FDA的药品评价和研究中心心血管和肾产品部主任Norman Stockbridge, M.D., Ph.D.说“在临床试验中, Brilinta在防止心脏病发作和死亡方面比Plavix[氯吡格雷]更有效，但优点是与阿司匹林[aspirin]维持剂量75至100毫克每天1次时见到。”
批准日期：2011年7月20日；公司：AstraZeneca
Manufacturer:
AstraZeneca Pharmaceuticals

Pharmacological Class:
P2Y12 platelet inhibitor (cyclopentyltriazolopyrimidine).

Active Ingredient(s):
Ticagrelor 90mg; tablets.

Indication(s):
To reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina or non-ST-elevation myocardial infarction [MI] or ST-elevation MI).

Pharmacology:
Ticagrelor is a platelet activation and aggregation inhibitor mediated by the P2Y12 class of ADP receptors. Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Both ticagrelor and its active metabolite are approximately equipotent.

Clinical Trials:
In a randomized, double-blind study, the use of ticagrelor was compared to a regimen of clopidogrel, both given in combination with aspirin and other standard therapy in patients with acute coronary syndromes. Patients were treated for at least 6 months and for up to 12 months.

The primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints.

At study completion, ticagrelor has been shown to significantly reduce the rate of a combined endpoint of cardiovascular death, MI or stroke compared to clopidogrel (9.8% vs. 11.7%, respectively, hazard ratio [HR] 0.84). The difference between treatments on the composite resulted from effects on CV death (HR 0.79) and MI (HR 0.84); each was statistically significant when considered as a secondary endpoint and there was no difference on strokes. There was also a decrease in all-cause mortality.

Among 11,298 patients with PCI receiving any stent during this study, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%).

Legal Classification:
Rx

Adults:
Initiate loading dose: 180mg once, then continue with 90mg twice daily. After the initial loading dose of aspirin (usually 325mg), take ticagrelor with maintenance dose of aspirin 75–100mg daily. ACS patients: may start ticagrelor after receiving a loading dose of clopidogrel.

Children:
Not established.

Contraindication(s):
History of intracranial hemorrhage. Active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage). Severe hepatic impairment.

Warnings/Precautions:
Do not start in patients planned to undergo urgent CABG. When possible, discontinue at least 5 days before any surgery. Suspect bleeding in hypotensive patients who have recently undergone coronary angiography, PCI, CABG, or other surgery. Older age, history of bleeding disorders, undergoing percutaneous invasive procedures, concomitant anticoagulants, fibrinolytics, higher doses of aspirin, and chronic NSAID use: increased risk of bleeding. Avoid interruption of treatment; if temporarily discontinued, restart as soon as possible. Premature discontinuation increases risk for CV events (eg, MI, stent thrombosis, death). Effectiveness reduced with aspirin maintenance dose >100mg; avoid. Moderate hepatic impairment. Pregnancy (Cat. C). Nursing mothers: not recommended.

Interaction(s):
Concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, telithromycin,) or potent CYP3A inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, phenobarbital): not recommended. Potentiates simvastatin, lovastatin; avoid >40mg/day doses. Monitor digoxin during ticagrelor initiation and dose adjustments.

Adverse Reaction(s):
Bleeding (may be fatal), dyspnea, headache, cough, dizziness, GI upset, atrial fibrillation, hyper- or hypotension, back pain, fatigue, chest pain.

