Treatment methods for atrial fibrillation

Abstract

Patients with paroxysmal or persistent atrial fibrillation whose untreated atrial fibrillation exceeds the threshold level are eligible for treatment with a drug that can control the patient's heart rhythm (e.g., budiodarone). Eligible patients are treated with the drug while their heart rate is monitored using a wearable device, and if a given drug dose is deemed ineffective, the dose is adjusted until an effective dose is determined for the patient or the patient is deemed unresponsive to the drug and is discontinued from treatment.

Description

Technical Field

[0001] Disclosed is a method for treating atrial fibrillation (AFib) in patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and determined to potentially benefit from drug therapy.

[0002] Reference to Related Applications This application claims the benefit of U.S. Provisional Application 63 / 525,093, filed Jul. 5, 2023, the entire contents of which are hereby incorporated by reference in their entirety. [[ID=~]]

Background Art

[0003] Atrial fibrillation is a serious medical condition often characterized by an abnormal heart rhythm with a rapid heart rate. There are three basic types of atrial fibrillation: paroxysmal, persistent, and permanent. Paroxysmal atrial fibrillation and persistent atrial fibrillation are characterized by periods of spontaneous atrial fibrillation that occur during sinus rhythm, while permanent atrial fibrillation is characterized by a continuous state of atrial fibrillation and can only be treated indirectly with medications such as anticoagulants.

[0004] Failure to treat paroxysmal atrial fibrillation and persistent atrial fibrillation increases the risk of stroke, heart failure, and death. These increased risks vary depending on the degree of atrial fibrillation in a given patient. The variation in increased risk depends on the degree of atrial fibrillation in a given patient. Untreated patients suffering from paroxysmal or persistent atrial fibrillation experience disease progression over time from paroxysmal atrial fibrillation to persistent atrial fibrillation, or from persistent atrial fibrillation to permanent atrial fibrillation.

[0005] Some patients with paroxysmal or persistent atrial fibrillation have short, transient atrial fibrillation episodes lasting less than one hour each, and / or have a cumulative atrial fibrillation load of less than five hours in any given 24-hour period. Such patients have what is referred to herein as mild atrial fibrillation. These patients have a significantly lower risk of stroke, congestive heart failure, and death than similar patients with longer or more frequent atrial fibrillation episodes. Patients with persistent atrial fibrillation are at the highest risk of stroke, congestive heart failure, and death and typically do not respond to medical intervention.

[0006] Current drug therapies for patients with atrial fibrillation (ATF) aim not to control AFL, but rather to minimize the risk of stroke associated with AFL-related thrombus formation, often through the prescription of anticoagulants. Such anticoagulant use is not a panacea and comes with costs. The rationale for prescribing anticoagulants is that while the risk of harm from anticoagulant use is significant, the risk of harming patients with AFL is lower than if AFL were left untreated. According to a report cited by Market Insider, QuarterWatch's 2016 Annual Report (Institute for Safe Medication Practices.(2016).Quarterwatch:Monitoring FDA MedWatch reports.Annual Report Issue), anticoagulant use accounted for the highest number of adverse events among all prescription and over-the-counter medications in 2016, specifically resulting in 21,996 serious injuries in the United States (including 3,018 reported deaths). Clinical trials have repeatedly shown high rates of injury with anticoagulants, causing bleeding in 8% to 19% of patients treated for one year. A 2016 QuarterWatch report estimated that 6.3% of patients treated with anticoagulants for one year required emergency room visits due to drug side effects, and 3.1% required hospitalization.

[0007] Approximately two-thirds of patients with atrial fibrillation are symptomatic, exhibiting symptoms ranging from mild to debilitating. Physical symptoms include, but are not limited to, general malaise, fatigue during exercise or exertion, faintness, lightheadedness, confusion, tachycardia and / or arrhythmia, palpitations or pounding in the chest, shortness of breath, dizziness, weakness, confusion, sweating, chest pain and / or chest tightness. However, regardless of the severity of any physical symptoms, the corresponding mental anxiety regarding the potential heart problem can be serious and may manifest as psychological symptoms such as anxiety, stress, and / or depression. These psychological symptoms, in turn, can worsen the patient's atrial fibrillation and become a serious health problem in themselves. Therefore, alleviating the symptoms of atrial fibrillation is an important aspect of treating symptomatic patients with atrial fibrillation.

[0008] Studies have shown that the risk of stroke and / or heart failure is independent of whether a patient has symptoms associated with atrial fibrillation, regardless of whether their atrial fibrillation is symptomatic or asymptomatic. See, for example, Flaker, et al., “Asymptomatic Atrial Fibrillation: Demographic Features and Prognostic Information from the Atrial Fibrillation Follow-Up Investigation of Rhythmic Management (AFFIRM) Study,” American Heart Journal, April 2005, pages 657-663 (which is incorporated herein by reference in its entirety). Whether a patient is aware of or unaware of periodic atrial fibrillation episodes does not correlate with differences in the risk of stroke and congestive heart failure. Rather, it suggests that symptomatic patients are more aware of their condition and more likely to seek medical intervention.

[0009] The difficulty with conventional medical interventions for paroxysmal and persistent atrial fibrillation lies in the fact that the sporadic and unpredictable nature of each atrial fibrillation episode makes it difficult for clinicians to accurately assess the severity of a patient's atrial fibrillation and the effectiveness of the medications used to treat it. Unlike conventional pharmacotherapy, which measures drug effectiveness by using standardized tests (e.g., cholesterol tests) that measure specific targets after a certain period of time since the start of treatment, clinicians cannot use electrocardiogram (EKG) information obtained during routine consultations to determine the number of atrial fibrillation episodes a patient has experienced since previous consultations, the duration of each atrial fibrillation episode, or the atrial fibrillation load.

[0010] Therefore, several problems remain in the treatment of patients with paroxysmal and persistent atrial fibrillation using pharmacotherapy. These include the inability of clinicians to assess the severity of a patient's atrial fibrillation necessary to determine whether the patient's atrial fibrillation requires pharmacotherapy, whether a given drug is effective for a given patient, at what dosage the drug is effective for the patient, whether the patient will not respond to or will cease to respond to the drug during pharmacotherapy, and whether the patient should be excluded from pharmacotherapy. [Overview of the project]

[0011] A method for identifying and determining the eligibility of patients for pharmacotherapy with drugs to control heart rhythm is disclosed, and patients identified and eligible are most likely to benefit from such drugs. In the method described herein, patients with mild atrial fibrillation have a very low risk of stroke or heart failure, and treatment is not necessary for such patients because the risks associated with pharmacotherapy may be greater. Similarly, patients with persistent atrial fibrillation are also considered unlikely to benefit from the above pharmacotherapy. Therefore, the method identifies patients with paroxysmal or persistent atrial fibrillation who are eligible for further evaluation to determine whether their atrial fibrillation is beyond a mild level (discussed in more detail below). Upon completion of the evaluation, patients with persistent or mild atrial fibrillation are deemed ineligible for pharmacotherapy, and as a result, a carefully defined subset of patients eligible for pharmacotherapy is provided.

[0012] Patients with atrial fibrillation are evaluated by monitoring their heart rhythm for a sufficient period of time, at least 7 days, or to provide baseline levels of atrial fibrillation without any drug therapy (e.g., baseline levels of symptoms associated with atrial fibrillation, baseline number of atrial fibrillation episodes during the period, and / or baseline atrial fibrillation load during the period). Typically, this evaluation period (hereinafter referred to as the eligibility period) is at least one week, at least two weeks, but longer periods of one month (e.g., four weeks) or more may be considered, during which the patient is monitored. The longer the period, the more accurate a measurement of the patient's atrial fibrillation level may be provided. Patients determined to have mild or persistent atrial fibrillation are not eligible, and the remaining patients are considered eligible or qualified to receive drug therapy.

[0013] In some embodiments, the method includes: a) an eligibility protocol based on heart rhythm data generated by a wearable during an eligibility period for assessing whether a patient is likely to benefit from drug therapy; b) a treatment protocol for determining and maintaining an effective dose of drug for the patient (the treatment protocol uses a wearable to assess the patient's heart rhythm data to evaluate the effectiveness of one or more doses of the drug administered in an iterative process until an effective dose is achieved, or if not achieved, the patient is excluded from treatment); and c) using a wearable to monitor the heart rhythm data of an eligible patient receiving an effective dose of drug, confirming that the administered dose remains effective, or, if not effective, adjusting the amount of drug administered to achieve a new effective dose, or, if still ineffective, determining that the patient is refractory to the treatment and excluding the patient from drug therapy.

[0014] In one embodiment, an eligible patient initiates pharmacotherapy with a first (approved) dose of the drug. The first dose of the drug may be selected by the attending clinician based on the patient's baseline data. In one embodiment, the first dose is the approved minimum dose. In another embodiment, the first dose is any approved dose less than the approved maximum dose. During pharmacotherapy, the patient's heart rhythm and, optionally, symptoms associated with atrial fibrillation are monitored. Heart rhythm monitoring is performed using a wearable device (e.g., one described herein) to assess the effectiveness of pharmacotherapy.

[0015] Once monitoring is initiated, the patient's heart rhythm (and optionally, symptoms associated with atrial fibrillation) is assessed to evaluate whether the drug is effective at that dose. The minimum evaluation period length and minimum temporal resolution must be selected to accurately characterize the patient's level of atrial fibrillation at that dose. The evaluation period length must be sufficient to obtain a stable concentration of the drug in vivo. For example, the evaluation period length may be at least 3 days, at least 1 week, and at least 2 weeks after the initiation of drug therapy. Alternatively, the minimum evaluation period may begin when the drug reaches a steady-state blood concentration (e.g., at least 2-3 days after the initiation of budiodarone therapy) and have lengths such as at least 1 day, at least 3 days, at least 1 week, and at least 2 weeks. Alternatively, the evaluation period may begin when the patient's level of atrial fibrillation reaches a steady state (e.g., substantially unchanged between consecutive evaluation periods). In eligible patients who demonstrate effective results at a given dose, that dose is maintained. Furthermore, in eligible patients who have shown effective results with the prescribed dose, one or more dose adjustments may be made by reducing the dose to identify the lowest effective dose. In eligible patients who have not shown effective results with the first dose (or given dose), one or more dose adjustments will be made by increasing the dose of the drug until the patient shows effective results (for example, by reducing the duration of atrial fibrillation episodes, maximum duration, number of episodes during a given period, atrial fibrillation load, etc., and / or by reducing the risk of stroke and / or congestive heart failure, as disclosed elsewhere in this specification) or until the patient no longer shows effective results even with the approved maximum dose. Such patients are considered unresponsive to the drug and are therefore not eligible for drug therapy and are excluded from drug therapy.

[0016] In some cases, patients who achieve effective results with a given dose may experience and / or be at risk of drug side effects. Based on such side effects and risks, clinicians may decide to adjust the dose by reducing the dose in order to maintain efficacy while reducing side effects and the risk of side effects.

[0017] These methods provide a process for identifying specific, limited patient populations most likely to benefit from pharmacotherapy with drugs that control heart rhythm (e.g., budiodarone). Such patient populations would not be identified by conventional methods. These methods define a subset of patients by excluding patients with persistent atrial fibrillation, thereby excluding approximately 50% of patients with atrial fibrillation. Furthermore, these methods define an even more limited subset of patients by further excluding patients identified as having mild atrial fibrillation (as described herein). Patients with mild atrial fibrillation have a limited risk of stroke and heart failure, and therefore the benefit of pharmacotherapy aimed at reducing such risks by modulating heart rhythm is limited. Patients in this limited subset are deemed suitable to receive pharmacotherapy.

[0018] In another embodiment, eligible patients undergoing drug therapy are evaluated for efficacy at increasing drug doses until a therapeutic outcome is achieved or until the patient is deemed unresponsive and excluded from treatment. This approach centers on continuous monitoring of the patient's heart rhythm (and optionally, symptoms associated with atrial fibrillation) to assess whether and when the patient responds to the drug. Monitoring is performed on a time scale and with sufficient resolution to accurately assess the level of atrial fibrillation in eligible patients during treatment. Patients who achieve effective outcomes from a given drug dose represent a specific patient subgroup that responds to drug therapy. For responding patients, monitoring continues throughout treatment to ensure that the given drug dose determined to be effective remains effective. If, at any point, the drug dose is determined to no longer be effective for the patient, a dose adjustment is made. For eligible patients undergoing drug therapy, dose adjustments are made with continuous monitoring until the patient becomes unresponsive and is excluded from treatment.

[0019] The methods described herein offer a new paradigm in the treatment of atrial fibrillation in subclasses of patients, addressing the fundamentally sporadic and unpredictable characteristics of atrial fibrillation. Patients who will benefit from drug therapy are identified, and those who will not benefit are excluded. Furthermore, patients who initially showed efficacy with the drug but subsequently became refractory to it can be identified and subsequently excluded from treatment. Thus, unlike current atrial fibrillation therapies where measuring the effect of a drug is difficult or impossible, the methods defined herein continuously confirm efficacy in a specially defined subgroup of atrial fibrillation patients by excluding patients who are unlikely to benefit from drug therapy before treatment while being monitored, and then excluding patients who do not respond while being monitored during drug therapy.

[0020] A key advantage achieved by the methods described herein is that, by using these methods as a first course of treatment for eligible patients, it becomes possible to treat atrial fibrillation by subjecting only patients who have been excluded from drug therapy (e.g., before or after the initiation of drug therapy) when their atrial fibrillation is severe enough to require ablation, to electrophysiological intervention (ablation). By targeting treatment to patients most likely to benefit from drug therapy, and by dynamically defining the eligible patient population even after the initiation of treatment, the unnecessary use of very expensive and invasive ablation procedures for patients who would respond to significantly less expensive and less invasive drug therapy is avoided.

[0021] In one embodiment, the pharmacotherapy comprises the administration of budiodarone, the IUPAC title of ([(2S)-butan-2-yl]2-[3-[4-[2-(diethylamino)ethoxy]-3,5-diiodobenzoyl]-1-benzofuran-2-yl]acetate), or a pharmaceutically acceptable salt thereof. Budiodarone is a compound that has been shown to be useful in reducing the risk of stroke in patients with paroxysmal and / or persistent atrial fibrillation, including patients with atrial fibrillation that is refractory to other therapies. See, for example, U.S. Patent No. 9,549,912, which is incorporated herein by reference in its entirety.

[0022] In one embodiment, the patient eligibility period described herein provides clinicians with a baseline assessment of the degree of both prolonged atrial fibrillation episodes (more than approximately 5 hours or more than approximately 5.5 hours) and / or atrial fibrillation overload (more than 5 hours) during a given 24-hour period. In patients administered budiodarone at a given dose, a valid result is determined if the patient exhibits one or more of the following, compared to corresponding baseline assessment data during a comparison period beginning from the start of budiodarone administration at that dose: a) A reduction in the number of atrial fibrillation episodes lasting more than approximately 5 hours or more than approximately 5.5 hours, wherein such atrial fibrillation episodes are reduced by at least 30% during the comparison period, or b) Maximum atrial fibrillation load in any 24-hour segment is reduced by at least 30% during the comparison period, or c) Symptoms are reduced during the comparison period, in which case the patient is a symptomatic patient whose symptoms are related to atrial fibrillation.

