The role of antithrombotic therapy in patients with chronic. Heart Failure

Transcription

1 Heart Failure Radomized Trial of Warfari, Aspiri, ad Clopidogrel i Patiets With Chroic Heart Failure The Warfari ad Atiplatelet Therapy i Chroic Heart Failure (WATCH) Trial Barry M. Massie, MD; Joseph F. Collis, ScD; Susa E. Ammo, MS, RN, FNP; Paul W. Armstrog, MD; Joh G.F. Clelad, MD; Michael Ezekowitz, MD; Syed M. Jafri, MD; William F. Krol, PhD; Christopher M. O Coor, MD; Kevi A. Schulma, MD; Koo Teo, MD; Stuart R. Warre, PharmD; for the WATCH Trial Ivestigators Backgroud Chroic heart failure remais a major cause of mortality ad morbidity. The role of atithrombotic therapy i patiets with chroic heart failure has log bee debated. The objective of this study was to determie the optimal atithrombotic aget for heart failure patiets with reduced ejectio fractios who are i sius rhythm. Methods ad Results This prospective, radomized cliical trial of ope-label warfari (target iteratioal ormalized ratio of 2.5 to 3.0) ad double-blid treatmet with either aspiri (162 mg oce daily) or clopidogrel (75 mg oce daily) had a 30-moth erollmet period ad a miimum of 12 moths of treatmet. We erolled 1587 me ad wome 18 years of age with symptomatic heart failure for at least 3 moths who were i sius rhythm ad had left vetricular ejectio fractio of 35%. The primary outcome was the time to first occurrece of death, ofatal myocardial ifarctio, or ofatal stroke. For the primary composite ed poit, the hazard ratios were as follows: for warfari versus aspiri, 0.98 (95% CI, 0.86 to 1.12; P 0.77); for clopidogrel versus aspiri, 1.08 (95% CI, 0.83 to 1.40; P 0.57); ad for warfari versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P 0.39). Warfari was associated with fewer ofatal strokes tha aspiri or clopidogrel. Hospitalizatio for worseig heart failure occurred i 116 (22.2%), 97 (18.5%), ad 89 (16.5%) patiets treated with aspiri, clopidogrel, ad warfari, respectively (P 0.02 for warfari versus aspiri). Coclusio The primary outcome measure ad the mortality data do ot support the primary hypotheses that warfari is superior to aspiri ad that clopidogrel is superior to aspiri. (Circulatio. 2009;119: ) Key Words: aticoagulats aspiri clopidogrel heart failure warfari The role of atithrombotic therapy i patiets with chroic heart failure has bee a subject of debate for may years. Iitial cotrolled cliical trials i cardiac patiets were coducted to determie whether aticoagulatio could reduce the high icidece of embolic evets, particularly strokes, observed i these patiets. 1 3 These trials foud substatial cliical beefit from aticoagulatio, icludig reductios i embolic evets ad deaths. Because may patiets i these trials had heart failure accompaied by atrial fibrillatio ad valvular disease, their relevace to curret cliical practice for heart failure patiets i sius rhythm seems limited. Give that heart failure is associated with a hypercoagulable state ad that both sudde deaths ad deaths resultig from progressive heart failure may be caused by urecogized atherothrombotic evets, a clear ratioale for aticoagulatio i chroic heart failure exists. 4 6 Although a posthoc aalysis of the Studies of Left Vetricular Dysfuctio (SOLVD) trial idicated that warfari therapy was associated with lower mortality ad morbidity rates, 7 o large prospective cliical trial limited Cotiuig medical educatio (CME) credit is available for this article. Go to to take the quiz. Received Jue 24, 2008; accepted Jauary 12, From the Departmet of Veteras Affairs, Sa Fracisco, Calif (B.M.M., S.E.A.); Cooperative Studies Program Coordiatig Ceter, Veteras Affairs Medical Ceter, Perry Poit, Md (J.F.C., W.F.K.); Uiversity of Alberta, Edmoto, Alberta, Caada (P.W.A.); Castle Hill Hospital, East Yorkshire, UK (J.G.F.C.); Lakeau Istitute for Medical Research, Wyewood, Pa (M.E.); Hery Ford Hospital, Detroit, Mich (S.M.J.); Duke Uiversity Medical Ceter, Durham, NC (C.M.O., K.A.S.); McMaster Uiversity Medical Ceter, Hamilto, Otario, Caada (K.T.); ad Cooperative Studies Program Cliical Research Pharmacy, Veteras Affairs Medical Ceter, Albuquerque, NM (S.R.W.). The olie-oly Data Supplemet is available with this article at Cliical trial registratio iformatio URL: Uique idetifier: NCT Correspodece to Joseph F. Collis, ScD, CSPCC (151E), PO Box 1010, 362T, Boiler House Rd, Perry Poit, MD joseph. collis2@va.gov 2009 America Heart Associatio, Ic. Circulatio is available at DOI: /CIRCULATIONAHA

