201200131 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種決奈達隆（dronedarone)於製備用於預 防患有永久性心房纖維性顫動之患者的心血管疾病住院或 死亡或心金管事件（尤其係中風、急性冠心症或心血管死 亡）的藥物之用途。 【先前技術】 2-正丁基-3-[4-(3-二正丁基胺基丙氧基）苯甲醯基]·5_τ 磺醢胺基苯并呋喃或決奈達隆（dr〇nedar〇ne)及其醫藥上可 接受的鹽係描述於歐洲專利案EP 〇 471 609 B 1中。 決奈達隆係影響4弓、舒、及納通道之多通道阻斷劑且具 有抗腎上腺素性》 決奈達隆係用於治療具有心房纖維性顫動或心房撲動史 之患者之抗心律不齊劑。 心房纖維性顫動（AF)影響約23〇萬北美人及45〇萬歐盟 人’且因為人口老齡化’正成為日益嚴重的公眾健康問 題。 AF係其中上心室以不協調及無組織方式跳動之病症， 其造成極不規則且快速的心律（即，不規則心跳）。當血液 自心室不完全泵出時，其可淤積並凝結。如果血液凝塊 在心房中形成’退出心臟，並阻斷大腦中的動脈，則導致 中風。因此，約1 5〇/0之令風係由於AF所致。但是，中風亦 可使其他病症（例如高血壓）複雜化。此外，出血性中風可 係利用避免血栓形成（尤其係在患有af之患者中）之處方抗 155857.doc 201200131 凝血劑進行治療的併發症。 AF隨著年齡的增長曰益頻繁，且經常係由與年齡相關 之心臟變化、身體或心理壓力、刺激心臟的藥劑（如咖啡 因）引起，或係由於心血管疾病。預期在未來2〇年内，患 者數量將增加一倍。如果無適當管理，則AF可導致嚴重的 併發症，如中風及充血性心臟衰竭。 由於大部份研究並未評估與心房纖維性顫動相關之併發 症（如中風），因此抗心律不齊藥物對該等評估指標之作用 係未知（Cochrane Collaboration，The Cochrane Library， 2008, 2) ° 此外，包括AF患者之抗心律不齊藥物之兩項大型研究 (AFFIRM (D.G. Wyse等人，The New England Journal of201200131 VI. Description of the Invention: [Technical Field] The present invention relates to a dronedarone for preparing a cardiovascular disease hospitalization or death or a heart tube for preventing a patient suffering from permanent atrial fibrillation The use of drugs for events (especially stroke, acute coronary heart disease or cardiovascular death). [Prior Art] 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzylidene]·5_τ sulfonylaminobenzofuran or dronedarone (dr〇 Nedar〇ne) and its pharmaceutically acceptable salts are described in European Patent No. EP 471 609 B1. The dronedarone affects the multi-channel blockers of 4 bow, sputum, and nanochannels and has anti-adrenalin. The dronedarone is used to treat anti-arrhythmia in patients with a history of atrial fibrillation or atrial flutter. Qi agent. Atrial fibrillation (AF) affects approximately 230,000 North Americans and 450,000 EU people 'and because the population is aging' is becoming a growing public health problem. The AF system is a condition in which the upper ventricle beats in an uncoordinated and unorganized manner, which causes a very irregular and rapid heart rhythm (i.e., irregular heartbeat). When blood is not completely pumped out of the ventricle, it can accumulate and condense. If a blood clot forms in the atria, exiting the heart and blocking the arteries in the brain, it causes a stroke. Therefore, the wind system of about 15 〇 / 0 is due to AF. However, stroke can complicate other conditions, such as high blood pressure. In addition, hemorrhagic stroke can be used to prevent thrombosis (especially in patients with af). 155857.doc 201200131 Complications for treatment with coagulants. AF increases frequently with age and is often caused by age-related changes in the heart, physical or psychological stress, agents that stimulate the heart (such as caffeine), or cardiovascular disease. It is expected that the number of patients will double in the next two years. If not properly managed, AF can cause serious complications such as stroke and congestive heart failure. Since most studies have not evaluated complications associated with atrial fibrillation (such as stroke), the role of antiarrhythmic drugs in these assessments is unknown (Cochrane Collaboration, The Cochrane Library, 2008, 2) ° In addition, two large studies of antiarrhythmic drugs in patients with AF (AFFIRM (DG Wyse et al., The New England Journal of
Medecine，2002，第 347卷，第 1825 至 1833 頁）及 af_chf(d.Medecine, 2002, vol. 347, pp. 1825 to 1833) and af_chf(d.
Roy等人，The New England Journal of Medecine，2008， 第358卷，第2667至2677頁））顯示速率及心律組之間的中風 率無顯著差異（在心律組中所建議之抗心律不齊藥物主要 係胺蛾酮（amiodarone))。 血栓栓塞事件（包括中風）係患有心房纖維性顫動之患者 之主要併發症。尚未完全瞭解此等血栓栓塞事件之病因。 根據主要假設，心房纖維性顫動導致心房中之血瘀，其促 使血液凝塊形成，且如果血液凝塊到達全身循環，則由此 引起血栓栓塞事件，如中風。因此，認為預防心房纖維性 顫動或抗凝可預防血栓栓塞事件及中風。大量臨床研究已 證實，適當的抗凝可預防血栓栓塞事件（包括中風）(Fuster 155857.doc 201200131 等人）。然而，所有使用抗心律不齊藥物之隨機臨床試驗 儘管有效地維持心律控制或治療組中之竇性心律，但並未 顯示中風發病率的下降。 舉例而言’在AFFIRM試驗中，wyse等人比較心律控制 (63〇/〇胺碘_及41〇/。索他洛爾（s〇tal〇1)係最常用的抗心律不 齊藥物）與速率控制方法。如Wyse等人之文章中之表3所 示’儘管相比於速率控制組（35%)，心律控制組中更高數 量之患者（63%)在5年後維持竇性心律，但是中風或TIA之 發病率在心律控制組（80/2033)與速率控制組（77/2〇27)中類 似。 在STAF試驗中’ Carlsson等人比較心律控制（42%胺蛾 嗣）與速率控制方法。如Carlsson等人之文章中之表2所 示’儘管在該研究結束時’相比於速率控制組，心律控制 組中具有竇性心律之患者極顯著地絕對增加29〇/0，但是中 風或TIA之發病率數值係心律控制組（5/1 〇〇)高於速率控制 組（1/100)。 在HOT CAF6中’ Opolski等人比較速率及心律控制方 法。如Opolski等人之文章之表2中所示，在心律控制組 中’ 3/104個患者於後續期間罹患中風，而在速率控制組 中為0/101個。 在J-RHYTHM試驗中，〇gawa等人比較心律控制（85%之 患者係使用I類抗心律不齊藥物）與速率控制方法。