I will not discuss off label use or investigational use in my presentation. Consultant for: Astra Zeneca, BayerHealthcare, Boehringer Ingelheim,

Transcription

1 I will not discuss off label use or investigational use in my presentation. Consultant for: Astra Zeneca, BayerHealthcare, Boehringer Ingelheim, Daiichi- Sankyo, Lilly, Sanofi-Aventis Honoraria from: Astra Zeneca, BayerHealthcare, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Sanofi-Aventis

2 Anticoagulants in Special Populations: In Patients Undergoing Non Cardiac Surgery Dietrich C. Gulba, MD, PhD Professor of Medicine KKO St. Marien Hospital Oberhausen, Germany

3 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) prcedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

4 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) prcedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

5 Basic considerations that guide perioperative anticoagulation therapy I. After termination of oral anticoagulation it takes an average 3 days (Coumadin/Warfarin) or 5 days with (Acetocumarol/Marcumar) to reach subtherapeutic levels

6 Basic considerations that guide perioperative anticoagulation therapy I. After termination of oral anticoagulation it takes an average 3 days (Coumadin/Warfarin) or 5 days with (Acetocumarol/Marcumar) to reach subtherapeutic levels II. The European Guidelines allow (additional) two days with subtherapeutic INR

7 Procedure related sequel Thrombotic Risk Low Risk: Dental Ophtalmological Skin Medium Risk Minor or medium gastrointetinal Heart Lung High Risk Orthopedic Malignancy Infection Urogenital Central nervous system

8 Low Risk: Dental Ophtalmological Skin Procedure related sequel Bleeding Risk Medium Risk Minor or medium gastrointetinal Heart Lung High Risk Orthopedic Malignancy Infection Urogenital Central nervous system Thrombotic Risk Low Risk: Dental Ophtalmological Skin Medium Risk Minor or medium gastrointetinal Heart Lung High Risk Orthopedic Malignancy Infection Urogenital Central nervous system

9 Low Risk: Dental Ophtalmological Skin Procedure related sequel Bleeding Risk Medium Risk Minor or medium gastrointetinal Heart Lung High Risk Orthopedic Malignancy Infection Urogenital Central nervous system Thrombotic Risk Low Risk: Dental Ophtalmological Skin Medium Risk Minor or medium gastrointetinal Heart Lung High Risk Orthopedic Malignancy Infection Urogenital Central nervous system The same risks for thrombosis and bleeding Individual risk constellation also to be considered

10 Basic considerations that guide perioperative anticoagulation therapy I. After termination of oral anticoagulation it takes an average 3 days (Coumadin/Warfarin) or 5 days with (Acetocumarol/Marcumar) to reach subtherapeutic levels II. The European Guidelines allow (additional) two days with subtherapeutic INR III. Many surgical procedures can safely be performed with full or mildely subtherapeutic anticoagulation

11 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) procedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

12 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. Stroke rate [%/year] Stroke rate expected During low INR period adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* 0* ,3 0,8 0,007 0, ,2 1,4 0,011 0, ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * Spontaneous strokeincidnece 1-1,2%/year

13 CHADS2-VASc Score and AF associated thromboembolic risk Data from the European Heart Survey % CHADS2 Index

14 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. Stroke rate [%/year] Stroke rate expected During low INR period adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* 0* ,3 0,8 0,007 0, ,2 1,4 0,011 0, ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * Spontaneous strokeincidnece 1-1,2%/year

15 Cerebrales Embolierisiko einer vom CHADS2-VASc Score % CHADS2 Index

16 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. Stroke rate [%/year] Stroke rate expected During low INR period adjusted extrapol. for 3d for 7 d Stroke Risk Calculator: 0 1 0* 0* 0* 0* ,3 0,8 0,007 0, ,2 1,4 0,011 0,026 Expected Stroke Risk ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 = Risk/year X No. Low INR days 365 * Spontaneous strokeincidnece 1-1,2%/year

17 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. Stroke rate [%/year] Stroke rate expected During low INR period adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* 0* ,3 0,8 0,007 0, ,2 1,4 0,011 0, ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * Spontaneous strokeincidnece 1-1,2%/year