2 Massie et al WATCH Trial for Chroic Heart Failure 1617 to heart failure patiets i sius rhythm has addressed this questio. 8 Editorial p 1559 Cliical Perspective p 1624 May patiets with chroic heart failure are treated with aspiri. A posthoc aalysis of SOLVD has suggested that patiets receivig aspiri may gai less beefit from agiotesi-covertig ezyme (ACE) ihibitio i terms of survival or hospitalizatio for worseig of heart failure. 9 Meta-aalyses of ACE ihibitor trials i patiets with heart failure ad left vetricular dysfuctio after myocardial ifarctio (MI) have yielded mixed results but are geerally cosistet with some weakeig of ACE ihibitor beefit. 10,11 Whether these fidigs should affect the use of this aget remais cotroversial. More recetly, a study of 279 patiets radomized to ope-label aspiri 300 mg QD, warfari (target iteratioal ormalized ratio [INR] of 2.5 to 3.0), or o atithrombotic therapy foud a excess of heart failure hospitalizatios i the aspiri group compared with both warfari ad o atithrombotic aget patiets. 12 The fidig that aspiri reduces the beefit of ACE ihibitors could relate to kow adverse effects of prostagladi ihibitio i patiets with heart failure. 13 This may be more importat i patiets treated with ACE ihibitors because the hemodyamic effects of these agets are partially mediated by ehaced prostagladi sythesis The Warfari ad Atiplatelet Therapy i Chroic Heart Failure (WATCH) trial was udertake to determie the optimal atithrombotic aget for heart failure patiets with reduced ejectio fractios who are i sius rhythm. 4 Two primary hypotheses were addressed: that aticoagulatio with warfari is superior to atiplatelet therapy with aspiri i prevetig major cardiovascular outcomes ad that clopidogrel, a atiplatelet aget with a prostagladi-idepedet mechaism of actio, is superior to aspiri i this populatio. Aspiri was compared with clopidogrel rather tha a placebo because it was ot judged feasible or ethical to radomize heart failure patiets with coroary artery disease to receive o atithrombotic therapy. Methods The WATCH trial desig ad baselie characteristics of erolled patiets have bee described previously 4 ad are preseted briefly here. Patiet Populatio Patiets were recruited betwee October 1999 ad Jue 2002 from 142 ceters i the Uited States, Caada, ad the Uited Kigdom. Patiets 18 years of age were eligible if they had symptomatic heart failure (New York Heart Associatio class II to IV) for 3 moths before etry, had a left vetricular ejectio fractio 35% measured withi 3 moths by ay stadard techique, were i sius rhythm, ad were treated with a diuretic ad a ACE ihibitor for at least 60 days (uless ot tolerated). For patiets who could ot tolerate a ACE ihibitor, treatmet with hydralazie plus log-actig itrates or a agiotesi II receptor atagoist was recommeded. -Blocker use was strogly ecouraged. Other heart failure treatmets were at the discretio of the ivestigators. The primary exclusio criteria were cotraidicatios or specific idicatios for ay of the study medicatios, immiet procedures ecessitatig withdrawal or use of the study medicatios, heart failure from correctable causes, serious comorbid coditios expected to limit life expectacy, or other coditios that would iterfere with protocol adherece. All subjects provided writte iformed coset. The study protocol was approved by the Huma Rights Committee of the Perry Poit, Md, Departmet of Veteras Affairs (VA) Cooperative Studies Program Coordiatig Ceter (CSPCC), by local regulatory authorities i Caada ad the Uited Kigdom, ad by the Istitutioal Review Board or Ethics Committee at each participatig site. Study Desig WATCH was a multiatioal, prospective, radomized trial i which patiets were assiged to 1 of 3 treatmet arms: aspiri 162 mg or clopidogrel 75 mg daily provided i a double blid, double-dummy maer or ope-label warfari titrated to a target INR of 2.5 to 3.0 with a desigated acceptable rage of 2.0 to 3.5. There was o loadig dose for either clopidogrel or aspiri. Warfari therapy, which was maaged by either the ivestigative team or a aticoagulatio cliic, was iitiated at 4 mg daily except i subjects 70 years of age or takig amiodaroe; they were started at 3 mg daily. INR was determied after 1 week, ad dose was adjusted i icremets of 1 mg as frequetly as ecessary to achieve a INR of 2.5 to 3.0. The target INR rage of 2.5 to 3.0 was chose because postifarctio trials achievig INR values i this rage have show superiority of warfari over aspiri, whereas those with lower INR targets ad values have ot Moitorig visits were at the discretio of the resposible practitioers but maximally at 6-week itervals. Patiets were see at 3-moth itervals, with iterim telephoe cotacts at 6-week itervals. These calls were scripted