盘点｜EHJ 2019心脏病重点研究梳理系列-心力衰竭

2020年1月22日 343点热度 0人点赞 0条评论

在过去的一年出现了许多有关心力衰竭的新概念，也涌现出许多关于心力衰竭的本质、治疗和预后的大量数据，这些革新的步伐正在加快，我们也期待在未来的十年中会有更多令人兴奋的突破。

心血管疾病的预后在很大程度上取决于我们延缓或预防心力衰竭的发生和发展的能力¹。因此，人们的注意力正逐渐开始转向心力衰竭的早期诊断和干预。譬如，2型糖尿病(T2DM)²或冠心病(CAD)³患者的预后相对较好，但如果血浆利钠肽浓度升高，则提示重要的心脏或肾功能障碍。但是如果采用钠尿肽作为一个简单的心力衰竭“通用定义”，虽然有助于心衰的早期诊断和治疗，然而患病率和医疗服务需求将会大幅度增加⁴。

流行病学和预防

在心脏病学中，“预防”一词常被用来指推迟疾病的发生，换句话说即为“拖延”。认识到“预防”和“拖延”之间的区别非常重要，否则会在制定将来的医疗需求和成本时出现问题。老年人存在更多的并发症，会使疾病的管理变得更为复杂，但也可能需要给他们提供更多的干预机会，因此，管理老年患者需要更多的时间和资源。

来自英国的一份关于心力衰竭的详细报告显示，心衰的中位发病年龄已上升至约80岁，这主要归功于高血压治疗，动脉粥样硬化等其他危险因素管理的改善以及心肌梗死治疗水平的提升。遗憾的是，这一报告中没有提及左心室射血分数(LVEF)的数据。

英国初级保健诊断路径的分析也显示，这项关键的指标也没有完成^6-8。此外，其他国家的类似数据需求也非常迫切^9,10。最近发表的几项大型流行病学调查和对大型试验的分析^11,12有助于在各国之间比较心力衰竭的人口统计学、病因学和管理现状。

盐皮质激素受体拮抗剂（MRA）是有效的降压药物，可以改善LVEF，降低（HFrEF）和保留（HFpEF）心力衰竭患者的预后¹³。目前有研究致力于观察MRA是否能够对其他潜在的促进心力衰竭进展的因素产生作用，譬如炎症和纤维化^14,15。

一项对英国生物银行367703名参与者的分析表明，肥胖的遗传倾向与患心力衰竭的风险升高有关¹⁶。然而，该分析中心力衰竭的发生率仅为1%（4803例），并且诊断标准不健全，风险增加幅度不大（OR 1.22; 95% CI 1.06-1.41）。对这一人群的进一步分析表明，心肺健康和握力与未来心力衰竭的发生率之间有很强的相关性¹⁷。

一项对瑞典4403例考虑进行减肥手术的人群随访22年的研究发现，2003例接受减肥手术（体重减轻25-35公斤; 术后1年BMI 32 kg/m²）的受试者中有188（9%）例出现心力衰竭，而2030例未接受手术（1年后BMI 40 kg/m²）的受试者中有266（13%）例出现心力衰竭¹⁸。

尽管这些数据表明肥胖和患心力衰竭的风险之间存在一定联系，但其实肥胖本身也有可能引发类似的症状。一旦心力衰竭发生，肥胖的患者死亡率较低，但这也可能反映出早期诊断的作用而并非是因为肥胖具有保护作用¹⁹。我们需要有效干预肥胖的随机对照试验（RCT）来证明减肥是否改善症状（有可能）和临床结果（不确定）。

一份来自“社区动脉粥样硬化风险”（ARIC）研究的报告证实了流感与心力衰竭住院之间的联系，加强了指南中对接种流感疫苗的推荐²⁰。

有一项相关的RCT正在进行中²¹。

妇女健康倡议激素治疗试验将27374名女性随机分组接受不同的激素替代治疗，其延长随访（中位随访时间为18.9年）结果显示，这类激素替代治疗对HFrEF或HFpEF的发生率没有影响²²。

