Methods of treating atrial fibrillation with bundarone

Abstract

For paroxysmal or persistent AFib patients, if its untreated AFib level exceeds a threshold level of AFib, treatment is eligible with a drug (e.g., Bronidalon) capable of controlling the patient's heart rhythm. A qualified patient is subjected to drug treatment while monitoring its heart rate using a wearable device. If it is considered that the administered dose of medicament is invalid, adjusting the dose until an effective dose is determined for the patient; if the patient is confirmed to be non-reactive to the drug, the treatment is withdrawn.

Description

TECHNICAL FIELD

[0001] Disclosed are methods for treating atrial fibrillation (AFib) in patients diagnosed with paroxysmal or persistent AFib and determined to be likely to benefit from medical therapy.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application 63 / 525,093, filed July 5, 2023, the entirety of which is incorporated by reference herein in its entirety. BACKGROUND

[0004] AFib is a serious disease characterized by abnormal heart rhythm, often with an increased heart rate. There are three basic types of AFib: paroxysmal, persistent, and permanent. Paroxysmal and persistent AFib are characterized by spontaneous episodes of AFib during periods of sinus rhythm, while permanent AFib is characterized by a persistent atrial fibrillation state that can only be indirectly treated with medication (e.g., blood thinners).

[0005] Untreated paroxysmal and persistent AFib increases the risk of stroke, congestive heart failure, and death. The degree of this increased risk varies depending on the severity of the AFib in a particular patient. The variability of the increased risk also depends on the severity of the AFib in a particular patient. Untreated patients with paroxysmal or persistent AFib will progress from paroxysmal to persistent AFib, or from persistent to permanent AFib, respectively, over time.

[0006] Some patients with paroxysmal or persistent AFib experience brief episodes of AFib, each lasting less than 1 hour, and / or accumulate less than 5 hours of AFib burden over any 24-hour period. Such patients are referred to herein as “mild AFib patients.” Mild AFib patients have a significantly reduced risk of stroke, congestive heart failure, and death compared to their peers who experience longer or more frequent episodes of AFib. de minimis AFib”). Permanent AFib patients suffer the highest risk of stroke, congestive heart failure, and death, and are generally unresponsive to medical intervention.

[0007] Currently, medication for AFib patients is not intended to control their AFib, but rather to reduce the stroke-related risk caused by thrombosis resulting from AFib by, for example, prescribing blood thinners. The use of such blood thinners is not a panacea, but comes at a cost. The rationale for prescribing blood thinners is that, despite the significant risks associated with their use, they pose a lower risk of harm to AFib patients than AFib itself, which is left untreated. According to a report cited by MarketInsider, the QuarterWatch 2016 Annual Report (Institute for Safe Medication Practices. (2016). Quarterwatch: Monitoring FDA MedWatch reports . Annual Report Issue), in 2016, adverse events resulting from the use of anticoagulants were the most common among all prescription or over-the-counter drugs, specifically, 21,996 serious injury events in the United States, including 3,018 deaths were reported. In clinical trials, anticoagulants have repeatedly demonstrated high rates of harm, with 8% to 19% of patients experiencing bleeding in those receiving a year of treatment. The QuarterWatch 2016 report estimated that 6.3% of patients exposed to anticoagulants for a year would require emergency department visits for adverse drug reactions, and 3.1% would require hospitalization.

[0008] Approximately two-thirds of AFib patients have symptoms, with symptom severity ranging from mild to debilitating. Physical symptoms include, but are not limited to, general weakness, weakness with exercise or exertion, syncope, dizziness, confusion, rapid and / or irregular heartbeat, a fluttering or pounding sensation in the chest, shortness of breath, lightheadedness, weakness, confusion, sweating, chest pain, and / or a sense of oppression. However, regardless of the degree of physical symptoms, the corresponding psychological anxiety of the patient about the underlying cardiac problem can be severe and can manifest as psychological symptoms such as anxiety, depression, and / or depression. In turn, these psychological symptoms exacerbate the patient’s AFib, and these psychological symptoms are serious health problems in their own right. Thus, the ability to reduce AFib symptoms is an important aspect of treating symptomatic AFib patients.

[0009] Regardless of whether a patient's AFib is symptomatic or asymptomatic, studies have shown that the risk of stroke and / or heart failure is not related to whether the patient experiences symptoms associated with AFib. See, e.g., Flaker, et al., "Asymptomatic Atrial Fibrillation: Demographic Features and Prognostic Information from the Atrial Fibrillation Follow-Up Investigation of Rhythmic Management (AFFIRM) Study," J. Am. Coll. Cardiol., Vol. 45, No. 5, March 2005, pp. 657-663, the entire contents of which are incorporated herein by reference. Whether or not a patient is aware of periodic AFib episodes does not correlate with a difference in risk of stroke or congestive heart failure. Rather, this indicates that symptomatic patients are more aware of their condition and are more likely to seek medical intervention. American Heart Journal

[0010] The difficulty with conventional medical intervention for paroxysmal and persistent AFib is that the episodic and unpredictable nature of each episode of AFib makes it impossible for a clinician to properly assess the extent of a patient's AFib or the efficacy of a drug used to treat the AFib. Unlike conventional drug therapy, where the efficacy of a drug is measured by using standardized tests that measure a particular goal (e.g., a cholesterol test) after a period of time following the initiation of therapy, a clinician cannot use electrocardiogram (EKG) information collected during a routine office visit to determine how many episodes of AFib a patient has experienced since the last office visit, the duration of each episode of AFib, or the AFib burden.

[0011] Accordingly, several problems remain in the use of drug therapy for patients with paroxysmal and persistent AFib. These problems include the inability of a clinician to determine: the extent of a patient's AFib, which is necessary to determine whether a patient's AFib requires drug therapy; whether a particular drug is effective for a particular patient; what dosage of a drug that is effective for a patient is; and whether or when a patient receiving drug therapy is non-responsive to the drug and should be withdrawn from the drug therapy. SUMMARY

[0012] ​This article discloses methods for identifying and qualifying patients who are eligible for drug therapy with heart rate control medications, among whom the identified and qualified patients are most likely to benefit from the medication. In the methods described herein, patients with mild AFib are not recommended for treatment because their risk of stroke or heart failure is extremely low, as the associated risks of drug therapy may be higher for these patients. Similarly, patients with permanent AFib are considered unlikely to benefit from the drug therapy. Therefore, these methods identify patients with paroxysmal or persistent AFib as eligible for further evaluation to determine whether their AFib exceeds the mild level (discussed in detail below). Upon completion of the evaluation, patients with either permanent or mild AFib are excluded from drug therapy, thus providing a precisely defined subset of patients eligible for drug therapy.

[0013] In the absence of any pharmacological treatment, cardiac rhythm monitoring is performed on patients with AFib for at least 7 days or a sufficiently long period to provide baseline AFib levels (e.g., baseline levels of AFib-related symptoms, baseline number of AFib episodes during that period, and / or baseline AFib burden during that period) for assessment. Typically, this assessment period for patient monitoring (referred to herein as the eligibility period) is at least 1 week, at least 2 weeks, but longer periods of 1 month (e.g., 4 weeks) or longer may be considered. Longer periods provide a more accurate measurement of the patient's AFib levels. Patients identified as having mild or permanent AFib will be disqualified, and the remaining patients are considered capable or eligible for pharmacological treatment.

[0014] In some implementations, the method includes: a) developing a eligibility protocol based on heart rhythm data generated by a wearable device during the eligibility period to determine whether a patient is likely to benefit from drug treatment; b) developing a treatment protocol to determine and maintain an effective dose of the drug for the patient. This treatment protocol uses the wearable device to monitor the patient's heart rhythm data to determine the efficacy of one or more doses of the drug administered during iterations until an effective dose is achieved, or, if efficacy is not achieved, to discontinue treatment; and c) using the wearable device to monitor the heart rhythm data of an eligible patient who has been administered an effective dose of the drug to ensure that the administered dose remains effective, or, if ineffective, adjust the amount of drug administered to achieve a new effective dose, or, if ineffective, determine that the patient is now unresponsive to the treatment and discontinue the drug treatment.

[0015] In one implementation, eligible patients begin drug treatment at the first (approved) dose of the drug. The first dose may be selected by the attending physician based on the patient's baseline data. In one implementation, the first dose is the lowest approved dose. In another implementation, the first dose is any approved dose less than the maximum approved dose. Cardiac rhythm monitoring is performed on patients receiving drug treatment, and optionally, symptoms associated with AFib are monitored. Cardiac rhythm monitoring is performed using wearable devices (e.g., as described herein) to determine the efficacy of the drug treatment.

[0016] Once monitoring begins, the patient's heart rhythm (and optional AFib-related symptoms) should be assessed to determine the effectiveness of the drug at that dose. The shortest assessment period duration and minimum time resolution should be selected to accurately characterize the patient's AFib levels at that dose. The assessment period duration should be sufficient to allow the drug to reach a stable concentration in the body. For example, the assessment period duration could be at least 3 days, at least 1 week, and at least 2 weeks after the start of treatment. Alternatively, the shortest assessment period could begin when the drug reaches steady-state plasma concentrations (e.g., at least 2–3 days after the start of budiodarone treatment) and last for at least 1 day, at least 3 days, at least 1 week, and at least 2 weeks. Alternatively, the assessment period could begin when the patient's AFib levels reach steady state (e.g., no significant change between consecutive assessment periods). Eligible patients showing effective results at a given dose should maintain that dose. Alternatively, eligible patients showing effective results at a given dose may determine the lowest effective dose through one or more dose adjustments by reducing the dose. Eligible patients who do not show effective results at the first dose (or a given dose) may have their dose adjusted one or more times by increasing the drug dose until they show effective results (e.g., by reducing the duration of AFib attacks, maximum duration, number of attacks within a given duration, AFib load, etc., and / or by reducing the risk of stroke and / or congestive heart failure, as described elsewhere in this document), or if they do not show effective results even at the highest approved dose. Such patients are considered unresponsive to the drug and are therefore disqualified and excluded from drug treatment.

[0017] In some cases, patients who achieve effective results at a given dose may experience drug side effects and / or face risks arising from them. Clinicians can adjust the dose based on these side effects and / or risks, aiming to reduce the side effects or risk of side effects while maintaining efficacy.

[0018] These methods provide a procedure for identifying a unique and exclusive patient population most likely to benefit from drug therapy with a heart rate-controlling agent (e.g., bunidarone). This patient population cannot be identified using conventional methods. These methods define a patient subset by excluding patients with permanent AFib, thereby eliminating approximately 50% of AFib patients. Furthermore, these methods define an even more stringent patient subset by further excluding patients identified as having mild AFib (as described herein). Patients with mild AFib have a limited risk of stroke and / or heart failure, thus limiting the benefit of drug therapy to reduce such risks by regulating heart rate. This stringent patient subset is then eligible for drug therapy with the medication.

[0019] In another implementation, eligible patients receiving drug therapy are evaluated to determine the efficacy of the drug after increasing the dosage, until a therapeutic effect is achieved or until the patient is deemed unresponsive and excluded from treatment. At the heart of this approach is continuous monitoring of the patient's heart rhythm (and optionally, AFib-related symptoms) to determine whether and when the patient has responded to the drug. The time span and temporal resolution of the monitoring should be sufficient to accurately determine the AFib levels of eligible patients during treatment. Those patients who achieve effective results from the drug dosage represent a unique subgroup of patients who respond to drug therapy. Patient monitoring continues for responsive patients during treatment to ensure that the given dosage of the drug that has proven effective for the patient remains effective. If at any point it is determined that the drug dosage is no longer effective for the patient, a dosage adjustment is made. For eligible patients receiving drug therapy, monitoring continues while dose adjustments are made, if or until the patient becomes unresponsive to treatment and is discontinued.

[0020] The methods described in this paper provide a novel paradigm for treating a subgroup of AFib patients that addresses the potentially sporadic and unpredictable nature of the disease. Patients who would benefit from drug treatment are identified, while those who would not benefit are excluded. Furthermore, patients who initially showed drug efficacy but later developed resistance to the drug are identified and subsequently excluded from treatment. Therefore, unlike current AFib treatments where any drug efficacy is difficult or impossible to measure, the methods described in this paper consistently establish efficacy within a specifically defined subgroup of AFib patients by monitoring the exclusion of patients unlikely to benefit from drug treatment before treatment and by monitoring the exclusion of unresponsive patients during drug treatment.

[0021] A significant advantage of the methods described in this paper is that, using these methods as a first-line treatment for eligible patients, only those excluded from drug therapy (e.g., before or after drug therapy initiation) can be referred for electrophysiological intervention (ablation) to treat their AFIb, provided that their AFIb is severe enough to warrant ablation. Targeted therapy is administered to patients most likely to benefit from drug therapy, and the eligible patient population is dynamically defined after treatment initiation, thus avoiding the unnecessary use of costly and highly invasive ablation procedures for patients who respond to significantly lower-cost, less invasive drug therapies.

[0022] In one embodiment, the drug treatment comprises administration of bunidarone or a pharmaceutically acceptable salt thereof, the IUPAC name of bunidarone being (2-[3-[4-[2-(diethylamino)ethoxy]-3,5-diiodobenzoyl]-1-benzofuran-2-yl]acetic acid[(2 S [(-But-2-yl) ester]. Bunidarone is a compound that has been shown to reduce the risk of stroke in patients with paroxysmal and / or persistent AFib, including those who have not responded to other treatments, see, for example, U.S. Patent No. 9,549,912, the entire contents of which are incorporated herein by reference.

[0023] In one implementation, the patient eligibility period described herein provides clinicians with a baseline assessment of the extent of prolonged AFIb attacks (longer than approximately 5 hours or approximately 5.5 hours) and / or AFIb load exceeding 5 hours in any given 24-hour period. For patients receiving a given dose of bunidarone, a valid outcome is defined as one or more of the following relative to the corresponding baseline assessment data during the comparison period following the initiation of bunidarone at the stated dose: a) Reduce the number of AFib seizures lasting longer than approximately 5 hours or approximately 5.5 hours, wherein said reduction results in a decrease of at least 30% in such AFib seizures relative to the comparison period; or b) The maximum AFib load is reduced by at least 30% relative to the comparison period within any 24-hour time period; or c) Symptoms were reduced compared to the comparison period, in which the patients were symptomatic and their symptoms were related to AFib.

