Dr Calum Young Cardiologist Tauranga

Transcription

1 Dr Calum Young Cardiologist Tauranga 8:30-9:25 WS #93: New Oral Anticoagulant Drugs and Management of AF 9:35-10:30 WS #105: New Oral Anticoagulant Drugs and Management of AF (Repeated)

2 GPCME 2016: Anticoagulation in 2016 Calum Young Cardiologist Tauranga

3 Format Why worry? The Burden of AF Five cases Discussion with each case A review of NOACs after Case Two A review of managing bleeding after Case Three Quiz (a very relaxed one!) Or, we can have a brief session on the basics and a longer tea break

4 The Burden of AF Overall prevalence in population is at least 1%, but rises with age (>10% of 80 year olds) Common incidental finding Management: Symptom control (rate versus rhythm control) Risk reduction Stroke Rate-related cardiomyopathy

5 The Burden of AF Overall prevalence in population is at least 1%, but rises with age (>10% of 80 year olds) Common incidental finding Management: Symptom control (rate versus rhythm control) Risk reduction Stroke Rate-related cardiomyopathy

6 The Burden of AF Stroke Risk: Is defined by (CHADS 2 -VASC 2 ): Congestive heart failure Hypertension Age (2 points if 75+ years) Diabetes Stroke/ TIA history (2 points) Vascular disease Sex

7 The Burden of AF Stroke Risk: NOT defined by: Pattern of AF (paroxysmal versus persistent) Left atrial size

8 The Burden of AF

9 What s Wrong With Warfarin?

10 What s Wrong With Warfarin? INR must be kept between strict boundaries (usually ) Risk of bleeds versus risk of stroke Fixed dose regimens a failure! Regular blood tests Rural patients, travellers, needle phobics, poor veins (although options now for finger-prick testing) Medication and dietary interactions Image problem: rat poison

11 What s Wrong With Warfarin? But Warfarin has been round for years Warfarin is cheap (INR testing* not necessarily so) Can be reversed with Vitamin K (orally or IV) *and you and your staff s non-reimbursed time

12 Case Studies One: Two: Three: Four: Five: Quiz Mrs Smith and her past brain bleed Which Drug or No Drug? NOACs and Googleitis I have AF and I need a stent! I have AF and a shiny new valve! Or: NOACs Summary and Managing Bleeds

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14 Case One 76 year old female Atrial fibrillation which is minimally symptomatic CHADS2-VASC2 score of three (age, gender) 12 years ago, admitted with headache and noted to have a subdural haematoma (conservatively managed)- full recovery How do you manage anticoagulation?

15 The Flipside of Anticoagulation Stroke Risk: Balance anticoagulation risk with bleeding risk (HAS-BLED) Hypertension Abnormal renal and liver function Stroke history Bleeding predisposition Labile INRs Elderly (>65 years) Drugs/ alcohol (include aspirin, NSAIDs)

16 The Flipside of Anticoagulation Stroke Risk: Balance anticoagulation risk with bleeding risk (HAS-BLED) Falls risk is generally considered now to have a minimal impact on decision to commence oral anticoagulation

17 The Flipside of Anticoagulation

18 The Flipside of Anticoagulation

19 The Flipside of Anticoagulation

20 The Flipside of Anticoagulation

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22 Figure 1. Cumulative risk of recurrent intracranial hemorrhage (ICH) and ischemic event (IE) without resumption of warfarin (A) and from the time point of resuming warfarin (B). Ammar Majeed et al. Stroke. 2010;41: Copyright American Heart Association, Inc. All rights reserved.

23 Figure 2. The total risk for a treatment horizon of 3 years of recurrent intracranial hemorrhage and of ischemic stroke according to the time point of resumption of anticoagulation. Ammar Majeed et al. Stroke. 2010;41: Copyright American Heart Association, Inc. All rights reserved.

24 Case studies

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26 Case Two Mr RB, NWU year old gentleman Vasculopathy: NSTEMI PCI RCA, with prior PCI RCA 2007 Past peripheral vascular surgery Renovascular disease with atrophic left kidney Creatinine 192, egfr 29 (stable) Paroxysmal AF- on warfarin (currently 3 and 4mg alternate days)

27 Case Two

28 Case Two How will you manage his anti-coagulation needs given this labile INR?

29 Case Two Not suitable for NOAC (renal function) Why the concern? Diet and concomitant medications Compliance issues Should we be more concerned about low or high INRs? High rates of ischaemic events once INR below 2.0 Home or Practice/ Pharmacy testing

30 Case Two What about non-pharmacological methods of stroke reduction?

31 Case Two What about non-pharmacological methods of stroke reduction? Watchman device FDA approved

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33 Case studies

34 The Era of NOACs

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37 NOACs in NZ Dabigatran (Pradaxa) available since 2011 in New Zealand Some criticism (eg from Haematologists) that introduction was hasty, and little consultation with them (or Cardiologists) Fully funded Licensed for: Non-valvular AF stroke prevention Post-operative DVT/ PE prophylaxis (75mg daily) And now, PE treatment