ISCHEMIA试验（在2019年美国心脏协会上发表）比较了早期冠状动脉血管重建术（主要是经皮）和保守治疗在稳定性冠心病（部分患者有轻度心衰和/或LVEF降低的症状）中的作用，结果发现血运重建并没有降低心肌梗死或死亡的风险，但却使中风的风险增加了近四倍，而且在4年的随访中并没有减少新发心衰的发生率。

诊断

欧洲心脏病学会心力衰竭协会提出了一种新的诊断HFpEF的评分系统²³。它的实用价值尚有待证实²⁴。目前，首选的还是更为简单的方法⁴。

充血

充血是心衰的核心^25-27。长期以来，一直应用影像学检查来识别心房和静脉系统的扩张，即血液动力学的充血，利钠肽是其有效的生物标志物²⁵。

近年来，影像学检查也可以用于发现组织中的积液（组织充血）^25,28-32，后者可能与生物标志物肾上腺髓质激素的增加相关³³。

影像学和生物标志物的结合对心衰的诊断既敏感又特异，是判断充血严重程度和预后的有用标志，也是治疗的潜在靶点。影像学检查仍然是确定心脏衰竭原因的首选方法。如果充血是心衰治疗的核心，那么相应地进行更好的监测³⁴和更有效的（利尿剂）干预（乙酰唑胺³⁵）应该能够改善预后。

年龄和预后

大型初级保健数据库的分析表明，对于80岁以上及以下的患者，新发心力衰竭的心血管（CV）预后在2002-2014年之间得到了显著改善（HR：0.73；95％CI 0.68–0.80）⁵。然而，在80岁以上的人群中，CV死亡率的下降完全被非CV死亡率的增加所抵消。

换句话说，治疗改变了老年患者的死亡方式，但并未改变整体死亡率（图1）。遗憾的是，研究缺少关于LVEF的信息。许多患者也可能是HFpEF，因此，要将CV死亡率的降低完全归因于心力衰竭的治疗时应谨慎。

调查和注册数据的系统回顾还表明，心力衰竭的预后已有改善。结局的重要决定因素是年龄和治疗中在心脏病方面的投入³⁶。衰弱指数代表生物学年龄而不是生理学年龄，可能是致残和死亡的更强有力的预测指标³⁷。

HFrEF的治疗指南未按年龄区分。瑞典心力衰竭注册研究发现，在年龄大于80岁的HFrEF患者中应用ACEI或β受体阻滞剂可降低死亡率^38,39。但是，这种观察性关联在除治疗效果外还有许多其他解释⁴⁰。

对MRA的三个RCT（RALES，EMPHASIS和TOPCAT-Americas）¹³进行的患者数据荟萃分析表明，对于75岁以上HFrEF的患者，MRA使死亡率降低了约25％，但对于HFpEF的获益尚不确定。

心力衰竭表型的多样性

精准医疗应是准确的，它要求对病人进行准确分类，以提供更多治疗信息。例如，肿瘤学的分类标准集中在遗传基因、肿瘤位置和扩散情况。但是，心脏衰竭是一种多系统疾病，它更加复杂^41-47。

目前，关于心力衰竭的分类标准包括充血的严重程度（根据症状、体征、血液生物标志物和影像学）、CAD、心率和节律、QRS时长、血清钾、肾功能、缺铁的指数、二尖瓣返流、浸润性心肌疾病（如淀粉样变性）和心室表型^41,48。

除了极少数的例外，心衰的最佳治疗方法只需要少量的信息，但这仍然会产生多种患者亚群，他们可能都有着不同的治疗需求^45,46。随着每一种新治疗方法的引入，此类亚群的数量将呈指数增长。尽管有多种可选的干预手段，精确医学在心力衰竭中仍处于起步阶段。