How Supplied:
Tabs—60, 180

Last Updated:
8/25/2011

随着抗血小板聚集药物快速发展，越来越多的抗血小板聚集药物进入临床。阿斯利康研发的新型抗凝药——替卡格雷更是有望成为格雷类口服抗血小板聚集和抗血栓类鼎足药物。
替卡格雷是一种新型的、具有选择性的小分子抗凝血药，也是第一个可逆的结合型口服P2Y12腺苷二磷酸受体拮抗剂，能可逆性地作用于血管平滑肌细胞(VSMC)上的嘌呤2受体亚型P2Y12，对ADP引起的血小板聚集有明显的抑制作用，能有效改善急性冠心病患者的症状。因为替卡格雷的可逆性抗血小板作用，尤为适用于那些需在先期进行抗凝治疗后再行手术的病人。
用小鼠的主动脉环进行的研究发现，氯吡格雷不能阻断血管平滑肌细胞收缩，可能是因为其活性代谢物在循环系统中极不稳定而不能起效；而替卡格雷可以阻断由P2Y12受体介导的ADP引起的血管平滑肌细胞收缩，即使是先使用氯吡格雷后发生收缩的血管平滑肌在加用替卡格雷后，收缩也会受到进一步抑制。空白对照组和氯吡格雷组的最大收缩率分别为59％和64％；当给予替卡格雷后，两组的收缩率分别达到33％和32％。
一项名为DISPERSE的多中心的Ⅱa期试验中，200名患有稳定型动脉粥样硬化的病人被随机给予替卡格雷(50，100或200mg，hid，或400mg，qd)或氯吡格雷(75mg，qd)加阿司匹林(75—100mg，qd)，用药时间为28天。结果表明，与氯吡格雷相比，替卡格雷(100mg或以上，bid)的起效更快、更持久、对血小板凝集的抑制作用更强(90％vs60％)。
所有使用替卡格雷患者对该药都能很好地耐受；使用替卡格雷药造成的所有出血事件大多不甚严重，只有在最大用药量(400mg，qd)时，出现1例比较大的出血事件；替卡格雷组有呼吸困难的情况出现，且发生率呈剂量依赖性：5O和100mg(bid)组的发生率为10％、200mg(bid)组为16％．400mg(qd)组则为20％，但情况并不严重，亦未发生与心力衰竭、支气管痉挛等相关的症状。由不良事件而导致的停药呈剂量相关，随着替卡格雷的剂量从5Omg，bid上升到400mg，qd，停药率从2．5％增加到8．6％，而氯吡格雷的停药率为2．7％。
抗凝剂市场去年全球销售额高达140多亿美元，近5年来以平均近10%的增长率快速扩增，成为各大制药巨头的必争之地。昨天，阿斯利康公司的抗凝新药Brilinta以7:1的投票结果获得FDA专家小组的批准推荐，有望成为抗凝剂市场的新宠，也使得抗凝剂市场竞争愈加激烈。
以下就现已上市的抗凝剂以及有望跻身于该治疗领域的后期在研新药做一简述。
BRILINTA
Brilinta通用名称是ticagrelor（替格瑞洛），属于环戊基三唑嘧啶类新型抗凝剂。阿斯利康希望Brilinta获准用于急性冠状动脉综合症（ACS）患者以减少心脏相关的不良事件。目前ACS治疗用药基本以Plavix（波立维，氯吡格雷）为主。与已上市的抗凝血药类似，Brilinta也可用于病人接受冠状动脉搭桥手术或血管成形术中清除动脉阻塞后的血栓。
阿斯利康此次申请主要基于一项在43个国家进行的、18624人参加名为PLATO的III期临床研究，旨在比较Brilinta与Plavix预防心血管疾病发作的效果。结果令人满意，为期一年的临床表明，与Plavix相比，Brilinta可降低16%的心脏病发作、中风以及心血管疾病死亡。但令人遗憾的是，在美国进行的研究中，约有9%的受试者未能受益。对此，有专家认为可能是由于美籍受试者基础用药阿司匹林用量较高。昨天，FDA专家小组高票支持该药获批。FDA有关官员表示，若该药获得批准，阿斯利康应进行上市后临床研究，以重点监测这一疗效差异的真实原因。
PLAVIX
波立维是赛诺菲安万特和百事美施贵宝的“利润大户”，去年的销售额高达近90亿美元，仅次于立普妥位居销售榜次席。但由于到2012年在美国专利保护到期，其销售份额将面临着仿制药的蚕食，而在欧洲，廉价的仿制药已经上市。Brilinta 一旦上市，将成为波立维的直接竞争对手。同样，廉价的波立维仿制药，也将成为Brilinta上市后面临的挑战。
EFFIENT
