WO2008066745A9

WO2008066745A9 - Prophlyaxis and treatment of atrial fibrillation with omega-3 fatty acids

Info

Publication number: WO2008066745A9
Application number: PCT/US2007/024283
Authority: WO
Inventors: Robert A Shalwitz; Roelof M L Rongen
Original assignee: Reliant Pharmaceuticals Inc; Robert A Shalwitz; Roelof M L Rongen
Priority date: 2006-11-22
Filing date: 2007-11-21
Publication date: 2008-08-28
Also published as: JP2010510313A; WO2008066745A1; EP2099295A4; EP2099295A1

Abstract

The present invention relates, generally, to methods of treatment and prophylaxis of atrial fibrillation in a subject, utilizing omega-3 fatty acids in a loading dose and thereafter in a maintenance dose.

Description

PROPHLYAXIS AND TREATMENT OF ATRIAL FIBRILLATION WITH

OMEGA-3 FATTY ACIDS

Field of the Invention

[0001] The present invention relates, generally, to methods of treatment and prophylaxis of atrial fibrillation in a subject, utilizing omega-3 fatty acids in a loading dose and thereafter in a maintenance dose. Description of the Related Art

[0002] Atrial fibrillation is one of the most common cardiac arrhythmias in humans, and it accounts for approximately one-third of hospitalizations for cardiac rhythm disturbance. It is estimated that two to three million people in America have this condition, and billions of dollars are spent on diagnosis and treatment. In addition, half a million new cases are diagnosed every year. [0003] Atrial fibrillation is a rhythm disturbance of the atria characterized by rapid, uncoordinated contractions resulting from abnormal electrical discharges in the heart. This results in a reduced ability of the atria to pump blood into the ventricles and often a pooling of blood occurs in parts of the atria. The stagnation of blood can result in the formation of clots, which can then travel through the blood vessels and cause blockage. Atrial fibrillation may increase the risk of stroke, ventricular arrhythmias, need for pacemaker therapy, and use of potentially harmful drugs.

[0004] Most people with atrial fibrillation have an underlying chronic cardiovascular condition, such as high blood pressure, coronary artery disease, or diseases of the heart valves or the heart muscle. However, atrial fibrillation can be caused by an acute reversible event such as the intake of certain drugs, physical or psychological stress, myocardial infarction, pericarditis, hyperthyroidism, or pulmonary embolism. Atrial fibrillation is also commonly developed after surgery, such as heart, thoracic, abdominal, hip, and other surgeries and procedures. In fact, atrial fibrillation is the most common complication after coronary artery bypass graft (CABG) surgery. There is a 10 - 15% incidence in this setting, and it is also manifested more commonly in the elderly.

[0005] Treatment options for atrial fibrillation include pharmacological and non- pharmacological methods. Pharmacological treatments include drugs which decrease the heart rate, such as digoxin, beta blockers, and calcium channel blockers. Anticoagulants such as warfarin may also be used to decrease the risk of clot formation associated with atrial fibrillation. Electrical cardioversion and chemical cardioversion with drugs such as sotalol, amiodarone, propafenone, fleicanide, disopyramide, and dofetilide are often performed to restore and maintain a normal sinus rhythm.

[0006] Recent studies have shown that consumption of fish is associated with reduced rates of atrial and ventricular arrhythmias and sudden death. While the mechanisms underlying this association are not completely understood, researchers believe that the antiarrhythmic effects are caused by the long-chain n-3 fatty acids, eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), which are abundant in fish and fish oils.

[0007] One form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA is sold under the trademark LOVAZA™. Such a form of omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, each incorporated herein by reference.

[0008] In a study by Jahangiri et al., isoproterenol-induced asynchronous contractions in rat atrial myocytes ceased upon administration of n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Jahangiri A. et al., Termination of asynchronous contractile activity in rat atrial myocytes by n-3 polyunsaturated fatty acids. MoI. Cell. Biochem. 2000; 206:33-41.

[0009] In a prospective epidemiological study of adults > 65 years by Mozaffarian et al., consumption of tuna or other broiled or baked fish was showed be inversely associated with incidence of atrial fibrillation. Mozaffarian D. et al., Fish intake and risk of incident atrial fibrillation. Circulation. 2004; 110:368-373.

[0010] In a study by Biscione et al., 40 patients with implanted pacemakers who presented with episodes of atrial tachyarrhythmia (AT) were administered 1 gram of polyunsaturated fatty acids as a single dose (eicosapentanoic and docosahexaenoic acid in a quantity not less than 850 mg and in a ratio of 0.9-1.5, respectively) every day for four months. The four month treatment period was preceded by a four month pretreatment period and followed by a four-month withdrawal period. The study showed that in the first four months, the number of pretreatment AT episodes was on average 444±1161 and the AT burden was 3.89%. During the treatment period, the number of AT episodes was decreased by 59% (p=0.037) to 181 ±436 (-59%, p=0.037) and the AT burden was decreased by 67% (p=0.065) to 1.06%. During the withdrawal period, the number of episodes of AT rose to 552±1717 and the total AT burden rose to 2.69%. Biscione F et al., Effetti degli acidi grassi omega-3 nella prevenzione delle aritmie atriali (Effects of omega-3 fatty acids in the prevention of atrial arrhythmia), ltal Heart J Suppl. 2005; 6(1):53-59. [0011] In a randomized, controlled clinical trial conducted by CaIo et al., individuals with normal sinus rhythm who underwent coronary artery bypass surgery (CABG) were treated with either a combination of EPA and DHA or a placebo for at least five days before CABG and until the day of hospital discharge. The dose of EPA and DHA both before and after surgery was 2 g/day. Postoperative atrial fibrillation developed in 33.3% of the subjects who were administered the placebo, compared to 15.2% of subjects who were administered EPA and DHA. In the CaIo et al. clinical trial, the subjects received a constant dose of 2 g/day, and there was no administration of a loading dose or bolus dose to help achieve steady state concentration of the PUFAs more quickly. CaIo L et al., N-3 Fatty Acids for the Prevention of Atrial Fibrillation After Coronary Artery Bypass Surgery. J Am Coll Cardiol. 2005; 45:1723-8. [0012] The use of a loading dose is often used when the time to reach steady state concentrations is appreciable, or when therapeutic levels must be achieved rapidly. The loading dose is used to "load" or "fill up" the volume of distribution with the drug. The volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration in the plasma. It describes the drug's ability to distribute over the body from the blood to the tissues. The time required for the drug to accumulate in the body is referred to as the drug's half-life. More specifically, the half-life of a drug is the time it takes for the plasma concentration of a drug to reach half of its original concentration at time zero, and it often helps to determine whether there is a need to provide a loading dose. One study by Katan et al. found that the mean half-life of EPA and DHA into plasma cholesteryl esters as fatty acids was 4.8 days and 10.3 days, respectively. The same study found that the mean half-life of EPA and DHA in erythrocytes as fatty acids was 28.1 days and 38.5 days, respectively. Katan et al., Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. J. Lipid Res. 1997; 38:2012-2022. It should be noted that the kinetics of omega-3 fatty acids are not classical and that free EPA, DHA, and/or ethyl esters thereof are not present in the blood in amounts anywhere near the relative amount ingested. Omega-3 fatty acids tend to be metabolized extensively in first pass in the liver for presentation and/or utilization in a broad range of biologically useful forms. As the kinetics of EPA and DHA are not classical (for example, the kinetics are dependent on the form of EPA and DHA and the location, such as erythrocyte membrane, serum cholesteruyl esters, adipose tissue), Katan et al. does not disclose establishing therapeutic levels of omega-3 fatty acids at an early point in therapy.

[0013] It is not always feasible or useful to give subjects a loading dose. Some agents have substantial or sometimes severe side effects when given to subjects in a high volume in a short time. Other agents have active metabolites which can only be developed by rate limited metabolic pathways. Yet other agents may have slow systemic onset of action regardless of initial doses.

[0014] It is described in the literature that omega-3 fatty acids have anti- coagulatory effects which may have negative interactions with other active agents (for example, warfarin) or may potentially increase bleeding risk during or after surgery or other procedures. See, for example, Buckley et al., Ann

Pharmacother. January 2004; 38(1):50-52.

[0015] In addition, it is not known which form, metabolite, or physical location of

EPA and/or DHA is causing anti-arrhythmic activity post-surgery.

[0016] DHA and EPA may have a beneficial effect in both the prophylaxis and treatment of atrial fibrillation. Consequently, there is a need in the art for a therapeutic regimen that includes the administration of DHA and EPA before a procedure which is known to be associated with the risk of atrial fibrillation, or at the beginning of more long-term treatment of atrial fibrillation. In addition, because of the long half-life of DHA and EPA and the length of time required to reach steady state concentrations of the drugs, it is desirable to achieve high levels of omega-3 fatty acids in the body as rapidly as possible for the most effective treatment.

Summary of the Invention

[0017] Embodiments of the present invention address the above-mentioned need for a therapeutic regimen for the treatment and prophylaxis of atrial fibrillation, which achieves therapeutic levels of omega-3 fatty acids at an early point in therapy.

[0018] One embodiment of the present invention is a method of treating or preventing atrial fibrillation in a subject, the method comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter in a maintenance dose amount, wherein the loading dose amount is about twice the maintenance dose amount or more.

[0019] Another embodiment of the present invention is a method of preventing atrial fibrillation in a subject after an interventional procedure, the method comprising administering an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days before or immediately after the interventional procedure, and thereafter in a maintenance dose amount after the interventional procedure, wherein the loading dose amount is about twice the maintenance dose amount or more.

[0020] Another embodiment of the invention is a method of treating atrial fibrillation in a subject, the method comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter a maintenance dose amount, wherein the amount of the loading dose is about twice the maintenance dose amount or more.

[0021] The goal of such therapy is the reduction of atrial fibrillation time or occurrences in these subjects. One such group of individuals with atrial fibrillation who would benefit from this therapy is patients with pacemakers for conditions such as atrioventricular node dysfunction and block, sinus node dysfunction, sinoatrial bradycardia disease, bradytachycardia syndrome, cardiac decompensation, chronic heart failure, chronic bifascicular and trifascicular block, hypertrophic obstructive cardiomyopathy, idiopathic dilated cardiomyopathy, long-QT syndrome, hypersensitive carotid sinus, and neurocardiogenic syncope. Detailed Description

[0022] The present invention relates to methods of treatment and prophylaxis of atrial fibrillation, utilizing omega-3 fatty acids in a loading dose and thereafter in a maintenance dose.

[0023] "Atrial fibrillation" refers to a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function, as discussed in the ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation (J Am Coll Cardiol. 2001. 38(4):1266i-1266lxx). Atrial fibrillation is characterized on an electrocardiogram (ECG) by the replacement of consistent P waves by rapid oscillations or fibrillatory waves that vary in size, shape, and timing, associated with an irregular, frequently rapid ventricular response when atrioventricular (AV) conduction is intact. Examples of different types of atrial fibrillation are acute, chronic, paroxysmal, intermittent, constant, persistent, and permanent. [0024] As used herein, the term "loading dose" refers to an initial dose given at the start of therapy. The term "maintenance dose" refers to the dose given after the loading dose or doses. In the presently claimed invention, the loading dose can be about twice the maintenance dose or more.

[0025] In one embodiment of the present invention, the loading dose of omega-3 fatty acids can be 1.5 to 8 times the maintenance dose. In a preferred embodiment, the loading dose of omega-3 fatty acids can be 2 to 10 grams/day. [0026] In one embodiment of the invention, the maintenance dose can be 1 to 4 grams/day.

[0027] The "loading dose period" is the amount of time in which the loading dose is administered. The "maintenance dose period" is the amount of time in which the maintenance dose is administered. In one embodiment of the presently claimed invention, the loading dose period can be 1 to 30 days, followed by a maintenance dose period. In a preferred embodiment, the loading dose period can be 1 to 14 days, most preferred 1 to 7 days, followed by the maintenance dose period.

[0028] In some preferred embodiments the omega-3 fatty acids comprise Lovaza™ omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, hereby incorporated by reference. In other preferred embodiments the omega-3 fatty acids are present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition. In still other preferred embodiments the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition. Preferably, the EPA and DHA are in a weight ratio of EPA:DHA of from 99:1 to 1:99, preferably from 1 :4 to 4:1 , more preferably from 1 :3 to 3:1 , and most preferably from 1 :2 to 2:1. The omega-3 fatty acids may also comprise pure EPA or pure DHA.

