Clo$ng vs bleeding: not as simple as we would like. OACs for stroke preven:on: Too many choices?

Transcription

1 Clo$ng vs bleeding: not as simple as we would like OACs for stroke preven:on: Too many choices? Paul Dorian University of Toronto St Michael s Hospital

2 . Speaker Disclosure Form Paul Dorian Disclosures: Honoraria, research support, and consulting for Bayer, Boehringer-Ingleheim, BMS, Pfizer, Portola, Sanofi

3 Alice came to a fork in the road. 'Which road do I take?' she asked. 'Where do you want to go?' responded the Cheshire Cat. 'I don't know,' Alice answered. 'Then,' said the Cat, 'it doesn't mader. Lewis Carroll, Alice in Wonderland We are our choices. Jean- Paul Sartre

4 The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy Age is the most important new risk factor for stroke European Heart J Sept 27, 2012

5 Outcomes With Aspirin or Apixaban in Rela:on to CHADS2 and CHA2DS2- VASc Scores in Pa:ents With AF : A Secondary Analysis of the AVERROES Study Gregory Y.H. Lip, MD; Stuart Connolly, MD; Salim Yusuf, MD; Olga Shestakovska, PhD; Greg Flaker, MD; Robert Hart, MD; Fernando Lanas, MD; Denis Xavier, MD; John Eikelboom, MD; Significant mul:variate predictors of stoke in ASA group Age > 75: HR 2.08 Female sex: HR 1.50 Prior stroke/tia : HR 2.07 Poor renal Fn. (egfr < 60 vs > 60) : HR 1.61 Permanent vs paroxysmal AF : HR 1.99 Hypertension, Diabetes, CHF, PVD - NOT predictors Circ EP Mar 2013 epub ahead of print

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7 Courtesy of Dr Chris Granger

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9 But in MY clinic, warfarin is very well managed and I rarely see complica:ons

10 Stroke/SE By Prior Warfarin Use ROCKET AF/ RE- LY/ ARISTOTLE RE- LY (150 mg) HR Warfarin naïve 0.63 Warfarin experienced 0.66 ROCKET- AF (ITT) Warfarin naive 0.76 Warfarin experienced 0.97 ARISTOTLE Warfarin naive 0.86 Warfarin experienced 0.73 Hazard Ra:o (95% CI) Study Drug Favors Warfarin P int =0.81 P int =0.16 P int = Efficacy of NOACS maintained in Warfarin experienced patients Connolly S et al NEJM 2009; Ezekowitz M et al Circulalon 2011; Patel M et al NEJM 2011; Granger CB et al NEJM 2011 CC- 10

11 Primary Efficacy Endpoint by Center TTR ROCKET AF/RE- LY/ARISTOTLE Efficacy of NOAC maintained at all levels of center TTR Treatment Group E/n (rate) Warfarin E/n (rate) p- value (interac:on) ROCKET AF % 45/1735 (1.77) 62/1689 (2.53) % 53/1746 (1.94) 63/1807 (2.18) % 54/1734 (1.90) 62/1758 (2.14) % 37/1676 (1.33) 55/1826 (1.80) RE- LY (Dabigatran 150 mg) 0.20 <57.1% 32/1509 (1.1) 54/1504 (1.92) % 32/1526 (1.04) 62/1514 (2.06) % 31/1484 (1.04) 45/1487 (1.51) >72.6% 38/1514 (1.27) 40/1509 (1.34) ARISTOTLE 0.29 < 58.0% 70/2266 (1.75) 88/2252 (2.28) % 54/2251 (1.30) 68/2278 (1.61) % 51/2256 (1.21) 65/2266 (1.55) > 72.2 % 36/2266 (0.83) 44/2251 (1.02) Wallen:n L. Lancet 2010;376: Wallen:n L. ARISTOTLE Trial and TTR. ESC, France, August, 2011 Hazard Ra:o (95% CI) Study Drug Favors Warfarin CC- 11

12 But my pa:ent is on ASA and is doing fine

13 AVERROES: Treatment effect of apixaban vs aspirin on major bleeding according to stroke risk strata by CHADS2 and CHA2DS2-VASc scores. Lip G Y et al. Circ Arrhythm Electrophysiol 2013;6:31-38 Copyright American Heart Association

14 Treatment effect of apixaban vs aspirin on ischemic stroke according to stroke risk strata by CHADS2 and CHA2DS2- VASc scores. Lip G Y et al. Circ Arrhythm Electrophysiol 2013;6:31-38 Copyright American Heart Association

15 But with renal dysfunction, the new anticoagulants are dangerous

16 AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 mg BID D 150 mg BID Warfarin D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin Age (yrs) P= P= < Creatinine clearance (ml/min) P=0.1 P= > Dabigatran better Warfarin better Dabigatran better Warfarin better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr

17 ROCKET: Safety outcomes by renal function CR Cl < vs > 50/ml/min Clinical endpoint (% per year) Rivaroxaban (N=7111) Warfarin (N=7116) HR (95% CI) Rivaroxaban vs warfarin P (interaction) Principal safety outcome* ( ) 0.98 ( ) 0.45 Major bleeding ( ) 0.95 ( ) 0.48 Hct or Hb drop ( ) 1.14 ( ) 0.65 Transfusion ( ) 1.17 ( ) 0.71 Critical organ ( ) 0.55 ( ) 0.39 Fatal bleeding ( ) 0.39 ( ) 0.53 Intracranial haemorrhage ( ) 0.81 ( ) Based on safety population on treatment * Rivaroxaban 20 mg od. Rivaroxaban 15 mg od v2 December