[0023] In one embodiment, symptomatic and eligible patients with atrial fibrillation are at risk of anxiety, stress, and / or depression due to their diagnosis and / or symptoms. Effective results may also include a reduction in the overall level of symptoms experienced by the patient. The reduction in the patient's symptoms and / or overall symptoms can be evaluated, for example, using the procedure of Example 9.

[0024] The comparison period described above is designed to provide a time limit for determining the effectiveness of drug therapy, and in the absence of such a limit, it may be interpreted as being indefinitely long, spanning several years or decades. Therefore, for the purposes of this specification, the comparison period is a certain period after the commencement of monitoring for the effectiveness described above, during which heart rhythm data obtained from the patient (e.g., via a wearable attached to and / or used by the patient) is analyzed and compared to the patient's previous heart rhythm data and / or atrial fibrillation data (e.g., baseline data obtained during the eligibility period and / or data obtained during previous comparison periods). In one embodiment, the comparison period is at least the length of the eligibility period described herein, or based on different periods such as daily, weekly, and at least about two weeks (e.g., 13, 14, or 15 days) or twice, three, or four times that length (i.e., at least about four weeks, at least about six weeks, or at least about eight weeks). For example, the comparison period may be at least longer than the point at which drug levels have substantially stabilized in the patient (e.g., at least 2-3 days, 7 days, or 14 days in patients administered budiodarone), or it may be shorter (e.g., continuous or one day or more) if the comparison period begins after drug levels have substantially stabilized in the patient (e.g., on day 2 or 3 after the start of budiodarone administration at a given dose).

[0025] Given that atrial fibrillation is a progressive disease even when effective drug therapy is used, it is not possible to distinguish between disease progression and drug effectiveness (similar to cancer chemotherapy), and therefore, comparison periods longer than 6 months do not necessarily indicate drug effectiveness. Accordingly, comparison periods in some embodiments are daily, weekly, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, and up to 24 weeks (24 weeks or less). Once the first comparison period is completed, the effectiveness of the drug can be confirmed. Subsequent comparison periods are then used to a) confirm that the drug dose remains effective in patients who respond, or b) confirm the effectiveness of a higher dose in patients who do not respond to the currently used dose. If a patient does not respond to the drug used at the maximum approved dose during the comparison period, the patient is excluded from treatment with that drug. In such cases, the patient may be subjected to electrophysiology (e.g., ablation) for treatment.

[0026] There is medical data indicating that in patients without atrial fibrillation episodes exceeding 5.5 hours, a significant reduction in stroke risk is achieved. For example, see Capucci (Capucci, A., et al. (2005). “Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with anti-tachycardia pacemakers.” Journal of the American College of Cardiology, 46(10), 1913-1920) and the TRENDS study (Glotzer, et al. (2009). The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circulation: Arrhythmia and Electrophysiology, 2(5), 474-480) (the entire contents of which are incorporated herein by reference). In one embodiment, the bupropion therapy is based on an approved dosage that reduces such long episodes by at least 50%, more preferably at least 80%, and even more preferably eliminates such long episodes during the comparison period. In another embodiment, the bupropion therapy is based on an approved dosage that reduces long atrial fibrillation episodes lasting more than 1 hour by at least 50%, preferably at least 80%, and even more preferably eliminates such long episodes during the comparison period. In any case, the ability to limit atrial fibrillation episodes during a comparison period exceeding 5.5 hours or more than 1 hour reduces the patient's stroke risk, and by the disappearance of such episodes during the comparison period, the patient transitions to a state recognized as a “safer state,” or more appropriately, a “safer state.”

[0027] Thus, in one embodiment, a method of treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bupropion, comprising: a) administering to the eligible patient a first dose of bupropion while monitoring using a wearable to collect the patient's heart rhythm data, the first dose being an approved therapeutic dose that is less than the approved maximum dose of bupropion; b) monitoring the eligible patient for the effectiveness of the first administered dose of bupropion during a comparison period of one or more days to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of bupropion is delayed for at least 7 days or 14 days after the start of treatment; c) if the first dose is evaluated as not effective for the patient by the end of the comparison period, making one or more dose adjustments of the amount of bupropion necessary to achieve an effective result using at least the same delay period and comparison period as in b), provided that the adjusted dose is below the approved maximum dose, or excluding the patient from bupropion therapy if an effective result is not achieved when evaluated at the approved maximum dose; d) continuously monitoring the patient's heart rhythm to confirm that the administered dose of bupropion continues to be effective if the first dose or the adjusted dose is effective for the patient, provided that if the administered dose is no longer effective, repeating step c) using the administered dose as the first dose. A method is provided that includes the above.

[0028] In one embodiment, the patient is eligible to receive treatment with budiodarone based on having at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not receiving budiodarone therapy. Furthermore, or alternatively, the patient is eligible to receive treatment with budiodarone based on having a baseline level of atrial fibrillation load of at least 5 hours during at least 7 or 14 days in which the patient is not receiving budiodarone therapy.

[0029] In one embodiment, the presence of prolonged episodes of atrial fibrillation is assessed while continuous monitoring is performed during administration of budiodarone at each evaluated dose, and the patient is notified if such episodes occur.

[0030] In one embodiment, the comparison period may be daily, weekly, bi-weekly, 1 month, 2 months, 3 months, 4 months, 5 months, or up to 6 months, with continuous monitoring. In another embodiment, the evaluation period may extend to 4, 6, 8, 12 weeks, or longer, to better characterize the patient having persistent atrial fibrillation.

[0031] In one embodiment, episodes of atrial fibrillation lasting at least about 5 hours or more than 5.5 hours are tracked (e.g., counted, recorded, and used to determine the effectiveness of administered medications, and used to alert the patient and / or clinician if such episodes occur a given number of times or at a given frequency, indicating that the patient is at risk of stroke and / or congestive heart failure). In another embodiment, episodes of atrial fibrillation lasting at least about 5.5 hours are tracked.

[0032] In one embodiment, symptoms associated with atrial fibrillation are assessed by the patient and reported (e.g., using a scorecard or equivalent) indicating the number and / or severity of the patient's symptoms daily or at the time of symptom occurrence.

[0033] In one embodiment, if an atrial fibrillation episode lasting at least approximately 5 hours or at least approximately 5.5 hours is detected during the eligibility period, comparison period, or any subsequent patient monitoring to evaluate the effectiveness of a given dose, an alert or alarm is sent to the patient (e.g., via a wearable that monitors the patient's heart rate rhythm data to be analyzed to evaluate the atrial fibrillation episode, or via a computing device connected to the wearable), the clinician evaluating the patient's atrial fibrillation (e.g., via a computing device accessible to the clinician and / or via a computing device that receives heart rate rhythm data from the patient's wearable), and / or a central analysis center that receives data from the patient's wearable.

[0034] The use of alerts is optional and is provided immediately after detection of a prolonged atrial fibrillation episode to notify clinicians and / or patients of the event. Comparison periods are independent of alerts and provide data that allows clinicians to compare the effectiveness of a drug over a certain period to baseline. In one embodiment, comparison periods are distinguished from immediate notification (alarm) to the patient and / or attending clinician of a prolonged atrial fibrillation episode that may require immediate attention. Comparison periods are intended to evaluate the effectiveness of a drug (e.g., budiodarone) compared to baseline, while immediate notification is intended to warn the patient that a visit to a medical institution may be necessary.

[0035] In one embodiment, a method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive treatment with budiodarone, A patient who is eligible to receive treatment with budiodarone, wherein eligibility requires that the patient has experienced at least one episode of prolonged atrial fibrillation lasting at least one hour during the eligibility assessment period, or has at least 2.5% atrial fibrillation load during the entire eligibility assessment period, the eligibility assessment period being at least two weeks during which the patient is not treated with the drug, a) Administering a first dose of the drug to an eligible patient while monitoring the patient using a wearable device to collect heart rhythm data of the eligible patient, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug; b) Monitoring the patient for the effectiveness of the first dose of the drug administered for a comparison period of one day or more in order to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least 7 or 14 days after the start of treatment, c) If the first dose administered is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay period and comparison period as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. A method is provided that includes this.

[0036] In one embodiment, a method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who is eligible to receive pharmacotherapy using a drug that suppresses atrial fibrillation episodes and / or shortens the duration of atrial fibrillation episodes, A patient who is eligible to receive treatment with the aforementioned drug, wherein eligibility requires that the patient has experienced at least one prolonged episode of atrial fibrillation lasting at least one hour during the eligibility assessment period, or has at least 2.5% atrial fibrillation load during the entire eligibility assessment period, the eligibility assessment period being at least two weeks during which the patient is not treated with the aforementioned drug, in the case of such a patient, a) Administering a first dose of the drug to an eligible patient while monitoring to collect heart rhythm data of the eligible patient using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug; b) Monitoring the patient for the effectiveness of the first dose of the drug administered for a comparison period of one day or more in order to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least 7 or 14 days after the start of treatment, c) If the first dose administered is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay period and comparison period as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results were not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose, and the monitoring A method is provided that includes this.

[0037] In one embodiment, a method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive drug therapy with pharmaceuticals, a) Administering a first dose of the drug to an eligible patient while monitoring the patient using a wearable device to collect heart rhythm data of the eligible patient, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug; b) Monitoring the patient for the effectiveness of the first dose of the drug administered for a comparison period of one day or more in order to evaluate whether the dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least 7 or 14 days after the start of treatment with the drug. c) If the first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay and comparison period as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm to ensure that the dose of budiodarone remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose, and continue monitoring. A method is provided that includes this.

[0038] In one embodiment, the patient is eligible to receive pharmacotherapy with the drug based on having at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not administered the drug. In another embodiment, the patient is eligible to receive pharmacotherapy with the drug based on having a baseline level of atrial fibrillation load of at least 5 hours during at least 7 or 14 days in which the patient is not administered the drug.

[0039] In one embodiment, a method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive treatment with budiodarone to suppress atrial fibrillation episodes and / or the duration of atrial fibrillation episodes, A patient who is eligible to receive treatment with budiodarone, wherein eligibility requires that the patient has experienced at least one episode of prolonged atrial fibrillation lasting at least one hour, or has at least 2.5% atrial fibrillation load during the entire eligibility assessment period, the eligibility assessment period being at least two weeks during which the patient is not treated with budiodarone, a) Administering a first dose of the drug to an eligible patient while monitoring the patient using a wearable device to collect heart rhythm data of the eligible patient, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose. b) In order to evaluate whether the dose is effective for each of the patients, monitor the patients for the effectiveness of budiodarone administered at the first therapeutic dose during the evaluation period using a wearable device, c) For patients who did not achieve effective results with the previous budiodarone dose at the end of the evaluation period, the dose adjustment shall be made to the amount of budiodarone necessary to achieve effective results using at least the length of the evaluation period, provided that the dose adjustment is less than or equal to the approved maximum dose, or, if effective results were not achieved when evaluated at the approved maximum dose, the patient shall be excluded from budiodarone therapy. d) For patients who have achieved effective results, continue monitoring the patient's heart rhythm to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat the protocol in c) as necessary. A method is provided that includes this.

[0040] In one embodiment of the above method, the eligibility assessment period and the evaluation period are at least about 7 days, at least about 14 days, or at least about 28 days.

[0041] In one embodiment, in the case of the method described herein, at least one prolonged episode of atrial fibrillation is at least about 5.5 hours, at least about 5 hours, at least about 1 hour, or at least about 30 minutes.

[0042] In one embodiment, in the case of the method described herein, at least one prolonged atrial fibrillation episode lasts at least about 5 hours within a 24-hour period.

[0043] In one embodiment, in the case of the method described herein, monitoring of the patient during budiodarone treatment is continued throughout the treatment.

[0044] In one embodiment, the patient's monitoring of the drug is performed periodically, however, the periodic monitoring is performed throughout the entire period.

[0045] The methods described herein may be used to reduce the risk of stroke in patients with paroxysmal or persistent atrial fibrillation, and these methods utilize a pharmaceutical product comprising budiodarone that suppresses atrial fibrillation episodes and / or the duration of atrial fibrillation episodes in the manner described herein. Patients with paroxysmal or persistent atrial fibrillation at risk of stroke include, in particular, patients with a high risk of stroke, such as those with a history of stroke, diabetes, hypertension, and those over 75 or 80 years of age.

[0046] The methods described herein may be used to reduce the risk of congestive heart failure in patients with paroxysmal or persistent atrial fibrillation, in which a drug comprising budiodarone is used to suppress atrial fibrillation episodes and / or the duration of atrial fibrillation episodes in the manner described herein. Patients with paroxysmal or persistent atrial fibrillation at risk of congestive heart failure include, in particular, patients at high risk of congestive heart failure, such as patients with diabetes, hypertension, and valvular heart disease.

[0047] Patients at high risk of stroke and / or congestive heart failure may be treated according to the methods described herein, even if such patients are classified as having mild atrial fibrillation and / or are not eligible before treatment, or are eligible if their atrial fibrillation baseline level is lower than that used for determining eligibility in lower-risk patients. For example, patients with a relatively low risk of stroke and congestive heart failure (e.g., who may be eligible for budiodarone therapy).

[0048] In one embodiment, a method for treating patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and at high risk of stroke and / or congestive heart failure is: (a) Monitoring the patient’s heart rate rhythm data, the heart rate rhythm data may be collected over a long period of time using a wearable device, (b) administering budiodarone (or other drug) to the patient in a first dose, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of budiodarone (or other drug), (c) Monitoring the patient for the effectiveness of the first dose of budiodarone (or other drug) administered during a comparison period of one day or more, in order to evaluate whether the dose is effective for the patient, the evaluation of the effectiveness of budiodarone (or other drug) is delayed for at least seven or fourteen days after the start of treatment, which may include such monitoring. The first dose may be the minimum approved dose. The dose may be evaluated as effective for the patient if, during the comparison period, it eliminates or reduces the number of atrial fibrillation episodes, for example, for at least about one hour or at least about 0.5 hours, or significantly reduces the patient's risk of stroke or congestive heart failure. For patients in whom a favorable outcome was not achieved with the first dose of budiodarone (or another drug) by the end of the comparison period, the method further includes step (d) dose adjustment to the amount of budiodarone (or another drug) necessary to achieve a favorable outcome using the same delay period and comparison period or longer, provided that the dose adjustment is no more than or equal to the approved maximum dose. A favorable outcome may be determined as described herein. If, at any point, a favorable outcome was not achieved when evaluated at the approved maximum dose, the method may further include step (e) excluding the patient from budiodarone (or another drug) treatment. For patients in whom a favorable outcome was achieved, the method may further include step (f) continuing to monitor the patient's heart rhythm to confirm that the dose of budiodarone (or another drug) remains favorable. If the dose is no longer favorable to the patient, step (d) dose adjustment, or if a favorable outcome was not achieved, step (e) excluding the patient from budiodarone (or another drug) treatment, is repeated. This method may be performed on patients with any level of paroxysmal or persistent atrial fibrillation, provided that such patients are at high risk of stroke and / or congestive heart failure. In one embodiment, the patient is eligible to receive the budiodarone treatment described herein.

