10.4081/btvb.2023.84
The survey on anticoagulated patients register (START-Register) is an independent, prospective, inception-cohort observational study aimed at providing information on patients on vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in Italy. In this study, we describe the cohort of atrial fibrillation (AF) patients in the START-Register and report outcomes and changes in anticoagulant prescription from 2011 to 2021. The study included 11,078 AF patients, enrolled in 47 Italian centers distributed all over the Country; the median age was 77 years (range 18-99 years); 6029 (54.3%) were men; 5135 (46.4%) were on VKAs, and 5943 (53.6%) were on DOACs. Warfarin was the most prescribed VKA (98.4%), and apixaban was the most prescribed DOAC (31.6%). Among DOAC users, 4022 (67.7%) patients were naive to anticoagulation, and 2562 (43.1%) patients were treated with a reduced dose. DOAC patients were significantly older than VKA patients (median age 79 years vs 76 years respectively, P&lt;0.001), but no gender difference was detected. The mean CHA2DS2VASc score was higher in DOAC users than in VKA users (3.7 vs 3.6; P=0.03). The mean HAS-BLED score was not different between the two groups. During follow-up, 542 bleeding events were recorded [2.44 per 100 patient-years (pt-yrs)]; 240 were major (1.08 per 100 pt-yrs), and 301 were clinically relevant non-major bleedings (1.34 per 100 pt-yrs). 146 thrombotic events were recorded during follow-up (0.66 per 100 pt-yrs). The total mortality rate was 3.5 per 100 pt-yrs; the mortality rate was 4.54 per 100 pt-yrs among patients on VKAs and 2.31 per 100 pt-yrs among patients on DOACs. During the last 10 years, in Italy, AF patient management has changed with the large spread of DOACs all over the Country. DOAC patients are frequently treated with reduced doses and show a lower mortality rate in comparison to patients on VKAs.
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Bleeding, Thrombosis and Vascular Biology
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Management of anticoagulation in atrial fibrillation patients in Italy: insight from the <i>Atrial Fibrillation-Survey on Anticoagulated Patients Register</i> (AF-START)
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Original Articles
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2023-04-30
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Bleed Thromb Vascul Biol
Gualtiero Palareti
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10.4081/btvb.2023.84
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Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 2016;74:1359-469.
Management of anticoagulation in atrial fibrillation patients in Italy: insight from the <i>Atrial Fibrillation-Survey on Anticoagulated Patients Register</i> (AF-START)
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                                                                                                             ORIGINAL ARTICLE

Management of anticoagulation in atrial fibrillation patients in Italy:
insight from the Atrial Fibrillation-Survey on Anticoagulated Patients
Register (AF-START)
Daniela Poli,1 Walter Ageno,2 Emilia Antonucci,3 Salvatore Bradamante,4 Eugenio Bucherini,5 Paolo Chiarugi,6
Antonio Chistolini,7 Benilde Cosmi,8 Anna Falanga,9 Antonio Insana,10 Domenico Lione,11 Rosa Maria Lombardi,12
Giuseppe Malcangi,13 Rossella Marcucci,1 Giuliana Martini,14 Lucilla Masciocco,15 Carmelo Paparo,16 Daniele Pastori,17
                                                              Simona Pedrini,18 Vittorio Pengo,19 Pasquale Pignatelli,17
                                                              Andrea Toma,20 Sophie Testa,21 Gualtiero Palareti3

  Correspondence: Daniela Poli, Center of Atherothrombotic Dis-
                                                                              1
                                                                                Center of Atherothrombotic Disease, Careggi University
  ease, Careggi University Hospital, Florence, Italy.                         Hospital, Florence; 2Short Stay Observation and Short
  Tel.: +39.055.7945453.                                                      Recovery Unit, Department of Internal Medicine, Circolo
  E-mail: polida@aou-careggi.toscana.it                                       Hospital and Macchi Foundation, ASST Sette Laghi, Varese;
                                                                              3
                                                                                Arianna Anticoagulazione Foundation, Bologna; 4Transfusion
  Citation: Poli D, Ageno W, Antonucci E, et al. Management of
                                                                              Center, Hemostasis and Thrombosis Center, Annunziata
  anticoagulation in atrial fibrillation patients in Italy: insight from
                                                                              Hospital, Taranto; 5Vascular Medicine and Angiology SS,




                                                                                                ly
  the Atrial Fibrillation-Survey on Anticoagulated Patients Register
  (AF-START). Bleeding, Thrombosis, and Vascular Biology                      AUSL Romagna, Ravenna; 6Clinical Chemical Analysis




                                                                                        on
  2023;2:84.                                                                  Organizational Unit, Pisana University Hospital, Pisa;
                                                                              7Department of Translational and Precision Medicine,
  Key words: atrial fibrillation, anticoagulation, bleeding event,            Sapienza University of Rome; 8Division of Angiology and




                                                                                  e
  stroke.                                                                     Blood Coagulation, S. Orsola-Malpighi University Hospital,
                                                                              Bologna; 9Thrombosis, Hemostasis Immunohematology and
  Contributions: DP, study conception, statistical analysis, and writ-
  ing of the initial draft of the manuscript; WA, GP, critical review
  of the draft; EA, statistical analysis; SB, EB, AC, BC, AF, AI, DL,
                                                                             us
                                                                              Transfusion Medicine Center, ASST Papa Giovanni XXIII,
                                                                              Bergamo; 10SC Chemical-Clinical Analysis and Microbiology
                                                                              Laboratory, Ordine Mauriziano Hospital, Turin; 11Complex
                                                                             al
  RML, GM, RM, GM, LM, DP, CP, SP, CP, VP, PP, AP, ST, data
  collection. All the authors read and commented on the paper and             Operating Unit of Clinical Pathology, A. Perrino Hospital,
                                                         ci

  approved its submission.                                                    Brindisi; 12Internal Medicine Organization Unit, Hemostasis
                                                                              and Thrombosis Center, University Hospital of Parma;
                                                       er


  Conflict of interest: the authors declare no potential conflict of in-      13
                                                                                 Hemophilia and Thrombosis Center, Polyclinic of Bari;
  terest.                                                                     14
                                                                                 Hemostasis Center, Civilian Hospitals of Brescia; 15Complex
                                                      m




                                                                              Operating Unit of Internal Medicine, Lastaria Hospital,
  Informed consent: the manuscript does not contain any individual
                                                                              Lucera (FG); 16Analysis Laboratory, Maggiore Chieri
                                           om




  person’s data in any form. Written informed consent was obtained
  from each patient before enrollment.                                        Hospital, Turin; 17Department of Clinical Internal Medicine,
                                                                              Anesthesiology and Cardiovascular Sciences, Thrombosis
  Funding: Arianna Anticoagulation Foundation supported the                   Center, Sapienza University of Rome; 18Laboratory Service,
                                    -c




  START Register. The Foundation had no role in the study design,             Poliambulanza Foundation Hospital, Brescia; 19Department of
  collection, analysis, and interpretation of data, in writing the report,    Cardio-Thoracic-Vascular Sciences, University Hospital of
                           on




  and in the decision to submit the paper for publication.                    Padua; 20Complex Operating Unit of Clinical Pathology, Oral
                                                                              Anticoagulant Therapy Outpatient Clinic, L. Cazzavillan
  Availability of data and materials: data and materials are available
                     N




  by the authors according to the Italian law on personal data pro-           Civilian Hospital, Arzignano (VI); 21Department of
  tection.                                                                    Laboratory Medicine, Hemostasis and Thrombosis Center,
                                                                              ASST Cremona, Italy
  Received: 12 May 2023.
  Accepted: 22 June 2023.

