op AF daarmee goedkoop en snel (1 minuut, geheel door patient zelf uit te voeren) en dus haalbaar Vereist geen logistieke aanpassingen vd praktijk Wanneer de diagnose gesteld is dient behandeling (rate-control en antistolling) overwogen te worden

10 Wie moet behandeld worden met OAC? Alle patienten met AF > 48 uur rondom cardioversie gedurende 1 maand voor en 1 maand na cardioversie Alle andere AF patienten afhankelijk van risico op thrombo-embolische complicaties

11 Risk factors for stroke in AF: CHADS2 Congestive heart failure (History of) hypertension Age > 75 years Diabetes Mellitus Prior stroke/tia (1 point) (1 point) (1 point) (1 point) (2 points) OAC in case score 2 Cage et al JAMA 2001

12 Wat is de Praktijk? Enrolment per Country 5333 patients 35 countries 182 hospitals European Society of Cardiology Euro Heart Survey Nieuwlaat et al EHJ 2005, 2007

13 VKA in High-Risk Patients by Country ARMENIA AUSTRIA BELGIUM BULGARIA CROATIA CYPRUS CZECH REPUBLIC DENMARK EGYPT FINLAND FRANCE GEORGIA GERMANY GREECE HUNGARY ISRAEL ITALY LITHUANIA MACEDONIA MOLDOVA POLAND PORTUGAL ROMANIA RUSSIAN FEDERATION SERBIA & MONTENEGRO SLOVAKIA SLOVENIA SPAIN SWEDEN SWITZERLAND THE NETHERLANDS TUNISIA TURKEY UKRAINE UNITED KINGDOM European Society of Cardiology Euro Heart Survey % Patients

14 Antithrombotics according to CHADS2 score % Patients No antithrombotic drug Other drug only Antiplatelet OAC + antiplatelet OAC only 0 (n=332) 1 (n=697) 2 (n=722) 3 (n=371) 4 (n=172) 5 (n=72) 6 (n=15) European Society of Cardiology Euro Heart Survey

15 Multivariate analysis antithrombotic guideline deviance Nieuwlaat et al. Am Heart J 2007

16 International Journal of Clinical Practice 2007

17 OAC prescription per CHADS 2 risk score without contraindications % Patients % Patients (n=61) GP 1 (n=95) 2 (n=76) 3 (n=59) % Patients (n=34) 0 0 (n=26) 1 (n=72) 2 (n=65) None ASA OAC 3 (n=64) 4-6 (n=30) Internists 20 Cardiologists 0 0 (n=180) 1 (n=285) 2 (n=184) CHADS 2 score 3 (n=98) 4-6 (n=52) Examine-AF

18 The AF-Clinic An integrated chronic care program for patients with atrial fibrillation Substitution of care by specialized nurses Management of AF according to guidelines Dedicate knowledge software Supervision by cardiologists Hendriks, Tieleman, European Heart Journal 2012

19 Database; to be used for correspondence, management, research activities; performance measures Visit 1 nurse Visit 2 nurse and cardiologist Follow-up visits by Nurse (cardiologist stand-by)

20 Methods PROBE: Prospective, Randomized, Open label, Blinded Endpoint trial, comparing AF-Clinic to routine clinical care Randomization of 712 pts with newly diagnosed AF into Nurse-led care group or Usual care group Inclusion criteria Age 18 years AF documented on ECG Exclusion criteria Unsatisfactorily treated co-morbidity (hypertension, heart failure, unstable angina) Follow-up at least 1 year

21 Primary endpoint (composite) Cardiovascular mortality Cardiovascular hospitalization for Heart failure Stroke Acute myocardial infarction Systemic embolism Bleeding Atrial Fibrillation Syncope Sustained ventricular tachycardia Cardiac arrest Life-threatening effects of drugs

22 Results: composite endpoint 35% RRR (HR 0.65, 95% CI ) Hendriks, Tieleman, European Heart Journal 2012

23 Cardiovascular hospitalization: 34% reduction % Endpoint Nurse-led Care Usual Care Heart failure Acute myocardial infarction Stroke Major bleeding Arrhythmic events Life-threatening effects of drugs Hendriks, Tieleman, European Heart Journal 2012

