DOI: 10.1161/CIRCULATIONAHA.115.016329
Stroke and Anticoagulation in Heart Failure Without Atrial Fibrillation: From Risk to Opportunity
Running title: Homma et al.; Stroke and Anticoagulation in HF Patients in SR
Shunichi Homma, MD; Siqin q Ye, MD, MS
Division of Cardiology, Dept of Medicine, Columbia University Medical Center, New York, NY
Addr Ad Address dres dr e s for es for Correspondence: Coorr rres e po es pond nden nd e cee: Shunichi Homma, Hom om mma m , MD Columbia University Medical Center PH 3-342, 622 W 168th St New York, NY 10032 Tel: 212-305-7934 Fax: 212-305-7934 E-mail: [email protected]
Journal Subject Codes: Anticoagulants:[184] Coumarins, Anticoagulants:[185] Other anticoagulants, Heart failure:[110] Congestive, Stroke treatment - medical:[70] Anticoagulants
Key words: Editorial, congestive heart failure, anticoagulant, sinus rhythm
1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
The association between heart failure and stroke risk has been described for more than three decades.1 Hypercoagulability and left ventricular blood stasis are thought to contribute to stroke risk in patients with heart failure,2 in addition to common risk factors such as hypertension and atrial fibrillation. Regardless of the mechanism, however, for the majority of patients with heart failure who do not have atrial fibrillation, this elevated stroke risk is appreciated but not managed. The current 2013 American College of Cardiology Foundation / American Heart Association Guideline on Management of Heart Failure states that “anticoagulation is not recommended in patients with chronic heart failure with reduced ejection fraction without atrial fibrillation, a prior thromboembolic event, or a cardioembolic source.”3 The 201 2012 12 ES E ESC C Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure similarly acknowledges ac ckn know owlledg ow ledg dgess the he eelevated l vated stroke risk, but recom le recommends mmends against ttreatment mme reatme re meent nt with anticoagulation.4 The T hee recommendations r commen re enda d tiionns are da arre based base ba seed on on the the results resuultss of previous prrevio ious io us rrandomized, ando omi mize zed, d ccontrolled on ntro oll lled ed d ttrials r al ri als th that att assessed as sse sess sssed e aanticoagulation ntic nt icoa ic oagu gula gu lati tiion nw with itth wa warf warfarin rfaarin rf arin n in in patients patiien pa ents tss with withh heart heaart he ar failure fail fa illurre but but without wit ithhout hout u atrial atr triial ffibrillation. ib bri rill llaatiion io These include includ de th the he WA WASH WASH, S , HE SH HELA HELAS, LAS, LA S, aand ndd W WATCH ATCH AT CH ttrials, ria i lss, as w well elll as el a tthe he W WARCEF ARCE AR CEF CE F tr trial riaal that was the largest and was conducted with patients receiving contemporary heart failure therapy.5-8 Consistently, these trials failed to show the benefit of warfarin for primary outcomes that included death and stroke. In addition, warfarin therapy in these trials was associated with increased bleeding, though the risk for the most devastating bleeding outcome, intracranial hemorrhage, remained very low and was not significantly different compared with aspirin. It is important to note, however, that when the stroke outcome is considered by itself, both WARCEF and subsequent meta-analyses including all four trials show that warfarin can effectively prevent stroke in patients with heart failure in sinus rhythm.8-10In the WARCEF trial,
2 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
the risk of stroke was only 0.72% per year in the warfarin arm, compared to 1.36% per year in the aspirin arm. Nonetheless, these numbers are a fraction of other adverse events such as death and heart failure hospitalizations. It is thus likely that the stroke prevention benefit of warfarin is hidden by competing risks from other clinical events. In this issue of Circulation, Abdul-Rahim et al. shed further light on the frequency of stroke in patients with heart failure without atrial fibrillation, while highlighting the potential for using predicted stroke risk to refine patient selection.11 In a rigorously performed analysis, the authors pooled 9,585 patients from the CORONA and GISSI-HF heart failure trials. In the subset of 6,054 patients without atrial fibrillation, a stroke rate of 