  Publisher’s note: all claims expressed in this article are solely those
  of the authors and do not necessarily represent those of their affili-      ABSTRACT
  ated organizations, or those of the publisher, the editors and the re-           The survey on anticoagulated patients register (START-Reg-
  viewers. Any product that may be evaluated in this article or claim         ister) is an independent, prospective, inception-cohort observa-
  that may be made by its manufacturer is not guaranteed or endorsed          tional study aimed at providing information on patients on
  by the publisher.                                                           vitamin K antagonists (VKAs) or direct oral anticoagulants
                                                                              (DOACs) in Italy. In this study, we describe the cohort of atrial
  ©
   Copyright: the Author(s), 2023                                             fibrillation (AF) patients in the START-Register and report out-
  Licensee PAGEPress, Italy
                                                                              comes and changes in anticoagulant prescription from 2011 to
  Bleeding, Thrombosis and Vascular Biology 2023; 2:84
  doi:10.4081/btvb.2023.84
                                                                              2021. The study included 11,078 AF patients, enrolled in 47 Ital-
                                                                              ian centers distributed all over the Country; the median age was
  This work is licensed under a Creative Commons Attribution-                 77 years (range 18-99 years); 6,029 (54.3%) were men; 5,135
  NonCommercial 4.0 International License (CC BY-NC 4.0).                     (46.4%) were on VKAs, and 5,943 (53.6%) were on DOACs.
                                                                              Warfarin was the most prescribed VKA (98.4%), and apixaban


                                               Bleeding, Thrombosis and Vascular Biology 2023; 2:84
32                                                                D. Poli et al.




was the most prescribed DOAC (31.6%). Among DOAC users, 4,022 (67.7%) patients were naive to anticoagulation, and 2,562 (43.1%)
patients were treated with a reduced dose. DOAC patients were significantly older than VKA patients (median age 79 years vs 76 years
respectively, P<0.001), but no gender difference was detected. The mean CHA2DS2VASc score was higher in DOAC users than in VKA
users (3.7 vs 3.6; P=0.03). The mean HAS-BLED score was not different between the two groups. During follow-up, 542 bleeding
events were recorded [2.44 per 100 patient-years (pt-yrs)]; 240 were major (1.08 per 100 pt-yrs), and 301 were clinically relevant non-
major bleedings (1.34 per 100 pt-yrs). 146 thrombotic events were recorded during follow-up (0.66 per 100 pt-yrs). The total mortality
rate was 3.5 per 100 pt-yrs; the mortality rate was 4.54 per 100 pt-yrs among patients on VKAs and 2.31 per 100 pt-yrs among patients
on DOACs. During the last 10 years, in Italy, AF patient management has changed with the large spread of DOACs all over the Country.
DOAC patients are frequently treated with reduced doses and show a lower mortality rate in comparison to patients on VKAs.


                                                                             viously described.15
Introduction                                                                      Participating centers were required to enroll patients con-
                                                                             secutively, without any a priori exclusion criteria other than
     Atrial fibrillation (AF) is associated with a fivefold increased
                                                                             short life expectancy or geographical inaccessibility, and to fol-
risk of stroke.1,2 AF-related strokes are more severe and have
                                                                             low up with patients for at least one year.
higher mortality and disability than strokes occurring in patients
                                                                                  Baseline demographic data and patients’ clinical character-
without AF.3,4 Adequate stroke prevention with oral anticoagulants
                                                                             istics, associated diseases, clinical indication for treatment, and




                                                                                                         ly
is recommended for most patients.5 However, the bleeding risk
                                                                             use of concomitant drugs were collected in a web-based case re-
associated with anticoagulation and the complex management re-




                                                                                                on
                                                                             port form. Naive patients were enrolled in the study within the
quired for patients on treatment with vitamin K antagonists
                                                                             first month of treatment with an oral anticoagulant, either VKAs
(VKAs) resulted in a limited adherence to these indications lead-            or DOACs. The patients who shifted to DOACs from VKAs
ing to the underuse of anticoagulant treatment.6 The introduction