与治疗相关的心衰分类是根据LVEF，它是左心室（LV）扩张的替代指标。在1980年代以前，只有非常专业的中心才具备能获取心功能指标的影像。那个年代的临床试验主要依靠胸部X光片而不是超声心动图来对心力衰竭进行诊断。

其后，诸如SOLVD、MERIT和CHARM等试验都将LVEF减低作为纳入标准，这些试验的成功促使欧洲心脏病学会（ESC）采用LVEF<40%作为HFrEF的标准定义⁴⁹。LVEF≥40%被定义为HFpEF，其中包括射血分数中间范围或射血分数轻度减低患者（HFmrEF）、正常（HFnEF）甚至超常（HFsnEF）的患者⁵⁰。

一项纳入>350000个定期收集的超声心动图的分析表明，无论患者是否诊断为心衰，LVEF 60-65%时风险最低。有趣的是，>70%的LVEF与30-40%的LVEF的风险相似（图2）⁵⁰。

2016年的ESC指南引入了HFmrEF的概念，主要有两个原因。首先，由于超声心动图测量的精确性不高，无法在10%范围内可靠的区分两个LVEF测量值。在HFrEF和HFnEF之间创建缓冲区意味着患者被错误分类的可能性会降低。这一创新性的概念意味着，一项HFpEF试验不能仅根据研究对象在LVEF 40-49%中的疗效，就称其对所有LVEF>40%的患者都有益。

其次，HFmrEF概念的引入挑战了LVEF<40%作为HFrEF的正确阈值的惯例。2016年ESC指南之后的一些分析表明，LVEF<50%的患者对治疗的反应与LVEF<40%的患者相似⁵¹。然而，这种结果可能反映了HFmrEF的狂热支持者的证实性偏见（表1）。

从整体上看，证据并不那么一致，特别是如果死亡率被视为一个关键结果时。将来许多试验将可能同时包括HFrEF和HFmrEF患者，甚至有些试验将包括HFmrEF、HFnEF和HFsnEF，但NT-proBNP应常规用于风险分层，并排除那些从药物治疗中获益甚微的低风险患者。

假设我们继续使用LVEF对患者进行分类，那么主要的问题是诊断阈值应该设为多少。对于HFrEF来说，不同的试验间也有很大的差异，如COPERNICUS的<25%，MADIT-II的<30%和RAFT的<35-40%等⁵¹。对于HFpEF，LVEF通常设置为>40%或>45%，没有上限。

最近的试验分析表明，对于NT-proBNP升高的患者，HFmrEF的LVEF上限应该提高到55%甚至60%，但目前似乎还为时过早，除非多个干预措施和临床终点的一致性得到证明，以及LVEF的测量精度得到提高。

在一项关于HFpEF和肺动脉高压的大型观察性研究中，研究者们观察到了右心室功能障碍而非左心室功能障碍的进展，并发现其与房颤和死亡的风险增加相关⁵²。尽管右心室功能障碍是一种强有力的预后标志物，但目前很少有关注右心室功能障碍的试验。

心房纤颤

约三分之一的门诊患者，尤其是那些HFpEF患者，以及超过半数的心力衰竭患者会出现AF，即使在校正了年龄和其他危险因素后，AF仍与不良预后相关⁵⁴。关于房颤合并心力衰竭的患者疾病管理的最佳策略究竟是控制心率还是恢复窦性心律，其争论仍在继续。

在临床实践中，治疗策略需要根据病人的情况进行调整。当房颤是症状和心功能恶化的主要驱动因素时，恢复窦性心律是合适的；但当房颤只是反映了潜在的心功能障碍的进展时，坚持恢复窦性心律可能就不合适了⁵⁵。

对于新发或阵发性房颤伴有明显症状恶化的患者，恢复窦性心律可能有助于改善症状。对于长期房颤和心房明显扩张的心力衰竭，恢复窦性心律和恢复心房收缩力的可能性较小。最佳的药物治疗方案包括抗凝、避免使用有毒的抗心律失常药物和宽松的心室率控制范围。

β受体阻滞剂是控制心率的首选药物，最好是将静息时心室率控制在70-90次/分⁴⁹；地高辛应该少用。遗憾的是，对比节律与心率控制的随机对照试验未能明确何为最佳的药物治疗策略。

有荟萃分析纳入四项对比节律控制与心率控制药物治疗策略的RCT试验(n= 2486)，结果发现两组患者的死亡率或血栓栓塞事件无差异，但因节律控制组的住院次数有所增加，尤其是因房颤而住院⁵⁶。

一项纳入6项比较房颤消融和心率控制的有效性试验(n= 1112)，发现射频消融降低了死亡率(0.51;95% CI 0.36-0.74)、再住院率(0.44;95% CI 0.26-0.76)、中风率(0.59:95% CI 0.23-1.51)，并改善生活质量⁵⁶。

然而，没有一个单独的试验能够提供一个可靠有力的结果，病人存在选择偏倚且心率控制策略不是最优的。因此，这个荟萃分析的结果应该被认为只是提出了一个假设，需要更多心力衰竭医生参与后续进一步的试验。

植入性装置

关于高能量的植入性装置在治疗心力衰竭中的作用的争论仍在继续。法国一项关于心脏再同步化治疗(CRT)的长期随访研究显示，接受CRT起搏（不使用除颤器）的患者的猝死率较低^57-59。

观察性研究和随机对照试验进行的系统回顾报告显示，CRT起搏和CRT-D在预防猝死方面的有效性差异正在缩小⁵⁸。

比较CRT起搏和CRT-D的随机对照试验正在进行中⁵⁹（Take home figure）。

根据心脏磁共振成像明确是心肌瘢痕情况是否能够帮助判断患者能否从植入式心律转复除颤器(ICD)中获得更多的益处还在研究当中⁶⁰。

SCD-HeFT研究的回顾性分析发现，2型糖尿病患者无法从ICD获益⁶¹。

一项患者个体数据水平的荟萃分析证实了MRA可减少猝死⁶²。

一项系统综述分析了22项对ICD植入者进行尸检的研究，发现24%的猝死不是心律失常导致的⁶³。

一项关于多点起搏的试验提示CRT不能改善临床或超声心动图的表现⁶⁴。

二尖瓣关闭不全

COAPT研究显示，经皮二尖瓣钳夹术可减少功能性（继发性）二尖瓣反流，显著改善发病率和死亡率，在美国医疗环境中具有中等成本效益（每生命年增加40361美元，每质量调整生命年增加55600美元）^65-68。MITRA.fr的两年随访结果则表明二尖瓣钳夹术无任何益处⁶⁹。

造成这种明显差异的一个可能原因是两个研究中左室功能障碍的严重程度与二尖瓣返流的严重程度之比存在差异^70,71。当返流程度与左室功能障碍的严重程度不成比例时，可能会导致疾病进展，纠正反流可能会改善预后。当返流与左室功能障碍的严重程度成比例时，修复二尖瓣返流则可能不太有用，因为心肌功能障碍仍然会导致疾病进展。这一概念简单而合理，但在实践中可能难以应用。

二尖瓣返流可减轻左室负荷，可能导致掩盖心脏功能障碍的情况。二尖瓣返流分为原发性和继发性的，有些患者的情况复杂，二者并存。更多的经验和更多的随机对照试验数据可能会帮助指导挑选出何种患者可从手术中获益。然而，优化指南推荐的治疗，包括利尿剂的剂量，可能帮助改善或解决继发于左室和二尖瓣环扩张的二尖瓣返流。目前还有一些其他正在开发的用于治疗二尖瓣返流⁷²和三尖瓣反流^73,74的技术。