如 Ogawa等人之文章之表3中所示，儘管在3年内，相比於速 率控制組’心律控制組中具有竇性心律之患者極顯著地絕 155857.doc 201200131 對增加29%，但是心律控制組（9/419)與速率控制組 (11/404)相比之症狀性中風之發病率係類似。 在SAFE-T試驗中，Singh等人比較用於治療患有持續性 心房纖維性顫動之患者之胺碘酮、索他洛爾及安慰劑。胺 碘酮及索他洛爾在增加心房纖維性顫動復發之時間上比安 慰劑顯著更有效（一廣泛使用的心律控制措施）(P<〇 〇〇1)。 在意向治療分析中，胺峨酮有效性係索他洛爾的六倍 (Ρ<0·001)’且在根據實際接受之治療之分析中，胺埃酮有 效性係索他洛爾的四倍（ρ<(Κ〇〇1"儘管存在此有效的心律 控制，但在所有組中，每100名患者中之後續數年之中風 數量係類似：對於胺碘酮而言係2 〇6(嚴重），對於索他洛 爾而言係2.71，且對於安慰劑而言係191，在安慰劑組中 觀察到最低的速率，且其具有最高之心房纖維性顫動復發 率（自第1866頁最後一段的末尾處算得）。 因此，根據相關技術目前的知識，投與用於預防心房纖 維性顫動之藥物不能被視為意味著預防中風。出乎意料 地，在ATHENA試驗（H〇hnl〇ser等人）中，決奈達隆已顯示 其可減少中風發病率。現在使用決奈達隆所觀察到之效果 並非單獨基於〜律控制，而是基於決奈達隆性質之獨特組 合，其包括（但不限於）：有效的心律控制、降低心率之效 果、降血壓效果（血管擴張劑作用）、對内皮功能之直接作 用及其他性質。 【發明内容】 本發明者現已在臨床上證明，決奈達隆⑷抓咖〇ne)降 低患有永m纖維性顫動之患者㈣血管疾病住院或 I55857.doc 201200131 死亡及心血管事件（如中風、急性冠心病或心血管死亡）之 發生率’而其他抗心律不齊化合物不顯示此作用。 本發明之標的物係決奈達隆或其一種醫藥上可接受的鹽 於製備用於患有永久性心房纖維性顫動之患者的藥物之用 途。 本發明之標的物係決奈達隆或其一種醫藥上可接受的鹽 於製備用於預防患有永久性心房纖維性顫動之患者的心血 管疾病住院及/或死亡的藥物之用途。 本發明之標的物亦係決奈達隆或其一種醫藥上可接受的 鹽於製備用於預防患有永久性心房纖維性顫動之患者的心 血管事件的藥物之用途。 患有「永久性心房纖維性顫動或撲動」之患者係指在投 與決奈達隆或其醫藥上可接受的鹽之整個週期中患有af或 AFL之患者。該等患者在投與決奈達隆或其醫藥上可接受 的鹽之整個週期中具有此心律（即，AF或AFL)之全部預期 心電圖（ECG) » 〜企官事件可定義為中風、急性冠心症（ACS)或心血管 死亡。 急性冠心症可定義為不安定之心絞痛或心肌梗塞。 因此，心血管事件亦可定義為中風、錢梗塞⑽）或心 血管死亡。 根據-實施例，本發明之標的物係決奈達隆或其一種醫 藥上可接又的冑於製備用於預防患有纟久性心房纖維性顫 動或。房撲動之患者的中風、acs或心血管死亡的藥物之 I55857.doc 201200131 用途。 根據一實施例，本發明之標的物亦係決奈達隆或其一種 醫藥上可接受的鹽於製備用於預防在投與決奈達隆或其醫 藥上可接受的鹽的整個週期中患有永久性心房纖維性顏動 或心房撲動之患者的中風、急性冠心症或心血管死亡（更 特定言之預防約2 0 %之中風、急性冠心症或心血管死亡）的 藥物之用途。 根據一實施例，本發明之標的物亦係決奈達隆或其一種 醫藥上可接受的鹽於製備用於預防患有永久性心房纖維.性 顫動或心房撲動之患者的中風的藥物之用途。 根據一實施例，本發明之標的物亦係決奈達隆或其一種 醫藥上可接受的鹽於製備用於預防患有永久性心房纖維性 顫動或心房撲動之患者的急性冠心症的藥物之用途。 根據一實施例，本發明之標的物亦係決奈達隆或其一種 醫藥上可接受的鹽於製備用於預防患有永久性心房纖維性 顫動或〜房撲動之患者的心▲管死亡的藥物之用途。 提及「決奈達隆（dronedarone)於製備用於治療/預防 決奈達隆用於治療/預 的藥物之用途j可理解為 防....... 0 與腦循環功能不全（其係伴隨認知功能逐漸退化之慢性 ;5巾風係急性或亞急性發展之腦血管原因之神 經缺損’其定義為由於腦血管中之干擾而持續超過24小時 之症狀’或定義為患有迅速消失症狀 關性腦損傷之成I 彳床相 155857.doc 201200131 此可係由於由血栓形成或栓塞所引起之缺血（缺少血液 供應），或由於出血（R.L. SaCC0等人，Str〇ke，2〇〇6 ;第” 卷，第577至617頁）。 中風可導致永久性神經損傷或死亡。其係美國與歐洲成 人殘疾之首要原因。 中風的風險因素包括高齡、高血壓、前中風史或暫時性 缺血性發作（ΉΑ)、糖尿病、高膽固醇、抽煙、心房纖維 性顫動等。高血壓係中風最重要的可變風險因素。 中風的症狀係類似於暫時性缺血性發作，但是持續時間 超過24小時。 中風、急性冠心症或心血管死亡之複合評估指標係心血 管結果試驗中之經典結果測量，其亦稱為MACE(主要不良 心血管事件）評估指標。此評估指標之包含顯示研究結果 對於中風之更廣泛的影響及相關性。 就臨床研究而言，預防「心血管疾病住院或死亡」及 「中風、急性冠心病或心血管死亡」構成所謂的複合標準 或組合評估指標。 以上百分比對應於平均值。 在決奈達隆之醫藥上可接受的鹽中，可提及鹽酸鹽。 經治療之患者可係具有心房纖維性顫動或心房撲動史之 患者。 表述「具有心房纖維性顫動或心房撲動史」意指患者先 前顯現至少一種心房纖維性顫動（AF)或心房撲動（八几^症 狀，且在投與決奈達隆時可具有竇性心律或心房纖維性顫 155857.doc 201200131 動或心房撲動。 亦將指定，表述「具有心房纖維性顫動或心房撲動史之 患者」、「具有當前心房纖維性顫動或撲動史之患者」或 具有當前心房纖維性顫動或撲動近史之患者」或「具有 陣發性或持久性心房纖維性顫動或撲動之患者」或「具有 當前陣發性或持久性心房纖維性顫動或撲動史之患者」或 具有當刖陣發性或持久性心房纖維性顫動或撲動近史之 患者」或「具有陣發性或間歇性心房纖維性顫動或心房撲 動及心房纖維性顫動或心房撲動之最近發作之患者，其具 有竇性心律或將經心臟復律」或「具有陣發性或持久性心 房纖維性顫動或心房撲動及心房纖維性顫動或心房撲動之 最近發作之患者’其具有竇性心律或將經心臟復律」意指 在過去已出現一或多次心房纖維性顫動或撲動之發作，及 /或在使用決奈達隆或其醫藥上可接受的鹽時正罹患心房 纖維性顫動或心房撲動之患者。更特定言之，該表述意指 在開始治療前的最近6個月内，患者已具有心房纖維性顫 動或撲動及竇性心律記錄。在開始投與決奈達隆或其醫藥 上可接受的鹽時’患者可具有竇性心律或心房纖維性顫動 或撲動。 亦將指定’術語「持久性」與「間歇性」係同義。 在本發明中’「心房纖維性顫動」意指心房纖維性顫動 及/或心房撲動。 在患有永久性心房纖維性顫動之患者中，可提及另外具 有至少一種以下風險因素之患者： -10· 155857.docRoy et al, The New England Journal of Medecine, 2008, Vol. 358, pp. 2667-2677)) There was no significant difference in the rate of stroke between the display rate and the rhythm group (recommended antiarrhythmic drugs in the rhythm group) Mainly amiodarone). Thromboembolic events (including stroke) are major complications in patients with atrial fibrillation. The etiology of these thromboembolic events has not been fully understood. According to the main hypothesis, atrial fibrillation causes blood stasis in the atria, which promotes the formation of blood clots, and if the blood clot reaches the systemic circulation, it causes a thromboembolic event, such as a stroke. Therefore, prevention of atrial fibrillation or anticoagulation can prevent thromboembolic events and strokes. A large number of clinical studies have confirmed that proper anticoagulation can prevent thromboembolic events (including stroke) (Fuster 155857.doc 201200131 et al). However, all randomized clinical trials using antiarrhythmic drugs, although effectively maintaining sinus rhythm in the rhythm control or treatment group, did not show a reduction in the incidence of stroke. For example, in the AFFIRM trial, wyse et al. compared heart rhythm control (63〇/melamine iodine and 41〇/. sotalol (s〇tal〇1) is the most commonly used antiarrhythmic drug) and Rate control method. As shown in Table 3 of the Wyse et al. article, although a higher number of patients (63%) in the heart rhythm control group