                                                                                          e
                                                                             were enrolled when VKA treatment was stopped and DOAC
of direct oral anticoagulants (DOACs) changed the landscape of               treatment was started. Also in these patients, the enrollment
anticoagulation, due to their ease of use and lower bleeding risk
with respect to warfarin demonstrated in registrative studies.7 Col-
lecting data from large cohorts of patients to assess clinical prac-
                                                                                   us
                                                                             started within the first month after the prescription of DOACs.
                                                                             Serum creatinine levels were measured by local hospital labo-
                                                                             ratories, and creatinine clearance (CrCl) was calculated using
                                                                           al
tice patterns and the safety and effectiveness of treatment                  the Cockroft-Gault formula.16 Renal failure was defined by an
strategies has been a goal of clinical research in the last 20 years,
                                                             ci

                                                                             estimated CrCl <30 mL/min.
and several prospective registries have been implemented.8-12 In                  Patients with non-valvular AF are stratified for stroke risk ac-
                                                           er


Italy, the marketing of DOACs started during the summer of 2013,             cording to the CHA2DS2VASc score,17 while baseline bleeding
and the reimbursement of these drugs required a specific prescrip-           risk is evaluated by using the HAS-BLED score.18 Participating
                                                          m



tion by specialists, such as cardiologists or internists. The possi-         centers are required to regularly follow up with enrolled patients
bility of prescription was extended to general practitioners only            and to provide detailed clinical reports of any relevant clinical
                                               om




in 2020. Therefore, the use of DOACs was limited in the first                outcome.
years after marketing because of the Italian health policy. The AF                Major bleeding and clinically relevant non-major bleeding
survey on anticoagulated patients register (START-Register) was              (CRNMB) were defined according to the classification proposed
                                         -c




designed to provide information on AF patients and anticoagulant             by the International Society on Thrombosis and Haemostasis.19,20
treatment with VKAs or DOACs in Italy; to describe prescription              Stroke diagnosis requires the abrupt onset of focal neurological
                                 on




patterns and to evaluate the risks and benefits of the various anti-         symptoms lasting at least 24 hours and supported by congruent
coagulant drugs. Two cohorts were enrolled, cohort 1 completed               ischemic lesions at computed tomography or magnetic reso-
data collection in 2015, and cohort 2 in 2021. Data on the AF
                            N




                                                                             nance imaging scan. Systemic embolism is defined by symp-
START-Register cohort 1 were previously published.13,14 In this              toms consistent with an acute loss of blood flow to a peripheral
study, we describe the characteristics of patients of the whole co-          artery, which is supported by objective evidence of embolism.
hort of the AF START-Register (cohorts 1 and 2) and report out-
come events that occurred during treatment and changes in
                                                                             Statistical analysis
anticoagulant prescription in the Register from 2011 to 2021.
                                                                                 A descriptive analysis was performed. Continuous variables
                                                                             are expressed as median and interquartile range or as mean ±
Materials and Methods                                                        standard deviation. Categorical variables are expressed as fre-
                                                                             quencies and percentages. Differences between continuous val-
    The START-Register is an observational, multicenter,                     ues were assessed using the unpaired t-test, and categorical
prospective cohort study that includes patients over 18 years old            variables were compared using the Chi-square test or Fisher
who start anticoagulation therapy, regardless of the drug and the            exact test, as appropriate. The incidence of bleeding events,
indication for treatment. The START-Register aims to collect                 thrombotic events, and death was calculated by dividing the
data on the incidence of adverse events in patients taking anti-             number of events by the person’s time at risk. The incidence rate
coagulants, as well as their determinants. The study design and              ratio together with the 95% confidence interval was calculated.
protocol were approved by the Ethical Committee of the S. Or-                P<0.05 were considered statistically significant. The data were
sola-Malpighi University Polyclinic Hospital (Bologna, Italy)                analyzed with the use of SPSS software for Windows, V.26
in October 2011 (N.142/2010/0/0ss) (NCT02219984). The                        (IBM, Armonk, New York, USA) and Stata V.14 statistical soft-
START-Register procedures and data collection have been pre-                 ware package (StataCorp, College Station, Texas, USA).