去年礼来和第一制药三共株式会社的Effient （prasugrel ，普拉格雷）获得FDA批准上市，已经对波立维构成挑战。Effient的临床研究表明其疗效优于波立维，但其最大的弱点是具有出血的风险，而正是这一黑框警告，使得其销售业绩不尽人意，但礼来公司对该药未来市场充满信心。
VORAPAXAR
默克公司的在研新药Vorapaxar为凝血酶受体拮抗剂，由先灵葆雅研发，能够防止引发心脏病和中风的血块凝固，可望与抗血小板药物如阿司匹林和波立维合用，用于预防心脏病发作和中风。旨在评价对急性冠脉综合征患者在标准治疗的基础上加用凝血酶受体拮抗剂Vorapaxar治疗能否减少动脉粥样硬化血栓形成等缺血事件的国际多中心、随机、双盲、设安慰剂对照的大规模临床研究（TRA?CER）已于2007年12月启动。默克声称计划于2011年向FDA提交上市批准申请。
ELINOGREL
Elinogrel是美国生物技术公司Portola研发的新药，去年诺华公司以7500万美元首付款和5亿美元阶段性付款获得该药物的III期临床研究和全球市场开发权。的在研抗凝血剂的全球独家权利。诺华计划今年开始III期临床研究，它也有望将成为波立维的另一替代者。
PRADAXA
Pradaxa（dabigatran etexilate，达比加群酯）是由德国勃林格殷格翰公司开发的一种新型的口服凝血酶抑制剂，是dabigatran的前体药物，属非肽类的凝血酶抑制剂。该药于2008年4月在德国和英国率先上市，用于预防膝关节置换术的静脉血栓栓塞。这是继华法林之后50年来上市的首个新类别口服抗凝血药物，是抗凝血治疗领域和潜在致死性血栓预防领域的一项重大进展，具有里程碑意义。 但对于达比加群或其他的口服抗凝血药物来说，用于房颤导致中风的预防用药才是最大的市场，达比加群的房颤Ⅲ期临床试验已经结束。勃林格殷格翰公司声称，该药物有望于2010年后期或2011前早期获得批准。 而鉴于中风预防标准治疗药物华法林最大的缺点是易于与食物或其他药物相互作用，需要进行血药检测。因此，有人称Pradaxa的上市是华法林时代的结束。
XARELTO
Xarelto（拜瑞妥，利伐沙班）为强生和拜尔公司研发的用于择期髋关节或膝关节置换手术成年患者的抗凝药物，以预防静脉血栓形成。2009年5月在美上市，我国也已上市。这只药物还有预防房颤患者中风的预防和其他临床疾病的潜力。
APIXABAN
由百时美施贵宝公司和辉瑞公司联合研制的抗栓药apixaban属于氨基苯并曝唑类化合物，是一种高选择性、可逆的凝血因子Xa抑制剂，口服有效。在最近公布的临床试验中，在择期全膝关节置换术的静脉血栓栓塞的发病率方面获得统计学上优于赛诺菲依诺肝素的理想效果
FDA批准血液稀释药Brilinta用于治疗急性冠脉综合征
7月20日，美国食品和药物管理局（FDA）批准血液稀释药物BRILINTA（替卡格雷）用于减少急性冠脉综合征（ACS）患者的心血管死亡和心脏病发作。
ACS包括引起一系列症状的多种疾病，如不稳定型心绞痛或心脏病发作，其可由于心脏血流量减少引发。Brilinta通过防止新的血液凝块的形成，从而保持血液在体内流动，帮助减少另外的心血管事件风险。
已经对Brilinta与阿司匹林联合用药进行了研究。针对卫生保健专业人员和患者一个黑框警告警告说，阿司匹林剂量高于100mg/d可减少药物的有效性。
FDA药物评价和研究中心心血管和肾脏产品部门主任Norman Stockbridge博士说道，在临床试验中，BRILINTA较氯吡格雷可更有效的预防心脏病发作和死亡，但这种获益只有司匹林的维持剂量为75-100mg/d时才可看到。
黑框警告还说道，正如其他的血液稀释剂，Brilinta可增加出血发生率，并且可引起显著的，有时甚至是致命性的出血。在临床试验中服用BRILINTA的患者报告的最常见的不良反应是出血和呼吸困难（喘息）。
BRILINTA被批准时要求进行风险评估和减灾战略，一种帮助确保药物的获益大于风险的计划。作为该计划的一部分，该公司必须对医生进行教育推广，提醒他们使用较高剂量阿司匹林的风险。此外，Brilinta还将有用药指南，告知患者最重要的用药信息。该指南将在每次开具处方时分发给每位患者。
BRILINTA由威尔明顿阿斯利康生产

