Vitamin K Antagonist Versus Direct Oral Anticoagulant Treatments in Hemophilia

Hemophilia A Clinical Trial

— KADOAH  

Official title:

Vitamin K Antagonist Versus Direct Oral Anticoagulant Treatments in Hemophilia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05804734
• Other study ID #: 2023_VKA-DOA_01
• Status: Completed
• Start date: June 1, 2021
• Est. completion date: December 31, 2021

Study information

• Verified date: March 2023
• Source: Groupe Maladies hémorragiques de Bretagne
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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 : patients with hemophilia 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.

Related Conditions & MeSH terms

• Anticoagulant-induced Bleeding
• Hemophilia A
• Hemophilia B
• Hemorrhage

Intervention

Drug:
• Vitamin K Antagonist - Drug
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.

Locations

Country	Name	City	State
France	Hemophilia treatment center of Brest	Brest
France	Hemophilia treatment center of caen	Caen
France	Hemophilia treatment center of Le Mans	Le Mans
France	Hemophilia treatment center of Nantes	Nantes
France	Hemophilia treatment center of Rennes	Rennes
France	Hemophilia treatment center of Rouen	Rouen

Sponsors (1)

Lead Sponsor	Collaborator
Groupe Maladies hémorragiques de Bretagne

Country where clinical trial is conducted

France, 

References & Publications (7)

Andrade JG, Verma A, Mitchell LB, Parkash R, Leblanc K, Atzema C, Healey JS, Bell A, Cairns J, Connolly S, Cox J, Dorian P, Gladstone D, McMurtry MS, Nair GM, Pilote L, Sarrazin JF, Sharma M, Skanes A, Talajic M, Tsang T, Verma S, Wyse DG, Nattel S, Macle L; CCS Atrial Fibrillation Guidelines Committee. 2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2018 Nov;34(11):1371-1392. doi: 10.1016/j.cjca.2018.08.026. — View Citation

Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, Lee CA, Ludlam CA, Williams M. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007 Aug 1;110 — View Citation

Ferraris VA, Boral LI, Cohen AJ, Smyth SS, White GC 2nd. Consensus review of the treatment of cardiovascular disease in people with hemophilia A and B. Cardiol Rev. 2015 Mar-Apr;23(2):53-68. doi: 10.1097/CRD.0000000000000045. — View Citation

Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups. Thrombosis. — View Citation

Guillet B, Cayla G, Lebreton A, Trillot N, Wibaut B, Falaise C, Castet S, Gautier P, Claeyssens S, Schved JF. Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry. Thromb — View Citation

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x. — View Citation

Schutgens RE, van der Heijden JF, Mauser-Bunschoten EP, Mannucci PM. New concepts for anticoagulant therapy in persons with hemophilia. Blood. 2016 Nov 17;128(20):2471-2474. doi: 10.1182/blood-2016-07-727032. Epub 2016 Sep 26. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison of the number of severe bleeding events occurring in patients with hemophilia receiving a vitamin K antagonist treatment versus patients with hemophilia receiving a direct oral anticoagulant treatment.	Number of severe bleeding events	All over the duration of the anticoagulant treatment in the period 2012-2021
Secondary	Comparison of the number of severe bleeding events occurring in patients with hemophilia receiving an anticoagulant treatment versus their cross-matched controls not receiving an anticoagulant treatment.	Number of severe bleeding events	All over the duration of the anticoagulant treatment in the period 2012-2021
Secondary	Description of the types of severe bleeding events occurring in patients with hemophilia receiving an anticoagulant treatment (either vitamin K antagonist or direct oral anticoagulant treatment).	Types of bleeding	All over the duration of the anticoagulant treatment in the period 2012-2021
Secondary	The influence of the HAS-BLED score on the risk of severe bleeding events in patients with hemophilia receiving an anticoagulant treatment.	HAS-BLED score	All over the duration of the anticoagulant treatment in the period 2012-2021
Secondary	The influence of a treatment with proton pomp inhibitor on the risk of gastrointerstinal bleeding events in patients with hemophilia receiving an anticoagulant treatment.	Number of gastrointestinal bleeding	All over the duration of the anticoagulant treatment in the period 2012-2021