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:84
                                   Management of anticoagulation in atrial fibrillation patients in Italy                                 33



                                                                          (18.8%) (P<0.001). Instead, the mean HAS-BLED score was not
Results                                                                   different between the two groups (0.9 and 0.8, respectively).
                                                                              During follow-up, 542 bleeding events were recorded [2.44
    The study included 11,078 AF patients, enrolled in 47 Italian
                                                                          per 100 patient-years (pt-yrs)]; 240 were major (1.08 per 100
centers. Participating centers are distributed all over the country:
                                                                          pt-yrs), and 301 were CRNMB (1.34 per 100 pt-yrs) (Table 2).
66.9% in northern Italy, 23.6% in central Italy, and 9.5% in south-
                                                                          Major bleeding was fatal in 25 cases (10.4%). Major bleedings
ern Italy. Patients were followed for a median time of 1.5 years
                                                                          were recorded in 119 patients on VKAs (rate 0.99 per 100 pt-
(range 0.1-9.7 years). Figure 1 reports VKAs and DOACs pre-
                                                                          yrs), and in 121 patients on DOACs (rate 1.19 per 100 pt-yrs).
scription patterns over time. No difference in the DOAC prescrip-
                                                                              During follow-up, 146 thrombotic events were recorded
tion rates was found in terms of the geographical distribution of
                                                                          (0.66 per 100 pt-yrs): 59 cases among patients on VKAs (rate
the participating centers.
                                                                          0.49 per 100 pt-yrs), and 87 cases among patients on DOACs
    The characteristics of patients are reported in Table 1. The
                                                                          (rate 0.86 per 100 pt-yrs). 783 patients died (rate 3.5 per 100 pt-
median age was 77 (range 18-99 years), and 6029 (54.3%) were
                                                                          yrs): 550 among patients on VKAs (rate 4.54 per 100 pt-yrs),
males. 5135 patients (46.4%) were on VKA treatment, whereas
                                                                          and 231 among patients on DOACs (rate 2.28 per 100 pt-yrs).
5943 patients (53.6%) were on DOACs.
                                                                          The causes of death were: bleeding in 25 cases (3.2%), and
    Warfarin was the most prescribed VKA (98.4% of cases),
                                                                          stroke in 10 cases (1.3%).
and apixaban was the most prescribed DOAC (31.6% of cases).
Among DOAC users, 4022 (67.7%) patients were naive to anti-




                                                                                            ly
coagulation, and 2562 (43.1%) patients were treated with a re-
duced dose.                                                               Discussion




                                                                                    on
    DOAC patients were significantly older than VKA patients                  We present here data from AF patients included in the whole
(median age 79 years vs 76 years respectively, P<0.001), but no           cohort of the AF START-Register. During 10 years of observa-
gender differences were detected. The median follow-up period             tion, we observed a progressive decline in warfarin prescription




                                                                               e
was 1.9 years for patients on VKAs and 1.3 years for patients             and a progressive increase in DOAC prescription, with DOACs
on DOACs (P<0.001).
    Patients on DOACs had paroxysmal AF, hypertension, throm-
bocytopenia, history of previous bleeding, and dementia and re-
                                                                       us being prescribed to more than 95% of patients enrolled during
                                                                          2021, the last year of observation. This finding is in agreement
                                                                          with what was reported in the majority of Western countries.21,22
                                                                  al
quired bed rest more frequently than patients on VKAs. VKA                    Patients included in the AF START-Register are older than
patients had history of heart failure, coronary artery disease, pe-       patients included in the Garfield AF, ORBIT AF,23 and PREFER
                                                   ci

ripheral occlusive arterial disease, and renal failure more fre-          AF study,10 with more than two-thirds of patients over 75 years
                                                 er


quently (Table 1). Similarly, VKA patients received concomitant           of age, in comparison to less than 50% in the other studies. How-
antiplatelet drugs more frequently than DOAC patients (13.8% vs           ever, stroke risk, calculated by CHA2DS2VASc score, and bleed-
                                                m