1.11% per year was observed. A risk model for stroke prediction was derived from five clinical predictors, including age, age,, N ew Y ok or New York Heart Association Class, diabetes treated with insulin, body mass index, and a history of pr rev vio iouus us stroke. str trok oke. The ok The he model was validated usingg an a independent independent cohort coh o orrt from fro the CHARM HFprevious R EF F trials. For Foor patients pattien entts classified cla lass ssif ss ifie if iedd in tthe he high he he te hest erttile ooff sstroke troke tro oke rrisk issk sk bby y tthe he mo m del, de l, sstroke t ok tr o e ra rat te REF highest tertile model, rate wa as 11.98% .98 9 % pe 98 pperr yyear eaar ar iin n th he de eri r va vati tion ti on ccohort oh hor ortt an nd 11.79% .779% 79% pe perr ye ear a inn th thee va ali lida dati da tiion o ccohort. ohort.. IIn oho n was the derivation and year validation patients in whom whhom NT-proBNP NTT pr proB BNP was was a measured, meaasu sure red, re d, NT-proBNP NT-p NT -p pro r BN NP further furt fu rthe rt her simplified he simp si mpli mp lifi li fied fi e and ed and improved imp mproved stroke risk prediction when added to the model. However, in interpreting these results, some caution must be taken given this is a retrospective analysis that combined two different clinical trials. Another concern is that only 16% of the 6,054 patients without atrial fibrillation received anticoagulant therapy at baseline, compared to 62% of patients with atrial fibrillation. The stroke rate in non-anticoagulated patients with atrial fibrillation was 2.17% per year, but since anticoagulation was not randomized, this risk may be over or underestimated. These factors may limit comparison between this group and the subgroup of patients without atrial fibrillation in the highest tertile of
3 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
predicted risk. Additionally, bleeding risk was not a part of this analysis, thereby precluding considerations of net clinical benefit that often serve as the basis for decisions regarding anticoagulation. However, the stroke rate for the highest risk tertile was similar to the 1.9% annual rate of stroke seen in atrial fibrillation patients with CHA2DS2-VASc score of 2, for whom anticoagulation is thought to have net clinical benefit and is recommended by current guidelines.12, 13 A recent decision analysis by Eckman and colleagues suggests that, for nonwarfarin oral anticoagulants, the stroke risk threshold for net clinical benefit could even be as low as 0.9% per year.14 Non-warfarin anticoagulants are also thought to have more consistent anticoagulation effect, and further analysis of the WARCEF patients has shown th that that, at, fo at forr he hear heart at ar failure patients in sinus rhythm, higher quality anticoagulation as reflected by time-in-therapeutic 15 range ang ngee is associated ass ssoc occiate teed with w th better clinical outcomes. wi s 15 s. It It is thus reasonable reason o ab on blee to to propose, as the authors
do that do, th a randomized, rando domi m ze zed, d controlled d, con ontr trol tr ollled ol led trial t ia tr i l should shhoulld test test whether whetther newer newerr oral newe oral al anticoagulants antticcoag oagula gulaant n s can caan prev pprevent reveent stroke tro oke in in heart heear artt failure faaillure ure patients paati tien ents ts in in sinus sinu si nuss rhythm. rh hyt ythm hm.. hm A substantial subs bssta tant nttia iall nu numb number mb ber ooff pa pati patients tiien e ts aare re aatt ri rrisk. sk. k O Off th thee es esti estimated tiima mateed 5. 55.7 7 mi mill million l io ll on Am Amer Americans e icans with er h heart failure, 2.6 million will have reduced ejection fraction.16 Using conservative assumptions, three quarters of those patients, or roughly 1.9 million, will be in sinus rhythm.17 A stroke risk of 1.8% per year for the 630,000 patients in the highest tertile of risk would translate into roughly 11,000 strokes each year. The question of whether newer oral anticoagulants can prevent stroke in heart failure patients in sinus rhythm can only be answered through an adequately powered randomized, controlled trial. The risk score for stroke prediction proposed by Abdul-Rahim et al., along with other selection approaches,8 could guide the identification of potential trial participants.
