A) Teaching Case B) Telefonanfragen der Hausärzte C) Dr House-Fälle

Transcription

1 A) Teaching Case B) Telefonanfragen der Hausärzte C) Dr House-Fälle Solothurn JH Beer, Baden

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4 Bruise Control I 1) Mein Patient klagt über häufiges Nasenbluten mit unterschiedlicher Heftigkeit, zuletzt und besonders lästig während eines Flugs nach Mallorca. Er steht unter NOAC (Rivaroxaban) wegen einer unprovozierten TVT vor 3 Monaten. Er hat R deshalb selber abgesetzt. Frage: Mehr Blutungen unter NOACs? Sind kleine Blutungen relevant? Management von Blutungen? Dauer der AK? Risiko-Abwägungen?

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8 RE-MEDY and RE-SONATE Extension Trials 2,486 pts 3m after VTE and OAC: vs 2x150mg Dabigatran vs placebo ctr Recurrent TE Bleeding Major Bleeds: 0.3% vs 0.0% MB orcr NMB: 5.3% vs 1,8% Any bleeding 10.5% 37/662=5.6% 5.9% 3/681=0.4% NEJM 2013; 368: 709

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10 Compliance 11% adherence <80% 30% missed some doses from daily, to 2x in 6 years 20% bleedings, 2x major 1x stroke 33% some degree of dyspepsia

11 Impact of Poor Adherence: Efficacy and Safety Issues Occasional toxicity Periodic loss of effectiveness Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories. Annu Rev Pharmacol Toxicol. 2012;52:

12 BMJ, , Vol. 347, p.11

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15 Major Bleeding NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi (2.87) 421 (3.57) Dabi (3.32) 421 (3.57) Riva 395 (3.6) 386 (3.4) Apixaban 327 (2.13) 462 (3.09) Favors NOAC Not head to head comparison For illustrative purpose only adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: Favors warfarin

16 Hemorrhagic Stroke NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi (0.12) 45 (0.38) (ITT) Dabi (0.10) 45 (0.38) (ITT) Riva (safety AT) Apixaban 29 (0.26) 50 (0.44) 40 (0.24) 78 (0.47) (ITT) Favors NOAC Favors warfarin ITT: Intention to Treat AT: as treated. Not head to head comparison For illustrative purpose only adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365:

17 Death From Any Cause NOAC Warfarin No. of events (%/yr) HR 95% CI Dabi 110 (ITT) Dabi 150 (ITT) Riva (ITT) 446 (3.75) 487 (4.13) 438 (3.64) 487 (4.13) (4.5) 632 (4.9) Riva (safety AT) 208 (1.87) 250 (2.21) Apixaban (ITT) 603 (3.52) 669 (3.94) Favors NOAC Favors warfarin Not head to head comparison For illustrative purpose only adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365:

18 Bleeds (GIT)

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20 Obere oder Untere GI-Blutungen mit Dabigatran Circ 2011; 123: 2363 (mai 31)

21 Cumulative risk Stroke/systemic embolism: RE-LY + RELY-ABLE All dabigatran patients patients D150: 1.25 %/yr D110: 1.54 %/yr HR: % CI: Warfarin (RE-LY only)* Dabigatran 150 mg BID Dabigatran 110 mg BID 0.02 No. at risk D110 D Years BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio Connolly SJ et al. AHA Scientific Sessions, 2012 / * data from RE-LY

22 Medicare Data USA covering patients > 65 years has been completed and

23 US-Postmarketing Mini Sentinel 0.5%/y 1.1%/y 0.25%/y 0.8%/y NEJM 2013; March 13

24 TH 2008; 100:1047

25 Bleeding Risk of the Excluded 40% 1. How many of the patients with OAC admitted for bleeding had exclusion criteria (How many of the patients with OAC admitted for infection had exclusion criteria) 23% Blood (may) 2008; 111: 4473

26 Exclusion Criteria not suitable for OAC (compliance, alcohol...) Cancer Comedication (eg plt inhibitors) Previous stroke Cardiac comorbidity Other comorbidity (renal) Blood 2008; 111: 4473

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29 Table 2 Drug drug interactions and recommendations toward dosing according to EHRA practical guide [20] Via Dabigatran Apixaban Rivaroxaban Atorvastatin P-Gp competition and CYP + 18 % (AUC) Minor increase No effect 3A4 inhibition Digoxin P-Gp competition No effect No effect No effect Verapamil P-Gp competition (weak CYP3A4 inhibition) % Moderate increase Minor increase Cave if CrCl ml/min Diltiazem P-Gp competition und CYP3A4 inhibition No effect + 40 % Minor increase Cave if CrCl ml/min Quinidine P-Gp competition + 50 % Moderate increase +50 % Amiodarone P-Gp competition % Moderate increase Minor increase Cave if CrCl ml/min Dronedarone P-Gp and CYP3A4 inhibition % Moderate increase Moderate increase Ketoconazole; itraconazole; P-Gp competition, CYP3A % % % voriconazole inhibition Fluconazole CYP3A4 inhibtion No data yet Moderate increase + 42 % Cyclosporin P-Gp Kompetition Strong increase Moderate increase + 50 % Clarithromycin; erythromycin P-Gp competition and % Strong increase % CYP3A4 inhibition HIV protease inhibitors P-Gp competition and Strong increase Strong increase % CYP3A4 inhibition Rifampicin; St John s wort; P-Gp and CYP3A4/CYP2J2-66 % - 54 % - 50 % phenytoin; carbamazepine inducers Antacids (PPI, H2B) GI absorption % No effect No effect Age 80 y. Increased plasma level Age 75 y. Increased plasma level Weight 60 kg Increased plasma level Red: Contraindicated/not recommended Orange: Reduce dose (dabigatran 2 x 110 mg; apixaban 2 x 2.5 mg; rivaroxaban 1 x 15 mg) Yellow: Consider dose reduction in presence of another yellow factor

