Anticoagulation Using new anticoagulants in AF, VTE and PE

Transcription

1 Anticoagulation Using new anticoagulants in AF, VTE and PE Dr Matthew Fay GP Principal The Willows Medical Practice:-Queensbury GPwSI and Co-Founder Westcliffe Cardiology Service Clinical Partner The Westcliffe Medical Group Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

2 Declaration of interests The practice has received funding from: Abbott, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Dawn, INRStar, Medtronic, Oberoi Consulting, Pfizer, Roche, Sanofi- Aventis, Servier. An advisor to: AF Association, Anticoagulation Europe, Arrhythmia Alliance, Heart Valve Voice, National Stroke Association, Syncope Trust A trustee of Thrombosis UK

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5 Learning Points Thrombosis DVT AF NOACs Food for thought

6 Thrombosis

7 Haemostasis Successful haemostasis depends on vessel wall coagulation system fibrinolytic system Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

8 Blood Vessels constrict to limit blood loss arteries, veins, capillaries mechanism not fully understood Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

9 PLATELETS On contact with fibrin or collagen platelets release granules which promote aggregation of adjacent platelets to form a mass which covers, for example, an endothelial defect. Contact with Fibrin or Collagen Release Granules Aggregate to form a mass E.g. Covering Endothelial Defect Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group 9

10 PLATELETS Platelet aggregation in this way is a normal phenomenon, and occurs continuously in the body to repair minor endothelial injury. In excess, a mass is formed in a vessel: THROMBOSIS Contact with Fibrin or Collagen Release Granules Aggregate to form a mass E.g. Covering Endothelial Defect Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group 10

11 Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group Coagulation System

12 Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

13 Coagulation Cascade Series of inactive components converted to active components Coagulation Cascade Fibrinogen Fibrin Soluble Solid Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

14 Coagulation 1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin Tight regulation therefore required Balance of procoagulant and anticoagulant forces Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

15 Control of Coagulation Thrombin destroys factors V and VIII Thrombin inhibitors anti-thrombin III* alpha 1 anti-trypsin alpha 2 macroglobulin protein C and S* * inherited deficiency may predispose to thrombosis Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

16 Fibrinolysis Breakdown of fibrin Plasminogen Plasmin Plasminogen activators Fibrinolytic therapy widely used streptokinase tpa Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

17 Endothelium Anti-thrombotic plasminogen activators prostacyclin nitric oxide thrombomodulin Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

18 Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group What is a Thrombosis

19 What is a Thrombosis? Solid mass of blood constituents Formed within the vascular system In life Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

20 Thrombosis is different to Clot! Clotting means coagulation which can occur within or outside the vascular system in life or post mortem. Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

21 Why does thrombosis occur? Abnormalities of the vessel wall atheroma direct injury inflammation Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

22 Why does thrombosis occur? Abnormalities of blood flow stagnation turbulence Abnormalities of blood components smokers post-partum post-op Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

23 Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group

24 PREDISPOSING FACTORS FOR THROMBOSIS Factors which promote thrombosis can be found in the blood vessel wall, or be concerned with the flow of blood or its constituents. This group of three factors is known as Virchow s triad. FLOW Virchow s Triad WALL BLOOD CONSTITUENTS Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group 24

25 TYPES OF THROMBI Thrombi can occlude a vessel which may result in necrosis of the part served (infarction). Occlusive Infarction Mural thrombus can release fragments (emboli) which can travel in the bloodstream to block distal vessels. Mural Embolism Thrombus on heart valves due to infection can also embolise. Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group Vegetation 25 Embolism

26 OUTCOMES OF THROMBOSIS Lysis Fibrosis Recanalisation Embolism Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group 26

27 Thrombosis-DVT

28 Deep Vein Thrombosis DVT is the formation of a thrombus in a deep vein. Usually in the legs; partially or completely obstructs blood flow. Annual incidence is about 1 in 1000 people. The most serious complication is pulmonary embolism. Only about a third of people with a clinical suspicion of DVT have the condition. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

29 Risk factors for DVT Risk factors include: Previous venous thromboembolism. Cancer (known or undiagnosed). Increasing age. Being overweight or obese. Male sex. Heart failure. Acquired or familial thrombophilia. Chronic low-grade injury to the vascular wall (for example vasculitis, hypoxia from venous stasis, or chemotherapy). Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

