Stroke Prevention in Atrial Fibrillation. Dr. LEUNG Tat Chi Godwin Specialist in Cardiology

Transcription

1 Stroke Prevention in Atrial Fibrillation Dr. LEUNG Tat Chi Godwin Specialist in Cardiology

2 Objectives What is atrial fibrillation (AF)? Who gets AF? Why does AF cause stroke? What are the current therapeutic options for patients with AF? What are the limitations of current therapeutic options?

3 What is Atrial Fibrillation? Quivering (fibrillation) of atria replaces normal pumping action Increased signalling frequency through AV node increases ventricular rate Absent atrial push decreases cardiac output and causes pooling of blood in the atria. AV=Atrioventricular

4 The Number of Patients with AF is Anticipated to Increase Introduction to Storke Prevention in AF *Assumes no further increase in the incidence of age adjusted AF (pink curve with 95% CI) and continued increase in incidence rate as evident in (purple curve) 4 Miyasaka Y, et al. Circulation 2006;114:

5 Complications of AF AF is often asymptomatic Symptoms of AF include: Cardiac palpitations (awareness of heartbeat, irregular rhythm) Dyspnoea (shortness of breath, especially with exertion) Fatigue, weakness Impaired quality of life Decreased cardiac function which may result in heart failure Syncope (loss of consciousness) Most clinically compelling:

6 Complications of AF AF is often asymptomatic Symptoms of AF include: Cardiac palpitations (awareness of heartbeat, irregular rhythm) Dyspnoea (shortness of breath, especially with exertion) Fatigue, weakness Impaired quality of life Decreased cardiac function which may result in heart failure Syncope (loss of consciousness) Most clinically compelling: STROKE 1 in 6 patients with AF have a stroke; 75,000 AF strokes per year in the US

7 Why Does AF Cause Stroke?

8 Stroke A Major Healthcare Burden Stroke is associated with a considerably high mortality rate: 15 million people suffer strokes each year worldwide and of these 5 million people die 1 Around 795,000 individuals experience stroke each year in the US; stroke accounts for 1 out of every 18 deaths 2 Stroke is a leading cause of serious, long term disability, including: Paralysis Pain Loss of speech, and comprehension Impaired memory, thought, and emotional processes 3 The absolute number of stroke cases continues to increase worldwide in association with an ageing population 1 1. WHO Available at 2. Lloyd Jones D, et al. Circulation 2009;119:e NINDS Available at

9 Who is at Risk for Developing Stroke in AF? Risk Factors Minor Moderate High Female gender Age 75 years Prior stroke, TIA, or systemic embolism Age years Hypertension Coronary artery disease Heart failure Thyrotoxicosis LVEF 35% Diabetes mellitus LVEF=Left ventricular ejection fraction; TIA=Transient ischaemic attack Fuster V. ACC/AHA/ESC Guidelines for the Management of Atrial Fibrillation. JACC 2001;38(4):

10 CHADS 2 Risk Stratification for Stroke Prevention in Patients with AF CHF +1 Hypertension +1 Age >75 years +1 Diabetes mellitus +1 Prior Stroke or TIA +2 Risk Category Score Low 0 Intermediate 1 High 2 1 or 2 points are assigned for each of the risk factors as shown above Stroke risk low, intermediate, or high is determined by the cumulative score CHADS 2 does not consider all risk factors: stroke risk may be underestimated Gage, et al. JAMA 2001;285: Gage, et al. Circulation 2004;110: Fuster, et al. Circulation 2006;114:e Singer, et al. Chest 2008;133:546S 592S.

11 Stroke Risk in AF Related to the CHADS 2 Score C CHF 1 H Hypertension 1 20 A Age >75 1 D Diabetes mellitus S 2 TIA/Stroke Stroke rate (% per year) n= n= n= n= n=220 5 n=65 6 n=5 CHADS 2 score Fuster V, et al. AHA/ACC/ESC Guidelines. Circulation 2006;114:e

12 Standard Management of AF Rate control: beta blockers, digoxin, calcium channel blockers Rhythm control: Medication: procainamide, disopyramide, flecainide, propafenone, amiodarone Cardioversion Ablation: surgical or procedural Pacemaker Stroke prevention: anticoagulants (e.g., warfarin)

13 ASA is Less Effective than VKAs for Stroke Prevention in AF Van Walraven C, et al. JAMA 2002;288:

14 VKAs Reduce Risk of Stroke in AF Patients by up to 62% Compared with Placebo VKA=Vitamin K antagonist Hart RG, et al. Ann Intern Med 1999;131:

15 Limitations of VKAs Narrow therapeutic window (INR ) Regular coagulation monitoring and dose adjustments required Failure to stay within the therapeutic range increases the risk of ischaemic stroke or adverse bleeding events Significant inter and intra patient variability in dose response, due to: Numerous interactions with food and concomitant drugs Unpredictable pharmacology Co morbid conditions Reluctance to prescribe VKAs Particularly to elderly patients because of high perceived risk of bleeding versus possible benefits Fear of intracranial haemorrhage, the most devastating bleeding event Ansell J, et al. Chest 2008;133 Suppl 6: 160S 198S. Ogilvie IM, et al. Am J Med 2010;123: Nieuwlaat R, et al. Eur Heart J 2005;26: Nieuwlaat R, et al. Eur Heart J 2006;27: Nieuwlaat R, et al. Am Heart J 2007;153:

16 VKAs Have a Narrow Therapeutic Window Adjusted odds ratios for ischaemic stroke and intracranial bleeding in randomised trials of VKAs for patients with AF INR=International normalised ratio. Fuster V, et al. AHA/ACC/ESC Guidelines. Circulation 2006;114:e

17 一成服華法林藥者誤食相冲食物入院明報 2011 年 10 月 7 日星期五明報專訊全港現有 16.8 萬人因心房顫動或其他原因需服用薄血藥華法林, 以控制血液凝固度減低中風風險, 但該藥和菜心龍井茶等超過 40 多種食物相冲, 病人易誤墮相冲陷阱調查發現有近一成服用華法林的受訪者, 曾因誤食相冲食物及誤服藥物劑量而要入院, 平均要留院 4 日香港醫院藥劑師學會藥物教育資源中心及病人組織關心您的心今年 4 至 6 月進行病人對薄血藥認知度的調查, 在瑪麗醫院及關心您的心訪問 306 名平均服用 3.7 年的病人, 有 9% 受訪者因誤食和華法林相冲食物而需入院, 平均留醫達 4 日接近 90% 無按規定食用須定量進食的食物,73% 則誤食應避免進食的食物, 逾半人表示不知道需要避免哪些食物及認為相冲食物太多, 難記得哪些須戒口薄血藥可減低血液濃稠度, 令血塊不易形成堵塞血管, 可減低中風風險, 醫學界已使用該藥逾 50 年, 正確使用可減少 62% 中風風險不過, 華法林屬於維他命 K 拮抗劑, 病人若服食高維他命 K 的食物易和藥物相冲, 引致不正常出血及出現不正常瘀傷, 最嚴重者可出現頭顱出血增加中風風險中年婦 6 次入院 56 歲的吳月娥服用華法林 30 年, 有 6 次因誤食相冲食物而入院她說, 一般醫生會教病人避免食用深綠色的蔬菜, 豆角木瓜白果等相冲食物因非綠色而經常被誤服現雖然有毋須限制飲食的新一代薄血藥, 但藥費每月要約 1000 元, 較華法林每月平均 20 元高服用華法林須每兩個月覆診一次, 每次私家醫生收費用約 800 元一次

18 Unmet Medical Need VKAs are highly effective for stroke prevention in AF patients Due to major limitations VKAs are used in only a proportion of the patients for whom oral anticoagulation is recommended VKA treatment is often suboptimal due to the narrow therapeutic index and variable pharmacokinetic properties Both under treatment and inconsistent INR control are associated with worse outcomes, higher rates of strokes, and bleeding events Therefore there is a need for a better oral anticoagulant OAC=Oral anticoagulant

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20 Targets for Anticoagulants Adapted from: Weitz et al. J Thromb Haemost 2005;3: , and Weitz et al. Chest 2008;133:

21 Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation

22 Rivaroxaban Selective, direct Factor Xa inhibitor 1 TF/VIIa High oral bioavailability 2 Rapid onset of action 3 X IX Half life: hours in young individuals hours in the elderly VIIIa Va IXa Rivaroxaban Dual mode of elimination: 5 1/3 of active drug excreted unchanged by the kidneys Xa 2/3 of drug metabolized by the liver; half of which is excreted renally, half excreted via the hepatobiliary route II IIa Fibrinogen Fibrin 1. Perzborn et al, 2005; 2. Kubitza et al, 2005a; 3. Kubitza et al, 2005b; 4. Kubitza et al, 2008; 5. Weinz et al, 2009 Adapted from Weitz et al, 2005; 2008