38 NOACs in NZ Dabigatran: AF: Dose 150mg BD, unless Age >75 or 80 years Impaired renal function, CrCl Post-operative DVT/ PE prophylaxis 220mg (or 150mg) once daily PE treatment 150mg BD

39 NOACs in NZ Re dabigatran and P-glycoprotein inhibitors: Do NOT need to adjust dose in presence of amiodarone use (but can elevate dabigatran levels 14-60%, nor with verapamil (21% dabigatran level increase) Avoid concomitant use with ketoconazole (150% dabigatran level increase) No clinical concerns with quinidine, clarithromycin

40 NOACs in NZ CARM received 345 reports of adverse reactions to dabigatran in the first three months A quarter involved prescriber error Up to a third of patients experience transient, or ongoing, dyspepsia (likely related to the tartaric acid in the dabigatran formulation)

41 NOACs in NZ Rivaroxaban (Xarelto) was funded via an early access programme in New Zealand until late mg once daily (10mg if CrCl 30-49) for non-valvular AF stroke prevention Also licensed for treatment of PE/ DVT

42 NOACs in NZ Apixaban (Eliquis) has limited funding via an early access programme in New Zealand via private Cardiologists only

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44 The Trials RE-LY, 2009: dabigatran ROCKET-AF, 2011: rivaroxaban ARISTOTLE, 2011: apixaban ENGAGE-AF, 2013: edoxaban

45 RE-LY Trial (2009)

46 Connolly SJ et al. N Engl J Med 2009;361:

47 Connolly SJ et al. N Engl J Med 2009;361:

48 Connolly SJ et al. N Engl J Med 2009;361:

49 Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Connolly SJ et al. N Engl J Med 2009;361:

50 Safety Outcomes, According to Treatment Group Connolly SJ et al. N Engl J Med 2009;361:

51 Treatment Group Connolly SJ et al. N Engl J Med 2009;361:

52 Other NOAC Trials

53 ROCKET-AF, 2011 Patel MR et al. N Engl J Med 2011;365:

54 ARISTOTLE, 2011 Granger CB et al. N Engl J Med 2011;365:

55 ENGAGE-AF, 2013 Giugliano RP et al. N Engl J Med 2013;369:

56 Other Advantages for NOACs Quick spontaneous offset of action No prolonged time off agent required prior to elective surgery, and therefore less likelihood of requiring bridging therapy with heparin/ LMWH Is a definite rebound effect for strokes when stopping oral anticoagulants Prompt onset of action on re-commencement Avoidance of post-operative heparin/ LMWH

57 Switching to NOACs If patient is on warfarin, wait until INR is <2.0 before commencing NOAC Bridging therapy with heparin/ LMWH should not generally be required

58 The Trials Aspirin is now not recommended for stroke prophylaxis in AF Nothing (CHADS 2 VASC 2 0-1), vs Formal OAC Therapy

59 Case Studies

60 Case Three A patient brings in this online article regarding Pradaxa. What are the main issues for discussion? How might you respond to patient concerns?

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62 Laboratory Monitoring of NOACs aptt TT DTI Specific Factor Xa assays INR levels are NOT reliable for NOAC monitoring

63 Laboratory Monitoring of NOACs Regulatory authorities do not recommend routine plasma measurement of NOAC activity Plasma levels may vary between individuals

64 Case Three New drugs Clinical Trials versus Real World What registries? The Hawthorne Effect Regulatory response to call for plasma monitoring of Dabigatran levels What role of patient selection? Does the presence of a reversal agent influence your response?

65 The Media and NOACs

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70 Management of Bleeding Supportive care: Fluid resuscitation Red blood cell transfusions Maintenance of renal function Identification of bleeding source Surgical intervention

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73 Issues with Pro-Coagulants TRALI Transfusion-Related Acute Lung Injury A severe reaction particularly to Fresh Frozen Plasma (FFP) Immune associations TACO Transfusion-Associated Circulatory Overload

74 Thirty-day mortality rate after a major bleeding event. Majeed A et al. Circulation. 2013;128: Copyright American Heart Association, Inc. All rights reserved.

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76 Rivaroxaban Reversal Andexanet alfa 97% reduction in anti-factor Xa activity immediately after infusion FDA review decision pending (by August 2016) Case Studies

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78 Case Four The patient with AF who needs PCI

79 Case Four The patient with AF who needs PCI Acknowledged that this is an individualised discussion that must be had with patient Strategy should revolve around minimising time on multiple blood-thinning agents Bare-metal stents versus Drug-eluting stents Biodegradable stents Drug-eluting balloons Case Studies

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81 Case Five 79 year old man Diagnosed with AF 2015 on incidental examination St Judes Mechanical Aortic Valve replacement 2011 for severe aortic stenosis Follow-up echo in 2013 showed satisfactory valve function and normal LV systolic function Warfarin levels have been labile for last 6 months What are the options for oral anti-coagulation?