[0049] In one embodiment, a patient having paroxysmal or persistent atrial fibrillation and at high risk of stroke and / or congestive heart disease may be treated with pharmacotherapy according to the method described herein. Budiodarone or other drugs that can reduce the number and / or duration of atrial fibrillation episodes may be administered in combination with an anticoagulant (e.g., an anticoagulant). For example, the attending clinician may further administer an anticoagulant in combination with budiodarone to reduce the patient's risk of stroke or heart failure. In one embodiment, a method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and at high risk of stroke and / or congestive heart failure may include: (a) monitoring the patient’s heart rhythm data, which may be collected over a long period of time using a wearable; (b) administering both an anticoagulant and budiodarone to the patient, wherein budiodarone is administered in a first dose, the first dose being an approved therapeutic dose less than the approved maximum dose of budiodarone; and (c) monitoring the patient for the effectiveness of the administered first dose of budiodarone for a comparison period of one day or more to evaluate whether the dose is effective for the patient, provided that the evaluation of the effectiveness of budiodarone is delayed for at least seven or fourteen days after the start of treatment. The first dose of budiodarone may be the approved minimum dose. For patients who did not achieve a favorable outcome with the first dose of budiodarone administered by the end of the comparison period, the method further includes (d) making one or more dose adjustments of the amount of budiodarone required to achieve a favorable outcome using the same delay period and comparison period or longer, to evaluate efficacy, provided that the dose adjustment is less than or equal to the approved maximum dose. A favorable outcome may be determined as described herein. If, at any point, a favorable outcome was not achieved when evaluated at the approved maximum dose, the method further includes (e) excluding the patient from budiodarone therapy. For patients who achieved a favorable outcome, the method further includes (f) continuously monitoring the patient's heart rhythm to confirm that the dose of budiodarone remains effective. The step of adjusting the dose (d) if the dose is no longer effective, or the step of excluding the patient from treatment (e) if a favorable outcome was not achieved, is repeated. This method may be performed on patients with any level of paroxysmal or persistent atrial fibrillation, provided that such patients are at high risk of stroke and / or congestive heart failure. In one embodiment, the patient is eligible to receive the budiodarone therapy described herein. [Brief explanation of the drawing]

[0050] [Figure 1] Figure 1 shows a chart illustrating how patient atrial fibrillation data is used in combination with budiodarone treatment.

[0051] [Figure 2] Figure 2 shows the electrocardiogram of a patient with intermittent atrial fibrillation. [Modes for carrying out the invention]

[0052] This disclosure relates to a method for monitoring the heart rhythm of patients diagnosed with atrial fibrillation (AFib) using a wearable device. Such monitoring enables therapeutic interventions that can be combined with the ability to adjust the dosage of medications used to obtain therapeutic endpoints. The following terms are defined below. Any terms not defined will be defined in context or by a medically acceptable definition.

[0053] The terms used herein are intended solely to describe specific embodiments and are not intended to limit them. Where used herein, the singular forms "a," "an," and "the" are intended to include the plural form unless otherwise specified by the context.

[0054] definition As used herein, the terms “optional” or “by option” mean that the events or circumstances described thereafter may or may not occur, and that such descriptions include both cases in which the events or circumstances occur and cases in which they do not occur.

[0055] As used herein, the term “approximately” when used before a numerical specification, such as temperature, time, quantity, concentration, and other terms including ranges, indicates an approximate value that may vary by (+) or (-) 15%, 10%, 5%, 1%, or any lower range and / or value between them. Preferably, when the term “approximately” is used in relation to a dose, it means that the dose may vary by + / - 10%.

[0056] As used herein, the terms “comprising” or “comprises” are intended to mean that the composition or method described includes the elements described, but does not exclude other elements.

[0057] As used herein, the term “essentially derived from” means, when used to define compositions and methods, to exclude any other elements that are essentially important to the purpose of the combination described herein. Thus, a composition essentially derived from the elements defined herein, or a method essentially derived from the protocols defined herein, does not exclude any other components that do not substantially affect the basic and novel features of the subject matter described in the claims.

[0058] As used herein, the term "consisting of" means excluding elements or substantial method steps that are in trace amounts of other components. Embodiments defined by each of these transitional clauses are within the scope of this disclosure.

[0059] As used herein, the terms “AFib” or “atrial fibrillation” refer to all variations of atrial fibrillation except persistent atrial fibrillation. Such variations include, but are not limited to, paroxysmal atrial fibrillation, persistent atrial fibrillation, and paroxysmal and persistent atrial fibrillation with low (≤2) and high (≥3) CHA2DS2-VASc scores. The CHA2DS2-VASc score represents congestive heart failure (C-1 point), hypertension (H-1 point), age 75 years or older (A-2 points), diabetes (D-1 point), stroke (S-2 points), vascular disease (V-1 point), age 65–74 years (A-1 point), and gender category (Sc-1 point for women), and is a clinical predictive rule for estimating the stroke risk in patients with non-rheumatic atrial fibrillation (AF). As shown above, the CHA2DS2-VASc score consists of 1 or 2 points for each constituent risk factor.

[0060] As used herein, the term “long-lasting atrial fibrillation” refers to the duration of an atrial fibrillation episode in a patient. This duration is related to the risk of stroke or heart failure. Obviously, the longer the duration of atrial fibrillation in a patient, the higher the risk. Therefore, in one embodiment, long-lasting atrial fibrillation is any atrial fibrillation episode that lasts for at least about 1 hour, provided that the atrial fibrillation is not permanent. On the other hand, long-lasting atrial fibrillation is further classified into two subsets: “medium-to-long-term” atrial fibrillation, which has a duration of at least about 24 hours or less (i.e., at least about 1 hour and up to 24 hours), and “long-lasting” atrial fibrillation, which includes atrial fibrillation episodes lasting longer than 24 hours but are not permanent atrial fibrillation.

[0061] As used herein, the term “mild atrial fibrillation” refers to atrial fibrillation in a patient with paroxysmal or persistent atrial fibrillation, where each episode lasts less than approximately 5.5 hours, less than approximately 5 hours, or less than approximately 1 hour, and / or the maximum atrial fibrillation load in any 24-hour period is less than approximately 5 hours. In a preferred embodiment, a patient with mild atrial fibrillation has sporadic atrial fibrillation episodes, each episode lasting less than approximately 1 hour, and / or the maximum atrial fibrillation load in any 24-hour monitoring period is less than approximately 3 hours. In another embodiment, the maximum atrial fibrillation load is less than approximately 2.5% of the total time in any two-week patient monitoring period.

[0062] As used herein, the term “paroxysmal atrial fibrillation” refers to sporadic and intermittent episodes of atrial fibrillation that last for seven days or less before returning to sinus rhythm. Typically, patients with mild atrial fibrillation may also be characterized as having paroxysmal atrial fibrillation, but this is not always the case.

[0063] As used herein, the term “persistent atrial fibrillation” refers to sporadic and intermittent episodes of atrial fibrillation that last for more than seven days and cannot return to sinus rhythm without medical intervention (e.g., electrical cardioversion).

[0064] As used herein, the term “persistent atrial fibrillation” refers to atrial fibrillation that persists consistently for a long period of time without clear return to sinus rhythm despite medical intervention (e.g., electrical cardioversion). Persistent atrial fibrillation is typically managed rather than treated.

[0065] As used herein, the term “moderate atrial fibrillation” refers to paroxysmal and persistent atrial fibrillation that is not characterized as mild atrial fibrillation.

[0066] As used herein, the term “approved dose” refers to the dose of the drug (i.e., budiodarone) that a regulatory body, such as the U.S. Food and Drug Administration, has determined to be suitable for commercial or clinical use.

[0067] As used herein, the terms “continuous” or “continuously” mean that monitoring is performed at all times while the patient is wearing the wearable. The terms “continuous” or “continuously” also include wearables that continuously monitor heart rhythm when worn and powered on, but can be removed for limited periods of time (e.g., for battery replacement, charging the wearable monitoring device, bathing, etc.).

[0068] As used herein, the terms “semi-continuous” or “semi-continuous” refer to monitoring performed automatically and periodically by the wearable at a set schedule (e.g., every 15 seconds, every 30 seconds, every minute, etc.) without the patient activating the wearable. The set schedule may be designed to monitor the heart rhythm with sufficient temporal resolution to detect atrial fibrillation episodes and / or to determine the length of long-lasting atrial fibrillation episodes.

[0069] As used herein, the term “wearable” means that the monitor is worn and / or attached to the patient on an ongoing basis, or that the patient can put on, take off, and begin monitoring the wearable without requiring assistance from a healthcare professional. Therefore, wearable wearables include devices worn on the skin and / or implanted under the patient’s skin.

[0070] As used herein, the term “monitoring heart rhythm” means any assessment that can be made of a patient’s heart rhythm, including, but not limited to, pulse rate, any aspect of the patient’s cardiac electric field, provided that such monitoring can identify when the patient is experiencing atrial fibrillation.

[0071] As used herein, the term “initiate monitoring” includes both automatic and physical initiation of patient monitoring. “Automatic initiation” occurs when the wearable is put on by the patient and monitoring begins automatically without any further action by the patient. “Physical initiation” means that the patient must activate monitoring by physically or verbally interacting with the wearable (e.g., pressing a button, providing a voice command).

[0072] As used herein, the term “transmitting device” means any device capable of transmitting data from a wearable. A transmitting device may be included within the wearable or it may be a separate device communicating with the wearable. This separate device may be a computer, such as a smartphone, tablet, laptop, or desktop.

[0073] As used herein, the term “clinician” refers to a medical professional qualified to determine whether a patient’s heart rhythm data correlates with sinus rhythm, atrial fibrillation, or any other type of arrhythmia.

[0074] As used herein, the term “attending clinician” refers to a healthcare professional treating a patient with atrial fibrillation. Such an attending clinician is typically a physician or a nurse.

[0075] The term "directly" in relation to the transmission of patient heart rate rhythm data refers to transmissions received by the attending clinician for evaluation, regardless of whether the transmission is stored on a cloud site or passes through multiple servers, etc.

[0076] The term “indirectly” in relation to the transmission of patient heart rhythm data refers to transmission to a clinician who evaluates the data and provides the clinician or healthcare provider with the data or conclusions drawn regarding the data. In such cases, the clinician may be a healthcare professional employed by a central analysis center or the clinician, who evaluates the heart rhythm data and provides instructions to the clinician on an ongoing basis or as contact is required due to changes in the patient’s condition. In one embodiment, the clinician is employed by a central analysis center, which is a facility that reviews the data generated by the instrument and provides diagnoses and / or recommendations transmitted to the clinician. The central analysis center has expertise in the instrument, the data it generates, and the ability to analyze that data.

[0077] As used herein, the term “baseline” refers to a patient having atrial fibrillation who is monitored during a pre-treatment period with budiodarone to measure the degree of atrial fibrillation load and the number of medium- to long-term and long-term atrial fibrillation episodes in any 24-hour period. In such cases, measuring the baseline during the pre-treatment period provides the current state of the disease. In most, though not all, cases, the baseline state of the disease is unknown to the attending clinician and is necessary information to determine whether subsequent drug therapy will be effective.

[0078] As used herein, the terms “effective,” “effective results,” or similar phrases mean the treatment of an eligible patient having moderate atrial fibrillation (or a patient in a specific condition, such as a patient who is at high risk of stroke and / or congestive heart failure but is shown to have mild atrial fibrillation), and such patient shows a reduction in any one or any combination of the following as a result of the treatment: • Reduction in the number of long-lasting (including longer-lasting) atrial fibrillation episodes compared to baseline; • Reduction in maximal atrial fibrillation load over a 24-hour period compared to baseline; and / or • In patients with symptomatic atrial fibrillation, relief of associated symptoms.

[0079] In combination with effective outcomes (e.g., as described above), the term “reduction” refers to a desired reduction (e.g., at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%) in the number of long-lasting atrial fibrillation episodes, the degree of atrial fibrillation burden, and / or the degree of atrial fibrillation symptoms compared to the patient’s corresponding baseline data. The desired reduction for effective outcomes in the patient may be selected to reduce the risk of stroke and / or congestive heart failure to a desired level. For example, the aforementioned Capucci and Trends study showed that the stroke risk in patients with atrial fibrillation who had atrial fibrillation episodes lasting 5.5–24 hours was 2.2 times higher than in patients without atrial fibrillation, and the stroke risk in patients with atrial fibrillation who had atrial fibrillation episodes lasting more than 24 hours was 3.1 times higher than in patients without atrial fibrillation. Therefore, the desired reduction may be the elimination of atrial fibrillation episodes lasting more than 24 hours or more than approximately 5.5 hours (e.g., more than 5.5 hours, more than 5 hours, etc.) (100% reduction).

[0080] The reduction may be evaluated after the comparison period described herein. For example, the reduction may be evaluated at least 7 days after the start of drug therapy or at least about 14 days after the start of drug therapy. For example, the reduction can be evaluated over any evaluation period during treatment at a given dose, such as the evaluation period from days 1 to 7 and the evaluation period from days 8 to 14 after the start of drug therapy in the case of a 7-day evaluation monitoring period.

[0081] A patient is said to “respond” to drug therapy (e.g., budiodarone therapy as disclosed herein) if an effective result can currently be demonstrated when the patient is administered an approved dose of budiodarone. In a preferred embodiment, before initiating treatment of the patient using the method described herein, the eligible patient is further evaluated to determine whether the patient is suitable to initiate the treatment. “Suitable patient” means a patient currently being treated with an anticoagulant or a patient determined to be thrombose-free. As used herein, “suitable patient” or “patient” means a patient who has experienced paroxysmal or persistent atrial fibrillation lasting about 6 hours or less, a patient who has experienced paroxysmal or persistent atrial fibrillation but has been determined to be thrombose-free by transesophageal echocardiography or other means of confirming that the patient is thrombose-free, or a patient who is known to have persistent or paroxysmal atrial fibrillation and is taking an anticoagulant.

[0082] In one embodiment, drug therapy eliminates the number of long-lasting atrial fibrillation episodes lasting approximately 5.5 hours or more than approximately 5 hours, and / or the number of long-lasting atrial fibrillation episodes lasting more than approximately 1 hour. In another embodiment, drug therapy reduces the number of patients experiencing long-lasting atrial fibrillation episodes lasting more than approximately 5.5 hours, more than approximately 5 hours, and / or more than approximately 1 hour.

[0083] In one embodiment, when measured at least 7 days after the start of drug therapy, preferably at least about 14 days after the start of drug therapy, drug therapy reduces symptoms associated with atrial fibrillation in symptomatic patients by at least about 15%, preferably at least about 25%, and more preferably at least 40%.