30 Temporary risk factors Risk factors that temporarily raise the likelihood of DVT: Immobility, significant trauma, or direct trauma to a vein. Hormone treatment (for example oestrogencontaining contraception or hormone replacement therapy). Pregnancy and the postpartum period. Dehydration. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

31 Differential Diagnosis? Physical trauma: Calf muscle tear or strain. Haematoma (collection of blood) in the muscle. Sprain or rupture of the Achilles tendon. Fracture. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

32 Differential Diagnosis? Cardiovascular disorders: Superficial thrombophlebitis. Post-thrombotic syndrome. Venous obstruction or insufficiency, or external compression of major veins (for example by a fetus during pregnancy, or cancer). Arteriovenous fistula and congenital vascular abnormalities. Acute limb ischaemia. Vasculitis. Heart failure. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

33 Differential Diagnosis? Other conditions including: Ruptured Baker's cyst. Cellulitis (commonly mistaken as DVT). Dependent (stasis) oedema. Lymphatic obstruction. Septic arthritis. Cirrhosis. Nephrotic syndrome. Compartment syndrome. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

34 When to suspect a DVT Suspect a DVT if the person has: Signs or symptoms of a DVT: Pain and swelling in one leg, although both legs may be affected. Tenderness, changes to skin colour and temperature, and vein distension. A risk factor for DVT previous VTE Immobility To exclude an alternative cause: Carry out a physical examination. Review the person's general medical history. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

35 Managing a suspected DVT Refer immediately if pregnant or given birth within the past 6 weeks. Requires same-day assessment and management as it is not possible to accurately assess the risk of DVT in primary care. For everyone else, use the two-level DVT Wells score to assess likelihood of DVT and inform further management. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

36 Using the two-level DVT Wells score Criteria Active cancer (treatment ongoing, within the last 6 months, or palliative). 1 Paralysis, paresis, or recent plaster immobilization of the legs 1 Recently bedridden for 3 days or more, or major surgery within the last 12 weeks requiring general or local anaesthetics Localized tenderness along the distribution of the deep venous system (such as the back of the calf) Entire leg is swollen. 1 Calf swelling by more than 3 cm compared with the asymptomatic leg (measured 10 cm below the tibial tuberosity). Pitting oedema (greater than on the asymptomatic leg) 1 Collateral superficial veins (non-varicose). 1 Previously documented DVT 1 If an alternative cause is considered more likely than DVT. -2 Score Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

37 Two-level DVT Wells score Validated, simple scoring system that takes into account previous DVT. o DVT is likely if the score is two points or more. o DVT is unlikely if the score is one point or less. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

38 Other methods of assessment Do not use: Individual symptoms and signs on their own. On their own they are poor predictors of the presence or absence of DVT. A positive Homans' sign (pain in the calf or popliteal region on passive, abrupt, forceful dorsiflexion of the ankle with the knee in a flexed position): Is insensitive and nonspecific. Can be painful, and there is a theoretical possibility of dislodging a thrombus. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

39 If DVT likely (>2 points) Refer for a proximal leg vein ultrasound scan to be carried out within 4 hours. If a proximal leg vein ultrasound scan cannot be carried out within 4 hours of being requested: Take a blood sample for D-dimer testing. Give an interim 24-hour dose of a anticoagulant Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

40 Which anticoagulant? Offer a choice of low molecular weight heparin (LMWH) Licensed LMWHs for DVT treatment include dalteparin, enoxaparin, and tinzaparin. Offer a choice of Xa Inhibitor Apixaban and Rivaroxaban Fondaparinux is a synthetic pentasaccharide that inhibits activated factor X but is parentral Choice of anticoagulant depends on: Comorbidities Contraindications Cost Local policy may also influence choice. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

41 If DVT unlikely (< 1point) Offer D-dimer testing. If negative D-dimer test - consider an alternative diagnosis to explain symptoms. If positive D-dimer test - refer for a proximal leg vein ultrasound scan to be carried out within 4 hours. If a proximal leg vein ultrasound scan cannot be carried out within 4 hours of being requested: Give an interim 24-hour dose anticoagulant Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested. Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.

