STROKE PREVENTION 5/11/2015. Stroke Incidence by Age. Cardiogenic Embolism is the most common cause of stroke

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1 (%) (%) 5/11/15 STROKE PREVENTION Stroke Incidence by Age T H E G E N E R A L P R A C T I C E E D U C A T I O N D A Y U N I V E R S I T Y O F Q U E E N S L A N D 3 1 O C T O B E R A S S O C I A T E P R O F E S S O R D A V I D C O L Q U H O U N U N I V E R S I T Y O F Q U E E N S L A N D, W E S L E Y & G R E E N S L O P E S H O S P I T A L S B R I S B A N E, A U S T R A L I A AUSTRALIA 12 AGE MALE FEMALE TOTAL -74 9,784 7,441 17, ,128 6,13 15,231 >85 6,9 9,69 16,61 D. C O L Q U H O U U Q. E D U. A U W W W. C O R E R E S E A R C H G R O U P. C O M S L I D E S P R E P A R E D B Y D A V I D C O L Q U H O U N & C I N D Y T A M S O N NEMESIS (Thrift et al, 9), Thrift et al, 12 Deloitte Access Economics Calculations Cardiogenic Embolism is the most common cause of stroke AF related Stroke is Prevented by Warfarin Warfarin compared to placebo At least 2/3 of strokes due to AF are prevented with warfarin 1 Anticoagulation is recommended with more than one risk factor 2 Stroke Stroke Death Death A meta-analysis of 29 trials in 28,44 patients showed that warfarin reduces ischaemic stroke and mortality 1 67% 67% 26% 26 % Figure 3: Age-Specific incidence rates for all ischemic stroke subtypes in Adelaide (9-1) Leyden JM et al. Stroke. 13;44(5): Hart RG, et al. Ann Intern Med. 7;146: Fuster V, et al. JACC. 6; 48: EVENTS/ 1 PATIENTYEARS Narrow Therapeutic Range with VKA for AF 1 4 Target INR (2.-3.) Ischaemic Stroke Intracranial Haemorrhage Anticoagulant benefit of warfarin optimized when INR is in a very narrow range Use of Oral Anticoagulation in AF: RESULTS FROM A GLOBAL REGISTRY 63.5 BASED ON 15,174 PATIENTS PRESENTING TO AN EMERGENCY DEPARTMENT WITH AF/AFL BETWEEN JAN. 8 AND APR. 11 OAC USE IN CHADS TIME IN THERAPEUTIC RANGE* < >4.5 INTERNATIONALNORMALISEDRATIO(INR) USE OF OAC IS UNACCEPTABLY LOW. WHEN OAC IS USED, INR CONTROL IS SUBOPTIMAL. *BASEDON3 MOSTRECENT INR VALUES Hylek EM, et al. N Eng J Med 3; 349: Healey et al. ESC 11 1