冠脉疾病

在COMPASS（n=27395）研究中，研究者将5902名患有CAD并被诊断为心力衰竭（主要为HFpEF）的患者随机分配接受阿司匹林100mg /天或利伐沙班5mg bd或阿司匹林+利伐沙班2.5mg bd治疗^75,76。该研究因主要终点（心血管死亡，中风或心肌梗死的综合症状）显著获益而提前停止。

进一步的分析表明，分配给联合治疗（HR：0.63；0.44-0.90）或单独使用利伐沙班（HR：0.75；0.53-1.06）的心力衰竭患者的全因死亡率降低，2年绝对差异为4％；获益与与沙库巴曲缬沙坦⁷⁷、达格列净⁷⁸（图3）在HFrEF患者中的作用程度相似。

这表明冠状动脉事件可能是导致HFpEF死亡的重要驱动因素(Take home figure)，利伐沙班对内皮功能、炎症反应和纤维化的影响不容小视。分析还表明，没有心力衰竭的人从利伐沙班的额外治疗中获益很少。

然而，对于HFrEF、窦性心律、近期因出院而导致心力衰竭加重的CAD患者，在基础的抗血小板治疗中加入利伐沙班2.5mg bd并不能改善总体预后，尽管有多种血管不良事件发生率减低（中风、心肌梗死以及猝死，主要是中风的减少）^79,80。这表明，对于稳定的CAD和更严重的心力衰竭患者，因心力衰竭加重而导致的住院治疗以及死亡不会受到抗血栓形成治疗的影响。

血管紧张素受体-脑啡肽酶抑制剂

射血分数降低的心力衰竭

随着在临床试验和临床实践中应用血管紧张素受体-脑啡肽酶抑制剂（ARNIs）的经验积累，研究有充分的理由将其视为用于治疗HFrEF的一线药物，而不是血管紧张素转化酶抑制剂（ACEi）或血管紧张素受体阻滞剂（ARB）。

在PIONEER-HF中⁸¹，因心衰加重住院的LVEF≤40％的881名患者被随机分配到沙库巴曲/缬沙坦或依那普利组，并随访8周以明确这类药物对NT-proBNP的血浆浓度的影响。其中大约三分之一的人患有新发心力衰竭。沙库巴曲/缬沙坦能够更显著地降低NT-proBNP的水平，同时还观察到其降低心肌损伤或应激、高敏感性心肌肌钙蛋白-T和可溶性ST2标记物的作用。这些效应在随机分组后的早期（1-4周内）即可出现。此外，接受沙库巴曲/缬沙坦治疗的患者在头8周内发生不良事件的风险低于依那普利对照组。

TRANSITION研究⁸²将1002例患者随机分配接受沙库巴曲/缬沙坦治疗，结果提示该药物早期给药无不良影响。

EVALUATE⁸³比较了沙库巴曲/缬沙坦和依那普利对HFrEF的主动脉僵硬度的影响，其中大多数受试者已经接受ACEi或ARB的长期治疗。治疗24周后，尽管主动脉僵硬程度方面与依那普利组的变化相似，但与依那普利相比，沙库巴曲/缬沙坦组的左室舒张末期和收缩期容积的略有减低；二尖瓣E波速度和左心房容量也有所下降，与左心房压力下降相一致。

观察性研究PROVE-HF⁸⁴也有相似的发现，并显示NT-proBNP的下降大部分发生在14天之内，这与在试验和临床实践中观察到的沙库巴曲/缬沙坦的临床早期获益相一致。

PRIME⁸⁵是一项RCT（n=118），用于比较沙库巴曲/缬沙坦和缬沙坦单药对LVEF在25％-49％之间已接受ACEi或ARB的患者的功能性二尖瓣关闭不全的影响。接受沙库巴曲/缬沙坦治疗的患者二尖瓣反流、左室舒张末期和左心房容积的减少程度更为明显，但两组左室射血分数增加的幅度均很小（约2.5％）。

PARADIGM-HF的进一步研究表明，与依那普利相比，沙库巴曲/缬沙坦可能能够改善胶原蛋白的代谢指标，尤其是减少I型胶原蛋白的合成，后者对增加心肌的硬度起重要作用⁸⁶。在IPRESERVE中，与安慰剂相比，厄贝沙坦对胶原蛋白生物标志物无明显影响⁸⁷。

射血分数保留的心力衰竭

PARAGON-HF研究在HFpEF（定义为LVEF>45％）患者中对比了沙库巴曲/缬沙坦与单药缬沙坦对发病率和死亡率的影响⁸⁸。这是自PEP-CHF⁸⁹以来首次要求患者使用利尿剂（可缓解充血症状和体征的一线治疗药物）治疗并由超声心动图提供心脏功能障碍证据的RCT。这也是HFpEF患者中进行的第一个大型试验，该试验要求所有受试者的血浆利钠肽浓度异常升高，这也是HFpEF中功能最强大、最广泛使用的可提示预后的标记物。本研究将沙库巴曲/缬沙坦与缬沙坦而不是安慰剂进行了比较，因为PARAGON-HF的受试者均存在ACEi和ARB的适应证，例如高血压和CAD。此前唯一将缬沙坦与安慰剂在HFpEF中进行比较的试验显示的是中性的结果⁹⁰。

以前的其他ARB的随机对照试验，包括坎地沙坦（CHARM-Preserved）和厄贝沙坦（I-PRESERVE）均未能显示出对HFpEF有任何实质性获益⁸⁸。患者在随机化前必须以一半的预期目标剂量依次耐受缬沙坦和沙库巴曲/缬沙坦，这模拟了临床实践（医生通常不会给不愿或不能服药的患者开药），并降低了由于依从性低而导致中性试验结果的风险。在筛选的10539名患者中，有4822例完成随机分配。

PARAGON-HF的主要终点结果为中性的（CV死亡或因心力衰竭而再次住院）⁹¹。（图4）有人认为P值非常接近0.05，结果“几乎”为阳性的。这也是关键所在。该试验表明，无论P值如何，沙库巴曲/缬沙坦对HFpEF患者的潜在益处均不大。总体而言，该治疗不太可能具有可行的成本-效益比。因此，我们应该寻找更有效的治疗方法，或者寻找能从中获益的亚组人群。

在中位随访35个月后，有23％的患者发生了一次主要不良事件，但是CV的年发生率和全因死亡年发生率仅分别为3％和5％，这与以前的关于HFpEF的试验相似以及在HYVET中被分配给安慰剂组的老年顽固性高血压患者相似⁹²。

尽管据报道，只有不到3％的患者在HYVET中发生心力衰竭，但吲达帕胺和培哚普利的组合降低了全因死亡率，并使心力衰竭的发生率降低了50％以上。这些患者中有许多可能在随机分组之前存在未经诊断的HFpEF。

与高血压试验相比，HFpEF试验中因心力衰竭而住院的比率更高，这很可能反映出研究潜在的测量偏倚，即对心力衰竭治疗感兴趣或有经验的临床医生更有可能诊断或报告心力衰竭事件。

总体而言，这些试验表明，无论是否诊断为HFpEF，如果患者有相似的合并症负担，其死亡率以及心血管疾病和各种原因住院的比率可能是相似的。但是也提示我们，许多高血压、CAD和T2DM的患者也很可能存在未诊断的心力衰竭。

亚组分析表明，在左室射血分数低于中位数（57％）的患者中，沙库巴曲/缬沙坦对主要终点的影响更大，但这几乎完全是由因心衰住院而不是心血管死亡引起的⁹³。此外，沙库巴曲/缬沙坦对女性患者的主要终点的影响也更大，无论LVEF水平如何都是如此，这也同样是由于因心衰住院率增加而不是心血管死亡率增加所致⁹⁴。

NT-proBNP的降低在不同性别中都类似。沙库巴曲/缬沙坦似乎对改善男性患者的生活质量有有益影响，但对女性患者却没有。新近发生心力衰竭而住院的患者的获益也更加明显⁹⁵。理解这些分析观察结果应同时结合其在主要终点方面的中性结果。研究中没有观察到药物对死亡风险的影响，且不同性别中药物对生活质量和住院风险的影响也存在差异。

在PARADIGM-HF研究中并未发现药物疗效存在性别差异。在HFpEF患者中进行的样本量更大的RCT研究PARALLAX-HF旨在探究沙库巴曲/缬沙坦对生活质量和运动能力的影响，将在2020年为临床实践提供更多参考证据。

药物疗效在女性和男性中有所不同吗?