42 Thrombosis-AF

43 Diagnosis of AF Personalised package of care and information Stroke prevention Symptomatic Asymptomatic Rate control strategies Symptomatic Rhythm Control Strategy Ablation strategies On-going annual assessment Nice AF Guideline DRAFT: January 2014 NICE AF Guideline June 2014

44 Stroke Risk

45 Stroke risk in AF: CHADS 2 CHADS 2 risk criteria Score Cardiac failure 1 Hypertension 1 Age >75 yrs 1 Diabetes mellitus 1 Stroke or TIA (previous history) 2

46 Stroke risk in AF: CHA 2 DS 2 VASc CHA 2 DS 2 VASc risk criteria Score Cardiac failure 1 Hypertension 1 Age >75 yrs 2 Diabetes mellitus 1 Stroke or TIA (previous history) 2 Vascular disease (IHD, PAD) 1 Age >75 yrs 1 Sex Category 1

47 AF PIE: FUTURE AF PIE: PAST Fuster V. Circulation 2012; epubl April 18

48 AVERROES Apixaban (%) Aspirin (%) Assessment that INR could be maintained in therapeutic range X Assessment that INR could not or was unlikely to be measured at requested intervals X Uncertainty about patients ability to adhere to instructions regarding VKA Therapy X CHADS 2 score of 1 and VKA therapy not recommended by physician X Patients refusal to take VKA Multiple reasons for unsuitability of VKA therapy X

49 Cumulative Risk AVERROES: Stroke or SEE 5600 patients, 36 countries, 522 centres RR= %CI= p<0.001 ASA mg/d Apixaban mg bd No. at Risk Months ASA Apix

50 AVERROES - Major Bleeding Cumulative Risk Apixaban ASA No. at Risk ASA Apix RR= %CI= P= 0.56 Months N Engl J Med. 2011;364:

51 Bleeding Risk

52 Bleeding risk in AF: HAS-BLED HAS-BLED risk criteria Points awarded Hypertension (i.e. Uncontrolled BP) 1 Abnormal renal and liver function (1 point each) 1 or 2 Stroke 1 Bleeding 1 Labile INRs 1 Elderly (e.g. age >65 years, frail condition) 1 Drugs or alcohol (1 point each) 1 or 2 Maximum 9 points NICE AF Guideline June 2014

53 Antiplatelet Use for Stroke Prevention in AF

54 Aspirin vs Placebo in Stroke Prevention in AF AFASAK-1 SPAF I EAFT ESPS-II LASAF, daily LASAF, alternate day UK-TIA, 300 mg daily UK-TIA, 1200 mg daily JAST Aspirin Trials SAFT ESPS II, Dipyridamole ESPS II, Combination All Trials Antiplatelet therapy reduces incidence of stroke by about 22% Hart R, et al. Ann Intern Med. 2007;146: % 50% 0% -50% -100% Favors Antiplatelet Favors Placebo/ Control

55 Vitamin K Oral Anticoagulant Use for Stroke Prevention in AF

56 Warfarin vs Placebo in Stroke Prevention in AF AFASAK-1 SPAF BAATAF CAFA SPINAF EAFT ALL Trials Warfarin reduces incidence of stroke by about 64% 100% 50% 0% -50% -100% Favors Warfarin Favors Placebo/ Control Hart R, et al. Ann Intern Med. 2007;146:

57 Time in therapeutic range (TTR) matters Cumulative survival Warfarin group % 61 70% 51 60% 41 50% 31 40% <30% Non warfarin Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124:37 41.

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59 Non Vitamin K Oral Anticoagulant Use for Stroke Prevention in AF

60 The perfect anticoagulant Effective Oral Fast onset of action Short half life Predictable pharmacokinetics No drug/food interactions Fully reversible Do the NOACs fulfill these criteria?