18 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* 0* ,3 0,8 0,007(0,008) 0,015(0,023) ,2 1,4 0,011 0, ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * inadaequate patient No. to allow an appropriate risk assessment (error > 0,1% per additional patient affected) * Spontaneous strokeincidnece 1-1,2%/year Stroke rate [%/year] Stroke rate expected During low INR period

19 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* 0* ,3 0,8 0,007 0, ,2 1,4 0,011 0, ,2 2,1 0,017 0, ,0 3,0 0,025 0, ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * Spontaneous stroke incidnece 1-1,2%/year Stroke rate [%/year] Stroke rate expected During low INR period * inadaequate patient No. to allow an appropriate risk assessment (error > 0,1% per additional patient affected) Assumption: acceptable stroke risk during subtherapuetic period: 0,1% or 1:1.000

20 Subtherapeutic INR Period and Inherrent Stroke Risc Stroke risc (%) 0,15 Assumption: accaptable stroke risc is 1 : ,1 0,05 3d CHADS-VASc Risk calculated on the basis of non valvular atrial fibrillation patients.

21 Subtherapeutic INR Period and Inherrent Stroke Risc Stroke risc (%) 0,3 Assumption: accaptable stroke risc is 1 : ,2 0,1 3d 7d CHADS-VASc Risk calculated on the basis of non valvular atrial fibrillation patients.

22 Subtherapeutic INR Period and Inherrent Stroke Risc Stroke risc (%) 0,6 Assumption: accaptable stroke risc is 1 : ,4 0,2 3d 7d 14d CHADS-VASc Risk calculated on the basis of non valvular atrial fibrillation patients.

23 Subtherapeutic INR Period and Inherrent Stroke Risc Stroke risc (%) 0,6 Assumption: accaptable stroke risc is 1 : ,4 0,2 3d 7d 14d CHADS-VASc Risk calculated on the basis of non valvular atrial fibrillation patients.

24 Cerebrales Embolierisiko einer vom CHADS2-VASc Score % CHADS2 Index

25 Hypo-anticoagulation (switching period) associated stroke risk CHADS- VASC score Patient No. adjusted extrapol. for 3d for 7 d 0 1 0* 0* 0* (0,009) 0* (0,019) ,3 0,8 0,007(0,008) 0,015(0,023) ,2 1,4 0,011(0,018) 0,026(0,042) ,2 2,1 0,017(0,026) 0,040(0,061) ,0 3,0 0,025(0,032) 0,057(0,077) ,7 4,0 0,032 0, ,8 5,2 0,043 0, ,6 6,8 0,056 0, ,7 9,7 0,080 0, ,2 15,2 0,125 0,292 * Spontaneous strokeincidnece 1-1,2%/year Stroke rate [%/year] Stroke rate expected During low INR period * inadaequate patient No. to allow an appropriate risk assessment (error > 0,1% per additional patient affected) Assumption: acceptable stroke risk during subtherapuetic period: 0,1% or 1:1.000

26 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) procedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

27 Artificial Valve Associated Thromboembolic Risk General risk factors: Advanced Age Left atrial enlargement Low LV ejection fraction / Congestive heart failure History of thromboembolism Increased fibrinogen Atrial fibrillation

28 Artificial Valve Associated Thromboembolic Risk Faktors that are Simultaneously Risk Factors for TE Risk in Atrial Fibrillation General risk factors: Advanced Age Left atrial enlargement Low LV ejection fraction / Congestive heart failure History of thromboembolism Increased fibrinogen Atrial fibrillation

29 Artificial Valve Associated Thromboembolic Risk Faktors that are Simultaneously Risk Factors for TE Risk in Atrial Fibrillation General risk factors: Advanced Age Left atrial enlargement Low LV ejection fraction / Congestive heart failure History of thromboembolism Increased fibrinogen Atrial fibrillation In essence: Thrombtic risk estimate model for atrial fibrillation patients largely applicable

30 Hence: Risk assessment for pts with artificial valves may also be based on the atrial fibrillation risk assessment models

31 Artificial Valve Associated Thromboembolic Risk Mechanical valve Ball valve > Tilting Disc valve > Bileaflet valve 1st generation (Starr Edwards, Bjork Shiley) >> 2nd & 3rd generation: (St. Jude Medical, Carbomedics, Medtronic Hall etc.)