[0024] In one implementation, eligible patients with AFib symptoms face the risk of anxiety, depression, and / or depressive symptoms due to their diagnosis and / or symptoms. A positive outcome can also be a reduction in the overall level of symptoms experienced by the patient. For example, the procedure in Example 9 can be used to assess the reduction of patient symptoms and / or overall symptoms.

[0025] The aforementioned comparison period is intended to provide a time limit for determining the efficacy of drug treatment. Without such a limitation, the comparison period could be considered to be indefinitely extended, lasting for years or decades. Therefore, for the purposes of this document, the comparison period refers to a period of time following the commencement of the aforementioned efficacy monitoring, during which cardiac rhythm data obtained from the patient (e.g., via wearable devices provided to and / or used by the patient) are analyzed to compare with the patient's previous cardiac rhythm data and / or AFib data (e.g., baseline data obtained during the eligibility period, and / or data obtained during previous comparison periods). In one implementation, the comparison period is at least as long as the eligibility period described herein, or based on different time periods, such as daily, weekly, and at least about 2 weeks (e.g., 13, 14, or 15 days) or two, three, or four times longer (i.e., at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks). In one instance, the length of the comparison period should be at least longer than the time it takes for the drug level in the patient to be substantially stable (e.g., at least 2-3 days, 7 days, 14 days, etc. in patients receiving bunidarone), or if the comparison period begins after the drug level in the patient has been substantially stable (e.g., 2 or 3 days after starting bunidarone at a given dose), the length of the comparison period can be shorter (e.g., continuously, or 1 day or longer).

[0026] It is recognized in the art that AFib is a progressive disease, even with effective drug treatment; therefore, a comparison period exceeding 6 months does not necessarily demonstrate drug efficacy, as disease progression and drug efficacy cannot be distinguished (similar to chemotherapy in cancer). Therefore, in some implementations, comparison periods are daily, weekly, 2-week, 4-week, 6-week, 8-week, 12-week, and no longer than 24 weeks. Once the first comparison period is completed, drug efficacy can be determined. Subsequent comparison periods are used to a) ensure that the drug dose remains effective for responsive patients; or b) determine the efficacy of higher doses for patients who do not respond to the currently used dose. If, during the comparison period, a patient does not respond to the drug at the highest approved dose, the patient is discontinued from drug treatment. In this case, the patient may be referred to an electrophysiology department for treatment (e.g., ablation).

[0027] Medical data indicate that patients who do not experience an AFib attack lasting more than 5.5 hours have a significantly reduced risk of stroke. See, for example, 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-tachycardiapacemakers.” Journal of the American College of Cardiology , 46(10), 1913-1920) and the TRENDS study (see 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, bunidarone treatment is based on an approved dose that reduces such long attacks by at least 50%, more preferably, at least 80%, and even more preferably, eliminates such long attacks during the comparison period. In another embodiment, bunidarone treatment is based on an approved dose that reduces AFib long attacks lasting more than 1 hour by at least 50%, preferably, at least 80%, and more preferably, eliminates such long attacks during the comparison period. In any case, the ability to limit AFib attacks lasting more than 5.5 hours or 1 hour during the comparison period reduces the patient's stroke risk, while eliminating such attacks during the comparison period puts the patient in a perceived "safer haven," or more accurately, into a "safer haven."

[0028] Therefore, in one embodiment, a method is provided for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, the method comprising: a) Administer a first dose of bunidarone to the eligible patient while monitoring with a wearable device to collect cardiac rhythm data of the eligible patient, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of bunidarone. b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of bunidarone in the eligible patients to determine whether the first dose is effective for the patients, provided that the efficacy of bunidarone is determined at least 7 or 14 days after the start of treatment. c) If the first dose is deemed ineffective for the patient at the end of the comparison period, then, using at least the same delay and comparison period as in b), one or more dose adjustments of binidarone may be made as needed to achieve an effective outcome, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective outcome is still not achieved at the maximum approved dose, the patient may be discontinued from binidarone treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm to ensure that the dose of bunidarone remains effective, provided that if the dose is no longer effective, step c) is repeated with that dose as the first dose.

[0029] In one implementation, the patient is deemed eligible for bunidarone treatment based on the following criteria: the patient experiences at least one AFib episode lasting at least approximately 5 hours or at least approximately 5.5 hours within at least 7 or 14 days prior to bunidarone treatment. Alternatively, the patient is deemed eligible for bunidarone treatment based on the following criteria: the patient's baseline AFib burden is at least 5 hours within at least 7 or 14 days prior to bunidarone treatment.

[0030] In one implementation, monitoring is performed continuously during each assessment dose of bunidarone, while determining whether there are prolonged AFib episodes, so as to notify the patient that such an episode is occurring or has occurred.

[0031] In one implementation, the comparison period can be daily, weekly, every two weeks, longer than one month, longer than two months, longer than three months, longer than four months, longer than five months, or up to six months, while continuous monitoring is performed. In another implementation, to better determine whether a patient has permanent AFib, the evaluation period is extended to four weeks, six weeks, eight weeks, twelve weeks, or longer.

[0032] In one implementation, AFib attacks are tracked for at least about 5 hours or 5.5 hours (e.g., by counting and recording to determine the efficacy of the administered medication, and to alert the patient and / or clinician when a given number of such attacks occurs or when such attacks occur at a given frequency (indicating a risk of stroke and / or congenital heart failure). In another implementation, AFib attacks are tracked for at least about 5.5 hours.

[0033] In one implementation, patients assess their symptoms related to AFib and report (e.g., using a scorecard or an equivalent tool) the frequency and / or severity of their symptoms each day or when they occur.

[0034] In one implementation, if an AFib episode lasting at least about 5 hours or at least about 5.5 hours or longer is detected during any period of eligibility confirmation, comparison, or subsequent monitoring of the patient to determine the efficacy of a given dose, an alert or alarm is issued to the patient (e.g., by monitoring the patient's heart rhythm data to determine the AFib episode via a wearable device, or via a computing device communicatively connected to the wearable device), the clinician determining the patient's AFib (e.g., by receiving heart rhythm data via a clinician-accessible computing device and / or from the wearable device on the patient), and / or a central analysis center receiving data from the patient's wearable device.

[0035] The use of an alert is optional and can be provided immediately upon detection of a prolonged AFib episode so that clinicians and / or patients are aware of the event. The comparison period is independent of the alert and provides data that allows clinicians to compare the efficacy of the drug over time to baseline. In one implementation, the comparison period differs from immediate notification (alert) to the patient and / or attending physician of a prolonged AFib episode that may require immediate attention. While the comparison period is designed to assess the efficacy of a drug (e.g., bunidarone) compared to baseline, immediate notification is intended to alert the patient to any potential medical attention they should seek.

[0036] In one embodiment, a method is provided for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, the method comprising: For patients who have been identified as eligible for treatment with bunidarone, wherein the eligibility requirement is that the patient experiences at least one prolonged AFib attack lasting at least 1 hour during the eligibility period, or an AFib load of at least 2.5% throughout the eligibility period, wherein the eligibility period is at least 2 weeks, during which the patient has not received treatment with the drug: a) Administering a first dose of the drug to an eligible patient while monitoring the patient’s heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the first dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the start of treatment. c) If the first dose administered is deemed ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in b), one or more dose adjustments of the drug may be made as needed to obtain an effective result, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, then the patient may be discontinued from drug treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

[0037] In one embodiment, a method is provided for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy with a medication that suppresses AFib episodes and / or shortens the duration of AFib episodes, the method comprising: for a patient who has been identified as eligible for drug therapy with the medication, wherein the identification requires that the patient experience at least one prolonged AFib episode lasting at least 1 hour during the identification period, or an AFib load of at least 2.5% throughout the identification period, wherein the identification period is at least 2 weeks, during which the patient has not received treatment with the medication: a) Administering a first dose of the drug to an eligible patient while monitoring the patient's heart rhythm using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the first dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the start of treatment. c) If the first dose administered is deemed ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in b), one or more dose adjustments of the drug may be made as needed to obtain an effective result, provided that the dose adjustment does not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, then the patient may be discontinued from drug treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

[0038] In one embodiment, a method is provided for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy, the method comprising: a) Administering a first dose of the drug to the eligible patient while monitoring with a wearable device to collect the patient's heart rhythm data, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the start of treatment with the drug. c) If the first dose is deemed ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in c), one or more dose adjustments of the drug may be made as needed to obtain an effective result, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, then the patient may be discontinued from drug treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm to ensure that the dose of bunidarone remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose as the first dose.

[0039] In one embodiment, the patient is deemed eligible for treatment with the drug based on the following criteria: the patient experiences at least one AFib attack lasting at least 5 hours or at least 5.5 hours within at least 7 or 14 days after not receiving the drug. In another embodiment, the patient is deemed eligible for treatment with the drug based on the following criteria: the patient's baseline AFib load is at least 5 hours within at least 7 or 14 days after not receiving the drug.

[0040] In one embodiment, a method is provided for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, wherein bunidarone suppresses AFib episodes and / or shortens the duration of AFib episodes, the method comprising: for a patient who has been identified as eligible for treatment with bunidarone, wherein the identification requires that the patient experience at least one prolonged AFib episode lasting at least 1 hour or an AFib load of at least 2.5% during the entire identification period, wherein the identification period is at least 2 weeks during which the patient has not received bunidarone treatment; a) Administer a first dose of the drug to an eligible patient while monitoring the patient’s heart rhythm using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose; b) During the evaluation period, wearable devices are used to monitor the efficacy of bunidarone administered to the patients at the first therapeutic dose to determine whether the dose is effective for each patient; c) For patients who did not achieve effective results with the previous dose of bunidarone at the end of the evaluation period, efficacy shall be determined by adjusting the dose of bunidarone one or more times as needed for at least the duration of the evaluation period to achieve effective results, provided that the dose adjustment does not exceed the maximum approved dose; or, if no effective results are achieved at the evaluation at the maximum approved dose, the patient shall be discontinued from bunidarone treatment; and d) For patients who do achieve effective results, continue to monitor their heart rhythm to ensure that the dosage of the drug remains effective, provided that if the dosage is no longer effective, the protocol in c) is repeated as needed.

[0041] In one implementation of the above method, the qualification confirmation period and the assessment period are at least about 7 days, at least about 14 days, or at least about 28 days.

[0042] In one implementation, for the method described herein, at least one long-duration AFib event is for at least about 5.5 hours, or at least about 5 hours, or at least about 1 hour, or at least about 30 minutes.

[0043] In one implementation, for the method described herein, at least one prolonged AFib episode lasts for at least about 5 hours within a 24-hour time period.

[0044] In one implementation, for the method described herein, the patient receiving bunidarone needs to be continuously monitored during the treatment.

[0045] In one implementation, monitoring of the patient using the drug is performed periodically, provided that periodic monitoring is performed throughout the entire monitoring period.

[0046] The methods described herein can be used to reduce the risk of stroke in patients with paroxysmal or persistent AFib, wherein these methods use medications that suppress AFib attacks and / or shorten the duration of AFib attacks, including bunidarone, in the manner described herein. Patients with paroxysmal or persistent AFib at risk of stroke include those with an elevated risk of stroke, such as those with a history of stroke, diabetes, hypertension, or those aged 75 years or older or 80 years or older.

[0047] The methods described herein can be used to reduce the risk of congestive heart failure in patients with paroxysmal or persistent AFib, wherein these methods use medications that inhibit AFib attacks and / or shorten the duration of AFib attacks, including bunidarone, in the manner described herein. Patients with paroxysmal or persistent AFib at risk of congestive heart failure include those with an elevated risk of congestive heart failure, such as patients with diabetes, hypertension, or valvular heart disease.

[0048] Patients at elevated risk of stroke and / or congestive heart failure may be treated according to the methods described herein, even if they are classified as having mild AFib and / or are not eligible prior to treatment, or if their baseline AFib levels are below the criteria for certifying low-risk patients. For example, patients at relatively low risk of stroke and / or congenital heart failure may be eligible for bunidarone treatment.

[0049] In one implementation, a method of treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and at increased risk of stroke and / or congestive heart failure may include: (a) Monitoring the patient's heart rhythm data, wherein heart rhythm data can be collected over a longer period of time using wearable devices. (b) Administering to the patient a first dose of bunidarone (or other medication), wherein the first dose is an approved therapeutic dose less than the maximum approved dose of bunidarone (or other medication); and (c) During a comparison period of one day or more, monitor the efficacy of the first dose of bunidarone (or other drugs) administered to the patient to determine whether the dose is effective for the patient, provided that the efficacy of bunidarone (or other drugs) is determined after a delay of at least 7 or 14 days following the start of treatment. The first dose may be the lowest approved dose. If, during the comparison period, the drug eliminates or reduces the number of AFib attacks for at least about 1 hour or at least about 0.5 hours, or otherwise significantly reduces the patient's risk of stroke or congestive heart failure, the dose may be determined to be effective for the patient. For patients who do not achieve an effective result with the first dose of bunidarone (or other drugs) at the end of the comparison period, the method further includes step (d): using the same delay and comparison period or a longer duration, make one or more dose adjustments as needed to achieve an effective result, thereby determining efficacy, provided that the dose adjustments do not exceed the maximum approved dose. An effective result may be determined as described herein. At any time, if an effective outcome is not achieved when assessed at the maximum approved dose, the method may further include step (e): discontinuing the patient from bunidarone (or other medication) treatment. For patients who do achieve an effective outcome, the method may further include step (f): continuing to monitor their heart rhythm to ensure the dose of bunidarone (or other medication) remains effective. If the dose is no longer effective in the patient, the dose adjustment in step (d) is repeated, or if no effective outcome is achieved, step (e): discontinuing the patient from bunidarone (or other medication) treatment is repeated. This method can be implemented for patients with any level of paroxysmal or persistent AFib, provided that the patient has an increased risk of stroke and / or congestive heart failure. In one implementation, the patient is eligible for treatment with bunidarone as described herein.

[0050] In one implementation, patients with paroxysmal or persistent AFib and an increased risk of stroke and / or congestive heart failure may be treated with medication as described herein. Bunidarone or other medications that can reduce the frequency and / or duration of AFib attacks may be used in combination with blood thinners (e.g., anticoagulants). For example, the attending physician may further combine blood thinners with bunidarone to reduce the patient's risk of stroke or heart failure. In one embodiment, a method of treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and at increased risk of stroke and / or congestive heart failure may include: (a) monitoring the patient's cardiac rhythm data, wherein the cardiac rhythm data may be collected over an extended period of time via a wearable device; (b) simultaneously administering a blood thinner and bunidarone to the patient, wherein bunidarone is administered at a first dose, wherein the first dose is an approved therapeutic dose less than the maximum approved dose of bunidarone; and (c) monitoring the efficacy of the first administered dose of bunidarone in the patient over a comparison period of one day or more to determine whether the dose is effective for the patient, provided that the efficacy of bunidarone is assessed at least 7 or 14 days after the start of treatment. The first dose of bunidarone may be the lowest approved dose. For patients who do not achieve a positive outcome at the end of the comparison period after administration of a first dose of bunidarone, the method further includes (d) adjusting the dose of bunidarone once or more as needed to achieve a positive outcome, thereby determining efficacy, provided that the dose adjustment does not exceed the maximum approved dose. A positive outcome can be determined as described herein. At any time, if a positive outcome is still not achieved when assessed at the maximum approved dose, the method further includes (e) discontinuing the patient from bunidarone treatment. For patients who do achieve a positive outcome, the method further includes (f) continuing to monitor their heart rhythm to ensure that the dose of bunidarone remains effective. If the dose is no longer effective, the dose adjustment of step (d) is repeated, or if a positive outcome is not achieved, step (e) is repeated to discontinue the patient from treatment. This method can be implemented for patients with any level of paroxysmal or persistent AFib, provided that the patient has an increased risk of stroke and / or congestive heart failure. In one implementation, the patient is eligible for treatment with bunidarone as described herein. Attached Figure Description

[0051] Figure 1 A chart was shown illustrating how patient AFib data could be combined with treatment using bunidarone; and

[0052] Figure 2 An electrocardiogram of a patient with intermittent AFib is shown. Detailed Implementation

[0053] This disclosure relates to a method for monitoring the heart rhythm of a patient diagnosed with atrial fibrillation (AFib) using a wearable device. Such monitoring allows for therapeutic interventions and enables adjustment of the dosage of medications used to achieve therapeutic endpoints. The following terms are defined. Undefined terms will be defined in the context of the discussion, or given their medically acceptable definition.

[0054] The terminology used herein is for the purpose of describing a particular implementation and is not intended to be limiting. Unless the context clearly indicates otherwise, the singular forms “a” and “the” used herein also include their plural forms.

[0055] Definitions

[0056] As used herein, the terms “optional” or “optionally” mean that the event or situation subsequently described may or may not occur, and the description includes both the possibility that the event or situation will occur and the possibility that it will not occur.

[0057] As used herein, the term “about” used before numerical values ​​(e.g., temperature, time, quantity, concentration, etc., including ranges) indicates an approximate value that may vary within a range of (+) or (-) 15%, 10%, 5%, 1%, or any subrange and / or value between these values. Preferably, when the term “about” is used with respect to a dose, it indicates that the dose may vary by + / - 10%.

[0058] As used herein, the term "comprising" means that the composition or method includes the listed elements, but does not exclude other elements.

[0059] As used herein, the term "consistently of" when used to define compositions and methods should exclude other elements that are essential to the purpose of the composition. Therefore, a composition consisting primarily of the elements defined herein, or a method consisting primarily of the schemes defined herein, does not exclude other components that will not materially affect the essential and novel features of the claimed subject matter.

[0060] As used herein, the term "composed of" should refer to the absence of other ingredients or substantial method steps beyond trace levels. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0061] As used herein, the term “AFib” or “atrial fibrillation” refers to all types of atrial fibrillation except for permanent AFib. These types include, but are not limited to, paroxysmal AFib, persistent AFib, and paroxysmal and persistent AFib with low CHA2DS2-VASc scores (2 or less) and high CHA2DS2-VASc scores (3 or more). The CHA2DS2-VASc score, representing congestive heart failure (C – 1 point), hypertension (H – 1 point), age ≥75 years (A – 2 points), diabetes (D – 1 point), stroke (S – 2 points), vascular disease (V – 1 point), age 65 to 74 years (A – 1 point), and sex (female Sc – 1 point), is a clinical predictive rule for assessing stroke risk in patients with nonrheumatic atrial fibrillation (AF). As mentioned above, each component risk factor accounts for 1 or 2 points in the CHA2DS2-VASc score.

[0062] As used herein, the term "long-duration AFib" refers to the length of time an AFib attack lasts in a patient. This length is associated with the risk of stroke and / or heart failure. Clearly, the longer the duration of an AFib attack, the higher the risk. Therefore, in one implementation, long-duration AFib refers to any AFib attack lasting at least about 1 hour, provided that the AFib is not permanent. In turn, long-duration AFib is further subdivided into two subcategories: "intermediate-long-duration" AFib and "longer-duration" AFib. "Intermediate-long-duration" AFib refers to an AFib attack lasting at least about 24 hours or less (i.e., at least about 1 hour and at most 24 hours), while "longer-duration" AFib includes AFib attacks lasting more than 24 hours but which are not permanent.

[0063] As used herein, the term "mild AFib" refers to an AFib episode in a patient with paroxysmal or persistent AFib lasting less than about 5.5 hours, less than about 5 hours, or less than about 1 hour, and / or a maximum AFib load of less than about 5 hours over any 24-hour period. In a preferred embodiment, a patient with mild AFib experiences occasional AFib episodes lasting less than about 1 hour, and / or a maximum AFib load of less than about 3 hours over any 24-hour monitoring period. In another embodiment, the maximum AFib load is less than about 2.5% of the total hours over any two-week patient monitoring period.

[0064] As used in this article, the term "paroxysmal AFib" refers to occasional and intermittent episodes of AFib lasting no more than 7 days, followed by a return to sinus rhythm. Often (but not always), patients with mild AFib are also classified as having paroxysmal AFib.

[0065] As used in this article, the term “persistent AFib” refers to occasional and intermittent AFib episodes that last for more than 7 days and may not be able to return to sinus rhythm without medical intervention (e.g., cardioversion).

[0066] As used in this article, the term "permanent AFib" refers to persistent and long-term AFib that does not show a significant return to sinus rhythm even after medical intervention (e.g., cardioversion). Permanent AFib is usually managed rather than treated.

[0067] As used in this article, the term “moderate AFib” refers to paroxysmal and persistent AFib that does not meet the characteristics of mild AFib.

[0068] As used in this article, the term “approved dose” refers to the dose of a drug (i.e., bunidarone) that a regulatory agency (e.g., the U.S. Food and Drug Administration) has determined to be suitable for commercial or clinical studies.

[0069] As used herein, the term “continuous” or “continuously” refers to continuous monitoring performed on a patient while wearing a wearable device. The term “continuous” or “continuously” covers continuous monitoring of heart rhythm while the wearable device is worn and powered on, but these devices may be removed for limited periods of time (e.g., to change batteries, charge the wearable monitoring device, shower, etc.).

[0070] As used herein, the term "semi-continuous" or "semi-continuously" refers to monitoring performed automatically and periodically by a wearable device according to a set schedule (e.g., every 15 seconds, every 30 seconds, every minute, etc.) without the patient activating the wearable device. This set schedule may be designed to monitor heart rate with a temporal resolution sufficient to detect AFib episodes and / or to allow determination of the duration of long-duration AFib episodes.

[0071] As used herein, the term "wearable" means that the monitor can be continuously turned on and / or connected to the patient, or that the patient can put on or remove the wearable device and start monitoring independently without the assistance of healthcare personnel. Therefore, wearable devices include those that are applied to the skin and / or implanted under the patient's skin.

[0072] As used in this article, the term “monitoring heart rhythm” refers to any assessment that can be made of a patient’s heart rhythm, including pulse rate, any aspect of the patient’s cardiac electric field, etc., as long as such monitoring can determine when the patient experienced AFib.

[0073] As used herein, the term “activation of monitoring” includes both automatic activation and physical activation of patient monitoring. “Automatic activation” means that the wearable device begins monitoring automatically once it is placed on the patient, without requiring any further action from the patient. “Physical activation” means that the patient needs to activate the monitoring through physical or verbal interaction with the wearable device (e.g., pressing a button, issuing a voice command, etc.).

[0074] As used herein, the term "transmission device" refers to any device capable of transmitting data from a wearable device. This transmission device can be built into the wearable device or a standalone device that communicates with the wearable device. Standalone devices can be smartphones, computers such as tablets, laptops, desktops, etc.

[0075] As used in this article, the term "clinician" refers to a healthcare professional qualified to determine whether a patient's heart rhythm data are related to sinus rhythm, atrial fibrillation, or other types of arrhythmia.

[0076] As used in this article, the term "attending physician" refers to a healthcare professional responsible for treating patients with AFib. These attending physicians are typically doctors or nurse practitioners.

[0077] When it comes to patient heart rhythm data transmission, the term "direct" means that the transmitted data is received by the attending physician for evaluation, regardless of whether the transmitted data is stored in the cloud or transmitted through multiple servers or other means.

[0078] In the context of patient heart rhythm data transmission, the term "indirect" refers to transmitting data to a clinician, who then evaluates the data and provides the data itself or conclusions drawn from it to the attending physician or healthcare provider. In this context, the clinician may be a healthcare professional employed by a central analytical center or the attending physician, responsible for evaluating the heart rhythm data and providing instructions to the attending physician on an ongoing basis or when contact is needed due to changes in the patient's condition. In one implementation, the clinician is employed by a central analytical center, which reviews the data generated by its instruments and makes diagnoses and / or recommendations, which are then transmitted to the attending physician. The central analytical center possesses expertise in the instruments, the generated data, and the ability to analyze that data.

[0079] As used herein, the term "baseline" refers to a patient with AFib who is monitored prior to treatment with bunidarone to determine the patient's AFib burden over any 24-hour period and the number of intermediate- to long-duration AFib episodes within a set timeframe. In this case, the baseline is measured at a set timeframe prior to drug treatment to provide information about the current state of the disease. In most (if not all) cases, the attending physician is unaware of the baseline state of the disease, which is essential information for determining the effectiveness of subsequent drug treatment.

[0080] As used herein, the terms “effective,” “effective outcome,” or similar expressions refer to treatment of eligible patients with moderate AFib (or patients with mild AFib who are at increased risk of stroke and / or congestive heart failure under certain conditions, such as stroke and / or congestive heart failure) who, as a result of receiving said treatment, exhibit a reduction in any one or any combination of the following: Compared to baseline, the number of long-duration (including longer-duration) AFIb seizures decreased; Compared to baseline, the maximum AFib load decreased over 24 hours; and / or For symptomatic AFib patients, their related symptoms are alleviated.

[0081] When the term "reduction" is used in conjunction with an effective outcome (e.g., as described above), it refers to a reduction in the number of prolonged AFib attacks, the severity of AFib burden, and / or the severity of AFib symptoms to a desired amount (e.g., at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, etc.) compared to the patient's corresponding baseline data. The desired reduction amount for an effective outcome in a patient can be selected to reduce the risk of stroke and / or congestive heart failure (CHF) to a desired level. For example, the Capucci and Trends study mentioned above showed that patients with AFib attacks lasting between 5.5 and 24 hours had a 2.2 times higher risk of stroke than individuals without AFib, and patients with AFib attacks lasting longer than 24 hours had a 3.1 times higher risk of stroke than individuals without AFib. Therefore, the desired reduction amount could be the elimination (100% reduction) of AFib attacks lasting longer than 24 hours or longer than about 5.5 hours (e.g., longer than 5.5 hours, longer than 5 hours, etc.).

[0082] Reduction can be assessed according to the comparison periods described herein. For example, reduction can be assessed at least 7 days after the start of drug treatment or at least approximately 14 days after the start of drug treatment. For example, reduction can be assessed during any assessment period during treatment at a given dose (e.g., a 7-day assessment monitoring period such as days 1–7 after the start of drug treatment, days 8–14 after the start of drug treatment, etc.).

[0083] A patient is considered “responsive” to drug treatment (e.g., the bunidarone treatment disclosed herein) if they currently demonstrate effective results after administration of an approved dose of bunidarone. In a preferred embodiment, eligible patients should be further evaluated to determine their suitability for initiating the treatment before using the methods described herein. The term “suitable patient” refers to a patient currently receiving blood thinner treatment or a patient identified as thromboembolic. As used herein, the terms “suitable patient” or “patient” refer to a patient who has experienced paroxysmal or persistent AFib for approximately 6 hours or less, or a patient who has experienced paroxysmal or persistent AFib but has been identified as thromboembolic using transesophageal echocardiography or other methods that confirm the absence of thrombus, or a patient known to have persistent or paroxysmal AFib and currently receiving blood thinners.

[0084] In one implementation, the drug treatment eliminated the number of prolonged AFib attacks lasting longer than about 5.5 hours or longer than about 5 hours, and / or eliminated the number of prolonged AFib attacks lasting longer than about 1 hour. In another implementation, the drug treatment reduced the number of prolonged AFib attacks lasting longer than about 5.5 hours or longer than about 5 hours and / or longer than about 1 hour.

[0085] In one embodiment, when measured at least 7 days after the start of drug treatment, preferably at least 14 days after the start of drug treatment, the drug treatment reduces AFib-related symptoms in symptomatic patients by at least about 15%, preferably at least about 25%, and more preferably at least 40%.

[0086] As used in this article, a "non-responsive patient" or "patient who does not respond to drug therapy" refers to a patient who has received drug therapy but has not met the above-mentioned evidence of effective outcome at any approved drug dose. In this case, the non-responsive patient is discontinued from drug therapy. After evaluation by the attending physician, such non-responsive patients may be referred for ablation to treat their AFib.

[0087] In one implementation, patients eligible for drug treatment have been identified as unresponsive to at least one other treatment for AFib, including ablation.

[0088] In one implementation plan, patients eligible to begin drug treatment are limited to those with symptoms of AFib.