[0084] As used herein, “patients who do not respond” or “patients who do not respond to drug therapy” means patients who are being treated with drug therapy and who do not meet the evidence of effective outcomes as defined above at any approved drug dose. In such cases, patients who do not respond are excluded from drug therapy. Patients who do not respond as assessed by the attending clinician may be subjected to ablation for the treatment of atrial fibrillation.

[0085] In one embodiment, patients eligible for drug therapy are identified as refractory to at least one other treatment for atrial fibrillation, including ablation.

[0086] In one embodiment, patients eligible for drug therapy are limited to those with symptomatic atrial fibrillation.

[0087] As used herein, “other methods for treating atrial fibrillation” may include ablation, administration of one or more anticoagulants and / or other thrombopreventive measures, heart rate control measures, and / or heart rhythm control measures. Examples of such methods for treating atrial fibrillation may include the administration of beta-blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol, propranolol, timolol), calcium channel blockers (e.g., verapamil, diltiazem), anticoagulants (warfarin, coumarin, jantoben, aspirin, apixaban, dabigatran, enoxaparin, heparin, rivaroxaban), sodium channel blockers (e.g., flecainide, propafenone, quinidine), and / or potassium channel blockers (e.g., amiodarone, dofetilide, sotalol).

[0088] If a patient has been treated with one or more prior methods and / or other methods for treating atrial fibrillation (e.g., other methods for treating atrial fibrillation as defined above), and the atrial fibrillation is considered unresponsive, / or inadequately responsive, and / or reduced responsive to one or more methods, the patient may be considered "refractory to one or more prior methods for treating atrial fibrillation" or "refractory to one or more other methods for treating atrial fibrillation." The "one or more prior treatments" may be ongoing and / or discontinued.

[0089] As used herein, the term “smart” refers to the computing power of a device. The computing power of “smart devices” (e.g., smartphones or tablets) as discussed herein enables user interaction (e.g., via a touchscreen) and / or the execution of applications on the smart device.

[0090] As used herein, the term “at least 2.5% atrial fibrillation load” means that, in the absence of treatment as provided herein (e.g., treatment with budiodarone and / or other rhythmic medications to alleviate the severity and / or duration of atrial fibrillation episodes and / or symptoms associated with atrial fibrillation), the patient has atrial fibrillation episodes in which the sum of the durations of each episode during the specified period is at least 2.5% of the total time of the specified period. Thus, for a patient monitored over 20 days (or 480 hours), at least 2.5% atrial fibrillation load means that the total (cumulative) time the patient experiences one or more atrial fibrillation episodes is at least 12 hours (2.5% of 480 hours). This atrial fibrillation load may be independent of the number of long-lasting atrial fibrillation episodes (if any). Thus, one or more atrial fibrillation episodes lasting a total of at least 12 hours may be a single episode or a number of episodes, each lasting less than one hour.

[0091] As used herein, the term "budiodarone" refers to (S)-sec-butyl 2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl) acetate and its pharmaceutically acceptable salts. Budiodarone, as a free base, is of the following formula: [ka] It is represented as follows. The term “budiodarone” encompasses all approved pharmaceutically acceptable salts of the free base. Acceptable salts of budiodarone include budiodarone tartrate or budiodarone citrate. In one embodiment, the pharmaceutically acceptable salt may be a polycarboxylate. As is recognized in the art, the salt dissociates from the free base in vivo. Therefore, when calculating serum blood levels of budiodarone, the molecular weight of the free base is used to determine the molar concentration. Furthermore, when administering salts other than tartrate, the dose of budiodarone tartrate used herein is also necessarily changed to reflect the change in molecular weight due to the different salt.

[0092] The term "wearable" refers to a device that can be worn by a user, for example, as an accessory, as clothing, and / or embedded in clothing, or a device that can be implanted under the skin of a patient.

[0093] As used herein, "wearable device attached" to a patient means that the wearable device is worn by the patient, implanted under the patient's skin, or otherwise secured to the patient in a manner that allows the patient's heart rhythm to be measured.

[0094] device The devices used in the methods described herein are designed to be fitted to a patient as part of the eligibility determination protocol and / or pharmacotherapy used for the patient described herein.

[0095] The wearables used for diagnosis are conventional and intended to inform clinicians whether or not a patient has atrial fibrillation, and / or, if the patient does have atrial fibrillation, potentially provide information about the patient's atrial fibrillation load and the number of atrial fibrillation episodes. Such diagnostic analyses cannot address the suitability, effectiveness, and / or dosage of pharmacotherapy beyond the scope of diagnosis. The pharmacotherapy methods described herein include identifying patients who are eligible to receive pharmacotherapy and / or monitoring eligible patients during treatment with pharmacotherapy to assess the effectiveness of the drug (e.g., reduction in the number of long-lasting atrial fibrillation episodes). Monitoring allows for dose adjustments to the patient until the patient is deemed to be responding to the treatment or, by not responding, deemed ineligible for pharmacotherapy. The pharmacotherapy methods described herein allow for continuous monitoring of the patient to determine an effective dose of the drug and to confirm that the patient continues to respond to that dose. Therefore, the wearables described herein are designed and / or selected to withstand long-term use and / or to be comfortable for the patient to use and / or to be easy for the patient to use.

[0096] In practice, wearables may include cardiac monitoring components, which may be assisted or unassisted components for measuring a patient's heart rhythm. Many wearables are wearable and removable by the patient, or implanted subcutaneously. The specific cardiac monitoring component used in a wearable is not mandatory, as long as it can accurately measure the heart rhythm. A wearable may report measured heart rhythm data by generating and / or transmitting data indicating the length of detected atrial fibrillation periods, and / or generating and / or transmitting data indicating the number of detected long-lasting atrial fibrillation episodes (e.g., over a period of interest such as a week or a month). Furthermore, or / or, a wearable may be configured to transmit heart rhythm data to a device configured to detect atrial fibrillation and / or determine the length of detected atrial fibrillation periods and / or the number of long-lasting atrial fibrillation episodes (e.g., over a period of interest). Wearables are approved by one or more regulatory agencies, such as the U.S. Food and Drug Administration (FDA).

[0097] Assisted component Assisted cardiac monitoring components may use photoplethysmography (PPG) to detect a patient's heart rate and heart rhythm. PPG is a conventional technique found in standard oxygen saturators, which measures the reflection of light in tissues to detect arterial pulsations and, consequently, heart rhythm patterns. However, to continuously and / or semi-continuously measure heart rhythm, it is necessary to consider the fact that the PPG signal generated when the patient moves is often distorted, weakened, and contains a considerable amount of noise compared to the detected data. To compensate for such deficiencies, algorithms may be used that sufficiently reduce distortion and / or noise and provide a reliable signal. In one embodiment, both a PPG sensor and an accelerometer are used, along with an algorithm that enables appropriate (e.g., a sufficient signal-to-noise ratio). When assisted in this way, PPG enables reliable detection of both heart rate and heart rhythm. For example, see Wojcikowski, et al., Photoplethysmographic time-domain heart rate measurement algorithm for resource-constrained wearable devices and its implementation, SENSORS 20, no.6(2020):1783 (which is incorporated herein by reference in its entirety).

[0098] In some embodiments, the cardiac monitoring component uses piezoelectric materials and / or electroactive polymers for rhythm to detect blood flow, thereby indirectly measuring the heart rhythm.

[0099] In some embodiments, the specificity of the measurement can be enhanced by combining PPG and / or piezoelectric measurements with electrocardiogram data from a single-electrode wearable (i.e., iEKG, as opposed to EKG, which refers to a conventional multi-electrode electrocardiogram). The iEKG (i.e., iECG) and PPG or piezoelectric data can be generated by two separate devices communicating via transceivers (e.g., an armband and a smartwatch) or by a single device (e.g., a smartwatch wristband (e.g., the Kardia® band of the iWatch)). When an arrhythmia is detected in the PPG data, the corresponding iECG data may be analyzed by an algorithm (e.g., within a time frame).

[0100] Unassisted component In another embodiment, the wearable may include a non-assisted cardiac monitoring component, such as a portable electrocardiograph. The portable electrocardiograph component may be wearable, voluntarily wearable by the patient, and / or capable of transmitting data via, for example, a built-in antenna or a Bluetooth® data transmission device. A wearable with a non-assisted cardiac monitoring component can measure heart rate and heart rhythm. The wearable may be configured to detect and record atrial fibrillation overload and / or long-lasting atrial fibrillation (episodes) (LEAF) over an observation period (e.g., about two weeks or more). The non-assisted cardiac monitoring component employs direct measurement, meaning the device reads electrical signals generated by the heart. Direct measurement is less susceptible to noise and distortion than indirect measurement, such as PPG measurement, and can transmit measurement data to the clinician without the use of algorithms and / or with reduced use of algorithms or data processing.

[0101] In some embodiments, the wearable may further include a dedicated accessory, such as a cardiac monitoring device, which can detect the electrical activity of the heart, including heart rhythm, through electrodes. The dedicated accessory may be able to initiate transmission and / or comprise a transmitting device and / or be connected to a transmitting device.

[0102] In some embodiments, the cardiac monitoring device may be a component that is an integral part of a single wearable, such as a smartwatch. By providing a single device that is wearable by the user and capable of monitoring the electric field of the user's heart, the electrical activity of the heart can be continuously monitored over a long period of time, such as several days or months.

[0103] In some embodiments, the cardiac monitoring device may include an analog-to-digital converter capable of digitizing measured electric field data (e.g., measured potential difference data) and transmitting and / or storing the measured data as digitized data in memory. The cardiac monitoring device may include an output unit capable of transmitting signals to an external circuit that hold information about the potential difference between the limbs and the body. The output unit can take various forms. In one case, the output unit may be a transceiver communicating with another transceiver / receiver (e.g., a watch or tablet) in another unit. In one embodiment, a central analysis center (e.g., a remote lab such as CORE Lab, and / or a remote data analysis center, and / or a server) may interpret and / or aggregate the atrial fibrillation data and / or LEAF data. The central analysis center may also transmit dose adjustment recommendations to the treating clinician without requiring the patient to visit the clinician (e.g., as part of a patient monitoring program). Furthermore, or / or, an artificial intelligence algorithm may be used to determine dose adjustments and transmit dose adjustment recommendations to the clinician.

[0104] Further aspects In one embodiment, the wearable may be a small consumer electronic device, such as a watch, armband, ring, strap, and / or wristband. The wearable may also include a housing that contains a cardiac monitoring component and any associated circuitry, CPU, etc. The wearable may also be worn on other parts of the user, including but not limited to the wrist, leg, neck, and / or body. The wearable may also include a dedicated accessory that can communicate with another electronic device, such as a tablet, laptop computer, desktop computer, and / or other similar device, and the dedicated accessory can communicate with a cloud network to transmit information from the device to a clinician. Furthermore, or / or, the dedicated accessory may be capable of transmitting information directly and / or via a network to a clinician.

[0105] Heart rate rhythm and iECG wearables may be Bluetooth®, Z-Wave, Zigbee®, and / or Advanced and Adaptive Network Technology (ANT) compatible. For example, an iECG and / or heart rate rhythm monitoring and / or recording device (e.g., PPG or piezoelectric heart rate rhythm monitoring and / or recording device) may be paired with an application which may be configured to automatically detect atrial fibrillation based on data from the iECG and / or heart rate rhythm monitoring and / or recording device. The iECG device and / or rhythm monitoring and / or recording device may be configured to transmit data to the application. The data can be transmitted using one or more data transfer methods such as Bluetooth®, Z-Wave, Zigbee®, or ANT protocol. The application may be configured to analyze the data using its own software. Based on the data from the iECG and / or heart rate rhythm monitoring and / or recording device, the application may be able to interpret and / or detect atrial fibrillation with a sensitivity of over 90% and a specificity of over 80%.

[0106] A patient wearing the wearable described herein can use the wearable to record heart rhythms and detect atrial fibrillation. Recording may be continuous or semi-continuous. Recording details can be programmed directly or indirectly (e.g., remotely) into the device. Atrial fibrillation data may be securely stored in a cloud-based data repository or similar using a highly secure protocol.

[0107] Examples of commercially available assisted and non-assisted wearables include, but are not limited to, the following: • MCOT® wearable, sold by Philips Biosciences (BEST, Netherlands). This device is a wearable patch that can automatically transmit iECG data wirelessly to a central device analysis center (e.g., CORE Labs). The system is configured to provide sufficient data to enable clinicians to determine whether dose increases and / or drug discontinuation are necessary. The ePatch long-wearing Holter monitoring system is sold by Philips Biosciences (BEST, Netherlands). This device is configured to record data indicating atrial fibrillation and / or long-lasting persistent atrial fibrillation (LEAF) (episodes). This device is configured to continuously record and / or store iECG data. This data is then centrally archived and analyzed. There are numerous other wearables that can be used instead of those described above, some of which are FDA approved, including, to name a few, the Zio from iRhythmtech (San Francisco, California, USA), the Frontier X2 from Fourth Frontier (Austin, Texas, USA), and wearables from VivaLink (Campbell, California, USA). The above wearables and other wearables described herein represent a non-exhaustive list of wearables suitable for use in the methods described herein. The specific wearable used is not particularly important, as long as it can measure heart rhythm (e.g., generate signals and / or data that can determine heart rhythm). The wearable used must be able to continuously or semi-continuously measure the heart rhythm of the patient wearing the wearable over the required period described herein (e.g., the period required for baseline determination, monitoring during drug therapy, etc.). Furthermore, the wearable must be small enough and / or comfortable enough for the patient to wear and / or wear over the required period.

[0108] methodology The disclosed method allows a clinician to identify eligible patients and / or treat them with budiodarone and evaluate the effectiveness of the treatment based on monitored heart rhythm data over a period of time. This period may be long-term, measuring weeks, months, and / or years. Monitoring may include monitoring heart rhythm data and / or using such heart rhythm data to determine the patient's atrial fibrillation status, which may be determined based on the patient's atrial fibrillation load, the number or duration of atrial fibrillation episodes over a period of time (e.g., frequency of atrial fibrillation episodes and / or long-lasting atrial fibrillation episodes), or one or more symptoms associated with atrial fibrillation. This represents a new paradigm in the treatment of atrial fibrillation, allowing clinicians to: • To assess the severity of the patient's illness; • Determining whether the patient is eligible to receive drug therapy; • Evaluate the effectiveness of the treatment in the short term (1-6 months) and / or long term (after 6 months); • Adjusting the dosage for the patient in order to achieve and / or maintain the treatment outcome; and / or • If a patient does not respond to treatment, exclude them from drug therapy.

[0109] In contrast, conventional monitoring of patients is typically for diagnostic purposes only, and is usually performed over a single short period of time, typically less than two weeks, using, for example, a Holter monitor or equivalent. With such diagnostic methods, clinicians can at best only confirm the presence of atrial fibrillation. In most cases, clinicians then prescribe anticoagulants to the patient. Alternatively, clinicians may administer pharmacotherapy to diagnosed patients, which may include heart rate reduction using beta-blockers and / or calcium channel blockers. In any case, once diagnosed, conventional monitoring is typically terminated.