10.1%; P<0.001). The mean CHA2DS2VASc score was higher in                 ing risk, calculated by HAS-BLED score, are similar to those of
DOAC than in VKA users (3.7 vs 3.6; P=0.03), and the proportion           patients included in the other studies.10,23
                                      om




of patients with a CHA2DS2VASc score ≤2 was significantly                     In our study, VKA patients had more frequently history of
higher among VKA patients (24.4%) than DOAC patients                      coronary artery disease and peripheral obstructive arterial dis-
                                -c
                        on
                   N




AVK, vitamin K antagonist; DOAC, direct oral anticoagulant.

Figure 1. Enrollment of patients on vitamin K antagonists or direct oral anticoagulants.


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:84
34                                                                            D. Poli et al.




ease. As a consequence, in these patients, a higher rate of con-                         DOACs with VKAs,7 and in the GARFIELD-AF study.24 Cen-
comitant antiplatelet treatment in comparison to patients on                             ters participating in AF START-Register are anticoagulation
DOACs was found. Similarly, renal failure was more frequent                              clinics and followed patients on VKAs with careful manage-
in VKA patients than in DOAC ones.                                                       ment, which is associated with a lower bleeding risk with respect
    In the AF START-Register patients, the bleeding risk was                             to routine management of anticoagulation.25
similar in both groups, even if the mortality rate due to bleeding                           In our cohort, patients on DOACs received a reduced dose
events was higher among patients on VKAs. This finding is dif-                           in 43.1% of the cases. A high prevalence of a reduced dose pre-
ferent from data reported in the registrative studies comparing                          scription was previously reported,26,27 even though in these stud-



Table 1. Characteristics of patients accordingly to the type of anticoagulant treatment.
                                                  All patients          Patients on VKAs                            Patients on DOACs                     P value
Patients, N (%)                                                  11078                         5135 (46.4)                 5943 (53.6)
Females, N (%)                                                5071 (45.7)                      2310 (45.0)                 2752 (46.3)                       0.2
Men, N (%)                                                    6029 (54.3)                      2825 (55.0)                 3191 (53.7)                       0.2
Median age (range) [IQR], years                           77 (18-99) [71-83]             76 (18-98) [70-82]            79 (20-99) [72-84]                  <0.001




                                                                                                                         ly
Age >75 years, N (%)                                          6896 (62.2)                      2390 (57.1)                 3966 (66.7)                     <0.001




                                                                                                                on
Total follow-up, years                                           22238                            12118                       10120
Median follow-up (range) [IQR], years                         1.5 (0.1-9.7)                    1.9 (0.1-9.7)              1.3 (0.1-8.9)
                                                                                                                                                           <0.001
                                                                [1.0-2.6]                        [0.9-3.5]                  [1.0-2.0]




                                                                                                             e
Paroxysmal AF, N (%)                                          2340 (39.6)                      1682 (32.8)                 2340 (39.6)                     <0.001
Hypertension, N (%)
Diabetes mellitus, N (%)
                                                              8889 (80.2)
                                                              2275 (20.5)
                                                                                                  us
                                                                                               4002 (77.9)
                                                                                               1048 (20.4)
                                                                                                                           4887 (82.2)
                                                                                                                           1226 (20.6)
                                                                                                                                                           <0.001
                                                                                                                                                             0.8
Heart failure, N (%)                                          2115 (19.1)                      1046 (20.4)                 1069 (18.0)                      0.001
                                                                                       al
Coronary artery disease, N (%)                                1869 (16.9)                      1019 (19.9)                 848 (14.3)                      <0.001
                                                                     ci

