. 2022 Jan;91(1):78-88.

doi: 10.1002/ana.26267. Epub 2021 Nov 29.

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation

Alexandros A Polymeris^{1

2}, Kosmas Macha³, Maurizio Paciaroni⁴, Duncan Wilson^{5

6}, Masatoshi Koga⁷, Manuel Cappellari⁸, Sabine Schaedelin⁹, Annaelle Zietz¹, Nils Peters^{1

2

10}, David J Seiffge^{5

11}, David Haupenthal³, Luise Gassmann³, Gian Marco De Marchis¹, Ruihao Wang³, Henrik Gensicke^{1

2}, Svenja Stoll³, Sebastian Thilemann¹, Nikolaos S Avramiotis¹, Bruno Bonetti⁸, Georgios Tsivgoulis^{12

13}, Gareth Ambler¹⁴, Andrea Alberti¹⁵, Sohei Yoshimura⁷, Martin M Brown⁵, Masayuki Shiozawa⁷, Gregory Y H Lip^{16

17}, Michele Venti¹⁵, Monica Acciarresi¹⁵, Kanta Tanaka⁷, Maria Giulia Mosconi¹⁵, Masahito Takagi⁷, Rolf H Jäger¹⁸, Keith Muir¹⁹, Manabu Inoue⁷, Stefan Schwab³, Leo H Bonati¹, Philippe A Lyrer¹, Kazunori Toyoda⁷, Valeria Caso¹⁵, David J Werring⁵, Bernd Kallmünzer³, Stefan T Engelter^{1

2}; NOACISP-LONGTERM, Erlangen Registry, CROMIS-2, RAF, RAF-DOAC, SAMURAI-NVAF and Verona Registry Collaborators