23 Summary of ROCKET Trial Design ROCKET AF evaluated the risk benefit profile of an oral, fixed, once daily dose of rivaroxaban without the need for coagulation monitoring compared with the current SoC Currently no data for once daily use of any oral anticoagulant in development for stroke prevention in AF ROCKET AF used the gold standard double blind study design ROCKET AF provided a reduced dose for patients with moderate renal impairment at study entry

24 ROCKET AF Study Design Randomized, double-blind, double-dummy, event-driven Non-valvular AF History of stroke, TIA or non-cns SE OR 2* of the following: CHF Hypertension Age 75 years Diabetes N=14,264 R Rivaroxaban 20 mg once daily** Warfarin target INR 2 3 End of study 30-day follow-up ~11 41 months*** *Enrollment of patients with 2 risk factors or without prior stroke/tia or non-cns SE was limited to 10% **Patients with CrCl ml/min: 15 mg rivaroxaban once daily ***Duration of therapy varied for each patient as study was event-driven ROCKET AF Study Investigators. Am Heart J 2010; Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

25 Atrial Fibrillation Risk Factors ROCKET AF Study Design Stroke, TIA or systemic embolus OR CHF Hypertension Age 75 Diabetes At least 2 or 3 required* Rivaroxaban 20 mg once daily (15 mg once daily for CrCl ml/min) Randomized Double Blind / Double Dummy Warfarin INR target: 2.5 ( inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism *Enrollment of patients without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10% ROCKET AF Study Investigators. Am Heart J 2010; Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

26 ROCKET AF Study Endpoints Primary efficacy endpoint Composite of stroke and systemic embolism (SE) Secondary efficacy endpoints Composite of stroke, SE, or cardiovascular death Composite of stroke, SE, cardiovascular death, or MI Individual components of the above endpoints Principal safety endpoint Composite of major and non major clinically relevant bleeding ROCKET AF Study Investigators. Am Heart J 2010; Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

27 Enrollment 45 countries, 1178 sites, 14,264 patients Canada: 750 United States: 1,932 Mexico: 168 Panama: 0 Venezuela: 20 Colombia: 268 Peru: 84 Brazil: 483 Chile: 287 Argentina: 569 Poland: 528 Finland: 16 Lithuania: 245 Sweden: 28 Hungary: 237 Norway: 49 Romania: 783 Czech Rep: 598 Bulgaria: 678 Denmark: 123 Russia: 1,292 Ukraine: 1,011 U.K.: 159 Netherlands: 161 Belgium: 96 Korea: 204 France: 71 China: 496 Spain: 250 Taiwan: 159 Germany: 530 India: 269 Hong Kong: 73 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Malaysia: 51 Italy: 139 Singapore: 44 Greece: 29 Turkey: 101 Israel: 189 Australia: 242 South Africa: 247 New Zealand: 116

28 ROCKET AF Patient Flow Rivaroxaban 7131 Randomized (n=14 264) Warfarin ITT population: 7090 all patients randomized (n=14 171) Patel et al. N Engl J Med 2011, Sept 8; 365(10): Safety population: all ITT patients who received 1 dose of study drug (n=14 143) Per-protocol population: all ITT patients without major predefined protocol violations (n=13 962)

29 ROCKET AF Baseline characteristics Characteristic (1) Rivaroxaban (N=7131) Warfarin (N=7133) Age, median (25th, 75th), years 73 (65, 78) 73 (65, 78) Female, % Body mass index, median, kg/m Blood pressure, median, mmhg Systolic Diastolic Clinical presentation, n (%) Type of atrial fibrillation Persistent 5786 (81.1) 5762 (80.8) Paroxysmal 1245 (17.5) 1269 (17.8) Newly diagnosed/new onset 100 (1.4) 102 (1.4) Previous ASA use 2586 (36.3) 2619 (36.7) Previous VKA use 4443 (62.3) 4461 (62.5) ITT population Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

30 ROCKET AF Baseline characteristics (2) Characteristic Rivaroxaban (N=7131) Warfarin (N=7133) CHADS 2 score, mean ± SD 3.48± ±0.95 2, n (%) 925 (13.0) 934 (13.1) 3, n (%) 3058 (42.9) 3158 (44.3) 4, n (%) 2092 (29.3) 1999 (28.0) 5, n (%) 932 (13.1) 881 (12.4) 6, n (%) 123 (1.7) 159 (2.2) Coexisting condition, n (%) Previous stroke/tia or SE 3916 (54.9) 3895 (54.6) Congestive heart failure 4467 (62.6) 4441 (62.3) Hypertension 6436 (90.3) 6474 (90.8) Diabetes mellitus 2878 (40.4) 2817 (39.5) Previous myocardial infarction 1182 (16.6) 1286 (18.0) Peripheral vascular disease 401 (5.6) 438 (6.1) Chronic obstructive pulmonary disease 754 (10.6) 743 (10.4) CrCl, median (25th, 75th), ml/min 67 (52, 88) 67 (52, 86) ITT population Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

