Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial

Patrick M Pullicino; Min Qian; Ralph L Sacco; Ron Freudenberger; Susan Graham; John R Teerlink; Douglas Mann; Marco R Di Tullio; Piotr Ponikowski; Dirk J Lok; Stefan D Anker; Gregory Y H Lip; Conrado J Estol; Bruce Levin; Jay P Mohr; John L P Thompson; Shunichi Homma; WARCEF Investigators

doi:10.1159/000365502

Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial

Cerebrovasc Dis. 2014;38(3):176-81. doi: 10.1159/000365502. Epub 2014 Oct 9.

Authors

Patrick M Pullicino¹, Min Qian, Ralph L Sacco, Ron Freudenberger, Susan Graham, John R Teerlink, Douglas Mann, Marco R Di Tullio, Piotr Ponikowski, Dirk J Lok, Stefan D Anker, Gregory Y H Lip, Conrado J Estol, Bruce Levin, Jay P Mohr, John L P Thompson, Shunichi Homma; WARCEF Investigators

Collaborators

WARCEF Investigators:
S Homma, J L P Thompson, P Pullicino, R Freudenberger, S Graham, J Teerlink, S Ammon, D Mann, J P Mohr, R L Sacco, B Massie, S Anker, A Labovitz, C Moy, C Moy, P Gilbert, L Gutmann, J Marler, S Homma, V Mejia, A Gabriel, S Borden, E Peña, C Harris, R Khadouri, D Gohs, M Brown, G Berry, D Disantis, M Scullin, P Smith, S Kohsaka, W Watson, L Guillory, J L P Thompson, B Levin, R Buchsbaum, M Del Valle, A Sanford, G Levy, K Tea, J Grier, L Swydan, B O'Hare, R Prodhan, R Arbing, E Flanagan, E Duverger, A Peljto, W Lo, A Tierney, A Henriquez, J Keen, G J del Zoppo, G W Albers, M Eliasziw, J A Hinchey, K C Johnston, A M Lowe, I L Piña, J A Swain, J R Teerlink, S Ammon, S Slomiak, L Cape, H J M Barnett, A Bruno, J D Easton, S Levine, D Sahlas, F Bleyer, P Carson, A Ellis, A Miller, S T Palmeri, A Labovitz, M Di Tullio, M Bierig, R Liu, C Donato, R Hart, C McKay, L Wilson, E Frey, K Hayward, P Stein-Beal, L Konczarek, M Diek, M Rohwedder, M Bohdanowicz-Zazula, C F Peerenboom-Fey, M Vissiennon, G Rex, M Varga, O Kovtun, V Orlyk, P Arenberger, J Jaros, A Ruiz, M Zimmermann, A Ellenberg, A Minagar, R Kelley, J McGee, P Jinkins, S Bezucha, S Graham, V Hart, M Bonora, R Sawyer, K Ammerman, P Ramappa, V Berchou, E Jones, E Olgren, B Hattler, C Anderson, B Watson, D Wolf, J Kosits, L Casazza, D Yip, J Meschia, A McPhail, K Greenan, R Rothbart, J Love, T Schrader, V Garman, M Stoddard, K Remmel, R Longaker, C Gerula, M Klapholz, J Kirmani, R Mattessich, M Di Tullio, C Rodriguez, A Gabriel, W Graettinger, A Baker, A Valencia, P Kosolcharoen, L Williams, V Sorrell, B Coull, D Bruck, E Ofili, M Frankel, P Jackson, M Nanna, S Sparr, W Almeida, R Libman, B Stephens, C DeMers, T Giles, L Roffidal, D Barratt, M Liston, C Lindsey, L Giron, W Felton 3rd, L Joseph, M Lee, J Bisognano, C Benesch, L Caufield, E Nishime, M Moussavian, E Polland, L Fischer, K Peterson, B McGinnis, M Tilem, G Allam, J Beebe, P Chang, S Sen, C Schuler, L J Chabert, L Arcement, M Charlet, E Falgout, M Malkowski, T Dugan, J Hobbs-Williams, A Warner, K Panizzon, J Johnson, J Dissin, D Karia, N Molakala, B Dandapani, R Vicari, E Anthony, I Katzan, R Hobbs, A Richmond, R Hughes, W Baker, M Applegate, B Drachman, S Khella, S Donovan, A Slim, D Pearce Moore, B Darrow, A Travis, A Mercando, R Pellegrino, N Jarmukli, T Ochalek, D Janosik, J Dizes, L C Pettigrew, D Taylor, J Hanna, S Bailey, R Berkowitz, S Mathus, V Virkud, S Shaw, R Freudenberger, S Nabhan, E Wirkowski, B George, E Smith, S Locke, C Landau, D Ferguson, H V Anderson, L Westbrook, M Apelian, S Khoury, J Leppo, T Bator, W Felton 3rd, M Lee, M Stoddard, R Longaker, U Thadani, J