[0089] As described herein, “other methods of treating AFib” may include ablation, administration of one or more blood thinners and / or implementation of other measures to prevent thrombosis, heart rate control measures and / or heart rhythm control measures. Examples of such methods of treating AFib may include administration of beta-blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol, propranolol, timolol), calcium channel blockers (verapamil, diltiazem), blood thinners (warfarin, coumarin, Jantoven, aspirin, apixaban, dabigatran, enoxaparin, heparin, rivaroxaban), sodium channel blockers (e.g., flecainide, propafenone, quinidine) and / or potassium channel blockers (e.g., amiodarone, dofetilide, sotalol).

[0090] If a patient has received one or more prior and / or other treatments for AFib (e.g., other treatments for AFib as defined above), and their AFib is identified as unresponsive and / or insufficiently responsive, and / or reduced responsiveness to that one or more treatments, the patient may be considered "ineffective to one or more prior treatments for their AFib" or "ineffective to one or more other treatments for their AFib." The "one or more prior treatments" may be ongoing and / or may have been discontinued.

[0091] As used herein, the term "smart" refers to the computing power of a device. The computing power of the "smart devices" discussed herein (e.g., smartphones or tablets) enables user interaction (e.g., via touchscreen) and / or the running of applications on the smart device.

[0092] As used herein, the term "at least 2.5% AFib burden" means that, without treatment according to this disclosure (e.g., without bunidarone and / or other cardiac rhythm medications that reduce the severity and / or duration of AFib episodes and / or AFib-related symptoms), the cumulative duration of each AFib episode within a specified time period is at least 2.5% of the total duration of the specified time period. Therefore, for a patient monitored for 20 days (or 480 hours), at least 2.5% AFib burden means that the total (cumulative) duration of one or more AFib episodes is at least 12 hours (2.5% of 480 hours). This AFib burden may not be related to the number of prolonged AFib episodes (if any). Therefore, one or more AFib episodes with a cumulative total of at least 12 hours can be a single episode or multiple episodes, each lasting less than 1 hour.

[0093] As used herein, the term "binderalon" refers to 2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl)acetic acid (S)-sec-butyl ester and its pharmaceutically acceptable salts. Binderalon, as a free base, has the following chemical formula: .

[0094] The term "bunidarone" includes pharmaceutically acceptable salts of its free base and covers all approved pharmaceutically acceptable salts. Acceptable salts of bunidarone include bunidarone tartrate or bunidarone citrate. In one embodiment, the pharmaceutically acceptable salt may be a polycarboxylate. As is known in the art, the salt dissociates from the free base in vivo. Therefore, when calculating the serum concentration of bunidarone, the molecular weight of the free base is used to determine the molar concentration. Furthermore, when administering salts other than tartrate, the dose of bunidarone tartrate used herein must be adjusted accordingly to reflect the change in molecular weight due to the different salts.

[0095] "Wearable devices" refers to any device that can be worn by a user, such as as an accessory, as clothing and / or embedded in clothing, or can be implanted subcutaneously into a patient's body.

[0096] As used in this article, a patient is considered to be "equipped with a wearable device" when the wearable device is worn by the patient, implanted subcutaneously, or otherwise attached to the patient in order to measure the patient's heart rhythm.

[0097] Instrument

[0098] The instruments used in the methods described herein are designed to be adapted to the patient as part of the eligibility verification protocol and / or the drug treatment used by the patient described herein.

[0099] Wearable devices used for diagnosis are standard equipment designed to inform clinicians whether a patient has AFib and / or, if so, may also provide information about the patient's AFib burden and frequency of AFib attacks. Such diagnostic analyses cannot address any issues beyond the scope of diagnosis regarding the suitability, efficacy, and / or dosage of drug therapy. The drug therapy methods described herein involve identifying eligible patients for drug therapy and / or monitoring eligible patients during treatment to determine the effectiveness of the drug (e.g., in reducing the frequency of prolonged AFib attacks). Monitoring allows for dose adjustments until the patient is deemed responsive to treatment or disqualified from drug therapy due to non-responsiveness. The drug therapy methods described herein allow for continuous monitoring of the patient to determine the effective dose of the drug and ensure that the patient remains responsive to that dose. Therefore, the wearable devices described herein are designed and / or selected to be durable for long-term use and / or comfortable and / or easy for patients to use.

[0100] In practice, wearable devices may include cardiac monitoring components, which can be assistive or non-assistive, for measuring a patient's heart rhythm. Many wearable devices can be worn and removed by the patient themselves or implanted subcutaneously. The specific cardiac monitoring component used in a wearable device is not important, as long as it accurately measures the heart rhythm. Wearable devices may be able to report measured heart rhythm data, such as data indicating the duration of detected AFib by generating and / or transmitting data indicating the number of episodes of long-duration AFib (e.g., within a period of interest, such as a week, a month, etc.). Additionally, or optionally, wearable devices may be configured to transmit heart rhythm data to a device configured to detect AFib and / or determine the duration of detected AFib and / or the number of episodes of long-duration AFib (e.g., within a period of interest). Wearable devices have received approval from one or more regulatory agencies, such as the U.S. Food and Drug Administration (FDA).

[0101] Accessory assembly

[0102] An auxiliary cardiac monitoring component can use photoplethysmography (PPG) to detect a patient's heart rate and rhythm. PPG is a standard technique in standard pulse oximeters, detecting arterial pulsations by measuring light reflection in tissues, thereby detecting heart rhythm patterns. However, for continuous and / or semi-continuous heart rhythm measurement, the fact that PPG signals generated by a patient during exercise are often distorted, weak, and contain significant noise relative to the detected data must be considered. To address these shortcomings, algorithms can be used to sufficiently reduce distortion and / or noise to provide a reliable signal. In one implementation, both the PPG sensor and the accelerometer are used in conjunction with an algorithm that is commensurate with it (e.g., a sufficient signal-to-noise ratio). With such assistance, PPG enables reliable detection of heart rate and rhythm. See, for example, Wojcikowski, et al., Photoplethysmographic time-domain heart rate measurement algorithm for resource-constrained wearable devices and its implementation Sensors 20, no.6 (2020): 1783, the entire contents of which are incorporated herein by reference.

[0103] In some implementations, the cardiac monitoring component uses piezoelectric materials and / or rhythm-electroactive polymers to detect blood flow, thereby indirectly measuring heart rhythm.

[0104] In some implementations, PPG and / or piezoelectric measurements can be combined with ECG data from a single-electrode wearable device (i.e., iEKG, as opposed to EKG, which refers to conventional multi-electrode ECG) to improve measurement specificity. The iEKG (i.e., iECG) and PPG or piezoelectric data can originate from two separate devices communicating via transceivers, such as an armband and a smartwatch, or from a single device, such as a wristband on a smartwatch (e.g., the Kardia™ Band on an iWatch). Once an arrhythmia is detected in the PPG data, the corresponding (e.g., real-time) iECG data can be analyzed using algorithms.

[0105] Without an accessory assembly

[0106] In another embodiment, the wearable device may include an unassisted cardiac monitoring component, such as a portable electrocardiograph. This portable electrocardiograph component may be wearable, allowing the patient to wear it freely, and / or capable of transmitting data via a built-in antenna or Bluetooth data transmission device. Wearable devices including unassisted cardiac monitoring components are capable of measuring heart rate and rhythm. The wearable device may be configured to detect and record AFib load and / or long-duration AFib (episodes) (LEAF) over an observation period (e.g., approximately 2 weeks or longer). Unassisted cardiac monitoring components employ direct measurement, i.e., the device reads the electrical signals generated by the heart. Compared to indirect measurements (e.g., PPG measurements), direct measurements are likely less susceptible to noise and distortion, allowing measurement data to be transmitted to clinicians without the need for algorithms, and / or reducing the use of any algorithms or data processing.

[0107] In some implementations, the wearable device may also include a dedicated accessory, such as a cardiac monitoring device, which can detect the electrical activity of the heart (including heart rhythm) via electrodes. This dedicated accessory may be able to initiate transmission and / or may include and / or connect to a transmission device.

[0108] In some implementations, the cardiac monitoring device can be part of a single wearable device (e.g., a smartwatch). By providing a single device that can be worn by a user and is capable of monitoring the user's cardiac electric field, the electrical activity of the heart can be continuously monitored over a longer period of time (e.g., days or even months).

[0109] In some implementations, the cardiac monitoring device may include an analog-to-digital converter (ADC) capable of digitizing measured electric field data (e.g., measured potential difference data) to transmit the measurement data as digital data and / or store it in memory. The cardiac monitoring device may include an output that can transmit a signal carrying information about the potential difference between the limb and the body to external circuitry. The output can take various forms. In one case, the output may be a transceiver for communicating with another transceiver / receiver in another unit (e.g., a watch or tablet). In one implementation, a central analysis center (e.g., a remote laboratory, such as a CORE laboratory, and / or a remote data analysis center and / or server) can interpret and / or summarize AFib data and / or LEAF data. The central analysis center may also transmit dose adjustment recommendations to treating physicians without requiring the patient to visit in person (e.g., as part of a patient monitoring program). Furthermore, or alternatively, artificial intelligence algorithms may be used to determine dose adjustments and transmit dose adjustment recommendations to physicians.

[0110] Other aspects

[0111] In one implementation, the wearable device can be a small consumer electronic device, such as a watch, armband, ring, watch strap, and / or wristband. The wearable device may include a housing containing cardiac monitoring components and any associated circuitry, CPU, etc. The wearable device may also be worn on other parts of the user's body, including but not limited to the wrist, legs, neck, and / or torso. The wearable device may include dedicated accessories capable of communicating with another electronic device (e.g., a tablet, laptop, desktop computer, and / or other similar device), which in turn can communicate with a cloud network to transmit information from the device to a clinician. Additionally, or optionally, the dedicated accessories may be able to transmit information directly and / or via a network to a clinician.

[0112] Heart rate and iECG wearable devices may support Bluetooth, Z-Wave, Zigbee, and / or Advanced Adaptive Networking (ANT) technologies. For example, an iECG and / or heart rate monitoring and / or recording device (e.g., a PPG or piezoelectric heart rate monitoring and / or recording device) may be paired with an application configured to automatically detect AFib based on data provided by the iECG and / or heart rate monitoring and / or recording device. The iECG device and / or heart rate monitoring and / or recording device may be configured to transmit data to the application. Data may be transmitted via one or more data transmission methods (e.g., Bluetooth, Z-Wave, Zigbee, or ANT protocols). The application may be configured to analyze the data using proprietary software. Based on data from the iECG and / or heart rate monitoring and / or recording device, the application may be able to interpret and / or detect AFib with >90% sensitivity and >80% specificity.

[0113] As described in this article, patients wearing wearable devices can use the devices to record heart rhythm and detect AFib. Recordings can be continuous and / or semi-continuous. Details of the recordings can be programmed directly or indirectly (e.g., remotely) into the device. AFib data can be securely stored, for example, in a cloud-based data repository using highly secure protocols.

[0114] Examples of commercially available assistive and non-assistive wearable devices include, but are not limited to, the following products: MCOT is sold by Philips Biosciences (Best, Netherlands). ® Wearable device. This device is a wearable patch that automatically transmits iECG data wirelessly to a central analysis center (e.g., a CORE laboratory). The system is configured to provide sufficient data for clinicians to determine whether to increase the dosage and / or discontinue the medication.

[0115] Philips Biosciences (Best, Netherlands) sells the ePatch long-wear Holter monitoring system. This device is configured to record data indicating AFib and / or prolonged AFib (LEAF) attacks. It is also configured to continuously record and / or store iECG data. This data will then be archived and centrally analyzed.

[0116] Many other wearable devices are available on the market, some of which have been approved by the FDA and can be used as alternatives to the devices mentioned above. Examples include, to name just a few, the Zio from iRhythmtech in San Francisco, California; the Frontier X2 from Fourth Frontier in Austin, Texas; and the VivaLink wearable device from Campbell, California. The above and other wearable devices discussed herein represent only a non-exhaustive list of wearable devices suitable for the methods described herein. The specific wearable device used is not important, as long as it can measure heart rhythm (e.g., generate signals and / or data that determine heart rhythm). The wearable device used should be able to continuously or semi-continuously measure the heart rhythm of the patient equipped with the wearable device during the desired time period described herein (e.g., the time period required for baseline determination, monitoring during drug treatment, etc.). Furthermore, the wearable device should be small and / or comfortable enough for the patient to wear and / or be equipped with for the desired time period.

[0117] Methodology

[0118] The disclosed method enables attending physicians to identify and / or treat eligible patients with bunidarone and assess the efficacy of treatment based on cardiac rhythm data monitored over a period of time. This period can be long, measured in weeks, months, and / or years. Monitoring may include monitoring cardiac rhythm data and / or using this data to determine the patient's AFib status, which can be determined based on one or more factors, such as the patient's AFib burden or the number or duration of AFib episodes over a period of time (e.g., the frequency of AFib episodes and / or prolonged AFib episodes) or AFib-related symptoms. This represents a new paradigm in the treatment of AFib because it allows clinicians to take one or more of the following actions: • Assess the severity of the patient's illness; • Determine if the patient is eligible for drug treatment; • Evaluate the efficacy of the treatment in the short term (1-6 months) and / or long term (after 6 months); • Adjusting the patient's medication dosage to achieve and / or maintain the therapeutic effect; and / or If the patient does not respond to treatment, the patient should be discontinued from medication.

[0119] In contrast, routine monitoring of patients is typically diagnostic in nature, such as monitoring using a Holter monitor or equivalent device for a single, short period, usually not exceeding two weeks. Such diagnostic methods at most allow clinicians to confirm the presence of AFib. In most cases, clinicians will subsequently administer blood thinners to the patient. Optionally, clinicians may also prescribe medication to confirmed cases, which may include the use of beta-blockers and / or calcium channel blockers to lower the heart rate. In any case, routine monitoring is usually discontinued once a diagnosis is made.

