Developing New Treatments for Heart Failure Focus on the Heart
Developing New Treatments for Heart Failure Focus on the Heart
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DOI：
10.1161/circheartfailure.115.002727
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发表时间：
2016-05-01
影响因子：
9.7
通讯作者：
Butler, Javed
中科院分区：
文献类型：
--
作者：
Gheorghiade, Mihai;Larson, Christopher J.;Butler, Javed
与20至30年前的心力衰竭（HF）治疗相比，使用阻断适应不良神经激素通路的药物治疗射血分数降低的动态心力衰竭（HF）已经取得了巨大的进步。然而，在过去的十年中，除了少数值得注意的例外，成功的药物开发项目的频率已经下降，因为大多数新疗法未能提供增量益处或引起安全性问题（如低血压）。此外，目前还没有专门针对保留射血分数的HF或恶化的慢性HF（包括急性失代偿性HF）的治疗被批准。在整个HF范围内，许多II期试验的初步结果都很有希望，但随后往往是不成功的III期研究，这突显了基础科学发现、早期药物开发和关键试验中明确临床试验之间转化过程的脱节。心衰药物开发的一个主要未满足的需求是能够识别同质的患者亚群，这些患者的潜在疾病是由特定机制驱动的，可以使用新的治疗药物进行靶向治疗。药物开发策略应该越来越多地考虑通过直接靶向心脏本身来促进反向重塑的治疗方法，而不是严格地专注于卸载心脏或靶向全身神经激素的药物。心脏成像技术的进步可以在药物开发过程的早期更集中、更直接地评估药物对心脏的影响。为了更好地了解和应对当前HF药物开发面临的一系列挑战，以便未来的努力有更好的成功机会，美国食品和药物管理局于2015年2月17日召开了一次会议，由临床医生、研究人员、监管机构和行业代表参加。下面的讨论总结了本次会议的关键要点。
Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeawaydialoguefromthis meeting.