The BRAKE-AF Study is a phase III, randomised, controlled, multicentric, open-label clinical trial to prove the noninferiority of ivabradine versus digoxin in the treatment of permanent atrial fibrillation. The total duration of the study is 3 years, with 24 months of enrolment, treatment and follow-up.

This is a non-commercial, investigator-driven clinical study funded through a public competitive call by Instituto de Salud Carlos III, Spanish Ministry of Economy (PI17/01272).

The study is coordinated by the main investigator from Hospital Universitario 12 de Octubre in Madrid; the sponsorship is performed by Dr. Adolfo Fontenla (Hospital Universitario 12 de Octubre). Several responsibilities are delegated to the Clinical Research Unit (Hospital 12 de Octubre, Madrid, Spain).

The study was planned according to the Good Clinical Practices. BRAKE-AF Study has been approved by the Ethics Committee and Spanish Health Authorities. All participating patients must give written informed consent before any study procedure occur.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Permanent Atrial Fibrillation (AF) at the time of randomization, with no prospect of cardioversion, antiarrhythmic treatment with group I or III drugs, or pulmonary vein ablation.

3. Symptoms attributable to AF associated with the presence of at least one of the following inadequate Heart rate (HR) control criteria:

   1. HR at rest > 110 bpm (on ECG -electrocardiogram- performed in the 14 days prior to inclusion).
   2. HR at rest between 80 and 110 bpm (on ECG performed in the 14 days prior to inclusion) and at least one of the following criteria:

   i. HR in exercise of moderate intensity > 130 bpm (measured in an ergometry or in a Holter-ECG performed in the 60 days prior to inclusion).

   ii. Average daytime HR > 80 bpm (measured on a Holter-ECG performed in the 60 days prior to inclusion).

4. Be receiving treatment with beta-blockers or non-dihydropyridine calcium channel blockers (verapamil or diltiazem) at the maximum dose recommended or tolerated by the patient.

5. Be able to voluntarily give their informed consent.

6. B|ood test carried out in the 6 months prior to inclusion' including: blood count, thyroid hormones and creatinine, in order to rule out secondary causes of poor HR control. The creatinine figure will be used to calculate the creatinine clearance in order to adjust the dose of patients who are randomized to the Digoxin group.

7. Transthoracic echocardiogram to rule out, eg, severe valvular heart disease, hypertrophic cardiomyopathy. The one performed in the year prior to inclusion in the study will be considered acceptable provided that the patient's clinical situation has been stable in that period of time.

Exclusion Criteria:

1. Previous treatment or patients with a known contraindication to Ivabradine or Digoxin or to any excipient of both drugs.
2. Paroxysmal or intermittent complete atrioventricular (AV) block in patients not carrying a pacemaker.
3. Decompensated heart failure requiring inotropic and I or intravenous diuretics in the week prior to randomization or in New York Heart Association (NYHA) functional class IV or on the cardiac transplant waiting list,
4. Acute pericarditis, acute myocarditis or constrictive pericarditis.
5. Obstructive hypertrophic cardiomyopathy.
6. Valvular disease requiring surgical or percutaneous correction.
7. Medical causes that justify poor control of heart rate: fever' anemia, hyperthyroidism, pheochromocytoma' etc.
8. Severe hypotension (blood pressure <90/50 mmHg).
9. Concomitant treatment with potent cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin) HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
10. Severe renal insufficiency (CrCl <30 ml/Kg/min) or in a hemodialysis program.
11. Severe hepatic insufficiency.
12. Major surgery (including cardiac surgery) in the month prior to randomization.
13. Severe concomitant illness that supposes a llfe expectancy of less than one year.
14. Impossibility of carrying out scheduled visits to the protocol.
15. Woman of childbearing age (under 50 years of age, except for those who present a gynecological report that proves the presence of menopause) and women who are breastfeeding.
16. Participation in a clinical trial in the previous 6 months.
17. Patients with acute myocardial infarction or unstable angina.
18. Patient with a recent stroke.
19. Patients with congenital long QT syndrome or treated with drugs that prolong this interval.