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DOI: 10.1161/CIRCULATIONAHA.115.016329
Alternatively, given the improved risk-benefit profile of newer oral anticoagulants, a more inclusive trial design similar to WARCEF may be appropriate. A better characterization of bleeding risk in this patient population may also improve the risk benefit balance and guide patient selection.18 The choice of endpoints will also need to be carefully considered in such a trial, given the competing risks of death and heart failure hospitalizations observed in the WATCH and WARCEF trials.7, 8 Since patients have consistently expressed strong preferences for avoiding severe stroke and often consider these worse than deaths,19 it will be reasonable to emphasize stroke outcomes in trial design. Ultimately, an innovative trial testing the effect of newer oral anticoagulants on stroke in patients with heart failure in sinus rhythm will represent represe seentt ann opportunity to align risk, treatment, and patient-centered outcomes.
Fun F unding nd Soour urce ces: ce s: Dr Dr. Ye is is supported supp su ppor pp orte or teed by b a NIH NIH K23 K23 career car aree eerr development ee deeve v lo lopm pm men ent award aw war ardd (K23 (K23 Funding Sources: HL121144). H L1121144). 12 .
Conflict of Interest In nte tere reest Disclosures: Disscllos o ur u es es:: Dr D Dr.. Ho Homm Homma mmaa re mm repo reports port po rtss re rt rece receiving ceiv ce ivin iv in ng co cons consulting nsul ns ulti ul ting ti ng ffees eees fr from om Boehringerr Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, and St. Jude Medical.
References: 1. Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke: The framingham study. JAMA. 1983;250:2942-2946. 2. Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow's triad revisited. J Am Coll Cardiol. 1999;33:1424-1426. 3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 accf/aha guideline for the management of heart failure: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2013;128:e240-327.
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DOI: 10.1161/CIRCULATIONAHA.115.016329
4. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P. Esc guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology. Developed in collaboration with the heart failure association (hfa) of the esc. Eur J Heart Fail. 2012;14:803-869. 5. Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C, Ford I, Trainer A, Poole-Wilson PA. The warfarin/aspirin study in heart failure (wash): A randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J. 2004;148:157164. antithrombotic 6. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacy of anti tith th hro romb mbot mb otic ot ic therapy herapy in chronic heart failure: The helas study. Eur J Heart Fail. 2006;8:428-432. M, Jafri SM, 7.. Massie Mas assi siee BM, si BM Collins Coll Co l in ll i s JF, Ammon SE, Armstrong Armstron ongg PW, on PW, Cleland JGF, JG , Ezekowitz Ezekowitz ze WF, O'Connor CM, Schulman KA, Teo K,, Wa Warren SR, Investigators Randomized Krol Kr oll W F, O 'C 'Con Conno norr CM no M, Sc S hulm hu lman lm a K an A, T eo K W rren en nS R, Inv nv vessti tiga gato to ors fftWT. tW WT. T. R ando an do omi mize zedd ze trial with failure: The warfarin riall of warfarin, warfari rin, n, aspirin, asp spir irin ir in,, and and clopidogrel clop cl opid idog id o re og rell in ppatients atienntss wi ith h cchronic h oni hr onic hear hheart eartt fa aillure ure: e: T h w he arfa fari rin n and an antiplatelet chronic heart failure trial. an ntiipl p atelet ttherapy h raapy he y inn ch hro onic nic he eartt fa fai iluure (watch) (watch (w h) tr tria iaal. Circulation. Circculaatiion. 2009;119:1616-1624. Ci 2009 09;;119 1 :166166-1 19 6-162 1624. 