31 ROCKET AF Primary Efficacy Endpoint Cumulative event rate (%) Stroke or Systemic Embolism HR 0.79 (0.66, 0.96) p<0.001 (non-inferiority) Warfarin Rivaroxaban 21 % RRR Days since randomization Number of subjects at risk Rivaroxaban Warfarin Per-protocol population as treated population Patel et al. N Engl J Med 2011, Sept 8; 365(10):

32 ROCKET AF Primary Efficacy Endpoint Stroke or Systemic Embolism Rivaroxaban n/n (% per year) Warfarin n/n (% per year) Hazard ratio (95% CI) Non-inf. p-value Sup. Per-protocol, 188/6958 (1.7) 241/7004 (2.2) 0.79 (0.66,0.96) <0.001* as-treated Safety, 189/7061 (1.7) 243/7082 (2.2) 0.79 (0.65,0.95) 0.02* as-treated ITT 269/7081 (2.1) 306/7090 (2.4) 0.88 (0.75,1.03) <0.001* 0.12 *Statistically significant Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

33 ROCKET AF Primary Efficacy Endpoint Stroke or Systemic Embolism Per-protocol, as-treated Safety, as-treated Rivaroxaban (% per year) Warfarin (% per year) Non-inf <0.001 p-value Sup ITT < Hazard Ratio and 95% CIs Favors Favors rivaroxaban warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

34 ROCKET AF Primary Efficacy Endpoint On and Off Treatment Cumulative event rate (%) Events during blinded treatment (on-treatment) Number of subjects at risk Warfarin Days since randomization Rivaroxaban Riva Warf ITT population; ITT on- and off-treatment: post hoc analyses Patel et al. N Engl J Med 2011, Sept 8; 365(10): Cumulative event rate (%) Events after early discontinuation (off-treatment) Rivaroxaban Warfarin Days since treatment discontinuation

35 ROCKET AF Primary Efficacy Endpoint On and Off Treatment Rivaroxaban n/n (% per year) Warfarin n/n (% per year) Hazard ratio (95% CI) Non-inf. p-value Sup. Hazard ratio and 95% CIs Per-protocol, as-treated 188/6958 (1.7) 241/7004 (2.2) 0.79 (0.66,0.96) <0.001 Safety, as-treated 189/7061 (1.7) 243 /7082 (2.2) 0.79 (0.65,0.95) 0.02 ITT 269/7081 (2.1) 306/7090 (2.4) 0.88 (0.75,1.03) < ITT, during treatment 188 (1.7) 240 (2.2) 0.79 (0.66,0.96) 0.02 ITT, after discontunuation 81 (4.7) 66 (4.3) 1.10 (0.79,1.52) 0.58 Primary efficacy endpoint: stroke or systemic embolism ITT during treatment, after discontinuation: post hoc analyses Favors rivaroxaban Favors warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

36 ROCKET AF Bleeding Analysis Rivaroxaban (N=7111) Warfarin (N=7125) Hazard ratio Parameter n (% per year) n (% per year) (95% CI) Principal safety 1475 (14.9) 1449 (14.5) 1.03 (0.96,1.11) endpoint Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Hazard ratio and 95% CIs Hemoglobin drop 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* ( 2 g/dl) Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* bleeding Intracranial 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* hemorrhage Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding 1185 (11.8) 1151 (11.4) 1.04 (0.96,1.13) Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001* Safety population as-treated analysis; *statistically significant Patel et al. N Engl J Med 2011, Sept 8; 365(10): Favors Favors rivaroxaban warfarin

37 ROCKET AF Secondary Endpoints Endpoints Rivaroxaban (N=7061) n (% per year) Warfarin (N=7082) n (% per year) Hazard ratio (95% CI) Composite of stroke, noncns SE, and vascular death Composite of stroke, non-cns SE, vascular death, and MI 346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)* 433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)* Components of major secondary endpoints All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03) Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06) Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02) Safety population on-treatment analysis *Statistically significant Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

