How To Understand How The Brain Can Be Affected By Cardiac Problems

Transcription

1 Workshop 2e: Atrial Fibrillation, Heads and Hearts how the brain can be affected by cardiac problems Matthew Walters

2 Heads and Hearts Cardiac disease and stroke Matthew Walters University of Glasgow

3 Why discuss stroke? # 1 cause of disability # 3 cause of death (12%) 130,000 per year in UK Approx 3 billion direct NHS costs annually 7% NHS beds Reverse the historical perception of stroke

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5 What I ll cover 5 Some historical perspective The burden of stroke attributable to heart rhythm problems, particularly Atrial Fibrillation (AF) Some new developments in the last few years

6 Disclosures I m the lead stroke consultant in north Glasgow I am involved in medicines regulation and rational prescribing I work in the Stroke Unit of the Western Infirmary in Glasgow 6 So I know about providing healthcare on a low budget

7 Historical perspective: Hippocrates The reason of an apoplexy..is stagnation or station of the blood, whereby all motion and action of the spirits is taken away... And that its motion is stop'd by sharp humours, or a plethora, or an afflux of cold humours On regimen in acute diseases, 400BC

8 AF and stroke To this variety of apoplexy those are most liable whose face and hands are constantly livid and whose pulse constantly unequal. Wepfer, 1658

9 What is AF?

10 What causes AF? There s a long list! High blood pressure Heart attacks or other heart disease Other sudden illnesses In about 1 in 10 cases no cause is found

11 Why is AF important? It can cause symptoms Palpitations Breathlessness Dizziness Chest pain It can cause stroke

12 Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622 Atrial fibrillation causes stroke Left atrial appendage thrombus

13 U.S. Population (x 1000) AF Population (x 10) Age Distribution of People With AF 30,000 20,000 U.S. Population Population with Atrial Fibrillation 10% of people over 75 in the UK have AF , Arch Int Med. 1995;155:471. Age, years

14 Thromboembolic events Control patients in AF trials Cerebral 49 (91%) AF is associated with a 5-fold increase in stroke risk Systemic 5 (9%)

15 Severity of ischaemic stroke in AF Severity of events in 1,092 control patients Moderate to severe: 23 (45%) Fatal: 5 (10%) Mild: 23 (45%)

16 Summary so far AF is common AF causes lots of strokes These strokes are generally severe ones How can we prevent them?

17 Oral Anticoagulants historical Spoiled sweet clover Dicoumarol discovered development Warfarin clinical use Warfarin / Vitamin K mechanism Dabigatran Rivaroxaban Apixaban High / low dose AZD0837 Warfarin / INR Ximelagatran clinical trials Warfarin clinical trials s 1970s s 1990s Heparin discovered Heparin clinical use Continous heparin infusion/ aptt LMWH discovered LMWH clinical trials Pentasaccharide clinical trials Injection

18 History Haemorrhagic disease of cattle in1920s Reduction in plasma prothrombin Traced to sweet clover Active agent structurally similar to vitamin K 1939 agent isolated (dicumarol) at University of Wisconsin (Wisconsin Alumni Research Foundation)

19 Historical context Pesticide (avoided the bait shy problem) Unsuccessful suicide attempt (>300mg)1951 Dwight Eisenhower 1956

20 Efficacy of warfarin Compared with Control in Five Studies No. of Events Patientyears AFASAK If we BAATAF treat patients with warfarin for 1 year CAFA we ll 14 prevent 478 about 30 strokes SPAF SPINAF Combined* *Total risk reduction for all 5 studies combined is 68% Risk Reduction, % Warfarin Better Warfarin Worse

21 Patients assigned to warfarin in AF trials Intensity of Anticoagulation When Stroke Occurred INR Ratio AFASAK CAFA SPAF I BAATAF SPINAF PT Ratio (ISI 2.4) ACCP recommendation: INR: Target range for individual study

22 Problems with warfarin in AF Although cheap and effective Doubles risk of bleeding Needs monitoring Food / drug interactions Until recently these factors weren t important due to paucity of alternatives...

23 Efficacy of aspirin vs control No. of Events Patientyears Risk Reduction (%) AFASAK Aspirin is far less effective at stroke SPAF prevention in people with AF EAFT Combined * Aspirin Better Aspirin Worse *Total risk reduction for all 3 studies combined is 21%

24 INR Clinic 2011

25 Warfarin Use in Eligible Patients (%) Warfarin for atrial fibrillation Limitations lead to under-treatment % 61% 57% 55% Overall Use 40 44% 35% 20 0 < Age (years) Go A et al. Ann Intern Med 1999;131:927.

26 Warfarin for AF Limitations lead to inadequate treatment Adequacy of Anticoagulation in Patients with AF in Primary Care Practice No warfarin 65% INR above target 6% INR in target range 15% Samsa GP, et al. Arch Intern Med 2000;160:967. Subtherapeutic INR 13%

27 Economic burden of AF and stroke The American Heart Association estimates that the direct and indirect cost of stroke in the US is $65.5 billion 1 A German Registry has shown that the overall first-year cost of AF is 18,517 2 A 15% reduction in stroke-related hospital admissions in the UK would save an estimated 30 million/year 3 1. Rosamond W et al. Circulation. 2008;117:e25 146; 2. Kolominsky-Rabas PL et al. Stroke. 2006;37: ; 3. Stewart S et al. Heart. 2004;90:

28 Summary so far AF causes lots of strokes These strokes are generally severe ones The cost of stroke to the NHS and society is huge Warfarin is effective at preventing stroke in AF but It needs to be closely monitored This is easier said than done What are the alternatives?

29 Phase III AF Trials Re-LY ROCKET- AF ARISTO TLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose (mg) 150, (15*) 5 (2.5*) 60*, 30* Freq BID QD BID QD N 18,113 14,266 18,206 >21,000 Design PROBE 2x blind 2x blind 2x blind AF criteria AF x 1 < 6 mths AF x 2 (>1 in <30d) AF or AFl x 2 <12 mths AF x 1 < 12 mths % VKA naive 50% 38% 43% 40% goal *Dose adjusted in patients with drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/tia/see PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

30 Summary of NOAC trials Class Effects: All three novel anticoagulants are non-inferior to warfarin in reducing the risk of stroke and systemic embolisation. All three agents reduce the risk of bleeding (fatal for Rivaroxaban, major for Apixaban, major at 110 mg for Dabigatran) and intracranial hemorrhage. The directionality and magnitude of the mortality reduction is consistent and approximates a RRR of 10% / year Differentiators: Dabigatran at a dose of 150 mg was associated with a reduction in ischaemic stroke Rivaroxaban is a once a day drug associated with a lower rate of fatal bleeding, and is taken once daily Apixaban was associated with a reduction in all cause but not CV mortality

31 Can we afford them? NOACS likely to be cost effective for patients at high risk (CHADS 2 >3) If CHADS 2 score of 3, ICER is under 20k If your warfarin clinic achieves excellent control (TTR > 65%) that figure will rise, and vice versa

32 Summary Paradigm shift in management of SPAF Use is progressively increasing as familiarity grows Economic models justify their use in specific circumstances Poor compliance, patient preference, geographic and social factors play a part in the decision We can t model these yet!

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34 The 3 Ps and natural history of atrial fibrillation Paroxysmal Self-Terminating Persistent Lasts > 7 Days Permanent Cardioversion Failed or Not Attempted Normal Sinus Rhythm Atrial Fibrillation Paroxysmal AF is as likely to cause stroke as persistent or permanent AF

35 Even when it s prescribed... TTR in clinical trials? 60-70% TTR in real life? 50% (in most studies, but some claim more)