8. Homma Hom omma ma S, S, Thompson Thom Th mps pson JLP, JLP LP, Sanford Sanf Sa nford AR, AR Mann Mann DL, L Sacco Sac acco co RL, RL,, Levin Lev evin in B, B, Pullicino Pull Pu llic icin i o PM PM, Freudenberger Freudenberge gerr RS, ge RS, Teerlink Teer Te erlink er nk JR, JR,, Graham Graaha ham m S, S Mohr Moh o r JP, JP, Massie Mass Ma ssie ss iee BM, BM, M Labovitz Lab abov ovit ov itzz AJ, it AJ, Di Tullio Tul u lio MR, Gabriel AP, Li GYH, Estol Ponikowski P, An Anker SD. Be Benefit warfarin Gabr Ga brie iell AP Lipp GY GYH H E stol st ol CJ, CJ Lok Lok DJ, DJ P oniiko on kows wski ki P Anke kerr SD Bene nefi fitt of w arfa ar fari rinn compared with aspirin in patients with heart failure in sinus rhythm: A subgroup analysis of warcef, a randomized controlled trial. Circ Heart Fail. 2013;6:988-997. 9. Lee M, Saver JL, Hong KS, Wu HC, Ovbiagele B. Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: A meta-analysis. Circ Heart Fail. 2013;6:287-292. 10. Kumar G, Goyal MK. Warfarin versus aspirin for prevention of stroke in heart failure: A meta-analysis of randomized controlled clinical trials. J Stroke Cerebrovasc Dis. 2013;22:12791287. 11. Abdul-Rahim AH, Perez A-C, Fulton RL, Jhund PS, Latini R, Tognoni G, Wikstrand J, Kjekshus J, Lip GY, Maggioni AP, Tavazzi L, Lees KR, McMurray JJ. Risk of stroke in chronic heart failure patients without atrial fibrillation: Analysis of the corona and gissi-hf trials. Circulation. 2015;131:XX-XXX.
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DOI: 10.1161/CIRCULATIONAHA.115.016329
12. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest. 2010;137:263-272. 13. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 aha/acc/hrs guideline for the management of patients with atrial fibrillation: Executive summary: A report of the american college of cardiology/american heart association task force on practice guidelines and the heart rhythm society. Circulation. 2014;130:2071-2104. 14. Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the tipping point: The decision to anticoagulate patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2011;4:14-21. 15. Homma S, Thompson JL, Qian M, Ye S, DiTullio M, Lip GY, Mann DL, Sacco RL, Levin B, Pullicino P, Freudenberger RS, Teerlink JR, Graham S, Mohr JP, Labovitz AJ, Buchsbaum R, Estol CJ, Lok DJ, Ponikowski P, Anker SD. Quality of anticoagulation control in preventing adverse events in heart failure patients in sinus rhythm: A warfarin aspirin reduced d ccardiac a di ar diac ac ejection fraction trial (warcef) substudy. Circ Heart Fail. 2015;In Press. 16. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres Desp pres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman DB, McGuire Li ich htm tman an JH, JH, Lisabeth Lis issabeth ab LD, Liu S, Mackey RH, Matchar Ma MccGu G irre DK, DK, Mohler ER, 3rd, Mussolino Nasir K,, Ne Neumar RW, Nichol Palaniappan L,, Pa Pandey Moy CS, Moy C , Muntner CS Muunt n neer P, M ussso s li lino noo ME, ME,, N asir as ir K eumarr R W, Nic iccho holl G,, P a an al ania iaapp ppan an L P ndey nd e ey PD, Stein Towfighi Turan TN, Virani Willey DK,, Reeves MJ, DK MJ, J, Rodriguez Rod drigu guez e CJ, ez CJ, J, Sorlie Sor orli leP li D, S teein JJ,, T ow wfigh figh hi A, A T uran T uran N, V iranii SS iran SS,, Wi Wil lley lle ey JJZ, Z, Woo W ooo D, Yehh RW, RW, Turner Turrneer MB. MB. Heart H arrt disease He disseasee and and stroke stro st roke ke sstatistics-2015 tattissticss-2 ta 20155 upd uupdate: pdatee: A rreport eppor port ffrom rom m tthe he american Circulation. 2015;131:e29-e322. am mer e ic ican an hheart eart ea rt aassociation. ssoc ss ocia iaatiion on. Circ C irccul ulat a io at ion n. 20 201 15;1 ;131 ;1 311:ee299-ee32 3222. Callans DJ. Atrial Treatment considerations 17. Anter E,, JJessup essu es suup M, M C allla lans n D J At J. A rial ri al ffibrillation ibri ib rill ri l at ll atio io on aand nd hheart eart ea rt ffailure: a lu ai ure re:: Tr Trea eatm ea tm men entt co cons n iderationss Circulation. forr a du fo dual al eepidemic. pide pi demi micc Ci Circ rcul ulat atio ionn 2009;119:2516-2525. 2009 20 09;1 ;119 19:2 :251 5166-25 2525 25 18. Ye S, Cheng B, Buchsbaum R, Lip G, Sacco R, Di Tullio M, Thompson JL, Homma S. Predicting major bleeding in patients with systolic heart failure treated with warfarin or aspirin. J Am Coll Cardiol. 2014;63 (12_S). 19. Stolker JM, Spertus JA, Cohen DJ, Jones PG, Jain KK, Bamberger E, Lonergan BB, Chan PS. Rethinking composite end points in clinical trials: Insights from patients and trialists. Circulation. 2014;130:1254-1261.