[0110] When clinically evaluating atrial fibrillation for clinical investigation, it is common to use implantable (invasive) devices that require surgical insertion and subsequent surgical removal. Such investigations are typically conducted to understand the underlying risks of stroke and congestive heart failure associated with atrial fibrillation load and / or duration of atrial fibrillation. See, for example, Turakhia MP et al., Circ. Arrhythm. Electrophysiol., 2015, 8(5):1040-7. In some cases, non-invasive means may be used to monitor the patient, but typically monitoring is short-term. See, for example, Go, et al., JAMA Cardiology, 2018, 3(7):601-608. In any case, such clinical evaluations have not addressed, or provided, methods for effectively delivering budiodarone to patients, then evaluating the effects of this drug on patients' atrial fibrillation burden or prolonged episodes of atrial fibrillation over a long period of time, and for adjusting the dose for patients to achieve desired therapeutic outcomes as an option.

[0111] Unlike previous protocols for treating atrial fibrillation using drugs that limit a patient's heart rate, the method described herein relates to treating a patient's heart rhythm to reduce the causes of stroke and heart failure and to alleviate or eliminate symptoms associated with atrial fibrillation. By combining the ability to continuously or semi-continuously monitor the heart rhythm with drugs suitable for limiting the number and severity of prolonged episodes of atrial fibrillation, clinicians can significantly reduce the risk of stroke or congestive heart failure. Furthermore, by monitoring patients after the initiation of drug therapy, clinicians can assess the effectiveness of the drugs and make necessary dose adjustments to enhance overall effectiveness or identify patients who do not respond to such drug therapy and should be excluded from treatment.

[0112] One embodiment of this approach is shown in Figure 1, which diagrams an iterative process for evaluating patients, determining their eligibility for budiodarone therapy, and treating eligible patients. In Figure 1, an exemplary cohort of patients diagnosed with paroxysmal and / or persistent atrial fibrillation is evaluated for atrial fibrillation load. Patients showing a favorable atrial fibrillation load ("yes" at the asterisk decision point) (in this case, ≥5%, but this atrial fibrillation load may have different thresholds such as 2.5% and / or patient or cohort-specific thresholds) are selected to continue the eligibility determination process, while those not meeting this threshold are excluded ("no" at the asterisk decision point). Patients may also be evaluated for the duration of atrial fibrillation episodes. In this particular embodiment, a patient is further eligible for budiodarone therapy if there is evidence of at least one atrial fibrillation episode lasting approximately 5 hours or more than approximately 5.5 hours in a one-month period, and / or two or more atrial fibrillation episodes lasting approximately 1 hour or more in a one-month period (decision point marked with an asterisk, "yes"). Patients who do not meet any of these criteria are excluded because they are presumed to have a very low risk of stroke or congestive heart failure (decision point marked with an asterisk, "no"). Eligible patients are given an escalating budiodarone regimen, which has been shown to significantly reduce atrial fibrillation episodes, including long-lasting atrial fibrillation episodes, and by definition reduces the atrial fibrillation load. In the methods described herein, other drugs that behave similarly to budiodarone may be used in place of, and / or in addition to, budiodarone.

[0113] In the iterative process shown in Figure 1, an escalation regimen is used to evaluate whether budiodarone is effective in treating long-lasting atrial fibrillation episodes and / or at what dose is effective. Because the atrial fibrillation load and / or the number and duration of long-lasting atrial fibrillation episodes vary from patient to patient, different doses of budiodarone may be effective in different patients. However, until now, clinicians prescribing budiodarone at a first dose have not known whether that dose is effective. As shown in Figure 1 and the following examples, the method described herein allows clinicians to evaluate the effectiveness of a first dose and / or adjust the dose in an escalation and / or tapering protocol in an iterative process until a treatment outcome is achieved and / or the patient is deemed unresponsive. Patients who do not show such a response are excluded from budiodarone therapy.

[0114] In an escalation regimen, the patient is initially given a low dose, and if the patient does not respond and / or responds poorly (e.g., "no" in the plus sign), the dose may be increased. If no evidence of efficacy of the drug is shown at the maximum dose, the patient is determined to be unresponsive. Alternatively, a tapering regimen may be used, in which the patient is given the highest dose of budiodarone, and efficacy is determined while gradually decreasing the dose. One advantage of the tapering protocol is that those who do not respond can be determined in the first iteration rather than the last. However, the escalation protocol may have the advantage of finding the minimum effective dose early and / or reducing the risk of side effects. A combination of escalation and tapering regimens can be used to fine-tune the minimum effective dose of budiodarone in a patient. For example, if a regimen of 200 mg of budiodarone twice daily is ineffective, but 400 mg of budiodarone twice daily is effective, the attending clinician may gradually reduce the dose to determine if 350 mg of budiodarone twice daily or 300 mg of budiodarone twice daily is effective. This is particularly beneficial if the patient experiences side effects with 400 mg of budiodarone twice daily, but does not (or experiences fewer) side effects with the lower but still effective doses of 350 mg or 300 mg twice daily.

[0115] In one embodiment, treatment with budiodarone may reduce the number and / or frequency of prolonged atrial fibrillation episodes and / or reduce the atrial fibrillation load. This is in contrast to drugs that reduce heart rate but have little to no effect on reducing the duration of atrial fibrillation episodes and the atrial fibrillation load. The atrial fibrillation load and prolonged atrial fibrillation episodes are distinct concepts. The atrial fibrillation load is determined by measuring the number and duration of each atrial fibrillation episode in the patient. Patients who only have very short-duration atrial fibrillation episodes may still be assigned a higher atrial fibrillation load than patients with a low frequency of prolonged atrial fibrillation episodes. Therefore, a patient with eight atrial fibrillation episodes, each lasting 45 minutes, during a given 24-hour period would be assigned a 25% (6 hours / 24 hours) atrial fibrillation load. In contrast, patients with one episode of atrial fibrillation lasting 5 hours within a 24-hour period are assigned a 20.8% atrial fibrillation load. However, the latter patients with one episode of atrial fibrillation may have a higher stroke risk than the former patients. Therefore, patients with an atrial fibrillation load of less than 2.5% may be determined to be very unlikely to have prolonged, persistent atrial fibrillation and thus not eligible for treatment with budiodarone.

[0116] Furthermore, the progression of a patient from paroxysmal atrial fibrillation to persistent atrial fibrillation, or from persistent atrial fibrillation to permanent atrial fibrillation, can be an undesirable progression of the disease. By reducing the duration of prolonged atrial fibrillation and the number of atrial fibrillation episodes, treatment of patients with budiodarone as disclosed herein can maintain the patient at the current stage of the disease for at least a longer period than if they were not treated with budiodarone (and may even show regression from persistent atrial fibrillation to paroxysmal atrial fibrillation), thereby suppressing disease progression.

[0117] In contrast, the treatment of atrial fibrillation with anticoagulants does not address the underlying cause of atrial fibrillation and does not reduce the burden of atrial fibrillation and / or the underlying concerns associated with medium- to long-term and long-term persistent atrial fibrillation episodes (e.g., increased risk of stroke, increased risk of congestive heart failure). Furthermore, the use of anticoagulants does not prevent or delay the progression from paroxysmal atrial fibrillation to persistent atrial fibrillation, or from persistent atrial fibrillation to permanent atrial fibrillation. In addition, the use of anticoagulants causes a separate set of bleeding-related problems. For example, as discussed above, approximately 6% of patients taking anticoagulants are expected to experience adverse events attributable to anticoagulant administration, requiring emergency department visits, and approximately 3% will require subsequent hospitalization. Most adverse events from anticoagulants are bleeding events, and catastrophic bleeding requires hospitalization. Catastrophic bleeding may include intra-abdominal bleeding (requiring surgery for recovery) or intracranial bleeding (fatal). Furthermore, while anticoagulants reduce the risk of stroke, they do not address the underlying causes that prolonged, persistent atrial fibrillation episodes cause or increase the risk of stroke in patients with atrial fibrillation.

[0118] Accordingly, in one embodiment, a patient taking anticoagulants for the treatment of atrial fibrillation and demonstrating efficacy with budiodarone therapy (e.g., as described herein) may be identified with respect to budiodarone therapy while being monitored, as described herein, for example. In one embodiment, if budiodarone therapy is found to sufficiently reduce the patient's stroke risk (e.g., by reducing one or more of the duration and / or frequency of atrial fibrillation episodes and / or atrial fibrillation load by the desired amount and / or by the amount associated with the reduction of stroke and / or congestive heart failure risk), the patient may be excluded from taking anticoagulants (e.g., by a clinician). Because budiodarone does not carry the risk of adverse effects of anticoagulants (e.g., bleeding), if budiodarone therapy is found to reduce a patient's stroke risk to the same extent as, or to the same extent as, the combined stroke and bleeding risk in, patients may be switched from anticoagulants to budiodarone therapy and excluded from taking anticoagulants. For example, if budiodarone therapy is found to reduce the duration of a patient's atrial fibrillation episodes to less than one hour (e.g., the longest episode during the evaluation period, the mean duration during the evaluation period, etc.), the patient may be excluded from taking anticoagulants (e.g., by a clinician). A patient's stroke risk may be determined based on their individual characteristics and risk factors, which are reflected in their CHA2DS2-VASc score (≤2), with paroxysmal atrial fibrillation and persistent atrial fibrillation having low CHA2DS2-VASc scores (≤2) and high CHA2DS2-VASc scores (≥3), respectively. Therefore, patients with different CHA2DS2-VASc scores may require different levels of atrial fibrillation reduction to be excluded from anticoagulant therapy.For example, if budiodarone therapy is found to reduce or eliminate episodes of atrial fibrillation lasting more than approximately 5.5 hours or more than 5 hours, or if it is found to reduce or eliminate episodes of atrial fibrillation lasting more than 1 hour, and / or if budiodarone therapy is found to reduce the atrial fibrillation load to less than 5% or less than 2.5% during the comparison period, patients with a low CHA2DS2-VASc score (e.g., 2 or less) may be excluded from taking anticoagulants. In patients with a high CHA2DS2-VASc score (e.g., 3 or more), a greater reduction in the level of atrial fibrillation may be necessary to exclude them from taking anticoagulants. For example, if budiodarone therapy is found to reduce or eliminate atrial fibrillation episodes lasting more than 1 hour, more than 0.5 hours, or more than 0.1 hours, and / or if budiodarone therapy is found to reduce the atrial fibrillation load to less than 1% during the comparison period, patients with a high CHA2DS2-VASc score may be excluded from taking anticoagulants. In one example, patients with a very high CHA2DS2-VASc score (e.g., 6 or higher) may be excluded from taking anticoagulants only if atrial fibrillation episodes lasting more than 0.1 hours are eliminated, or they may not be excluded from taking anticoagulants at all.

[0119] In light of the above, according to this disclosure, a patient's heart rhythm may be monitored over a long period to evaluate the effectiveness of a drug intended to control such prolonged episodes of atrial fibrillation. While a patient's heart rhythm can be monitored over a short period (e.g., 1, 2, or 3 days and up to 14 days) using devices such as a Holter monitor, such monitoring cannot provide a comprehensive and continuous analysis of the patient's atrial fibrillation, and / or an analysis of how drug treatment affects the number and duration of atrial fibrillation episodes over a long period (e.g., several months or more). Such short-term analysis provides only a diagnostic analysis and not a therapeutic analysis, and cannot provide a complete picture of the patient's cardiac health. Due to the sporadic and dynamic nature of atrial fibrillation (paroxysmal and persistent) and inter-patient variability, accurate measurement of the degree of a patient's atrial fibrillation and the benefit of drug therapy in the treatment of atrial fibrillation can only be obtained by monitoring over a long period, such as more than one month or more than three months.

[0120] Drug therapy There are many conditions under which a clinician can evaluate a patient based on static numerical values ​​that represent meaningful long-term averages. For example, in diabetes, a three-month hemoglobin A1C level (a blood test also known as an HbA1C test) provides an excellent indicator of the average daily blood glucose level. Furthermore, liver function, prostate health, and thyroid health can all be evaluated based on specific numerical values ​​that provide meaningful information to the clinician.

[0121] Clinicians treating paroxysmal and / or persistent atrial fibrillation have had to rely on short-term / intermittent monitoring of the patient's heart rhythm using EKG (electrocardiogram) and / or Holter monitors. However, such short-term monitoring can miss important data points that can only be obtained through long-term monitoring. This can lead clinicians to avoid drug therapy without having a means to monitor the effectiveness of the drug in the patient. Rather, patients diagnosed with atrial fibrillation may be given symptomatic and / or risk-reducing treatments such as anticoagulants. However, while anticoagulants reduce the risk of thrombus-related strokes (e.g., thrombi arising from atrial fibrillation), the risk of uncontrolled bleeding caused by anticoagulants increases accordingly, which can be fatal.

[0122] Drugs such as sotalol, as well as beta-blockers and calcium channel blockers, have been used to treat atrial fibrillation. Examples of calcium channel blockers include, but are not limited to, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil. Examples of beta-blockers include, but are not limited to, acebutolol, atenolol, bisoprolol, metoprolol, nadolol, nebivolol, and propranolol. There are also drugs with combination mechanisms of action, such as amiodarone. However, each of these medications is currently considered an inferior treatment for atrial fibrillation because they either fail to adequately control the heart rhythm or cause serious side effects in patients (for example, amiodarone has a long half-life, and accumulation after long-term use is associated with a wide range of toxicities, including effects on the lungs, liver, and eyes; its use requires strict monitoring of the recipient to detect early signs of irreversible and potentially fatal complications [see, for example, Wolkove N, Baltzan M, “Amiodarone pulmonary toxicity,” Canadian Respiratory Journal 16(2):43-8, 2009]).

[0123] Budiodarone, a drug with a combination mechanism of action, has been shown to reduce episodes of prolonged atrial fibrillation without significantly increasing the QT interval. Budiodarone has a cardiac ion channel effect pattern similar to that of amiodarone in its design, while also reducing late Na + Channel blockade is enhanced. Budiodarone's intentionally modified metabolism results in a shorter half-life than amiodarone, but avoids the accumulation-related toxicity seen with amiodarone, and it is completely inactivated and eliminated from the body within hours to days after discontinuation. The short half-life allows for rapid attainment of steady-state blood concentrations within 2-3 days of drug initiation, and, provided real-time information on efficacy (e.g., changes and / or reductions in atrial fibrillation load or prolonged episodes of atrial fibrillation) is available, dose adjustments can be made as needed to determine the minimum effective dose for each patient. Indeed, since prolonged episodes of atrial fibrillation are a substantial cause of thrombus formation that can lead to stroke and / or congestive heart failure, budiodarone represents a significant advance in the treatment of atrial fibrillation. However, atrial fibrillation is a diverse disease, and some patients require different drug dosages to achieve the desired outcome. As mentioned above, the inability to monitor patients in a manner that allows for assessment of drug efficacy is a major drawback of drug intervention. For this reason, clinicians have begun to opt for the use of anticoagulants and / or risk reduction measures instead of aggressive drug intervention.