24 Cardiovascular death: 72% reduction 4 % Endpoint Cardiac arrhythmic Cardiac non arrhythmic Vascular non cardiac 0 Nurse-led Care Usual Care Hendriks, Tieleman, European Heart Journal 2012

25 Results: guideline adherence Juiste vorm van antistolling: AF Clinic 99% versus care as usual 83%

26 Conclusion Nurse-led, guideline based, software- supported AF-Clinic, supervised by cardiologist improves clinical outcome in patients with atrial fibrillation in comparison to routine clinical care

27 Toekomst moeilijker: CHA 2 DS 2 vasc Prior myocardial infarction, peripheral artery disease, aortic plaque.

28 2010 ESC guidelines on antithrombotic therapy in AF recommendations based on the CHA 2 DS 2 -VASc score: Score of 2: Oral anticoagulation (INR ) Score of 1: Oral anticoagulation (INR ) (preferred option) or Aspirin ( mg/day) Score of 0: Aspirin ( mg/day) or no therapy (preferred option) ESC = European Society of Cardiology; INR = international normalized ratio ESC guidelines: Camm J et al. Eur Heart J 2010

29 Bleeding risk assessment with HAS-BLED HAS-BLED risk criteria Score HAS-BLED total score N Number of bleeds Bleeds per 100 patient-yrs* Hypertension 1 Abnormal renal or liver function (1 point each) 1 or 2 Stroke 1 Bleeding 1 Labile INRs Elderly (e.g. age >65 yrs) Drugs or alcohol (1 point each) 1 1 or INR=international normalized ratio Pisters R et al. Chest. 2010; ESC guidelines: Camm J et al. Eur Heart J 2010 *P value for trend = 0.007

30 Toekomst toch makkelijker? NOACs: alternatieven voor acenocoumarol Directe trombineblokkers Directe blokkers factor Xa dabigatran rivaroxaban apixaban

31 RE-LY : time to first stroke or systemic embolism 0.05 Warfarin RR 0.91 (95% CI: ) P<0.001 (NI) P=0.34 (Sup) Dabigatran 110 mg BID Cumulative hazard rates Dabigatran 150 mg BID RRR 34% RR 0.66 (95% CI: ) P<0.001 (NI) P<0.001 (Sup) Years BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:

32 Phase III RE-LY : major bleeding RR 0.80 (95% CI: ) P=0.003 (Sup) RR 0.93 (95% CI: ) Major bleeding (%/yr) RRR 20% 3.11 P=0.31 (Sup) Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Events/n: 322/ / /6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:

33 Phase III RE-LY : intracranial bleeding RR 0.31 (95% CI: ) P<0.001 (Sup) RR 0.40 (95% CI: ) Intracranial bleeding (%/yr) RRR 69% 0.30 P<0.001 (Sup) RRR 60% Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Events/n: 27/ / /6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:

34 De RE-LY studie: conclusies Dabigatran verminderd zowel bloedingen als thrombo-embolische complicaties Beide doses bieden voordelen tov warfarine 150 mg 2dd superieure effectiviteit, evenveel bloedingen 110 mg 2dd minder bloedingen, gelijke effectiviteit Beide doses minder cerebrale bloedingen Connolly SJ et al. N Engl J Med 2009;361: ;

35 ROCKET-AF: stroke and non-cns embolism non-inferiority analysis (ITT population) Primary efficacy outcome Warfarin Rivaroxiban 3 similar efficacy 60 Rivaroxaban 50 2 and safety 40 (fewer cerebral Cumulative event rate (%) bleeding) No. at risk Rivaroxaban Warfarin Days since randomization Event rates per 100 patient-years; ITT = intention to treat Patel MR et al. N Engl J Med 2011;365: HR 0.88 (95% CI: ) P<0.001 (non-inferiority) 35

36 ARISTOTLE Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin

37 Major Bleeding ISTH definition 31% RRR Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 No. at Risk Apixaban Warfarin

38 Conclusie n Screening op AF is mogelijk en noodzakelijk n Gestructureerde behandeling van ptn met AF op gespecialiseerde AF poli reduceert de morbiditeit en mortaliteit n Het gebruik van NOACs kan een verdere verbetering van de prognose van AF patienten geven