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Stroke and Anticoagulation in Heart Failure Without Atrial Fibrillation: From Risk to Opportunity Shunichi Homma and Siqin Ye Circulation. published online March 25, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2015/03/25/CIRCULATIONAHA.115.016329
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Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
Stroke and Anticoagulation in Heart Failure Without Atrial Fibrillation: From Risk to Opportunity
Running title: Homma et al.; Stroke and Anticoagulation in HF Patients in SR
Shunichi Homma, MD; Siqin q Ye, MD, MS
Division of Cardiology, Dept of Medicine, Columbia University Medical Center, New York, NY
Addr Ad Address dres dr e s for es for Correspondence: Coorr rres e po es pond nden nd e cee: Shunichi Homma, Hom om mma m , MD Columbia University Medical Center PH 3-342, 622 W 168th St New York, NY 10032 Tel: 212-305-7934 Fax: 212-305-7934 E-mail: [email protected]
Journal Subject Codes: Anticoagulants:[184] Coumarins, Anticoagulants:[185] Other anticoagulants, Heart failure:[110] Congestive, Stroke treatment - medical:[70] Anticoagulants
Key words: Editorial, congestive heart failure, anticoagulant, sinus rhythm
1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
The association between heart failure and stroke risk has been described for more than three decades.1 Hypercoagulability and left ventricular blood stasis are thought to contribute to stroke risk in patients with heart failure,2 in addition to common risk factors such as hypertension and atrial fibrillation. Regardless of the mechanism, however, for the majority of patients with heart failure who do not have atrial fibrillation, this elevated stroke risk is appreciated but not managed. The current 2013 American College of Cardiology Foundation / American Heart Association Guideline on Management of Heart Failure states that “anticoagulation is not recommended in patients with chronic heart failure with reduced ejection fraction without atrial fibrillation, a prior thromboembolic event, or a cardioembolic source.”3 The 201 2012 12 ES E ESC C Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure similarly acknowledges ac ckn know owlledg ow ledg dgess the he eelevated l vated stroke risk, but recom le recommends mmends against ttreatment mme reatme re meent nt with anticoagulation.4 The T hee recommendations r commen re enda d tiionns are da arre based base ba seed on on the the results resuultss of previous prrevio ious io us rrandomized, ando omi mize zed, d ccontrolled on ntro oll lled ed d ttrials r al ri als th that att assessed as sse sess sssed e aanticoagulation ntic nt icoa ic oagu gula gu lati tiion nw with itth wa warf warfarin rfaarin rf arin n in in patients patiien pa ents tss with withh heart heaart he ar failure fail fa illurre but but without wit ithhout hout u atrial atr triial ffibrillation. ib bri rill llaatiion io These include includ de th the he WA WASH WASH, S , HE SH HELA HELAS, LAS, LA S, aand ndd W WATCH ATCH AT CH ttrials, ria i lss, as w well elll as el a tthe he W WARCEF ARCE AR CEF CE F tr trial riaal that was the largest and was conducted with patients receiving contemporary heart failure therapy.5-8 Consistently, these trials failed to show the benefit of warfarin for primary outcomes that included death and stroke. In addition, warfarin therapy in these trials was associated with increased bleeding, though the risk for the most devastating bleeding outcome, intracranial hemorrhage, remained very low and was not significantly different compared with aspirin. It is important to note, however, that when the stroke outcome is considered by itself, both WARCEF and subsequent meta-analyses including all four trials show that warfarin can effectively prevent stroke in patients with heart failure in sinus rhythm.8-10In the WARCEF trial,
