VAI TRÒ THUỐC CHỐNG ĐÔNG ĐƯỜNG UỐNG MỚI TRONG PHÒNG NGỪA ĐỘT QUỴ Ở BỆNH NHÂN RUNG NHĨ KHÔNG DO BỆNH VAN TIM

Seniorprofessur Neurologie UniversitätsKlinikum und Universität Heidelberg Rationale for Stroke Prevention in AF  AF is associated with a 25% life-time risk of stroke 1  Cardio-emboli

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VAI TRÒ THUỐC CHỐNG ĐÔNG ĐƯỜNG UỐNG MỚI TRONG PHÒNG NGỪA ĐỘT QUỴ Ở BỆNH NHÂN RUNG NHĨ KHÔNG

DO BỆNH VAN TIM

Ts.Bs Đinh Hiếu Nhân

Đại Học Y Dược TpHCM

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I TỔNG QUAN

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Definitions of AF: A Simplified Scheme

Paroxysmal AF

 AF that terminates spontaneously or with intervention within 7 d of onset

 Episodes may recur with variable frequency

Persistent AF  Continuous AF that is sustained >7 d

Long-standing

persistent AF

 Continuous AF >12 mo in duration

Permanent AF  The term “permanent AF” is used when the patient and clinician make a

joint decision to stop further attempts to restore and/or maintain sinus rhythm

 Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of

AF

 Acceptance of AF may change as symptoms, efficacy of therapeutic interventions, and patient and clinician preferences evolve

Nonvalvular AF  AF in the absence of rheumatic mitral stenosis, a mechanical or

bioprosthetic heart valve, or mitral valve repair

AF indicates atrial fibrillation

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Seniorprofessur Neurologie UniversitätsKlinikum und Universität Heidelberg

Atrial fibrillation

 AF is the most common heart rhythm disturbance 1

 It is estimated that 1 in 4 individuals aged 40 years will

1 Lloyd-Jones DM et al Circulation 2004;110:1042-1046

2 Decision Resources Atrial Fibrillation Report Dec 2008

3 Go AS et al JAMA 2001;285:2370-2375

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Rationale for Stroke Prevention in AF

 AF is associated with a 25% life-time risk of stroke 1

 Cardio-embolic stroke has a 30-day mortality

of 25% and a 1 year mortality of almost 50% 2

 Cardio-embolic strokes are more severe and more often disabling than strokes of other etiology

 Once a stroke has happened the risk for subsequent

cardio-embolic stroke is increased 2-3fold

 AF-related stroke has a 1-year mortality of ~50% 3

1 Wolf PA et al Stroke 1991;22:983-988 2 Lin H-J et al Stroke 1996; 27:1760-1764

3 Marini C et al Stroke 2005;36:1115-1119

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Anticoagulation in AF: Stroke Risk Reduction

 In the past, the most widely used medications for stroke prevention in patients with AF were vitamin K-antagonists (VKAs) and aspirin

 VKAs are very effective in preventing stroke among AF- patients

• Almost 70% relative risk reduction vs placebo

Kirchhof P et al Working Group Report, 2009

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Stroke Risk Reduction in AF (Warfarin vs placebo)

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*Or moderate-to-severe left ventricular systolic dysfunction (LVEF ≤40%) Olesen JB, et al BMJ 2011;342:d124; Camm AJ, et al Eur Heart J 2010;31:2369-2429

Add points together

-1-year stroke rate

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II ĐIỀU TRỊ

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TIẾP CẬN ĐIỀU TRỊ RUNG NHĨ

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Management of Arrhythmia

Rate Control

Rhythm Control

Overview of AF Management

AF Detected

No antithrombotic therapy may be appropriate in selected

young patients with no stroke risk factors

ASA OAC

Assessment of

Thromboembolic Risk

(CHA2DS2-VASc score )

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Extrinsic Pathway (Tissue Factor)

Factor Xa Inhibitors (-AT)

Apixaban and Rivaroxaban

Fibrinogen Fibrin Clot Adapted with

permission from Nutescu et al

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Anticoagulation in AF: Stroke

Risk Reduction

• In the past, the most widely used medications for stroke prevention in patients with AF were vitamin K-antagonists (VKAs) and aspirin