Collaborators, Affiliations

Collaborators

NOACISP-LONGTERM, Erlangen Registry, CROMIS-2, RAF, RAF-DOAC, SAMURAI-NVAF and Verona Registry Collaborators:
Stefan T Engelter, Philippe A Lyrer, Leo H Bonati, David J Seiffge, Christopher Traenka, Alexandros A Polymeris, Annaelle Zietz, Nils Peters, Gian Marco De Marchis, Sebastian Thilemann, Nikolaos S Avramiotis, Henrik Gensicke, Lisa Hert, Benjamin Wagner, Fabian Schaub, Louisa Meya, Joachim Fladt, Tolga Dittrich, Urs Fisch, Kosmas Macha, David Haupenthal, Luise Gassmann, Ruihao Wang, Svenja Stoll, Stefan Schwab, Bastian Volbers, Gabriela Siedler, Bernd Kallmünzer, Manuel Cappellari, Bruno Bonetti, Paolo Bovi, Giampaolo Tomelleri, Nicola Micheletti, Cecilia Zivelonghi, Andrea Emiliani, Adrian Parry-Jones, Chris Patterson, Christopher Price, Abduelbaset Elmarimi, Anthea Parry, Arumug Nallasivam, Azlisham Mohd Nor, Bernard Esis, David Bruce, Biju Bhaskaran, Christine Roffe, Claire Cullen, Clare Holmes, David Cohen, David Hargroves, David Mangion, Dinesh Chadha, Djamil Vahidassr, Dulka Manawadu, Elio Giallombardo, Elizabeth Warburton, Enrico Flossman, Gunaratam Gunathilagan, Harald Proschel, Hedley Emsley, Ijaz Anwar, Ilse Burger, James Okwera, Janet Putterill, Janice O'Connell, John Bamford, John Corrigan, Jon Scott, Jonathan Birns, Karen Kee, Kari Saastamoinen, Kath Pasco, Krishna Dani, Lakshmanan Sekaran, Lillian Choy, Liz Iveson, Maam Mamun, Mahmud Sajid, Martin Cooper, Matthew Burn, Matthew Smith, Michael Power, Michelle Davis, Nigel Smyth, Roland Veltkamp, Pankaj Sharma, Paul Guyler, Paul O'Mahony, Peter Wilkinson, Prabel Datta, Prasanna Aghoram, Rachel Marsh, Robert Luder, Sanjeevikumar Meenakishundaram, Santhosh Subramonian, Simon Leach, Sissi Ispoglou, Sreeman Andole, Timothy England, Aravindakshan Manoj, Frances Harrington, Habib Rehman, Jane Sword, Julie Staals, Karim Mahawish, Kirsty Harkness, Louise Shaw, Michael McCormich, Nikola Sprigg, Syed Mansoor, Vinodh Krishnamurthy, Michela Giustozzi, Monica Acciarresi, Giancarlo Agnelli, Valeria Caso, Cecilia Becattini, Andrea Alberti, Michele Venti, Cataldo D'Amore, Maria Giulia Mosconi, Ludovica Anna Cimini, Maurizio Paciaroni, Fabio Bandini, Georgios Tsivgoulis, Chrissoula Liantinioti, Maria Chondrogianni, Shadi Yaghi, Karen L Furie, Prasanna Tadi, Marialuisa Zedde, Azmil H Abdul-Rahim, Kennedy R Lees, Paolo Bovi, Monica Carletti, Alberto Rigatelli, Manuel Cappellari, Jukka Putaala, Liisa Tomppo, Turgut Tatlisumak, Simona Marcheselli, Alessandro Pezzini, Loris Poli, Alessandro Padovani, Vieri Vannucchi, Luca Masotti, Sung-Il Sohn, Gianni Lorenzini, Rossana Tassi, Francesca Guideri, Maurizio Acampa, Giuseppe Martini, George Ntaios, George Athanasakis, Konstantinos Makaritsis, Efstathia Karagkiozi, Konstantinos Vadikolias, Nicola Mumoli, Franco Galati, Simona Sacco, Cindy Tiseo, Francesco Corea, Walter Ageno, Marta Bellesini, Giovanna Colombo, Giorgio Silvestrelli, Alfonso Ciccone, Alessia Lanari, Umberto Scoditti, Licia Denti, Michelangelo Mancuso, Miriam Maccarrone, Leonardo Ulivi, Giovanni Orlandi, Nicola Giannini, Tiziana Tassinari, Maria Luisa De Lodovici, Christina Rueckert, Antonio Baldi, Danilo Toni, Federica Letteri, Alessio Pieroni, Martina Giuntini, Enrico Maria Lotti, Yuriy Flomin, Odysseas Kargiotis, Theodore Karapanayiotides, Serena Monaco, Mario Maimone Baronello, Laszló Csiba, Lilla Szabó, Alberto Chiti, Elisa Giorli, Massimo Del Sette, Davide Imberti, Dorjan Zabzuni, Boris Doronin, Vera Volodina, Patrik Michel, Peter Vanacker, Kristian Barlinn, Lars-Peder Pallesen, Jessica Barlinn, Dirk Deleu, Gayane Melikyan, Faisal Ibrahim, Naveed Akhtar, Vanessa Gourbali, Kenichi Todo, Kazumi Kimura, Kensaku Shibazaki, Yoshiki Yagita, Eisuke Furui, Ryo Itabashi, Tadashi Terasaki, Yoshiaki Shiokawa, Teruyuki Hirano, Rieko Suzuki, Kenji Kamiyama, Jyoji Nakagawara, Shunya Takizawa, Kazunari Homma, Satoshi Okuda, Yasushi Okada, Koichiro Maeda, Tomoaki Kameda, Kazuomi Kario, Yoshinari Nagakane, Yasuhiro Hasegawa, Hisanao Akiyama, Satoshi Shibuya, Hiroshi Mochizuki, Yasuhiro Ito, Takahiro Nakashima, Hideki Matsuoka, Kazuhiro Takamatsu, Kazutoshi Nishiyama, Kanta Tanaka, Kaoru Endo, Tetsuya Miyagi, Masato Osaki, Junpei Kobayashi, Takuya Okata, Eijiro Tanaka, Yuki Sakamoto, Keisuke Tokunaga, Hotake Takizawa, Junji Takasugi, Soichiro Matsubara, Kyoko Higashida, Takayuki Matsuki, Naoto Kinoshita, Masayuki Shiozawa, Toshihiro Ide, Takeshi Yoshimoto, Daisuke Ando, Kyohei Fujita, Masaya Kumamoto, Teppei Kamimura, Muneaki Kikuno, Tadataka Mizoguchi, Takeo Sato