2 5/11/15 Anticoagulant underutilization in atrial fibrillation in Australia and Overseas Adelaide Stroke Study: Only 27% of those with known atrial fibrillation prior to CVA were on warfarin Of these patients 66% of the rest were on aspirin Canada (3-7): In patients with first stroke and known atrial fibrillation: Only 4% on warfarin (3/4 had INR <2.) 3% on antiplatelet therapy 29% no treatment 14 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society Antiplatelet Agents No studies, with the exception of the SPAF-1 (Stroke Prevention in Atrial Fibrillation) show benefit for aspirin alone in preventing stroke among patients with AF Antiplatelet therapy was compared with placebo or no treatment in 8 trials with a total of 4876 subjects It is important to recognise that the 19% reduction in stroke incident observed in this meta-analysis was driven by positive results from only 1 of these RCTs Aspirin was ineffective in preventing strokes in those >75 years of age and did not prevent severe strokes. Moreover, aspirin has not been studied in a population at low risk of AF. S. Ben Freeman, Bernard J Gersh and Gregory Y H Lip. European Heart Journal (15) 36, (Circulation, 14;13:e199-e267) December AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society Anticoagulants All 3 new oral anticoagulants represent important advances OVER warfarin because they have more predictable pharmacological profiles, fewer drug-drug interactions, an absence of major dietary effects, and less risk of intracranial bleeding than warfarin If patients are stable and they are satisfied with warfarin therapy it is important to discuss this option with patients who are candidates for the new agents Prevalence of Comorbidities in Heart Failure n = 4,366,489 after 65 years USA 12 data Hypertension 85% Hyperlipidemia 63% Diabetes 47% Arthritis 45% Anaemia 51% CHD 72% Kidney disease 45% Atrial fibrillation 29% Dementia 26% (Depression not adequately assessed) (Circulation, 14;13:e199-e267) December 14 Arnett DK et al. AHA/ACC/HHS Strategies to Enhance Application Cardiovascular Disease and Comorbid Conditions. CIRC 14;13: Prevalence of Heart Failure in 3 Index Cardiovascular Conditions Depression (%) - 56 (34.8%) / 4 (23.%) p =.17 Women versus Men with Chronic Atrial Fibrillation 12 Data Medicare patients 65 years USA Ischaemic Heart Disease Atrial Fibrillation Stroke n = 8,678, n = 2,556,839 n = 1,145,714 Heart Failure 36% 51% 37% A beneficiary with cardiovascular disease but without at least one comorbid chronic condition is the exception rather than the rule particularly important for some older adults, because clinicians must select from among treatments on the basis of evidence for risk and benefit Figure 3: Typical socio-demographic and risk profiles of women versus men with chronic Atrial Fibrillation in the SAFETY cohort 1 Arnett DK et al. AHA/ACC/HHS Strategies to Enhance Application Cardiovascular Disease and Comorbid Conditions. CIRC 14;13:

3 5/11/15 Prevalence of states of depressed mood severity and cases of MDD *P value for the association between AF type and none/mild vs. moderate/severe depressed mood. **P value for the association between AF type and none vs. mild/moderate/severe depressed mood. ***P value for the association between AF type and MDD. National Heart Foundation of Australia Recommended Screening Tool Patient Health Questionnaire (PHQ-2) YES/NO Version 1. During the past month, have you often been bothered by feeling down, depressed or hopeless? 2. During the past month, have you often been bothered by little interest or pleasure in doing things? * Yes to either question is sufficient for a provisional diagnosis of depression. Von Eisenhart Rothe AF et al. Europace 14;16: Colquhoun D, Bunker ST, Clarke DM et al. Med J Aust 13;198(9): Figure 2. Cardiovascular death free survival in relation to baseline level of depression symptoms and marital status in AF-CHF patients. Nancy Frasure-Smith et al. Circulation. 9;1:

4 5/11/15 ANTICOAGULATION AND RISK OF FALLS IN ELDERLY PATIENTS WITH ATRIAL FIBRILLATION PATIENT WITH A 5% PER YEAR STROKE RISK NEEDS TO FALL 295 TIMES PER YEAR FOR RISK OF SUBDURAL HEMATOMA TO OUTWEIGH STROKE REDUCTION BENEFIT. Arch Intern Med 1999; 159: PROPERTIES OF THE NEW ORAL ANTICOAGULANTS RECENT ORAL ANTICOAGULATION TRIALS PROPERTY APIXABAN 1 DABIGATRAN2 ETEXILATE) (AS RIVAROXABAN 3 Target Factor Xa IIa (Thrombin) Factor Xa Bioavailability 5% 6.5% 66% Cmax (hrs) t½ (hrs) Dosing bid bid qd Renal Excretion 27% 85% 66% t½ (hrs) AUC* t½ (hrs) AUC* t½ (hrs) AUC* CrCl > CrCl >5 to CrCl 3 to 5 CrCl < Product information, Eliquis (apixaban ), most recent amendment 29th of April, 13 2 Product information, Pradaxa (dabigatran etexilate), most recent amendment 25th January, 13 3 Product information, Xarelto (rivaroxaban), most recent amendment 3rd of April, 12 ATRIAL FIBRILLATION NOAC VS WARFARIN OUTCOME TRIALS Stroke or Systemic Embolism TRIAL GENDER WARFARIN % per year NOAC % per year RELY (Dabigatran) ROCKET (Rivaroxaban) ARISTOTLE (Apixaban) TIMI-Engage (Edoxaban) M 11, mg D Colquhoun, J Yen Ng, N Saiepour. CSANZ 15 Melbourne mg F 6, M 8, mg F 5, M 11, mg F 6, M 13, mg 1.9 mg F 8, Effect of treatment: Apixaban vs Warfarin Men Women Rate (%/yr) Adjusted Endpoint Apixaban Warfarin HR (95% CI) Stroke or systemic embolism.45 Male (.66, 1.5) Female (.54,.97) All-cause death.83 Male (.78, 1.2) Female (.71, 1.6) CV death.64 Male (.73, 1.6) Female (.61, 1.8) Major bleeding.6 Male (.64,.9) Female (.44,.72) Major or non-major clinically relevant bleeding.48 Male (.61,.79) Female (.53,.76) Intracranial bleeding.76 Male (.29,.64) Female (.22,.67) The efficacy and safety benefit of apixaban compared to warfarin in AF is independent of sex. Interaction P-Value 4