to idetify chages i cliical status, adverse evets, study ed poits, ad medicatio compliace. Study Ed Poits The primary ed poit was the composite of all-cause mortality, ofatal MI, ad ofatal stroke. Secodary ed poits icluded the 3 compoets of the primary ed poit ad hospitalizatios for heart failure. The primary safety ed poit was major bleedig episodes, defied as bleedig episodes leadig to death or disability (icludig loss of eurological or special seses fuctio), requirig surgical itervetio, or associated with a acute declie of hemoglobi 2 gm/dl or trasfusio of 1 U packed red cells or whole blood. Study Maagemet A Executive Committee, cosistig of ivestigators, heart failure researchers, ad CSPCC ad VA CSP Research Pharmacy Coordiatig Ceter represetatives, served as the decisio-makig body for the study. Operatioal aspects of the trial were oversee by the CSPCC, the study chairma s office, ad coordiatig offices i Caada ad the Uited Kigdom. The VA CSP Research Pharmacy Coordiatig Ceter was resposible for obtaiig, packagig, ad distributig the study drug supplies; workig with the regulatory agecies of the participatig coutries; ad moitorig ad reportig serious adverse evets. A idepedet Data ad Safety Moitorig Board was resposible for reviewig the study. Radomizatio ad Blidig The CSPCC geerated a radomizatio sequece for each site separately usig varyig block sizes of 3 or 6. The site coordiator/ site ivestigator called the CSPCC to obtai a radomizatio umber ad treatmet allocatio. Study medicatio was obtaied from the local pharmacy or dispesig uit o presetatio of the siged coset form. Oly patiets radomized to aspiri or clopidogrel were blided to treatmet received. I a emergecy, the blid could be broke by callig the VA CSP Research Pharmacy Coordiatig Ceter, the study chairma, the regioal coordiatig ceter, or the CSPCC. A sealed evelope provided to the local pharmacy or dispesig uit could be opeed as a default strategy. No attempt was made to

3 1618 Circulatio March 31, 2009 assess the adequacy of blidig. The mai outcome measures were adjudicated by a Ed Poit Committee made up of members blided to treatmet allocatio, icludig INR results. Sample Size ad Statistical Aalyses The prespecified statistical aalysis for the primary composite ed poit of death, ofatal MI, ad ofatal stroke was a log-rak test of the Kapla Meier product limit estimator of time to first evet based o itetio-to-treat. 23 The origial sample size of 1500 patiets for each of the 3 groups was determied usig the method of Lakatos. 24 This was based o a plaed erollmet period of 3 years, a mea follow-up period of 3.5 years, ad a estimated 18% aual evet rate, which would have 90% power to detect a 20% betwee-group differece i aual evet rates usig a type I error rate of (adjustig for the 3 pair-wise comparisos). 25 The itet-to-treat log-rak test also was used to compare the effect of treatmets o total mortality. Itet-to-treat 2 aalyses were used to compare treatmets o the dichotomous secodary outcome measures. Early Termiatio Because of slow erollmet, the study termiated prematurely i Jauary As a result, recruitmet eded i Jue 2002 (4 moths early), ad follow-up ceased 1 year later (16 moths early). With the early termiatio, 1587 patiets rather tha 4500 were radomized. As a result, the differece i aual evet rate that the study was powered to detect with the origial parameters (power of 90% ad a type I error rate of 0.017) icreased from 20% to 40%. Power to detect the origial 20% differece dropped from 90% to 41%. The authors had full access to ad take resposibility for the itegrity of the data. All authors have read ad agree to the mauscript as writte. Results Erollmet Of the 1587 patiets erolled, 937 patiets were from the Uited States (590 patiets i 44 VA sites ad 347 i 41 other US sites), 332 were from 28 Caadia sites, ad 318 came from 29 sites i the Uited Kigdom. Patiet baselie characteristics are show i Table 1. Although screeig iformatio was ot collected, the erolled populatio was typical of trials ivolvig patiets with moderate to severe systolic heart failure. Although patiets were required to have heart failure symptoms oly for 3 moths, Table 1 shows that 70% of the patiets had a heart failure diagosis for 2 years. The patiet characteristics were well balaced amog the 3 treatmet groups. Amog 70 baselie characteristics examied, the oly itergroup differece that reached statistical sigificace (P 0.05) was the prevalece of diabetes, which was highest i the warfari group (38%) ad lowest i the clopidogrel group (31%). Follow-Up ad Protocol Adherece The mea duratio of follow-up was 