[0124] The wearable devices and methods described herein continuously provide clinicians with sufficient data to determine the long-term efficacy of drugs in the treatment of paroxysmal and persistent atrial fibrillation. Therefore, methods that integrate data generated by wearables with drugs that can control and / or reduce the atrial fibrillation burden may enable more effective treatment of atrial fibrillation, which has been sought after in the art for many years. Furthermore, the ability to determine the long-term efficacy of drugs may enable dose adjustments for patients and effective control over episodes of persistent atrial fibrillation.

[0125] Treatment regimens using budiodarone Budiodarone has been shown to reduce prolonged atrial fibrillation episodes in patients, thereby lowering the risk of stroke and congestive heart failure. However, to achieve therapeutic effects with budiodarone in diverse patients with varying frequencies and durations of prolonged atrial fibrillation episodes, clinicians need to monitor the efficacy of each patient at a given dose. This represents a personalized medicine approach to diseases treatable with budiodarone.

[0126] If the patient does not respond to the given dose, the dose needs to be increased, and this process is repeated until the patient responds to or does not respond to the given higher dose. Patients who do not respond to any of the doses tested are excluded from budiodarone therapy.

[0127] Furthermore, patients with paroxysmal or persistent atrial fibrillation who are refractory to one or more conventional therapies for treating these conditions may be candidates for the methods and procedures described herein. Such patients are screened for treatment (eligibility is determined) by determining the baseline atrial fibrillation load and / or the number and extent of long-lasting atrial fibrillation episodes. The baseline may also be used to assess the relative reduction and / or complete disappearance of these symptoms based on budiodarone therapy and / or to identify patients who are not responsive to budiodarone therapy. Thus, a method for treating a patient with paroxysmal or persistent atrial fibrillation in whom the patient is refractory to one or more conventional therapies for treating atrial fibrillation is, In the case of a patient who is refractory to one or more conventional methods for treating atrial fibrillation and who is wearing a wearable device capable of monitoring and transmitting heart rhythm data, a) Identifying the number of prolonged episodes of atrial fibrillation and the degree of atrial fibrillation overload in the patient, such that the identified number and duration meet the criteria for the patient to be eligible for treatment with budiodarone by a clinician. b) Administering budiodarone to the patient at the minimum approved therapeutic dose, c) Monitoring the patient for the effectiveness of budiodarone administered at the minimum therapeutic dose using a wearable device to evaluate whether the dose is effective for the patient, wherein the monitoring of effectiveness is initiated at least about 7 days or at least about 2 weeks after the start of the treatment, d) For patients who did not achieve effective results at the minimum possible dose of the drug at the end of the second period, the dose of the drug shall be adjusted at least once to the extent necessary to achieve effective results, using at least the length of the second period, in order to evaluate its effectiveness, or, if effective results were not achieved when evaluated at the maximum approved dose, the patient shall be excluded from the treatment. e) For patients who have achieved effective results, continue monitoring the patient's heart rhythm to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat the procedures in c) and d) as necessary. It may include.

[0128] Because there is insufficient information to confirm the effectiveness of a given dose of any medication prescribed to reduce the number of prolonged, persistent atrial fibrillation episodes in patients being treated, clinicians may be forced to avoid doing so, especially considering the variability between patients and in the disease itself. Furthermore, many clinicians consider treating (reducing) heart rate, in combination with anticoagulants on an optional basis, to be a suitable way to treat atrial fibrillation. See, for example, Atrial Fibrillation - Treatment, https: / / www.nhs.uk / conditions / atrial-fibrillation / treatment / (where, in 2021, the authors were controlling heart rate as part of a suitable treatment approach for atrial fibrillation).

[0129] Herein, according to the method described herein, a clinician can evaluate the patient's heart rhythm data over a long period, such as at least about 3 months, at least about 6 months, at least about 12 months, and possibly over the rest of the patient's life, to determine the number and / or duration of long-lasting atrial fibrillation episodes, and whether budiodarone therapy is effective and continues to be effective.

[0130] For example, in one embodiment shown in the Examples and Figure 1, a clinician may start administration of budiodarone at a minimum level of approximately 200 mg twice daily (bid) and then evaluate whether that dose is effective in eliminating long-lasting atrial fibrillation episodes. The clinician may review the data at the initial dose level and make one or more dose adjustments to the patient as needed to reach a dose in which long-lasting atrial fibrillation episodes are substantially eliminated and / or eliminated. Generally, a stepwise dose increase may be approximately 200 mg bid. Thus, in this approach, the dose can be changed from approximately 200 mg twice daily to approximately 400 mg bid or approximately 600 mg bid, up to a maximum of approximately 800 mg bid, and potentially to a higher dose if the attending clinician determines that a higher dose would be beneficial. Furthermore, although not shown in Figure 1, the dose may be fine-tuned for the patient by selecting smaller or larger increments of dose adjustment (e.g., + / - 100 mg bid or + / - 300 mg bid), and the clinician may reduce the dose to achieve a sufficiently effective result, as long as the reduced dose yields the sufficiently effective results described herein.

[0131] system The methods described herein can be performed in a single device, such as a wearable, that can record, store, and transmit heart rate rhythm data. However, a system of multiple devices can also be used, however such a system may be... a) A wearable device that collects heart rhythm data from patients diagnosed with paroxysmal atrial fibrillation and / or persistent atrial fibrillation. b) A CPU configured to communicate and / or receive heart rate rhythm data or data based on heart rate rhythm data from a wearable, and to collect and store heart rate rhythm data and / or data based on heart rate rhythm data, c) A transmitting component (e.g., a device) that is part of the CPU (chest pain unit) and / or communicates with the CPU (chest pain unit) and is configured to directly and / or indirectly transmit data and / or information based on the data (e.g., alerts or alarms, the number of analyzed atrial fibrillation episodes, etc.) to one or more designated recipients (e.g., patients, one or more clinicians, etc.). Includes.

[0132] In one embodiment, the CPU can evaluate stored and / or received data to determine the presence and number of medium- to long-term and / or long-term atrial fibrillation episodes. The evaluation by the CPU may be continuous or periodic. The CPU may be programmed to alert clinicians and / or patients and / or central analysis centers (e.g., remote laboratories and / or analysis centers) of medium- to long-term and / or long-term atrial fibrillation episodes deemed dangerous to the patient (e.g., a number exceeding a threshold or a duration exceeding a threshold). Furthermore, the wearable may also include a storage unit for storing the collected data, which may be programmed to evaluate the stored data and alert clinicians and / or patients and / or central analysis centers of any potentially harmful irregularities in heart rhythm. The collected and / or evaluated data may be reviewed continuously or periodically by clinicians or healthcare professionals (e.g., continuously or periodically transmitted to a computing device accessible to clinicians and / or retrieved on request from a computing device accessible to clinicians). Regular evaluations may be, for example, once a day, once a week, twice a month, or once a month. Furthermore, the collected and / or evaluated data (on a wearable, CPU, central analysis center, or another computing device accessible to the patient and / or clinician) may be filtered for events deemed dangerous to the patient (e.g., the number of atrial fibrillation episodes exceeding a threshold number or duration exceeding a threshold period, atrial fibrillation load exceeding a threshold level), and if such events are detected, an alarm (or alert) may be triggered for the patient and / or sent to the clinician (e.g., by a wearable, CPU, a computing device accessible to the clinician, central analysis center, etc.). The use of alerts (alarms) is optional and may be provided immediately after detection of a prolonged atrial fibrillation episode to inform the clinician and / or patient of the event.The comparison period is independent of the alert and provides data that allows clinicians to compare the effectiveness of the drug over a certain period to baseline. [Examples]

[0133] In the following embodiments and throughout this specification, the following abbreviations have the following meanings. Unless otherwise defined, abbreviations have their conventional medical meanings. AFib or AF = atrial fibrillation Bid or bid = twice a day, bpm = number of beats per minute hr=hour, mg = milligram PPG = Photoplethysmography SD=standard deviation

[0134] Example 1 is provided to illustrate that atrial fibrillation episodes can be detected during continuous monitoring of a patient using a wearable device.

[0135] Examples 2–7 demonstrate the efficacy of budiodarone in the method described herein. In these examples, all patients had surgically implanted pacemakers and therefore carried many associated risks. See, for example, Pacemaker, https: / / www.mayoclinic.org / tests-procedures / pacemaker / about / pac-20384689 (last accessed October 26, 2022), which is incorporated herein by reference in its entirety.

[0136] Example 1 - Wearable device for continuous detection of atrial fibrillation in patients In this example, a male patient with non-persistent atrial fibrillation was fitted with an MCOT (Mobile Cardiac Outpatient Telemetry) wearable device, marketed by Philips BioSciences, Inc. (Best, Netherlands) and available by prescription in the United States. The MCOT device uses PPG (Passive Pulse Generator) combined with algorithms for evaluating heart rhythm and atrial fibrillation. The MCOT device is configured to wirelessly and seamlessly provide heart rhythm and atrial fibrillation data to a dedicated computer.

[0137] The patient was continuously monitored for 23.5 hours. Throughout the entire period, the patient's heart rhythm and heart rate were measured using an MCOT device. Figure 2 shows the electrocardiograms obtained during the monitoring period. Notably, 33 distinct atrial fibrillation episodes were detected and recorded, each separated by a period of sinus rhythm or other arrhythmia. Specific details of the electrocardiogram analysis are as follows: Number of atrial fibrillation episodes: 33 Maximum duration of atrial fibrillation: 3 hours and 2 minutes Heart rate (minimum / maximum): 48 / 94 beats per minute Atrial fibrillation load 36% The data above demonstrates that the wearable described herein can continuously monitor a patient's heart rhythm and provide a detailed analysis of the number of atrial fibrillation episodes and the degree of atrial fibrillation load.

[0138] Example 2 - Elimination of prolonged atrial fibrillation with budiodarone This example is a clinical trial evaluation of budiodarone in the treatment of six patients with paroxysmal or persistent atrial fibrillation who had previously experienced prolonged episodes of atrial fibrillation (over 24 hours). In this example, patients were subjected to different conditions (baseline, various doses of budiodarone, washout), and for each condition, the heart rhythm of individual patients in the patient cohort was continuously monitored over two weeks using a pacemaker. The objective of this example is to determine whether budiodarone reduces prolonged episodes of atrial fibrillation lasting over 24 hours. Different doses and evaluation results are provided in Table 1 below. [Table 1]

[0139] The results above indicate that budiodarone eliminated more than 70% of long-lasting atrial fibrillation episodes lasting more than 24 hours compared to baseline across all budiodarone dose levels, with little difference between the 200 mg bid, 600 mg bid, and 800 mg bid treatment levels. In contrast, both baseline and washout results showed the presence of long-lasting atrial fibrillation episodes lasting more than 24 hours. These results also show a significant reduction (more than 64%) in atrial fibrillation load (number of episodes and mean duration of episodes over a two-week period). This reduction correlates well with a reduced risk of patients progressing from paroxysmal atrial fibrillation to persistent atrial fibrillation or from persistent atrial fibrillation to permanent atrial fibrillation.

[0140] Example 3 - Disappearance of prolonged atrial fibrillation (over 24 hours) during a 12-week period. This example is a clinical trial evaluation of budiodarone in the treatment of six patients with paroxysmal or persistent atrial fibrillation who had previously experienced prolonged episodes of atrial fibrillation (more than 24 hours). In this example, each patient in the cohort was continuously monitored for heart rhythm data over 12 weeks using a pacemaker (surgically invasive procedure) and treated with different doses of budiodarone (2 weeks each). Furthermore, patients were under continuous monitoring and clinician supervision throughout this study.

[0141] The objective of this embodiment is to determine whether budiodarone treatment can reduce prolonged atrial fibrillation (atrial fibrillation episodes lasting more than 24 hours) by evaluating heart rhythm using a pacemaker in a clinical trial setting. The results of this analysis are provided in Table 2 below. [Table 2]

[0142] "Number of episodes" refers to the number of long-lasting atrial fibrillation episodes (i.e., episodes lasting more than 24 hours). "Duration" refers to the amount of time spent in long-lasting atrial fibrillation episodes (expressed in hours) and the percentage relative to the baseline measurement during the two-week period. Based on the results above, a 200 mg bid was sufficient to treat all patients in the study by eliminating the number of atrial fibrillation episodes lasting more than 24 hours. In this case, since a 200 mg bid dose of budiodarone was sufficient to eliminate these long-lasting atrial fibrillation episodes, there was no need to increase the dose to improve patient efficacy.

[0143] Example 4 - Reduction of prolonged, continuous atrial fibrillation (over 5 hours) during 12 weeks. This study evaluates the clinical trial of budiodarone in the treatment of six patients with paroxysmal or persistent atrial fibrillation who had previously experienced prolonged episodes of atrial fibrillation (more than 5 hours). In this study, each patient's heart rhythm was continuously monitored for 12 weeks using a pacemaker (surgically invasive procedure), and they were treated with different doses of budiodarone, each dose administered over a 2-week period. Furthermore, patients were continuously monitored and supervised by clinicians throughout the study.

[0144] The objective of this embodiment is to assess heart rhythm using a pacemaker in a clinical trial setting and to determine whether budiodarone reduces prolonged atrial fibrillation lasting more than 5 hours. The results of this analysis are provided in Table 3 below. [Table 3]

[0145] "Number of events" refers to the number of long-lasting atrial fibrillation episodes with a duration of more than 5 hours. "Duration" is expressed as the amount of time spent in atrial fibrillation episodes lasting more than 5 hours during a two-week period (expressed in hours) and as a percentage of the baseline measurement. In this study, all doses of budiodarone yielded a statistically significant benefit in reducing both the number of atrial fibrillation events and the duration of atrial fibrillation episodes lasting more than 5 hours. Both the 200 mg bid and the 600 mg bid yielded similar results, while the 400 mg bid was significantly better than the drug-free condition (baseline data obtained without budiodarone in each patient), but inferior to the 200 mg bid and the 600 mg bid. Ultimately, the 800 mg bid was the best. At all dose levels, the reduction in atrial fibrillation episodes lasting more than 5 hours was over 85%, and the corresponding reduction in atrial fibrillation load was over 90%.

[0146] In light of the relationship discussed above between prolonged atrial fibrillation episodes and increased risk of stroke and heart failure (see Singer, et al., “Temporal Association Between Episodes of Atrial Fibrillation and Risk of Ischemic Stroke,” JAMA Cardiology, 6(12):1364-1369(2021)), the following comparative examples measured the reduction in atrial fibrillation episodes lasting longer than one hour in patients.

[0147] Example 5: Reduction of prolonged, persistent atrial fibrillation (over 1 hour) during 12 weeks. This example is a clinical trial evaluation of budiodarone in the treatment of six patients with paroxysmal or persistent atrial fibrillation who had previously experienced prolonged episodes of atrial fibrillation (more than 1 hour). In this example, the patients' heart rhythms were continuously monitored for 12 weeks using pacemakers (surgically invasive procedure), and each dose level (different doses of budiodarone administered bid-as-you-go) was used for 2 weeks. Furthermore, the patients were under continuous monitoring and clinician supervision throughout this study.