5 Persistence % Persistence % 5/11/15 Persistence curve for patients initiated to warfarin in Australia Drugs don t work in patients who don t take them Dr Charles Everett Koop - Surgeon General USA Simons L. Persistence on warfarin: experience in Australia 6-9. Australian Family Physician Sept 13 42: Persistence curve for patients in Australia initiated to NOAC drugs and warfarin - 14 Persistence curve for patients in Australia initiated to individual NOAC drugs NOAC drugs Warfarin 1 Apixaban Dabigatran Rivaroxaban Months of therapy Months of therapy Improved persistence with non-vitamin K oral anticoagulants compared with warfarin in patients with atrial fibrillation: recent Australian experience. Simons L, Ortiz M, Freedman B, Waterhouse B, Colquhoun D, Thomas G. CSANZ 15 Melbourne. Improved persistence with non-vitamin K oral anticoagulants compared with warfarin in patients with atrial fibrillation: recent Australian experience. Simons L, Ortiz M, Freedman B, Waterhouse B, Colquhoun D, Thomas G. CSANZ 15 Melbourne. CHOICE OF ANTICOAGULANT BASED ON PATIENT CHARACTERISTICS CHARACTERISTIC DRUG CHOICE RATIONALE Mechanicalor valvular AF Warfarin Only Dabigatran has been studied and trial stopped early Liver dysfunction with elevated INR Poor compliance Stable on Warfarin? Any drug Depending on degree of liver failure NOAC Warfarin or a NOAC Warfarin persistence less than NOAC. Address compliance (eg depression screen PHQ2) Superiority of NOACs needs to be discussed (AHA Guidelines 14) CrCl <25 ml/min Warfarin NOACs not TGA approved CrCl <25-3 ml/min Apixaban Only NOAC TGA approved CrCl > 3 ml/min Heartburn or upper GI complaints Rivaroxaban, Apixaban or Dabigatran Rivaroxaban or Apixaban All TGA approved Recent GI bleed Apixaban Lowest GI bleeding rates Recent ischemic stroke on Warfarin Recent acute coronary syndrome Dabigatran 15 mg, Rivaroxaban or Apixaban Rivaroxaban or Apixaban Heartburn occurs in about 1% of patients on Dabigatran All are superior to warfarin?dabigatran greater benefit There is small MI signal with Dabigatran but not seen in published real-world experience Conclusions Atrial fibrillation increases with age. Higher stroke rate related to atrial fibrillation in women. Women less likely to be given anticoagulation. In randomised NOAC trials (n >,) women have greater stroke rates but greater absolute benefit with NOACs. Aspirin as a single agent or added to NOAC/warfarin causes more bleeding and usually paradoxically higher stroke rates. Women, like men, are grossly undertreated which is related to the slow uptake of the science and guidelines, as well as fear of possible side effects and perhaps even ageism and sexism. Medico-legal implications should not be underestimated for non - treatment and choosing less effective therapy. Major adaptation from Weitz & Gross, Hematology 12:

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