FDA APPROVES NEW MEDICINE BRILINTA™ (TICAGRELOR) FOR USE IN THE US
BRILINTA indicated to reduce heart attacks and cardiovascular death in patients with Acute Coronary Syndrome
WILMINGTON, Del. — July 20, 2011 /PRNewswire/ — AstraZeneca (NYSE: AZN) announced today that the US Food and Drug Administration (FDA) has approved BRILINTA™ (ticagrelor) tablets to reduce the rate of heart attack (myocardial infarction [MI]) and cardiovascular (CV) death in adult patients with acute coronary syndrome (ACS), compared to clopidogrel.
BRILINTA, a new oral antiplatelet medicine, is indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina [UA] non-ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined endpoint of CV death, MI or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention (PCI), BRILINTA reduces the rate of stent thrombosis. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.
David Brennan, Chief Executive Officer, AstraZeneca said: “The FDA approval of BRILINTA is good news for patients in the United States and represents a significant milestone as we seek to help ensure ACS patients around the world have access to this innovative medicine. With over one million people affected by ACS in the US each year, the fact that physicians have a new and more effective treatment option than clopidogrel to help reduce the rate of heart attack and cardiovascular death in these patients is an important advance.”
Now that BRILINTA is approved in the US, AstraZeneca will begin the process of working with hospital formularies, protocol committees, government and managed care reimbursement bodies to bring this medicine to patients. Navigating these steps, which are necessary before BRILINTA will be available to a substantial number of incident ACS patients, will be a key focus for the next 12 months.
The FDA approval is based upon data from the landmark PLATO (A Study of PLATelet Inhibition and Patient Outcomes) study, a superiority trial that compared treatment with BRILINTA to clopidogrel in 18,624 ACS patients worldwide.
BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding. In PLATO, there was no statistical difference in patients treated with BRILINTA compared to patients treated with clopidogrel in total major bleeding events (11.6% vs. 11.2%), including fatal and fatal/life-threatening bleeding events.2 Non-CABG (coronary artery bypass graft) major + minor bleeding events (8.7% vs. 7%) were more common with BRILINTA versus clopidogrel.
The most commonly observed adverse reactions associated with the use of BRILINTA vs. clopidogrel were bleeding (11.6% vs.11.2%) and a feeling of breathlessness called dyspnea (14% vs. 8%).
As with all AstraZeneca products, the company will work to ensure that physicians and patients understand both the benefits and risks associated with BRILINTA. For BRILINTA, one of the ways AstraZeneca will help ensure physicians and patients are appropriately informed about bleeding risk and the impact of aspirin dose on the effectiveness of BRILINTA is through a Risk Evaluation Mitigation Strategy (REMS).
According to the American Heart Association, over one million Americans are hospitalized with ACS every year. It is estimated that up to one in three patients could have a recurrent heart attack, or die within one year of their first CV event.¹
BRILINTA is now approved in 39 countries, including the US, Brazil, Australia, and Canada under the trade name BRILINTA and in the European Union under the trade name BRILIQUE™. BRILINTA is currently under regulatory review in an additional 45 countries, including Russia, India and China. BRILINTA is currently reimbursed in 7 countries.
ABOUT PLATO
PLATO was a large (18,624 patients in 43 countries) head-to-head patient outcomes study of ticagrelor versus clopidogrel, both given in combination with aspirin and other standard therapy, designed to establish whether ticagrelor could achieve a clinically meaningful reduction in cardiovascular end points in ACS patients, above and beyond those afforded by clopidogrel.
The study demonstrated that treatment with BRILINTA led to a greater reduction in the primary end point – a composite of CV death, MI, or stroke – compared to patients who received clopidogrel (9.8% vs. 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit versus clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continue to diverge throughout the 12 month treatment period.
The study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21 percent RRR in CV death (4% vs. 5.1%; 1.1% ARR; P=0.001) and a 16 percent RRR in MI compared to clopidogrel at 12 months (5.8% vs. 6.9%; 1.1% ARR; P<0.005).
In a post hoc analysis of PLATO, it was determined that more than 80 percent of patients worldwide, including more than 40 percent of patients in the US, received low maintenance doses of aspirin (100 mg or less). Results for US and non-US patients taking BRILINTA with these low maintenance doses of aspirin were similar. Maintenance doses of aspirin above 100 mg reduced the effectiveness of BRILINTA, and should be avoided. After any initial dose, BRILINTA should be used with maintenance aspirin doses of 75-100 mg per day. As with any unplanned subset analysis, the post hoc analysis should be treated with caution.
IMPORTANT SAFETY INFORMATION ABOUT BRILINTA (ticagrelor) TABLETS
BLEEDING RISK
BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding.
Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage.
Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery.
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA.
If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events.
ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75-100 mg per day.
Risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures and concomitant use of medications that increase the risk of bleeding.
If BRILINTA must be temporarily discontinued, it should be restarted as soon as possible.
The use of BRILINTA is also contraindicated in severe hepatic impairment. BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients treated with clopidogrel. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption.
BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers.
Avoid simvastatin and lovastatin doses greater than 40 mg. BRILINTA will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4.
Monitor digoxin levels with initiation of or any change in BRILINTA therapy, because of inhibition of the P-glycoprotein transporter.
There is limited clinical experience in patients at increased risk of symptomatic bradycardic events. In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively. In a Holter substudy of about 3,000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6%) than with clopidogrel (3.5%), in the acute phase; rates were 2.2% and 1.6% respectively after one month.
The most commonly observed adverse reactions associated with the use of BRILINTA vs. clopidogrel were bleeding (11.6% vs.11.2%) and dyspnea (14% vs. 8%).