2 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
the risk of stroke was only 0.72% per year in the warfarin arm, compared to 1.36% per year in the aspirin arm. Nonetheless, these numbers are a fraction of other adverse events such as death and heart failure hospitalizations. It is thus likely that the stroke prevention benefit of warfarin is hidden by competing risks from other clinical events. In this issue of Circulation, Abdul-Rahim et al. shed further light on the frequency of stroke in patients with heart failure without atrial fibrillation, while highlighting the potential for using predicted stroke risk to refine patient selection.11 In a rigorously performed analysis, the authors pooled 9,585 patients from the CORONA and GISSI-HF heart failure trials. In the subset of 6,054 patients without atrial fibrillation, a stroke rate of 1.11% per year was observed. A risk model for stroke prediction was derived from five clinical predictors, including age, age,, N ew Y ok or New York Heart Association Class, diabetes treated with insulin, body mass index, and a history of pr rev vio iouus us stroke. str trok oke. The ok The he model was validated usingg an a independent independent cohort coh o orrt from fro the CHARM HFprevious R EF F trials. For Foor patients pattien entts classified cla lass ssif ss ifie if iedd in tthe he high he he te hest erttile ooff sstroke troke tro oke rrisk issk sk bby y tthe he mo m del, de l, sstroke t ok tr o e ra rat te REF highest tertile model, rate wa as 11.98% .98 9 % pe 98 pperr yyear eaar ar iin n th he de eri r va vati tion ti on ccohort oh hor ortt an nd 11.79% .779% 79% pe perr ye ear a inn th thee va ali lida dati da tiion o ccohort. ohort.. IIn oho n was the derivation and year validation patients in whom whhom NT-proBNP NTT pr proB BNP was was a measured, meaasu sure red, re d, NT-proBNP NT-p NT -p pro r BN NP further furt fu rthe rt her simplified he simp si mpli mp lifi li fied fi e and ed and improved imp mproved stroke risk prediction when added to the model. However, in interpreting these results, some caution must be taken given this is a retrospective analysis that combined two different clinical trials. Another concern is that only 16% of the 6,054 patients without atrial fibrillation received anticoagulant therapy at baseline, compared to 62% of patients with atrial fibrillation. The stroke rate in non-anticoagulated patients with atrial fibrillation was 2.17% per year, but since anticoagulation was not randomized, this risk may be over or underestimated. These factors may limit comparison between this group and the subgroup of patients without atrial fibrillation in the highest tertile of
3 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on March 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016329