Affiliations

¹ Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.
² Neurology and Neurorehabilitation, University Hospital for Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.
³ Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
⁴ Neurology - Stroke Unit, IRCCS MultiMedica, Milan, Italy.
⁵ Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
⁶ New Zealand Brain Research Institute, Christchurch, New Zealand.
⁷ Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
⁸ Stroke Unit - Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁹ Clinical Trial Unit, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
¹⁰ Stroke Center, Klinik Hirslanden, Zurich, Switzerland.
¹¹ Department of Neurology, Inselspital University Hospital Bern, University of Bern, Bern, Switzerland.
¹² Second Department of Neurology, Attikon University Hospital, National & Kapodistrian University of Athens, Athens, Greece.
¹³ Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
¹⁴ Department of Statistical Science, University College London, London, UK.
¹⁵ Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.
¹⁶ Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart and Chest Hospital, Liverpool, UK.
¹⁷ Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹⁸ Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
¹⁹ Institute of Neuroscience & Psychology, University of Glasgow and Queen Elizabeth University Hospital, Glasgow, UK.

PMID: 34747514
PMCID: PMC9300111
DOI: 10.1002/ana.26267

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation

Alexandros A Polymeris et al. Ann Neurol. 2022 Jan.

. 2022 Jan;91(1):78-88.

doi: 10.1002/ana.26267. Epub 2021 Nov 29.

