title: Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.
abstract: BACKGROUND
  Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves.
  
  
  RESULTS
  We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10).
  
  
  CONCLUSIONS
  More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.). avezum@dantepazzanese.org.br.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avezum
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Schulte
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Fernando
authors.initials: F
authors.lastname: Lanas
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Prem
authors.initials: P
authors.lastname: Pais
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Cetin
authors.initials: C
authors.lastname: Erol
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Rafael
authors.initials: R
authors.lastname: Diaz
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Bahit
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Jozef
authors.initials: J
authors.lastname: Bartunek
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Shinya
authors.initials: S
authors.lastname: Goto
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: From Research Division, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham, NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); St. John's Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of Medicine, Turkey (C.E.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (R.D.); INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. d'Annunzio University, Chieti, Italy and Fondazione Toscana G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Fu Wai Hospital, Beijing, China (J.Z.).
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D006349:Heart Valve Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D013923:Thromboembolism / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin
keywords: apixaban; atrial fibrillation; heart diseases; hemorrhage; oral anticoagulant; stroke; valvular heart disease