maintained sinus rhythm after 5 years compared to the rate control group (35%), stroke or The incidence of TIA was similar in the heart rate control group (80/2033) and the rate control group (77/2〇27). In the STAF trial, Carlsson et al. compared heart rhythm control (42% amine moth) with rate control methods. As shown in Table 2 of Carlsson et al., 'Although at the end of the study', patients with sinus rhythm in the heart rhythm control group had a significant and absolute increase of 29 〇/0 compared to the rate control group, but stroke or The incidence rate of TIA was higher in the heart rate control group (5/1 〇〇) than in the rate control group (1/100). In HOT CAF6, 'Opolski et al. compare rate and heart rate control methods. As shown in Table 2 of the Opolski et al. article, '3/104 patients in the heart rhythm control group suffered from stroke during the follow-up period, compared to 0/100 in the rate control group. In the J-RHYTHM trial, 〇gawa et al. compared heart rhythm control (85% of patients used class I antiarrhythmic drugs) and rate control methods. As shown in Table 3 of the Ogawa et al. article, although within 3 years, compared with the rate control group, the patients with sinus rhythm in the heart rhythm control group were significantly more than 155857.doc 201200131 increased by 29%, but the heart rate The incidence of symptomatic stroke was similar in the control group (9/419) compared to the rate control group (11/404). In the SAFE-T trial, Singh et al. compared amiodarone, sotalol, and placebo for the treatment of patients with persistent atrial fibrillation. Amiodarone and sotalol are significantly more effective than placebo in increasing the time to recurrence of atrial fibrillation (a widely used heart rhythm control measure) (P<〇 〇〇 1). In the intention-to-treat analysis, the amiodarone was six times more effective than sotalol (Ρ<0·001)' and in the analysis according to the actual accepted treatment, the efficacy of amitone was four in sotalol. Times (ρ<(Κ〇〇1" Despite this effective heart rhythm control, the number of strokes in each of the 100 patients in the following years was similar in all groups: 2 〇6 for amiodarone ( Severe), 2.71 for sotalol and 191 for placebo, the lowest rate observed in the placebo group, and with the highest recurrence rate of atrial fibrillation (from the end of page 1866) Therefore, according to the current knowledge of the related art, administration of a drug for preventing atrial fibrillation cannot be considered to mean prevention of stroke. Unexpectedly, in the ATHENA test (H〇hnl〇ser Among others, dronedarone has been shown to reduce the incidence of stroke. The effects observed with dronedarone are not based solely on the control of the law, but rather on the unique combination of the properties of dronedarone, including (but not limited to): Yes The heart rate control, the effect of lowering the heart rate, the blood pressure lowering effect (the action of the vasodilator), the direct action on the endothelial function, and other properties. [Inventors] The present inventors have now clinically proved that Dronedarone (4) grabs the coffee 〇ne) Reduce the incidence of patients with permanent m fibrillation (IV) Hospitalization of vascular disease or I55857.doc 201200131 The incidence of death and cardiovascular events (such as stroke, acute coronary heart disease or cardiovascular death) and other antiarrhythmic compounds This effect is not shown. The subject matter of the present invention is the use of dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for a patient suffering from permanent atrial fibrillation. The use of nedarin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention of hospitalization and/or death of cardiovascular disease in a patient suffering from permanent atrial fibrillation. The subject matter of the present invention is also The use of dalong or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention of cardiovascular events in a patient with permanent atrial fibrillation. A patient with "permanent atrial fibrillation or flutter" refers to a patient who has af or AFL during the entire cycle of administration of dronedarone or a pharmaceutically acceptable salt thereof. All expected electrocardiograms (ECG) of this rhythm (ie, AF or AFL) throughout the cycle of Dallon or its pharmaceutically acceptable salts » The