18 Apixaban versus Warfarin: Effect on Major Bleeding According to Kidney Function Apixaban Warfarin Hazard Ratio P Value %/yr (n) %/yr (n) (95% CI) for interaction Cockcroft-Gault egfr ml/min > (96) 1.84 (119) 0.80 (0.61, 1.04) > (157) 3.21 (199) 0.77 (0.62, 0.94) (73) 6.44 (142) 0.50 (0.38, 0.66) CKD-EPI egfr ml/min > (64) 2.30 (100) 0.62 (0.45, 0.85) > (190) 2.58 (219) 0.86 (0.71, 1.04) (73) 6.78 (143) 0.48 (0.37, 0.64) Cystatin C egfr ml/min > (99) 2.19 (146) 0.66 (0.51, 0.86) > (120) 3.62 (162) 0.74 (0.58, 0.93) (60) 5.47 (85) 0.65 (0.47, 0.91) Apixaban vs Warfarin Hohnloser S. Eur Heart J Nov;33(22):

19 But there are no antidotes for the new agents. In case of urgent surgery, patients will bleed.

20 Table 4. Major Bleeding in Patients with Urgent Surgery Table 5. Major Bleeding by Timing of Preop Study Drug Discontinuation Healey J. Circulation. 2012;126:

21 ROCKET Primary Safety Outcomes Major >2 g/dl Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death Rivaroxaban Event Rate or N (Rate) Warfarin Event Rate or N (Rate) HR (95% CI) 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) P-value Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

22 HAS Bled Published online October 2, 2012

23 Mortality amongst patients with major bleed : five Phase III trials of Dabigatran Patient characteristics Mortality dabigatran* Mortality warfarin OR (95% CI) Patients with major bleeding, n Age <75 years 8.4% 12.9% 0.62 ( ) Age 75 years 9.8% 13.2% 0.72 ( ) CrCl 50 ml/min 9.6% 13.2% 0.69 ( ) CrCl <50 ml/min 8.9% 12.9% 0.66 ( ) ASA 8.8% 10.0% 0.86 ( ) No ASA 9.5% 14.0% 0.64 ( ) Majeed A. et al. Management and Outcomes of Major Bleeding on Dabigatran or Warfarin, American Society of Hematology Conference, Atlanta, GA, Dec 2012 *Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major bleed included. Analysis not adjusted for covariates ASA = acetylsalicylic acid; CrCl = creatinine clearance; OR = odds ratio 23 Dec 2012

24 But the new agents have not been around long enough. It is too early to evaluate them properly.

25 Dabigatran and Postmarkelng Reports of Bleeding Mary Ross Southworth, Pharm.D., Marsha E. Reichman, Ph.D., and Ellis F. Unger, M.D. March 13, 2013DOI: /NEJMp %/y 0.75%/y

26 Courtesy of Dr Chris Granger

27 What kind of tea do you want? "There s more than one kind of tea?...what do you have? "Let s see... Blueberry, Raspberry, Ginseng, Sleepylme, Green Tea, Green Tea with Lemon, Green Tea with Lemon and Honey, Liver Disaster, Ginger with Honey, Ginger Without Honey, Vanilla Almond, White Truffle Coconut, Chamomile, Blueberry Chamomile, Decaf Vanilla Walnut, Constant Comment and Earl Grey. - "I.. Uh...What are you having?... Did you make some of those up? Bryan Lee O'Malley, Sco1 Pilgrim's Precious Li1le Life

28 Modifica:on of Outcomes With Aspirin or Apixaban in Rela:on to CHADS2 and CHA2DS2- VASc Scores in Pa:ents With Atrial Fibrilla:on A Secondary Analysis of the AVERROES Study Gregory Y.H. Lip, MD; Stuart Connolly, MD; Salim Yusuf, MD; Olga Shestakovska, PhD; Greg Flaker, MD; Robert Hart, MD; Fernando Lanas, MD; Denis Xavier, MD; John Eikelboom, MD; Circ Arrhythm Electrophysiol. 2013;6:31-38

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30 The beginning and the end Anlcoagulants work Anlcoagulants are scary Warfarin works well Warfarin is very very hard to use and take There are beder alternalves They have to be used with care

31 Atrial fibrillalon in the 21 st century The problem: AF is a disease of aging Lifelme incidence is 25% AF oven diminishes quality of life ; it is also an important cause of stroke ( 20%- 25% of all strokes) and stroke is the only manifestalon of AF in many elderly palents The solu:on Stroke is largely preventable BUT prevenlon is complicated different drugs available, all can cause bleeding How do we approach this issue?

32 ARISTOTLE - Bleeding in Rela:on to Centers TTR Center TTR E Apixaban Rate/100 person yrs E Warfarin Rate/100 person yrs HR (95% CI) Adjusted Interaclon P Major bleeding 0.10 < (0.39, 0.72) (0.43, 0.82) (0.71, 1.21) > (0.55, 0.93) Major and clinically relevant bleeding < (0.42, 0.66) (0.51, 0.80) (0.65, 0.97) > (0.62, 0.90) CC- 32

33 Rates of hemorrhage during warfarin therapy for atrial fibrillation Gomes et al CMAJ, February 5, 2013, 185(2) E121 33