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Safety Signal Evaluation of a Risk of Syncope and Dizziness Not Related to Bleeding or Stroke in Direct Oral Anticoagulant–Treated Patients

  • Ophir Lavon
    Correspondence
    Address correspondence to: Ophir Lavon, MD, Clinical Pharmacology and Toxicology Unit, Carmel Medical Center, Michal St 7, Haifa, 3436212 Israel
    Affiliations
    Clinical Pharmacology and Toxicology Unit, Carmel Medical Center, Haifa, Israel

    Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Search for articles by this author
  • Daisy Cohen
    Affiliations
    Clinical Pharmacology and Toxicology Unit, Carmel Medical Center, Haifa, Israel
    Search for articles by this author

      Abstract

      Purpose

      In clinical studies, rivaroxaban treatment has been associated with increased incidence of syncope not related to bleeding, anemia, or stroke. The study objective was to evaluate the occurrence of dizziness and/or syncope not related to bleeding, anemia, or stroke in patients treated with direct oral anticoagulants (DOACs).

      Methods

      A retrospective, observational, comparative study of adult patients diagnosed with atrial fibrillation and treated with DOACs was conducted using digital retrieval of medical records. Primary outcomes were an emergency department (ED) visit or hospitalization due to syncope, fall, or dizziness. Cases related to bleeding, anemia, or stroke were excluded. Separate examination of a sample of records validated the data.

      Findings

      Of 6467 eligible patients, 256 (4%) were hospitalized or referred to the ED due to fall, syncope, or dizziness during a mean observation period of 20.1 months. After multivariate regression analysis, statistically independent risk factors were found to be age (hazard ratio [HR] = 1.04, P < 0.0001) and benzodiazepine use (HR = 1.33, P = 0.03). No statistically significant difference was found among the different DOAC types regarding the primary outcome (apixaban and rivaroxaban HR = 0.97, P = 0.85; dabigatran and rivaroxaban HR = 1.2, P = 0.386).

      Implications

      The study results failed to confirm the claimed association between the use of a DOAC and syncopal symptoms unrelated to bleeding, anemia, or stroke in this relatively large Israeli patient population. Age and benzodiazepine treatment were significant independent risk factors of these events.

      Keywords

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      References

        • Chan N
        • Sobieraj-Teague M
        • Eikelboom JW
        Direct oral anticoagulants: evidence and unresolved issues.
        Lancet. 2020; 396: 1767-1776
        • Julia S
        • James U
        Direct oral anticoagulants: a quick guide.
        Eur Cardiol. 2017; 12: 40-45
        • Martínez-Rubio A
        • Alcazar MD
        • Cadena AS
        • Martínez-Torrecilla R
        Using direct oral anticoagulants in patients with atrial fibrillation: assessment, monitoring and treatment reversal.
        Eur Cardiol. 2016; 11: 118-122
        • Patel MR
        • Mahaffey KW
        • Garg J
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365 (2011): 883-891
      1. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 365:981–92.

        • Connolly SJ
        • Ezekowitz MD
        • Yusuf S
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Halperin JL
        • Dorian P
        Trials of novel oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation.
        Curr Cardiol Rev. 2014; 10: 297-302
        • Makam RCP
        • Hoaglin DC
        • McManus DD
        • et al.
        Efficacy and safety of direct oral anticoagulants approved for cardiovascular indications: systematic review and meta-analysis.
        PLoS One. 2018; 13e0197583
        • Raschi E
        • Bianchin M
        • Gatti M
        • Squizzato A
        • De Ponti F
        Comparative effectiveness and safety of direct oral anticoagulants: overview of systematic reviews.
        Drug Saf. 2019; 42: 1409-1422
        • Douros A
        • Durand M
        • Doyle CM
        • Yoon S
        • Reynier P
        • Filion KB.
        Comparative effectiveness and safety of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis of observational studies.
        Drug Saf. 2019; 42: 1135-1148
        • Hori M
        • Matsumoto M
        • Tanahashi N
        • et al.
        Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study.
        Circ J. 2012; 76: 2104-2111
      2. Xarelto® (Rivaroxaban). Australian Product Information. Available online at: https://www.tga.gov.au/sites/default/files/auspar-rivaroxaban-191022-pi.pdf.