predicted risk. Additionally, bleeding risk was not a part of this analysis, thereby precluding considerations of net clinical benefit that often serve as the basis for decisions regarding anticoagulation. However, the stroke rate for the highest risk tertile was similar to the 1.9% annual rate of stroke seen in atrial fibrillation patients with CHA2DS2-VASc score of 2, for whom anticoagulation is thought to have net clinical benefit and is recommended by current guidelines.12, 13 A recent decision analysis by Eckman and colleagues suggests that, for nonwarfarin oral anticoagulants, the stroke risk threshold for net clinical benefit could even be as low as 0.9% per year.14 Non-warfarin anticoagulants are also thought to have more consistent anticoagulation effect, and further analysis of the WARCEF patients has shown th that that, at, fo at forr he hear heart at ar failure patients in sinus rhythm, higher quality anticoagulation as reflected by time-in-therapeutic 15 range ang ngee is associated ass ssoc occiate teed with w th better clinical outcomes. wi s 15 s. It It is thus reasonable reason o ab on blee to to propose, as the authors
do that do, th a randomized, rando domi m ze zed, d controlled d, con ontr trol tr ollled ol led trial t ia tr i l should shhoulld test test whether whetther newer newerr oral newe oral al anticoagulants antticcoag oagula gulaant n s can caan prev pprevent reveent stroke tro oke in in heart heear artt failure faaillure ure patients paati tien ents ts in in sinus sinu si nuss rhythm. rh hyt ythm hm.. hm A substantial subs bssta tant nttia iall nu numb number mb ber ooff pa pati patients tiien e ts aare re aatt ri rrisk. sk. k O Off th thee es esti estimated tiima mateed 5. 55.7 7 mi mill million l io ll on Am Amer Americans e icans with er h heart failure, 2.6 million will have reduced ejection fraction.16 Using conservative assumptions, three quarters of those patients, or roughly 1.9 million, will be in sinus rhythm.17 A stroke risk of 1.8% per year for the 630,000 patients in the highest tertile of risk would translate into roughly 11,000 strokes each year. The question of whether newer oral anticoagulants can prevent stroke in heart failure patients in sinus rhythm can only be answered through an adequately powered randomized, controlled trial. The risk score for stroke prediction proposed by Abdul-Rahim et al., along with other selection approaches,8 could guide the identification of potential trial participants.
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DOI: 10.1161/CIRCULATIONAHA.115.016329
Alternatively, given the improved risk-benefit profile of newer oral anticoagulants, a more inclusive trial design similar to WARCEF may be appropriate. A better characterization of bleeding risk in this patient population may also improve the risk benefit balance and guide patient selection.18 The choice of endpoints will also need to be carefully considered in such a trial, given the competing risks of death and heart failure hospitalizations observed in the WATCH and WARCEF trials.7, 8 Since patients have consistently expressed strong preferences for avoiding severe stroke and often consider these worse than deaths,19 it will be reasonable to emphasize stroke outcomes in trial design. Ultimately, an innovative trial testing the effect of newer oral anticoagulants on stroke in patients with heart failure in sinus rhythm will represent represe seentt ann opportunity to align risk, treatment, and patient-centered outcomes.
Fun F unding nd Soour urce ces: ce s: Dr Dr. Ye is is supported supp su ppor pp orte or teed by b a NIH NIH K23 K23 career car aree eerr development ee deeve v lo lopm pm men ent award aw war ardd (K23 (K23 Funding Sources: HL121144). H L1121144). 12 .
Conflict of Interest In nte tere reest Disclosures: Disscllos o ur u es es:: Dr D Dr.. Ho Homm Homma mmaa re mm repo reports port po rtss re rt rece receiving ceiv ce ivin iv in ng co cons consulting nsul ns ulti ul ting ti ng ffees eees fr from om Boehringerr Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, and St. Jude Medical.
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Stroke and Anticoagulation in Heart Failure Without Atrial Fibrillation: From Risk to Opportunity Shunichi Homma and Siqin Ye Circulation. published online March 25, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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