61 Indications and Dosing Dabigatran Apixaban Edoxaban Rivaroxaba n Prevention of VTE post THR/TKR 110mg bd 2.5mg bd 10mg od Prevention of CVA in AF 150mg bd (110mg bd) 5mg bd (2.5mg bd) 60mg od 20mg od Treatment of acute VTE 150mg bd 10mg bd for 7/7 60mg od 15mg bd for 3/52 5mg bd 20mg od SPC Dabigatran, Rivaroxaban, Apixaban

62 Renal function Anticoagulant Creatinine clearance (ml/min) <15 Apixaban 5mg bd 2.5mg bd AVOID Dabigatran 150mg bd (110mg bd) AVOID Edoxaban 60mg 30mg AVOID Rivaroxaban 15mg od 15mg od AVOID

63 How do NOACs affect the coagulation screen?

64 Coagulation tests with Anticoagulant Drugs Test UFH LMWH Warfarin Rivaroxaban Apixaban Dabigatran PT - - /- -/ -/ APTT -/ -/ -/ Fibrinogen Thrombin Time Anti-Xa - - Haemoclot Rivaroxaban and Apixaban: The PT and APTT cannot be used to determine whether anticoagulant drug present

65 Switching from one anticoagulant to another

66 Switching from warfarin to NOAC Apixaban Wait till INR < 2.0 Dabigatran Wait till INR < 2.0 Edoxaban Wait till INR < 2.5 Rivaroxaban Wait till INR < 3.0 AF Wait till INR < 2.5 DVT, PE

67 What to do if a dose of a NOAC is missed? Once daily regimens Take the forgotten dose up to 12hrs after time of usual intake Twice daily regimens Take the forgotten dose up till 6hrs after time of usual intake ESC Practical Guide on the use of NOAC 2013

68 Bleeding Local measures Stop NOAC temporarily Tranexamic acid Coagulation screen Renal function Discuss with haematologist if ongoing issue

69 Elective minor (when warfarin would not be stopped) Dabigatran Rivaroxaban Apixaban Minor dental work 12 hours post dose hours post dose >24 hours post dose Major dental work 24 hours post dose Next dose > 4 hours post procedure 24 hours post dose Next dose > 4 hours post procedure hours post dose Next dose > 4 hours post procedure Upper/lower Endoscopy + simple biopsy Cataract removal Joint injection 24 hours post dose Next dose > 4 hours post procedure 24 hours post dose Next dose > 4 hours post procedure hours post dose Next dose > 4 hours post procedure NHS GGC Guidance based on SPC Dabigatran, Rivaroxaban, Apixaban

70 Emergency Surgery and Bleeding

71 Warfarin Vitamin K IV 6 hours PO 24 hours Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X Reversal within 30 minutes Can assess INR for effectiveness/safety

72 NOACs No specific reversal agent Well-adsorbed to activated charcoal give within two hour of swallowing Dialysis Dabigatran yes Rivaroxaban, apixaban no General principles Check coagulation screen Assess effect Check renal function Assess half life Products largely speculation/ based on non-clinical data off-licence use; safety issues (thrombosis)

73 Vitamin K - no Immediate Effect on INR Schematic diagram showing effect of vitamin K on INR Vitamin K has a slow onset (>24 hours) 1 Vitamin K supports generation of normal, functioning clotting factors in the liver Effectivity of INR normalization depending on VKA used (different half-lifes; (from 9 11 hours for acenocoumarol, to hours for phenprocoumon) 1,2 4 Vitamin K injection PD profile (INR) of VKA t ½ of VKA ~4 5 days INR 3 PD profile (INR) after administration of vitamin K 2 Day 1 Day 2 1. Heidbuchel et al, 2013; 2. Scharf et al, 2009

74 Emergencies in Anticoagulated Patients Schematic diagram showing PK/PD characteristics of VKA and rivaroxaban Reversal strategies may be required if action of drug is long and needs to be antagonized in emergency situations t ½ of VKA ~4 5 days Schematic diagram PD profile (INR) of VKA PK/PD profile of rivaroxaban t ½ of rivaroxaban 5 9 hours (young) or hours (elderly) Day 1 Day 2 PD, pharmacodynamic; PK, pharmacokinetic; t ½, half-life 1. Makris et al, 2012; 2. Kubitza et al, 2005; 3. Kubitza et al, 2008