[0148] The objective of this embodiment is to determine whether budiodarone reduces prolonged atrial fibrillation (duration exceeding 1 hour) by evaluating heart rhythm using a pacemaker in a clinical study setting. The results of this analysis are provided in Table 4 below. [Table 4]

[0149] In this example, a significant reduction was observed in the number of prolonged atrial fibrillation episodes (over 1 hour) during a two-week period. As described above, "number" refers to the number of prolonged atrial fibrillation episodes that occurred during the two-week period, and "duration" refers to the number of hours during which prolonged atrial fibrillation episodes were detected during the two-week period.

[0150] Example 6: Reduction in atrial fibrillation episodes lasting longer than 6 minutes during a 12-week period. This embodiment demonstrates the robust properties of budiodarone in reducing both atrial fibrillation overload and atrial fibrillation episodes lasting longer than 6 minutes (0.1 hours) in six patients with paroxysmal or persistent atrial fibrillation who had previously experienced prolonged atrial fibrillation episodes (longer than 1 hour). In this embodiment, each patient's heart rhythm was continuously monitored using a pacemaker for 12 weeks. Patients were treated with different doses of budiodarone, each dose administered over 2 weeks. Furthermore, patients were continuously monitored and supervised by a clinician throughout this study.

[0151] The results are summarized in Table 5, which confirms that in the clinical trial setting, a pacemaker was used to assess heart rhythm and that budiodarone not only reduces prolonged atrial fibrillation lasting more than one hour, but also significantly reduces episodes lasting more than six minutes (0.1 hours). [Table 5]

[0152] "Number of episodes" refers to the number of atrial fibrillation episodes lasting longer than 6 minutes (0.1 hours) for all study patients during the study period (4 weeks at baseline, 2 weeks at each experimental dose). "Duration" (hours) refers to the cumulative duration (hours) during the study period in which study patients were measured as having atrial fibrillation episodes lasting longer than 6 minutes. The results above demonstrate that budiodarone reduces the number of long-lasting atrial fibrillation episodes and short-lasting atrial fibrillation episodes, thereby providing further protection against stroke and heart failure and significantly reducing the atrial fibrillation burden.

[0153] In patients with paroxysmal and persistent atrial fibrillation and a high CHA2DS2-VASc score (≥3), atrial fibrillation episodes lasting longer than 6 minutes may increase the risk of stroke and / or congestive heart failure. The CHA2DS2 score represents congestive heart failure, hypertension, age (over 65 years = 1 point, over 75 years = 2 points), diabetes, and previous stroke / transient ischemic attack (2 points). VASc represents vascular disease (peripheral artery disease, previous myocardial infarction, aortic atherosclerosis), and gender (female) is also included in this scoring system. The data in Table 5 show that all doses of budiodarone tested significantly reduced the number of atrial fibrillation episodes lasting longer than 6 minutes, and at higher concentrations of 600 mg bid or 800 mg bid, these episodes were reduced by more than 80%.

[0154] Table 6 summarizes the percentage of time patients experienced atrial fibrillation episodes lasting more than 6 minutes on average, and the number of such episodes per week. With budiodarone doses of 600 mg bid and 800 mg bid, the percentage of atrial fibrillation episodes was reduced by 90%. [Table 6]

[0155] The percentage of time atrial fibrillation in patients is a key parameter directly related to the risk factors for stroke and / or congestive heart failure, especially in patients with high CHA2DS2-VASc scores. In Table 6, patients using 200 mg budiodarone twice daily experienced a 76.7% reduction in the percentage of time atrial fibrillation, a further 90% reduction with 600 mg budiodarone twice daily, and a further 94.8% reduction with 800 mg budiodarone twice daily.

[0156] Measurement of the longest atrial fibrillation episode during the period of 7-12 weeks in Example 7 This example is a clinical trial evaluation of six patients treated with different doses of budiodarone, with each dose being tested continuously over a two-week period to determine the longest atrial fibrillation episode experienced at each dose. In this example, each patient's heart rhythm was continuously monitored for 12 weeks using a pacemaker. The different doses and results of this evaluation are provided in Table 7 below. [Table 7]

[0157] The results above demonstrate the variability in prolonged atrial fibrillation (lasting 5 hours or more) among patients treated with different doses of budiodarone. In subjects 4 and 5, treatment with 200 mg of budiodarone twice daily was sufficient to resolve all prolonged atrial fibrillation episodes (longer than 5 hours) in these patients. However, in subject 1, an 800 mg bid of budiodarone was required to resolve all prolonged atrial fibrillation episodes (longer than 5 hours), and in subject 6, a 600 mg bid of budiodarone was required to resolve all episodes. This data highlights the need for long-term monitoring of patients in combination with budiodarone dose adjustments to appropriately treat patients with paroxysmal or persistent atrial fibrillation presenting with prolonged atrial fibrillation episodes.

[0158] The results from Examples 2-7 confirm that using an appropriate amount of budiodarone in combination with monitoring the heart rhythm of the patient being treated can reduce all episodes of prolonged atrial fibrillation lasting more than 5 hours, along with a reduction in overall atrial fibrillation load. These results indicate that progression from paroxysmal atrial fibrillation to persistent atrial fibrillation, or from persistent atrial fibrillation to permanent atrial fibrillation, can be reduced or prevented.

[0159] The administration of budiodarone by this method may be carried out using a pharmaceutical composition containing approximately 1% to 99% budiodarone and the remaining pharmaceutically acceptable excipients, such as corn starch, cellulose, stearic acid, water, or other components. The pharmaceutical composition may be formulated in any form, for example, including one or more of the following: tablets, capsules, powders, and / or other preparations for oral administration; preparations for parenteral administration (such as solutions suitable for one or more of intravenous or intramuscular administration); suppositories and / or enemas; skin preparations and / or transdermal preparations.

[0160] Example 8 - Disappearance of atrial fibrillation episodes lasting more than 5.5 hours or more than 5 hours with long-term budiodarone treatment. This example is a clinical trial evaluation of 72 patients treated with placebo (15 patients), 200 mg bid budiodarone (16 patients), 400 mg bid budiodarone (16 patients), or 600 mg bid budiodarone (13 patients) over a 3-month period (12 weeks, with the first month covering weeks 1-4, the second month covering weeks 5-8, and the third month covering weeks 9-12) sandwiched between baseline and washout periods (four weeks before and four weeks after the 12-week experimental period, during which budiodarone was not administered). In this example, patients' heart rhythms were continuously monitored using pacemakers over the 5-month study period. Table 8 shows the median duration (hours) of atrial fibrillation episodes for each condition (placebo, 200 mg bid, 400 mg bid, 600 mg bid). These results indicate that a statistically significant dose-response and a substantial reduction in the duration of atrial fibrillation episodes were observed at all doses administered during the second and third months of treatment, and even at the first month for the 400 mg bid and 600 mg bid. [Table 8]

[0161] The p-value was calculated using the dose-response Jonckheere-Terpstra test.

[0162] Table 9 shows more detailed results for the 600 mg bid dose compared to placebo. Table 9 shows the number (N) of atrial fibrillation episodes, the mean (with standard deviation (SD)) and median duration (hours) of atrial fibrillation episodes for each month of the experiment in the placebo control group and the 600 mg bid dose group, as well as the maximum duration of atrial fibrillation episodes. [Table 9]

[0163] During the first month following the initiation of budiodarone administration, the mean duration of episodes was reduced to less than 5 hours or less than 5.5 hours (1.4 ± 0.7 (standard error) hours). By 2–3 months after the initiation of treatment (months 2 and 3), all atrial fibrillation episodes exceeding 5 hours or more than 5.5 hours had disappeared, and the mean duration of episodes was reduced to less than 1 hour (0.4 ± 0.2 (standard error) hours and 0.7 ± 0.3 (standard error) hours, respectively). When treatment with budiodarone 600 mg bid was confirmed at months 2 and 3, there were no patients with high atrial fibrillation load in patients receiving budiodarone. Compared to a mean atrial fibrillation load of approximately 35% at baseline, the mean atrial fibrillation load at month 2 in treated patients was approximately 0.5%, and the mean atrial fibrillation load at month 3 in treated patients was approximately 0.8%. This data shows that the methods disclosed herein can be used to significantly reduce or even eliminate atrial fibrillation episodes lasting more than 5 hours or more than 5.5 hours. These methods can also significantly reduce or eliminate the substantial duration of atrial fibrillation overload, for example, by reducing or eliminating more than 10%, more than 5%, or more than 2.5% of atrial fibrillation overload within a given 24-hour period.

[0164] Example 9 - Relief of symptoms in symptomatic patients This example demonstrates that patients with atrial fibrillation syndrome can be evaluated for the relief of symptoms associated with atrial fibrillation and / or overall symptoms. Patients in the Example 8 experiment were evaluated for the relief of symptoms associated with atrial fibrillation by verifying patient-reported outcomes. Patients were surveyed 3 months after treatment with placebo or each budiodarone dose. Table 10 contains the results of the outcomes reported by these patients. [Table 10]

[0165] The results above show that 64.7% of placebo patients reported that their symptoms worsened or did not improve with placebo, compared to 33% across all three doses of budiodarone. Similarly, the percentage of patients who reported moderate, significant, or complete relief of symptoms was 17.7% in the placebo group, compared to 48% across all three doses of budiodarone.

[0166] The results in Table 10 show a dose-dependent improvement in self-reported atrial fibrillation symptoms with budiodarone treatment compared to placebo. (P-values ​​compared to placebo were calculated using the Cochran-Mantel-Haenszel mean score test, and P-value dose-response was calculated using the Jonckheere-Terpstra test).

[0167] Patients were examined for specific symptoms associated with atrial fibrillation (e.g., palpitations and shortness of breath during exercise). Patients rated their symptoms on a scale of 1-6 (1=no symptoms, 2=very few, 3=slight, 4=considerable, 5=many symptoms, 6=very many symptoms), and those with a self-reported symptom score of 2 or higher at baseline were included for symptom follow-up. Table 11 shows dose-dependent improvement in these symptoms compared to placebo: [Table 11]

[0168] Example 10 - Programming a wearable device Wearables can be programmable (e.g., by clinicians, patients, and / or remotely by, for example, a central analysis center). A wearable can be programmed to acquire a patient's heart rate rhythm data. The data thus generated can be queryed and / or analyzed by the CPU on the wearable, and / or transmitted to another device for querying and / or analysis. An example of wearable programming is that it can be used to monitor a patient's heart rate rhythm and transmit the data directly and / or indirectly to, for example, a clinician, as follows: A. User Interface: Step-by-step functionality based on programming an atrial fibrillation monitoring system, including a wearable device, and providing information to the attending clinician via the network. B. The collected data is in a readable format for access by clinicians and other authorized individuals. C. A readable display must be made available at all times to authorized clinicians, and only authorized clinicians should be permitted to save the data and / or reset the monitoring system after performing one or more of the following steps 1-15. D. The patient's drug exposure, dosage, and / or any other medications may be obtained by the clinician from the patient's medical records as needed, for example, by integrating the monitoring system with the patient's medical records (e.g., electronic medical records). E. Only steps 1-14 need to be entered manually, but step 14 is optimal and can be overwritten by the clinician simply by pressing manual reset (step 15). F. All data may be retained after review by the attending clinician, who may be permitted to program the consolidation of previous observation periods, regardless of whether or not atrial fibrillation medications, including budiodarone, were used (Step 17). The G system is user-friendly, and the attending clinician only needs to do the following four things each time: 1) enter the patient or code to access the data, 2) review the data display, 3) enter the budiodarone dose in step 14 if desired, and then 4) press manual reset to save the data. H. The attending clinician accesses the saved data, consolidates the observation periods, and compares the characteristics of atrial fibrillation with different doses of budiodarone or no medication (Step 17).

[0169] Each step is shown in Table 12 below. [Table 12]

[0170] Each of steps 4-13 may be included in or excluded from the wearable programming, as long as at least one of these steps is included (e.g., at the clinician's discretion). In one embodiment, steps 4-7 may be performed, corresponding data may be collected, and one or more of steps 8-13 may be excluded. In another embodiment, steps 4, 5, 8, and 9 may be included, and steps 5, 6, and 10-13 may be excluded. In yet another embodiment, steps 4, 5, 10, and 11 may be included, and steps 6, 7, 8, 9, 12, and 13 may be excluded. In yet another embodiment, steps 4, 5, 12, and 13 may be included, and steps 6-11 may be excluded.

[0171] In yet another embodiment, the attending clinician may program the wearable according to one or more of steps 4-13. [Table 13]

[0172] Embodiment Specific embodiments are shown below.

[0173] Embodiment I-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive budiodarone therapy, a) Administering a first dose of budiodarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient's heart rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of budiodarone or a pharmaceutically acceptable salt thereof. b) To evaluate whether the first dose is effective for the patient, monitor the eligible patient for the effectiveness of the administered first dose of budiodarone or a pharmaceutically acceptable salt thereof for a comparison period of one day or more, provided that the evaluation of the effectiveness of budiodarone (where the therapy is budiodarone or a pharmaceutically acceptable salt thereof) is delayed by at least 7 or 14 days after the initiation of budiodarone therapy at the first dose, and monitor the patient. c) If the first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of budiodarone necessary to achieve effective results using at least the same delay and comparison periods as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from budiodarone therapy. d) If the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of budiodarone remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

[0174] Embodiment I-2. The method according to Embodiment I-1, wherein the patient is eligible to receive budiodarone therapy (wherein the therapy is budiodarone or a pharmaceutically acceptable salt thereof) based on at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not receiving budiodarone therapy.

[0175] Embodiment I-3. The method according to Embodiment I-1, wherein the patient is eligible to receive budiodarone therapy (wherein the therapy is budiodarone or a pharmaceutically acceptable salt thereof) based on having a baseline level of atrial fibrillation load for at least 5 hours during at least 7 or 14 days in which the patient is not administered budiodarone therapy.

[0176] Embodiment I-4. The method according to any one of Embodiments I-1 to I-3, wherein the monitoring in step b) is performed continuously.

[0177] Embodiment I-5. The method according to any one of Embodiments I-1 to I-4, wherein the efficacy of the budiodarone therapy at the dose (wherein the therapy is budiodarone or a pharmaceutically acceptable salt thereof) is evaluated by comparing the baseline level of atrial fibrillation with the corresponding level of atrial fibrillation during the comparison period.

[0178] Embodiment I-6. The method according to any one of Embodiments I-1 to I-5, wherein the comparison period is one or more of approximately 1 day, approximately 1 week, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or up to approximately 6 months.

[0179] Embodiment I-7. The method according to any one of Embodiments I-1 to I-5, wherein a second comparison period of similar length is followed after the first comparison period.

[0180] Embodiment I-8. The method according to any one of Embodiments I-1 to I-7, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

[0181] Embodiment I-9. The method according to any one of Embodiments I-1 to I-8, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

[0182] Embodiment I-10. The method according to any one of Embodiments I-1 to I-9, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

[0183] Embodiment I-11. The method according to any one of Embodiments I-1 to I-10, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate.