[0120] In cases of clinical evaluation of AFib for research purposes, implantable (invasive) devices that require surgical implantation and subsequent surgical removal are typically used. Such studies usually aim to understand the potential risk of stroke and congestive heart failure associated with AFib load and / or AFib duration. See, for example, the literature Turakhia MPet al., Circ. Arrhythm. Electrophysiol ., 2015, 8(5):1040-7. In some cases, non-invasive methods are sometimes used to monitor patients, but the monitoring duration is usually short. For example, see the literature Go, et al., JAMA Cardiology , 2018, 3(7):601-608. However, such clinical assessments have failed to address or provide a method for how to effectively deliver bunidarone to patients and assess the effects of the drug on patients’ AFib burden or prolonged AFib attacks over long periods of time, while selectively adjusting the dosage to achieve the desired therapeutic effect.

[0121] Unlike previous approaches that used medications to limit a patient's heart rate to treat AFib, the method described in this article aims to treat the patient's heart rhythm to reduce triggers for stroke and heart failure, and to alleviate or eliminate AFib-related symptoms. By combining the ability to continuously or semi-continuously monitor the heart rhythm with appropriate medications that limit the frequency and severity of prolonged AFib episodes, clinicians can significantly reduce the risk of stroke or congestive heart failure. Furthermore, by monitoring patients after initiating drug therapy, clinicians can now assess the efficacy of the medication, adjust the dosage as needed to improve overall efficacy, or identify patients who are unresponsive to the treatment and discontinue it.

[0122] Figure 1 One implementation of the method is depicted, illustrating an iterative process for assessing patients, confirming their eligibility for bunidarone treatment, and treating eligible patients. Figure 1In this study, an AFIb load assessment was performed on an exemplary patient cohort diagnosed with paroxysmal and / or persistent AFIb. Patients exhibiting an appropriate AFIb load (“Yes” at the star decision point), where the AFIb load is 5% or higher (but this AFIb load threshold may vary, e.g., 2.5%, and / or patient- and / or population-specific thresholds), were optionally allowed to proceed with the eligibility process, while those not meeting this threshold were excluded (“No” at the star decision point). Patients may also undergo an assessment of the duration of AFIb attacks. In this particular implementation, a patient is further confirmed as eligible for bunidarone treatment if they have at least one AFIb attack lasting longer than approximately 5 hours or approximately 5.5 hours within a 1-month timeframe, and / or two or more AFIb attacks lasting longer than approximately 1 hour within a 1-month timeframe (“Yes” at the star decision point). Patients not meeting any of these criteria were excluded (“No” at the star decision point) because their risk of stroke or congestive heart failure may be very low. Eligible patients are treated with an escalating bunidarone regimen that has been shown to significantly reduce AFib attacks, including prolonged AFib attacks, and by definition, this reduces the AFib burden. In the methods described herein, other medications with similar effects to bunidarone may be used as alternatives to bunidarone and / or in combination with bunidarone.

[0123] exist Figure 1 During the iterative process, an escalation strategy was used to determine the effectiveness and / or effective dose of bunidarone in treating prolonged AFib attacks. Given that the frequency and duration of AFib load and / or prolonged AFib attacks vary from patient to patient, different doses of bunidarone may be effective in different patients. However, to date, clinicians prescribing the first dose of bunidarone have been unsure whether that dose is effective. Figure 1 As described in the examples below, the methods described herein allow clinicians to assess the efficacy of a first dose during iterations and / or adjust the dose in an escalating and / or decreasing pattern until a therapeutic effect is achieved, and / or the patient is deemed a non-responder. For such non-responders, they are discontinued from bunidarone treatment.

[0124] In an escalation regimen, a low dose is first administered to the patient. If the patient does not respond or responds poorly (e.g., marked "No" at the plus sign), the dose can be increased. If the patient still shows no evidence of drug efficacy at the maximum dose, they are identified as an unresponsive patient. Alternatively, a tapering regimen can be used, in which the patient is first given the highest dose of bunidarone, and then efficacy is determined by tapering the dose. One advantage of the tapering regimen is that unresponsive patients can be identified on the first attempt rather than the last. However, the escalation regimen can have the benefit of finding the lowest effective dose first and / or reducing the risk of side effects. Combining escalation and tapering regimens can be used to fine-tune the lowest effective dose of bunidarone administered to a patient. For example, if a 200 mg twice-daily dose of bunidarone is ineffective while a 400 mg twice-daily dose is effective, the attending physician can adjust the dose in a tapering manner to determine whether a 350 mg twice-daily or a 300 mg twice-daily dose of bunidarone is effective. This regimen is particularly beneficial if patients experience side effects when given 400 mg twice daily of bunidarone, but do not experience (or do not experience the same level of) side effects when given a lower but still effective dose of 350 mg or 300 mg twice daily.

[0125] In one implementation, treatment with bunidarone may reduce the number and / or frequency of prolonged AFib attacks, and / or may reduce AFib burden. This contrasts with medications that lower heart rate but have little effect on shortening the duration of AFib attacks and / or reducing AFib burden. AFib burden and prolonged AFib attacks are different concepts. AFib burden is determined by measuring the number of attacks and the duration of each AFib attack. A patient with only very short-duration AFib attacks may still be considered to have a high AFib burden compared to a patient with infrequent prolonged AFib attacks. Therefore, if a patient has 8 AFib attacks, each lasting 45 minutes, within a given 24-hour period, their AFib burden is determined to be 25% (6 hours / 24 hours). In contrast, a patient with a single 5-hour AFib attack within a 24-hour period is considered to have an AFib burden of 20.8%. However, the latter patient with a single AFib attack may have a higher stroke risk than the former patient. Therefore, patients with an AFib burden of less than 2.5% are unlikely to have a long duration of AFib and may therefore be deemed ineligible for bunidarone treatment.

[0126] Furthermore, converting a patient from paroxysmal AFib to persistent AFib, or from persistent AFib to permanent AFib, can be an undesirable disease progression. As described in this article, treating patients with bunidarone by reducing the severity and frequency of long-duration AFib can allow them to remain at their current disease stage for at least a longer period than without bunidarone treatment (and may even see a reversal from persistent to paroxysmal AFib), thereby inhibiting disease progression.

[0127] In contrast, treating AFib with blood thinners does not address the underlying cause of AFib, nor does it alleviate the AFib burden and / or the potential problems associated with intermediate- to long-duration and prolonged AFib episodes (e.g., increased stroke risk, increased CHF risk). Furthermore, blood thinners do not prevent or slow the progression from paroxysmal AFib to persistent AFib, or from persistent AFib to permanent AFib. Moreover, blood thinners can trigger another series of bleeding problems. For example, as mentioned earlier, approximately 6% of patients receiving blood thinners are expected to experience adverse events requiring emergency department visits, and approximately 3% require subsequent hospitalization. Most adverse events caused by blood thinners are bleeding events, with severe bleeding requiring hospitalization. Severe bleeding may include intraperitoneal hemorrhage (requiring surgical recovery) or intracranial hemorrhage (fatal). In addition, while blood thinners reduce stroke risk, they do not address the underlying cause of or increase in stroke risk in patients with prolonged AFib episodes.

[0128] Therefore, in one implementation, patients receiving blood thinners for AFib and showing efficacy with bunidarone treatment (e.g., as described herein) can be identified through monitoring for bunidarone treatment, for example, as described herein. In one implementation, if bunidarone treatment is found to adequately reduce the patient's risk of stroke (e.g., by reducing one or more of the duration and / or frequency of AFib attacks and / or AFib burden to the required amount, and / or to the amount associated with a reduction in the risk of stroke and / or CHF), the patient may discontinue the blood thinner (e.g., by a clinician). Since bunidarone does not carry the risk of adverse reactions associated with blood thinners (e.g., bleeding), if bunidarone treatment is found to adequately reduce the patient's risk of stroke to a level comparable to the stroke risk of patients receiving blood thinners, or comparable to the combined risk of stroke and bleeding of patients receiving blood thinners, the patient receiving blood thinners may receive bunidarone treatment and discontinue the blood thinner. For example, if bunidarone treatment is found to reduce the duration of an AFib attack to less than 1 hour (e.g., longest attack during the assessment period, average duration during the assessment period, etc.), the patient can discontinue the blood thinner (e.g., by the clinician). The risk of stroke in a patient can be determined based on individual characteristics and risk factors, which can be obtained through the patient's CHA2DS2-VASc score (2 or less), such as low CHA2DS2-VASc scores (2 or less) and high CHA2DS2-VASc scores (3 or above) in patients with paroxysmal and persistent AFib. Therefore, patients with different CHA2DS2-VASc scores may require different levels of AFib reduction before blood thinners can be discontinued. For example, in patients with a low CHA2DS2-VASc score (e.g., 2 or below), blood thinners may be discontinued if bunidarone treatment reduces or eliminates AFib attacks lasting longer than approximately 5.5 hours or longer than 5 hours, or reduces or eliminates AFib attacks lasting longer than 1 hour, and / or if bunidarone treatment reduces the AFib burden to below 5%, below 2.5%, etc., during the comparison period. For patients with a high CHA2DS2-VASc score (e.g., 3 or above), a greater reduction in AFib levels may be required to discontinue blood thinners. For example, blood thinners may be discontinued in patients with a high CHA2DS2-VASc score if bunidarone treatment reduces or eliminates AFib attacks lasting longer than 1 hour, longer than 0.5 hours, or longer than 0.1 hours, and / or if bunidarone treatment reduces the AFib burden to below 1%, etc., during the comparison period.In one instance, for patients with a very high CHA2DS2-VASc score (e.g., 6 or above), blood thinners may only be discontinued after eliminating AFib episodes lasting longer than 0.1 hours, or they may not be able to discontinue blood thinners at all.

[0129] In light of the foregoing, according to this disclosure, long-term monitoring of a patient's heart rhythm can be performed to determine the efficacy of medications designed to control such prolonged AFib episodes. Devices such as Holter monitors can be used to monitor a patient's heart rhythm for short periods (e.g., 1 day, 2 days, 3 days, or even up to 14 days), but such monitoring cannot comprehensively and continuously analyze how a patient's AFib and / or drug treatment affect the frequency and duration of AFib episodes over long periods (e.g., months or longer). Such short-duration analyses provide only diagnostic analysis, not treatment analysis, and therefore cannot comprehensively reflect the patient's cardiac health status. Because AFib has an sporadic and dynamic nature (paroxysmal and persistent) and varies among patients, only through long-term monitoring (e.g., more than 1 month, more than 3 months, etc.) can an accurate measurement of the severity level of a patient's AFib and the benefit of drug treatment in treating AFib be obtained.

[0130] Drug therapy

[0131] In many cases, physicians can assess patients based on static values ​​that represent meaningful long-term averages. For example, in diabetes, three-month hemoglobin A1C levels (also known as HbA1C testing, a blood test) provide an excellent indicator of average daily blood glucose levels. Furthermore, liver function, prostate health, thyroid health, and other conditions can be assessed using specific values ​​that provide meaningful information for clinicians.

[0132] Clinicians treating paroxysmal and / or persistent AFib must rely on brief / intermittent monitoring of the patient's heart rhythm, such as via EKG (electrocardiogram) and / or Holter monitoring. However, such brief monitoring may miss crucial data points that can only be obtained through long-duration monitoring. This may lead clinicians to avoid drug therapy when the effectiveness of the medication cannot be monitored. Instead, patients diagnosed with AFib may receive treatments to relieve symptoms and / or reduce risks, such as blood thinners. However, while blood thinners can reduce the risk of thrombosis-related stroke (e.g., thrombosis caused by AFib), they also correspondingly increase the risk of uncontrollable bleeding caused by blood thinners, which can even lead to death.

[0133] Drugs such as sotalol, as well as beta-blockers and calcium channel blockers, have been used to treat AFib. 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. Drugs with combined mechanisms of action also exist, such as amiodarone. However, each of these drugs is currently considered ineffective in treating AFib because they either fail to adequately control heart rhythm or produce serious side effects in patients (e.g., amiodarone has a long half-life and accumulates in the body with prolonged use, leading to various toxicities, including pulmonary, hepatic, and ocular effects; patients using this drug need close monitoring for early signs of irreversible and potentially fatal complications [e.g., see Wolkove N, Baltzan M., “Amiodarone pulmonary toxicity,” Canadian Respiratory Journal 16(2): 43-8, 2009]).

[0134] Bunidarone is a drug with a complex mechanism of action that has been shown to reduce prolonged AFib episodes without significantly prolonging the QT interval. Bunidarone is designed to act on cardiac ion channels in a similar manner to amiodarone, but enhances late-stage Na+ ionization. + Channel blocking effect. Bunidarone's deliberately modified metabolic pathway results in a much shorter half-life than amiodarone, thus avoiding the accumulation-related toxicities common with amiodarone, and it is completely inactivated and cleared from the body within hours to days after discontinuation. The shortened half-life allows for rapid achievement of steady-state plasma concentrations within 2–3 days of starting treatment, and enables dose adjustment as needed to determine the minimum effective dose for each subject, provided real-time information on efficacy is available (e.g., changes and / or reductions in AFib load and / or prolonged AFib attacks). Indeed, bunidarone has made significant progress in the treatment of AFib, as prolonged AFib attacks are a major cause of thrombosis, which can lead to stroke and / or congestive heart failure. However, AFib is a variable disease, and some patients require different drug doses to achieve the desired effect. As mentioned earlier, the inability to monitor patients in a way that can assess drug effectiveness has been a major drawback of pharmacological interventions. This has led clinicians to choose blood thinners and / or risk-reducing measures rather than aggressive pharmacological interventions.

[0135] The wearable devices and methods described herein can continuously provide clinicians with sufficient data to determine the long-term effectiveness of drug treatment for paroxysmal and persistent AFIb. Therefore, combining data generated by wearable devices with drugs capable of controlling prolonged AFIb and / or reducing AFI burden may contribute to more effective AFIb treatment, which is a long-standing need in the field. Furthermore, the ability to determine the long-term effectiveness of drugs may facilitate dose adjustments for patients to effectively control prolonged AFI attacks.

[0136] Treatment regimen using bunidrolol

[0137] Bunidarone has been shown to reduce the frequency of long-duration AFib attacks, thereby lowering the risk of stroke and congestive heart failure. However, to treat a broad patient population with varying frequencies and durations of long-duration AFib attacks using bunidarone, clinicians need to monitor efficacy for each patient at a given dose. This represents a personalized approach to medicine for diseases treatable with bunidarone.

