Finnish AntiCoagulation in Atrial Fibrillation (FinACAF)
Conditions: Atrial Fibrillation
Sponsor: Helsinki University Central Hospital

 
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Research Protocol 
Finnish AntiCoagulation in Atrial Fibrillation (FinACAF)  
Version 02.07.2024 
A nationwide register study on the risk of stroke and other cardiovascular events 
among atrial fibrillation patients with different oral anticoagulation treatments 
  
Steering Committee 
Primary 
Investigator 
Mika Lehto, MD, PhD, Docent, Helsinki University Hospital 
(HUH) 
Member 
Juhani 
Airaksinen, 
MD, 
PhD, 
Professor, 
Turku University Hospital (TUH) 
Member 
Pirjo Mustonen, MD, PhD, Docent, TUH 
Member 
Jukka Putaala, MD, PhD, Docent, HUH 
Member 
Jari Haukka, PhD, Docent, University of Helsinki  
Member 
Miika Linna, Adj. Prof., PhD, Aalto University 
Study members and collaborators (at present) 
Olli Halminen, MSc, Aalto University 
Jussi Niiranen, MD, HUH 
Paula Tiili, MD, HUH 
Saga Itäinen-Strömberg, MD, HUH 
Aapo Aro, MD, PhD, Docent, HUH 
Tuukka Helin, MD, PhD, HUH 
Tero Penttilä, MD, PhD, Tampere 
University Hospital (TaUH) 
Janne Kinnunen, MD, HUH  
Juha Hartikainen, MD, PhD, Professor, 
Kuopio University Hospital 
Alex Luojus, MD, HUH 
Santeri Jolkkonen, LL, KSKS 
Kati Kaartinen, MD, PhD, HUH 
Jussi Jaakkola, MD, PhD, TUH 
Lotta Joutsi-Korhonen, MD, PhD, Docent, 
HUH 
Jaakko Inkovaara, MD, TaUH  
Ksenia Kalatsova, MD, HUH 
Heini Jyrkilä, MD, HUH 
Elis Kouki, BM, HUH 
Leena Martola, MD, PhD, HUH  
Jaana Kuoppala, PhD, Docent, HUH  
Elin Karlsson, BM, HUH 
Tuomas Kiviniemi, PhD, Docent, TUH 
Mika Niemelä, MD, PhD, Professor, HUH  
Mikko Niemi, MD, PhD, Professor, 
Helsinki University 
Mawaddah Toonsi, MD, HUH 
Konsta Teppo, MD, TUH 
 

 
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BACKGROUND 
Atrial fibrillation (AF) is the most common sustained arrhythmia, its prevalence increases with 
age, and it presents with a wide spectrum of symptoms and severity. Previously, it has been 
estimated that number of AF patients is about 150 000 in Finland, and this number will be 
increased at least two-fold until year 2050. AF resulting in an increased risk of stroke and 
systemic thromboembolism is also by far the most common indication for oral anticoagulation 
(OAC) treatment (Käypä hoito 2017). 
Anticoagulation therapy in AF patients is very effective in decreasing the risk of stroke, but 
OAC also needs large extent of health care resources, and is costly. It has been estimated that 
average service provider costs in Finland were approximately 940 euros higher in warfarin users 
compared with non-users annually (Hallinen 2014). In a very recent national analysis, it was 
found that the costs of complications associated with anticoagulation treatment even exceeds 
the costs of the treatment. With an estimation of about 1000 euros annually and more than 100 
000 AF patients, the costs of treatment are huge, and taking into account the costs of 
complications, it is crucial to have current national data of OAC therapy in AF patients. This 
information is urgently needed for “leading with data” during changing world of medico-
economical arrangements. 
OAC, while decreasing the risk of embolic events and mortality, also increases the risk of 
bleeding complications. The benefits of Vitamin K antagonist (VKA), as warfarin, depend 
strongly on maintaining the International Normalized Ratio (INR) within a relatively narrow 
range (2.0-3.0). This was also shown in our previous publication of the FinWAF-study, where 
our major finding regarding the main objectives was that the higher the time in therapeutic range 
(TTR), the better the outcome. TTR is defined as the duration of time in which the patient’s 
INR values were within a desired range and thus is a better measure of the quality of VKA 
treatment than just INR values. Especially, the risk of stroke, bleeding events, and mortality 
were markedly decreased with better TTR. (Lehto et al. 2017). Also, our data demonstrated a 
direct relationship between the quality of warfarin therapy and the incidence of MI in patients 
with AF. This was worldwide a novel finding. 
However, the follow-up of FinWAF study finished by the end of year 2011, while the first non-
vitamin K antagonist anticoagulant (NOAC) for stroke prevention in AF patients received 
marketing authorization in late 2011. Thus, FinWAF study consisted only AF patients treated 
with warfarin. 
The NOACs currently on market — apixaban, edoxaban, dabigatran and rivaroxaban — have 
been widely studied in indication of stroke prevention in AF patients, and they have proved to 
be at least as effective and at least as safe compared to warfarin (Ruff et al. 2015). The NOACs 
are superseding warfarin as the anticoagulant of AF patients. In the high-income countries, the 
proportion of anticoagulated patients on a NOAC is more than 50%, while in Finland this 
proportion is about 40%. The Social Insurance Institution of Finland and the national guidelines 
– Eteisvärinän Käypä hoito 2017 – considers warfarin treatment balance to be satisfactory if 
TTR of 80% is reached. This was based on our finding in the FinWAF-study where we found 
that outcomes continued to improve with increasing TTR values up to a TTR ≥ 80%. However, 
without the data of NOAC treated patients, the optimal OAC treatment was not thoroughly 
evaluated. 

 
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The present study is a register study in focusing on AF. The study provides real-world data on 
current OAC treatment practices, treatment balance and its consequences in whole Finland. 
Evidence on TTR through INR monitoring specifically addresses the reimbursement question 
and the possible unmet medical need for new oral OAC treatment of AF patients. Including also 
patients who were withhold of any OAC therapy provides a unique information of the spectrum 
of treatment of all AF patients. The new and so far limitedly investigated point of view in the 
present study is to include socio-economic data, with information of taxable incomes and 
education of the patients. 
 
2. 
RESEARCH QUESTIONS 
The aim of this study is to evaluate the incidence and risk of stroke, systemic thromboembolic 
events, myocardial infarction, major bleeding events, and mortality in relation to different 
attitudes regarding stroke prevention treatment among AF patients.  
An important part of the study is assessment of cost effectiveness of different OAC therapies. 
Also, when the socio-economic status of patients is included, we can study relations of socio-
economic status with treatments the patients are given, the quality of OAC as well as with the 
major outcomes. 
INR target is defined as 2.0-3.0 according to current care treatment guidelines (ESC 2016, 
Eteisvärinän Käypähoito 2017). The risks mentioned above are separately evaluated with 
different management levels of warfarin therapy as well as with different NOACs and in patients 
without OAC treatment. The study population is also characterized according to co-morbidity, 
interactive medications and antiarrhythmic drugs in use. Additional study questions are related 
to initiation, discontinuation and duration of OAC treatment. The interactions with anemia and 
kidney dysfunction, as well as thrombocytopenia in association with different treatment 
schemes and outcomes will also be studied.  
Because all the available contacts with the health care institutions and organizations are 
evaluated this database allows a unique possibility to investigate cost effectiveness in relation 
to different OAC treatments. 
 
3. 
OBJECTIVES 
Primary Objectives 
1. To investigate risk of stroke, systemic thromboembolism, bleeding events and myocardial 
infarction among AF patients in relation to different OAC treatments including warfarin 
treatment with the data of different TTR levels compared also with patients without any 
OAC treatment. 
 
2. To investigate risk of all-cause and cardiovascular death in relation to different OAC 
treatments including warfarin treatment with the data of different TTR levels compared 
also with patients without any OAC treatment. 

 
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Secondary Objectives 
3. To investigate use of health care services in relation to different OAC treatments.  
 
4. To investigate cost effectiveness in relation to different OAC treatments. 
 
5. To investigate relations of socio-economic status with treatments the patients are given, the 
quality of OAC as well as with the major outcomes. 
 
6. To investigate relations of presence of dementia and psychiatric illness with treatments the 
patients are given, the quality of OAC, as well as with the major outcomes. 
 