39

40 Waarom een AF poli Gestructureerde aandacht voor onderliggend lijden Afweging TE risico versus bloedingsrisico Betere selectie ritme versus rate-control Beter voorlichting van belang voor compliance (mn van belang bij behandeling met NOACs)

41 Mant et al Lancet 2007

42 Mant et al Lancet 2007

43 Mant et al Lancet 2007

44 Mant et al Lancet 2007

45 ROCKET-AF: stroke and non-cns embolism superiority analysis n Rivaroxaban is niet superieur in Intention to treat analyse (12% RRR) n wel superieur in on-treatment analyse (21% RRR) Favours rivaroxaban Favours warfarin Event rates per 100 patient-years; error bars = 95% confidence intervals; based on safety on-treatment or ITT populations; CI = confidence interval; CNS = central nervous system; HR = hazard ard ratio; ITT = intention-to to-treattreat Patel MR et al. N Engl J Med 2011;365:

46 Warfarin superior in reducing the stroke risk in AF patients Control worse Control better Warfarin vs Placebo RRR 64% (95% CI: 49 74%) Aspirin vs Placebo RRR = 19% (95% CI: 1 to 35%) Warfarin vs Aspirin RRR 38% (95% CI: 18 52%) RRR (%) Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857 67

47 Baseline characteristics Characteristics Nurse-led Care (N = 356) Usual Care (N = 356) Age - yr 66 ± ± 12 Male sex - no (%) 197 (55.3) 221 (62.1) Type of AF - no (%) Paroxysmal 190 (53.4) 203 (57.0) Persistent 68 (19.1) 44 (12.4) Permanent 75 (21.1) 84 (23.6) Symptomatic AF - no (%) 294 (82.6) 296 (83.1) History of underlying disease Hypertension 187 (52.5) 193 (54.2) Diabetes mellitus 50 (14.0) 46 (12.9) Previous stroke / TIA 44 (12.4) 45 (12.6) Coronary artery disease 33 (9.3) 38 (10.7) Myocardial infarction 19 (5.3) 22 (6.2) Congestive heart failure 25 (7.0) 25 (7.0) Peripheral vascular disease 13 (3.7) 20 (5.6) Hyperthyroidism 12 (3.4) 12 (3.4) Mitral or aortic valve disease 12 (3.4) 21 (5.9) No underlying heart disease 6 (1.7) 7 (2.0)

48 Baseline characteristics Characteristics Nurse-led Care (N = 356) Usual Care (N = 356) CHADS2 score - no (%) (30.0) 95 (26.7) (34.3) 135 (37.9) >1 127 (35.7) 126 (35.4) Threatment - no (%) Beta-blocker 164 (46.1) 187 (52.5) Digitalis 59 (16.6) 43 (12.1) Verapamil 44 (12.4) 18 (5.1) Vaughan-Williams class I & III 105 (29.1) 88 (24.7) Vitamin K antagonist 218 (61.2) 188 (52.8) Aspirin 118 (33.1) 108 (30.3) Echocardiographic findings Size of left atrium, long axis - mm 42 ± 6 43 ± 8 LV end-diastolic size - mm 49 ± 6 49 ± 6 LV end-systolic size - mm 34 ± 6 34 ± 6 LV ejection fraction - % 57 ± ± 12

49 ROCKET-AF: safety outcomes Based on safety on-treatment population CI = confidence interval; Hgb = haemoglobin; HR = hazard ratio Patel MR et al. N Engl J Med 2011;365:

50 AVERROES: Stroke or systemic embolism in pts unsuitable for VKA therapy 0.05 Hazard ratio with apixaban, 0.45 (95% CI, ) p<0.001 Cumulative Hazard Aspirin Apixaban Time (months) Adapted from Connolly SJ et al. N Engl J Med 2011;364:

51 Averroes: similar rates of major bleeding Hazard ratio with apixaban, 1.13 (95% CI, ) p= Cumulative hazard Apixaban Aspirin No. at Risk Time (months) Aspirin Apixaban CI, confidence interval Connolly SJ et al. N Engl J Med 2011;364: