Methods for reducing the risk of stroke through drug therapy to reduce the frequency and duration of atrial fibrillation - Patents.com

Abstract

Methods of treating AFib patients are disclosed by monitoring the cardiac rhythm of the AFib patient to determine the presence and / or number of long-term AFib episodes and, optionally, the degree of AFib burden. Patients who meet threshold requirements are eligible for treatment of AFib by administration of budiodarone. Continued monitoring of the patient confirms that the patient is responsive to budiodarone therapy and that responsiveness is maintained, including providing the patient with a dose adjustment to achieve budiodarone therapy. Continued monitoring thereafter confirms that the patient remains responsive. These methods allow for treatment of AFib and accordingly reduce or delay the risk of stroke and / or congestive heart failure in the treated patient.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. patent application Ser. No. 63 / 297,426, filed January 7, 2022; and U.S. patent application Ser. No. 63 / 334,852, filed April 26, 2022; and U.S. patent application Ser. No. 17 / 978,835, filed November 1, 2022, the disclosures of which are incorporated by reference in their entireties herein. [Background technology]

[0002] Methods and devices are disclosed for reducing the risk of stroke and / or congestive heart failure in patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) by determining whether the patient is eligible for a medication that reduces the number and / or duration of AFib episodes and then treating the patient with the medication.

[0003] Prior Art AFib is a serious medical condition characterized by abnormal heart rhythms, often accompanied by a fast heart rate. If left untreated, AFib significantly increases the risk of stroke, congestive heart failure, and death.

[0004] AFib has been classified into at least three groups: patients with intermittent AFib episodes that last no longer than seven days before returning to normal, either spontaneously or with treatment, are defined as having paroxysmal AFib, patients with intermittent AFib episodes that last longer than seven days before returning to normal are defined as having persistent AFib, and patients who constantly experience AFib are defined as having permanent AFib.

[0005] The irregularities in heart rhythm that underlie AFib result in the accumulation of blood in the upper chambers of the heart. The longer blood remains in the upper chambers, the greater the chance that blood there will coagulate and form clots. If these clots leave the heart, they can travel to the brain and cause a stroke. In some cases, these clots cause the patient to have a transient ischemic attack (TIA). Such TIAs may cause the patient to experience weakness on one side of the body, slurred speech, or visual impairment, which are temporary in nature. In other cases, these clots cause debilitating strokes that can result in anything from loss of functionality, such as speech and mobility, to complete coma or death.

[0006] AFib is also associated with an increased risk of stroke as well as congestive heart failure, which is a severely debilitating condition and terminal in the long term. The risk of stroke and / or congestive heart failure in patients with AFib is significantly higher than in those with normal heart rhythm, and this risk increases with the duration and number of each AFib episode (collectively AFib burden). For example, the recent ENGAGE clinical trial evaluated patients' risk of stroke, which is listed in Table 1 below. [Table 1]

[0007] Recent studies have shown that the increased risk of stroke and / or congestive heart failure is independent of whether a patient's AFib is symptomatic or asymptomatic.See, for example, Flaker, et al., "Asymptomatic Atrial Fibrillation: Demographic Features and Prognostic Information from the Atrial Fibrillation Follow-Up Investigation of Rhythmic Management (AFFIRM) Study," AMERICAN HEART JOURNAL, April 2005, pages 657-663, which is incorporated herein by reference in its entirety.In other words, a patient's awareness of periodic AFib episodes does not mean that the risk of stroke or congestive heart failure is reduced or eliminated.

[0008] It is also recognized that long-term AFib episodes (i.e., AFib episodes lasting more than one hour) increase the risk of stroke, and that the risk of stroke increases with the duration of these episodes. The longer the episode lasts, the higher the risk of stroke. Thus, AFib episodes lasting more than one hour are referred to as "long-term" episodes. Such long-term episodes are further divided into two subsets: "medium-long" episodes lasting about one hour to about 24 hours or less, and "very long" episodes lasting more than about 24 hours but are not persistent AFib. However, not all patients with paroxysmal or persistent AFib exhibit long-term AFib. In fact, AFib burden is related to, but distinct from, medium-long and very long-term AFib. For example, patients with low AFib burden may experience long-term AFib episodes, although less frequently. Similarly, patients with high AFib burden may experience multiple short AFib episodes but few or no long-term episodes. Being able to distinguish between AFib burden and long-term AFib is essential to address the risks of stroke, congestive heart failure, etc. This is particularly important for treating clinicians who must evaluate the efficacy of pharmacotherapy designed to reduce the number and duration of AFib episodes.

[0009] Furthermore, early studies comparing AFib rate control with rhythm control found little difference in outcomes (e.g., Hohnloser SH, Kuck KH, Lilienthal J, PIAF investigators. Rhythm or rate control in atrial fibrillation-Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. The Lancet. 2000 Nov 25;356(9244):1789-94, Wyse DG, Waldo AL, DiMarco JP et. al. A comparison of rate control and rhythm control in patients with atrial fibrillation. New England Journal of Medicine. 2002 Dec 5;347(23):1825-33).However, with increased early diagnosis of AFib and advances in treatment strategies, including modern antiarrhythmic drugs (many of which have serious side effects such as QT prolongation), recommended lifestyle changes, and catheter ablation, early rhythm control has been shown to be possible and associated with long-term improvements in patient outcomes (Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F. Early rhythm-control therapy in patients with atrial fibrillation. New England Journal of Medicine. 2020 Oct 1;383(14):1305-16, Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, Poole JE, Bahnson TD, Lee KL, Mark DB, CABANA Investigators. Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021 Apr 6;143(14):1377-90). However, such approaches did not address the challenge of treating patients in the later stages of AFib, including those who are refractory to such contemporary therapies, or how to identify non-responsive compared to responsive patients, especially when AFib is asymptomatic.

[0010] Several drugs are designed to treat AFib, including beta-blockers and calcium channel blockers. Many of these drugs are designed to control heart rate, not heart rhythm. However, stroke risk is related to the prolongation of AFib episodes, not the underlying heart rate. Recently, budiodarone (disclosed in U.S. Pat. No. 9,549,912, which is incorporated by reference in its entirety) has been shown to control heart rhythm and significantly reduce long-term AFib episodes. However, not all AFib patients exhibit long-term AFib episodes, so indiscriminate administration of such heart rhythm drugs to patients experiencing AFib is not recommended. Even for patients with medium-long and / or very long-term AFib episodes treated with budiodarone, the degree of reduction in AFib episodes is dose-dependent and varies from patient to patient due to age, sex, weight, degree of disease progression, and other factors known in the art. In addition, as with other drug therapies, there is a certain number of patients who do not respond.

[0011] There are many wearables available that can diagnose the presence of AFib in patients, including watches, cardiac Holter monitors, patches, etc., but the ability to simply diagnose is different from the ability to continuously assess the presence of long-term AFib in patients with paroxysmal or persistent AFib. Currently, continuous monitoring of a patient's cardiac rhythm is possible with wearables such as patches and / or devices. The latter include wireless transmitting devices (such as the mobile cardiac outpatient telemetry (MCOT) sold by Philips Biosciences, Best, The Netherlands) that allow seamless collection of a patient's cardiac rhythm data. To date, such devices have been used primarily in untreated patients suspected of having AFib, and therefore primarily for diagnosis. There is currently no example of how these devices should or could be used in conjunction with drug therapy to assess responsive and non-responsive patients to drugs designed to reduce long-term AFib episodes. This includes allowing the clinician to monitor disease progression and / or regression in treated patients and titrating the amount of drug to achieve the initial therapeutic benefit or titrating the patient to restore or maintain therapeutic benefit at the lowest possible dose.

[0012] Thus, clinicians are left with minimal short-term data on the patient's heart rhythm for this period, typically up to two weeks, which is typically used only for diagnostic purposes and not to evaluate the effectiveness of drugs to reduce mid- and very long-term AFib episodes. Such limited data may also blind clinicians to conditions where isolated AFib episodes occur infrequently but are long-term, which may be easily missed if only short-term data is used. Furthermore, and perhaps more seriously, many diagnostic devices are not compatible with monitoring and / or drug therapy. This is because diagnosis requires short-term monitoring, whereas drug therapy requires continuous long-term monitoring of the patient by the clinician to evaluate whether the prescribed drug is effective in both reducing the number of long-term AFib episodes and reducing the patient's AFib burden.

[0013] Thus, there is an ongoing conundrum. If a clinician does not know the long-term value of either AFib burden or long-term AFib episodes in a patient, how can the clinician consider pharmacotherapy with an agent such as budiodarone to reduce both AFib burden and long-term AFib episodes? Furthermore, if the clinician prescribes the agent, how can the clinician know if the administration of the agent is effectively reducing the episodes of long-term AFib episodes? In the absence of such information, clinicians often protect their patients by prescribing anticoagulants such as rivaroxaban (Xarelto®), which reduces clotting caused by AFib. However, the use of such anticoagulants comes at a cost. For example, Market Insider reported that the use of Xarelto resulted in over 15,000 adverse events in 2016 alone. See, for example, Report: More than 15,000 Adverse Events Linked to Xarelto in 2016, https: / / markets.businessinsider.com / news / stocks / report-more-than-15-000-adverse-events-linked-to-xarelto-in-2016-1002203317 (last accessed: October 28, 2022).

[0014] In view of the above, there is a continuing need for improved patient monitoring so that clinicians can accurately quantify the number and duration of long-term AFib episodes and AFib burden in patients. There is also a need to link these patients with long-term AFib, including intermediate-long term AFib or very long term AFib, as being suitable for treatment with budiodarone, and potentially to create a registry of such patients. There is also a need to enable clinicians to directly or indirectly determine whether administration of budiodarone is effective, thereby allowing them to adjust dosing accordingly or to exclude non-responsive patients from budiodarone therapy. Summary of the Invention

[0015] Methods and devices are disclosed that are useful in qualifying patients with symptomatic or asymptomatic paroxysmal or persistent AFib for treatment with antiarrhythmic drugs such as budiodarone. Such treatment is designed to reduce or eliminate the risk of stroke or congestive heart failure in patients who exhibit long-term AFib episodes and a threshold level of AFib burden. In particular, the methods and devices described herein allow such patients' cardiac rhythms to be continuously or semi-continuously monitored and the AFib burden of such patients and the duration of such episodes to be evaluated. This allows clinicians to evaluate such monitored patients to determine whether they have the required number of long-term AFib episodes and a threshold level of AFib burden. Patients who meet such evaluation criteria are considered "eligible" candidates to start budiodarone therapy.

[0016] Patients who have been identified as having long-term AFib episodes and AFib burden at the threshold level by conventional methods such as Holter monitoring are preferably monitored as described above before taking budiodarone to assess the baseline number and duration of long-term AFib episodes and AFib burden to determine whether subsequent pharmacotherapy will be effective. In any event, all eligible patients placed on budiodarone therapy will continue to be monitored after initiation of therapy. Such ongoing monitoring allows clinicians to assess the efficacy of the drug for the patient. In summary, the methods disclosed herein provide budiodarone pharmacotherapy as a form of personalized medicine, where the severity of disease in an eligible patient corresponds to an appropriate dose of budiodarone that is minimally effective for the patient, or, if the patient is a non-responder, disqualifies the patient from budiodarone therapy. The methods disclosed herein avoid the use of excessive amounts of budiodarone in treating AFib, while recognizing that some patients require more budiodarone than others to achieve treatment. Furthermore, the ability to exclude non-responders from therapy represents a new paradigm of treatment by limiting therapy to those patients who are responders.

[0017] In one embodiment, the overall efficacy of budiodarone in one or more patients can be improved by restricting continued administration of the drug to patients who demonstrate therapeutic benefit. In one example, eligible patients are those who have been identified or confirmed to meet a minimum threshold. Eligible patients who demonstrate efficacy with budiodarone initially and / or after dose adjustments are continued on therapy, while patients lacking such efficacy (non-responders) are excluded from therapy. Given the variability in the underlying AFib burden and number of prolonged AFib episodes in patient cohorts, budiodarone is effective in many patients, but not all. Using the methods and devices described herein in combination with budiodarone therapy allows clinicians to determine whether a given patient is eligible for budiodarone therapy and / or whether the therapy is providing effective results, thereby allowing clinicians to maintain therapy only for patients who will benefit from budiodarone treatment, and at the lowest dose necessary to achieve effective results.

[0018] This represents a major advance in the treatment of symptomatic and asymptomatic paroxysmal or persistent AFib in patients who may or may not have long-term AFib episodes and / or who may or may not benefit from budiodarone, which is not possible with protocols that limit the use of these devices to diagnostic use only.

[0019] Using the wearables described herein, clinicians can qualify for treatment with budiodarone only those patients with paroxysmal and / or persistent AFib who exhibit a threshold level of long-term AFib episodes and / or AFib burden. Furthermore, clinicians can subsequently monitor these patients to assess whether their AFib is responsive to such treatment and whether a budiodarone dose adjustment is warranted. Clinicians can then remove non-responsive patients from such therapy. This solves a long-standing problem in the art: how to control long-term AFib to reduce the risk of stroke and congestive heart failure.

[0020] If desired, such eligible patients can be included in a national registry, thereby allowing clinicians to prescribe budiodarone only to such enrolled patients. Patients who demonstrate efficacy with budiodarone initially and / or after dose adjustments will be retained on the registry, while patients lacking such efficacy will be excluded from the registry.

[0021] The devices (wearables) described herein address a critical gap in generating information to allow clinicians to adequately assess a patient's long-term cardiac rhythm, particularly information related to assessing a patient's AFib burden and the number and duration of long-term AFib episodes before and / or after the initiation of budiodarone therapy. Furthermore, the continued availability of such information after the initiation of treatment allows clinicians to titrate the amount of budiodarone administered to achieve the desired therapeutic effect at a reduced effective dose (e.g., at a minimally effective dose). Furthermore, these methods and / or devices elicit patient participation through self-monitoring, a widely accepted method of improving patient compliance with a dosing regimen. This, in turn, enhances the long-term effectiveness of any antiarrhythmic drug therapy in reducing or eliminating the long-term risk of stroke.

[0022] In one embodiment, the wearable is wearable and removable by a patient who may be diagnosed with or is being evaluated for paroxysmal or persistent AFib. The wearable may include at least one electrode and / or optical sensor that continuously or semi-continuously monitors the patient's cardiac rhythm when the wearable is worn, and / or may be configured to receive data from the at least one electrode and / or optical sensor. The wearable may alternatively include a processing unit (e.g., a processor, central processing unit (CPU), microprocessor, digital signal processor, computing device, etc.) configured to collect and optionally evaluate cardiac rhythm data to determine the presence and / or number of long-term AFib episodes. The processing unit may alternatively be configured to store the cardiac rhythm data. The wearable may alternatively include a transmitting component (e.g., a transmitting device) configured to access data in the processing unit (e.g., wirelessly and / or via a network connecting the transmitting component and the processing unit). The transmitting component may be capable of initiating direct or indirect communication to a computing device accessible to the patient and / or a clinician and / or another caregiver of the patient, which communication may provide cardiac rhythm data and / or data derived from an evaluation of the cardiac rhythm data.

[0023] In another embodiment, a method of monitoring an AFib-treated patient for one or more long-term AFib episodes may include wearing a wearable that can be put on and taken off. The wearable may include at least one electrode or optical sensor capable of continuously or semi-continuously monitoring cardiac rhythm. The wearable may include a transmitting device and / or circuitry in communication with the transmitting device and the at least one electrode or optical sensor. Alternatively, the wearable may include a CPU capable of collecting cardiac rhythm data, evaluating the data for the presence of a long-term AFib episode; and storing the data. The method may further include transmitting the cardiac rhythm data to the patient and / or the patient's caregiver, which may enable the caregiver to analyze one or more long-term AFib episodes.

[0024] In another embodiment, the method is for reducing the risk of one or more of: transition from paroxysmal AFib to persistent AFib in a patient with paroxysmal AFib; transition from persistent AFib to permanent AFib in a patient with persistent AFib; or stroke in an AFib patient, where the patient is receiving budiodarone treatment, which treatment may reduce and / or prevent long-term AFib episodes. The method may include evaluating cardiac rhythm data collected by a wearable worn by the patient. The wearable may include at least one electrode or optical sensor capable of continuously or semi-continuously monitoring the cardiac rhythm. The wearable may include a transmitting device and / or circuitry in communication with the at least one electrode or optical sensor and the transmitting device. Alternatively, the wearable may include a CPU capable of collecting cardiac rhythm data, evaluating the data for the presence of long-term AFib episodes; and storing the data. The method may further include adjusting the dose of budiodarone to reduce further long-term AFib episodes (e.g., as deemed necessary by a clinician), thereby reducing the risk of one or more of: a) transition from paroxysmal AFib to persistent AFib, b) transition from persistent AFib to permanent AFib, and / or c) stroke.

[0025] In another embodiment, a system may include a wearable that collects cardiac rhythm data from a patient diagnosed with paroxysmal AFib or persistent AFib, a CPU in communication with the wearable and capable of collecting and / or storing the data, and a transmitting device in communication with the CPU and capable of transmitting the data to one or more designated recipients.

[0026] In another embodiment, the method may be for reducing the risk of stroke or congestive heart failure in patients with paroxysmal AFib and / or patients with persistent AFib who are being treated with a pharmaceutical agent. The method may include obtaining cardiac rhythm data of the patient from a wearable attached to the patient, the wearable may include at least one electrode or optical sensor capable of continuously or semi-continuously monitoring the cardiac rhythm, a transmitting device capable of initiating data transmission, circuitry communicating the at least one electrode or optical sensor with the transmitting device, and a CPU configured to collect and store the cardiac rhythm data. In one embodiment, the wearable is used prior to treatment with the pharmaceutical agent (e.g., budiodarone) to obtain baseline data regarding the number and duration of AFib episodes. The obtained baseline data is used to qualify or disqualify the patient for treatment with the pharmaceutical agent. In another embodiment, the wearable is used during treatment with the medication, and the method includes, or further includes, evaluating the cardiac rhythm data and evaluating the effectiveness of the medication by correlating the presence and / or absence of long term AFib episodes to a dose of the medication and determining whether the dose of the medication is effective or ineffective in reducing or eliminating long term AFib episodes in the patient; if ineffective, increasing the dose one or more times until the dose is effective to reduce the risk of stroke or congestive heart failure.

[0027] In one embodiment, the wearable is programmable (e.g., by a clinician). In one embodiment, the wearable is programmed to transmit all cardiac rhythm data and / or only data for long term AFib episodes.

[0028] For the purposes of this disclosure, any AFib episode having a duration of at least 1 hour is considered a "long-term" episode. However, for clarity, long-term episodes also include a subset of episodes that are further defined as "medium-long term" episodes. Such medium-long term episodes range from at least about 1 hour up to about 24 hours. AFib episodes that are in the range of more than about 24 hours but are not permanent are classified as very long term episodes. These subsets allow clinicians to better evaluate the benefits of budiodarone therapy, for example, in transitions where a higher proportion of patients with a history of long-term AFib episodes experience medium-long term episodes rather than very long term episodes.

[0029] In one embodiment, the intermediate to long term AFib episodes range from about 1 hour to about 24 hours, and in another embodiment, such intermediate to long term AFib episodes range in duration from at least 5 hours to up to about 24 hours.

[0030] In one embodiment, once the initial set of collected data is sent from a computing device, such as a central processing unit (CPU), that data is discarded from the CPU so that new data can be collected.

[0031] In one embodiment, a method for assessing whether a patient with paroxysmal or persistent AFib is eligible for budiodarone therapy comprises: a) Selecting patients with paroxysmal or persistent AFib with unknown AFib burden over a period of time and / or unknown number of long-term AFib episodes; b) i) at least one electrode and / or optical sensor that continuously or semi-continuously monitors the patient's cardiac rhythm when the wearable is worn; ii) a CPU for collecting and storing said cardiac rhythm data; iii) a sending component connected to said data in said CPU; the transmitting component can initiate a communication directly or indirectly to a clinician where the data is optionally stored; attaching the wearable to said patient; c) collecting and transmitting cardiac rhythm data directly or indirectly to said clinician, who evaluates said data for the presence and number of intermediate to long-term and / or long-term AFib episodes, and the degree of AFib burden; d) qualifying the patient for budiodarone therapy if the data indicate the required number of prolonged AFib episodes and the required AFib burden; A method is provided, comprising:

[0032] In one embodiment, the CPU may also evaluate the stored data to determine the presence and number of mid- to long-term and / or very long-term AFib episodes. Evaluation by the CPU may be continuous or periodic. In another embodiment, the CPU may be programmed to alert the clinician and / or patient of mid- to long-term and / or very long-term AFib episodes.

[0033] In one embodiment, the patient is fitted with a wearable, which may be a patch, watch, wristband, strap, ring, or any other device that attaches to the body and can be operated as described above. The wearable should be worn by the patient except for temporary disengagement periods such as showering, swimming, battery changes, etc.

[0034] In one embodiment, a method for assessing whether a patient eligible for budiodarone therapy should receive or be disqualified from a dose adjustment comprises: a) selecting patients who are eligible for and prescribed budiodarone therapy by a clinician; i) at least one electrode and / or optical sensor that continuously or semi-continuously monitors the patient's cardiac rhythm when the wearable is worn; ii) a CPU for collecting and storing said cardiac rhythm data; iii) a sending component connected to said data in said CPU; the transmitting component can initiate a communication directly or indirectly to a clinician where the data is optionally stored; attaching the wearable to the patient; b) collecting and transmitting cardiac rhythm data directly or indirectly to such clinician and having such data evaluated for the presence and number of prolonged AFib episodes and the degree of AFib burden; c) adjusting the dose of budiodarone, if necessary, to access an appropriate dose for the patient; and d) assessing whether the collected data indicate that the patient is responsive or non-responsive to budiodarone therapy; Including, The above treatment is maintained for responding patients and terminated for non-responding patients. A method is provided.

[0035] In yet another embodiment, patients who are initially responsive to budiodarone therapy are continuously or periodically monitored to ensure that each of said patients remains responsive to said budiodarone dose, and if not, the clinician can adjust the budiodarone dose or discontinue budiodarone therapy as necessary.

[0036] In one embodiment of the method, the data is directly or indirectly transmitted to a clinician who can assess the presence or absence of mid-long term AFib and / or very long term AFib, and optionally the degree of AFib burden.The data can be stored and / or analyzed at a central analysis center, such as a "cloud" laboratory or similar location (such as a core laboratory), where a qualified medical professional can analyze the data and advise the responsible clinician regarding the patient's response and adjustments to the recommended treatment.In summary, these preferred methods allow remote patient monitoring (RPM), and the patient is not responsible for mailing patches for analysis, visiting the hospital, etc.

[0037] In one embodiment, the number of long AFib episodes required and the degree of AFib burden required to qualify for budiodarone pharmacotherapy may include one or more long AFib episodes (e.g., at least a threshold number) of one or more minimum lengths (e.g., at least 1 hour, at least 5 hours, at least 24 hours, etc., and any 1 hour duration between 1 hour and 24 hours) over a period of time (e.g., over 2 weeks, 1 month, 2 months, etc.). By way of example, the number of long AFib episodes required may include at least one AFib episode lasting more than 5 hours over a month, and / or at least two AFib episodes lasting more than 1 hour over a month. The degree of AFib burden required may be at least a minimal AFib burden (e.g., 0% (no AFib burden required), 1%, 2%, etc.). The number of long AFib episodes required and the degree of AFib burden required may be set as appropriate. Specific examples are shown in Table 2 below as part of a non-exhaustive list. [Table 2]

[0038] In one embodiment, the wearable may include a storage device for storing collected data, which may be programmed to evaluate the stored data and alert a clinician or a central analysis center of potentially harmful cardiac rhythm irregularities. The collected and / or evaluated data may be continuously or periodically reviewed by a clinician or medical personnel (e.g., continuously or periodically pushed to a clinician-accessible computing device and / or pulled upon request by a clinician-accessible computing device). Periodic evaluation may be, for example, daily, weekly, twice monthly, monthly, etc. The data collection process may continue indefinitely, for example, until a clinician determines that the patient's cardiac rhythm data meets or does not meet the required number of long-term AFib episodes and / or the required degree of AFib burden. Preferably, data collection continues for at least 14 days, 30 days, 45 days, 2 months, or at least 12 weeks, or at the discretion of the attending clinician based on the patient's medical history and risk factors. Patients who fail to meet established criteria for eligibility assessment will not be included in budiodarone therapy.

[0039] In one embodiment, the eligible patient is placed on budiodarone therapy. Such therapy involves the administration of budiodarone or a pharmaceutical composition comprising budiodarone twice daily in an amount ranging from about 200 mg twice daily to about 800 mg twice daily. A preferred administration involves escalating amounts of budiodarone, with the patient initially receiving 200 mg of budiodarone twice daily. Responsive patients are left on that dose, while non-responsive patients are titrated in 200 mg increments until the patient becomes responsive or becomes non-responsive at all dose levels tested. In the latter case, the patient is ineligible for budiodarone therapy. In one embodiment, the eligible patient thus treated is refractory to one or more other methods for treating AFib, with the methods described herein remaining as a treatment option.

[0040] The serum half-life of budiodarone is about 6-7 hours after administration. Typically, the steady-state drug concentration is about 5 times the serum half-life. In this case, the steady-state would be about 30-35 hours. Once the steady-state is achieved and the drug has had time to act, monitoring of the patient's cardiac rhythm can begin at any time thereafter, including about 3 days after initiation of treatment, and preferably at least 14 days after initiation of budiodarone therapy. The latter is preferred as it allows sufficient time for the drug to become effective.

[0041] In one embodiment, the wearable may be a watch, a strap, a wristband, a ring, or a strap. In one embodiment, the watch is a smartwatch.

[0042] In one embodiment, there is provided a method for reducing a patient's risk of progression from paroxysmal to persistent AFib, or from persistent to permanent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; Administer an initial dose of budiodarone to the patient; monitoring the effectiveness of said administration and optionally adjusting the patient's budiodarone dose at least once as needed to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of progression from paroxysmal AFib to persistent AFib or from persistent AFib to permanent AFib in said patient; and Maintain the above monitoring to verify continued efficacy of budiodarone; A method is provided, comprising:

[0043] In one embodiment, a method for reducing the risk of heart failure in a patient diagnosed with paroxysmal AFib or persistent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; Administer an initial dose of budiodarone to the patient; monitoring the effectiveness of said administration and, if desired, adjusting the dose of budiodarone at least once as needed to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of heart failure in said patient; and Maintain the above monitoring to verify continued efficacy of budiodarone; A method is provided, comprising:

[0044] In one embodiment, a method for reducing the risk of stroke in a patient diagnosed with paroxysmal AFib or persistent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; Administer an initial dose of budiodarone to the patient; monitoring the effectiveness of said administration and, optionally, adjusting the dose of budiodarone one or more times as needed to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of stroke in said patient; and Maintain the above monitoring to verify continued efficacy of budiodarone; A method is provided, comprising:

[0045] In another embodiment, a method for reducing the risk of stroke or congestive heart failure in a patient with paroxysmal AFib or persistent AFib receiving medicinal treatment, comprising: a clinician obtaining cardiac rhythm data of the patient from a wearable worn by the patient; The wearable comprises: a) at least one electrode or optical sensor for continuous or semi-continuous monitoring of cardiac rhythm; b) a transmitting device capable of initiating data transmission; c) a circuit connecting the above two; and d) a CPU for collecting and storing the cardiac rhythm data; said clinician evaluating said data to determine the effectiveness of said medication by relating the presence or absence of long-term AFib episodes to the dose of medication used; The clinician confirms that the dosage of the medication is effective or ineffective in reducing or eliminating long-term AFib episodes; if ineffective, the clinician increases the dose of the drug one or more times until the dose is effective and reduces the risk of stroke or congestive heart failure, provided that if the drug remains ineffective when the maximum dose of the drug is reached, the patient is removed from treatment with the drug; A method is provided.

[0046] In another embodiment, there is provided a method for reducing the risk of stroke or heart failure in a patient diagnosed with AFib and treated with budiodarone to inhibit long term AFib episodes in the patient, comprising: Evaluating the patient's cardiac rhythm data collected by a wearable and transmitted to the clinician from a wearable worn by the patient, the wearable comprising: a) at least one electrode or optical sensor for continuous or semi-continuous monitoring of cardiac rhythm; b) A transmitting device; c) a circuit connecting the two; and d) i) collecting cardiac rhythm data and evaluating said data for the presence of long-term AFib episodes; and ii) store the above data; CPU; Evaluating the data to determine the effectiveness of the drug by relating the presence or absence of long-term AFib episodes to the dose of the drug used; To confirm that the dosage of the above medicine is effective or ineffective in reducing or eliminating long-term Aib episodes; and Adjusting the dose of budiodarone as deemed necessary by the treating clinician to further reduce long-term AFib episodes and thereby reduce the risk of stroke or heart failure; or discontinuing treatment of the patient with budiodarone if the patient is deemed non-responsive to budiodarone therapy; A method is provided, comprising: [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 illustrates how a patient's AFib data is combined with treatment with budiodarone.

[0048] [Diagram 2] FIG. 2 shows the cardiac curve of a patient with intermittent AFib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] The present disclosure is directed to a method for monitoring the cardiac rhythm of a patient diagnosed with atrial fibrillation (AFib). Such monitoring allows for therapeutic intervention, coupled with the ability to adjust the administration of pharmaceutical agents used, to achieve therapeutic endpoints that reduce the risk of stroke and / or heart failure. However, before discussing this disclosure in more detail, the following terms will first be defined. Terms not defined are provided in the context or are given a medically acceptable definition.

[0050] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0051] definition As used herein, the terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and further mean that the description encompasses instances where the said event or circumstance occurs as well as instances where the said event or circumstance does not occur.

[0052] As used herein, the term "about" when used prior to the designation of numerical values ​​(e.g., temperature, time, amount, concentration, and the like), including ranges, indicates an approximation that may vary by ±15%, ±10%, ±5%, ±1%, or any subrange and / or value in between. Preferably, the term "about" when used in reference to a dosage means that the dose may vary by ±10%.

[0053] As used herein, the term "comprising" or "comprises" is intended to mean that a composition or method contains the recited elements and does not exclude other elements.

[0054] As used herein, the term "consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of essential importance in the combination for the described purpose. That is, a composition consisting essentially of the elements as defined herein, or a method consisting essentially of the steps as defined herein, does not exclude other materials that do not materially affect the basic and novel characteristics of the claimed subject matter.

[0055] As used herein, the term "consisting of" is intended to mean excluding other ingredients or substantial method steps beyond trace elements. Embodiments defined by each of these transitional phrases are within the scope of this disclosure.

[0056] As used herein, the terms "AFib" and "atrial fibrillation" refer to all variants of atrial fibrillation, except for permanent AFib. Such variants include, but are not limited to, paroxysmal AFib, persistent AFib, and paroxysmal and persistent AFib with low CHA2DS2-VASc scores (2 or less), and paroxysmal and persistent AFib with high CHA2DS2-VASc scores (3 or more). The CHA2DS2-VASc score represents congestive heart failure, hypertension, age 75 or older (2x), diabetes, stroke (2x), vascular disease, age 65-74, and gender category (female), and is a clinical prediction rule for estimating the risk of stroke in people with non-rheumatic atrial fibrillation (AF). The CHA2DS2-VASc score is composed of one point for each of the above constituent risk factors, with two points represented as (2x).

[0057] As used herein, the term "long-term AFib" refers to the length of time that an AFib episode lasts in a patient, which is associated with the risk of stroke and / or heart failure. Obviously, the longer a patient is in AFib, the higher the risk. Thus, in one embodiment, long-term AFib is any AFib episode that lasts more than 1 hour, but the AFib is not permanent. Long-term AFib is further classified by the subset of "medium-long-term" AFib, which has a duration of about 24 hours or less (i.e., more than 1 hour and up to 24 hours), and "very long-term" AFib, which includes AFib episodes that last more than 24 hours but are not permanent AFib.

[0058] As used herein, the term "continuous" or "continuously" refers to monitoring occurring constantly while the patient is wearing the wearable. The term "continuous" or "continuously" also encompasses the wearable constantly monitoring cardiac rhythm when worn and powered, but may be turned off for limited periods of time (e.g., battery replacement, bathing, etc.).

[0059] As used herein, the terms "semi-continuous" or "semi-continuously" refer to periodic, automatic monitoring by the wearable on a set schedule (e.g., every 15 seconds, every 30 seconds, every minute, etc.) without the patient activating the wearable. Set Schedule A schedule designed to monitor cardiac rhythm with sufficient temporal resolution to allow detection of AFib episodes and / or determination of the length of long term AFib episodes.

[0060] As used herein, the term "wearable" means that a patient can attach and remove the wearable from their own body and begin monitoring without the need for assistance from an attending medical professional. As such, wearable wearables do not include implantable (invasive) devices such as pacemakers.

[0061] As used herein, the term "monitoring cardiac rhythm" means any assessment that can be made of a patient's cardiac rhythm, including pulse rate, electrical field appearance of the patient's heart, etc., provided that such monitoring can ascertain when a patient is experiencing AFib.

[0062] As used herein, the term "initiating monitoring" encompasses both automatic initiation and physical initiation. "Automatic initiation" occurs when the wearable automatically begins monitoring immediately after being placed on the patient, without further action by the patient. "Physical initiation" means that the patient is required to activate monitoring by physically or verbally interacting with the wearable (e.g., pressing a button, giving a voice command, etc.).

[0063] As used herein, the term "transmitting device" refers to any device capable of transmitting data from a wearable. The transmitting device may be included in the wearable or may be a separate device in communication with the wearable. The separate device may be a smartphone, a pad, a laptop, a desktop computer, etc.

[0064] As used herein, the term "clinician" refers to a medical professional qualified to determine whether a patient's cardiac rhythm data correlates to sinus rhythm, atrial fibrillation, or other types of arrhythmia.

[0065] As used herein, the term "treating clinician" refers to a medical professional who is treating a patient with AFib. Such treating clinicians are typically physicians or nurse practitioners.

[0066] The term "directly," as it relates to the transmission of a patient's cardiac rhythm data, means that the transmission is received by the attending clinician for evaluation, regardless of whether the transmission is deposited on a cloud site, routed through a number of servers, etc.

[0067] The term "indirectly," as it relates to the transmission of a patient's cardiac rhythm data, refers to the data being transmitted to a clinician who evaluates the data and provides the data or conclusions drawn regarding the data to an attending clinician or health care provider. In such cases, the clinician may be a medical professional employed by a central analysis center, attending clinician, etc., who evaluates the cardiac rhythm data and provides guidance to the attending clinician on an ongoing basis or when a change in the patient's condition requires contact. In one embodiment, the clinician is employed by a central analysis center, which reviews data generated by the facility's equipment and makes a diagnosis and / or recommendation that is transmitted to the attending clinician. The central analysis center has expertise in the equipment, the data generated, and the ability to analyze the data.

[0068] As used herein, a patient who is "responsive to budiodarone therapy" exhibits a reduction in the number and / or duration of long-term AFib episodes. This reduction may be at least a certain percentage (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.) reduction in one or more of the episode number of long-term AFib episodes and / or the duration of long-term AFib episodes. In one embodiment, a responsive patient is one who exhibits at least a 10% reduction in at least one of the following when measured over a 12-week period: a) The number of prolonged AFib episodes lasting over 24 hours compared to the number requested during the eligibility assessment; b) The number of prolonged AFib episodes lasting more than 5 hours compared to the number requested during the eligibility assessment; c) The number of prolonged AFib episodes lasting more than one hour compared to the number determined during the qualification assessment; or d) Reduction in AFib burden compared to the burden determined during qualification. In yet other embodiments, the responsive patient exhibits at least a 20% reduction, at least a 30% reduction, at least a 40% reduction, at least a 50% reduction, and / or at least a 60% reduction in one or more of a-d above over a 12 week period.

[0069] As used herein, a "non-responsive patient" or a patient who is "non-responsive to budiodarone therapy" is a patient who has been treated with budiodarone therapy and who does not meet the definition of a responsive patient as defined above. A patient may be non-responsive to budiodarone therapy by non-response to the maximum tolerated dose and treatment may be discontinued.

[0070] As used herein, "other methods of treating AFib" may include one or more anticoagulants and / or other measures to prevent blood clots, control heart rate, and / or control heart rhythm. Examples of such methods of treating AFib may include beta-blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol, propranolol, timolol), calcium channel blockers (verapamil, diltiazem), anticoagulants (warfarin, coumarin, yantobene, aspirin, apixaban, dabigatran, enoxaparin, heparin, rivaroxaban), sodium channel blockers (e.g., flecainide, propafenone, quinidine), potassium channel blockers (e.g., amiodarone, dofetilide, sotalol).

[0071] A patient may be considered "refractory to one or more prior methods for treating AFib" or "refractory to one or more other methods for treating AFib" if the patient has been treated with one or more prior methods and / or other methods for treating AFib (e.g., other methods for treating AFib as defined above) and the AFib is deemed to be non-responsive and / or inadequately responsive and / or decreasingly responsive to the one or more methods. The "prior treatment(s)" may be ongoing and / or may have been completed.

[0072] As used herein, the term "smart" refers to the computing capabilities of a device. The computing capabilities of the smart devices discussed herein may enable user interaction (e.g., via a touch screen) and / or execution of applications on the smart device.

[0073] As used herein, the term "AFib burden of at least 2.5%" means that in the absence of the disclosed treatment (e.g., treatment with budiodarone and / or other cardiac rhythm drugs), the patient has AFib episodes and the cumulative duration of each episode during a set period is at least 2.5% of the total amount of time during the set period. Thus, for a patient monitored for 20 days (i.e., 480 hours), an AFib burden of at least 2.5% means that the total (cumulative) period during which the patient experiences one or more AFib episodes is at least 12 hours (2.5% of 480 hours). This AFib burden may be independent of the number of long-term AFib episodes, if any. Thus, the one or more AFib episodes totaling at least 12 hours may be one episode or many episodes each less than one hour long.

[0074] As used herein, the term "budiodarone" refers to (S)-sec-butyl 2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl)acetate, and pharma- ceutical acceptable salts thereof. Budiodarone has the formula: [ka] and pharma- ceutical acceptable salts thereof, such as budiodarone tartrate or budiodarone citrate. In some embodiments, the pharma-ceutical acceptable salts may be other polycarboxylates. As is understood in the art, salts dissociate from the free base in the body. Thus, when calculating serum levels of budiodarone, the molecular weight of the free base is used to determine the molar concentration. In addition, when a salt other than the tartrate is administered, the dosage of budiodarone tartrate used herein must be altered to reflect the change in molecular weight due to the different salts.

[0075] The term "wearable" refers to any device that can be worn by a user, for example, as an accessory, as clothing, and / or embedded in clothing, etc. In one embodiment, a wearable device herein may be capable of measuring the cardiac rhythm of its user without an implant (such as a surgical implant and / or a subcutaneous implant).

[0076] As used herein, a patient is "wearing a wearable" if the wearable is worn by or otherwise secured to the patient such that the patient's cardiac rhythm can be measured.

[0077] As used herein, the term "baseline" refers to a patient who has AFib and has been monitored to determine the extent of AFib burden and the number of long-term AFib episodes for a set period of time prior to budiodarone treatment. In such cases, the baseline measurement prior to treatment for a set period of time provides the current disease state. In most, if not all, cases, the baseline disease state is unknown to the treating clinician and is necessary information to determine whether subsequent budiodarone treatment will be effective.

[0078] instrumentation The instrumentation used in the methods described herein may be used for drug therapy as described herein, as opposed to being used solely for diagnosis. Using wearables solely for diagnosis is traditional, with the goal of informing the clinician whether the patient has AFib and / or, if the patient has AFib, the patient's AFib burden and number of AFib episodes. Such diagnostic analysis cannot address the suitability, efficacy, and / or dosage of drug therapy, which are beyond diagnosis. The drug therapy methods described herein include identifying patients eligible for drug therapy and / or monitoring eligible patients during treatment with the drug therapy to evaluate the efficacy of the drug (e.g., efficacy in reducing the number of long-term AFib episodes). This monitoring may allow the patient to be dose-adjusted until the patient is deemed responsive to the therapy or is ineligible for drug therapy due to failure to respond. The drug treatment methods described herein may allow for limited (e.g., one or more discrete time periods, such as about 2 weeks, about 4 weeks, or about 6 weeks) and / or indefinite (e.g., no pre-set end date) monitoring of a patient to establish eligibility for drug intervention and / or to ensure that the patient is and / or remains responsive. Thus, the wearables described herein are designed and / or selected to be robust for extended use and / or comfortable and / or easy for the patient to use.

[0079] In practice, the wearable may include a cardiac monitoring element, which may be an assisted or unassisted element, for measuring the patient's cardiac rhythm. The wearable may be wearable and removable by the patient and does not involve invasive techniques common to non-wearables such as pacemakers, implantable cardioverter defibrillators (ICDs), etc. The particular cardiac monitoring element used in the wearable is not essential, provided that the wearable is capable of accurately measuring the cardiac rhythm. The wearable may be capable of reporting the measured cardiac rhythm data, such as by generating and / or transmitting data indicative of the duration of the detected AFib periods (e.g., over a period of interest, such as a week, a month, etc.) and / or by generating and / or transmitting data indicative of the number of detected long-term AFib episodes. Also, or alternatively, the wearable may be configured to transmit the cardiac rhythm data to a device configured to detect AFib (e.g., over a period of interest) and / or determine the duration of the detected AFib periods and / or the number of long-term AFib episodes. The wearable has been approved by one or more regulatory agencies, such as the U.S. Food and Drug Administration (FDA).

[0080] Assist elements Assisted cardiac monitoring elements may use photoplethysmography (PPG) to detect heart rate and rhythm. PPG is a conventional technology found in standard oximeters, which detects arterial pulsation and, accordingly, heart rhythm patterns by measuring light reflection in tissue. However, to measure heart rhythm continuously and / or semi-continuously, one must take into account the fact that PPG signals generated during patient movement are often distorted, weak, and noisy. To account for such deficiencies, algorithms may be used that reduce distortion and / or noise by a sufficient amount to provide a reliable signal. In one embodiment, both a PPG sensor and an accelerometer are used with algorithms that allow for adequate (e.g., sufficient signal-to-noise ratio). When so assisted, PPG may allow for reliable detection of both heart rate and rhythm. See, e.g., Wojcikowski, et al., Photoplethysmographic time-domain heart rate measurement algorithm for resource-constrained wearable devices and its implementation, SENSORS 20, no. 6 (2020): 1783, which is incorporated by reference in its entirety.

[0081] In some embodiments, the cardiac monitoring components use piezoelectric materials and / or rhythmic electroactive polymers to indirectly measure cardiac rhythm by detecting blood flow.

[0082] In some embodiments, a combination of PPG and / or piezoelectric measurements can be combined with electrocardiogram data from a unipolar wearable (iECG, as opposed to ECG, which refers to traditional multi-electrode electrocardiogram) to increase the specificity of the measurements. The iECG and PPG or piezoelectric data can come from two separate devices communicating via transceivers (e.g., armband and smartwatch) or from a single device (e.g., wristband + smartwatch (e.g., Kardia Band + iWatch). When an arrhythmia is detected in the PPG data, the corresponding (e.g., time-matched) iECG data can be analyzed by an algorithm.

[0083] Non-assisted elements In another embodiment, the wearable may include an unassisted cardiac monitoring element, such as a portable electrocardiogram. The portable electrocardiogram element may be voluntarily wearable, mountable, and / or capable of transmitting data, such as via an internal antenna. A wearable with an unassisted cardiac monitoring element may measure heart rate and rhythm. The wearable may be configured to detect and record AFib burden and / or long-term AFib (episodes) (LEAF) over an observation period (e.g., about two weeks or more). The unassisted cardiac monitoring element employs direct measurement, meaning that the device reads electrical signals generated by the heart. Direct measurement may be less affected by noise and distortion than indirect measurements, such as PPG measurements, which may allow measurement data to be transmitted to a clinician without the use of algorithms and / or with reduced use of algorithms and data processing.

[0084] In some embodiments, the wearable may include a specialized accessory, such as a cardiac monitoring device that can detect cardiac electrical activity, including cardiac rhythm, via electrodes. The specialized accessory may be capable of initiating transmissions and / or may include and / or be connected to a transmitting device.

[0085] In some embodiments, the cardiac monitoring device may be an integral part of a single wearable device, such as a smartwatch, providing a single device that can be worn by a user and that is capable of monitoring the electrical field of the user's heart, allowing for continuous monitoring of the electrical activity of the heart over extended periods of time, such as days or even months.

[0086] In some embodiments, the cardiac monitoring device may include an analog-to-digital converter that can digitize the measured electric field data (e.g., measured potential difference data) for transmission and / or store the measured data in memory as digitized data. The cardiac monitoring device may include an output that can transmit a signal carrying information about the potential difference between the limbs to an external circuit. This output may take a variety of forms. In some cases, the output may be a transceiver that communicates to another transceiver / receiver in another unit (e.g., a watch or tablet). In one embodiment, a central analysis center (e.g., a remote lab such as a core lab and / or a remote data analysis center and / or a server) may interpret and / or summarize the AFib data and / or LEAF data. The central analysis center may also send dose adjustment recommendations to the treating clinician, eliminating the need for the patient to visit their own physician (e.g., as part of a patient monitoring program). Additionally or alternatively, an artificial intelligence algorithm may be used to determine dose adjustments and may send dose adjustment recommendations to the physician.

[0087] Further Aspects In one embodiment, the wearable may be a small consumer electronic device, such as a watch, an armband, a ring, a strap, and / or a wristband. The wearable may include a housing that includes a cardiac monitor element, associated circuitry, a CPU, and the like. The wearable may also be worn on other parts of the user, including, but not limited to, the wrist, leg, neck, and / or torso. The wearable may include specialized accessories capable of communicating with another electronic device, such as a tablet, laptop computer, desktop computer, and / or other similar device, which may then communicate to a cloud network to transmit information from the device to a clinician. Additionally or alternatively, the specialized accessories may be capable of transmitting information to a clinician directly and / or over a network.

[0088] The cardiac rhythm wearable and the iECG wearable may be Bluetooth, Z-Wave, Zigbee, and / or Advanced Network Technology and Adaptive Network Technology (ANT) enabled. For example, the iECG device and / or cardiac rhythm monitoring and / or recording device (e.g., PPG or piezoelectric cardiac rhythm monitoring and / or recording device) may be paired with an application that may be configured to automatically detect AFib based on data from the iECG device and / or cardiac rhythm monitoring and / or recording device. The iECG device and / or rhythm monitoring and / or recording device may be configured to transmit data to the application. The data may be transmitted using one or more of Bluetooth, Z-Wave, Zigbee, or ANT protocols. The application may be configured to analyze the data using proprietary software. Based on the data from the iECG device and / or cardiac rhythm monitoring and / or recording device, the application may be able to interpret and / or detect AFib with greater than 90% sensitivity and greater than 80% specificity.

[0089] A patient with a wearable as described herein can use the wearable to record heart rhythm and detect AFib. Recording can be continuous and / or semi-continuous. Recording specifications can be programmed directly or indirectly (e.g., remotely) into the device. AFib data may be stored securely, such as in a cloud-based data repository using highly secure protocols.

[0090] Examples of commercially available assisted and non-assisted wearables include, but are not limited to: MCOT® Wearable sold by Philips Biosciences (Best, The Netherlands). This device is a wearable patch that can automatically transmit iECG data via a wireless connection to a central analysis center (e.g., a core lab). The system is configured to provide sufficient data to allow the clinician to determine whether a dose increase and / or discontinuation is appropriate. ePatch Extended Wear Holter Monitoring System sold by Philips Biosciences (Best, The Netherlands). The device is configured to record data indicative of AFib and / or Long Term AFib (Episodes) (LEAF). The device is configured to continuously record and / or store iECG data. This data is then archived and centrally analyzed. There are a number of other wearables, some of which are FDA cleared and can be used instead of the ones mentioned above, including, by way of example only, Zio by iRhythm Technologies, Inc. (San Francisco, CA, USA); Frontier X2 by Fourth Frontier, Inc. (Austin, TX, USA); and wearables by VivaLink Medical, Inc. (Campbell, CA, USA), to name a few. The above and other wearables discussed herein are a non-exhaustive list of wearables suitable for use in the methods described herein. The specific wearable to be used is not important so long as it is capable of measuring the cardiac rhythm (e.g., generating a signal and / or data from which the cardiac rhythm can be determined). The wearable used should be capable of measuring the cardiac rhythm of the patient wearing the wearable continuously or semi-continuously for the required period of time as described herein (e.g., the period of time required to determine a baseline, the period of time required for monitoring during drug therapy, etc.). Additionally, the wearable should be small enough and / or comfortable enough for the patient to wear and / or wear the wearable for the required period of time.

[0091] methodology The disclosed method allows the attending clinician to identify eligible patients and / or treat them with a drug therapy and further to evaluate the efficacy of the therapy based on cardiac rhythm data monitored over a period of time. The period of time may be a long-term period, measured in weeks, months, and / or years. Monitoring may include monitoring cardiac rhythm data and / or using the cardiac rhythm data to determine the patient's AFib status, which may be determined based on one or more of the patient's AFib burden or the number or duration of AFib episodes (e.g., frequency of AFib episodes and / or long AFib episodes) over the period of time. This is a new paradigm in AFib treatment, as it allows the clinician to do one or more of the following: Assess the extent of disease in the patient; Determine whether a patient is eligible for drug therapy; Evaluate the effectiveness of treatments in the short term (1-6 months) and / or long term (beyond 6 months); administering dosage adjustments to patients to achieve and / or maintain therapeutic benefit; and / or If the patient is non-responsive to the above treatment, the patient is removed from drug therapy.

[0092] In contrast, conventional patient monitoring is typically diagnostic in nature, for example, performed using a Holter monitor or equivalent during a single short period, typically not exceeding two weeks. Such diagnostic methods at best allow clinicians to confirm the presence of AFib. In most cases, clinicians will then administer anticoagulants to the patient. Alternatively, clinicians may administer pharmacotherapy to the diagnosed patient, which may include heart rate reduction using beta-blockers and / or calcium channel blockers. Nevertheless, once a diagnosis is made, conventional monitoring is typically terminated.

[0093] When clinical evaluation of AFib is performed for clinical research purposes, it is usually done using implantable (invasive) devices that require surgical insertion and subsequent surgical removal. Such studies are typically performed to understand the potential risks of stroke and congestive heart failure associated with AFib burden and / or AFib duration. See, e.g., Turakhia MP et al., Circ Arrhythm Electrophysiol., 2015, 8(5):1040-7. In some cases, non-invasive means of monitoring patients have been used, but monitoring is typically short-term. See, e.g., Go, et al., JAMA Cardiology, 2018, 3(7):601-608. However, such clinical evaluations have not been able to assess the effect of budiodarone on the patient's AFib burden or long-term AFib episodes over an extended period of time after delivery to the patient, and to examine how to adjust the patient's dose to achieve the desired therapeutic effect, if desired.

[0094] Unlike conventional protocols for treating AFib using drugs that limit the patient's heart rate, the methods described herein are directed to treating the patient's heart rhythm to reduce the underlying causes of stroke and heart failure. The ability to continuously or semi-continuously monitor heart rhythm, combined with appropriate drugs that limit the number and severity of long-term AFib episodes, allows clinicians to significantly reduce the risk of stroke and congestive heart failure. Furthermore, by monitoring patients after initiating drug therapy, clinicians can now assess the efficacy of the drug and adjust the dose as necessary to enhance overall efficacy, or identify patients who are non-responders to such therapy and remove them from therapy.

[0095] One embodiment of this approach is shown in FIG. 1, which diagrams an iterative process for evaluating patients, qualifying them for budiodaron therapy, and treating eligible patients. In FIG. 1, an exemplary cohort of patients diagnosed with paroxysmal and / or persistent AFib is evaluated for AFib burden. Those who exhibit adequate AFib burden (star decision point "yes"), in this case 5% or more, however, this AFib burden may be a different threshold, such as 2.5%, and / or a patient- and / or cohort-specific threshold may be selected to continue the eligibility evaluation process, while those who do not meet this threshold are excluded (star decision point "no"). Patients may also be evaluated for the duration of AFib episodes. In this particular embodiment, patients are further considered eligible for budiodaron therapy (star decision point "yes") if they exhibit at least one AFib episode lasting longer than 5 hours during a one-month period and / or two or more AFib episodes lasting longer than 1 hour during a one-month period. Patients who do not meet any of these criteria are excluded (no asterisk) because they are likely at very low risk for stroke or congestive heart failure. Eligible patients are placed on an escalating dose regimen of budiodarone that has been shown to significantly reduce AFib episodes, including long-term AFib episodes, and by definition, reduces AFib burden. Instead of and / or in addition to budiodarone, other agents that behave similarly to budiodarone may be used in the methods described herein.

[0096] In the iterative process of FIG. 1, a titration regimen is employed to assess whether and / or at what dose budiodarone is effective in treating long-term AFib episodes. Given that AFib burden and / or the number and duration of long-term AFib episodes vary from patient to patient, different doses of budiodarone may be effective in different patients. However, until now, clinicians who prescribe budiodarone for the first dose did not know whether the dose was effective. In accordance with FIG. 1 and the examples below, the methods described herein allow clinicians to assess efficacy at the first dose and / or adjust the dose in an iterative process of titration and / or tapering protocols until a therapeutic effect is achieved and / or the patient is deemed a non-responder. Such non-responders are removed from budiodarone therapy.

[0097] In an escalation regimen, the patient is initially administered a low dose and the dose may be increased if the patient is non-responsive and / or responds inadequately (e.g., plus sign "no"). The patient may be determined to be non-responsive if he or she does not respond to the maximum dose. Additionally or alternatively, a tapering regimen may be employed in which the highest dose of budiodarone is administered to the patient, efficacy is determined, and the dose is tapered. One advantage of a tapering protocol is that non-responders can be determined at the first iteration rather than at the end. However, an escalation protocol may have the advantage of finding the lowest effective dose first and / or reducing the risk of side effects.

[0098] In one embodiment, treatment of a patient with budiodarone may result in a reduction in the number and / or frequency of long-term AFib episodes and / or a reduction in AFib burden. This is in contrast to drugs that reduce heart rate but do little to reduce AFib episode duration and / or AFib burden. AFib burden and long-term AFib episodes are separate. With regard to AFib burden, the number and duration of each AFib episode in a patient are measured to determine AFib burden. A patient who has a sufficient number of AFib episodes, even if very short, may be assigned to a higher AFib burden than a patient who has infrequent long-term AFib episodes. Thus, a patient who has 8 AFib episodes, each lasting 45 minutes, during a given 24-hour period would be assigned to an AFib burden of 25% (6 hours / 24 hours). In contrast, a patient who has one AFib episode lasting 5 hours during a 24-hour period would be assigned to an AFib burden of 20.8%. However, patients with a single AFib episode may be at higher risk of stroke than those with a single AFib episode. Thus, patients with an AFib burden of less than 2.5% are highly unlikely to have long-term AFib and may therefore be ineligible for budiodaron treatment.

[0099] Furthermore, transitioning a patient from paroxysmal to persistent AFib, or from persistent to permanent AFib, may be undesirable as it may represent unnecessary disease progression. Because budiodarone reduces the extent of long-term AFib and the number of AFib episodes, the combination of these reductions may halt the progression of the disease and, in some cases, such transitions may be reversible.

[0100] In comparison, the treatment of AFib with anticoagulants does not address the causes of AFib and does not reduce the potential concerns associated with AFib burden and / or with intermediate and very long-term AFib episodes. Furthermore, the use of anticoagulants does not prevent a patient from progressing from paroxysmal AFib to persistent AFib or from persistent AFib to permanent AFib. Furthermore, the use of anticoagulants brings about another set of problems associated with bleeding, including bleeding that can lead to death.

[0101] Thus, according to the present disclosure, a patient's cardiac rhythm may be monitored over a long period of time to assess the effectiveness of drugs intended to regulate such long-term episodes. Although a device such as a Holter monitor can be used to monitor a patient's cardiac rhythm for a short period of time (e.g., 1, 2, or 3 days, up to 14 days), such monitoring does not provide a comprehensive, continuous analysis of the patient's AFib and / or the effect of drug treatment on the number and duration of AFib episodes over a long period of time (e.g., weeks or more). Such short-term analysis only provides a diagnostic analysis, not a therapeutic analysis, and does not provide a complete picture of the patient's cardiac health. Due to the erratic and ever-changing nature of AFib and variability from patient to patient, an accurate measurement of a patient's AFib can only be obtained by monitoring for a long period of time, such as more than one month, more than three months, etc.

[0102] Drug therapy There are many conditions where a patient can be assessed by their clinician based on a static number that represents a meaningful long-term average. For example, in diabetes, a three-month hemoglobin A1C level (also known as the HbA1C test, which is a blood test) is a good indicator of average daily blood glucose levels. Also, liver function, prostate health, and thyroid health can all be assessed based on specific numbers that give meaningful information to the clinician.

[0103] Clinicians treating paroxysmal and / or persistent AFib have had to rely on short-term monitoring of a patient's heart rhythm, such as an ECG (electrocardiogram) and / or a Holter monitor. However, such short-term monitoring may miss important data points that can only be obtained by monitoring over a longer period of time. This may lead clinicians to avoid drug therapy without the means to monitor the effectiveness of the drug in the patient. Rather, patients diagnosed with AFib may receive treatments to reduce symptoms and / or risks, such as anticoagulants. However, while anticoagulants reduce the risk of clot-related strokes (e.g., blood clots resulting from AFib), there is a corresponding increase in the risk of uncontrolled bleeding, which can be fatal.

[0104] Medications such as sotalol, beta-blockers, and calcium channel blockers have been used to treat AFib. Examples of calcium channel blockers include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil. Examples of beta-blockers include acebutolol, atenolol, bisoprolol, metoprolol, nadolol, nebivolol, and propranolol. There are also drugs with mixed mechanisms of action, such as amiodarone. Amiodarone has a long half-life, and accumulation of amiodarone after chronic use is associated with a variety of toxicities, including pulmonary, hepatic, and ocular effects; its use requires close supervision of recipients to detect early signs of irreversible and potentially fatal complications (see, e.g., Wolkove N, Baltzan M., "Amiodarone pulmonary toxicity," Canadian Respiratory Journal 16(2): 43-8, 2009).

[0105] Budiodarone is a drug with a mixed mechanism of action that has been shown to reduce long-term AFib episodes without causing a significant increase in the QT interval. Budiodarone has a pattern of cardiac ion channel action that is intentionally similar to amiodarone, inhibiting late Na+ + It has enhanced channel blockade. The deliberately altered metabolism of budiodarone allows for a half-life that is significantly shorter than that of amiodarone, while avoiding the accumulation-related toxicity seen with amiodarone and allowing for complete inactivation and elimination from the body within hours to days of cessation. The shortened half-life allows for a rapid achievement of steady-state blood levels within 2-3 days of initiation of dosing, and with available real-time information on efficacy (e.g., changes and / or reductions in AFib burden and / or prolonged AFib episodes), doses can be efficiently adjusted as needed to establish a minimum effective dose for each subject. Indeed, budiodarone is an important advance in the treatment of AFib, since prolonged AFib episodes are a substantial cause of blood clot formation that may lead to stroke and / or congestive heart failure. However, AFib is a heterogeneous disease and varies from patient to patient, with some patients requiring different doses of budiodarone to be therapeutically effective compared to others.

[0106] Drugs to achieve the desired result As previously mentioned, a major drawback of pharmaceutical interventions has been the inability to monitor patients in a manner that would allow assessment of drug effectiveness, leading clinicians to opt for the use of anticoagulants and / or risk reduction procedures instead of proactive pharmaceutical interventions.

[0107] The wearables and methods described herein continually provide clinicians with sufficient data to determine the long-term effectiveness of medications in treating paroxysmal and persistent AFib. Thus, methods that integrate data generated by wearables with medications that can control long-term AFib and / or reduce AFib burden may allow for more effective treatment of AFib, a long-standing need in the art. Furthermore, being able to determine the long-term effectiveness of medications may allow for adjustments of patient dosing to achieve effective control of long-term AFib episodes.

[0108] Treatment regimens using budiodarone Budiodarone has been shown to reduce the risk of stroke and congestive heart failure by reducing patients' long-term AFib episodes. However, achieving treatment with budiodarone across a range of patients with varying frequency and duration of long-term AFib episodes requires clinicians to monitor each patient for efficacy at a given dose. As such, it represents a personalized medicine approach to diseases treatable with budiodarone.

[0109] If the patient is non-responsive at that dose, an increase in dosage is warranted and the process is repeated until the patient is determined to be responsive or non-responsive at a given higher dose. Patients who are non-responsive at all doses tested are removed from budiodarone therapy.

[0110] Still further, patients with either paroxysmal or persistent AFib and refractory to one or more previous therapies for treating the disease may be candidates for the methods and procedures described herein. Such patients may be screened for treatment by determining their baseline AFib burden and / or the number and severity of prolonged AFib episodes. The patient's baseline may also be used to assess the relative reduction in these symptoms and / or the complete disappearance of these symptoms based on budiodarone therapy, and / or to identify the patient as a non-responder to budiodarone therapy. Thus, the method of treating a patient with paroxysmal or persistent AFib and refractory to one or more previous therapies for treating AFib includes: a) selecting patients who are refractory to one or more prior methods for treating AFib; b) identifying the number of prolonged AFib episodes and the extent of AFib burden that meets the criteria for a clinician to qualify the patient for budiodarone treatment; c) fitting said patient with a wearable, said wearable comprising: i) at least one electrode and / or optical sensor that continuously or semi-continuously monitors the patient's cardiac rhythm when the wearable is worn; ii) a CPU that collects and stores the cardiac rhythm data; and iii) a transmitting component configured to access the data in the CPU, the transmitting component being capable of initiating a communication directly or indirectly to a clinician; d) collecting and transmitting cardiac rhythm data directly or indirectly to a clinician and having said data evaluated for the presence and number of prolonged AFib episodes and the degree of AFib burden; e) optionally adjusting the dose of budiodarone to determine an appropriate dose for the patient; and f) assessing whether the collected data indicate that the patient is responsive or non-responsive to budiodarone therapy; May contain The above therapy is maintained for responding patients and terminated for non-responding patients.

[0111] Without sufficient information to confirm the efficacy of a given dose of a prescribed drug to reduce the number of long-term AFib episodes in treated patients, clinicians will inevitably avoid administering such drugs, especially given the variability in patients and the disease itself. Furthermore, many clinicians consider treating (reducing) heart rate to be the appropriate treatment for AFib, optionally with anticoagulation. See, for example, Atrial Fibrillation-Treatment, https: / / www.nhs.uk / conditions / atrial-fibrillation / treatment / where, in 2021. The authors considered heart rate regulation to be part of the appropriate approach to treat AFib. Overall, the use of wearables capable of generating data on a patient's response to a given dose of budiodarone over an extended period of time was not envisaged. The methods described herein now enable a clinician to evaluate a patient's cardiac rhythm data over a period of at least two weeks, at least one month, at least three months, and / or at least six months, and potentially for the rest of the patient's life, to determine the number and / or duration of long-term AFib episodes; based on that determination, to evaluate whether the patient should be placed on budiodarone therapy; and, if so, to evaluate the patient's response to various doses of budiodarone.

[0112] In one embodiment, as described in the Examples and FIG. 1, for example, a clinician may start budiodarone at a minimum of about 200 mg twice a day (bid) and then evaluate whether the dose is effective in eliminating long-term AFib episodes. The clinician may review the data at the initial dose level and make one or more dose adjustments, for example, as necessary to arrive at a dose at which the patient is substantially free of long-term AFib episodes and / or is free of long-term AFib episodes. Typically, the increment in dosing may be about 200 mg twice a day. Thus, in this approach, dosing may be varied from about 200 mg twice a day to about 400 mg twice a day, or even to about 600 mg twice a day, up to a maximum of about 800 mg twice a day, and possibly even higher, if the attending clinician determines that a higher dose would be beneficial.

[0113] system The methods described herein can be performed on a single device, such as a wearable, that can record, store and transmit cardiac rhythm data, however, multiple device systems can also be used, provided such systems include: a) a wearable that collects cardiac rhythm data from patients diagnosed with either paroxysmal atrial fibrillation and / or persistent atrial fibrillation; b) a CPU in communication with the wearable that collects and stores the data; and c) A transmitting device in communication with said CPU for directly and / or indirectly transmitting said data to one or more intended recipients. EXAMPLES

[0114] In the examples below and throughout the specification, the following abbreviations have the following meanings. If an abbreviation is not defined, it is intended to have its ordinary medical meaning. AFib or AF = atrial fibrillation Bid or bid = twice a day bpm=beats / minute hrs=hours mg = milligrams PPG = photoplethysmography SD=standard deviation

[0115] Example 1 is provided to demonstrate that the use of a wearable can detect AFib episodes during continuous monitoring of a patient.

[0116] Examples 2-7 establish the utility of budiodarone in the methods described herein. In these examples, all patients had surgically implanted pacemakers and therefore carried a number of associated risks. See, e.g., Pacemaker, https: / / www.mayoclinic.org / tests-procedures / pacemaker / about / pac-20384689 (last accessed: October 26, 2022), which is incorporated herein by reference in its entirety.

[0117] Example 1: Wearable to Continuously Detect AFib in Patients In this example, a male patient with non-permanent AFib is fitted with an MCOT wearable device sold by Philips Biosciences (Best, The Netherlands) and commercially available by regulation in the United States. The MCOT device employs PPG combined with algorithms to assess cardiac rhythm and AFib. The MCOT device is configured to wirelessly and seamlessly provide cardiac rhythm and AFib data to a dedicated computer.

[0118] The patient was continuously monitored over a period of 23.5 hours. Throughout the period, the MCOT device measured the patient's cardiac rhythm and heart rate. Figure 2 provides the cardiac curves obtained during the monitoring period. Notably, 33 isolated AFib episodes were detected and recorded, each separated by periods of sinus rhythm or other arrhythmias. Specific details of the cardiac curve analysis are as follows: Number of AFib episodes: 33 Longest AFib duration: 3 hours 2 minutes Heart rate (min / max) 48 / 94 beats / min AFib load 36% The above data demonstrated that a wearable as described herein was capable of continuously monitoring a patient's cardiac rhythm and provided detailed analysis of the number of AFib episodes and the extent of AFib burden.

[0119] Example 2: Elimination of Long-Term AFib with Budiodarone This example is a clinical trial evaluation of budiodarone in treating six patients with paroxysmal or persistent AFib who had previously presented with long-term AFib episodes (>24 hours). In this example, the patients' cardiac rhythms were continuously monitored with a pacemaker over a two-week period and treated with various doses of budiodarone. The purpose of this example is to determine whether budiodarone reduces long-term AFib lasting more than 24 hours. The various doses and the results of this evaluation are shown in Table 3 below. [Table 3]

[0120] The above results show that budiodarone eliminated more than 70% of long-term AFib episodes lasting longer than 24 hours at all dose levels compared to baseline, with only minor differences between the 200 mg twice daily, 600 mg twice daily, and 800 mg twice daily treatment levels. In contrast, both baseline and off-dose results show the presence of long-term AFib episodes lasting longer than 24 hours. These results also show a significant reduction (more than 64%) in AFib burden (number of episodes over 2 weeks, mean duration of episodes). This reduction correlates well with a reduction in the risk of patients transitioning from paroxysmal to persistent AFib or from persistent to permanent AFib.

[0121] Example 3: Elimination of Very Long Term AFib (>24 hours) Over 12 Weeks This example is a clinical trial evaluation of budiodarone in treating six patients with paroxysmal or persistent AFib who had previously presented with long-term AFib episodes (>24 hours). In this example, the patients' cardiac rhythms were continuously monitored with a pacemaker (surgical invasive approach) over a 12-week period and treated with various doses of budiodarone (2 weeks each). In addition, during the study, the patients were under continuous monitoring and constant supervision by a clinician.

[0122] The purpose of this example is to determine whether budiodaron treatment can reduce very long-term AFib (AFib episodes lasting longer than 24 hours) in a clinical trial setting using a pacemaker to assess cardiac rhythm. The results of this analysis are shown in Table 4 below. [Table 4]

[0123] "Number" indicates the number of very long AFib episodes (i.e., with a duration of more than 24 hours). "Duration" indicates the amount of time spent in the very long period during the two-week period in hours and as a percentage of the baseline measurement. In accordance with the results above, 200 mg twice daily was sufficient to treat all patients in this study by eliminating the number of AFib episodes lasting more than 24 hours. In this case, dose escalation was not necessary to improve efficacy in patients because the dose of 200 mg twice daily budiodarone was sufficient to eliminate these long AFib episodes.

[0124] Example 4: Reduction of Long-Term AFib (>5 hours) Over 12 Weeks This example is a clinical trial evaluation of budiodarone in treating six patients with paroxysmal or persistent AFib who had previously presented with long-term AFib episodes (>5 hours). In this example, the patients' cardiac rhythms were continuously monitored with a pacemaker (surgical invasive approach) over a 12-week period and treated with various doses of budiodarone (2 weeks each). In addition, during the study, the patients were under continuous monitoring and constant supervision by a clinician.

[0125] The purpose of this example is to determine whether budiodaron treatment reduces long-term AFib lasting longer than 5 hours in a clinical trial setting using pacemakers to assess cardiac rhythm. The results of this analysis are shown in Table 5 below. [Table 5]

[0126] "Number" indicates the number of long-term AFib episodes with a duration of more than 5 hours. "Duration" indicates the amount of time spent in AFib with a duration of more than 5 hours over a 2-week period, in hours and as a percentage of the baseline measurement. In this example, all doses of budiodarone provided a significant benefit in reducing both the number and duration of AFib episodes longer than 5 hours, with 200 mg twice daily and 600 mg twice daily providing similar results, while 400 mg twice daily results were significantly better than the no-medication condition but inferior to 200 mg twice daily and 600 mg twice daily. And 800 mg twice daily performed best. At all doses, the reduction in AFib episodes longer than 5 hours was 85% or more, and the corresponding reduction in AFib burden was 90% or more.

[0127] Given the previously discussed association between longer AFib episodes and increased risk of stroke and heart failure (see, e.g., 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 example measured reduction in AFib episodes lasting 1 hour or longer.

[0128] Example 5: Reduction in Long-Term AFib (>1 hour) Over 12 Weeks This example is a clinical trial evaluation of budiodarone in treating six patients with paroxysmal or persistent AFib who had previously presented with long-term AFib episodes (>1 hour). In this example, the patients' cardiac rhythms were continuously monitored with a pacemaker (surgical invasive approach) over a 12-week period and treated with various doses of budiodarone (2 weeks each). In addition, during the study, the patients were under continuous monitoring and constant supervision by a clinician.

[0129] The purpose of this example is to determine whether budiodarone reduces long-term AFib (lasting more than 1 hour) in a clinical trial setting that uses a pacemaker to assess heart rhythm. The results of this analysis are shown in Table 6 below. [Table 6]

[0130] In this example, a significant reduction in the number of long term AFib episodes (>1 hour) over a two week period is shown. As above, "number" refers to the number of long term AFib episodes during the two week period, and "duration" refers to the amount of time during the two week period spent in a long term AFib episode.

[0131] Example 6: Reduction in AFib episodes longer than 6 minutes over a 12 week period This example shows the robustness of budiodarone in reducing both AFib burden and AFib episodes longer than 6 minutes (0.1 hours) in six patients with either paroxysmal or persistent AFib who had previously presented with long-term AFib episodes (>1 hour). In this example, the patients' cardiac rhythms were continuously monitored by a pacemaker over a two-week period. The patients were treated with various doses of budiodarone (each for two weeks). In addition, the patients were under continuous monitoring and supervision by a clinician during the study.

[0132] The results of this example are summarized in Table 7 and confirm that budiodarone not only reduces long-term AFib lasting longer than 1 hour, but also significantly reduces episodes longer than 6 minutes (0.1 hours) in a clinical trial setting using a pacemaker to assess cardiac rhythm. [Table 7]

[0133] "Number" indicates the number of AFib episodes longer than 6 minutes in all tested patients during the study period (4 weeks for the baseline and 2 weeks for the experimental period). "Duration" (in hours) indicates the cumulative duration (in hours) during the study period that the test patient was measured to be in an AFib episode longer than 6 minutes. The above results show that budiodarone not only reduces the number of long AFib episodes, but also reduces short AFib episodes, providing additional protection against stroke and heart failure, significantly reducing the AFib burden.

[0134] For paroxysmal AFib patients with high CHA2DS2-VASc scores (≥3) and persistent AFib patients, AFib episodes longer than 6 minutes may lead to an increased risk of stroke and / or congestive heart failure. The data in Table 7 show that all doses of budiodarone tested significantly reduced the number of AFib episodes longer than 6 minutes, with the higher doses of 600 mg twice daily or 800 mg twice daily reducing these episodes by more than 80%.

[0135] Table 8 summarizes the mean number of minutes and hours per week that patients were in an AFib episode lasting longer than 6 minutes. The percentage of time in AFib was reduced by 90% with budiodaron at doses of 600 mg twice daily and 800 mg twice daily. [Table 8]

[0136] The percent time in AFib in patients is an important parameter that is directly related to risk factors for stroke and / or congestive heart failure, especially in patients with high CHA2DS2-VASc scores. In Table 8, there was a 76.7% reduction in percent time in AFib in patients using 200 mg budiodarone twice daily, which further reduced to 90% in patients using 600 mg budiodarone twice daily and to 94.8% in patients using 800 mg budiodarone twice daily.

[0137] Example 7: Measurement of the longest AFib episode during a 12-week period This example is a clinical trial evaluation in which six patients were treated with different doses of budiodarone for two weeks each to determine the longest duration of AFib episodes experienced at each dose. In this example, the patients' cardiac rhythms were continuously monitored by pacemakers over a two-week period. The various doses and the results of this evaluation are shown in Table 9 below. [Table 9]

[0138] The above results show that there is variability in long-term AFib (cases longer than 5 hours) in patients treated with various doses of budiodarone. In subjects 4 and 5, treatment with 200 mg budiodarone twice daily was sufficient to eliminate all long-term AFib episodes (>5 hours) in these patients. However, subject 1 required 800 mg budiodarone twice daily to eliminate all long-term AFib episodes (>5 hours), while subject 6 required 600 mg budiodarone twice daily to eliminate all budiodarone episodes. This data establishes how long patient monitoring combined with budiodarone dose adjustments may be required to adequately treat patients with paroxysmal or persistent AFib exhibiting long-term AFib episodes.

[0139] The results of Examples 2-7 confirm that the use of appropriate doses of budiodarone in conjunction with monitoring the cardiac rhythm of treated patients can reduce all prolonged AFib episodes greater than 5 hours, as well as reduce the overall AFib burden. This latter result indicates that progression of patients from paroxysmal to persistent AFib or from persistent to permanent AFib can be reduced or prevented.

[0140] Administration of budiodarone according to the present methods may be carried out using a pharmaceutical composition comprising about 1%-99% budiodarone, with the remainder being pharma- ceutically acceptable excipients, such as cornstarch, cellulose, stearic acid, water, or other ingredients. The pharmaceutical composition may be formulated in any form, including, by way of example only, one or more of tablets, capsules, powders, and / or other formulations for oral administration; parenteral administration, such as liquids suitable for one or more of intravenous administration, intramuscular administration, and the like; suppositories and / or enemas; dermal and / or transdermal formulations, and the like.

[0141] Example 8: Programming a Wearable In an embodiment, the wearable may be programmable (e.g., by a clinician, by the patient, and / or remotely, e.g., by a central analysis center). The wearable may be programmed to capture the patient's cardiac rhythm data. The data so generated may be interrogated and / or analyzed by a CPU on the wearable and / or transmitted to another device for interrogation and / or analysis. One example of programming the wearable may enable the wearable to be used to monitor the patient's cardiac rhythm and relay that data, for example, to a clinician, directly and / or indirectly, as follows: A. User Interface: A step function for programming AFib monitoring systems, including wearables, and relying on networked information to the attending clinician. B. Collected data is provided in a readable format that is accessible to clinicians and other authorized individuals. C. A readable display must be available to authorized clinicians at all times, and only authorized clinicians should be permitted to store data and / or reset the monitoring system after one or more of steps 1-15 below. D. Drug exposure, dosage, and other medications administered to a patient can be retrieved by clinicians from the patient's medical record as needed, for example, by integrating the monitoring system with the patient's medical record (e.g., electronic medical record). E. Only steps 1-14 require manual input, although step 14 is optional and can be overridden by the clinician simply pressing step 15 Manual Reset. F. All data may be reviewed and stored by the treating clinician, who may be authorized to program the integration of past observation periods (step 17), whether on or off AFib medication, including budiodarone. G. The system is user friendly and the attending clinician only needs to do four things each time: 1) enter the patient or code to access the data, 2) view the data display, 3) enter the budiodarone dose in step 14 if desired, and 4) press manual reset and save data. H. To compare the characteristics of AFib at different doses of budiodarone or without the drug, the attending clinician accesses the stored data and aggregates the observation periods (step 17).

[0142] Each step is described in Table 10 below. [Table 10]

[0143] Each of steps 4-13 may or may not be included in the programming of the wearable (e.g., at the discretion of the clinician), provided that at least one of these steps is included. In one embodiment, steps 4-7 may be performed and corresponding data may be collected, and one or more of steps 8-13 may be excluded. In another embodiment, steps 4, 5, 8, and 9 may be included, and steps 5, 6, and 10-13 may be excluded. In another embodiment, steps 4, 5, 10, and 11 may be included, and steps 6, 7, 8, 9, 12, and 13 may be excluded. Steps 4, 5, 12, and 13 may be included, and steps 6-11 may be excluded.

[0144] In yet another embodiment, the attending clinician may program the wearable according to one or more of steps 4-13. [Table 11]

[0145] Embodiment Provided below are certain specific embodiments.

[0146] Embodiment I-1 1. A method for assessing whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) is eligible for budiodarone therapy, comprising: a) Selecting patients with paroxysmal or persistent AFib; b) i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the patient's cardiac rhythm when the wearable is attached to the patient; ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; and iii) a transmitting component configured to transmit data based on the cardiac rhythm data in the first computing device to a second computing device accessible to a clinician; and attaching a wearable to the patient, the wearable comprising: c) transmitting to the second computing device said data indicative of at least one of the presence of long-term AFib episodes, the absence of long-term AFib episodes, the number of long-term AFib episodes, and optionally the degree of AFib burden; and d) qualifying the patient for budiodarone therapy based on a determination that the data meets at least one of a threshold number of long AFib episodes and / or a threshold AFib burden; A method comprising:

[0147] Embodiment I-2 The method of embodiment I-1, wherein the first computing device is configured to evaluate the stored cardiac rhythm data to determine the presence of long-term AFib episodes and the number of long-term AFib episodes, thereby determining data based on the cardiac rhythm data.

[0148] Embodiment I-3 The method of embodiment I-2, wherein said evaluating is continuous.

[0149] Embodiment I-4 The method of any of embodiments I-2 or I-3, wherein said evaluation is additionally or alternatively semi-continuous.

[0150] Embodiment I-5 The method of any of embodiments I-1 to I-4, wherein the first computing device is programmed to alert at least one of the clinician or the patient based on the data that a long-term AFib episode that places the patient at risk of stroke has been detected.

[0151] Embodiment I-6 The method of any of embodiments I-1 to I-5, wherein qualifying the patient for budiodarone therapy comprises confirming, based on the data, that the patient meets at least one of the following criteria: a) at least one AFib episode of at least 5 hours in any 30 day period, or at least two episodes of at least 1 hour in any 30 day period, plus an AFib burden of at least 2.5% in any 30 day period; b) at least one AFib episode of at least 5 hours in any 30 day period, or at least two episodes of at least 1 hour in any 30 day period, plus an AFib burden of at least 5% in any 30 day period; c) at least one AFib episode of at least 5 hours during a 30-day period plus an AFib burden of at least 2.5% during a 30-day period; d) at least one AFib episode of at least 5 hours during a 30-day period plus an AFib burden of at least 5% during a 30-day period; e) at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 2.5% in a 30-day period; or f) At least two AFib episodes of at least one hour during a 30-day period plus an AFib burden of at least 5% during a 30-day period.

[0152] Embodiment I-7 The method of any of embodiments I-1 to I-6, wherein the wearable is one or more of a patch, watch, wristband, strap, ring, or device that attaches to the body when worn, and the wearable is configured to measure cardiac rhythm and transmit cardiac rhythm data directly or indirectly to the second computing device.

[0153] Embodiment I-8 The method according to embodiments I-1 to I-7, wherein the patient is refractory to one or more other methods of treating AFib.

[0154] Embodiment II-1 1. A method of treating a patient diagnosed with paroxysmal atrial fibrillation or persistent atrial fibrillation (AFib), comprising: administering budiodarone to said patient; Including, The above patient, A wearable is attached to the patient to be identified, the wearable comprising: at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the cardiac rhythm of the patient to be identified when the wearable is attached to the patient to be identified; a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm of the patient to be identified; and a transmitting component configured to transmit data based on the cardiac rhythm data of the patient to be identified in the first computing device to a second computing device accessible to a clinician; To be equipped with; data of the patient to be identified is transmitted to the second computing device, the data indicating at least one of the presence of a long-term AFib episode, the absence of any long-term AFib episodes, the number of long-term AFib episodes, and optionally the extent of AFib burden; and making a determination that the data meets at least one of a threshold number of long AFib episodes and / or a threshold AFib burden; Patients were identified as candidates for budiodarone treatment based on: The patient identified as a candidate for the budiodarone treatment is determined to have budiodarone-responsive AFib. method.

[0155] Embodiment II-2 The method of embodiment II-1, wherein the patient identified as a candidate for budiodarone is refractory to one or more other methods of treating AFib.

[0156] Embodiment III-1 1. A method for assessing whether a patient eligible for budiodarone therapy should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy, comprising: a) selecting said eligible patient, said eligible patient being: undergoing budiodarone therapy, which includes treatment with a dose of budiodarone or a pharmaceutical composition containing budiodarone; The wearer is fitted with a wearable that: i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the cardiac rhythm of the qualified patient when the wearable is worn; ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; and iii) a transmitting component configured to transmit data based on the cardiac rhythm data in the first computing device to a second computing device accessible to a clinician; c) collecting and transmitting cardiac rhythm data to the second computing device, the second computing device configured to evaluate the cardiac rhythm data for the presence and number of long AFib episodes and the extent of AFib burden; d) optionally adjusting the dose of budiodarone to assess the appropriate dose for the patient; and e) assessing from the collected cardiac rhythm data whether the patient is responsive, partially responsive, or non-responsive to budiodarone therapy; Including, The above therapy is maintained for responsive patients, adjusted for partially responsive patients, and terminated for non-responsive patients. method.

[0157] Embodiment III-2 The method according to embodiment III-1, wherein said dose of budiodarone is at least about 200 mg twice daily.

[0158] Embodiment III-3 The method according to any one of embodiments III-1 to III-2, wherein the dose of budiodarone is about 200 mg twice a day to about 800 mg twice a day.

[0159] Embodiment III-4 The method of embodiment III-3, wherein the dose of budiodarone is selected from about 200 mg twice daily, about 400 mg twice daily, 600 mg twice daily, and about 800 mg twice daily.

[0160] Embodiment III-5 The method according to any one of embodiments III-1 to III-4, wherein budiodarone is administered as a pharmaceutical composition.

[0161] Embodiment III-6 The method according to any of embodiments III-1 to III-5, wherein the wearable monitoring is maintained in the case of a responsive patient to ensure that the patient remains responsive.

[0162] Embodiment III-7 The method of embodiment III-6, wherein the patient who is initially responsive to budiodarone but later becomes non-responsive undergoes a budiodarone dose adjustment, provided that if the dose adjustment fails to return the patient to a budiodarone-responsive state, the patient is removed from treatment with budiodarone.

[0163] Embodiment III-8 The method according to any one of embodiments III-1 to III-7, wherein the responsive patient is enrolled in a registry that identifies the patient as eligible for treatment with budiodarone, and being listed in the registry is a requirement for administration of budiodarone.

[0164] Embodiment III-9 The method according to embodiments III-1 to III-8, wherein the data generated by the wearable is transmitted directly or indirectly to a clinician who can assess the presence or absence of long-term AFib and, optionally, the degree of AFib burden for the patient.

[0165] Embodiment III-10 The method of embodiment III-9, wherein the data is first transmitted to a remote laboratory where qualified medical personnel analyze the data.

[0166] Embodiment III-11 The qualified health care professional identifies the patient as eligible for treatment with budiodarone and provides the information to the treating clinician, The employee has confirmed that the patient is eligible; and Any data generated by or analyses performed by any of the abovementioned practitioners; The method according to embodiment III-10, wherein

[0167] Embodiment III-12 The Qualified Healthcare Professional shall determine whether the patient is responsive to treatment with a given dose of budiodarone; If the qualified health care practitioner determines that the patient is currently non-responsive, the practitioner: A recommendation that the patient undergo a dose adjustment to restore responsiveness to the patient; or Recommendation to terminate budiodarone treatment in such non-responsive patients if they are being treated with the maximum prescribed dose; providing said determination to the treating clinician along with one or more of: The method according to any one of embodiments III-10 to III-11.

[0168] Embodiment III-13 The method of any one of embodiments III-1 to III-12, wherein evaluating the collected cardiac rhythm data includes evaluating cardiac rhythm data beginning collection at least 3 days after initiation of budiodarone administration or initiation of budiodarone dose adjustment.

[0169] Embodiment III-14 The method of any one of embodiments III-1 to III-13, wherein evaluating the collected cardiac rhythm data includes evaluating cardiac rhythm data beginning collection at least 14 days after initiation of budiodarone administration or initiation of budiodarone dose adjustment.

[0170] Embodiment IV-1 1. A method for reducing a patient's risk of progression from paroxysmal to persistent AFib, or from persistent to permanent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; administering budiodarone to said patient at a dosage; monitoring the effectiveness of said administration and, optionally, adjusting said dose as necessary to achieve a reduction in either or both of the AFib burden and long-term AFib, which dose adjustment results in a reduction in the risk of progression from paroxysmal AFib to persistent AFib or from persistent AFib to permanent AFib; and Continue to monitor these patients for continued efficacy of budiodarone; A method comprising:

[0171] Embodiment IV-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be disqualified from budiodarone therapy according to any of embodiments III-1 to III-14; The method of embodiment IV-1, comprising one or more of:

[0172] Embodiment V-1 1. A method for reducing the risk of heart failure in a patient diagnosed with paroxysmal AFib or persistent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; administering budiodarone to said patient at a dosage; monitoring the effectiveness of administration of the dose and adjusting the dose as necessary to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of heart failure in the patient; and Continue to monitor these patients for continued efficacy of budiodarone; A method comprising:

[0173] Embodiment V-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any one of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy according to any of embodiments III-1 to III-14; The method of embodiment V-1, comprising one or more of:

[0174] Embodiment VI-1 1. A method for reducing the risk of stroke in a patient diagnosed with paroxysmal AFib or persistent AFib, comprising: To identify patients with paroxysmal or persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; administering budiodarone to said patient at a dosage; monitoring the effectiveness of said administration and, if desired, adjusting said dose as necessary to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of stroke in said patient; and Continue to monitor these patients for continued efficacy of budiodarone; A method comprising:

[0175] Embodiment VI-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any one of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy according to any of embodiments III-1 to III-15; The method of embodiment VI-1, comprising one or more of:

[0176] Embodiment VII-1 1. A method of treating a patient with paroxysmal or persistent AFib that is refractory to one or more prior methods for treating AFib, comprising: a) selecting patients who are refractory to one or more prior methods for treating AFib; b) To determine the number of prolonged AFib episodes and the degree of AFib burden in these patients; c) qualifying the patient for budiodarone treatment at a dose based on the number of prolonged AFib episodes and the degree of AFib burden; d) outfitting said patient with a wearable comprising: i) at least one of an electrode or an optical sensor that continuously or semi-continuously monitors the patient's cardiac rhythm when the wearable is attached to the patient; ii) a first computing device configured to collect and store cardiac rhythm data based on the patient's monitored cardiac rhythm; and iii) a transmitting component configured to transmit data based on the cardiac rhythm data in the first computing device to a second computing device accessible to a clinician; e) collecting and transmitting data based on said cardiac rhythm data to said second computing device, where said data is evaluated for the presence and number of long AFib episodes and the extent of AFib burden; f) optionally adjusting the administration of budiodarone to said patient to assess the appropriate dose for said patient; and g) assessing whether the collected cardiac rhythm data indicates that the patient is responsive or non-responsive to budiodarone therapy; Including, The above therapy is maintained for responsive patients and terminated for non-responsive patients. method.

[0177] Embodiment VII-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any one of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy according to any of embodiments III-1 to III-15; The method of embodiment VII-1, comprising one or more of:

[0178] Embodiment VIII-1 1. A method for reducing the risk of a patient with paroxysmal AFib transitioning to persistent AFib, comprising: To identify patients with paroxysmal AFib who have an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; administering budiodarone to said patient at a dosage; monitoring the effectiveness of said administration and, if desired, adjusting said dose as necessary to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of said transition in said patient; and Continue to monitor these patients for continued efficacy of budiodarone; A method comprising:

[0179] Embodiment VIII-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any one of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy according to any of embodiments III-1 to III-15; The method according to embodiment VIII-1, comprising one or more of:

[0180] Embodiment IX-1 1. A method for reducing the risk of a patient with persistent AFib transitioning to permanent AFib, comprising: To identify patients with persistent AFib, with an AFib burden of at least 2.5% and at least one prolonged AFib episode during a 4-week period; administering budiodarone to said patient at a dosage; monitoring the effectiveness of said administration and, if desired, adjusting said dose as necessary to achieve a reduction in either or both of the AFib burden and long-term AFib, thereby reducing the risk of said transition in said patient; and Continue to monitor these patients for continued efficacy of budiodarone; A method comprising:

[0181] Embodiment IX-2 Additionally or alternatively, assessing whether said patient is eligible for budiodarone therapy according to any of embodiments I-1 to I-8; Treating said patient according to any one of the embodiments II-1 to II-2; or assessing whether the patient should receive a dose adjustment of budiodarone therapy or be ineligible for budiodarone therapy according to any of embodiments III-1 to III-15; The method of embodiment IX-1, comprising one or more of:

Claims

1. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: a) monitoring cardiac rhythm data of said eligible patients who have received an initial dose of budiodarone of at least 200 mg twice daily; wherein during the eligibility assessment period during which the eligible patient did not receive budiodarone therapy: The eligible patient is eligible for budiodarone therapy based on experiencing one or more of: a baseline number of prolonged AFib episodes meeting a threshold number of prolonged AFib episodes; or the patient's baseline AFib burden meeting a threshold AFib burden. b) for at least about 3 days after initiation of administration of the first dose, the monitored cardiac rhythm data: number of prolonged AFib episodes, the length of the prolonged AFib episode, or one or more of the degrees of AFib burden assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; Here, the evaluation is For the eligible patient, the first dose was collected during the eligibility period. number of prolonged AFib episodes, the length of the prolonged AFib episode, or AFib load and the first dose of budiodarone is evaluated as effective if one or more of the following are reduced compared to baseline data. d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustment is terminated; and e) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said qualified patient, providing said information that such determination has been made as an indication to assist in the decision to disqualify said qualified patient from budiodarone therapy and to terminate budiodarone therapy for said disqualified patient; A method comprising:

2. 10. The method of claim 1, wherein the qualified patient is refractory to one or more other methods of treating AFib.

3. The eligibility assessment period is at least about 14 days, and the eligible patient receives, during the eligibility assessment period: a) at least one AFib episode lasting at least 5 hours or at least two AFib episodes lasting at least 1 hour plus an AFib burden of at least 2.5%; b) at least one AFib episode lasting at least 5 hours or at least two AFib episodes lasting at least 1 hour plus an AFib burden of at least 5%; c) at least one AFib episode lasting at least 5 hours plus an AFib burden of at least 2.5%; d) at least one AFib episode lasting at least 5 hours plus an AFib burden of at least 5%; e) at least two AFib episodes of at least 1 hour plus an AFib burden of at least 2.5%; or f) at least two AFib episodes of at least 1 hour plus an AFib burden of at least 5%; 10. The method of claim 1, wherein the patient is considered eligible for budiodarone therapy based on experiencing one or more of the following:

4. 10. The method of claim 1, wherein the cardiac rhythm data is collected by a wearable comprising one or more of a patch, a watch, a wristband, a strap, a ring, or a device that adheres to the body.

5. 5. The method of claim 4, wherein at least one of the electrodes or optical sensors continuously monitors the cardiac rhythm of the qualified patient.

6. 5. The method of claim 4, wherein at least one of the electrodes or optical sensors semi-continuously monitors the cardiac rhythm of the qualified patient.

7. 5. The method of claim 4, wherein the wearable is programmed to alert at least one of a clinician or the qualified patient that a prolonged AFib episode that places the patient at risk for stroke has been detected based on the cardiac rhythm data.

8. 10. The method of claim 1, further comprising, if the effective dose is assessed for the qualified patient, monitoring cardiac rhythm data of the qualified patient during budiodarone therapy at the effective dose to confirm a determination that the effective dose remains effective for the qualified patient.

9. If the confirmation indicates that the effective dose is no longer effective for the qualified patient, providing the no longer effective information as an indication that the budiodarone dose should be adjusted, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated for effectiveness; or If an effective dose adjustment results in an adjusted dose exceeding 800 mg twice daily, providing this information as an indicator to assist in the decision to ineligible the eligible patient for budiodarone therapy and to terminate budiodarone therapy for the ineligible patient; The method of claim 8 further comprising:

10. As an indicator to assist in determining that no effective budiodarone dose is available for the eligible patient, The effective dose for the eligible patient is assessed as ineffective; and No effective dose was assessed below 800 mg twice daily administered consecutively; The method of claim 1 , further comprising providing the information:

11. 2. The method of claim 1, wherein the evaluation is performed such that the dose is evaluated as effective if the number of prolonged AFib episodes lasting at least 5 hours over a period of at least 2 weeks in the eligible patients administered the dose of budiodarone is reduced by at least 85% compared to not administering budiodarone.

12. 2. The method of claim 1, wherein the evaluation is performed such that the dose is evaluated as effective if the number of prolonged AFib episodes lasting at least 1 hour over a period of at least 2 weeks in the eligible patients administered a dose of budiodarone is reduced by at least 66% compared to not administering budiodarone.

13. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: a) monitoring cardiac rhythm data of said eligible patients who have received an initial dose of budiodarone of at least 200 mg twice daily; wherein during the eligibility assessment period during which the eligible patient did not receive budiodarone therapy: The eligible patient is eligible for budiodarone therapy based on experiencing one or more of: a baseline number of prolonged AFib episodes meeting a threshold number of prolonged AFib episodes; or the patient's baseline AFib burden meeting a threshold AFib burden. b) the monitored cardiac rhythm data for at least about 3 days after initiation of administration of the first dose. number of prolonged AFib episodes, the length of the prolonged AFib episode, or degree of AFib burden, assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; Here, the evaluation is For the eligible patient receiving the initial dose, the initial dose of budiodarone is evaluated as effective if the initial dose reduces prolonged AFib episodes. d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustments are terminated; and e) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said qualified patient, providing said information that such determination has been made as an indication to assist in the decision to disqualify said qualified patient from budiodarone therapy and to terminate budiodarone therapy for said disqualified patient; A method comprising:

14. 14. The method of claim 13, wherein the evaluation is performed such that the effective dose is evaluated as effective for the qualified patient if it eliminates prolonged AFib episodes lasting at least 1 hour.

15. The method of claim 4 , wherein the wearable is configured to measure cardiac rhythm data and transmit the cardiac rhythm data directly or indirectly to a computing device.

16. 10. The method of claim 1, wherein the monitoring of the cardiac rhythm data is performed continuously or semi-continuously, and the cardiac rhythm data is assessed periodically over a period of at least about three days.

17. The evaluation is For the eligible patients, the effective dose was collected during the eligibility assessment period. Number of prolonged AFib episodes lasting over 24 hours; Number of prolonged AFib episodes lasting over 5 hours; the number of prolonged AFib episodes lasting more than one hour; or AFib load; The effective dose of budiodaron is evaluated as effective if one or more of the following are reduced by at least 10% compared to baseline data: The method of claim 1.

18. The initial dose of budiodarone is Approximately 200 mg twice daily; Approximately 400 mg twice daily; about 600 mg twice daily; or Approximately 800 mg twice daily; The method of claim 1, wherein the method is one of:

19. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: a) monitoring cardiac rhythm data of said eligible patients who have received an initial dose of budiodarone of at least 200 mg twice daily; wherein during the eligibility assessment period during which the eligible patient did not receive budiodarone therapy: The eligible patient is eligible for budiodarone therapy based on experiencing one or more of: a baseline number of prolonged AFib episodes meeting a threshold number of prolonged AFib episodes; or the patient's baseline AFib burden meeting a threshold AFib burden. b) the number of prolonged AFib episodes in said monitored cardiac rhythm data for at least about 3 days after initiation of administration of said first dose; the length of the prolonged AFib episode, or degree of AFib burden, assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; For the eligible patient, the first dose was collected during the eligibility period. number of prolonged AFib episodes, the length of the prolonged AFib episode, or AFib load and the first dose of budiodarone is evaluated as effective if one or more of the following are reduced compared to baseline data. d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustment is terminated; e) if the effective dose is assessed for the qualified patient, monitoring the qualified patient's cardiac rhythm data during budiodarone therapy at the effective dose to confirm a determination that the effective dose remains effective for the qualified patient; and f) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said qualified patient, providing said information that such determination has been made as an indication to assist in the decision to disqualify said qualified patient from budiodarone therapy and to terminate budiodarone therapy for said disqualified patient; A method comprising:

20. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: wherein eligibility is based on baseline data regarding AFib severity in the patient indicating that the patient had one or more of a prolonged AFib episode of at least 1 hour or a maximum AFib burden of at least 5 hours over an eligibility period in which the patient did not receive budiodarone therapy; a) monitoring cardiac rhythm data of said eligible patients who have received an initial dose of budiodarone of at least 200 mg twice daily; b) the monitored cardiac rhythm data for at least about 3 days after initiation of administration of the first dose. number of prolonged AFib episodes, the length of the prolonged AFib episode, or degree of AFib burden, assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; Here, the evaluation is For the eligible patient, the first dose was collected during the eligibility period. number of prolonged AFib episodes; the length of the prolonged AFib episode; or AFib load; The first dose of budiodarone is evaluated as effective if one or more of the following are reduced or eliminated by at least 10% compared to baseline data: d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustments are terminated; and e) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said patient, providing said information that such determination has been made as an indication to assist in determining whether said patient should be disqualified from budiodarone therapy; A method comprising:

21. 21. The method of claim 20, wherein the qualified patient is refractory to one or more other methods of treating AFib.

22. The eligibility assessment period is at least about 14 days, and the eligible patient receives, during the eligibility assessment period: a) at least one AFib episode lasting at least 5 hours or at least two AFib episodes lasting at least 1 hour plus an AFib burden of at least 2.5%; b) at least one AFib episode lasting at least 5 hours or at least two AFib episodes lasting at least 1 hour plus an AFib burden of at least 5%; c) at least one AFib episode lasting at least 5 hours plus an AFib burden of at least 2.5%; d) at least one AFib episode lasting at least 5 hours plus an AFib burden of at least 5%; e) at least two AFib episodes of at least 1 hour plus an AFib burden of at least 2.5%; or f) at least two AFib episodes of at least 1 hour plus an AFib burden of at least 5%; 21. The method of claim 20, wherein the patient is eligible for budiodarone therapy based on having experienced one or more of the following:

23. 21. The method of claim 20, wherein the cardiac rhythm data is collected by a wearable comprising one or more of a patch, a watch, a wristband, a strap, a ring, or a device that adheres to the body.

24. 24. The method of claim 23, wherein at least one of the electrodes or optical sensors continuously monitors the cardiac rhythm of the qualified patient.

25. 24. The method of claim 23, wherein at least one of the electrodes or optical sensors semi-continuously monitors the cardiac rhythm of the qualified patient.

26. 24. The method of claim 23, wherein the wearable is programmed to alert at least one of a clinician or the qualified patient that a prolonged AFib episode that places the patient at risk for stroke has been detected based on the cardiac rhythm data.

27. 24. The method of claim 23, wherein the wearable is configured to measure cardiac rhythm data and transmit the cardiac rhythm data directly or indirectly to a computing device.

28. 24. The method of claim 23, wherein the monitoring of the cardiac rhythm data is performed continuously or semi-continuously, and the cardiac rhythm data is assessed periodically for a period of at least about two weeks.

29. 24. The method of claim 23, further comprising, if the effective dose is assessed for the qualified patient, monitoring cardiac rhythm data of the qualified patient during budiodarone therapy at the effective dose to confirm a determination that the effective dose remains effective for the qualified patient.

30. If the confirmation indicates that the effective dose is no longer effective for the eligible patient, providing the information that the budiodarone is no longer effective as an indication that the previously effective dose of budiodarone should be adjusted, provided that the adjusted effective dose does not exceed 800 mg twice daily, and that the previously effective dose of budiodarone to be adjusted should be evaluated for effectiveness; or If the previously effective dose adjustment results in an adjusted dose exceeding 800 mg twice daily, providing this information as an indicator to assist in the decision to ineligible the eligible patient for budiodarone therapy and to terminate budiodarone therapy for the ineligible patient; 30. The method of claim 29, further comprising:

31. As an indicator to assist in determining that no effective budiodarone dose is available for the eligible patient, The effective dose for the eligible patient is evaluated as ineffective; and No effective doses have been evaluated below 800 mg twice daily administered consecutively; 24. The method of claim 23, further comprising providing the information:

32. 24. The method of claim 23, wherein the evaluation is performed such that the initial dose or the adjusted dose of budiodarone is evaluated as effective if the number of prolonged AFib episodes lasting at least 5 hours over a period of at least 2 weeks in the eligible patient administered the initial dose or the adjusted dose of budiodarone is reduced by at least 85% compared to not administering budiodarone.

33. 24. The method of claim 23, wherein the evaluation is performed such that the initial dose or the adjusted dose of budiodarone is evaluated as effective if the number of prolonged AFib episodes lasting at least 1 hour over a period of at least 2 weeks in the eligible patient administered the initial dose or the adjusted dose of budiodarone is reduced by at least 66% compared to not administering budiodarone.

34. 24. The method of claim 23, wherein the evaluation is performed such that an effective dose of budiodarone is evaluated as effective for the qualified patient if the effective dose eliminates prolonged AFib episodes lasting at least 1 hour.

35. The evaluation is For the eligible patients, the effective dose was collected during the eligibility assessment period. Number of prolonged AFib episodes lasting over 24 hours; Number of prolonged AFib episodes lasting over 5 hours; the number of prolonged AFib episodes lasting more than one hour; or AFib load; The effective dose of budiodaron is evaluated as effective if one or more of the following are reduced by at least 10% compared to baseline data:

24. The method of claim 23.

36. The initial dose of budiodarone is Approximately 200 mg twice daily; Approximately 400 mg twice daily; about 600 mg twice daily; or Approximately 800 mg twice daily; 24. The method of claim 23, wherein the

37. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: a) monitoring cardiac rhythm data of said eligible patients receiving an initial dose of budiodarone of at least 400 mg twice daily; wherein during the eligibility assessment period during which the eligible patient did not receive budiodarone therapy: The eligible patient is eligible for budiodarone therapy based on experiencing one or more of: a baseline number of prolonged AFib episodes meeting a threshold number of prolonged AFib episodes; or the patient's baseline AFib burden meeting a threshold AFib burden. b) for at least about 3 days after initiation of administration of the first dose, the monitored cardiac rhythm data: number of prolonged AFib episodes, the length of the prolonged AFib episode, or one or more of the degrees of AFib burden assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; Here, the evaluation is For the eligible patient, the first dose was collected during the eligibility period. number of prolonged AFib episodes, the length of the prolonged AFib episode, or AFib load and the first dose of budiodarone is evaluated as effective if one or more of the following are reduced compared to baseline data. d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustment is terminated; and e) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said qualified patient, providing said information that such determination has been made as an indication to assist in the decision to disqualify said qualified patient from budiodarone therapy and to terminate budiodarone therapy for said disqualified patient; A method comprising:

38. 1. A method for assisting in determining whether a patient suffering from paroxysmal or persistent atrial fibrillation (AFib) and eligible for budiodarone therapy is responsive to said budiodarone therapy or should be disqualified from said budiodarone therapy, comprising: a) monitoring cardiac rhythm data of said eligible patients who have received an initial dose of budiodarone of at least 600 mg twice daily; wherein during the eligibility assessment period during which the eligible patient did not receive budiodarone therapy: The eligible patient is eligible for budiodarone therapy based on experiencing one or more of: a baseline number of prolonged AFib episodes meeting a threshold number of prolonged AFib episodes; or the patient's baseline AFib burden meeting a threshold AFib burden. b) for at least about 3 days after initiation of administration of the first dose, the monitored cardiac rhythm data: number of prolonged AFib episodes, the length of the prolonged AFib episode, or one or more of the degrees of AFib burden assessing one or more of: c) providing the results assessed in b) above to assist in assessing whether the initial dose of budiodarone is effective in treating AFib; Here, the evaluation is For the eligible patient, the first dose was collected during the eligibility period. number of prolonged AFib episodes, the length of the prolonged AFib episode, or AFib load and the first dose of budiodarone is evaluated as effective if one or more of the following are reduced compared to baseline data. d) if the initial dose is assessed to be ineffective, providing the information that such assessment has been made as an indication that the initial budiodarone dose should be adjusted one or more times, provided that the adjusted dose does not exceed 800 mg twice daily, and that the adjusted budiodarone dose should be evaluated to determine whether it is effective, provided that if an effective dose is assessed, dose adjustment is terminated; and e) whenever it is determined that a budiodarone dose of 800 mg or more twice daily is not effective for said qualified patient, providing said information that such determination has been made as an indication to assist in the decision to disqualify said qualified patient from budiodarone therapy and to terminate budiodarone therapy for said disqualified patient; A method comprising:

39. 1. A pharmaceutical composition comprising budiodarone for budiodarone therapy to treat patients with paroxysmal or persistent AFib, comprising: the patient is refractory to one or more other prior methods of treating AFib; a) continuously or semi-continuously monitoring the patient's cardiac rhythm data; b) administering an initial dose of the pharmaceutical composition to the patient; c) the cardiac rhythm data is Number of prolonged AFib episodes, or degree of AFib burden, and assessing the value of AFib, including one or more of: d) if the assessed cardiac rhythm data demonstrates that the pharmaceutical composition at the initial dose is effective for the patient, an evaluation is performed; e) if said evaluation indicates that said pharmaceutical composition at said initial dose is not effective for said patient, said pharmaceutical composition is administered at a higher dose and steps c-d are repeated for said patient at said higher dose; f) provided that if said evaluation indicates that said pharmaceutical composition at said initial dose is effective for said patient, said pharmaceutical composition is maintained at said effective dose and steps c-d are repeated for said patient; and g) terminating administration of the pharmaceutical composition to said patient whenever it is determined that no dose of budiodarone less than the maximum tolerated dose is effective for said patient; wherein the pharmaceutical composition at a certain dose is evaluated as effective if the AFib value of the patient to whom the pharmaceutical composition is administered at that dose is reduced compared to the baseline AFib value for the patient who has not been administered the pharmaceutical composition.

40. 40. The pharmaceutical composition of claim 39, wherein the patient is eligible for budiodarone therapy based on the baseline AFib value meeting a threshold.

41. over a 30-day period in which the patient was not receiving budiodarone therapy; a) at least one AFib episode of at least 5 hours in a 30-day period or at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 2.5% in said 30-day period; b) at least one AFib episode of at least 5 hours in a 30-day period or at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 5% in said 30-day period; c) at least one AFib episode of at least 5 hours in a 30-day period plus an AFib burden of at least 2.5% in said 30-day period; d) at least one AFib episode of at least 5 hours in a 30-day period plus an AFib burden of at least 5% in said 30-day period; e) at least two AFib episodes of at least one hour in a 30-day period plus an AFib burden of at least 2.5% in that 30-day period; or f) at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 5% in said 30-day period; 41. The pharmaceutical composition of claim 40, wherein the patient is eligible for budiodarone therapy based on experiencing one or more of the following:

42. 40. The pharmaceutical composition of claim 39, wherein the cardiac rhythm data is collected by a wearable attached to the patient.

43. 43. The pharmaceutical composition of claim 42, wherein the cardiac rhythm data is monitored continuously or semi-continuously by receiving the continuously or semi-continuously collected cardiac rhythm data from the wearable.

44. 43. The pharmaceutical composition of claim 42, wherein the wearable comprises one or more of a patch, a watch, a wristband, a strap, a ring, or a device that adheres to the body.

45. 43. The pharmaceutical composition of claim 42, wherein the wearable is programmed to alert at least one of a clinician or the eligible patient that a prolonged AFib episode that places the patient at risk for stroke has been detected based on the cardiac rhythm data.

46. 43. The pharmaceutical composition of claim 42, wherein the wearable is programmed to alert at least one of a clinician or the qualified patient that a prolonged AFib episode of 5 hours or more has been detected based on the cardiac rhythm data.

47. 40. The pharmaceutical composition of claim 39, wherein the AFib value comprises the number of prolonged AFib episodes lasting over 24 hours.

48. 40. The pharmaceutical composition of claim 39, wherein the AFib values ​​comprise the number of prolonged AFib episodes lasting over 5 hours.

49. 40. The pharmaceutical composition of claim 39, wherein the AFib value comprises the number of prolonged AFib episodes lasting over one hour.

50. 40. The pharmaceutical composition of claim 39, wherein the value of AFib comprises AFib load.

51. 40. The pharmaceutical composition of claim 39, wherein the dose is assessed as effective if the AFib value of the patient being administered the pharmaceutical composition at that dose is reduced by at least 10% compared to the corresponding baseline AFib value.

52. the AFib values ​​include the number of prolonged AFib episodes lasting over 5 hours; 40. The pharmaceutical composition of claim 39, wherein the dose is assessed as effective if the AFib value of the patient being administered the pharmaceutical composition at that dose is reduced by at least 85% compared to the corresponding baseline AFib value.

53. the AFib values ​​include the number of prolonged AFib episodes lasting at least 1 hour; 40. The pharmaceutical composition of claim 39, wherein the dose is assessed as effective if the AFib value of the patient being administered the pharmaceutical composition at that dose is reduced by at least 66% compared to the corresponding baseline AFib value.

54. 40. The pharmaceutical composition of claim 39, wherein the initial dose is 200 mg twice daily.

55. 40. The pharmaceutical composition of claim 39, wherein the initial dose is 800 mg twice daily.

56. 40. The pharmaceutical composition of claim 39, wherein said evaluation is performed periodically at least once a month.

57. 40. The pharmaceutical composition of claim 39, wherein the one or more preceding methods of treating AFib include one or more of a beta-blocker, a calcium channel blocker, an anticoagulant, a sodium channel blocker, or a potassium channel blocker.

58. 40. The pharmaceutical composition of claim 39, wherein the monitoring is maintained while a dose is effective for the patient.

59. 1. A pharmaceutical composition comprising budiodarone for inhibiting the progression of a patient from paroxysmal atrial fibrillation (AFib) to persistent AFib or from persistent AFib to permanent AFib, comprising: the patient is eligible for and responsive to budiodarone therapy at an initial dose of budiodarone; the patient's cardiac rhythm data is monitored for a period of at least six months to confirm continued response to the budiodarone therapy; if during said monitoring said patient becomes non-responsive to said initial dose, then said dose of budiodarone is increased to a higher dose and said pharmaceutical composition is administered until said patient becomes responsive to budiodarone therapy at said higher dose, or else said budiodarone therapy is maintained at said initial dose; and The pharmaceutical composition, wherein the patient's cardiac rhythm data is monitored to confirm that the patient has been prevented from progressing from paroxysmal to persistent AFib or from persistent AFib to permanent AFib.

60. 60. The pharmaceutical composition of claim 59, wherein the monitoring is continuous or semi-continuous.

61. 60. The pharmaceutical composition of claim 59, wherein the patient is eligible based on having an AFib burden of at least 2.5% plus at least one prolonged AFib episode over a period of about 4 weeks prior to the budiodarone therapy.

62. 60. The pharmaceutical composition of claim 59, wherein the patient's cardiac rhythm is monitored based on cardiac rhythm data measured by a wearable worn by the patient.

63. 60. The pharmaceutical composition of claim 59, wherein the inhibition in the patient converts the patient from persistent AFib to paroxysmal AFib or sinus rhythm or from paroxysmal AFib to sinus rhythm as confirmed by monitored cardiac rhythm data of the patient.

64. 1. A pharmaceutical composition comprising budiodarone for inhibiting the progression of a patient from paroxysmal atrial fibrillation (AFib) to persistent AFib or from persistent AFib to permanent AFib, comprising: the patient is refractory to one or more prior methods of treating AFib and is eligible for and responsive to budiodarone therapy with an initial dose of budiodarone; the patient's cardiac rhythm data is monitored for a period of at least six months to confirm continued response to the budiodarone therapy; if during said monitoring said patient becomes non-responsive to said initial dose, then said dose of budiodarone is increased to a higher dose and said pharmaceutical composition is administered until said patient becomes responsive to budiodarone therapy at said higher dose, or else said budiodarone therapy is maintained at said initial dose; and The pharmaceutical composition, wherein the patient's cardiac rhythm data is monitored to confirm that the patient has been prevented from progressing from paroxysmal to persistent AFib or from persistent AFib to permanent AFib.

65. 65. The pharmaceutical composition of claim 64, wherein the patient's cardiac rhythm data is monitored continuously or semi-continuously.

66. 65. The pharmaceutical composition of claim 64, wherein the patient is eligible based on having an AFib burden of at least 2.5% plus at least one prolonged AFib episode over a period of about 4 weeks prior to the budiodarone therapy.

67. 65. The pharmaceutical composition of claim 64, wherein the patient's cardiac rhythm is monitored based on cardiac rhythm data measured by a wearable worn by the patient.

68. 65. The pharmaceutical composition of claim 64, wherein the inhibition in the patient converts the patient from persistent AFib to paroxysmal AFib or sinus rhythm or from paroxysmal AFib to sinus rhythm as confirmed by monitored cardiac rhythm data of the patient.

69. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of progression to persistent atrial fibrillation (AFib) in a patient with paroxysmal atrial fibrillation, comprising: the patient is eligible for and responsive to budiodarone therapy at an initial dose of budiodarone; the patient's cardiac rhythm data is monitored for a period of at least six months to confirm continued response to the budiodarone therapy; if during said monitoring said patient becomes non-responsive to said initial dose, then said dose of budiodarone is increased to a higher dose and said pharmaceutical composition is administered until said patient becomes responsive to budiodarone therapy at said higher dose, or else said budiodarone therapy is maintained at said initial dose; and The pharmaceutical composition, wherein the patient's cardiac rhythm data is monitored to confirm that the patient has been prevented from progressing from paroxysmal to persistent AFib or from persistent AFib to permanent AFib.

70. 70. The pharmaceutical composition of claim 69, wherein the patient is refractory to one or more prior methods of treating AFib.

71. 70. The pharmaceutical composition of claim 69, wherein the patient's cardiac rhythm data is monitored continuously or semi-continuously.

72. 70. The pharmaceutical composition of claim 69, wherein the patient is eligible based on having an AFib burden of at least 2.5% plus at least one prolonged AFib episode over a period of about 4 weeks prior to the budiodarone therapy.

73. 70. The pharmaceutical composition of claim 69, wherein the inhibition for the patient converts the patient from paroxysmal AFib to sinus rhythm as confirmed by the monitored cardiac rhythm data of the patient.

74. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of progression to permanent atrial fibrillation (AFib) in a patient with persistent AFib, comprising: the patient is eligible for and responsive to budiodarone therapy at an initial dose of budiodarone; the patient's cardiac rhythm data is monitored for a period of at least six months to confirm continued response to the budiodarone therapy; if during said monitoring said patient becomes non-responsive to said initial dose, then said dose of budiodarone is increased to a higher dose and said pharmaceutical composition is administered until said patient becomes responsive to budiodarone therapy at said higher dose, or else said budiodarone therapy is maintained at said initial dose; and The pharmaceutical composition, wherein the patient's cardiac rhythm data is monitored to confirm that the patient has been prevented from progressing from paroxysmal to persistent AFib or from persistent AFib to permanent AFib.

75. 75. The pharmaceutical composition of claim 74, wherein the patient is refractory to one or more prior methods of treating AFib.

76. 75. The pharmaceutical composition of claim 74, wherein the patient's cardiac rhythm data is monitored continuously or semi-continuously.

77. 75. The pharmaceutical composition of claim 74, wherein the patient is eligible based on having an AFib burden of at least 2.5% plus at least one prolonged AFib episode over a period of about 4 weeks prior to the budiodarone therapy.

78. 75. The pharmaceutical composition of claim 74, wherein the inhibition in the patient converts the patient from persistent AFib to paroxysmal AFib or sinus rhythm as confirmed by the patient's monitored cardiac rhythm data.

79. 1. A method for aiding in the assessment of whether a patient with either paroxysmal or persistent atrial fibrillation (AFib) is eligible for budiodarone therapy, comprising: a) obtaining data from a wearable attached to the patient, wherein the patient is suffering from paroxysmal AFib or persistent AFib, and wherein the wearable comprises: i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the patient's cardiac rhythm when the wearable is attached to the patient; ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; and iii) a transmitting component configured to transmit data based on the cardiac rhythm data in the first computing device to a second computing device accessible to a clinician; b) the presence of prolonged AFib episodes, absence of prolonged AFib episodes, Number of prolonged AFib episodes, or degree of AFib burden, transmitting the data indicative of at least one of: c) determining, based in part on data collected over a period of at least two weeks during which the patient was not receiving budiodarone therapy, at least one of the baseline number of prolonged AFib episodes experienced by the patient over that period and / or the patient's baseline AFib burden over that period; d) providing the result of the determination in step c) as an indication for qualifying the patient for budiodarone therapy based on a determination that at least one of the baseline number of prolonged AFib episodes and / or the baseline AFib burden meets at least one of a threshold number of prolonged AFib episodes and / or a threshold AFib burden; and e) continuously or semi-continuously monitoring data on the number of prolonged AFib episodes and / or AFib burden after initiating budiodarone therapy from a wearable attached to said patient; A method comprising:

80. 80. The method of claim 79, wherein the first computing device is configured to determine data based on the cardiac rhythm data by assessing the stored cardiac rhythm data to determine the presence and number of long AFib episodes.

81. 81. The method of claim 80, wherein said assessment is continuous over said period of time.

82. 81. The method of claim 80, wherein said assessment is semi-continuous over said period of time.

83. 80. The method of claim 79, wherein the first computing device is programmed to alert at least one of the clinician or the patient based on the data that a prolonged AFib episode has been detected that places the patient at risk for stroke.

84. the period during which the patient has not received budiodarone therapy is at least 30 days in duration; and The patient is eligible for budiodarone therapy if, based on data collected over the period, the patient meets the following criteria: a) at least one AFib episode of at least 5 hours in a 30-day period, or at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 2.5% in said 30-day period; b) at least one AFib episode of at least 5 hours in a 30-day period or at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 5% in said 30-day period; c) at least one AFib episode of at least 5 hours in a 30-day period plus an AFib burden of at least 2.5% in said 30-day period; d) at least one AFib episode of at least 5 hours in a 30-day period plus an AFib burden of at least 5% in said 30-day period; e) at least two AFib episodes of at least one hour in a 30-day period plus an AFib burden of at least 2.5% in that 30-day period; or f) at least two AFib episodes of at least 1 hour in a 30-day period plus an AFib burden of at least 5% in said 30-day period; 80. The method of claim 79, comprising determining that at least one of:

85. the wearable is one or more of a patch, watch, wristband, strap, ring, or device that adheres to the body when worn; and the wearable is configured to measure a cardiac rhythm and transmit cardiac rhythm data directly or indirectly to the second computing device; 80. The method of claim 79.

86. 80. The method of claim 79, wherein the patient is refractory to one or more other methods of treating AFib.

87. 80. The method of claim 79, wherein a prolonged AFib episode is defined as an AFib episode lasting at least 5 hours.

88. 80. The method of claim 79, wherein the patient is selected from among a plurality of candidate patients on the basis of suffering from paroxysmal or persistent AFib.

89. 1. A method for aiding in the assessment of whether a patient with either paroxysmal or persistent atrial fibrillation (AFib) is eligible for budiodarone therapy with cardiac rhythm monitoring, comprising: a) obtaining data from a wearable attached to the patient, wherein the patient is suffering from paroxysmal AFib or persistent AFib, and wherein the wearable comprises: i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the patient's cardiac rhythm when the wearable is attached to the patient; and ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; b) the presence of prolonged AFib episodes, absence of prolonged AFib episodes, Number of prolonged AFib episodes, or degree of AFib burden, transmitting the data indicative of at least one of the following to a second computing device accessible to a clinician; c) determining, based on data collected over a period of at least two weeks during which the patient was not receiving budiodarone therapy, at least one of the patient's baseline number of prolonged AFib episodes experienced over that period and / or the patient's baseline AFib burden over that period; and d) providing the result of the determination in step c) as an indication for qualifying the patient for future budiodarone therapy with non-invasive cardiac rhythm monitoring based on a determination that at least one of the baseline number of prolonged AFib episodes and / or the baseline AFib burden meets at least one of a threshold number of prolonged AFib episodes and / or a threshold AFib burden; A method comprising:

90. 1. A method for aiding in the assessment of whether a patient with either paroxysmal or persistent atrial fibrillation (AFib) is eligible for budiodarone therapy with cardiac rhythm monitoring, comprising: a) obtaining data from a wearable attached to the patient, wherein the patient is suffering from paroxysmal AFib or persistent AFib, and wherein the wearable comprises: i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the patient's cardiac rhythm when the wearable is attached to the patient; and ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; b) the presence of prolonged AFib episodes, absence of prolonged AFib episodes, Number of prolonged AFib episodes, or degree of AFib burden, transmitting the data indicative of at least one of the following to a second computing device accessible to a clinician; c) determining the baseline number of prolonged AFib episodes experienced by the patient over a period of at least two weeks during which the patient was not receiving budiodarone therapy, based on data collected over that period; and d) providing the result of the determination in step c) as an indication for qualifying the patient for future budiodarone therapy with non-invasive cardiac rhythm monitoring based on a determination that the baseline number of prolonged AFib episodes meets a threshold number of prolonged AFib episodes; A method comprising:

91. 1. A method for aiding in the assessment of whether a patient with either paroxysmal or persistent atrial fibrillation (AFib) is eligible for budiodarone therapy with cardiac rhythm monitoring, comprising: a) obtaining data from a wearable attached to the patient, wherein the patient is suffering from paroxysmal AFib or persistent AFib, and wherein the wearable comprises: i) at least one of an electrode or an optical sensor configured to continuously or semi-continuously monitor the patient's cardiac rhythm when the wearable is attached to the patient; and ii) a first computing device configured to collect and store cardiac rhythm data based on the monitored cardiac rhythm; b) the presence of prolonged AFib episodes, absence of prolonged AFib episodes, Number of prolonged AFib episodes, or degree of AFib burden, transmitting the data indicative of at least one of the following to a second computing device accessible to a clinician; c) determining the patient's baseline AFib burden over a period of at least two weeks based on data collected over that period during which the patient was not receiving budiodarone therapy; and d) providing the result of the determination in step c) as an indication for qualifying the patient for future budiodarone therapy with non-invasive cardiac rhythm monitoring based on a determination that the baseline AFib burden meets a threshold AFib burden; A method comprising:

92. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of a patient diagnosed with paroxysmal AFib or persistent AFib experiencing heart failure, comprising: A patient identified as having either paroxysmal or persistent AFib and having an AFib burden of at least 2.5% plus at least one prolonged AFib episode lasting about 1 hour over a 4-week period is administered a dose of the pharmaceutical composition, the effectiveness of administration of said dose is monitored, and if said monitoring indicates that administration of said dose is not effective, said dose is adjusted to reduce the number of prolonged AFib episodes lasting at least about 1 hour during a 4-week monitoring period beginning at least 3 days after initiation of administration of said dose, thereby reducing the risk of said patient experiencing heart failure; and monitoring of the patient is maintained to ensure continued effectiveness of the pharmaceutical composition; Pharmaceutical compositions.

93. 93. The pharmaceutical composition of claim 92, wherein adjusting the dose comprises adjusting the dose amount to a maximum dose based on the monitoring, and wherein the administration is stopped when the monitoring indicates that administration of the maximum dose is not effective.

94. 93. The pharmaceutical composition of claim 92, wherein said dose adjustment comprises adjusting said dose to eliminate prolonged AFib episodes lasting at least about 1 hour.

95. 93. The pharmaceutical composition of claim 92, wherein said dose adjustment comprises adjusting said dose to reduce the number of prolonged AFib episodes lasting at least about 6 minutes over said 4-week monitoring period.

96. 93. The pharmaceutical composition of claim 92, wherein the dose adjustment comprises adjusting the dose to reduce the AFib burden to about 3% or less over a one week period.

97. 93. The pharmaceutical composition of claim 92, wherein the monitor comprises continuous or semi-continuous monitoring of the patient's cardiac rhythm data via a wearable device.

98. 98. The pharmaceutical composition of claim 97, wherein the monitoring continues for at least six months.

99. 93. The pharmaceutical composition of claim 92, wherein the 4-week monitoring period begins at least 14 days after initiation of administration of the dose.

100. 93. The pharmaceutical composition of claim 92, wherein the dose adjustment to reduce either or both of AFib burden and long-term AFib is based on the patient's risk level for experiencing heart failure.

101. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of stroke in patients diagnosed with paroxysmal AFib or persistent AFib, A patient identified as having either paroxysmal or persistent AFib, with an AFib burden of at least 2.5% plus at least one prolonged AFib episode lasting about 1 hour during a 4-week period, is administered a dose of the pharmaceutical composition, the effectiveness of administration of said dose is monitored, and if said monitoring indicates that administration of said dose is not effective, said dose is adjusted as necessary to reduce the number of prolonged AFib episodes lasting at least about 1 hour during a 4-week monitoring period beginning at least 3 days after initiation of administration of said dose, thereby reducing the risk of stroke in said patient; and The patient is monitored to ensure continued efficacy of budiodarone; Pharmaceutical compositions.

102. 102. The pharmaceutical composition of claim 101, wherein adjusting the dose comprises adjusting the dose amount to a maximum dose based on the monitoring, and wherein administration of the budiodarone is stopped when the monitoring indicates that administration of the maximum dose is not effective.

103. 102. The pharmaceutical composition of claim 101, wherein adjusting the dose comprises adjusting the dose to eliminate prolonged AFib episodes lasting at least about 1 hour.

104. 102. The pharmaceutical composition of claim 101, wherein adjusting the dose comprises adjusting the dose to reduce the number of prolonged AFib episodes lasting at least about 6 minutes.

105. 102. The pharmaceutical composition of claim 101, wherein the dose adjustment comprises adjusting the dose to reduce the AFib burden to about 3% or less over a one week period.

106. 102. The pharmaceutical composition of claim 101, wherein the monitor comprises continuous or semi-continuous monitoring of the patient's cardiac rhythm data.

107. 107. The pharmaceutical composition of claim 106, wherein the monitoring continues for at least six months.

108. 102. The pharmaceutical composition of claim 101, wherein the 4-week monitoring period begins at least 14 days after initiation of administration of the dose.

109. 102. The pharmaceutical composition of claim 101, wherein the dose adjustment to reduce the number of prolonged AFib episodes lasting at least 1 hour is based on the patient's risk level of experiencing a stroke.

110. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of a patient diagnosed with paroxysmal AFib or persistent AFib experiencing heart failure, comprising: A patient identified as having either paroxysmal or persistent AFib and having an AFib burden of at least 2.5% plus at least one prolonged AFib episode lasting about 1 hour over a 4-week period is administered a dose of the pharmaceutical composition, the effectiveness of administration of said dose is monitored, and if said monitoring indicates that administration of said dose is not effective, said dose is adjusted to reduce the number of prolonged AFib episodes lasting at least about 1 hour during a 4-week monitoring period and to reduce the risk of said patient experiencing heart failure; and monitoring of the patient to ensure continued effectiveness of the pharmaceutical composition is maintained for at least six months; Pharmaceutical compositions.

111. 1. A pharmaceutical composition comprising budiodarone for reducing the risk of stroke in patients diagnosed with paroxysmal AFib or persistent AFib, A patient identified as having either paroxysmal or persistent AFib and having an AFib burden of at least 2.5% plus at least one prolonged AFib episode lasting about 1 hour over a 4-week period is administered a medicament comprising the pharmaceutical composition at a dose of budiodarone, the effectiveness of administration of said dose is monitored, and if said monitoring indicates that administration of said dose is not effective, said dose is adjusted as needed to reduce the number of prolonged AFib episodes lasting at least about 1 hour during a 4-week monitoring period and reduce the risk of stroke in said patient; and monitoring of the patient to ensure continued effectiveness of the pharmaceutical composition is maintained for at least six months; Pharmaceutical compositions.

Images