针对两项大型临床试验中的12058例HFrEF患者的一项分析发现，即使在调整了病因学和NT-proBNP等关键预后变量后，女性患者的症状比男性患者更为严重，二者LVEF相似，但女性患者预后明显好于男性（HR：0.68；0.62-0.89）⁹⁶。

对PARAGON-HF和PARADIGM-HF这两项研究的联合分析表明，HFrEF和HFpEF患者的生活质量的下降幅度类似，但女性患者的生活质量普遍低于男性⁹⁷。

在一项针对HFrEF患者的观察性分析中，BIOSTAT研究也发现，尽管女性患者的β受体阻滞剂和血管紧张素转换酶抑制剂的治疗剂量较低，但女性的预后通常优于男性⁹⁸。有趣的是，男性和女性患者的心率是一样的，而心率是指导β受体阻滞剂剂量的药效学指标。

对于TOPCAT试验中的HFpEF患者，女性患者的死亡率下降幅度更大，但心力衰竭住院率则没有明显差异⁹⁹。

在PARAGON-HF试验（HFpEF）中，无论LVEF多少，女性患者的获益大于男性，但这种差异主要来源于因心力衰竭住院率的差异（而非死亡率）⁹⁴。男性和女性患者的一个明显区别是身材的差异性。心脏再同步化治疗被认为在女性患者的有效性优于男性，但一旦根据身高进行调整，差异性就消失了¹⁰⁰。

许多药物经肾脏排出，肾小球滤过率（eGFR）通常与体表面积（BSA）相关，但治疗药物的剂量通常不会根据体表面积进行调整。根据Dubois公式，体重64公斤、身高160厘米的女性（或小个子男性）的BSA为1.67平方米；体重85公斤、身高180厘米的男性（或大个子女性）的BSA为2.05平方米。

那么女性（或小个子男性）的eGFR为100mL/min，而男性（或大个子女性）的eGFR为123mL/min。如果一种药物经肾脏被代谢清除，那么是否小个子的人需要减低剂量以达到同样的血浆治疗浓度和临床效益？

钠-葡萄糖协同转运蛋白-2 (SGLT2)抑制剂

钠-葡萄糖协同转运蛋白-2 (SGLT2)主要存在于肾近端小管，在其他器官也有分布，但分布较少，SGLT1在肠和心肌中含量丰富。SGLT2抑制剂(SGLT2i)可增加尿液中的含糖量，改善血糖控制情况，使其发展成为治疗T2DM的药物，并可导致渗透性利尿，降低血浆容量^101,102。

SGLT1抑制剂可降低肠道对葡萄糖的吸收，从而导致腹泻，但可对心肌能量的利用产生有利的影响¹⁰³。大多数SGLT2i具有高度选择性，包括达格列净和恩格列净，但索格列净的选择性较差¹⁰³。

EMPA-REG纳入了7020例T2DM患者，其中约10%有心力衰竭（未测量LVEF），结果显示恩格列净降低了因心力衰竭住院和死亡的风险¹⁰⁴。在开始服用恩格列净的几周内，体重和血压下降，红细胞压积上升，符合其利尿作用的影响。随后其他在T2DM患者进行的关于SGLT2i的RCT也有类似的发现。