official event can be defined as stroke, acute coronary heart disease (ACS) or heart Vascular death. Acute coronary heart disease can be defined as unstable angina or myocardial infarction. Therefore, cardiovascular events can also be defined as stroke, money infarction (10), or cardiovascular death. According to an embodiment, the subject matter of the present invention is that dronedarone or a medicinal drug thereof is prepared for the prevention of prolonged atrial fibrillation or. The use of drugs for stroke, acs or cardiovascular death in patients with atrial flutter I55857.doc 201200131 Use. According to an embodiment, the subject matter of the present invention is also dronedarone or a pharmaceutically acceptable salt thereof for use in the prevention of the administration of dronedarone or a pharmaceutically acceptable salt thereof throughout the cycle. A drug with a permanent atrial fibrillation or atrial flutter, a stroke, acute coronary heart disease, or cardiovascular death (more specifically, prevention of about 20% of stroke, acute coronary heart disease, or cardiovascular death) use. According to an embodiment, the subject matter of the present invention is also dronedarone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing stroke in a patient suffering from permanent atrial fibrillation or atrial flutter. use. According to an embodiment, the subject matter of the present invention is also dronedarone or a pharmaceutically acceptable salt thereof for the preparation of an acute coronary heart disease for preventing a patient suffering from permanent atrial fibrillation or atrial flutter. The use of the drug. According to an embodiment, the subject matter of the present invention is also dronedarone or a pharmaceutically acceptable salt thereof for the preparation of a heart ▲ tube death for preventing a patient suffering from permanent atrial fibrillation or atrial flutter Use of the drug. Mention that "dronedarone" in the preparation of a drug for the treatment/prevention of dronedarone for the treatment/pre-treatment can be understood as prevention of .... 0 and cerebral circulation dysfunction (its Department of chronic degeneration with cognitive function; 5 cases of acute or subacute development of cerebrovascular causes of neurological deficit 'is defined as symptoms that persist for more than 24 hours due to disturbances in the cerebral blood vessels' or defined as suffering from rapid disappearance The development of a closed brain injury I 彳 相 155857.doc 201200131 This may be due to ischemia caused by thrombosis or embolism (lack of blood supply), or due to bleeding (RL SaCC0 et al, Str〇ke, 2〇〇 6; vol. 577-617. Stroke can cause permanent nerve damage or death. It is the leading cause of disability in adults in the United States and Europe. Risk factors for stroke include advanced age, high blood pressure, history of pre-stroke or temporary Ischemic seizures (糖尿病), diabetes, high cholesterol, smoking, atrial fibrillation, etc. Hypertension is the most important variable risk factor for stroke. The symptoms of stroke are similar to transient ischemic attacks. It lasts for more than 24 hours. The composite assessment of stroke, acute coronary heart disease or cardiovascular death is a classic outcome measure in the cardiovascular outcome trial, also known as the MACE (Major Adverse Cardiovascular Event) Assessment Index. This includes showing the broader impact and relevance of the findings on stroke. For clinical research, prevention of "cardiovascular hospitalization or death" and "stroke, acute coronary heart disease or cardiovascular death" constitutes a so-called composite standard or combination The above percentages correspond to the mean. Among the pharmaceutically acceptable salts of dronedarone, the hydrochloride can be mentioned. The treated patient can be a patient with a history of atrial fibrillation or atrial flutter. "Having a history of atrial fibrillation or atrial flutter" means that the patient has previously developed at least one type of atrial fibrillation (AF) or atrial flutter (eight symptoms) and may have sinus rhythm when administering dronedarone Or atrial fibrillation 155857.doc 201200131 or atrial flutter. Also designated, the expression "has atrial fibrillation or atrial flutter" "Patient patients", "patients with current atrial fibrillation or flutter history" or patients with current atrial fibrillation or fluttering history" or "paroxysmal or persistent atrial fibrillation or flutter "patients" or "patients with current paroxysmal or persistent atrial fibrillation or flutter history" or patients with paroxysmal or persistent atrial fibrillation or fluttering history" or "with Patients with recent or episodes of atrial fibrillation or atrial flutter and atrial fibrillation or atrial flutter with sinus rhythm or cardioversion or "with paroxysmal or persistent atrial A patient with a recent onset of fibrillation or atrial flutter and atrial fibrillation or atrial flutter, who has sinus rhythm or cardioversion, means that one or more atrial fibrillation or flutter has occurred in the past. A seizure, and/or a patient with atrial fibrillation or atrial flutter when using dronedarone or a pharmaceutically acceptable salt thereof. More specifically, the expression means that the patient has had atrial fibrillation or flutter and sinus rhythm records during the last 6 months prior to initiation of treatment. The patient may have sinus rhythm or atrial fibrillation or flutter when starting to cast dronedarone or its pharmaceutically acceptable salt. The term 'permanence' is also synonymous with the term "intermittent". In the present invention, "atrial fibrillation" means atrial fibrillation and/or atrial flutter. In patients with permanent atrial fibrillation, patients with at least one of the following risk factors may be mentioned: -10· 155857.doc
201200131 -年齡，尤其係等於或大於70歲，或甚至大於75歲， - 南血壓， -糖尿病， -先前腦血管意外或全身性栓塞， -由超音波心動描記術測得，左心房直徑大於或等於 mm > 由二維（2D)超音波心動描記術測得，左心室射出分率小 於 40%。 在患有永久性心房纖維性顫動之患者中，亦可提及具有 對應於至少一種以下疾病之其他風險因素之患者. - 南血壓， -結構性心臟病， -心搏過速 -冠心病， -非風濕性心臟瓣膜病， -缺血性擴張型心肌病， -針對AF/AFL之消融史，例如導管消融或手術消融， -除AF/AFL以外之室上性心搏過速， -心臟瓣膜手術史， -非缺血性擴張型心肌病， -肥厚型心肌病， -風濕性心臟瓣膜病， -持續性心室性心搏過速’ -先天性心臟病， 155857.doc -11 - 201200131 •非AF/AFL原因之消融史’例如導管消融， -心室纖維性顫動’ 及/或至少一種選自下列之心臟裝置： -起搏器， -植入式心律轉復除顫器。 本發明之另一目標係一種醫藥組合物，其包含決奈達隆 或其一種醫藥上可接受的鹽作為活性成分。該醫藥組合物 包含有效劑量之至少一種根據本發明之式（1)化合物、或其 與醫藥上可接受的酸之加成鹽、或其水合物或溶劑化物， 及至少一種醫藥上可接受的賦形劑。該等賦形劑係根據所 需之醫藥物形式及投藥途徑選自熟習此項技術者已知之常 見賦形劑。 在用於經口、舌下、皮下、肌内、靜脈内、表面、局 部、氣管内、鼻内、穿皮或直腸投藥之根據本發明之醫藥 組合物中，決奈達隆或其一種鹽、溶劑化物或水合物可作 為與習知醫藥賦形劑之混合物’以單位劑型投與動物及人 類，以用於預防或治療上述病狀。適合之單位劑型包括口 服劑型，例如錠劑、硬或軟明膠膠囊、粉劑、粒劑及口服 溶液或懸浮液；舌下、經頰、氣管内、眼内、或鼻内投藥 形式；適於吸入、局部、穿皮、皮下、肌内或靜脈内遞送 之投藥形式；直腸投藥形式及植入物。當外用時，本發明 化合物可呈乳膏、凝膠、軟膏或洗劑形式使用。 在用於治療劑時’將決奈達隆及其醫藥上可接受的鹽併 入醫藥組合物中。 此等醫藥組合物包含有效劑量之至少決奈達隆或其一種 155857.doc •12- 201200131 醫藥上可接受的鹽及至少一種醫藥上可接受賦形劑。 該等賦形劑係根據所需之醫藥物形式及投藥 習此項技術者已知之常見賦形劑。 、… 在用於經口、舌下、皮下、肌内、靜脈内、表面1 部、氣管内、鼻内、穿皮或直腸投藥之醫藥組合物中，： 奈達隆或-種其醫藥上可接受的鹽可作為與習知醫藥賦： 劑之混合物，以單位劑型投與患有上述疾病之動物及人 類。 適合之單位劑型包括口服劑型’例如錠劑、硬或軟明膠 膠囊、粉劑、粒劑及口服溶液或懸浮液；舌下、經頰、氣 管内、眼内、或鼻内投藥形式；#由吸入之投藥形式；局 部、穿皮、皮下、肌内或靜脈内投藥形式；直腸投藥形式 及植入物。當外用時，本發明化合物可里乳膏、凝膠、軟 膏或洗劑形式使用。 舉例而言，呈錠劑形式之決奈達隆或其一種醫藥上可接 受的鹽之單位劑型可包含下列成分： 成分 mg 決奈達隆鹽酸鹽(相當於400 mg基劑） 426 甲基羥丙基纖維素 21,1 乳糖單水合物 46,55 改質玉米澱粉 45,5 聚乙稀吼》各咬酮 65 >白洛沙姆407(P〇l〇xamer 407) 40 無水膠態矽石 2,6 硬脂酸鎂 3,25 650 I55857.doc -13· 201200131 成分 mg 決奈達隆鹽酸鹽(相當於400 mg基劑） 426 微晶纖維素 65 無水膠態矽石 2,6 無水乳糖 42,65 聚乙烯°比略α定酮 13 泊洛沙姆407 40 聚乙二醇6000(Macrogol 6000) 57,5 硬脂酸鎂 3,25 650 成分 mg 決奈達隆鹽酸鹽(相當於400 mg基劑） 426 微晶纖維素 26 玉米澱粉 45,5 聚乙烯吡咯啶酮 65 泊洛沙姆407 40 無水膠態矽石 3,25 硬脂酸鎂 3,25 乳糖單水合物 41,65 650 155857.doc 14 201200131 成分 mg 決奈達隆鹽酸鹽(相當於200 mg基劑） 213 微晶纖維素 13 玉米澱粉 22,75 聚乙烯吡咯啶酮 32,5 泊洛沙姆407 20 無水膠態矽石 1,3 硬脂酸鎂 1,625 乳糖單水合物 20,825 325 該醫藥組合物可隨食物每天服用一次或兩次。 每天經口投與之決奈達隆劑量可達800 mg，分一或多次 服用，例如一或兩次。 更明確言之，所投與之決奈達隆劑量可隨食物一起服 用。 更明確言之，每天經口投與之決奈達隆劑量可達800 mg，分兩次隨餐服用。 每曰經口投與之決奈達隆劑量可依每日兩次之頻率，隨 餐（例如隨早餐及晚餐）服用。 更明確言之，該兩次服用可包含相同量的決奈達隆。 在特定情況下，更高或更低劑量可係適合；該等劑量係 155857.doc -15· 201200131 包含於本發明之範圍内。根據一般實際操作，適於各患者 之劑量係由醫師根據投藥途徑、該患者之體重、疾病、身 體表面'心臟輸出量及反應而確定。 本發明亦關於一種預防心血管疾病住院或死亡或心血管 事件之方法，其包括投與有效劑量之至少決奈達隆或其一 種醫藥上可接受的鹽給患有永久性心房纖維性顗動之患 者。 本發明亦關於一種預防中風之方法，其包括投與有效劑 量之至少決奈達隆或其一種醫藥上可接受的鹽給患有永久 性心房纖維性顫動之患者。 本發明亦關於一種製造物件，其包括 a) 包裝材料， b) 決奈達隆或其醫藥上可接受的鹽，及 0含於該包裝材料内之標籤或包裝插頁’其指出決奈 達隆或其醫藥上可接受的鹽係用於患有永久性心房 纖維性顫動之患者。 更特定s之，含於包裝材料内之該標籤或包裝插頁指出 決奈達隆或其醫藥上可接受的鹽係用於預防患有永久性心 房纖維性顫動之患者的心血管疾病住院或死亡或心血管事 件。 【實施方式】 在被稱為ATHENA之預期、多國、雙盲、隨機、多中 心、安慰劑對照平行組試驗期間，經由決奈達隆鹽酸鹽提 供決奈達隆或其醫藥上可接受的鹽相對於安慰劑於預防心 155857.doc -16 - 201200131 ▲管疾病住院或死亡中之效力。 在患有永久性心房纖維性顫動之患者之子組中，經由決 奈達隆鹽酸鹽提供決奈達隆或其醫藥上可接受的鹽相對於 安慰劑於預防心血管疾病住院或死亡或心血管事件（如中 風）中之效力。 I·患者選擇 合適的患者具有心房纖維性顫動或心房撲動史及/或在 招募時可具有正常竇性心律或患有心房纖維性顫動或撲 動。 