The Danish Non-vitamin K Antagonist Oral Anticoagulation Study in Patients With Atrial Fibrillation

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 stroke prevention 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-AF 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 non-valvular atrial fibrillation and atrial flutter across Danish hospitals and cardiology clinics. The aim of the present study is to: 1) examine if the four NOACs are equally effective in preventing strokes, death and hospitalizations 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 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 non-valvular atrial fibrillation or atrial flutter that are selected by the physician to be eligible for NOAC treatment.

Endpoints

* Primary efficacy outcome: a composite endpoint of stroke, myocardial infarction, thromboembolic event or all-cause death.
* Secondary efficacy outcomes: Individually components of the primary endpoints; stroke, myocardial infarction, 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 2 years as intention-to-treat analysis. In addition, the prespecified endpoints will be evaluated after 5 and 10 years.

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

• Dabigatran Etexilate Oral Capsule (Drug): After cluster randomization, the cluster will use dabigatran to all their patients with non-valvular atrial fibrillation when possible for six months. Hereafter the cluster will use the other three NOACs for six months one at the time. It is the clusters and not the patient that are randomized.
• Rivaroxaban Oral Tablet (Drug): After cluster randomization, the cluster will use rivaroxaban to all their patients with non-valvular atrial fibrillation when possible for six months. Hereafter the cluster will use the other three NOACs for six months one at the time. It is the clusters and not the patient that are randomized.
• Edoxaban Oral Tablet (Drug): After cluster randomization, the cluster will use edoxaban to all their patients with non-valvular atrial fibrillation when possible for six months. Hereafter the cluster will use the other three NOACs for six months one at the time. It is the clusters and not the patient that are randomized.
• Apixaban Oral Tablet (Drug): After cluster randomization, the cluster will use apixaban to all their patients with non-valvular atrial fibrillation when possible for six months. Hereafter the cluster will use the other three NOACs for six months one at the time. It is the clusters and not the patient that are randomized.

Primary outcomes

• Primary efficacy outcome: A composite endpoint of stroke, myocardial infarction, thromboembolic event or all-cause death. [2 years.]: First occurrence of stroke, myocardial infarction, thromboembolic event or all-cause death. 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.

Secondary outcomes

• Primary safety outcome: bleeding requiring hospitalization. [2 years.]: First occurrence of bleeding requiring hospitalization. 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.
• Secondary efficacy outcome: Stroke [2 years.]: 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.
• Secondary efficacy outcome: Myocardial infarction. [2 years.]: 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.
• Secondary efficacy outcome: Thromboembolic event. [2 years.]: 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.
• Secondary efficacy outcome: All-cause death. [2 years.]: 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. Information of prescribed drug will be obtained using information from the Danish Registry of Medicinal Product Statistics.

Other outcomes

• Discontinuation of therapy [2 years]: Drug discontinuation will be examined using information from the Danish Registry of Medicinal Product Statistics.
• Adherence to therapy. [2 years]: Drug adherence will be examined using information from the Danish Registry of Medicinal Product Statistics.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* A diagnosis of atrial fibrillation or atrial flutter 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 atrial fibrillation or atrial flutter.

• Gunnar H Gislason, MD, PhD, Study chair, Danish Heart Foundation