• VKAs are very effective in preventing stroke among AF- patients

– Almost 70% relative risk reduction vs placebo

Kirchhof P et al Working Group Report, 2009

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Underutilization of OAKs in Atrial

Fibrillation

Go et al Ann Intern Med 1999 Waldo et al J Am Coll Cardiol 2005 Birman-Deych et al Stroke 2006 Monte et al Eur Heart J 2006

Samsa et al Arch Intern Med 2000 Nieuwlaat et al Eur Heart J 2006 Friberg et al Eur Heart J 2006 Boulanger et al Int J Clin Pract 2006 Gage et al Stroke 2000 Hylek et al Stroke 2006

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And When AC Was Given, The TTR Was

Far From Good

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75% BN ĐIỀU TRỊ KHÔNG HIỆU QUẢ

HAY KHÔNG ĐIỀU TRỊ

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VKAs have a narrow therapeutic

International normalized ratio

Adjusted odds ratios for ischaemic stroke and intracranial

bleeding in relation to intensity of anticoagulation

Target INR

Adapted from Wann et al Circulation 2011;123;e269-e367

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Factor Xa Inhibitors And Direct Thrombin Inhibitors For Stroke Prevention in AF

DTI, direct thrombin inhibitor

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Metaanalysis

 This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3

clinical trials for stroke prevention or systemic embolic

events in patients with atrial fibrillation

 New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial

haemorrhage, and mortality, and with similar major

bleeding as for warfarin, but increased gastrointestinal

bleeding

Ruff et al Lancet 2014

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Metaanalysis

 Primary endpoint

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Metaanalysis

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Favours NOAC Favours warfarin

1.5

Not head-to-head comparison – no clinical conclusions can be drawn – adapted from references 1–5

*Edoxaban dose halved (from 60 mg to 30 mg OD in the high-dose group; from 30 mg to 15 mg OD in the low-dose group) if creatinine clearance (CrCl) 30–50 mL/min, weight ≤60 kg, or concomitant verapamil, quinidine, or dronedarone

1 Connolly et al N Engl J Med 2009; 2 Pradaxa®: EU SPC, 2015; 3 Granger et al N Engl J Med 2011;

4 Patel et al N Engl J Med 2011; 5 Giugliano et al N Engl J Med 2013

Stroke/SE: Reduced or Similar Risk With NOACs

0.52–0.810.65

0.66–0.950.79

0.73–1.090.89

0.73–1.040.87

0.96–1.341.13

0.75–1.03 0.88

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Only Dabigatran 150 mg BID Reduces the Risk of

0.75–1.17 0.94

No head-to-head comparison Bold values indicate statistical significance

Adapted from references1–4;1 Pradaxa®: EU SPC, 2016; 2 Patel et al N Engl J Med 2011; 3 Lopes et al Lancet 2012; 4

Giugliano et al N Engl J Med 2013

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1 Connolly et al N Engl J Med 2010; 2 Patel et al N Engl J Med 2011; 3 Granger et al N Engl J Med 2011;

4 Giugliano et al N Engl J Med 2013

All NOAC regimens reduce the risk of ICH

Favours NOAC Favours warfarin

0.35–0.750.51

0.37–0.93 0.59

0.17–0.560.31

0.14–0.490.26

No of events (%/yr)

0.38–0.770.54

0.30–0.580.42

0.47–0.93 0.67

0.19–0.450.30

0.28–0.600.41

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NOAC vs Warfarin Atrial Fibrillation Studies –

Asian Representation

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Adapted from Europace (2015) 17, ii31–ii39

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Systemic stroke/embolization events

Relative

Risk

Reduction

* p<0.05 Europace (2015) 17, ii31–ii39

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Ischemic stroke events

Relative

Risk

Reduction

* p<0.05 Europace (2015) 17, ii31–ii39

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Haemorrhagic stroke events

Relative

Risk

Reduction

* p<0.05 Europace (2015) 17, ii31–ii39

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Major bleeding events

Relative

Risk

Reduction

* p<0.05 Europace (2015) 17, ii31–ii39

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FDA Study Of >118 000 Medicare Patients comparing Dabigatran 150 mg BID and Rivaroxaban 20 mg OD

Dabigatran was associated with a statistically significantly lower risk of major extracranial bleeding, major GI bleeding, and ICH compared with rivaroxaban

Major GI bleeding ICH Thromboembolic stroke Death

Graham et al JAMA Intern Med 2016

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III ĐIỀU TRỊ CHỐNG HUYẾT KHỐI QUA CÁC KHUYẾN CÁO

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Management of Arrhythmia

Rate Control

Rhythm Control

Overview of AF Management

AF Detected

No antithrombotic therapy may be appropriate in selected

young patients with no stroke risk factors

ASA OAC

Assessment of

Thromboembolic Risk

(CHA2DS2-VASc score )

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TIẾP CẬN ĐIỀU TRỊ RUNG NHĨ

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Risk-Based Antithrombotic Therapy

For patients with nonvalvular AF with prior stroke, transient

ischemic attack, or a CHA2DS2-VASc score of 2 or greater, oral

anticoagulants are recommended Options include:

Among patients treated with warfarin, the INR should be

determined at least weekly during initiation of antithrombotic

therapy and at least monthly when anticoagulation (INR in range)

is stable

For patients with nonvalvular AF unable to maintain a therapeutic

INR level with warfarin, use of a direct thrombin or factor Xa

inhibitor (dabigatran, rivaroxaban, or apixaban) is recommended

Re-evaluation of the need for and choice of antithrombotic therapy

at periodic intervals is recommended to reassess stroke and

bleeding risks

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Recommendations Class Level

In AF patients who suffer a stroke, aspirin should be considered for

prevention of secondary stroke until the initiation or resumption of oral

anticoagulation

IIa B

Systemic thrombolysis with rtPA is not recommended if the INR is above 1.7

(or, for patients on dabigatran, if aPTT is outside normal range)

III (harm) C

NOACs are recommended in preference to VKAs or aspirin in AF patients with

After TIA or stroke, combination therapy of OAC and an antiplatelet is not

recommended

III (harm) B

After intracranial haemorrhage, oral anticoagulation in patients with AF may

be reinitiated after 4–8 weeks provided the cause of bleeding or the relevant

risk factor has been treated or controlled

IIb B

European Heart Journal - doi:10.1093/eurheartj/ehw 210

Secondary stroke prevention

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*Mild = NIHSS score <8; moderate = NIHSS score 8–16; severe = NIHSS score >16

NIHSS, National Institutes of Health Stroke Scale Personal communication, Hans-Christoph Diener, 2015

Initiation or resumption of anticoagulation depends

on severity of stroke*

stroke

Moderate stroke

Severe stroke

As soon as imaging

has excluded a

cerebral haemorrhage

3–5 days after symptom onset

5–7 days after stroke onset

2 weeks after stroke onset

Day

Time to re-initiation depends on infarct size:

1 – 3 – 6 – 12 day rule

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IV SỬ DỤNG VÀ ĐIỀU TRỊ BIẾN CHỨNG XUẤT HUYẾT

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Dose Selection of Oral Anticoagulant Options for Patients With

Nonvalvular AF and CKD

(Based on Prescribing Information for the United States)*

Renal Function Warfarin Dabigatran† Rivaroxaban† Apixaban†

20 mg QD with the evening meal (CrCl >50 mL/min)

5.0 or 2.5 mg BID‡

15 mg QD with the evening meal (CrCl 30–50 mL/min)

5.0 or 2.5 mg BID‡

15 mg QD with the evening meal (CrCl 15–30 mL/min)

No recommendation¶

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Prothrombin Complex Concentrate (PCC) and Fresh Frozen Plasma (FFP)

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Idarucizumab To Reverse Dabigatran

Anticoagulation Education Task Force White Paper

Ageno et al Thromb Haemost 2016

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Idarucizumab: Mechanism of Action

Image to scale

Idarucizumab

Dabigatran Thrombin

Provides immediate, complete, and sustained reversal of dabigatran’s

anticoagulant action

Only acts against dabigatran, with no

procoagulant effect, does not interfere with any other process in the coagulation cascade or other anticoagulants

Humanized Fab fragment, binds with high affinity to dabigatran, preventing

dabigatran from binding to thrombin

Schiele et al Blood 2013; Stangier et al ISTH 2015, Pollack et al N Engl J Med 2015

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3 Dabigatran cho thấy hiệu quả vượt trội trong điều trị phòng ngừa

độ quỵ trên BN rung nhĩ Thuốc đối kháng Idarucizumab hiệu quả trong điều trị biến cố xuất huyết

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