[0184] Embodiment I-12. The method according to any one of Embodiments I-1 to I-11, further comprising providing an electrophysiological intervention to the patient if, in step c), the patient is excluded from budiodarone therapy (wherein the therapy is budiodarone or a pharmaceutically acceptable salt thereof).

[0185] A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive budiodarone therapy (where the therapy is budiodarone or a pharmaceutically acceptable salt thereof), In the case of a patient who is eligible to receive budiodarone therapy (where the therapy is budiodarone or a pharmaceutically acceptable salt thereof), eligibility requires that the patient has experienced at least one long-lasting episode of atrial fibrillation lasting at least one hour over an eligibility period, or has at least 2.5% atrial fibrillation load over the entire eligibility period, the eligibility period being at least two weeks during which the patient is not treated with budiodarone, a) Administering a first dose of budiodarone to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of budiodarone; b) Monitoring the patient for the effectiveness of the first dose of budiodarone administered for a comparison period of one day or more in order to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of budiodarone is delayed by at least 7 or 14 days after the initiation of budiodarone therapy at the first dose. c) If the administered first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of budiodarone necessary to achieve effective results using at least the same delay and comparison periods as in b), wherein the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from budiodarone therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of budiodarone remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

[0186] Embodiment II-2. The method according to Embodiment II-1, wherein the monitoring in step b) is performed continuously.

[0187] Embodiment II-3. The method according to any one of Embodiments II-1 to II-2, wherein the effectiveness of the therapy is evaluated by comparing the baseline level of atrial fibrillation with the corresponding atrial fibrillation level during the comparison period.

[0188] Embodiment II-4. The method according to any one of Embodiments II-1 to II-3, wherein the comparison period is one or more of approximately 1 day, approximately 1 week, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or up to approximately 6 months.

[0189] Embodiment II-5. The method according to any one of Embodiments II-1 to II-4, wherein a second comparison period of similar length is followed after the first comparison period.

[0190] Embodiment II-6. The method according to any one of Embodiments II-1 to II-5, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

[0191] Embodiment II-7. A method according to any one of Embodiments II-1 to II-6, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

[0192] Embodiment II-8. The method according to any one of Embodiments II-1 to II-7, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

[0193] Embodiment II-9. The method according to any one of Embodiments II-1 to II-8, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate.

[0194] Embodiment II-10. The method according to any one of Embodiments II-1 to II-9, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from budiodarone therapy in step c).

[0195] Embodiment III-1 A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive drug therapy with pharmaceuticals, a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug. b) Monitoring the patient for the effectiveness of the first dose of the drug administered to him for a comparison period of one day or more in order to evaluate whether the dose is effective for him, provided that the evaluation of the effectiveness of the drug is delayed by at least 7 or 14 days after the start of drug therapy with the drug at the first dose, c) If the first dose is evaluated as ineffective for the patient by the end of the comparison period, make one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay period and comparison period as in b), provided that the dose adjustment is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

[0196] Embodiment III-2. The method according to Embodiment III-1, wherein the patient is eligible to receive pharmacotherapy with the drug based on at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not administered the drug.

[0197] Embodiment III-3. The method according to any one of Embodiments III-1 to III-2, wherein the patient is eligible to receive pharmacotherapy with the drug on the basis that the patient has a baseline level of atrial fibrillation load of at least 5 hours during at least 7 or 14 days in which the patient is not administered the drug.

[0198] Embodiment III-4. The method according to any one of Embodiments III-1 to III-3, wherein the monitoring in part c) is performed continuously.

[0199] Embodiment III-5. The method according to any one of Embodiments III-1 to III-4, wherein the efficacy of the drug therapy with the drug at the dose is evaluated by comparing the baseline level of atrial fibrillation with the corresponding level of atrial fibrillation during the comparison period.

[0200] Embodiment III-6. The method according to any one of Embodiments III-1 to III-5, wherein the comparison period is one or more of approximately 1 day, approximately 1 week, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or up to approximately 6 months.

[0201] Embodiment III-7. The method according to any one of Embodiments III-1 to III-6, wherein a second comparison period of the same length is followed after the first comparison period.

[0202] Embodiment III-8. A method according to any one of Embodiments III-1 to III-7, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

[0203] Embodiment III-9. The method according to any one of Embodiments III-1 to III-8, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

[0204] Embodiment III-10. The method according to any one of Embodiments III-1 to III-9, wherein one or more symptoms associated with atrial fibrillation are evaluated using one or more patient reports of the number or severity of the one or more symptoms.

[0205] Embodiment III-11. The method according to any one of Embodiments III-1 to III-10, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from drug therapy in step c).

[0206] Embodiment IV-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and who is eligible to receive drug therapy with pharmaceuticals, In the case of a patient who is eligible to receive drug therapy with the aforementioned drug, eligibility requires that the patient has experienced at least one episode of prolonged atrial fibrillation lasting at least one hour during the eligibility assessment period, or has at least 2.5% atrial fibrillation load during the entire eligibility assessment period, the eligibility assessment period being at least two weeks during which the patient is not treated with the aforementioned drug, a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug. b) Monitoring the patient for the effectiveness of the administered first dose of the drug for a comparison period of one day or more in order to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least 7 or 14 days after the initiation of drug therapy with the first dose, c) If the administered first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay and comparison periods as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

[0207] Embodiment IV-2. The method according to Embodiment IV-1, wherein the monitoring in step b) is performed continuously.

[0208] Embodiment IV-3. The method according to any one of Embodiments IV-1 to IV-2, wherein the efficacy of the drug therapy with the drug at the dose is evaluated by comparing the baseline level of atrial fibrillation with the corresponding atrial fibrillation level during the comparison period.

[0209] Embodiment IV-4. The method according to any one of Embodiments IV-1 to IV-3, wherein the comparison period is one or more of approximately 1 day, approximately 1 week, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or up to approximately 6 months.

[0210] Embodiment IV-5. The method according to any one of Embodiments IV-1 to IV-4, wherein a second comparison period of similar length is followed after the first comparison period.

[0211] Embodiment IV-6. The method according to any one of Embodiments IV-1 to IV-5, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

[0212] Embodiment IV-7. The method according to any one of Embodiments IV-1 to IV-6, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

[0213] Embodiment IV-8. The method according to any one of Embodiments IV-1 to IV-7, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

[0214] Embodiment IV-9. The method according to any one of Embodiments IV-1 to IV-8, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from the drug therapy in step c).

[0215] Embodiment V. Use of budiodarone or a pharmaceutically acceptable salt thereof for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy, according to any of the embodiments described above.

[0216] Embodiment VI. A composition for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy, according to any of the above embodiments, the composition being budiodarone or a pharmaceutically acceptable salt thereof (e.g., budiodarone tartrate or budiodarone citrate).

Claims

1. A method for treating patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who are eligible to receive budiodarone therapy, a) Administering a first dose of budiodarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of budiodarone or a pharmaceutically acceptable salt thereof, b) To evaluate whether the first dose is effective for the patient, monitor the eligible patient for the effectiveness of the administered first dose of budiodarone or a pharmaceutically acceptable salt thereof for a comparison period of one day or more, provided that the evaluation of the effectiveness of budiodarone is delayed by at least seven or fourteen days after the initiation of budiodarone therapy at the first dose. c) If the first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of budiodarone or a pharmaceutically acceptable salt thereof, using at least the same delay and comparison period as in b), provided that the adjusted dose is less than or equal to the approved maximum dose; or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from budiodarone therapy. d) If the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of budiodarone or a pharmaceutically acceptable salt thereof remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

2. The method according to claim 1, wherein the patient is eligible to receive budiodarone therapy based on at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not receiving budiodarone therapy.

3. The method according to claim 1, wherein the patient is eligible to receive budiodarone therapy on the basis that he or she has a baseline level of atrial fibrillation load of at least 5 hours during at least 7 or 14 days in which the patient is not administered budiodarone therapy.

4. The method according to any one of claims 1 to 3, wherein monitoring in step b) is performed continuously.

5. The method according to any one of claims 1 to 4, wherein the efficacy of the budiodarone therapy at the dose is evaluated by comparing the baseline level of atrial fibrillation with the corresponding level of atrial fibrillation during the comparison period.

6. The method according to any one of claims 1 to 5, wherein the comparison period is one or more of approximately 1 day, approximately 1 week, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or up to approximately 6 months.

7. The method according to claim 6, wherein a second comparison period of the same length is followed after the first comparison period.

8. The method according to any one of claims 1 to 7, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

9. The method according to any one of claims 1 to 7, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

10. The method according to any one of claims 1 to 9, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

11. The method according to any one of claims 1 to 10, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate.

12. The method according to any one of claims 1 to 11, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from budiodarone therapy in step c).

13. A method for treating patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who are eligible to receive budiodarone therapy, In the case of a patient who is eligible to receive budiodarone therapy, eligibility requires that the patient has experienced at least one long-lasting atrial fibrillation episode lasting at least one hour over the eligibility period, or has at least 2.5% atrial fibrillation load over the entire eligibility period, the eligibility period being at least two weeks during which the patient is not treated with budiodarone, a) Administering a first dose of budiodarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of budiodarone; b) Monitoring the patient for the effectiveness of the first dose of budiodarone or a pharmaceutically acceptable salt thereof administered to the patient for a comparison period of one day or more, provided that the evaluation of the effectiveness of budiodarone is delayed by at least seven or fourteen days after the initiation of budiodarone therapy at the first dose. c) If the administered first dose is evaluated as ineffective in the patient by the end of the comparison period, perform one or more dose adjustments of budiodarone or a pharmaceutically acceptable salt thereof, using at least the same delay and comparison periods as in b), wherein the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from budiodarone therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of budiodarone or a pharmaceutically acceptable salt thereof remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

14. The method according to claim 13, wherein monitoring in step b) is performed continuously.

15. The method according to claim 13 or 14, wherein the efficacy of the budiodarone therapy at the dose is evaluated by comparing the baseline level of atrial fibrillation with the corresponding level of atrial fibrillation during the comparison period.

16. The method according to any one of claims 13 to 15, wherein the comparison period is one or more of approximately one day, approximately one week, approximately one month, approximately two months, approximately three months, approximately four months, approximately five months, or up to approximately six months.

17. The method according to claim 16, wherein a second comparison period of the same length is followed after the first comparison period.

18. The method according to any one of claims 13 to 17, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

19. The method according to any one of claims 13 to 18, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

20. The method according to any one of claims 13 to 19, wherein one or more symptoms associated with atrial fibrillation are evaluated by the patient using reports from one or more patients regarding the number or severity of the one or more symptoms.

21. The method according to any one of claims 13 to 20, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate.

22. The method according to any one of claims 13 to 21, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from budiodarone therapy in step c).

23. A method for treating patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who are eligible to receive drug therapy with pharmaceuticals, a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug; b) Monitoring the patient for the effectiveness of the first dose of the drug administered for a comparison period of one day or more in order to evaluate whether the dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least seven or fourteen days after the start of drug therapy with the drug at the first dose, c) If the first dose is evaluated as ineffective for the patient by the end of the comparison period, make one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay period and comparison period as in b), provided that the dose adjustment is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

24. The method according to claim 23, wherein the patient is eligible to receive pharmacotherapy with the drug based on at least one episode of atrial fibrillation lasting at least about 5 hours or at least about 5.5 hours during at least 7 or 14 days in which the patient is not administered the drug.

25. The method according to claim 23, wherein the patient is eligible to receive pharmacotherapy with the drug on the basis that the patient has a baseline level of atrial fibrillation load of at least 5 hours during at least 7 or 14 days in which the patient is not administered the drug.

26. The method according to any one of claims 23 to 25, wherein monitoring in part c) is performed continuously.

27. The method according to any one of claims 23 to 26, wherein the efficacy of the drug therapy with the drug at the aforementioned dosage is evaluated by comparing the baseline level of atrial fibrillation with the corresponding atrial fibrillation level during the comparison period.

28. The method according to any one of claims 23 to 27, wherein the comparison period is one or more of approximately one day, approximately one week, approximately one month, approximately two months, approximately three months, approximately four months, approximately five months, or up to approximately six months.

29. The method according to claim 28, wherein a second comparison period of the same length is followed after the first comparison period.

30. The method according to any one of claims 23 to 29, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

31. The method according to any one of claims 23 to 29, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

32. The method according to any one of claims 23 to 31, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

33. The method according to any one of claims 23 to 32, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from the drug therapy in step c).

34. A method for treating patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who are eligible to receive drug therapy with pharmaceuticals, In the case of a patient who is eligible to receive drug therapy with the aforementioned drug, eligibility requires that the patient has experienced at least one episode of prolonged atrial fibrillation lasting at least one hour during the eligibility assessment period, or has at least 2.5% atrial fibrillation load during the entire eligibility assessment period, the eligibility assessment period being at least two weeks during which the patient is not treated with the aforementioned drug, a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rate rhythm data using a wearable, wherein the first dose is an approved therapeutic dose that is less than the approved maximum dose of the drug; b) Monitoring the patient for the effectiveness of the first dose of the drug administered for a comparison period of one day or more in order to evaluate whether the first dose is effective for the patient, provided that the evaluation of the effectiveness of the drug is delayed by at least seven or fourteen days after the initiation of drug therapy with the first dose, c) If the administered first dose is evaluated as ineffective for the patient by the end of the comparison period, perform one or more dose adjustments of the amount of the drug necessary to achieve effective results using at least the same delay period and comparison period as in b), provided that the adjusted dose is less than or equal to the approved maximum dose, or, if effective results are not achieved when evaluated at the approved maximum dose, exclude the patient from the drug therapy. d) If the dose of the first dose or adjusted dose is effective for the patient, continue monitoring the patient's heart rhythm data to confirm that the dose of the drug remains effective, provided that if the dose is no longer effective, repeat step c) using the dose as the first dose. Methods that include...

35. The method according to claim 34, wherein monitoring in step b) is performed continuously.

36. The method according to claim 34 or 35, wherein the efficacy of the drug therapy with the drug at the aforementioned dosage is evaluated by comparing the baseline level of atrial fibrillation with the corresponding atrial fibrillation level during the comparison period.

37. The method according to any one of claims 34 to 36, wherein the comparison period is one or more of approximately one day, approximately one week, approximately one month, approximately two months, approximately three months, approximately four months, approximately five months, or up to approximately six months.

38. The method according to claim 37, wherein a second comparison period of the same length is followed after the first comparison period.

39. The method according to any one of claims 34 to 38, for monitoring an atrial fibrillation episode lasting more than approximately 5 hours.

40. The method according to any one of claims 34 to 38, for monitoring an atrial fibrillation episode lasting more than approximately 5.5 hours.

41. The method according to any one of claims 34 to 40, wherein one or more symptoms associated with atrial fibrillation are evaluated using reports from one or more patients regarding the number or severity of the one or more symptoms.

42. The method according to any one of claims 34 to 41, further comprising subjecting the patient to an electrophysiological intervention if the patient is excluded from drug therapy in step c).

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