Clinical trial NCT03129555: The Danish Non-vitamin K Antagonist Oral Anticoagulation Study in Patients With Venous Thromboembolism (DANNOAC-VTE)
Official title: The Danish Non-vitamin K Antagonist Oral Anticoagulation Study. A Cluster Randomized Study Comparing Safety and Efficacy of Edoxaban, Apixaban, Rivaroxaban and Dabigatran for Oral Anticoagulation in Patients With Venous Thromboembolism.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Deep Vein Thrombosis
Pulmonary Embolism
Keywords: Non-vitamin K antagonist oral anticoagulation
Non-vitamin K Antagonist Oral Anticoagulants
Direct-acting Oral Anticoagulants
Novel oral anticoagulant drugs
Lead sponsor: Herlev and Gentofte Hospital
Sponsor class: OTHER
First posted: 2017-04-26
Enrollment: 5000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Cluster randomized cross-over study
Primary purpose: TREATMENT

Brief summary: No randomized head-to-head comparison between the individual Non-vitamin K Antagonist Oral Anticoagulants (NOAC) exists. The DANNOAC-VTE study is a nationwide cluster randomized cross-over study comparing efficacy and safety of the four NOACs, edoxaban, apixaban, rivaroxaban and dabigatran for oral anticoagulation in venous thromboembolism across Danish hospitals.

Detailed description: No randomized head-to-head comparison between the individual Non-vitamin K Antagonist Oral Anticoagulants (NOAC) exists, but such data are warranted to evaluate if the four NOACs are equal in treatment of venous thromboembolism (VTE) without an additional cost of increased bleeding risk. Furthermore, classic randomized trials are highly selective, as elderly and/or fragile patients and patients with comorbidity are underrepresented. Therefore, there is a need of randomized trials that include a broader population of patients.

The DANNOAC-VTE study is a nationwide cluster randomized cross-over study comparing efficacy and safety of the four NOACs, edoxaban, apixaban, rivaroxaban and dabigatran for oral anticoagulation in VTE across Danish hospitals. The aim of the present study is to: 1) examine if the four NOACs are equally effective in treatment of VTE without increasing the risk of major bleeding requiring hospitalization; 2) conduct a randomized study that includes elderly and fragile patients and patients with comorbidity that would otherwise not be included in a traditional randomized clinical trial.

For a variety of reasons, Danish hospitals and clinicians often prefer one particular NOAC. This can make work simpler for the busy clinician, although there may also be economic advantages on a local or a regional larger scale. For a period of two years, this study will replace this individually or hospital preferred selection with a random selection. The hospitals and clinics that participate in this study will be randomly selected to primarily use one specific NOAC for 6 months at a time during a total period of two years. This only applies to patients with VTE that are selected by the physician to be eligible for NOAC treatment. VTE refers to deep vein thrombosis and pulmonary embolism, or a combination of both.

Endpoints

* Primary efficacy outcome: a composite endpoint of new venous thromboembolism or all-cause death.
* Secondary efficacy outcomes: Individually components of the primary endpoints; new venous thromboembolism or all-cause death.
* Primary safety outcome: bleeding requiring hospitalization.
* Other effect measures:

  1. discontinuation of therapy.
  2. adherence to therapy.
  3. other reasons of admission to hospital than included in the primary and secondary endpoint.
* Sensitivity analyses:

  1. primary endpoint stratified by gender.
  2. primary endpoint stratified by age (≤65, 65-75, \>75 years of age).
  3. primary endpoint stratified by levels of the CHA2DS2VASc score (0-1, 2-3, \>3).
  4. primary endpoint with exclusion of clusters with non-compliance greater than 20% of cluster randomization.
  5. primary endpoint where the actual treatment is used instead of the allocated treatment.
  6. primary safety endpoint stratified by HAS-BLED score.

Information of endpoints and comorbidity is obtained from the Danish National Patient Register based on ICD-10 diagnostic codes and information of vital status and date of death will be obtained from the Central Person Register. Drug discontinuation and adherence will be examined using information from the Danish Registry of Medicinal Product Statistics. The prespecified endpoints will be evaluated after 6 months as intention-to-treat analysis. In addition, the prespecified endpoints will be evaluated after 12 months and 5 years.

A cluster is defined as a hospital or a cardiology clinic. The Clusters will be enrolled in the study from 1. of April 2023 to 1. October 2023.

Eligibility criteria: Inclusion Criteria:

* A diagnosis of VTE in outpatient clinic or as discharge diagnosis after hospitalization.
* A claimed prescription of a NOAC from a Danish pharmacy within 14 days of discharge or outpatient clinic visit.

Exclusion Criteria:

* A prescription of a NOAC within 90 days prior to hospitalization or outpatient clinic visit for VTE.
* Patients with NOAC preference apart from preference consistent with current cluster randomized NOAC.
* Other contraindications mentioned in the "Summary of Product Characteristics" for the respective NOAC.

Primary outcomes:
measure: Primary efficacy outcome: a composite endpoint of new venous thromboembolism or all-cause death.
timeFrame: 6 months.
Secondary outcomes:
measure: Secondary efficacy outcome: New venous thromboembolism.
timeFrame: 6 months.
measure: Secondary efficacy outcome: All-cause death.
timeFrame: 6 months.
measure: Primary safety outcome: bleeding requiring hospitalization.
timeFrame: 6 months.
Other outcomes:
measure: Discontinuation of therapy.
timeFrame: 6 months.
measure: Adherence to therapy.
timeFrame: 6 months.
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen NV
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen S
country: Denmark
facility: Amager Hospital
city: Copenhagen Ø
country: Denmark
facility: Rigshospitalet
city: Copenhagen
country: Denmark
facility: Bispebjerg and Frederiksberg Hospital
city: Esbjerg
country: Denmark
facility: Esbjerg Hospital
city: Frederikssund
country: Denmark
facility: Nordsjællands Hospital - Frederiksund
city: Gentofte
country: Denmark
facility: Herlev Gentofte Hospital
city: Glostrup
country: Denmark
facility: Glostrup Hospital - Department of Emergency Medicine
city: Glostrup
country: Denmark
facility: Glostrup Hospital - Department of Medicine / Cardiology
city: Glostrup
country: Denmark
facility: Glostrup Hospital - Department of Neurology
city: Herlev
country: Denmark
facility: Herlev-Gentofte Hospital - Department of Medicine
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital - Hillerød
city: Hjørring
country: Denmark
facility: Hjørring Hospital
city: Holbæk
country: Denmark
facility: Holbæk Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Næstved
country: Denmark
facility: Næstved Hospital
city: Odense
country: Denmark
facility: Odense University Hospital - Department of Cardiology
city: Odense
country: Denmark
facility: Odense University Hospital - Department of Emergency Medicine
city: Odense
country: Denmark
facility: Odense University Hospital - Department of Geriatrics
city: Roskilde
country: Denmark
facility: Zealand University Hospital - Department of Neurology
city: Roskilde
country: Denmark
facility: Zealand University Hospital Roskilde - Department of Cardiology
city: Rønne
country: Denmark
facility: Bornhoms Hospital
city: Slagelse
country: Denmark
facility: Slagelse Hospital
city: Svendborg
country: Denmark
facility: Odense University Hospital Svendborg
city: Vejle
country: Denmark
facility: Vejle Hospital
Study officials:
affiliation: Herlev Gentofte Hospital
name: Gunnar H Gislason, MD, PhD
role: STUDY_CHAIR
References: