Design and protocols of the GIRAF prevention trial: A randomized, prospective, parallel, two-center study to compare cognitive outcomes in subjects with atrial fibrillation using warfarin or dabigatran
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with cognitive impairment and dementia. Cognitive and functional impairments have been neglected in clinical trials with patients affected by AF. Dabigatran is a new drug, which can offer a more stable long-term anticoagulant therapy compared to warfarin. This advantage could be associated with a minor incidence of cognitive and functional decline. The objective of the study is to evaluate the effects of dabigatran compared with warfarin on cognitive and functional impairments, thrombin production, bleeding occurrence and cerebrovascular complications in elderly patients with AF.
Methods: A randomized, prospective parallel, two-center, active-controlled trial will be performed in a sample of 200 patients with AF randomly designated to take dabigatran (150 mg twice daily) or warfarin (once daily, dose controlled by INR between 2 and 3). After one and two years, subjects will be assessed considering cognitive outcomes. Additionally, patients will be submitted to brain magnetic resonance imaging (MRI) at the beginning and ending of study to identify possible cerebrovascular events, as well as carotid ultrasonography to search for atherosclerotic disease.Conclusions: The GIRAF study expects to provide data about prevention of cognitive and functional impairments among patients on anticoagulant therapy for AF, and to explore new concepts on potential prevention of cognitive decline and benefits for AF patients and their relatives.
Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. Can Med Assoc J. 2012;184(6):E329-36.
Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Brantes MC et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm. 2012;9(11):1762-8.
Thacker EL, McKnight B, Psaty BM, Longstreth WT, Sitlani CM, Dublin S, et al. Atrial fibrillation and cognitive decline – A longitudinal cohort study. Neurology. 2013;81:119-25.
Mavaddat N, Roalfe A, Fletcher K, Lip GYH, Hobbs R, Fitzmaurice D et al. Warfarin Versus Aspirin for Prevention of Cognitive Decline in Atrial Fibrillation – Randomized Controlled Trial (Birmingham Atrial Fibrillation Treatment of the Aged Study). Stroke. 2014;45:1381-6.
Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15(3):244-52.
Fornari LS, Calderaro D, Nassar IB, Lauretti C, Nakamura L, Bagnatori R et al. Misuse of antithrombotic therapy in atrial fibrillation patients: frequent, pervasive and persistent. J Thromb Thrombolysis. 2007;23(1):65-71.
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.
Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards. Stroke. 2006;37(9):2220-41.
Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State" – A practical method for grading the cognitive state of patients for the clinicians. J Psychiat Res. 1975;12:189-98.
Brucki SM, Nitrini R, Caramelli P, Bertolucci PH, Okamoto IH. Sugestões para utilização do Mini-Exame do Estado Mental no Brasil. Arq Neuropsiquiatr. 2003;61:777-81.
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695-9.
Memória CM, Yassuda MS, Nakano EY, Forlenza OV. Brief screening for mild cognitive impairment: validation of the Brazilian version of the Montreal cognitive assessment. Int J Geriatr Psychiatry. 2013;28:34-40.
Benton A, Hamsher K. Multilingual Aphasia Examination. Iowa City: AJA Associates; 1989.
Machado TH, Fichman HC, Santos EL, Carvalho VA, Fialho PP, Koenig AM et al. Normative data for healthy elderly on the phonemic verbal fluency task – FAS. Dement Neuropsychol. 2009;3:55-60.
Wechsler D. WAIS-III Administration and Scoring Manual. New York: The Psychological Corporation, 1997.
Stuss DT, Bisschop SM, Alexander MP, Levine B, Katz D, Izukawa D. The trail making test: A study in focal lesion patients. Psychol Assess. 2001;13:230-9.
Tombaugh TN, Hubley AM. The 60-item Boston naming test: Norms for cognitively intact adults aged 25 to 88 years. J Clin Exp Neuropsychol. 1997;19:922-32.
Sunderland T, Hill JL, Mellow AM, et al. Clock drawing in Alzheimer's disease. A novel measure of dementia severity. J Am Geriatr Soc. 1989;37(8):725-9.
Aprahamian I, Martinelli JE, Neri AL, Yassuda MS. The Clock Drawing Test A review of its accuracy in screening for dementia. Dement Neuropsychol. 2009;3(2):74-80.
Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PE, Sauaia N et al. Testes neuropsicológicos de aplicação simples para o diagnóstico de demência. Arq Neuropsiquiatr. 1994;52:457-65.
Nitrini R, Caramelli P, Porto CS, Charchat-Fichman H, Formigoni AP, Carthery-Goulart MT et al. Brief cognitive battery in the diagnosis of mild Alzheimer’s disease in subjects with medium and high levels of education. Dement Neuropsychol. 2007;1:32-6.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308-14.
Camozzato AL, Kochhann R, Simeoni C, Konrath CA, Pedro Franz A, Carvalho A et al. Reliability of the Brazilian Portuguese version of the Neuropsychiatric Inventory (NPI) for patients with Alzheimer's disease and their caregivers. Int Psychogeriatr. 2008;20:383-93.
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-73.
Paradela EM, Lourenço RA, Veras RP. Validation of geriatric depression scale in a general outpatient clinic. Rev Saude Publica 2005;39:918–23.
Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): Development and cross-validation. Psychol Med. 1994;24:145¬-53.
Sanchez MA, Lourenço RA. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): cross-cultural adaptation for use in Brazil. Cad Saude Publica. 2009;25:1455-65.
Toledo AASFT, Nitrini R, Bottino CMC, Caramelli P. Brazilian research on cognitive impairment and dementia from 1999 to 2013. Dement Neuropsychol. 2014;8(4):394-8.
Jabos V, Cutler MJ, Day JD, Bunch TJ. Atrial fibrillation and dementia. Trends in Cardiovasc Med. 2015;25:44-51.
Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B et al. Trajectory of Cognitive Decline After Incident Stroke. J Am Med Assoc. 2015;314(1):41-51.
O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L et al. Vascular cognitive impairment. Lancet Neurol. 2003;2:89-98.
Cao L, Pokorney SD, Hayden K, Welsh-Bohmer K, Newby LK. Cognitive Function: Is There More to Anticoagulation in Atrial Fibrillation Than Stroke? J Am Heart Assoc. 2015;4:e001573.