Peripheral occlusive arterial disease, N (%)                    648 (5.8)                       332 (6.5)                   316 (5.3)                       0.004
                                                                   er


COPD, N (%)                                                   1355 (12.2)                       623 (12.1)                 732 (12.3)                        0.03
Active cancer, N (%)                                            308 (2.8)                       140 (2.7)                   168 (2.8)                        0.5
                                                                  m



Dementia, N (%)                                                 341 (3.1)                       113 (2.2)                   228 (3.8)                      <0.001
Anemia, N (%)                                                   300 (2.7)                       145 (2.8)                   155 (2.6)                        0.5
                                                      om




Platelet count <100.000/µL, N (%)                               102 (0.9)                        59 (1.1)                    43 (0.7)                        0.02
Bed rest, N (%)                                                 94 (0.8)                         28 (0.5)                    66 (1.1)                      <0.001
                                               -c




Frequent falls, N (%)                                           221 (2.0)                       109 (2.1)                   112 (1.9)                        0.7
Previous bleeding, N (%)                                        412 (3.7)                       122 (2.4)                   290 (4.9)                      <0.001
                                      on




Previous stroke, N (%)                                        1688 (15.2)                       725 (14.1)                 963 (16.2)                       0.004
Renal function (5907/5943)
                                N




 eGFR <30 mL/min                                               560 (5.1)                        369 (7.2)                   191 (3.2)                      <0.001
 30-60 mL/min                                                 4721 (42.6)                      2092 (41.0)                 2629 (44.2)                     <0.001
 >60 mL/min                                                   5669 (51.2)                      2618 (51.3)                 3051 (51.3)                      0.7
Antiplatelet drugs, N (%)                                     1306 (11.8)                       707 (13.8)                 599 (10.1)                      <0.001
Psychotropic drugs, N (%)                                       936 (8.4)                       384 (7.5)                   552 (9.3)                       0.003
Mean CHA2DS2VASc score (SD)                                     3.7 (1.5)                        3.6 (1.6)                  3.7 (1.5)                        0.03
CHA2DS2VASc ≤2, N (%)                                         2374 (21.4)                      1255 (24.4)                 1119 (18.8)                     <0.001
Mean HAS-BLED score (SD)                                        2.1 (0.8)                        2.0 (0.9)                  2.1 (0.8)                        0.4
HAS-BLED ≥3, N (%)                                            2840 (25.6)                      1335 (26.0)                 1505 (25.3)                       0.4
Anticoagulant Treatment, N (%)
 Naive                                                                                         5135 (100.0)                4022 (67.7)
 Warfarin                                                                                       5053 (98.4)                     -
 Apixaban                                                                                            -                     1880 (31.6)
 Dabigatran                                                                                          -                     1397 (23.5)
 Edoxaban                                                                                            -                     1101 (18.5)
 Rivaroxaban                                                                                                               1565 (26.3)
DOAC reduced dose, N (%)                                                                                                   2562 (43.1)
N, number; VKAs, vitamin K antagonists; DOACs, direct oral anticoagulants; AF, atrial fibrillation; IQR, interquartile range; SD, standard deviation; COPD, chronic ob-
structive pulmonary disease.


                                                 Bleeding, Thrombosis and Vascular Biology 2023; 2:84
                                         Management of anticoagulation in atrial fibrillation patients in Italy                                                    35