招募患者時考慮以下納入標準： 納入標準： U必須存在下列風險因素中之一者： •年齡等於或大於7〇歲， •高血壓（服用至少兩種不同類型之抗高血壓藥）， -糖尿病， •細中風史（暫時性缺企性事件或完全腦中風）或全 身性栓塞史， _由超音波心動描記術測得，左心房直徑大於或等 於 50 mm， 由一維超音波摇記術測得，左心室射出分率小於 4 0 % ;或 年齡等於或大於70歲，或甚至大於75歲，其可與 至少一種以下風險因素組合： °高血屋（服用至少兩種不同類型之抗高血 155857.doc 17 201200131 壓藥）， 〇糖尿病， 〇細中風史（暫時性缺血性事件或完全腦中 風）或全身性栓塞史， 〇由超音波心動描記術測得，左心房直徑 大於或專於5〇 mm， 〇由二維超音波描記術測得，左心室射出 分率小於40% ; 2) 可獲得最近六個月内之一心電圖，其顯示患者曾經 或現在患有心房纖維性顫動/撲動， 3) 可獲得最近六個月内之—心電圖，其顯示患者曾經 或現在具有竇性心律。 II.持續時間及療法 研究藥物治療單元（安慰劑或相當於4〇〇 mg基劑之決奈 達隆鹽酸鹽）係使各患者在上午的早餐期間或早餐後不久 服用一片錠劑並在晚上的晚餐期間或晚餐後不久服用一片 键劑。 且可 計算 治療持續時間取決於該試驗中各患者的招募時間 包括12個月至30個月。 III·結果 利用非參數型卡普蘭-邁耶（Kaplan_Meier)估計法 結果 ° 考克斯（Cox)比例風險模型用 對風險）。 於評估風險比例（亦稱為相 155857.doc -18- 201200131 相對風險（RR)係經決奈達隆治療之患者具有事件的風險 與經女慰劑治療之患者具有相同事件的風險的比例。 事件減少百分比係如下計算： x=l -RR。 在該試驗中所包括之4628名患者中，2301名患者係經決 奈達隆鹽酸鹽治療之組部份》 處於「永久性心房纖維性顫動或撲動」之患者或「發展 成永久性心房纖維性顫動之患者」係在對投與決奈達隆或 其醫藥上可接受的鹽之整個週期中具有此心律之全部預期 ECG之患者。 473名參與者已被確定為患有永久性心房纖維性顫動或 撲動之患者。 在此子組中，295名患者係屬於安慰劑治療組，而178名 患者係屬於決奈達隆鹽酸鹽治療組。 因此’決奈達隆組中之「永久性心房纖維性顫動」之發 病率係顯著較低。 ΠΙ·1關於減少CV疾病住院或死亡之結果 在安慰劑組中’報告95例事件，而在決奈達隆鹽酸鹽治 療組中為46例。 相對風險計算值係等於0 74(ρ=〇 〇9)，即：cv疾病住院 或死亡之相對風險降低26〇/〇。 ΙΠ.2關於減少Cv疾病住院之結果 在安慰劑組中，報告85例事件，而在決奈達隆鹽酸鹽治 療組中為37例。 155857.doc •19- 201200131 相對風險計算值係等於0.67(95% CI 0.46至0.99， p=0.04)，即：CV疾病住院之相對風險降低33%。 III.3關於預防中風、急性冠心症（ACS)或心血管死亡之結果 在安慰劑組中，報告24例事件，而在決奈達隆鹽酸鹽治 療組中為12例。 相對風險計算值係等於0.805，即：中風、急性冠心症_ (ACS)或心血管死亡之相對風險降低20%。 155857.doc -20-201200131 - Age, especially equal to or greater than 70 years old, or even greater than 75 years old, - South blood pressure, - Diabetes, - Previous cerebrovascular accident or systemic embolism, - Measured by ultrasonic echocardiography, the diameter of the left atrium is greater than or Equal to mm > The left ventricular ejection fraction is less than 40% as measured by two-dimensional (2D) ultrasound cardiography. In patients with permanent atrial fibrillation, patients with other risk factors corresponding to at least one of the following diseases may also be mentioned. - South blood pressure, - Structural heart disease, - Tachycardia - Coronary heart disease, - Non-rheumatic valvular heart disease, - ischemic dilated cardiomyopathy, - history of ablation of AF/AFL, such as catheter ablation or surgical ablation, - supraventricular tachycardia other than AF/AFL, - heart History of valve surgery, - non-ischemic dilated cardiomyopathy, - hypertrophic cardiomyopathy, - rheumatic valvular heart disease, - persistent ventricular tachycardia - congenital heart disease, 155857.doc -11 - 201200131 • History of ablation of non-AF/AFL causes 'eg catheter ablation, - ventricular fibrillation' and/or at least one cardiac device selected from the group consisting of: - pacemaker, - implantable cardioverter defibrillator. Another object of the present invention is a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition comprises an effective amount of at least one compound of the formula (1) according to the invention, or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient. Such excipients are selected from the usual excipients known to those skilled in the art, depending on the pharmaceutical form desired and the route of administration. In a pharmaceutical composition according to the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration, dronedarone or a salt thereof The solvate or hydrate can be administered to the animal and human in a unit dosage form as a mixture with a conventional pharmaceutical excipient for the prevention or treatment of the above conditions. Suitable unit dosage forms include oral dosage forms such as lozenges, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, or intranasal administration; Administration forms for local, transdermal, subcutaneous, intramuscular or intravenous delivery; rectal administration forms and implants. When used topically, the compounds of the invention may be used in the form of a cream, gel, ointment or lotion. In the case of a therapeutic agent, dronedarone and its pharmaceutically acceptable salt are incorporated into a pharmaceutical composition. Such pharmaceutical compositions comprise an effective amount of at least dronedarone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Such excipients are in accordance with the desired pharmaceutical form and administration of the usual excipients known to those skilled in the art. , in a pharmaceutical composition for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration: Nidalon or its medicine An acceptable salt can be administered as a mixture with a conventional pharmaceutical agent in a unit dosage