32 Artificial Valve Associated Thromboembolic Risk Mechanical valve Ball valve > Tilting Disc valve > Bileaflet valve 1st generation (Starr Edwards, Bjork Shiley) >> 2nd & 3rd generation: (St. Jude Medical, Carbomedics, Medtronic Hall etc.) Tricuspid position > Mitral >> Aortic

33 Artificial Valve Associated Thromboembolic Risk Mechanical valve Ball valve > Tilting Disc valve > Bileaflet valve 1st generation (Starr Edwards, Bjork Shiley) >> 2nd & 3rd generation: (St. Jude Medical, Carbomedics, Medtronic Hall etc.) Tricuspid position > Mitral >> Aortic Bioprosthesis and valvular repair carry a low thrombotic risk

34 Hence: Risk assessment for pts with artificial valves may also be based on the atrial fibrillation risk assessment models But: For the additional valve specific thromboembolic risk factors, the CHADS-VASc-Score certainly underestimates the thromboembolic risk of such pts.

35 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) procedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

36 Subtherapeutic INR Period and Inherrent Stroke Risc Suggested Model for Risc calculation in none lone AF patients: Add points for each of the following conditions: Aortic valve: Bioprothesis: 0 ; 2 nd or 3 rd gen. mechanical valve: 1; 1 st gen. mechanical: 3

37 Subtherapeutic INR Period and Inherrent Stroke Risc Suggested Model for Risc calculation in none lone AF patients: Add points for each of the following conditions: Aortic valve: Bioprothesis: 0 ; 2 nd or 3 rd gen. mechanical valve: 1; 1 st gen. mechanical: 3 Mitral Valve: Repair: 0; Bioprothesis:1; 2 nd or 3 rd gen. mechanical: 2; 1 st gen. mechanical: 3

38 Subtherapeutic INR Period and Inherrent Stroke Risc Suggested Model for Risc calculation in none lone AF patients: Add points for each of the following conditions: Aortic valve: Bioprothesis: 0 ; 2 nd or 3 rd gen. mechanical valve: 1; 1 st gen. mechanical: 3 Mitral Valve: Repair: 0; Bioprothesis:1; 2 nd or 3 rd gen. mechanical: 2; 1 st gen. mechanical: 3 Other: Large atrium with low flow, flow in LAA < 0,25m/sec, spontaneous Echo contrast, or TEE proven thrombus : 1

39 Subtherapeutic INR Period and Inherrent Stroke Risc Suggested Model for Risc calculation in none lone AF patients: Add points for each of the following conditions: Aortic valve: Bioprothesis: 0 ; 2 nd or 3 rd gen. mechanical valve: 1; 1 st gen. mechanical: 3 Mitral Valve: Repair: 0; Bioprothesis:1; 2 nd or 3 rd gen. mechanical: 2; 1 st gen. mechanical: 3 Other: Large atrium with low flow, flow in LAA < 0,25m/sec, spontaneous Echo contrast, or TEE proven thrombus : 1 In Summary: For patients with valvular or other structural heart disease add 1 (aortic bioprothesis) up to 4 (artificial mitral valve & large LA with spontaneous Echo contrast) additional risk points

40 Subtherapeutic INR Period and Inherrent Stroke Risc Suggested Model for Risc calculation in none lone AF patients: Add points for each of the following conditions: Aortic valve: Bioprothesis: 0 ; 2 nd or 3 rd gen. mechanical valve: 1; 1 st gen. mechanical: 3 Mitral Valve: Repair: 0; Bioprothesis:1; 2 nd or 3 rd gen. mechanical: 2; 1 st gen. mechanical: 3 Other: Large atrium with low flow, flow in LAA < 0,25m/sec, spontaneous Echo contrast, or TEE proven thrombus : 1 In Summary: For patients with valvular or other structural heart disease add 1 (aortic bioprothesis) up to 4 (artificial mitral valve & large LA with spontaneous Echo contrast) additional risk points In artificial valve patients in SR you may substract 1 point

41 Subtherapeutic INR Period and Inherrent Stroke Risc Stroke risc (%) 0,6 Assumption: accaptable stroke risc is 1 : ,4 0, Risk calculated on the basis of non valvular atrial fibrillation patients. Suggested Model for Risc calculation in none lone AF patients: For patients with valvular or other structural heart disease add 1 (aortic bioprthesis) up to 4 (artificial mitral valve & large LA with spontaneous Echo contrast) additional risk points 8 9 3d 7d 14d modified CHADS-VASc