Authors

Collaborators

NOACISP-LONGTERM, Erlangen Registry, CROMIS-2, RAF, RAF-DOAC, SAMURAI-NVAF and Verona Registry Collaborators:
Stefan T Engelter, Philippe A Lyrer, Leo H Bonati, David J Seiffge, Christopher Traenka, Alexandros A Polymeris, Annaelle Zietz, Nils Peters, Gian Marco De Marchis, Sebastian Thilemann, Nikolaos S Avramiotis, Henrik Gensicke, Lisa Hert, Benjamin Wagner, Fabian Schaub, Louisa Meya, Joachim Fladt, Tolga Dittrich, Urs Fisch, Kosmas Macha, David Haupenthal, Luise Gassmann, Ruihao Wang, Svenja Stoll, Stefan Schwab, Bastian Volbers, Gabriela Siedler, Bernd Kallmünzer, Manuel Cappellari, Bruno Bonetti, Paolo Bovi, Giampaolo Tomelleri, Nicola Micheletti, Cecilia Zivelonghi, Andrea Emiliani, Adrian Parry-Jones, Chris Patterson, Christopher Price, Abduelbaset Elmarimi, Anthea Parry, Arumug Nallasivam, Azlisham Mohd Nor, Bernard Esis, David Bruce, Biju Bhaskaran, Christine Roffe, Claire Cullen, Clare Holmes, David Cohen, David Hargroves, David Mangion, Dinesh Chadha, Djamil Vahidassr, Dulka Manawadu, Elio Giallombardo, Elizabeth Warburton, Enrico Flossman, Gunaratam Gunathilagan, Harald Proschel, Hedley Emsley, Ijaz Anwar, Ilse Burger, James Okwera, Janet Putterill, Janice O'Connell, John Bamford, John Corrigan, Jon Scott, Jonathan Birns, Karen Kee, Kari Saastamoinen, Kath Pasco, Krishna Dani, Lakshmanan Sekaran, Lillian Choy, Liz Iveson, Maam Mamun, Mahmud Sajid, Martin Cooper, Matthew Burn, Matthew Smith, Michael Power, Michelle Davis, Nigel Smyth, Roland Veltkamp, Pankaj Sharma, Paul Guyler, Paul O'Mahony, Peter Wilkinson, Prabel Datta, Prasanna Aghoram, Rachel Marsh, Robert Luder, Sanjeevikumar Meenakishundaram, Santhosh Subramonian, Simon Leach, Sissi Ispoglou, Sreeman Andole, Timothy England, Aravindakshan Manoj, Frances Harrington, Habib Rehman, Jane Sword, Julie Staals, Karim Mahawish, Kirsty Harkness, Louise Shaw, Michael McCormich, Nikola Sprigg, Syed Mansoor, Vinodh Krishnamurthy, Michela Giustozzi, Monica Acciarresi, Giancarlo Agnelli, Valeria Caso, Cecilia Becattini, Andrea Alberti, Michele Venti, Cataldo D'Amore, Maria Giulia Mosconi, Ludovica Anna Cimini, Maurizio Paciaroni, Fabio Bandini, Georgios Tsivgoulis, Chrissoula Liantinioti, Maria Chondrogianni, Shadi Yaghi, Karen L Furie, Prasanna Tadi, Marialuisa Zedde, Azmil H Abdul-Rahim, Kennedy R Lees, Paolo Bovi, Monica Carletti, Alberto Rigatelli, Manuel Cappellari, Jukka Putaala, Liisa Tomppo, Turgut Tatlisumak, Simona Marcheselli, Alessandro Pezzini, Loris Poli, Alessandro Padovani, Vieri Vannucchi, Luca Masotti, Sung-Il Sohn, Gianni Lorenzini, Rossana Tassi, Francesca Guideri, Maurizio Acampa, Giuseppe Martini, George Ntaios, George Athanasakis, Konstantinos Makaritsis, Efstathia Karagkiozi, Konstantinos Vadikolias, Nicola Mumoli, Franco Galati, Simona Sacco, Cindy Tiseo, Francesco Corea, Walter Ageno, Marta Bellesini, Giovanna Colombo, Giorgio Silvestrelli, Alfonso Ciccone, Alessia Lanari, Umberto Scoditti, Licia Denti, Michelangelo Mancuso, Miriam Maccarrone, Leonardo Ulivi, Giovanni Orlandi, Nicola Giannini, Tiziana Tassinari, Maria Luisa De Lodovici, Christina Rueckert, Antonio Baldi, Danilo Toni, Federica Letteri, Alessio Pieroni, Martina Giuntini, Enrico Maria Lotti, Yuriy Flomin, Odysseas Kargiotis, Theodore Karapanayiotides, Serena Monaco, Mario Maimone Baronello, Laszló Csiba, Lilla Szabó, Alberto Chiti, Elisa Giorli, Massimo Del Sette, Davide Imberti, Dorjan Zabzuni, Boris Doronin, Vera Volodina, Patrik Michel, Peter Vanacker, Kristian Barlinn, Lars-Peder Pallesen, Jessica Barlinn, Dirk Deleu, Gayane Melikyan, Faisal Ibrahim, Naveed Akhtar, Vanessa Gourbali, Kenichi Todo, Kazumi Kimura, Kensaku Shibazaki, Yoshiki Yagita, Eisuke Furui, Ryo Itabashi, Tadashi Terasaki, Yoshiaki Shiokawa, Teruyuki Hirano, Rieko Suzuki, Kenji Kamiyama, Jyoji Nakagawara, Shunya Takizawa, Kazunari Homma, Satoshi Okuda, Yasushi Okada, Koichiro Maeda, Tomoaki Kameda, Kazuomi Kario, Yoshinari Nagakane, Yasuhiro Hasegawa, Hisanao Akiyama, Satoshi Shibuya, Hiroshi Mochizuki, Yasuhiro Ito, Takahiro Nakashima, Hideki Matsuoka, Kazuhiro Takamatsu, Kazutoshi Nishiyama, Kanta Tanaka, Kaoru Endo, Tetsuya Miyagi, Masato Osaki, Junpei Kobayashi, Takuya Okata, Eijiro Tanaka, Yuki Sakamoto, Keisuke Tokunaga, Hotake Takizawa, Junji Takasugi, Soichiro Matsubara, Kyoko Higashida, Takayuki Matsuki, Naoto Kinoshita, Masayuki Shiozawa, Toshihiro Ide, Takeshi Yoshimoto, Daisuke Ando, Kyohei Fujita, Masaya Kumamoto, Teppei Kamimura, Muneaki Kikuno, Tadataka Mizoguchi, Takeo Sato