1.9 years (media, 21 moths), yieldig 3073 patiet-years of exposure. Figure 1 describes patiet follow-up experiece ad vital status at the ed of the study. Of the 1587 patiets radomized, 523 received aspiri, 524 received clopidogrel, ad 540 received warfari. The figure idicates that there were 282 deaths, 13 patiets termiated from the study because of a heart trasplat, ad 76 patiets lost to follow-up, icludig 31 at 3 termiated early because of site regulatory issues. There were few differeces betwee treatmet groups. Of the 76 patiets lost to follow-up, 22 were determied to be alive as of March 1, Figure 1 also shows the reasos that patiets were permaetly discotiued from study drug. Although o differece existed betwee treatmet groups regardig overall drug discotiuatio, warfari was discotiued by choice (32 patiets) more frequetly tha aspiri (16 patiets) or clopidogrel (19 patiets). Warfari patiets also were more likely to have their study medicatio discotiued because of hemorrhage ad icreased bleedig risk but were less likely to have study medicatios stopped as a result of atrial fibrillatio, embolic/occlusive evets, ad cardiovascular evets. I additio, 52 (9.9%) of the aspiri patiets, 48 (9.2%) of the clopidogrel patiets, ad 59 (10.9%) of the warfari patiets had their medicatios stopped temporarily durig the study. For patiets whose study medicatios were discotiued either permaetly or temporarily, 81 (26.8%) discotiued clopidogrel or aspiri patiets received ostudy warfari, 94 (55.6%) discotiued warfari patiets received ostudy aspiri, ad 72 (48.0%) discotiued clopidogrel patiets received ostudy aspiri. O the basis of retured tablet couts, 80% of the prescribed double-blid aspiri ad clopidogrel tablets were take. Whe documeted periods of temporary or permaet discotiuatios were excluded, 93% of doses were used. After the iitial 6-week titratio phase, the mea INR value i the warfari arm was , with 70.4% of measuremets fallig withi the acceptable rage (2.0 to 3.5), 20.3% fallig below 2.0, ad 9.3% fallig above 3.5. The media INR was 2.5. Primary ad Secodary Ed Poits Primary Composite Ed Poit ad Its Compoets Figure 2A shows the evet curves of the primary composite ed poit of all-cause mortality, ofatal MI, or ofatal stroke. For the warfari versus aspiri compariso, the uadjusted hazard ratio (HR) was 0.98 (95% CI, 0.86 to 1.12; P 0.77). The HR for the clopidogrel versus aspiri compariso was 1.08 (95% CI, 0.83 to 1.40; P 0.57), ad the HR for the warfari versus clopidogrel compariso was 0.89 (95% CI, 0.68 to 1.16; P 0.39). Figure 2B shows the evet curves for all-cause mortality. The HR for warfari versus aspiri was 0.98 (95% CI, 0.85 to 1.13; P 0.75); for clopidogrel versus aspiri, 1.04 (95% CI, 0.78 to 1.38; P 0.80); ad for warfari versus clopidogrel, 0.92 (95% CI, 0.69 to 1.23; P 0.58). The umbers of primary ed poits were similar across treatmet groups (Table 2), as were the umbers of deaths ad ofatal MIs. Although the umbers of ofatal strokes were small (9, 11, ad 1 i the aspiri, clopidogrel, ad warfari groups, respectively), both the aspiri-warfari ad the clopidogrel-warfari differeces reached omial statistical sigificace (P 0.01 i both cases). Three of the ofatal strokes (1 i each treatmet group) were classified by the Ed Poit Committee as hemorrhagic coversio. All others were ohemorrhagic. There were 6 fatal strokes; 3, 1, ad 2 i the aspiri, clopidogrel, ad warfari groups, respectively. For all strokes (fatal ad ofatal), the differeces for the aspiri-warfari ad clopidogrel-warfari com-

4 Massie et al WATCH Trial for Chroic Heart Failure 1619 Table 1. Baselie Patiet Characteristics Aspiri ( 523) Clopidogrel ( 524) Warfari ( 540) Combied ( 1587) Age, mea SD, y Me, (%) 443 (85) 452 (86) 458 (85) 1353 (85) White, (%) 419 (80) 395 (75) 411 (76) 1225 (77) Black, (%) 58 (11) 77 (15) 70 (13) 205 (13) Cause of heart failure, (%) Defiite/probable ischemic CM 375 (72) 376 (72) 412 (76) 1163 (73) Primary CM 107 (20) 126 (24) 101 (19) 334 (21) Other 41 (8) 22 (4) 27 (5) 90 (6) Years diagosed with heart failure, (%) 1 61 (12) 62 (12) 51 (9) 174 (11) 1to (20) 93 (18) 109 (21) 305 (19) (69) 367 (70) 379 (70) 1104 (70) Comorbid illesses, (%) Prior MI 302 (58) 292 (56) 322 (60) 916 (58) Hypertesio 249 (48) 249 (48) 267 (49) 765 (48) Diabetes 178 (34) 162 (31) 206 (38) 546 (34) Prior stroke 23 (4) 30 (6) 34 (6) 87 (5) PVD 60 (11) 53 (10) 67 (12) 180 (11) COPD 44 (8) 39 (7) 41 (8) 124 (8) Baselie assessmets NYHA class, (%) II 219 (42) 231 (44) 249 (46) 699 (44) III 296 (57) 284 (54) 282 (52) 862 (54) IV 8 (1) 9 (2) 9 (2) 26 (2) Heart failure admissio withi 6 