Table 2. Adverse events recorded during follow-up.
                                                All patients,                                  Patients on VKAs,                      Patients on DOACs,
                                            N (rate×100 pt-yrs)                                N (rate×100 pt-yrs)                    N (rate×100 pt-yrs)
All bleedings                                                 542 (2.44)                              291 (2.40)                             251 (2.48)
Major bleedings                                               240 (1.08)                              119 (0.99)                             121 (1.19)
 ICH                                                          76 (0.34)                                45 (0.37)                              31 (0.32)
 GI bleed                                                     63 (0.28)                                26 (0.21)                              37 (0.37)
Anemia requiring blood transfusion >2 RCU                      85 (0.38)                               39 (0.32)                              46 (0.45)
Intra articular                                                7 (0.03)                                2 (0.02)                               5 (0.05)
Retroperitoneal                                                5 (0.02)                                1 (0.01)                               4 (0.04)
Hematuria                                                      3 (0.01)                                2 (0.02)                               1 (0.01)
Metrorrhagia                                                   1 (0.00)                                1 (0.01)                                   -
Fatal bleedings                                                25 (0.11)                               19 (0.16)                              6 (0.06)
CRNMB                                                         301 (1.34)                              171 (1.41)                             130 (1.28)
Median time to bleedings (range), years                      0.8 (0.1-7.0)                           1.2 (0.1-6.7)                          0.9 (0.1-5.8)
Thrombotic events                                              84 (0.37)                               36 (0.30)                              48 (0.47)




                                                                                                              ly
Stroke                                                         52 (0.23)                               21 (0.17)                              31 (0.30)




                                                                                                     on
TIA                                                            21 (0.09)                               12 (0.10)                              9 (0.09)
Arterial embolism                                              5 (0.02)                                1 (0.01)                               4 (0.04)
Intracardiac thrombosis                                        5 (0.02)                                1 (0.01)                               4 (0.04)




                                                                                              e
Fatal stroke                                                   10 (0.04)                               8 (0.07)                               2 (0.02)
Median time to stroke (range), years
Death
                                                             1.4 (0.1-7.0)
                                                              781 (3.50)
                                                                                     us              1.3 (0.1-6.5)
                                                                                                      550 (4.54)
                                                                                                                                            1.2 (0.1-5.4)
                                                                                                                                             231 (2.28)
                                                                             al
N, number; VKAs, vitamin K antagonists; DOACs, direct oral anticoagulants; pt-yrs, patient-years; CRNMB, clinically relevant non-major bleeding; GI, gastrointestinal
bleeding; ICH, intracranial bleeding; TIA, transient ischemic attack; RCU, red cell units.
                                                           ci
                                                         er
                                                        m



ies a percentage ranging from 16% and 22% was reported. The
use of reduced doses of DOACs is more frequent in routine clin-                         Conclusions
                                            om




ical practice than in clinical trials.28,29 Moreover, when reduced
                                                                                            During the last 10 years, in Italy, the management of AF pa-
doses were prescribed, frequent underdosing has been reported,
                                                                                        tients has changed because of the large diffusion of DOACs, in
with an increased risk of thrombotic complications due to inad-
                                                                                        line with international guidelines.31 DOAC patients are fre-
                                     -c




equate anticoagulation.28,30 The elevated median age of our co-                         quently treated with low-dose DOACs. The AF START-Register
hort may have contributed to the elevated prescription of a
                            on




                                                                                        included a large cohort of elderly patients recruited all over the
reduced dose, as it is known that older age is associated with an-                      Country and confirmed the low bleeding risk for VKA patients
ticoagulant underdosing.27                                                              followed by Italian anticoagulation clinics; however, these pa-
                      N




                                                                                        tients have a higher mortality rate, that is double as compared
Strengths and limitations of the study                                                  to DOAC patients. This finding is partially explained by the
                                                                                        higher prevalence of arterial diseases and reduced renal function
    Strengths of our study include the prospective design, the
                                                                                        reported in these patients.
large cohort with a long duration of follow-up, and the partici-
pation of highly experienced centers.
    This study has also several limitations. Firstly, caution
should be required when interpreting comparisons between two                            References
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Online supplementary material:
List of participating centers and investigators who contributed to the START2 AF Registry.

                                             Bleeding, Thrombosis and Vascular Biology 2023; 2:84