Affiliations

¹ Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.
² Neurology and Neurorehabilitation, University Hospital for Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.
³ Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
⁴ Neurology - Stroke Unit, IRCCS MultiMedica, Milan, Italy.
⁵ Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
⁶ New Zealand Brain Research Institute, Christchurch, New Zealand.
⁷ Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
⁸ Stroke Unit - Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁹ Clinical Trial Unit, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
¹⁰ Stroke Center, Klinik Hirslanden, Zurich, Switzerland.
¹¹ Department of Neurology, Inselspital University Hospital Bern, University of Bern, Bern, Switzerland.
¹² Second Department of Neurology, Attikon University Hospital, National & Kapodistrian University of Athens, Athens, Greece.
¹³ Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
¹⁴ Department of Statistical Science, University College London, London, UK.
¹⁵ Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.
¹⁶ Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart and Chest Hospital, Liverpool, UK.
¹⁷ Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹⁸ Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
¹⁹ Institute of Neuroscience & Psychology, University of Glasgow and Queen Elizabeth University Hospital, Glasgow, UK.

PMID: 34747514
PMCID: PMC9300111
DOI: 10.1002/ana.26267

Abstract

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years.

Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk.

Results: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR_≥85y = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR_<85y = 0.79, 95%-CI [0.66, 0.95]) in simple (p_interaction = 0.129), adjusted (p_interaction = 0.094) or weighted (p_interaction = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1).

Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88.

PubMed Disclaimer

Conflict of interest statement

MP: speaker honoraria from Sanofi‐Aventis, Boehringer‐Ingelheim, Bayer, BMS, Daiichi‐Sankyo, Pfizer (all manufacturers of anticoagulants). MK: speaker honoraria from Bayer, Nippon Boehringer‐Ingelheim, Daiichi‐Sankyo. MC: consulting fees from Boehringer‐Ingelheim, Pfizer/BMS; advisory board Daiichi‐Sankyo. GMDM: consultant/speaker honoraria from Bayer, travel honoraria from Pfizer. ST: travel grants from BMS/Pfizer. GYHL: Consultant and speaker for BMS/Pfizer, Boehringer‐Ingelheim and Daiichi‐Sankyo; no fees are received personally. LHB: consultancy or advisory board fees or speaker's honoraria from Bayer and BMS. PAL: research grants from Bayer, travel grants from Bayer, Pfizer, advisory board compensation from Bayer, Pfizer, Daiichi‐Sankyo, BMS. KT: lecture honoraria (modest) from Daiichi‐Sankyo, Bayer Yakuhin, Nippon Boehringer‐Ingelheim, BMS. DJW: personal fees from Bayer, Portola (manufacturer of the anticoagulant reversal agent andexanet alfa). STE: research support from Pfizer, Daiichi‐Sankyo; compensation from Stago (manufacturer of coagulation testing systems) for educational material; travel/speaker honoraria from Bayer, Boehringer‐Ingelheim, BMS, Daiichi‐Sankyo; advisory board Bayer, Boehringer‐Ingelheim, BMS. The remaining authors declare no relevant conflicts.

Figures

**FIGURE 2**
Weighted Kaplan–Meier curves for the composite outcome stratified to anticoagulant type (DOAC / VKA) and age group (≥85 / <85 years)

**FIGURE 3**
Hazard ratio estimates for the effect of DOAC vs. VKA on the primary composite outcome and all its individual components (accounting for competing risks) stratified to patients aged ≥85 versus <85 years based on the weighted model

**FIGURE 4**
Net clinical benefit of DOAC over VKA with 95% confidence intervals stratified to age group (≥85 / <85 years), using three previously published ICH weights

**FIGURE 5**
Rate of the composite outcome by age as a continuous variable stratified to type of anticoagulant (DOAC / VKA). The solid lines represent the estimates for each year of age from the weighted model without interaction term and the shaded areas the 95%‐CI.

See this image and copyright information in PMC

References

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Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation

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Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation

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