mo, (%) 175 (34) 184 (35) 187 (35) 546 (35) Heart rate, mea (SD), bpm Systolic BP, mea (SD), mm Hg Ejectio fractio, mea (SD) Hemoglobi, mea SD, g/dl Creatiie, mea SD, mg/dl Baselie medicatios, (%) ACE ihibitor 458 (88) 457 (87) 474 (88) 1389 (87) ARB 55 (11) 54 (10) 57 (11) 166 (10) -Blocker 362 (69) 368 (70) 381 (71) 1111 (70) Loop diuretic 515 (98) 519 (99) 530 (98) 1564 (99) Digoxi 272 (52) 264 (50) 270 (50) 806 (51) Spiroolactoe 160 (31) 143 (27) 144 (27) 447 (28) Warfari 5 (1) 3 (1) 7 (1) 15 (1) Curret smokig, (%) Yes 85 (16) 85 (16) 95 (18) 265 (17) Never 110 (21) 137 (27) 110 (21) 357 (23) Former 324 (62) 293 (57) 325 (61) 942 (60) CM idicates cardiomyopathy; PVD, peripheral vascular disease; COPD, chroic obstructive pulmoary disease; NYHA, New York Heart Associatio; ad ARB, agiotesi receptor blocker. *Primarily, the cause of heart failure was cosidered valve disease or other i some patiets. Defiite ischemic cardiomyopathy was defied by the presece of prior MI, positive agiogram, or prior revascularizatio. Probable ischemic cardiomyopathy also icluded those with a stress-iduced perfusio defect or wall motio abormality. parisos were ot quite as sigificat (both P 0.016) as for ofatal cases oly (Table 2). However, whe cetral ervous system bleedig was added to all strokes (Table 2), o sigificat differeces were foud for ay of the treatmet group comparisos. Whe these primary aalyses were cosidered for each geder group ad each racial group (white, black, other) separately, similar results were see. The oly exceptio was for ofatal strokes i wome, i whom there were oly 2 ofatal strokes (0.9% of wome).

5 1620 Circulatio March 31, 2009 Figure 1. Patiet flow ad vital status at the ed of the WATCH study. LV idicates left vetricular; CABG, coroary artery bypass graft surgery; ad GI, gastroitestial. Heart Failure Hospitalizatios I the aspiri group, 116 patiets (22.2%) were hospitalized at least oce for worseig heart failure compared with 89 patiets (16.5%) i the warfari arm (Table 2), a omially sigificat icrease (P 0.019). The total umber of heart failure admissios also was greater with aspiri compared with warfari (218 versus 155; P 0.001). Whe time to heart failure admissio or death was cosidered, o differeces were foud. The HRs ad 95% CIs were as follows: for warfari versus aspiri, 0.94 (95% CI, 0.84 to 1.04; P 0.22); for clopidogrel versus aspiri, 0.97 (95% CI, 0.78 to 1.21; P 0.79); ad for warfari versus clopidogrel, 0.90 (95% CI, 0.72 to 1.12; P 0.37). Systemic Embolisms There were oly 10 total systemic (peripheral arterial, abdomial, real, pulmoary, ad other) embolisms (Table 2). Of these 10, 4 were pulmoary embolisms. There were o sigificat differeces betwee treatmet groups. There was oly 1 death, a warfari patiet with a pulmoary embolism. Bleedig Evets Major bleedig episodes (Table 2) were more frequet i warfari patiets compared with clopidogrel (P 0.01) but ot aspiri (P 0.22) patiets. Six patiets had 7 cetral ervous system bleedig episodes o warfari compared with 3 patiets o aspiri ad 1 patiet o clopidogrel. There also were more patiets with mior bleedig episodes i the warfari group tha i the clopidogrel group (P 0.025) ad a similar tred i the aspiri group (P 0.054). Atrial Fibrillatio ad Gastroitestial Itolerace Atrial fibrillatio occurred i 10% of patiets at some time durig their follow-up. There were o differeces betwee treatmet groups (10.3%, 10.3%, ad 9.3% for aspiri, clopidogrel, ad warfari, respectively). Patiets were routiely questioed about symptoms of gastroitestial itolerace at each visit. There were 49.9% who reported dyspepsia or epigastria discomfort at some time, 41.2% who reported diarrhea, 29.2% who reported ausea or vomitig, ad 22.5% who reported other symptoms of gastroitestial itolerace. Differeces betwee treatmet groups were foud oly for diarrhea; fewer aspiri patiets reported diarrhea tha either clopidogrel (35.4% versus 43.9; P ) or warfari (35.4% versus 44.4%; P ) patiets. Ischemic Versus Noischemic Group Comparisos Patiets were divided ito ischemic (defiite or probable) ad oischemic groups, ad aalyses for the primary outcome measure, its compoets, ad bleedig evets were coducted for each group separately. For the ischemic patiets, the oly sigificat differeces were for strokes; warfari did better tha either aspiri (0.0% versus 1.6%; P 0.01) or clopidogrel (0.0% versus 2.7%; P ). For the oischemic patiets, the oly sigificat fidig was for major hemorrhage; clopidogrel patiets (0.7%) had fewer major hemorrhages tha warfari patiets (6.3%) (P ). The small sample sizes, especially for the oischemic patiets (total 424 patiets), most likely reduced the likelihood of fidig other differeces. Discussio With 3000 patiet-years of follow-up, the WATCH trial is the largest radomized trial to date examiig atithrombotic therapies i patiets with chroic heart failure. Although the trial was discotiued prematurely, the WATCH results suggest that for the primary composite ed poit ad allcause mortality, major differeces betwee aticoagulatio with warfari ad atiplatelet therapy with either aspiri or clopidogrel are ulikely. Although the 327 primary ed poits observed were oly 23% of the protocol-specified 1440 evets, the 95% cofidece limits aroud these results exclude 20% differeces betwee warfari ad aspiri for both the primary composite ed poit ad total mortality. Similarly, 90% CIs exclude a 20% differece favorig clopidogrel over aspiri for these ed poits. Therefore, these results do ot support our 2 primary hypotheses that warfari is superior to aspiri i prevetig major cardiovascular outcomes ad that clopidogrel is superior to aspiri i this populatio; ideed, our results exclude these hypotheses with a high degree of certaity. For 2 prespecified secodary ed poits, ofatal stroke ad hospitalizatios for worseig heart failure, some support is provided for the first hypothesis that warfari may be superior to aspiri i prevetig cardiovascular outcomes. These differeces are ot small ad are potetially cliically importat. Give the early study termiatio ad the umber of potetial aalyses, our results should be iterpreted with cautio. The tred for more mior bleedig i the warfari group tha the aspiri group also eeds to be take ito

6 Massie et al WATCH Trial for Chroic Heart Failure 1621 Figure 2. A, Plot of the proportio of patiets experiecig the primary composite ed poit of death, ofatal MI, or stroke durig the course of the WATCH trial (warfari vs aspiri, P 0.77; warfari vs clopidogrel, P 0.39; aspiri vs clopidogrel, P 0.59). B, Plot of the proportio of patiets who died durig the course of the WATCH trial (warfari vs aspiri, P 0.75; warfari vs clopidogrel, P 0.58; aspiri vs clopidogrel, P 0.80). accout whe the use of warfari is cosidered. We fid o support from the secodary aalyses that clopidogrel is superior to aspiri. The relatively low icidece of stroke amog our patiets is oteworthy. For patiets ot assiged to warfari, the icidece of stroke was oly 1.0 evet per 100 patiet-years of follow-up, a fidig cosistet with observatios from other trials coducted i the past 2 decades. 26,27 Based o posthoc aalyses of atrial fibrillatio trials, 28 this is far lower tha for heart failure patiets i atrial fibrillatio for whom aticoagulatio is strogly recommeded. However, ofatal strokes ad all strokes were less frequet i the warfari arm tha i the groups assiged to either atiplatelet aget. These fidigs, which represet the first prospective, cotrolled data i patiets required to be i sius rhythm at baselie, are cosistet with may physicias belief that aticoagulatio may prevet stroke i patiets with chroic systolic heart failure. These results should be tempered by the fidigs of more bleedig episodes with warfari. Compared with aspiri patiets, the warfari group experieced a 26% relative reductio (5.7% absolute decrease) i the proportio of patiets hospitalized for heart failure. Takig ito accout multiple hospitalizatios, warfari was associated with a 40% reductio i heart failure admissios compared with aspiri (6.0 evets per 100 patiet-years

7 1622 Circulatio March 31, 2009 Table 2. Number of Patiets With Evets ad Total Number of Evets as Classified by Ed Poit Committee Treatmet Aspiri Clopidogrel Warfari P by 2 (Patiets With Evets) Patiets, Patiets, % Evets, Patiets, Patiets, % Evets, Patiets, Patiets, % Evets, Aspiri vs Clopidogrel Aspiri vs Warfari Clopidogrel vs Warfari Death, ofatal MI, or ofatal stroke All deaths reported Nofatal MI Nofatal stroke All strokes Hospitalizatio with decompesated cogestive heart failure All systemic embolisms All pulmoary embolisms Major hemorrhage CNS bleeds CNS bleeds or stroke Mior bleeds Total patiets CNS idicates cetral ervous system. follow-up). Oe possible mechaism for this differece is that aspiri may iterfere with the icrease i prostagladi levels that occurs i heart failure that is further ehaced by ACE ihibitors. Prostagladis such as prostacycli ad prostagladi E 1 have vasodilator, atriuretic, ad atiaggregatory activity, which appears to play a compesatory role i patiets with heart failure. Although these data caot be cosidered defiitive, the magitude of reductio potetially achievable by avoidig aspiri is similar to that observed with the most effective pharmacological therapies for heart failure such as ACE ihibitors ad -blockers Moreover, the relative ad absolute differeces betwee warfari ad aspiri are similar to those observed i the Warfari ad Aspiri Study i Heart Failure. 