42 Anticoagulation in Patients Undergoing Non Cardiac Surgery Basic considerations: Stop of oral coumadins (switch) procedure related risks etc How can the CHADS-VASc score be transfered into a simple switch algorithm Special conditions with carriers of artificial valves Considerations and suggestions for the adaptation of the CHADS-Vasc score to the risk of carriers of artificial valves Considerations and suggestions for a practical switch algorithm to be used in patients anticoagulated with one of the new oral anticoagulants

43 Wissenschaftliche Information Anwendung geht über die arzneimittelrechtliche Zulassung hinaus. Bridging: Dosing Scheme Tab: Alternative Umstellung einer oralen Antikoagulation auf niedermolekulares Heparin entnommen aus: Omran H. et al. Niedermolekulares Heparin oder unfraktioniertes Heparin bei der Umstellung dauerhaft oral antikoagulierter Patienten vor interventionellen Eingriffen Med Welt 2001;52:

44 Switch of anticoagulation with new anticoagulants Necessary clearing period Dabigatran 24 to 36h Last dose evening two days before operation Resume therapy Evening after operation 4,5 nm (4) First dose after resumption of therapy DVT prevention dose (75mg) Each additional dose Full dose (110 mg or 150 bd) Pts. with certain circumstances (renal failure or hepatic disease etc.) may require longer clearing periods clinical judgement may be required

45 Dabigatran-Plasmakonzentration (ng/ml) Plasmakoncentration Dabigatranetexilat 150mg, single dose Mittelwerte nüchtern Pantoprazol postprandial Zeit (Stunden) Stangier J, et al. J Clin Pharmacol 2005; 45:

46 Pharmacology Rivaroxaban Mode of action Rivaroxaban Direct F Xa-Inhibitor Prodrug Mean terminal half life time No (8) 7-11 h (9) t max 2-4 h (9) K i Bioavailability Accumulation 0,4 ± 0,02 nm (7) 80% - 100% (9) No Accumulation up to 30 mg 2x/d (6) cealing effect Exkretion ~2/3 renal ( 1/3 metabolized) ~1/3 faeces/bile(5,7,9) Dabigatran: Pradaxa-Fachinformation Stangier J et al. J Clin Pharmacol 2005; Br J Clin Pharmacol Weitz JI et al. Thromb Haemost Wienen W et al. Thromb Haemost Rivaroxaban: Kibitza D et al. Clin Pharm Ther 2005; Eur J Clin Pharmacol 2005; Perzborn E et al. J Thromb Haemost Weinz C et al. Drug Metab Rev Xarelto-Fachinformation 2008

47 Inhibition of Faktor-Xa-Activity (%) Pharmacology of RIVAROXABAN Rivaroxaban 5 mg 2x/d (N = 7) Rivaroxaban 10 mg 2x/d (N = 7) Rivaroxaban 20 mg 2x/d (N = 7) Rivaroxaban 30 mg 2x/d (N = 8) Placebo (N = 21) Kubitza D et al. Eur J Clin time (d) Pharmacol 2005.

48 Suggested Bridging Dosing Scheme for the New Oral Antikoagulants

49 Suggested Bridging Dosing Scheme for the New Oral Antikoagulants Dabigatran: Stop Treatment two days before surgery Resume full dose treatment the day after surgery

50 Suggested Bridging Dosing Scheme for the New Oral Antikoagulants Dabigatran: Stop Treatment two days before surgery Resume full dose treatment the day after surgery Rivaroxaban: Stop treatment the day before surgery Resume full dose treatment the day after surgery

51 Suggested Bridging Dosing Scheme for the New Oral Antikoagulants Dabigatran: Stop Treatment two days before surgery Resume full dose treatment the day after surgery Rivaroxaban: Stop treatment the day before surgery Resume full dose treatment the day after surgery If the surgeon is uneasy with the early restart of antithrombotic therapy, start re-anticoagulation first with a thromboprohylactic dose

52 Summary From the European Heart Survey Cohort (CHADS-VASc Score) a good estimate of the subtherapeutic anticoagulation risk in atrial fibrillation patients can bwe derived A modified CHADS-VASc Score may also apply for artificial valve carriers With the new oral anticoagulants (Dabigatran, Rivaroxaban) simplified swithing shemes apply

53 Thank You For Your attention!