      3. Pradaxa - summary of product characteristics (2022). Available online at: https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdf.

      4. Eliquis - summary of product characteristics (2022). Available online at: https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf.

        • Schneeweiss S
        A basic study design for expedited safety signal evaluation based on electronic healthcare data.
        Pharmacoepidemiol Drug Saf. 2010; 19: 858-868
        • Charlson ME
        • Pompei P
        • Ales KL
        • MacKenzie CR
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Patel D
        • Ackermann RJ
        Issues in geriatric care: falls.
        FP Essent. 2018; 468: 18-25
        • Bor A
        • Matuz M
        • Csatordai M
        • Szalai G
        • Bálint A
        • Benkő R
        • et al.
        Medication use and risk of falls among nursing home residents: a retrospective cohort study.
        Int J Clin Pharm. 2017; 39: 408-415
        • Pfortmueller CA
        • Lindner G
        • Exadaktylos AK
        Reducing fall risk in the elderly: risk factors and fall prevention, a systematic review.
        Minerva Med. 2014; 105: 275-281
        • De Jong MR
        • Van der Elst M
        • Hartholt KA
        Drug-related falls in older patients: implicated drugs, consequences, and possible prevention strategies.
        Ther Adv Drug Saf. 2013; 4: 147-154
        • Papakonstantinopoulou K
        • Sofianos I
        Risk of falls in chronic kidney disease.
        J Frailty Sarcopenia Falls. 2017; 2: 33-38
        • Morris R
        • Lewis A
        Falls and cancer.
        Clin Oncol (R Coll Radiol). 2020; 32: 569-578
        • Aljehani MS
        • Crenshaw JR
        • Rubano JJ
        • Dellose SM
        • Zeni Jr, JA
        Falling risk in patients with end-stage knee osteoarthritis.
        Clin Rheumatol. 2021; 40: 3-9
        • Montana CL
        • Bhorade AM
        Glaucoma and quality of life: fall and driving risk.
        Curr Opin Ophthalmol. 2018; 29: 135-140
        • Andres TM
        • McGrane T
        • McEvoy MD
        • Allen BFS
        Geriatric pharmacology: an update.
        Anesthesiol Clin. 2019; 37: 475-492
        • Trifirò G
        • Spina E
        Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems.
        Curr Drug Metab. 2011; 12: 611-620
      5. Council for International Organizations of Medical Sciences (CIOMS) (2010) Practical aspects of signal detection in pharmacovigilance. Report of CIOMS Working Group VIII, Geneva. Available online at: https://cioms.ch/wp-content/uploads/2018/03/WG8-Signal-Detection.pdf.

        • Trifirò G
        • Pariente A
        • Coloma PM
        • et al.
        Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor?.
        Pharmacoepidemiol Drug Saf. 2009; 18: 1176-1184
        • Coloma PM
        • Trifirò G
        • Patadia V
        • Sturkenboom M
        Postmarketing safety surveillance: where does signal detection using electronic healthcare records fit into the big picture?.
        Drug Saf. 2013; 36: 183-197
        • Cepeda MS
        • Boston R
        • Farrar JT
        • Strom BL
        Comparison of logistic regression versus propensity score when the number of events is low and there are multiple confounders.
        Am J Epidemiol. 2003; 158: 280-287
        • Shah BR
        • Laupacis A
        • Hux JE
        • Austin PC
        Propensity score methods gave similar results to traditional regression modeling in observational studies: a systematic review.
        J Clin Epidemiol. 2005; 58: 550-559