7. To investigate use of private health care system, cost and imbursement of it, and cost of 
reimbursed transportation services. 
 
8. To investigate risk of dementia in relation to different OAC treatments as well as with 
different socio-economic positions 
 
9. To investigate risk of stroke, systemic thromboembolism, myocardial infarction, and major 
bleeding events among AF patients after initiation of OAC treatment. 
 
10. To investigate risk of stroke, systemic thromboembolism, and major bleeding events in 
relation to time from AF diagnosis to time of initiation of OAC treatment. 
 
11. To investigate risk of stroke, systemic thromboembolism, myocardial infarction, and major 
bleeding events among AF patients who have stopped using OAC for any reason. 
 
Exploratory Objectives 
 
12. To investigate incidence of anemia and renal impairment among AF patients in relation to 
different OAC treatments including warfarin treatment with different TTR levels. 
 
13. To investigate risk of stroke, systemic thromboembolism, myocardial infarction, and 
bleeding events among AF patients in relation to discontinuation of OAC treatment due to 
surgical operations and interventions. 
 
14. To investigate how long it takes to achieve INR target in treatment initiators. 
 
15. To investigate the quality of warfarin treatment (TTR level). 
 
16. To characterize the use of antiarrhythmic medication in AF patients 
 
17. To characterize the use of medications with known interactions with OAC, and the 
association of the use of these medications with the main outcomes. 
 

 
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18. To characterize the use of other cardiovascular medications in AF patients (ACE-inhibitors, 
ARBs, beta blocking agents, antiarrhythmics, cardiac glycosides, diuretics etc.), and the 
association of the use of these medications with the main outcomes. 
 
19. To characterize the use of other medications with a meaningful role in AF patients (diabetes 
and lipid lowering medication, drugs for gastrointestinal acid related disorders etc.), and the 
association of the use of these medications with the main outcomes. 
 
20. To investigate how long it takes to achieve elective cardioversion performed (procedure 
code TFP20) in OAC treatment initiators. 
 
21. To investigate risk of stroke, systemic thromboembolism, and bleeding events associated 
with different procedures (cardioversion, AF-ablation etc.). 
 
22. To investigate the use of blood products in the study cohort. 
 
23. To investigate risk of stroke, systemic thromboembolism, and bleeding events particularly 
in the subgroup of patients with diagnosis of cancer. 
 
24. To investigate recurrent stroke and bleeding risk. This will be done particularly in patients 
with co-morbidity of vascular disease (coronary heart disease, peripheral arterial disease, 
carotid/intracranial atherosclerotic disease). 
 
25. To investigate ECG-database collected from the laboratory databases:  
AF pattern: 
• Only atrial fibrillation/flutter present in the ECGs 
• Both AF and sinus rhythm present 
From the last ECG with sinus rhythm 
• P-wave analysis (PA, PD, PPA V1, P-axis), PR-interval, (RAE, LAE, BAE), 
From the last ECG 
• QRS duration, QTc, left ventricular hypertrophy, bundle branch blocks, late QRS 
transition, (R<S in V4), QRS axis, T-wave axis, T-wave amplitude (in V2-V6, I, 
aVL, aVF) 
Prevalence of ECG findings in AF population and their correlations with endpoints are 
studied. 
 
 

 
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4. 
STUDY DESIGN  
Overview of Study Design  
The study with cohort design is conducted as a nationwide retrospective register-based linkage 
study using data obtained from the Finnish health care registers. The study population consists 
of all AF patients during 1.1.2004 – 31.12.2018, with a special emphasis on patients of selected 
hospital district areas where laboratory data is also available. Index date is defined as the date 
of first time of diagnosis of AF during 1.1.2004 – 31.12.2018; ICD-10-code I48 in any of the 
used registries.   
Follow-up of the patients starts on the index date, and ends on 31.12.2018, at time of death or 
at time of emigration whichever occurs first. Treatment and co-morbidity history are gathered 
from the period 1.1.2004 – 31.12.2018.  
 
Study Population 
The study population consists of all AF patients in Finland during 1.1.2004 – 31.12.2018. The 
included geographically defined hospital districts with the laboratory data (1.1.2010 – 
31.12.2018) are Northern Ostrobotnia, Northern Savonia, Central Finland, Tampere University 
Hospital district, Southwest, and Helsinki and Uusimaa (Figure 1). The catchment population 
of these hospital districts is about 4.2 million; 77 % of the total Finnish population 5.5 million. 
Figure 1. The included hospital districts with laboratory data. 
 