82 NOACs in NZ In March 2013, CARM reported three NZ cases of blood clots in mechanical valve patients using dabigatran (off label) RE-ALIGN study (published NEJM, September 2013) was terminated early after studying 252 mechanical valve patients randomised to warfarin or dabigatran- due to excess risk with dabigatran

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84 NOACs in NZ Patients with mechanical heart valves (or severe underlying native valve issues- especially mitral stenosis) should NOT be treated with NOACs Warfarin is the only suitable agent in this group of patients Patients with bioprosthetic valves and AF can be treated with NOACs Case Studies

85 The Quiz

86 Question One: Which patient with atrial fibrillation would be the best potential candidate for dabigatran? a. 78 year old male with a mechanical mitral valve replacement b. 38 year old female with severe mitral stenosis c. 82 year old male with a bioprosthetic mitral valve replacement d. 72 year old female with a creatinine clearance of 18 e. 42 year old male with mechanical aortic valve replacement

87 Question Two: What statement is true? a. Apixaban is available for selected public Cardiology patients via an early access programme b. Rivaroxaban is given once daily c. Edoxaban is widely available overseas but not yet in New Zealand d. Overseas regulatory authorities have recommended avoiding commencing new patients on dabigatran pending new safety data e. Warfarin is safer than the new anticoagulant agents because it can be reversed by Vitamin K

88 Question Three: What statement is true? a. An INR level gives a good indication of plasma dabigatran levels b. Vitamin K can help reverse the effects of dabigatran c. Prior to elective surgery, dabigatran should be withheld for a week prior to the operation date d. When restarting dabigatran after surgery, subcutaneous low-molecular weight heparin should be given as bridging therapy for 3 days e. The half-life of dabigatran is hours

89 Question Four: What factor is least important when selecting appropriate patients (and dose) for NOACs? a. Age b. Patient weight c. Estimated risk of falls d. Renal function e. History of prior bleeding episodes

90 Question Five: What statement is true? a. Apixaban is a direct thrombin inhibitor b. Patients on dabigatran can choose to open the capsules and take the contents in a glass of water if that is easier for them c. Rivaroxaban cannot be packaged in blister packaging d. An antidote for dabigatran is potentially available in NZ e. You can switch a patient from warfarin to dabigatran as soon as the INR is less than 3.0

91 Question Six: My patient with a CHADS2-VASC2 score of 3 had a recent successful cardioversion, and has normal LV systolic function If he remains well and in sinus rhythm, we can stop his oral anticoagulation at 6 week follow-up: YES or NO? (or depends)

92 Quiz Answers

93 Question One: Which patient with atrial fibrillation would be the best potential candidate for dabigatran? a. 78 year old male with a mechanical mitral valve replacement b. 38 year old female with severe mitral stenosis c. 82 year old male with a bioprosthetic mitral valve replacement d. 72 year old female with a creatinine clearance of 18 e. 42 year old male with mechanical aortic valve replacement

94 Question Two: What statement is true? a. Apixaban is available for selected public Cardiology patients via an early access programme b. Rivaroxaban is given once daily c. Edoxaban is widely available overseas but not yet in New Zealand d. Overseas regulatory authorities have recommended avoiding commencing new patients on dabigatran pending new safety data e. Warfarin is safer than the new anticoagulant agents because it can be reversed by Vitamin K

95 Question Three: What statement is true? a. An INR level gives a good indication of plasma dabigatran levels b. Vitamin K can help reverse the effects of dabigatran c. Prior to elective surgery, dabigatran should be withheld for a week prior to the operation date d. When restarting dabigatran after surgery, subcutaneous low-molecular weight heparin should be given as bridging therapy for 3 days e. The half-life of dabigatran is hours

96 Question Four: What factor is least important when selecting appropriate patients (and dose) for NOACs? a. Age b. Patient weight c. Estimated risk of falls d. Renal function e. History of prior bleeding episodes

97 Question Five: What statement is true? a. Apixaban is a direct thrombin inhibitor b. Patients on dabigatran can choose to open the capsules and take the contents in a glass of water if that is easier for them c. Rivaroxaban cannot be packaged in blister packaging d. An antidote for dabigatran is potentially available in NZ e. You can switch a patient from warfarin to dabigatran as soon as the INR is less than 3.0

98 Question Six: My patient with a CHADS2-VASC2 score of 3 had a recent successful cardioversion, and has normal LV systolic function If he remains well and in sinus rhythm, we can stop his oral anticoagulation at 6 week follow-up: YES or NO? (or depends) Case Studies

99 Summary Current studies indicate that NOACs have a net benefit over warfarin Lower strokes Lower bleeding risk The lack of reversal agent for NOACs should be part of the routine patient discussion, but the issue is not necessarily straightforward Supportive therapies etc

100 Summary Currently fully-funded agents are: Warfarin Dabigatran Early-access funding for: Apixaban (generally private patients only) No current funding for: Rivaroxaban

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