[0138] If the patient does not respond to the dose, it is necessary to increase the dose and repeat this process until it is determined that the patient responds or does not respond at a given higher dose. Patients who do not respond to all test doses should be discontinued from brendarone treatment.

[0139] Furthermore, patients with paroxysmal or persistent AFib who have previously received one or more treatments for their disease may be suitable for the methods and procedures described herein. Such patients can be screened (eligible) for treatment by determining their baseline AFib burden and / or the frequency and severity of their prolonged AFib episodes. Their baseline data can also be used to assess the relative reduction and / or complete elimination of these symptoms after bunidarone treatment, and / or to determine whether the patient is unresponsive to bunidarone treatment. Therefore, a method for treating patients with paroxysmal or persistent AFib, wherein one or more previous treatments for their AFib are ineffective, may include: For patients who have not responded to one or more previous treatments for AFib, and who are equipped with wearable devices that can monitor heart rhythm data and transmit that data; a) Determine the number of prolonged AFib episodes and the degree of AFib burden in the patient, wherein the determined number and duration meet the criteria for a clinician to prescribe bunidarone treatment for the patient. b) Administer bunidarone to the patient at the lowest approved therapeutic dose; c) Using a wearable device to monitor the efficacy of the minimum therapeutic dose of bunidarone administered to the patient to determine whether the dose is effective for the patient, wherein the efficacy monitoring begins at least about 7 days or at least about 2 weeks after the start of treatment; d) For patients who, at the end of the second time period, still do not achieve effective results at the lowest possible dose, efficacy may be assessed by adjusting the dose of the drug once or more as needed, using at least the duration of the second time period; or, if no effective results are achieved when assessed at the maximum approved dose, the patient may be discontinued from the treatment; and e) For patients who have achieved effective results, continue to monitor their heart rhythm to ensure that the dosage of the drug remains effective, and repeat steps c) and d as needed if the dosage is no longer effective.

[0140] Because there is a lack of sufficient information to determine the efficacy of any prescribed medication at a given dose in reducing the frequency of prolonged AFib attacks in patients, clinicians generally avoid doing so, especially given individual patient variability and the inherent variability of the disease itself. Furthermore, many clinicians consider treating (lowering) heart rate to be an appropriate approach to treating AFib, optionally in combination with blood thinners. For example, see the literature Atrial Fibrillation – Treatment, https: / / www.nhs.uk / conditions / atrial-fibrillation / treatment / , in which the authors, in 2021, considered controlling heart rate as part of an appropriate approach to treating AFib.

[0141] Now, based on the methods described in this article, clinicians can assess a patient’s heart rhythm data over a longer period of time (e.g., at least about 3 months, at least about 6 months, at least about 12 months, or even for the rest of the patient’s life) to determine the number and / or duration of long-duration AFib episodes, and whether bunidarone treatment is effective and remains effective.

[0142] In one implementation scheme, such as Figure 1As illustrated in the examples, for instance, a clinician may begin bunidarone administration at the lowest level of approximately 200 mg twice daily (bid), and then determine whether this dose is effective in eliminating prolonged AFib attacks. The clinician may review data from the initial dosing level and, for example, adjust the patient's dose once or more as needed to achieve a dose that results in substantially no and / or no prolonged AFib attacks. Generally, dose increments may be approximately 200 mg twice daily. Therefore, in this approach, the dose may be adjusted from approximately 200 mg bid to approximately 400 mg bid, or approximately 600 mg bid, and so on, up to approximately 800 mg bid, and possibly higher if the attending physician deems a higher dose beneficial. Furthermore, or alternatively (although...) Figure 1 (Not shown in the text) Smaller or larger dose adjustment increments can be selected (e.g., + / - 100 mg bid or + / - 300 mg bid, etc.) to fine-tune the patient's dose, and clinicians can reduce the dose to achieve sufficient effective results, as long as the reduced dose also achieves sufficient effective results as described in this article.

[0143] System

[0144] The methods described herein can be implemented in a single device, such as a wearable device capable of recording, storing, and transmitting heart rhythm data. However, systems comprising multiple devices can also be used, provided that such systems include: a) Wearable devices for collecting cardiac rhythm data from patients diagnosed with paroxysmal atrial fibrillation and / or persistent atrial fibrillation; b) A CPU configured to communicate with and / or receive heart rhythm data or heart rhythm-based data from the wearable device, and to collect and store heart rhythm data and / or heart rhythm-based data; and c) A transmission component (e.g., a device) that is part of or communicates with the CPU (chest pain unit) and is configured to directly and / or indirectly send data and / or data-based information (e.g., warnings or alerts, analyzed number of AFib attacks, etc.) to one or more designated recipients (e.g., patients, one or more clinicians, etc.).

[0145] In one implementation, the CPU is capable of evaluating stored and / or received data to determine the presence and frequency of intermediate- to long-duration and / or longer-duration AFib attacks. The CPU's evaluation can be continuous or periodic. The CPU is programmable to alert clinicians and / or patients and / or central analytical centers (e.g., remote laboratories and / or analytical centers) to intermediate- to long-duration and / or longer-duration AFib attacks identified as dangerous to the patient (e.g., exceeding a threshold number of attacks or a threshold duration). The wearable device may also, or optionally, include a storage unit for storing the collected data, and this storage unit is programmable to evaluate the stored data and alert clinicians and / or patients and / or central analytical centers to any potentially harmful arrhythmias. Clinicians or healthcare professionals can view the collected and / or evaluated data continuously or periodically (e.g., data can be continuously or periodically pushed to a clinician-accessible computing device, and / or pulled upon request from a clinician-accessible computing device). Periodic evaluations can be, for example, daily, weekly, twice monthly, monthly, etc. Additionally, or optionally, the collected and / or evaluated data (on wearable devices, CPUs, central analytical centers, or other computing devices accessible to patients and / or clinicians) can be screened for events identified as risky to the patient (e.g., exceeding a threshold number of attacks or a threshold duration, or exceeding a threshold AFib burden level). If such an event is detected, an alert (or warning) can be triggered for the patient and / or sent to the clinician (e.g., via wearable devices, via CPUs, via clinician-accessible computing devices, at a central analytical center, etc.). The use of warnings (alerts) is optional and can be provided immediately after the detection of prolonged AFib attacks so that clinicians and / or patients are aware of the event. The comparison period is independent of the warning and provides data that allows clinicians to compare the efficacy of the drug over time to a baseline.

[0146] Embodiment

[0147] In the following embodiments and throughout the specification, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its conventional medical meaning.

[0148] AFib or AF = Atrial fibrillation

[0149] Bid or bid = twice daily

[0150] bpm = heart rate per minute

[0151] hrs = hours

[0152] mg = milligram

[0153] PPG = Photoplethysmography

[0154] SD = Standard Deviation

[0155] Example 1 demonstrates the ability to detect AFib attacks during continuous monitoring of a patient using a wearable device.

[0156] Examples 2-7 demonstrate the utility of bunidarone in the methods described herein. In these examples, the patients had previously undergone surgical implantation of a pacemaker and therefore faced numerous associated risks. For example, see the literature Pacemaker, https: / / www.mayoclinic.org / tests-procedures / pacemaker / about / pac-20384689 (last accessed: October 26, 2022), the entire contents of which are incorporated herein by reference.

[0157] Embodiment 1 - Wearable device for continuous detection of AFib in patients

[0158] In this embodiment, a male patient with non-permanent AFib was equipped with a MCOT (Mobile Cardiac Outpatient Telemetry) wearable device sold by Philips BioSciences (Best, Netherlands), which is available by prescription in the United States. The MCOT device uses a PPG-integrated algorithm to determine heart rhythm and AFib. The MCOT device is configured to wirelessly and seamlessly provide heart rhythm and AFib data to a dedicated computer.

[0159] The patient underwent 23.5 hours of continuous monitoring. Throughout this period, the MCOT device measured the patient's heart rhythm and heart rate. Figure 2 Electrocardiograms (ECGs) obtained during the monitoring period are provided. Notably, a total of 33 independent AFib episodes were detected and recorded, each interspersed with periods of sinus rhythm or other arrhythmias. Specific details of the ECG analysis are as follows: AFib attacks occurred 33 times. The longest AFib time is 3 hours and 2 minutes. Heart rate (minimum / maximum) 48 / 94 beats per minute AFib load 36% The data above indicate that the wearable device described in this article can continuously monitor the patient's heart rhythm and provide a detailed analysis of the number of AFib attacks and the degree of AFib burden.

[0160] Embodiment 2 - Elimination of long duration AFib using bunidrolol

[0161] This example is an evaluation of a clinical trial of bunidarone in six patients with paroxysmal or persistent AFib who had previously experienced prolonged AFib episodes (greater than 24 hours). In this example, patients experienced different conditions (baseline, different doses of bunidarone, washout period), and for each condition, the heart rhythm of each patient in the population was continuously monitored with a pacemaker over a two-week period. The aim of this example was to determine whether bunidarone could reduce prolonged AFib episodes lasting longer than 24 hours. Table 1 below provides the different doses and results of this evaluation: Table 1

[0162] These results indicate that, compared to baseline, bunidarone eliminated over 70% of long-duration AFib attacks lasting longer than 24 hours at all dose levels, with little difference between treatment levels of 200 mg bid, 600 mg bid, and 800 mg bid. In contrast, both baseline and washout results showed the presence of long-duration AFib attacks lasting longer than 24 hours. These results also indicate a significant reduction in AFib burden (the product of the number of attacks and the average duration of attacks over a 2-week period) (a reduction of over 64%). This reduction is strongly associated with a reduced risk of patients transitioning from paroxysmal AFib to persistent AFib or from persistent AFib to permanent AFib.

[0163] Embodiment 3 - Elimination of longer duration AFib (>24 hours) over a 12 week period

[0164] This example is an evaluation of a clinical trial of bunidarone in six patients with paroxysmal or persistent AFib who had previously experienced prolonged AFib episodes (greater than 24 hours). In this example, each patient in the population underwent continuous cardiac rhythm monitoring via pacemaker (surgical invasive procedure) for 12 weeks and was treated with different doses of bunidarone (every 2 weeks). Furthermore, patients received continuous monitoring and ongoing supervision by clinicians throughout the trial.

[0165] The purpose of this embodiment is to assess heart rhythm using a pacemaker in a clinical research setting to determine whether bundalone treatment can reduce prolonged duration of AFib (AFib episodes lasting longer than 24 hours). The results of this analysis are presented in Table 2 below: Table 2

[0166] "Number of occurrences" indicates the number of AFib attacks of longer duration (i.e., duration greater than 24 hours). "Duration" indicates the duration (in hours) of the longer duration over a 2-week period and the percentage relative to the baseline measurement. Based on the above results, 200 mg bid was sufficient to treat all patients in the study, eliminating AFib attacks lasting longer than 24 hours. In this case, there was no need to increase the dose to improve efficacy for the patients, as a 200 mg bid dose of bunidarone was sufficient to eliminate these long-duration AFib attacks.

[0167] Embodiment 4 - Reduction of long duration AFib (>5 hours) over a 12 week period

[0168] This example is an evaluation of a clinical trial of bunidarone in six patients with paroxysmal or persistent AFib who had previously experienced prolonged AFib episodes (greater than 5 hours). In this example, each patient's heart rhythm was continuously monitored via pacemaker (surgical intervention) over a 12-week period, and they were treated with different doses of bunidarone, each administered for two weeks. Furthermore, patients underwent continuous monitoring and clinical supervision throughout the trial.

[0169] The purpose of this embodiment is to assess heart rhythm using a pacemaker in a clinical research setting to determine whether brunidaron can reduce long-duration AFib lasting more than 5 hours. The results of this analysis are presented in Table 3 below: Table 3

[0170] "Number of occurrences" indicates the number of long-duration AFib attacks lasting longer than 5 hours. "Duration" indicates the duration (in hours) of AFib lasting longer than 5 hours within a 2-week time period and the percentage relative to baseline measurements. In this example, all doses of bunidarone demonstrated statistically significant benefits in reducing the number of AFib events and the duration of AFib attacks exceeding 5 hours, with similar results at 200 mg bid and 600 mg bid, while 400 mg bid was significantly better than the untreated state (baseline data for each patient without bunidarone), but less effective than 200 mg bid and 600 mg bid. Finally, 800 mg bid yielded the best results. At all dose levels, the reduction in AFib attacks longer than 5 hours exceeded 85%, and the corresponding reduction in AFib burden exceeded 90%.

[0171] Given the previously discussed relationship between prolonged AFib episodes and increased risk of stroke and heart failure (e.g., 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 cases measured the reduction in AFib attacks of 1 hour or longer in patients.

[0172] Embodiment 5 - Reduction of long duration AFib (>1 hour) over a 12 week period

[0173] This example is an evaluation of a clinical trial of bunidarone in six patients with paroxysmal or persistent AFib who had previously experienced prolonged AFib episodes (greater than 1 hour). In this example, each patient's heart rhythm was continuously monitored via pacemaker (surgical intervention) over a 12-week period, and they were treated with different dose levels (daily administration of different doses of bunidarone, each dose level administered for two weeks). Furthermore, patients underwent continuous monitoring and clinical supervision throughout the trial.

[0174] The purpose of this embodiment is to assess heart rhythm using a pacemaker in a clinical research setting to determine whether brunidaron can reduce long-duration AFib (duration > 1 hour). The results of this analysis are presented in Table 4 below: Table 4

[0175] This embodiment demonstrates a significant reduction in the frequency of prolonged AFib (>1 hour) attacks over a 2-week period. As mentioned above, "frequency" indicates the number of prolonged AFib attacks that occurred within the 2-week period, and "duration" indicates the number of hours of prolonged AFib attacks detected within the 2-week period.

[0176] Embodiment 6 - Reduction of AFib episodes greater than 6 minutes over a 12 week period

[0177] This example demonstrates the robustness of bunidarone in reducing AFib burden and AFib episodes longer than 6 minutes (0.1 hours) in six patients with paroxysmal or persistent AFib who had a history of prolonged AFib episodes (longer than 1 hour). In this example, each patient's heart rhythm was continuously monitored via pacemaker over a 12-week period. Patients were treated with different doses of bunidarone, each dose level administered for two-week periods. Furthermore, patients underwent continuous monitoring and clinician supervision throughout the trial.

[0178] The results are summarized in Table 5, which confirms that bunidarone can reduce long-duration AFib lasting more than 1 hour not only in clinical research settings where pacemakers are used to assess heart rhythm, but also significantly reduce episodes lasting more than 6 minutes (0.1 hours).

[0179] Table 5

[0180] "Number of occurrences" indicates the number of AFib episodes longer than 6 minutes (0.1 hours) in all test patients during the trial period (4 weeks at baseline, 2 weeks for each experimental dose). "Duration" (in hours) indicates the cumulative duration (in hours) of AFib episodes longer than 6 minutes measured in test patients during the trial period. These results indicate that bunidarone reduces the number of long-duration AFib episodes and reduces short-duration AFib episodes, thereby further preventing stroke and heart failure and significantly reducing AFib burden.

[0181] For patients with paroxysmal and persistent AFib with a high CHA2DS2-VASc score (3 or higher), AFib attacks 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 (>65 = 1 point, >75 = 2 points), diabetes, and a history of stroke / transient ischemic attack (2 points)). VASc represents vascular disease (peripheral artery disease, history of myocardial infarction, aortic atherosclerosis), and the scoring system also includes a sex classification (female). The data in Table 5 show that at all tested doses of bendalone, the number of AFib attacks lasting longer than 6 minutes was significantly reduced, and at higher concentrations (600 mg bid or 800 mg bid), these attacks were reduced by more than 80%.

[0182] Table 6 provides the percentage of AFib episodes lasting longer than 6 minutes per week and the number of hours. With bunidarone at doses of 600 mg bid and 800 mg bid, the percentage of AFib episodes was reduced by 90%.

[0183] Table 6

[0184] The percentage of time to aspirin (AFib) is a key parameter directly associated with risk factors for stroke and / or congestive heart failure, especially in patients with high CHA2DS2-VASc scores. In Table 6, patients receiving 200 mg bunidarone twice daily experienced a 76.7% decrease in their AFib time percentage; those receiving 600 mg bunidarone twice daily saw a further 90% decrease; and those receiving 800 mg bunidarone twice daily experienced an even greater 94.8% decrease.

[0185] Embodiment 7 - Measurement of longest AFib episode length over a 12 week period

[0186] This example is a clinical trial evaluation in which six patients were treated with different doses of bunidarone, with each dose tested for two weeks to determine the longest duration of AFib episodes experienced by patients at each dose. In this example, each patient's heart rhythm was continuously monitored with a pacemaker over a 12-week period. The different doses and results of this evaluation are shown in Table 7 below: Table 7

[0187] The results above demonstrate the variability of prolonged AFib (≥5 hours) in patients treated with different doses of bunidarone. In subjects 4 and 5, treatment with 200 mg bunidarone twice daily was sufficient to eliminate all prolonged AFib (>5 hours) episodes. However, subject 1 required 800 mg bunidarone twice daily to eliminate all prolonged AFib (>5 hours) episodes, while subject 6 required 600 mg bunidarone twice daily to eliminate all AFib episodes. These data suggest that for patients with paroxysmal or persistent AFib experiencing prolonged AFib episodes, appropriate treatment requires long-term patient monitoring combined with bunidarone dose adjustments.

[0188] The results of Examples 2 through 7 indicate that using an appropriate dose of bunidarone while monitoring the heart rhythm of treated patients can reduce all long-duration AFib episodes longer than 5 hours and alleviate the overall AFib burden. These results suggest that the progression from paroxysmal AFib to persistent AFib, or from persistent AFib to permanent AFib, can be reduced or prevented.

[0189] According to this method, bunidarone can be administered using a pharmaceutical composition comprising about 1% to 99% bunidarone, with the remainder being pharmaceutically acceptable excipients such as corn starch, cellulose, stearic acid, water, or other components. The pharmaceutical composition can be formulated in any form, and by way of example only, may include one or more of the following: tablets, capsules, powders, and / or other formulations for oral administration; solutions for parenteral administration, such as those suitable for intravenous or intramuscular administration; suppositories and / or enemas; and skin and / or transdermal formulations.

[0190] Embodiment 8 - Long term bunidrolol therapy eliminates AFib episodes over 5.5 hours or 5 hours

[0191] This embodiment is an evaluation of a 3-month (12-week) clinical trial, with 72 patients participating. These patients received either placebo (15 patients), 200 mg bid bunidarone (16 patients), 400 mg bid bunidarone (16 patients), or 600 mg bid bunidarone (13 patients). Baseline and washout periods (4 weeks before and after the 12-week trial period, during which bunidarone was not administered) were defined before and after the trial. In this embodiment, patients' heart rhythm was continuously monitored using a pacemaker during the 5-month study period. Table 8 shows the median duration (in hours) of AFib attacks under each condition (placebo, 200 mg bid, 400 mg bid, 600 mg bid). These results indicate that statistically significant dose-response and a significant reduction in the duration of AFib attacks were observed at all administered doses during the 2–3 month treatment period, with this effect observed even as early as the first month for both 400 mg bid and 600 mg bid.

[0192] Table 8

[0193] The p-value was calculated using the dose-response Jonckheere-Terpstra test.

[0194] Table 9 shows more detailed results for the 600 mg bid dose group compared to placebo. Table 9 provides the number of AFib attacks (N), mean duration (with standard deviation (SD)) and median duration (in hours) of AFib attacks per month during the trial period for both the placebo control group and the 600 mg bid dose group.

[0195] Table 9

[0196] Within one month of initiating bunidarone administration, the mean attack duration decreased to less than 5 hours or 5.5 hours (1.4 ± 0.7 (standard error) hours). At 2–3 months of treatment initiation (months 2 and 3), all AFib attacks lasting longer than 5 hours or 5.5 hours were eliminated, and the mean attack duration decreased to less than one hour (0.4 ± 0.2 (standard error) hours and 0.7 ± 0.3 (standard error) hours, respectively). At months 2 and 3, none of the patients receiving bunidarone had a high AFib load upon administration of 600 mg bid. Compared to a mean AFib load of approximately 35% at baseline, the mean AFib load in treated patients was approximately 0.5% at month 2 and approximately 0.8% at month 3. These data suggest that the approach disclosed herein can be used to significantly reduce or even eliminate AFib attacks lasting longer than 5 hours or 5.5 hours. These methods can also significantly reduce or eliminate periods of significant AFib load, for example, reducing or eliminating AFib load by more than 10%, more than 5%, or more than 2.5% within a given 24-hour period.

[0197] Embodiment 9 - Symptom relief in symptomatic patients

[0198] This example illustrates how the reduction of AFib-related symptoms and / or overall symptoms can be assessed in symptomatic AFib patients. In the experiment of Example 8, patients assessed the reduction of AFib-related symptoms based on validated patient-reported outcomes. Patients were surveyed after 3 months of treatment with either placebo or each bunidarone dose. Table 10 lists these patient-reported outcomes: Table 10

[0199] These results indicate that, compared to the average of 33% across all three doses of bunidarone, 64.7% of patients in the placebo group reported that the placebo either worsened their symptoms or provided no improvement. Similarly, 17.7% of patients in the placebo group reported moderate, significant, or complete symptom relief, compared to an average of 48% across all three doses of bunidarone.

[0200] The results in Table 10 show that, compared with placebo, bunidarone treatment improved patient-reported AFib symptoms in a dose-dependent manner. (P-values ​​for placebo were calculated using the Cochran-Mantel-Haenszel mean test; P-values ​​for dose response were calculated using the Jonckheere Terpstra test).

[0201] Patients were investigated for specific AFib-related symptoms, including experiences of palpitations and shortness of breath during physical activity. Patients rated their symptoms on a scale of 1–6 (1 = no symptoms; 2 = very few; 3 = few symptoms; 4 = many symptoms; 5 = many symptoms; 6 = very many symptoms), and patients with a baseline self-reported symptom score >2 were included in symptom follow-up. Table 11 shows the dose-dependent improvement in these symptoms compared to placebo: Table 11

[0202] Embodiment 10 - Programming of wearable device

[0203] Wearable devices can be programmable (e.g., programmable by clinicians, patients, and / or remotely (e.g., through a central analysis center)). Wearable devices can be programmed to capture a patient's heart rhythm data. The resulting data can be queried and / or analyzed by the CPU on the wearable device, and / or can be transmitted to another device for querying and / or analysis. One example of programming a wearable device is enabling it to monitor a patient's heart rhythm and transmit the data directly and / or indirectly to (e.g.) a clinician, as detailed below.

[0204] A. User Interface: Used for programming the step functions of the AFib monitoring system, which involves wearable devices and relies on information transmitted to the attending physician via a network.

[0205] B. The collected data is presented in a readable format for access by clinicians and other authorized personnel.

[0206] C. The readable display should always be available to authorized clinicians, and the clinicians should only be authorized to save data and / or reset the monitoring system after completing one or more of the steps in 1-15.

[0207] D. Clinicians may retrieve information about the medications, dosages, and / or any other medications administered to a patient 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).

[0208] E. Steps 1 through 14 are the only steps that require manual input, but step 14 is the best. Clinicians can simply press "Manually reset step 15" to override step 14.

[0209] F. All data may be saved after being reviewed by the attending physician. The attending physician also has the right to set up the integration of previous observation periods (step 17), regardless of whether drugs (including bunidarone) were used to treat AFib.

[0210] G. The system is user-friendly, and the attending physician only needs to do four things each time: 1) enter the patient information or code to access the data, 2) view the data display, 3) if necessary, enter the dose of bunidarone in step 14, and then 4) click "Manually reset and save data".

[0211] H. The attending physician can access the stored data and integrate the observation period to compare the characteristics of different doses of bunidarone or AFib under no-drug conditions (step 17).

[0212] Table 12 below lists each step: Table 12

[0213] In the programming of a wearable device, each step in steps 4-13 may be included or excluded (e.g., as determined by a clinician), provided that at least one of these steps is included. In one embodiment, steps 4-7 may be performed and corresponding data collected, while one or more steps 8-13 may be excluded. In another embodiment, steps 4, 5, 8, and 9 may be included, while steps 5, 6, and 10-13 may be excluded. In yet another embodiment, steps 4, 5, 10, and 11 may be included, while steps 6, 7, 8, 9, 12, and 13 may be excluded. In yet another embodiment, steps 4, 5, 12, and 13 may be included, while steps 6-11 may be excluded.

[0214] In another implementation, the attending physician may program the wearable device according to one or more of steps 4-13.

[0215] List of abbreviations:

[0216] Embodiments

[0217] The following are some implementation schemes.

[0218] Implementation Scheme I-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, the method comprising: a) Administer a first dose of bunidarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient’s heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of bunidarone or a pharmaceutically acceptable salt thereof. b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of bunidarone or a pharmaceutically acceptable salt thereof administered in the eligible patients to determine whether the first dose is effective for the patients, provided that the efficacy of bunidarone is determined at least 7 or 14 days after the initiation of treatment with the first dose (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof). c) If the first dose is deemed ineffective for the patient at the end of the comparison period, then, using at least the same delay and comparison period as in b), one or more dose adjustments of binidarone may be made as needed to achieve an effective outcome, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective outcome is still not achieved when evaluated at the maximum approved dose, then the patient may be discontinued from binidarone treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's cardiac rhythm data to ensure that the dose of bunidarone remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose as the first dose.

[0219] Implementation Scheme I-2. The method according to Implementation Scheme I-1, wherein the patient is identified as eligible for treatment with bunidarone (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof) based on the following criteria: the patient has experienced at least one AFib attack lasting at least about 5 hours or at least about 5.5 hours within at least 7 or 14 days after the patient has not been treated with bunidarone.

[0220] Implementation Scheme I-3. The method according to Implementation Scheme I-1, wherein the patient is identified as eligible for treatment with bunidarone (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof) based on the following criteria: the patient’s baseline level of AFib load is at least 5 hours for at least 7 or 14 days after the patient has not been treated with bunidarone.

[0221] Implementation scheme I-4. The method according to any one of implementation schemes I-1 to I-3, wherein the monitoring in step b) is performed continuously.

[0222] Implementation Scheme I-5. The method according to any one of Implementation Schemes I-1 to I-4, wherein the efficacy of the bunidarone treatment (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof) at the administered dose is evaluated by comparing the baseline level of AFib with the corresponding level of AFib during the comparison period.

[0223] Implementation Scheme I-6. The method according to any one of Implementation Schemes I-1 to I-5, wherein the comparison period is one or more of about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

[0224] Implementation scheme I-7. The method according to any one of implementation schemes I-1 to I-5, wherein the first comparison period is followed by a second comparison period of similar duration.

[0225] Implementation scheme I-8. The method according to any one of implementation schemes I-1 to I-7, wherein AFib attacks are monitored for more than about 5 hours.

[0226] Implementation scheme I-9. The method according to any one of implementation schemes I-1 to I-8, wherein AFib attacks are monitored for more than about 5.5 hours.

[0227] Implementation scheme I-10. The method according to any one of implementation schemes I-1 to I-9, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

[0228] Implementation Scheme I-11. The method according to any one of Implementation Schemes I-1 to I-10, wherein the bunidarone or a pharmaceutically acceptable salt thereof is bunidarone tartrate.

[0229] Implementation Scheme I-12. The method according to any one of Implementation Schemes I-1 to I-11 further includes: if the patient withdraws from bunidarone treatment (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof) in step c), then the patient is referred for electrophysiological intervention.

[0230] Implementation Scheme II-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone ( wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof), the method comprising: For patients who have been identified as eligible for treatment with bunidarone (wherein the treatment is bunidarone or a pharmaceutically acceptable salt thereof), wherein the eligibility requirement is that the patient experiences at least one prolonged AFib attack lasting at least 1 hour during the eligibility period, or an AFib load of at least 2.5% throughout the eligibility period, wherein the eligibility period is at least 2 weeks, during which the patient has not received bunidarone treatment: a) Administer a first dose of bunidarone to the eligible patient while monitoring the patient’s heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of bunidarone; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of bunidarone administered in the patients to determine whether the first dose is effective for the patients, provided that the efficacy of bunidarone is determined at least 7 or 14 days after the initiation of treatment with the first dose. c) If the first dose administered is deemed ineffective for the patient at the end of the comparison period, then, using at least the same delay and comparison period as in b), one or more dose adjustments of binidarone may be made as needed to achieve an effective outcome, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective outcome is still not achieved when evaluated at the maximum approved dose, then the patient may be discontinued from binidarone treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's cardiac rhythm data to ensure that the dose of bunidarone remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose as the first dose.