Turner, S Goldman, S Daugherty, A Adler, T Rennie, M Malkowski, D Chupka, R Katz, L Witkin, W S Burgin, C Weber, Milton S Hershey, J Boehmer, P Frey, M Wilson, H Tworek, G Mallis, D Mauceri, R Schneider, W Schneider, G Ortiz, M Lichtenberger, B Hott, D Patrick, S Dunlap, S J Kim, S Pezzella, D Aubin, L Nikolaidis, J Wong, D Leifer, M Rossi, G Torre, J Arredondo, J Lynch, A Metcalf, J Gonzalez, B Donley, T Cappola, K Craig, B Bozkurt, M Bolos, T Noonan, C Alteri, P Ponikowski, L Kowalczyk, A Cwynar, D Drazek, J Biegus, A Sokoloskiego, R Szelemej, M Jurczok, R Serafin, A Jurczyk, M Ogorek, D Kopcik, B Metzkier-Wyrwa, A Szczepanska, M Dluzniewski, W Wicha, M Kuch, K Kuc, R Piotrowski, O Lesniak, M Krauze-Wielicka, J Herman, S Nowakowska, T Pasierski, B Kozlowski, K Wolkowska, A Juszczak, J Michalska, I Jedlinski, P Miekus, M Konarzewski, P Berkowski, N Jacek, Z Kalarus, A Duszanska, J Tarchalski, P Czaja, Z Gaciong, J Gora, A Kleinrok, G Prokop-Lewicka, H Haddad, R Davies, L Sitwell, J Donaldson, T To, R Yufe, B Donelly, T Huynh, R Cote, B St Jacques, D Borts, G Tullio, A M Sindilar, T Winder, E Janzen, C Walker, G Moe, N Bayer, A Konig, M Arnold, D Spence, J Smith, R Bessoudo, P Bailey, A McNulty, S Nawaz, C Dewar, M Rajda, M MacFarlane, J Minuk, C Schanz, A Penn, L Atkins, A Ducharme, H Brown, S Zieroth, A Muñoz, D Lok, J B M ten Holter, C Huls, P Bruggink-Andre, A van Bujisen-Nutters, M Daniels, A Coppes, M van Zagten, N Elzebroek, K Hamroui, P L M de Kort, J Vuijsters, N Holwerda, W Hermans, R van der Loo, E Wajon, G Hageman, G v Buchem-Damming, E Ronner, A Wissenburg-van Lieshout, H Niekus, M W J van Hessen, G A M Verheul, G Linssen, L te Pas, J Plomp, P A R de Milliano, R Breedveld, M J Bos, M Houra, D Beran, R Lebedova, J Carda, E Bednarova, J Vosmerova, G Marcinek, T Drasnar, O Najmanova, M Dunaj, E Pechackova, M Kuchar, P Jansky, J Simon, H Dvorakova, P Gregor, M Maruskova, L Svoboda, Z Lorenc, P Kralicek, L Pollak, Z M Krobot, J Spinar, M Nemec, L Spinarova, R Kuba, F Padour, I Padourova, M Padour, M Michalova, L Golan, M Hajkova, J Povolny, L Krizova, D Horak, P Kucera, I Malek, B Krizova, J Svoboda, R Ferkl, L Regos, L Csuros, O Lovasz, G Kiss, S Timar, N Torok, A Hajnalne, B Palossy, A Nagy, P Fulop, G Jakab, A Ronaszeki, M Bodi, M Satori, I Edes, I Varga, A Kovacs, L Berente, E Péterfai, R Pauer, K Toth, E Nagy, B Benczur, K Karsay, T Végh, R Nagy, P Karpati, Z Davidovits, J Borbola, J Vanyi, B Oze, A Bujdoso, I Kosa, L Baliko, M Natour, M Morgil, E Hartmann, H Morgil, R Winkler, S Gass, S Baumann, M Jeserich, J Rodl, M Dzaiy, S Anker, G Turhan, K Wolf, S Genth-Zotz, T Siebert, C Jakobs, M Kiorwantsi, B Pieske, R Wachter, M Schoenauer, S Voigt, H Schunkert, A Boguschewski, M Resch, R Wensel, V Schumann, P Heidrich, O Girina, Y Prokopovych, M Lebedynska, I Sorokina, O Karpenko, N Brodi, S Klochkov, L Voronkov, Y Besaga, O Novikova, K Amosova, O Yaremenko, K Balaban, V Kovalenko, N Polenova, I Sakharchuk, A Ogorodnichuk, L Rudenko, Y Tutov, A Parkhomenko, E Yakimenko, S Kolomiets, V Yurlov, S Tikhonova, C Estol, A Elizalde, B Mangariello, C Zaidman, F Guerlloy, P Gitelman, K Crotto, S Sassone, J Aiub, F Novoa, R Lopez Santi, P Romia, O Montaña, D Malchik, F Sokn, P Schygiel, R Porcile, F Soria Tito, J Thierer, P Avellana, C Rapallo, M Calderon, R MacFadyen, R Haynes, J Partridge, L Dérera, M Kokles, S Mehešová, A Zachar, M Hranai, T Varadyova, T Göbö, J Litvinova, P Loviska, L Rudenko, Y Tutov, A Parkhomenko