38 ROCKET AF Primary Efficacy Endpoint Rivaroxaban Subgroup Analysis Warfarin n/n (%) n/n (%) p-value* Overall 189/ / Sex 0.92 Male 103/ / Female 86/ / Age (years) 0.11 <75 107/ / / / Weight (kg) / / / / >90 34/ / CrCl (ml/min) 0.72 <50 50/ / / / >80 47/ / *p-value for interaction Safety population on-treatment analysis Patel et al. N Engl J Med 2011, Sept 8; 365(10): Hazard ratio and 95% CIs Favors rivaroxaban Favors warfarin

39 ROCKET AF Primary Efficacy Endpoint Subgroup Analysis Rivaroxaban Warfarin Hazard ratio and 95% CIs n/n (%) n/n (%) p-value* Overall 189/ / CHADS / / / / / / / / / / Congestive heart failure 0.66 Yes 106/ / No 83/ / Hypertension 0.85 Yes 174/ / No 15/ / Diabetes 0.60 Yes 70/ / No 119/ / Prior MI 0.25 Yes 25/ / No 164/ / Prior stroke/tia/non-cns SE 0.04 Yes 136/ / No 53/ / *p-value for interaction Safety population on-treatment analysis Favors rivaroxaban Favors warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

40 ROCKET AF Primary Efficacy Endpoint Rivaroxaban *p-value for interaction Safety population on-treatment analysis Subgroup Analysis Warfarin n/n (%) n/n (%) Overall 189/ / p- value* Prior ASA use 0.94 Yes 70/ / No 119/ / Prior VKA use 0.42 Yes 114/ / No 75/ / AF type 0.30 Persistent 159/ / Paroxysmal 28/ / Newly diagnosed 2/ / Hazard ratio and 95% CIs Favors rivaroxaban Favors warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

41 ROCKET AF Primary Efficacy Endpoint Rivaroxaban Subgroup Analysis Warfarin n/n (%) n/n (%) Overall 189/ / Asia-Pacific 30/ / *p-value for interaction Safety population on-treatment analysis p- value* Race 0.49 White 151/ / Black 5/ / Asian 27/ / Other 6/ / Region 0.62 North America 20/ / Latin America 33/ / West Europe 28/ / East Europe 78/ / Hazard ratio and 95% CIs Favors rivaroxaban Favors warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

42 ROCKET AF Primary Efficacy Endpoint Center Based INR Control* cttr Rivaroxaban (% per year) Warfarin (% per year) Hazard ratio (95% CI) Hazard ratio and 95% CIs Better INR control % (0.48,1.03) % (0.62,1.29) % (0.62,1.28) % (0.49,1.12) cttr, center-based time in therapeutic range Based on Rosendaal method with all INR values included *p-value for interaction = 0.74 Safety population (N=7061 [rivaroxaban], N=7082 [warfarin]) Favors rivaroxaban Favors warfarin Patel et al. N Engl J Med 2011, Sept 8; 365(10):883 91

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44 ROCKET AF Conclusions Based on the pre specified primary efficacy outcome: A once daily fixed dose regimen of rivaroxaban was non inferior to warfarin for prevention of stroke or non CNS systemic embolism Rivaroxaban was superior to warfarin while patients were taking study drug The sensitivity analysis in the ITT population using the data up to site notification showed a benefit for rivaroxaban, but did not reach superiority Safety: Similar rates of bleeding and adverse events Increase in GI bleeds but importantly fewer intracranial hemorrhages, critical organ bleeds and less fatal bleeding with rivaroxaban Conclusion: Rivaroxaban, once approved in the indication, is a once daily, proven alternative to warfarin with non inferior efficacy in all population and superior efficacy during treatment, similar overall bleeding, and fewer intracranial hemorrhages and fatal bleeds

45 Pharmacologic Properties Rivaroxaban Dabigatran Target Factor Xa Factor IIa Formulation Tablet Capsule Dosing for SPAF Once daily Twice daily Bioavailability >80% for 10 mg dose; > 80% for 20 mg dose when administered with food ~6.5% t ½ 5-13 hours hours Cmax 2-4 hours hours Clearance of Active Drug ~33% renal excretion, ~66% metabolic degradation ~20% biliary, ~80% renal Pro-drug No Yes CYP450 Metabolism Yes None Drug-Drug Interactions Concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp (e.g. ketoconazole) Concomitant treatment with strong P- glycoprotein (P-gp) inhibitors, (i.e. oral ketoconazole) Food Interaction No No Connolly et al, 2009, Briefing Package FDA Adcom 2010

46 Thank you

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