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Original research
Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation
  1. Anthony P Carnicelli1,
  2. Sana M Al-Khatib1,
  3. Denis Xavier2,
  4. Frederik Dalgaard3,
  5. Peter D Merrill1,
  6. Daniel M Wojdyla1,
  7. Basil S Lewis4,
  8. Michael Hanna5,
  9. John H Alexander1,
  10. Renato D Lopes1,
  11. Lars Wallentin6,
  12. Christopher B Granger1
  1. 1Duke Clinical Research Institute, Durham, North Carolina, USA
  2. 2St John's Medical College, Bangalore, Karnataka, India
  3. 3Cardiology, Gentofte Hospital, Hellerup, Hovedstaden, Denmark
  4. 4Lady Davies Carmel Medical Center, Haifa, Israel
  5. 5Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, New Jersey, USA
  6. 6Uppsala Clinical Research Center, University of Uppsala, Uppsala, Sweden
  1. Correspondence to Professor Christopher B Granger, Duke Clinical Research Institute, Durham, NC 27701, USA; christopher.granger{at}duke.edu

Abstract

Aims The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.

Methods/Results We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.

Conclusion Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

  • atrial fibrillation
  • atrial flutter
  • pharmacology
  • stroke
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Footnotes

  • Twitter @CarnicelliAnt, @F_dalgaard

  • Contributors Conceptualisation: AC, SMA-K, DX, DMW, CBG. Methodology: AC, SMA-K, DX, PDM, DMW, BSL, MH, JHA, RDL, LW, CBG. Statistical analysis: PDM, DMW. Writing: AC, PDM. Review/editing: AC, SMA-K, DX, DMW, PDM, DMW, BSL, MH, JHA, RDL, LW, CBG. Supervision: SMA-K, JHA, RDL, CBG. Overall content: CBG.

  • Funding This work was supported by Bristol-Myers Squibb, Co Princeton, NJ, USA and Pfizer Inc., New York, NY, USA.

  • Competing interests AC reports grant funding from the National Institutes of Health. SMA-K reports grants and personal fees from Medtronic, grants and personal fees from Abbott, personal fees from Bristol Myer Squibb, personal fees from Pfizer, outside the submitted work. DX reports grants from Cadila Pharmaceuticals, grants from Boehringer Ingelheim, grants from Astra Zeneca India, grants from Sanofi Aventis, grants from Pfizer, grants from Bristol Myers Squibb, grants from United Kingdom Medical Research Council, grants from Wellcome Trust, outside the submitted work. BSL reports grants and personal fees from Pfizer, personal fees from BMS, during the conduct of the study; grants from Bayer Healthcare, grants from Daiichi Sankyo, outside the submitted work. MH reports other from BRISTOL-MYERS SQUIBB, during the conduct of the study; other from BRISTOL-MYERS SQUIBB, outside the submitted work. JHA reports grants from Bristol-Myers Squibb during the conduct of the study; personal fees from AbbVie, grants from Astra Zeneca, grants and personal fees from Bayer, grants from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from CryoLife, grants and personal fees from CSL Behring, grants from Ferring, grants from GlaxoSmithKline, personal fees from Novo Nordisk, personal fees from Pfizer, personal fees from Portola, grants and personal fees from XaTek outside the submitted work. RDL reports other from Bayer, other from Boehringer Ingleheim, grants and other from Bristol-Myers Squibb, other from Daiichi Sankyo, grants and other from Glaxo Smith Kline, grants and other from Medtronic, other from Merck, grants and other from Pfizer, other from Portola, grants and other from Sanofi, outside the submitted work. LW reports grants from Bristol-Myers Squibb/Pfizer, during the conduct of the study; grants from AstraZeneca, grants from GlaxoSmithKline, grants from Merck & Co, from Abbott, grants from Roche, grants from Boehringer Ingelheim, outside the submitted work; In addition, LW has a patent EP2047275B1 licensed to Roche Diagnostics, and a patent US8951742B2 licensed to Roche Diagnostics. CBG reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, during the conduct of the study; personal fees from Abbvie, grants from AKROS, grants from Apple, grants from AstraZeneca, personal fees from Bayer Corporation US, grants and personal fees from Boehringer Ingelheim, personal fees from Boston Scientific Corporation, personal fees from CeleCor Therapeutics, personal fees from Correvio, grants from Daiichi Sankyo, personal fees from Espero BioPharma, grants from Glaxo SmithKline, grants and personal fees from Janssen Pharaceutica Products, LP, personal fees from Medtronic Inc, grants from Medtronic Foundation, personal fees from Merck, personal fees from Novo Nordisk, grants from Novartis Pharmaceutical Company, personal fees from Rhoshan Pharmaceuticals, personal fees from Roche Diagnostics, outside the submitted work. For complete disclosures, see https://dcri.org/about-us/conflict-of-interest/.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available. No data available.

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