[0029] As used herein, the term "omega-3 fatty acids" includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811 , each hereby incorporated by reference), precursors or salts thereof and mixtures thereof. Examples of omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long- chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. The omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates. Commercial examples of omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251 , F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway). [0030] Another preferred composition includes omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight. Preferably, the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention.

[0031] The omega-3 fatty acids can be present in an amount from about 300 mg to about 10 grams, more preferably about 500 mg to about 6 grams, and most preferably from about 750 mg to about 4 grams. This amount may be in one or more dosage forms, preferably one dosage form. The omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same. [0032] The most preferred form of omega-3 fatty acids is LOVAZA™ omega-3 fatty acids (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):

[0033] The active ingredients of the present invention, omega-3 fatty acids, may be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients"). Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.

[0034] Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils. The use of surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical art, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.

[0035] In some preferred embodiments, the omega-3 fatty acids may be administered in a loading dose amount for a loading dose period prior to an interventional procedure. Examples of such interventional procedures include coronary arterial bypass graft (CABG) surgery, aortic valve replacement, mitral valve replacement, balloon angioplasty, thoracic surgery, abdominal surgery, hip surgery, and other surgeries and procedures. In a preferred embodiment, the interventional procedure can be CABG surgery.

[0036] In some preferred embodiments, the omega-3 fatty acids may be administered with other pharmaceutical compounds. These pharmaceutical compounds may include cardiovascular drugs. Examples include antiarrhythmics of Type IA (such as disopyramide, procainamide, and quinidine), Type 1 B (such as tocainide, lidocaine, and mexiletine), Type 1 C (such as flecainide, moricizine, propafenone, and indecainide), Type Il (beta blockers such as atenolol, propranolol, and esmolol), Type III (such as amiodarone, bretylium, dofetilide, ibutilide, and sotalol), and Type IV (calcium channel blockers such as verapamil and diltiazem). Further, digoxin, anticoagulants (such as warfarin and heparin), and antiplatelet agents (such as aspirin, ticlopidine, and clopidogrel) may be administered. [0037] Throughout this application, various patents and publications have been cited. The disclosures of these patents and publications in their entireties are hereby incorporated by reference into this application, in order to more fully describe the state of the art to which this invention pertains. [0038] The invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure.

[0039] While the present invention has been described for what are presently considered the preferred embodiments, the invention is not so limited. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the detailed description provided above.

Claims

Claims:

1. A method of treating or preventing atrial fibrillation in a subject comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter in a maintenance dose amount, wherein the loading dose amount is about twice the maintenance dose amount or more.

2. The method of claim 1 , wherein the amount of the loading dose is 1.5 to 8 times the amount of the maintenance dose.

3. The method of claim 1 , further comprising administering one or more additional antiarrhythmic agents.

4. The method of claim 1 , wherein the loading dose period is from 1 to 7 days.

5. The method of claim 1 , wherein the amount of loading dose is 1.5 to 10 grams per day.

6. The method of claim 1 , wherein the maintenance dose is 750 mg to 4 grams per day.

7. A method of preventing atrial fibrillation in a subject after an interventional procedure comprising administering an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days before or immediately after the interventional procedure, and thereafter in a maintenance dose amount after the loading dose episode, wherein the loading dose amount is about twice the maintenance dose amount or more.

8. The method of claim 7, wherein the amount of the loading dose is 1.5 to 8 times the amount of the maintenance dose.

9. The method of claim 7, further comprising administering one or more additional antiarrhythmic agents.

10. The method of claim 7, wherein the loading dose period is from 1 to 7 days.

11. The method of claim 7, wherein the amount of loading dose is 1.5 to 10 grams per day

12. The method of claim 7, wherein the maintenance dose is 750 mg to 4 grams per day.

13. The method of claim 7, wherein the interventional procedure is one or more of coronary artery bypass graft (CABG) surgery, aortic valve replacement, mitral valve replacement, balloon angioplasty, thoracic surgery, abdominal surgery, hip surgery, and other surgeries and procedures.

14. The method of claim 7, wherein the omega-3 fatty acids are administered in the loading dose amount before and immediately after the interventional procedure.

15. A method of treating atrial fibrillation in a subject comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter in a maintenance dose amount, wherein the loading dose amount is about twice the maintenance dose amount or more.