Affiliation

¹ University of Kent, Canterbury, UK.

Abstract

Background and purpose: WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) ≤ 35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified.

Methods: We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100 PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value.

Results: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100 PY) was greater than patients without (0.89/100 PY) (rate ratio 2.68, p < 0.001). Fourteen of 219 (6.4%) patients with ejection fraction (EF) <15% and 70 of 2,079 (3.4%) with EF ≥ 15% had IIS. In the multiple regression analysis stroke at baseline (p < 0.001) and EF <15% vs. ≥ 15% (p = 0.005) remained significant predictors of IIS. IIS rate was 2.04/100 PY in patients with EF <15% and 0.95/100 PY in patients with EF ≥ 15% (p = 0.009). IIS rate in patients with baseline stroke and reduced EF was 5.88/100 PY with EF <15% decreasing to 2.62/100 PY with EF <30%.

Conclusions: In a WARCEF exploratory analysis, prior stroke and EF <15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF.

Publication types

Comparative Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Aged
Anticoagulants / therapeutic use*
Aspirin / therapeutic use*
Female
Fibrinolytic Agents / therapeutic use*
Heart Failure / drug therapy*
Humans
Male
Middle Aged
Recurrence
Stroke / prevention & control*
Stroke Volume
Warfarin / therapeutic use*

Substances

Anticoagulants
Fibrinolytic Agents
Warfarin
Aspirin

Abstract

Publication types

MeSH terms

Substances

Grants and funding