form for administration to animals and humans having the above-mentioned diseases. Suitable unit dosage forms include oral dosage forms such as lozenges, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, or intranasal administration; #by inhalation Form of administration; topical, transdermal, subcutaneous, intramuscular or intravenous administration; rectal administration and implants. When used externally, the compound of the present invention can be used in the form of a cream, gel, ointment or lotion. For example, a unit dosage form of dronedarone or a pharmaceutically acceptable salt thereof in the form of a tablet may comprise the following ingredients: Ingredient mg dronedarone hydrochloride (equivalent to 400 mg base) 426 methyl Hydroxypropyl cellulose 21,1 lactose monohydrate 46,55 modified corn starch 45,5 polyethylene 吼 吼 each biting ketone 65 > white oxas 407 (P〇l〇xamer 407) 40 anhydrous gelatinous state Vermiculite 2,6 Magnesium stearate 3,25 650 I55857.doc -13· 201200131 Ingredient mg dronedarone hydrochloride (equivalent to 400 mg base) 426 microcrystalline cellulose 65 anhydrous colloidal vermiculite 2 6 anhydrous lactose 42,65 polyethylene ° ratio slightly ketone 13 poloxamer 407 40 polyethylene glycol 6000 (Macrogol 6000) 57,5 magnesium stearate 3,25 650 mg mg dronedarone hydrochloride (equivalent to 400 mg base) 426 microcrystalline cellulose 26 corn starch 45,5 polyvinylpyrrolidone 65 poloxamer 407 40 anhydrous colloidal vermiculite 3,25 magnesium stearate 3,25 lactose monohydrate 41,65 650 155857.doc 14 201200131 Ingredient mg dronedarone hydrochloride (equivalent to 200 mg base) 213 microcrystalline cellulose 13 corn starch 22,7 5 polyvinylpyrrolidone 32,5 poloxamer 407 20 anhydrous colloidal vermiculite 1,3 magnesium stearate 1,625 lactose monohydrate 20,825 325 This pharmaceutical composition can be taken once or twice daily with food. The dose of dronedarone administered orally daily can reach 800 mg, one or more times, for example one or two times. More specifically, the dronedarone dose administered can be taken with food. To be clear, the dose of dronedarone administered orally every day can reach 800 mg, which is taken twice in a meal. Each dose of dronedarone administered orally can be taken at a frequency of twice a day, with meals (eg, with breakfast and dinner). More specifically, the two doses may contain the same amount of dronedarone. In certain instances, higher or lower dosages may be suitable; such dosages are 155857.doc -15. 201200131 are included within the scope of the invention. According to general practice, the dosage appropriate for each patient is determined by the physician based on the route of administration, the weight of the patient, the disease, the body's surface output, and the response. The invention also relates to a method of preventing hospitalization or death or cardiovascular events of cardiovascular disease comprising administering an effective amount of at least dronedarone or a pharmaceutically acceptable salt thereof for permanent atrial fibrillation The patient. The invention also relates to a method of preventing stroke comprising administering an effective amount of at least dronedarone or a pharmaceutically acceptable salt thereof to a patient suffering from permanent atrial fibrillation. The invention also relates to a manufactured article comprising a) a packaging material, b) dronedarone or a pharmaceutically acceptable salt thereof, and a label or package insert containing 0 in the packaging material Long or its pharmaceutically acceptable salts are used in patients with permanent atrial fibrillation. More specifically, the label or package insert contained in the packaging material indicates that dronedarone or a pharmaceutically acceptable salt thereof is used to prevent cardiovascular disease hospitalization in patients with permanent atrial fibrillation or Death or cardiovascular events. [Embodiment] Providing dronedarone or its pharmaceutically acceptable via dronedarone hydrochloride during an expected, multinational, double-blind, randomized, multicenter, placebo-controlled, parallel group trial called ATHENA The effectiveness of the salt relative to placebo in the prevention of heart disease 155857.doc -16 - 201200131 ▲ tube disease hospitalization or death. In a subgroup of patients with permanent atrial fibrillation, dronedarone