30 Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg Jun;101(7): BJS 2014

31 Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg Jun;101(7): BJS 2014

32 Lai A et al. Perioperative management of patients on new oral anticoagulants. Br J Surg Jun;101(7): BJS 2014

33 Perioperative Bridging Strategy Becomes Easier Blood 2012; 120:2954

34 Bridging Strategy: Postop Restart Blood 2012; 120:2954

35 TE - Risk Stratification perioperatively Blood 2012; 120:2954

36 Stratification perioperatively: High Bleeding Risk Blood 2012; 120:2954

37 Stratification perioperatively: Low Bleeding Risk Blood 2012; 120:2954

38 Higher Recurrence Rates in Unprovoked VTE Cumulative Incidence of VTE Recurrence (%) After discontinuation of anticoagulation, VTE recurrence is more than 2-fold higher in patients with an unprovoked vs provoked VTE Data from Italy Unprovoked (n=864, 53%) Provoked (n=762, 47%) 40.8% 52.6% % 22.5% % 6.6% Time After Discontinuation of Anticoagulation (years) Prandoni P et al. Haematologica. 2007;92:

39 Approach to Long-Term and Extended Treatment of VTE (After Acute Treatment Through 3 to 6 Months After Diagnosis) Patient with PE or DVT* stable on acute phase treatment Etiology of VTE Transient risk factor Unprovoked VTE Malignancy Treat with VKA or approved NOAC Treat with VKA or approved NOAC Treat with LMWH Discontinue treatment after 3 mo. Consider extended treatment (>6 mo.) Consider extended treatment (>6 mo.) Low to moderate Bleeding risk? High VTE recurrence risk Continue treatment indefinitely with VKA or approved NOAC Discontinue treatment after 3 to 6 mo. High VTE recurrence risk Low VTE recurrence risk or high bleeding risk Consider discontinuing treatment in women at low risk of VTE recurrence or if strong patient preference to discontinue Continue LWMH or switch to approved NOAC or a VKA Discontinue AC or continue LMWH, or switch to approved NOAC or VKA * Upper or lower extremity. AC=anticoagulation; LMWH=low molecular weight heparin; NOAC=novel oral anticoagulant; VKA=vitamin K antagonist. Wells et al. JAMA. 2014;311(7):

40 Acute treatment 5-21 days* Mid-term treatment 3-12 months* Extended treatment LMWH Dabigatran 150 mg b.i.d. Edoxaban 60 mg/d Dabigatran 150 mg b.i.d. Edoxaban 60 mg/d Rivaroxaban 15 mg b.i.d. Rivaroxaban 20 mg/d Rivaroxaban 20 mg/d Apixaban 10 mg b.i.d. Apixaban 5 mg b.i.d. Apixaban 5 mg b.i.d. or Apixaban 2.5 mg b.i.d. * depending on study design Figure 2: acute and extended treatment of VTE with DOACs Holy, Beer Sem TH 2014

41 Novel Anticoagulants Dosing acc to renal function 41 GFR Dabigatran (Pradaxa ) Rivaroxaban (XARELTO ) Apixaban (Eliquis ) 60 ml/min 2x150 mg 20 mg 2x5 mg 50 ml/min 40 ml/min 2x110 mg 15 mg 2x2.5 mg (if in comb.: - 80 J. or - 60 kg 30 ml/min 15 mg 15 ml/min 10 ml/min Bei Patienten mit schwerer Niereninsuffizienz (Kreatinin-Clearance ml/min) ist Vorsicht geboten, da hier nur begrenzte klinische Daten vorliegen. Bei diesen Patienten wurde eine signifikant erhöhte Rivaroxaban Plasmakonzentration (im Mittel 1,6 fach) gemessen. Sie müssen von Beginn der Behandlung an sorgfältig auf Anzeichen und Symptome für Blutungskomplikationen und Anämie überwacht werden und die plasmatische Gerinnung sollte kontrolliert werden. Bei jedem ungeklärten Hämoglobin- oder Blutdruckabfall sollte nach der Blutungsquelle gesucht werden. GFR: Glomeruläre Filtrationsrate, TEP: Totalendoprothese, VHF: Vorhofflimmern, TVT: tiefe Beinvenenthrombose Eliquis (Apixaban) Swiss SmPC available at Pradaxa (Dabigatran) Swiss SmPC available at Xarelto (Rivaroxaban Swiss SmPC available at

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