Vitamin K Antagonist Versus Direct Oral Anticoagulant Treatments in Hemophilia
Condition: Hemophilia A; Hemophilia B; Anticoagulant-induced Bleeding
MeSH terms: Hemophilia A; Hemophilia B; Hemorrhage
Study type: Observational

Summary: 
      Hemophilia is a rare X-linked bleeding disorder responsible for deficiency of coagulation
      factor VIII (FVIII) or IX (FIX). The main clinical manifestation is increased bleeding
      throughout the life which is directly correlated to the severity of the hemophilia, either
      mild (FVIII/FIX: 6-40), moderate (FVIII/FIX: 1-5%), or severe (FVIII/FIX<1%). Thanks to new
      therapies and long-term specialized follow-up by hemophilia treatment centers (HTCs), the
      life expectancy of patients with hemophilia (PWH) has improved considerably, even reaching
      that of the general population (1).

      Healthcare professionals are so more confronted to PWH with age-related pathologies, in
      particular cardiovascular pathologies such as atrial fibrillation, acute coronary syndromes
      or thromboembolic events (arterial or venous). It is now recommended in PWH that an
      anticoagulant treatment (AC) be prescribed as in the general population (2,3,4). The recently
      published COCHE study demonstrated a significantly increased risk of bleeding in PWH
      receiving antithrombotic treatment. This bleeding risk depended significantly on the type of
      antithrombotic treatment, which was higher for anticoagulant vs antiplatelet drugs, on basal
      levels of FVIII or FIX, and on the HAS-BLED score (5).

      Nowadays in the general population, among anticoagulant drugs, direct oral anticoagulants
      (DOACs) are preferred to vitamin K antagonist (KVA), thanks to their reduced risk of bleeding
      particularly intracerebral bleeding and better anticoagulant stability over time (6).
      However, we do not yet know precisely whether DOACs could occupy the same place in the PWH
      population because of the lack of evidence-based data due to the very small number of these
      patients, although some authors already recommend them over KVA. The KADOAH study was
      therefore set up to try to provide initial elements for future recommendations. Its main
      objective was to compare the level of bleeding risk of PWH treated with VKA vs DOACs.
    

Detailed description: 
      The KADOAH study is an observational, retrospective and multicenter case-control study
      conducted in Hemophilia Treatment Centers (HTC) of the French Grand-Ouest interregion
      including HTCs of Brest, Caen, Le Mans, Nantes, Rennes and Rouen.

      Objectives of the KADOAH study are:

        -  To compare the risk of bleeding events of 2 types of long-term anticoagulant treatment,
           vitamin K antagonists (VKA) versus Direct Oral Anticoagulants (DOAC), in patients with
           hemophilia,

        -  To describe the different types of bleeding events that occur during anticoagulant
           treatments in patients with hemophilia,

        -  To investigate for the influence of the HAS-BLED score on the risk of bleeding events in
           patients with hemophilia receiving a long-term anticoagulant treatment.

      Inclusion criteria:

        -  Cases :

        -  Males at any ages with hemophilia of any severity and of any type,

        -  Patients having received or receiving a long-term anticoagulant treatment (during at
           least 6 consecutive months) during the period from 2012 to 2021,

        -  Regular follow-up in a hemophilia treatment center.

        -  Controls cross-matched with cases on :

        -  Age (+/- 5 years),

        -  Hemophilia type (either A or B)

        -  Hemophilia severity (for mild hemophilia: same basal factor level +/- 5%),

        -  HAS-BLED score (same score +/- 1).

      Exclusion criteria:

        -  Lost to medical follow-up,

        -  Refusal to participate in the study,

        -  Unable to understand the study's French letter of non-opposition and information.

      Collected data:

      All data collected in this study were issued from the medical files at the moment of the
      inclusion in the study. They include:

        -  The age,

        -  The hemophilia's type,

        -  The hemophilia's severity and last basal factor VIII or IX level,

        -  The treatment with anticoagulant drug for cases including :

        -  Type of drug (either VKA or DOAC)

        -  Duration of treatments

        -  Treatments dosages,

        -  Compliance of treatments,

        -  Indications,

        -  If stopped prematurely, reasons for stopping.

        -  The occurrence of severe bleeding events (SBE) following the ISTH definition (7):

        -  The number of SBE per patient,

        -  The types of SBE,

        -  The treatment of SBE.

        -  The HAS-BLED score calculated with the presence or absence of the following items:

        -  High arterial pressure,

        -  Abnormal renal and/or liver functions,

        -  Hemorrhagic stroke,

        -  Bleeding antecedent,

        -  Age >65 years,

        -  Treatments altering the hemostasis (out of the anticoagulants) and/or alcohol
           intoxication.

        -  The CHA2DS-VASc score calculated with the presence or absence of the following items:

        -  Cardiac insufficiency/left ventricular dysfunction,

        -  High arterial pressure,

        -  Age ≥ 75 years, or age = 65 - 74 years,

        -  Diabetes,

        -  History of thrombotic events (transient ischemic cerebral attack or stroke, venous
           thromboembolic events)

        -  Associated treatment with a proton pomp inhibitor or other gastric protector,

      Statistical analyses Descriptive characteristics were analyzed with median values, their
      25-75% interquartile ranges (IQR) and minimum-maximum values (MIN-MAX), or mean values with
      standard deviation (SD). The Fisher's exact test will be performed to compare proportions in
      contingency tables and the t Student test to compare continuous variables. An approximate 95%
      confidence interval will be determined (95% CI) for every statistical analysis and a p-value
      <0.05 will be considered statistically significant. The GraphPad v7.0 (Prism Software Inc.
      San Diego CA) will be used to perform the statistical analyses.
    

Intervention name(s): Vitamin K Antagonist - Drug
Intervention type(s): Drug
Intervention description(s): Only clinical data (number and types of severe bleeding events, HAS-BLED score, CHA2DS2-VASc score) are collected during the follow-up:
For cases when they received an anticoagulant treatment and during the 12 months preceding this treatment,
For controls during the same periods of their cross-matched cases when reciving anticoagulant treatment.
Other intervention name(s): direct oral anticoagulant
Intervention MeSH terms: Vitamin K; Anticoagulants
Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        The study includes only patients with hemophilia: cases who are patients having received an
        anticoagulant treatment (cases) for at least 6 months during the period 2112-2021, and
        controls without anticoagulant treatment cross-matched with cases on the age, the severity
        and type of hemophilia, and the HAS-BLED score.

        All the data collected in this study are issued from the medical files.
      
Keywords: Hemophilia A; Hemophilia B; Anticoagulant-induced Bleeding