or its pharmaceutically acceptable salt is provided via dronedarone hydrochloride to prevent cardiovascular disease hospitalization or death or heart The effectiveness of a vascular event such as a stroke. I. Patient Selection Suitable patients have a history of atrial fibrillation or atrial flutter and/or may have normal sinus rhythm or atrial fibrillation or flutter when recruited. Consider the following inclusion criteria when recruiting patients: Inclusion criteria: U must have one of the following risk factors: • Age is equal to or greater than 7 years old, • High blood pressure (take at least two different types of antihypertensive drugs), - Diabetes , • History of fine stroke (temporary lack of sexual events or complete stroke) or history of systemic embolism, _ measured by ultrasound echocardiography, left atrial diameter greater than or equal to 50 mm, by one-dimensional ultrasound It is measured that the left ventricular ejection fraction is less than 40%; or the age is equal to or greater than 70 years, or even greater than 75 years, which can be combined with at least one of the following risk factors: ° High blood house (take at least two different types of resistance High blood 155857.doc 17 201200131 pressure), diarrhea, history of stroke (temporary ischemic event or complete stroke) or systemic embolism, 〇 measured by ultrasound cardiography, left atrial diameter greater than Or specializes in 5〇mm, 〇 measured by two-dimensional ultrasound, the left ventricular ejection fraction is less than 40%; 2) can obtain an electrocardiogram in the last six months, which shows that the patient has been or is present With atrial fibrillation / flutter, 3) can be obtained within the last six months - the electrocardiogram, which showed that patients had or now have sinus rhythm. II. Duration and Therapy Study The drug treatment unit (placebo or dronedarone hydrochloride equivalent to 4 mg base) allows each patient to take a lozenge during breakfast in the morning or shortly after breakfast. Take a tablet during the evening dinner or shortly after dinner. The duration of treatment can be calculated depending on the recruitment time of each patient in the trial, including 12 months to 30 months. III. Results Using the non-parametric Kaplan_Meier estimation method Results ° Cox proportional hazard model for risk). The proportion of risk assessed (also known as phase 155857.doc -18-201200131 relative risk (RR) is the proportion of patients who have been treated with dronedarone with a risk of having the same event as a patient treated with female consolation. The percentage reduction in events was calculated as follows: x = l - RR. Of the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride, in "permanent atrial fibrosis" A patient who trembles or flutters or a patient who develops permanent atrial fibrillation is a patient who has all of the expected ECGs with this rhythm throughout the cycle of administration of dronedarone or its pharmaceutically acceptable salt. 473 participants have been identified as having permanent atrial fibrillation or flutter. In this subgroup, 295 patients were in the placebo group and 178 patients were in dronedarone hydrochloride. The salt treatment group. Therefore, the incidence of "permanent atrial fibrillation" in the dronedarone group was significantly lower. ΠΙ·1 on the reduction of hospitalization or death of CV disease in the placebo group 'reported 95 cases thing 46 cases were compared in the dronedarone hydrochloride treatment group. The relative risk calculation was equal to 0 74 (ρ=〇〇9), ie the relative risk of hospitalization or death of cv disease was reduced by 26〇/〇. ΙΠ.2 Results of hospitalization for reducing Cv disease In the placebo group, 85 events were reported, compared with 37 in the dronedarone hydrochloride treatment group. 155857.doc •19- 201200131 Relative risk calculation is equal to 0.67 (95% CI 0.46 to 0.99, p=0.04), ie the relative risk of hospitalization for CV disease was reduced by 33%. III.3 Results for prevention of stroke, acute coronary heart disease (ACS) or cardiovascular death in the placebo group Of the 24 events reported, 12 were in the dronedarone hydrochloride group. The relative risk was calculated to be 0.805, which is the relative risk of stroke, acute coronary heart disease (ACS) or cardiovascular death. Reduce by 20%. 155857.doc -20-