12 It should be kept i mid, however, that whe a aalysis of the time to first hospitalizatio or death was coducted, the differeces disappeared. May physicias ad patiets are appropriately cocered about the safety of aticoagulatio i heart failure patiets because they usually are older, geerally are takig multiple medicatios, ad may have sigificat fluctuatios i liver fuctio, food itake, ad drug absorptio related to cogestio. 19,33,34 I that regard, warfari treatmet i our trial was associated with more frequet bleedig episodes compared with clopidogrel ad a osigificat excess of bleedig compared with aspiri. However, warfariassociated bleedig complicatios occurred at a frequecy similar to that observed i aticoagulatio trials i post-mi ad atrial fibrillatio patiets. Although warfari was related to a lower icidece of stroke compared with the other 2 drugs, whe cetral ervous system bleedig ad stroke were combied, these differeces disappeared. Thus, the elevated risks for bleedig (major, mior, ad cetral ervous system) versus the lower risk for stroke must be cosidered whe warfari is begu, especially give the low rates of embolic evets. Several limitatios could have affected our results. The higher umber of diabetic patiets i the warfari group, with their higher risks, could have uderestimated the ability of warfari to reduce thromboembolic evets. However, the warfari group had few such evets i our study. Aother cocer is that patiets with symptoms for oly 3 moths were erolled. This may have resulted i a healthier subset of patiets with lower evet rates (eg, ejectio fractio may have improved after cotiuatio of heart failure treatmet), although 70% of our patiets had bee diagosed for at least 2 years. A idicatio that our sample may have bee a healthier subset of the patiet populatio is the lower-thaexpected evet rate. Although our evet rate was estimated to be 18% aually for our sample size estimates, as see i

8 Massie et al WATCH Trial for Chroic Heart Failure 1623 Figure 2A, it took almost 2 years to reach a 18% evet rate. O the other had, our study may be a truer reflectio of heart failure patiets i geeral. The early termiatio of the study, which reduced follow-up time by 16 moths ad reduced the umber of evets, made fidig treatmet differeces more difficult as a result of low statistical power. Future studies with a loger follow-up time may be eeded to fid treatmet differeces. Fially, the target INR rage of 2.5 to 3.0 for warfari is relatively arrow ad may limit geeralizability to everyday practice. However, our medium INR was 2.5, ad 70% of the actual INRs were betwee 2.0 ad 3.5. Give the absece of sigificat differeces i the primary ed poit or i survival, this study does ot justify a systematic avoidace of aspiri i patiets with chroic heart failure i sius rhythm. The WATCH results also do ot provide supportive data to reiforce the recet recommedatios of the Seveth Cosesus Coferece o Atithrombotic Therapy to avoid aspiri i patiets with oischemic dilated cardiomyopathy ad i other heart failure patiets with o evidece of or major risk factors for vascular disease. 11 These results also provide o evidece to support the use of aspiri. Although the use of warfari rather tha aspiri or clopidogrel may have resulted i reduced strokes i our populatio, this beefit may be offset by icreased risk from bleedig. Overall, our primary outcome measure ad mortality results do ot support our 2 primary hypotheses that aticoagulatio with warfari is superior to atiplatelet therapy with aspiri i prevetig major cardiovascular outcomes ad that clopidogrel is superior to aspiri i this populatio. Sources of Fudig This trial was supported ad admiistered by the Cooperative Studies Program of the Office of Research ad Developmet, Departmet of Veteras Affairs. Study drugs ad urestricted grats were provided by Bristol Myers Squibb, Saofi-Sythelabo, ad Dupot pharmaceutical compaies. Disclosures Dr Massie has received research grats from Bristol-Myers Squibb ad Saofi-Avetis. Dr Schulma has received research grats from Bristol-Myers Squibb, ad Saofi-Avetis ad does cosultig for Saofi-Avetis. Dr Ezekowitz has served as a cosultat to Bristol- Myers Squibb ad Saofi-Avetis. The other authors report o coflicts. Refereces 1. Wishart JH, Chapma CB. Dicumarol therapy i cogestive heart failure. N Egl J Med. 1948;239: Harvey WP, Fich CA. Dicumarol prophylaxis of thromboembolic disease i cogestive heart failure. N Egl J Med. 1950;242: Griffith GC, Stragell R, Leviso DC. A study of the beeficial effects of aticoagulat therapy i cogestive heart failure. A Iter Med. 1952;37: Massie BM, Krol WF, Ammo SE, Armstrog PW, Clelad JG, Collis JF, Ezekowitz M, Jafri SM, O Coor CM, Packer M, Schulma KA, Teo K, Warre S. The Warfari ad Atiplatelet Therapy i Heart Failure Trial (WATCH): ratioale, desig, ad baselie patiet characteristics. J Card Fail. 2004;10: Lip GYH, Gibbs CR. Does heart failure cofer a hypercoagulable state? Virchow s triad revisited. J Am Coll Cardiol. 