 
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Inclusion Criteria 
Patients fulfilling the following criteria are included in the study: 
• 
 patient has an International Classification of Diseases (ICD-10 version 10) diagnosis 
code I48 for AF during 1.1.2004-31.12.2018 in any of the used registries 
 
Exclusion Criteria 
• 
Patients with permanent residence in Finland less than 12 months prior to index date.  
 
 
 
Data Source/Data Collection Process 
The studied outcomes (endpoint variables of interest) and co-mordities with ICD-10-codes, 
collected laboratory variables, medications of interest with their ATC-codes as well as ECG 
parameters collected from MUSE (ECG in the HUH only) for each individual from all ECGs 
are given in the Appendix. 
Figure 2. The study timelines 
 
 
 
 

 
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The registers used in the study 
Register 
Register Holder 
Information obtained 
National Prescription 
Register 
Kela – The Social Insurance 
Institution of Finland 
Drug purchases (ATC codes) 
National Reimbursement 
Register 
Kela 
Reimbursement decisions for 
chronic diseases 
Finnish Care Register, 
HILMO  
National Institute for Health and 
Welfare 
Diagnoses (ICD10 codes) and 
interventions with codes 
Finnish Care Register, 
AvoHILMO 
National Institute for Health and 
Welfare 
Diagnoses (ICD-10 and 
ICPC-2) and interventions 
with codes 
National Causes of Death 
Register 
Statistics Finland 
Deaths and causes of deaths.  
National Cancer Registry 
Finnish Cancer Registry 
Registry of all cancer cases 
in Finland. 
Laboratory databases 
HUSLAB, Helsinki; TYKSLAB, 
Turku; FIMLAB, Tampere and 
FIMLAB, Central Finland; ISLAB, 
Kuopio; and NORDLAB, Oulu 
INR and other relevant 
laboratory measurements 
Population Register 
Population Register Center 
Places of domicile 
Social HILMO 
National Institute for Health and 
Welfare 
Other institutionalizations 
than hospitalization 
Tax Register 
Tax Administration 
Taxes 
The Register of Completed 
Education and Degrees 
Statistics Finland 
Education of the patients 
 
5. 
STUDY SCHEDULE 
Milestone 
Due date 
Study protocol approved by the steering committee 
Q3 / 2017 
Ethics committee approval 
Q4 / 2017 
Data permit approvals and Receipt of data from register holders 
Q4 / 2018 
Data collection completed  
Q3 / 2019 
Preliminary analyses and report of the data 
Q1 / 2020 
Manuscripts of the abstracts of the main results 
Q3/ 2020 
Manuscripts of the main results 
Q4 / 2020 – Q1 / 2021 

 
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6. 
ETHICAL ASPECTS 
This study will comply with the European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Code of Conduct as well as Clinicaltrials.gov and will be 
registered into the ENCePP e-register (http://www.encepp.eu) and Clinicaltrials.gov/ct2/hom. 
The ethical permission is permitted by ethical committee of the Medical Faculty of Helsinki 
University, Helsinki Finland (nr. 15/2017 and nr. 15/2024) and the study permission from the 
Helsinki University Hospital (HUS/46/2018). The data permits are also be requested from the 
Social Insurance Institute (SII) (138/522/2018), the National Institute for Health and Welfare 
(THL) (THL/2101/5.05.00/2018), Population Register Centre (VRK/1291/2019-3), Statistics 
Finland (TK-53-1713-18 / u1281) and Tax Register (VH/874/07.01.03/2019). The THL will 
perform pseudonymization of the data. 
This is a register-based study and patients will not be contacted in any phase of the study. Thus, 
no patient consents will be needed according to Finnish legislation. 
All patient data handled by the researchers will anonymous, ensuring full data protection of the 
patients. 
 