[0231] Implementation scheme II-2. The method according to implementation scheme II-1, wherein the monitoring in step b) is performed continuously.

[0232] Implementation scheme II-3. The method according to any one of implementation schemes II-1 to II-2, wherein the efficacy of the treatment is assessed by comparing the baseline level of AFib with the corresponding level of AFib during the comparison period.

[0233] Implementation scheme II-4. The method according to any one of implementation schemes II-1 to II-3, wherein the comparison period is one or more of about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

[0234] Implementation scheme II-5. The method according to any one of implementation schemes II-1 to II-4, wherein the first comparison period is followed by a second comparison period of similar duration.

[0235] Implementation scheme II-6. The method according to any one of implementation schemes II-1 to II-5, wherein AFib attacks are monitored for more than about 5 hours.

[0236] Implementation scheme II-7. The method according to any one of implementation schemes II-1 to II-6, wherein AFib attacks are monitored for more than about 5.5 hours.

[0237] Implementation scheme II-8. The method according to any one of implementation schemes II-1 to II-7, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

[0238] Implementation scheme II-9. The method according to any one of implementation schemes II-1 to II-8, wherein the bunidarone or a pharmaceutically acceptable salt thereof is bunidarone tartrate.

[0239] Implementation scheme II-10. The method according to any one of implementation schemes II-1 to II-9 further includes: if the patient withdraws from bunidarone treatment in step c), the patient is referred for electrophysiological intervention.

[0240] Implementation Plan III-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy, the method comprising: a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the drug treatment was started at the first dose. c) If the first dose is deemed ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in c), one or more dose adjustments of the drug may be made as needed to obtain an effective result, provided that the dose adjustments do not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, then the patient may be discontinued from drug treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm data to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

[0241] Implementation scheme III-2. The method according to implementation scheme III-1, wherein the patient is identified as eligible for drug treatment with the drug based on the following criteria: the patient has experienced at least one AFib attack lasting at least about 5 hours or at least about 5.5 hours within at least 7 or 14 days after the patient has not been given the drug.

[0242] Implementation scheme III-3. The method according to any one of implementation schemes III-1 to III-2, wherein the patient is identified as eligible for drug treatment with the drug based on the following criteria: the patient's baseline level of AFib load is at least 5 hours for at least 7 or 14 days after the patient has not been given the drug.

[0243] Implementation scheme III-4. The method according to any one of implementation schemes III-1 to III-3, wherein the monitoring in step c) is performed continuously.

[0244] Implementation scheme III-5. The method according to any one of implementation schemes III-1 to III-4, wherein the efficacy of the drug when administered at the dosage is evaluated by comparing the baseline level of AFib with the corresponding level of AFib during the comparison period.

[0245] Implementation scheme III-6. The method according to any one of implementation schemes III-1 to III-5, wherein the comparison period is one or more of about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

[0246] Implementation scheme III-7. The method according to any one of implementation schemes III-1 to III-6, wherein the first comparison period is followed by a second comparison period of similar duration.

[0247] Implementation scheme III-8. The method according to any one of implementation schemes III-1 to III-7, wherein AFib attacks are monitored for more than about 5 hours.

[0248] Implementation scheme III-9. The method according to any one of implementation schemes III-1 to III-8, wherein AFib attacks are monitored for more than about 5.5 hours.

[0249] Implementation scheme III-10. The method according to any one of implementation schemes III-1 to III-9, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

[0250] Implementation scheme III-11. The method according to any one of implementation schemes III-1 to III-10 further includes: if the patient withdraws from drug treatment in step c), referring the patient for electrophysiological intervention.

[0251] Implementation Scheme IV-1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy, the method comprising: For patients who have been identified as eligible for treatment with the drug, wherein the eligibility requirement is that the patient experiences at least one prolonged AFib episode lasting at least 1 hour during the eligibility period, or an AFib load of at least 2.5% throughout the eligibility period, wherein the eligibility period is at least 2 weeks, during which the patient has not received treatment with the drug: a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the first dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the start of treatment with the first dose. c) If the first dose administered is deemed ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in b), one or more dose adjustments of the drug may be made as needed to obtain an effective result, provided that the dose adjustment does not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, then the patient may be discontinued from drug treatment; and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm data to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

[0252] Implementation scheme IV-2. The method according to implementation scheme IV-1, wherein the monitoring in step b) is performed continuously.

[0253] Implementation scheme IV-3. The method according to any one of implementation schemes IV-1 to IV-2, wherein the efficacy of the drug when administered at the dosage is evaluated by comparing the baseline level of AFib with the corresponding level of AFib during the comparison period.

[0254] Implementation scheme IV-4. The method according to any one of implementation schemes IV-1 to IV-3, wherein the comparison period is one or more of about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

[0255] Implementation scheme IV-5. The method according to any one of implementation schemes IV-1 to IV-4, wherein the first comparison period is followed by a second comparison period of similar duration.

[0256] Implementation scheme IV-6. The method according to any one of implementation schemes IV-1 to IV-5, wherein AFib attacks are monitored for more than about 5 hours.

[0257] Implementation scheme IV-7. The method according to any one of implementation schemes IV-1 to IV-6, wherein AFib attacks are monitored for more than about 5.5 hours.

[0258] Implementation scheme IV-8. The method according to any one of implementation schemes IV-1 to IV-7, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

[0259] Implementation scheme IV-9. The method according to any one of implementation schemes IV-1 to IV-8 further includes: if the patient withdraws from drug treatment in step c), referring the patient for electrophysiological intervention.

[0260] Implementation Plan V. Use of bunidarone or a pharmaceutically acceptable salt thereof in the treatment of patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone according to any of the above implementation plans.

[0261] Implementation Scheme VI. A composition for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone according to any of the above implementation schemes, wherein the composition is bunidarone or a pharmaceutically acceptable salt thereof (e.g., bunidarone tartrate or bunidarone citrate).

Claims

1. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, the method comprising: a) Administer a first dose of bunidarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient’s heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of bunidarone or a pharmaceutically acceptable salt thereof. b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of bunidarone or a pharmaceutically acceptable salt thereof administered in the eligible patients to determine whether the first dose is effective for the patients, provided that the efficacy of bunidarone is determined at least 7 or 14 days after the initiation of treatment with the first dose. c) If the first dose is deemed ineffective for the patient at the end of the comparison period, the patient is given at least the same delay and comparison period as in b), and one or more dose adjustments are made as needed to obtain an effective result by adjusting the amount of binidarone or a pharmaceutically acceptable salt thereof, provided that the dose adjustment does not exceed the maximum approved dose; or, if an effective result is still not obtained when evaluated at the maximum approved dose, the patient is discontinued from binidarone treatment. and d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's cardiac rhythm data to ensure that the dose of bunidarone or its pharmaceutically acceptable salt remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose as the first dose.

2. The method of claim 1, wherein the patient is deemed eligible for treatment with bunidarone based on the following criteria: the patient has experienced at least one AFib attack lasting at least about 5 hours or at least about 5.5 hours within at least 7 or 14 days prior to receiving bunidarone treatment.

3. The method of claim 1, wherein the patient is deemed eligible for bunidarone treatment based on a baseline level of at least 5 hours of AFib load during at least 7 or 14 days without bunidarone treatment.

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

5. The method according to any one of claims 1 to 4, wherein the efficacy of the bunidarone treatment at the administered dose is evaluated by comparing the baseline level of AFib with the corresponding level of AFib 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 about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

7. The method of claim 6, wherein the first comparison period is followed by a second comparison period of similar duration.

8. The method according to any one of claims 1 to 7, wherein AFib attacks are monitored for more than about 5 hours.

9. The method according to any one of claims 1 to 7, wherein AFib attacks are monitored for more than about 5.5 hours.

10. The method according to any one of claims 1 to 9, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

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

12. The method according to any one of claims 1 to 11, further comprising: If the patient withdraws from bunidarone treatment in step c), the patient is referred for electrophysiological intervention.

13. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for treatment with bunidarone, the method comprising: For patients who have been identified as eligible for treatment with bunidarone, the eligibility requirement is that the patient experiences at least one prolonged AFib episode lasting at least 1 hour during the eligibility period, or has an AFib load of at least 2.5% throughout the eligibility period, wherein the eligibility period is at least 2 weeks and the patient has not received bunidarone treatment during this period: a) Administer a first dose of bunidarone or a pharmaceutically acceptable salt thereof to the eligible patient while monitoring the patient’s heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of bunidarone; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of bunidarone or a pharmaceutically acceptable salt thereof administered to the patient to determine whether the first dose is effective for the patient, provided that the efficacy of bunidarone is determined at least 7 or 14 days after the initiation of treatment with the first dose. c) If the first dose administered is determined to be ineffective for the patient at the end of the comparison period, then at least the same delay and comparison period as in b) shall be used, and effective results shall be obtained by one or more dose adjustments to an amount of bunidarone or a pharmaceutically acceptable salt thereof, provided that the dose adjustment does not exceed the maximum approved dose. Alternatively, if no effective results are obtained when evaluated at the maximum approved dose, the patient may be discontinued from bunidarone treatment. as well as d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's cardiac rhythm data to ensure that the dose of bunidarone or its pharmaceutically acceptable salt remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose as the first dose.

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

15. The method of any one of claims 13 or 14, wherein the efficacy of the bunidarone treatment at the administered dose is evaluated by comparing the baseline level of AFib with the corresponding level of AFib 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 about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

17. The method of claim 16, wherein the first comparison period is followed by a second comparison period of similar duration.

18. The method according to any one of claims 13 to 17, wherein AFib attacks are monitored for more than about 5 hours.

19. The method according to any one of claims 13 to 18, wherein AFib attacks are monitored for more than about 5.5 hours.

20. The method according to any one of claims 13 to 19, wherein the patient’s one or more symptoms related to AFib are assessed using reports of the frequency or severity of one or more of the patient’s symptoms.

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

22. The method according to any one of claims 13 to 21, further comprising: If the patient withdraws from bunidarone treatment as described in step c), the patient is referred for electrophysiological intervention.

23. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy, the method comprising: a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the drug treatment was started at the first dose. c) If the first dose is determined to be ineffective for the patient at the end of the comparison period, then at least the same delay and comparison period as in c) shall be used, and the amount of the drug shall be adjusted one or more times as needed to obtain an effective result, provided that the dose adjustment does not exceed the maximum approved dose; Alternatively, if no effective results are obtained when evaluated at the maximum approved dose, the patient may be discontinued from the drug treatment. as well as d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm data to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

24. The method of claim 23, wherein the patient is deemed eligible for drug treatment with the drug based on the following criteria: the patient has experienced at least one AFib attack lasting at least about 5 hours or at least about 5.5 hours within at least 7 or 14 days after the patient has not been given the drug.

25. The method of claim 23, wherein the patient is identified as eligible for drug treatment with the drug based on the following criteria: the patient's baseline level of AFib load is at least 5 hours for at least 7 or 14 days after the patient has not been given the drug.

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

27. The method according to any one of claims 23 to 26, wherein the efficacy of treatment with the drug at the administered dose is evaluated by comparing the baseline level of AFib with the corresponding level of AFib 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 about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

29. The method of claim 28, wherein a second comparison period of similar duration follows the first comparison period.

30. The method according to any one of claims 23 to 29, wherein AFib attacks are monitored for more than about 5 hours.

31. The method according to any one of claims 23 to 29, wherein AFib attacks are monitored for more than about 5.5 hours.

32. The method according to any one of claims 23 to 31, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

33. The method according to any one of claims 23 to 32, further comprising: If the patient withdraws from drug therapy as described in step c), the patient will be referred for electrophysiological intervention.

34. A method for treating a patient diagnosed with paroxysmal or persistent atrial fibrillation (AFib) and eligible for drug therapy, the method comprising: For patients who have been identified as eligible for treatment with the drug, wherein the eligibility requirement is that the patient experiences at least one prolonged AFib episode lasting at least 1 hour during the eligibility period, or an AFib load of at least 2.5% throughout the eligibility period, wherein the eligibility period is at least 2 weeks, during which the patient has not received treatment with the drug: a) Administering a first dose of the drug to the eligible patient while monitoring the patient's heart rhythm data using a wearable device, wherein the first dose is an approved therapeutic dose that is less than the maximum approved dose of the drug; b) During a comparison period of 1 day or more, monitor the efficacy of the first dose of the drug administered to the patient to determine whether the first dose is effective for the patient, provided that the efficacy of the drug is determined at least 7 or 14 days after the start of treatment with the first dose. c) If the first dose administered is determined to be ineffective for the patient at the end of the comparison period, then using at least the same delay and comparison period as in b), the dosage of the drug may be adjusted one or more times as needed to obtain an effective result, provided that the adjusted dosage does not exceed the maximum approved dosage. Alternatively, if no effective results are obtained when evaluated at the maximum approved dose, the patient may be discontinued from the drug treatment. as well as d) If the first dose or the adjusted dose is effective for the patient, continue to monitor the patient's heart rhythm data to ensure that the dose of the drug remains effective, provided that if the dose is no longer effective, step c) is repeated with the dose of the drug as the first dose.

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

36. The method according to any one of claims 34 or 35, wherein the efficacy of treatment with the drug at the administered dose is evaluated by comparing the baseline level of AFib with the corresponding level of AFib 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 about 1 day, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months or up to about 6 months.

38. The method of claim 37, wherein the first comparison period is followed by a second comparison period of similar duration.

39. The method according to any one of claims 34 to 38, wherein AFib attacks are monitored for more than about 5 hours.

40. The method according to any one of claims 34 to 38, wherein AFib attacks are monitored for more than about 5.5 hours.

41. The method according to any one of claims 34 to 40, wherein one or more symptoms associated with AFib are assessed using reports of the frequency or severity of one or more of the patient's symptoms.

42. The method according to any one of claims 34 to 41, further comprising: If the patient withdraws from drug therapy as described in step c), the patient will be referred for electrophysiological intervention.

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