1999;33: Uretsky BF, Thygese K, Armstrog PW, Clelad JG, Horowitz JD, Massie BM, Packer M, Poole-Wilso PA, Ryde L. Acute coroary fidigs at autopsy i heart failure patiets with sudde death: results from the Assessmet of Treatmet With Lisiopril ad Survival (ATLAS) trial. Circulatio. 2000;102: Al-Khadra AS, Salem DN, Udelso JE, Rad WM, Smith JJ, Kostam MA. Warfari aticoagulatio ad survival: a cohort aalysis from the Studies of Left Vetricular Dysfuctio. J Am Coll Cardiol. 1998;31: Lip GY, Gibbs CR. Aticoagulatio for heart failure i sius rhythm: a Cochrae systematic review. Quart J Med. 2002;95: Al-Khadra AS, Salem DN, Rad WM, Udelso JE, Smith JJ, Kostam MA. Atiplatelet agets ad survival: a cohort aalysis from the Studies of Left Vetricular Dysfuctio (SOLVD) trial. J Am Coll Cardiol. 1998;31: Teo KK, Yusuf S, Pfeffer M, Torp-Pederse C, Kober L, Hall A, Pogue J, Latii R, Collis R, for the ACE Ihibitors Collaborative Group. Effects of log-term treatmet with agiotesi-covertig-ezyme ihibitors i the presece or absece of aspiri: a systematic review. Lacet. 2002;360: Hall D. The aspiri-agiotesi-covertig ezyme trade-off: the halve ad halve ot. J Am Coll Cardiol. 2000;35: Clelad JGF, Fidlay I, Jafri S, Sutto G, Falk R, Bulpitt C, Pretice C, Ford I, Traier A, Poole-Wilso PA. The Warfari/Aspiri Study i Heart Failure (WASH): a radomized trial comparig atithrombotic therapies for patiets with heart failure. Am Heart J. 2004;148: Dzau VJ, Packer M, Lilly LS, Swartz SL, Holleberg NK, Williams GH. Prostagladis i severe cogestive heart failure: relatio to activatio of the rei-agiotesi system ad hypoatremia. 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9 1624 Circulatio March 31, SOLVD Ivestigators. Effect of ealapril o survival i patiets with reduced left vetricular ejectio fractios ad cogestive heart failure. N Egl J Med. 1991;325: Garg R, Yusuf S. Overview of radomized trials of agiotesicovertig ezyme ihibitors o mortality ad morbidity i patiets with heart failure. JAMA. 1995;273: Hjalmarso A, Goldstei S, Fagerberg B, Wedel H, Waagstei F, Kjekshus J, Wikstrad J, El Allaf D, Vítovec J, Aldershvile J, Halie M, Dietz R, Neuhaus KL, Jáosi A, Thorgeirsso G, Duselma PH, Gullestad L, Kuch J, Herlitz J, Rickebacher P, Ball S, Gottlieb S, Deedwaia P. Effects of cotrolled-release metoprolol o total mortality, hospitalizatios, ad well-beig i patiets with heart failure. JAMA. 2000;283: Brophy JM, Joseph L, Rouleau JL. -Blockers i cogestive heart failure: a Bayesia meta-aalysis. A Iter Med. 2001;134: Peig-va Beest FJA, Va Meege E, Rosedaal FR, Stricker BH. Characteristics of aticoagulat therapy ad comorbidity related to overaticoagulatio. Thromb Haemost. 2001;86: Visser LE, Bleumik GS, Trieekes PH, Vulto AG, Hofma A, Stricker BH. The risk of overaticoagulatio i patiets with heart failure o coumari aticoagulats. Br J Haematol. 2004;127: CLINICAL PERSPECTIVE The Warfari ad Atiplatelet Therapy i Chroic Heart Failure (WATCH) trial was a radomized, partially blid, multiatioal, multiceter study of aspiri, clopidogrel, ad warfari to determie the optimal atithrombotic aget for heart failure patiets with reduced ejectio fractios who are i sius rhythm. The primary outcome measure (a composite of mortality, ofatal stroke, ad ofatal myocardial ifarctio) ad mortality-oly results did ot support our 2 primary hypotheses that aticoagulatio with warfari is superior to atiplatelet therapy with aspiri i prevetig major cardiovascular outcomes ad that clopidogrel is superior to aspiri i this populatio. Although the use of warfari i our populatio may have resulted i fewer strokes, this beefit may be offset by icreased risk from bleedig. Physicias should balace the icreased bleedig risks with decreased stroke risk whe cosiderig the use of warfari. Give the absece of sigificat differeces i the primary ed poit or survival, this study does ot justify a systematic avoidace of aspiri i patiets with chroic heart failure i sius rhythm. Go to to take the CME quiz for this article.