7. 
STUDY GROUP AND ASSIGNMENT 
The academic researchers, study lead, PI Mika Lehto and Juhani Airaksinen, Pirjo Mustonen as 
well as Jukka Putaala, Jari Haukka and Miika Linna have operated with the study from the 
planning phase, and are the steering group of the study. Jari Haukka is the leading 
epidemiologist and statistician of the study. Miika Linna, adjunct professor from Aalto 
University will be responsible of cost-effectiveness studies of the FinACAF.  
Because of the vast amount of data, there will be several different aspects to be explored in the 
FinACAF study. Presently it is planned to have several separate Academic Theses prepared 
from the FinACAF data. 
During the FinACAF -study we will have several collaborators. The steering committee is 
consisted of national experts on the field of atrial fibrillation and OAC from Helsinki University 
Hospital and University of Helsinki, Turku University Hospital and University of Turku, 
Central Finland Central Hospital and University of Eastern Finland as well as Aalto University. 
The steering committee has large amount of contacts with national and international experts and 
researchers, and there will be collaboration with all reasonable connections to get the best 
benefit of this vast database.  
 
8. 
ESTIMATION OF COSTS 
Estimation of costs for the national authorities and data holders for study approvals and data 
permissions is estimated to be 40 000 €. 
Thereafter the main cost will be to cover support for academic researchers; Mika Lehto, Juhani 
Airaksinen, Pirjo Mustonen, Jukka Putaala, Miika Linna, Olli Halminen, Jari Haukka and Juha 
Hartikainen as well as Jussi Niiranen, Paula Tiili, Saga Itäinen-Strömberg, Anita Ylimäki, Aapo 

 
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Aro, Tuukka Helin, Tero Penttilä, Alex Luojus, Janne Kinnunen, Santeri Jolkkonen, Kati 
Kaartinen, Lotta Joutsi-Korhonen, Jaakko Inkovaara, Ksenia Kalatsova, Mikko Niemi, Jaana 
Kuoppala, Jarno Satopää, Miikka Korja, Mika Niemelä, Heini Jyrkilä, Elis Kouki, Leena 
Martola and Elin Karlsson. Because of the very large amount of data, there will be also new, 
presently unnamed academic researchers during the FinACAF-project. It is estimated that at 
least 84 months of full-time research work per year during the years 2019 - 2023 would be 
essential. 
Other costs for material (e.g. laptops) and immaterial (e.g. software, costs for printing and open 
access publication) as well congress excursions are estimated to be 30 000 €. 
 
9. 
SIGNIFICANCE OF THE RESULTS 
The most important discoveries will be to find out Finnish atrial fibrillation patients 
characteristics, how are they treated and what are their risks for different endpoints, especially 
mortality. A very central substudies will be cost-effectiveness with different treatments and 
investigations of socio-economical profile associations with clinical endpoints. Most probably 
our findings will have guidance for national regimens and guidelines when atrial fibrillation 
patients are treated. Also, knowledge of cost-effectiveness as well as patients’ socio-economical 
profiles will markedly help “leading with data” when the increasing number of AF patients are 
treated. 
 
10. 
REFERENCES 
Finnish Medical Society Duodecim. Atrial Fibrillation (online). Current Care Guideline. 
Working group set up by the Finnish Medical Society Duodecim and the Finnish Cardiac 
Society. Helsinki, 2017. Available online at: www.kaypahoito.fi    
Hallinen T, Soini EJ, Asseburg C et al. Warfarin treatment among Finnish patients with atrial 
fibrillation: retrospective registry study based on primary healthcare data. BMJ Open. 
2014;4:e004071. 
Lehto M, Niiranen J, Korhonen P, Mehtälä J, Khanfir H, Hoti F, Lassila R, Raatikainen P. 
Quality of Warfarin Therapy and Risk of Stroke, Bleeding, and Mortality among Patients with 
Atrial Fibrillation: Results from the Nationwide FinWAF Registry. Pharmacoepidemiology and 
Drug Safety. 2017;26:657-665.  
Linna M, Keto J, Piuhola J, Vesalainen R, Hällberg V, Laine J. Eteisvärinäpotilaan sosiaali- ja 
terveydenhuoltopalvelujen käyttö komplikaation jälkeen. Suomen Lääkärilehti. 2017;72:1856-
1861. 
Kela 2019. http://www.kela.fi/laake351 
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral 
anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised 
trials. Lancet 2014; 383: 955–962.