75 Rivaroxaban-Induced Anticoagulation Reversal with PCC PT in seconds Placebo PCC 20 mg rivaroxaban was administered bid for 2.5 days followed by PCC (Prothrombin Complex Concentrate - Cofact, 50 U/kg body weight) Prolongation of PT was reversed completely by PCC ETP was reversed by PCC with an overshoot in effects Limitation 10 PT agent used showed low sensitivity to rivaroxaban PCC Time Prolongation of PT in this study was approximately 4 seconds at maximum Rivaroxaban (2.5 days) Eerenberg et al. Circulation 2011;124:

76 Specific Reversal Agents for Non-VKA Oral Anticoagulants Company Compound Factor Xa inhibitor Reversal for: Factor IIa inhibitor LMWH/ fondaparinux Status Portola Pharmaceuticals PRT064445/ (andexanet alfa) Universal No Yes (antithrombinmediated Factor Xa inhibition) Phase II completed One phase III with apixaban completed; rivaroxaban and edoxaban - onngoing Boehringer Ingelheim BI (idarucizumab) No Specific for dabigatran No Phase I completed; 3 phase III started 4 Perosphere, Inc. PER977 (aripazine) Universal Universal Universal Phase I completed 5

77 Dabigatran antidote: idarucizumab Disclaimer: idarucizumab is not currently licensed for use Date of prep: March 2015 UK/CVS b

78 Idarucizumab development process Monoclonal mouse antibody developed with high dabigatran binding affinity Monoclonal antibody was then humanized and directly expressed as a Fab fragment in mammalian cells Fab region Mouse Human Fc region Chimeric Fab Humanized Fab Mouse antibody van Ryn J. Presented at the AHA Congress, Los Angeles, USA. 5 November Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928 Disclaimer: idarucizumab is not currently licensed for use Date of prep: March 2015 UK/CVS b

79 Idarucizumab characteristics Fully humanized antibody fragment (Fab) Potently binds dabigatran No prothrombotic or antithrombotic effects Short half-life No endogenous targets Intravenous administration van Ryn J. Presented at the AHA Congress, Los Angeles, USA. 5 November Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928 Disclaimer: idarucizumab is not currently licensed for use Date of prep: March 2015 UK/CVS b

80 Idarucizumab mode of action Dabigatran inhibiting thrombin Dabigatran bound to plasma proteins Thrombin Dabigatran molecule Unbound dabigatran Antidote (idarucizumab) Idarucizumab alters the equilibrium dabigatran dissociates from thrombin Idarucizumab rapidly binds to dabigatran in the plasma Disclaimer: idarucizumab is not currently licensed for use Date of prep: March 2015 UK/CVS b

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82 Created 2/1/2016 Dr. Matthew Fay: Westcliffe Medical Group Practical Considerations

83 Starting a patient on a NOAC Check patient is not taking interacting drugs Counsel patient: it is an anticoagulant Head injury, trauma, melaena, significant GI bleed, prolonged epistaxis, large ecchymoses/ haematoma Compliance- important to take as advised (od Rivaroxaban, bd Apixaban, bd Dabigatran) Baseline FBC, renal and liver function

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85 Summary of use of NOACs Benefits of novel anticoagulants Non inferior/superior to warfarin More stable anticoagulation (in patients poorly controlled on warfarin) Shorter half life No requirement for anticoagulant monitoring Fewer drug-drug interactions No food-drug interactions Less intracranial bleeding But Limited reversal options Increased drug costs compared to warfarin Current lack of familiarity

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87 Fig 2 Cumulative incidences for major adverse cardiovascular event during two year followup for patients receiving warfarin versus no oral anticoagulant. Ying Xian et al. BMJ 2015;351:bmj.h by British Medical Journal Publishing Group

88 Fig 3 Major adverse cardiovascular event (MACE) and home time according to warfarin treatment at discharge, overall and in clinically relevant subgroups. Ying Xian et al. BMJ 2015;351:bmj.h by British Medical Journal Publishing Group

89 Learning Points Thrombosis DVT AF NOACs Food for thought

90 Thank you for your