有荟萃分析表明，SGLT2i是最有降低心衰发生率的潜能降糖药^105-107，同时有一些观察数据引起了对胰岛素治疗的关注¹⁰⁸。

对恩格列净、卡格列净和达格列净治疗T2DM的随机对照试验（包括>3万名患者）进行的荟萃分析显示，这类药物能够为已确诊的CV患者带来获益¹⁰⁹。

在因心衰住院或心血管死亡方面，在合并有多个危险因素但是没有已诊断的心血管疾病的13672名患者中年发生率为0.6%，在已经有粥样硬化疾病的20650例患者中年发生率为3%，在基线时就存在心率事件的3891例患者中发生率为6%；这些人群中SGLT2i可分别使上述不良事件风险降低16%、24%、29%，没有证据表明各种SGLT2i之间存在异质性。

在这些试验中，规模最大的DECLARE¹¹⁰包括17160例患者，其中671例患有HFrEF, 1316例患有HFpEF或LVEF不明。在亚组分析中¹¹¹，达格列净降低了HFrEF患者的因心力衰竭住院的发生率和CV死亡率，但没有降低其他患者组的死亡率（图5）。

DAPA-HF^78,112纳入了4744名患者，平均随访18.3个月，证明在指南推荐的治疗方案的基础上加用达格列净可将HFrEF患者的住院风险30%、死亡率降低18%，每治疗100名患者每年可预防3-5例住院、2例死亡（图6）。与安慰剂相比，达格列净几乎不会出现严重药物相关不良事件，尤其是肾脏相关事件。

这些益处在不同的亚组中似乎是一致的，尽管有证据表明充血更严重（更差的NYHA等级或更高的NT-proBNP）的患者可能获益更少。重要的是，不论年龄大小，T2DM患者和非T2DM患者的获益是相似的¹¹³。达格列净改善了生活质量¹¹⁴。

另一项较小的RCT研究（DEFINE）¹¹⁵对263个病人随访了12周证实了这一结果；与安慰剂相比，大约六分之一的患者获益，无论是预防症状恶化还是改善症状。

在DAPA-HF中，从研究初始到服药后8个月，经安慰剂校正的体重下降为0.87kg，这与NT-proBNP和收缩压的小幅下降以及红细胞压积和血清肌酐的小幅升高有关。

这些发现再次证实了SGLT2i可增加利尿、利用糖尿的渗透作用、干扰肾单元中的钠-氢交换等机制发挥它们的治疗作用¹¹⁶。SGLT2i的作用出现较早，与服药后即刻的血流动力学作用一致。然而，也有研究对SGLT2i的影响已经提出了替代或补充的解释。

一个小的RCT表明恩格列净可刺激红细胞生成素的产生，导致红细胞压积上升和铁蛋白下降，铁蛋白是炎症和缺铁的标志物，不影响铁蛋白饱和度（铁蛋白饱和只是缺铁的标志物）¹¹⁷。

然而，在RED-HF试验中，给予外源性促红细胞生成素并没有降低发病率或死亡率¹¹⁸。还有人提出SGLT2i可增加酮类物质的产生，后者可能是更有效的心肌能量底物；阻断心肌钠-氢交换器-3，改善心肌功能，减少纤维化^119,120。

一项RCT研究¹²¹在无心衰的T2DM患者中使用恩格列净，发现其对心功能和心脏重塑无明显作用。我们正在等待对比SGLT2i对HFrEF和HFpEF患者心脏功能影响的随机对照试验。未来的试验将确认在DAPA-HF中观察到的益处是否属于类效应，以及它们对HFpEF或在充血较严重的患者是否有效^122,123。

急性心力衰竭

关于serelaxin（重组人松弛素-2）的两个大型RCT研究都未能证实最初的RELAX-AHF¹²⁴试验的结果。RELAX-AHF-EU是一项开放标签的RCT （n=2688），其结果提示serelaxin组和安慰剂组的低死亡率（≤2%）和14天心衰再入院率（<1%）无明显差异，尽管serelaxin组5天内心衰恶化率有所降低了[6.7% - 4.5% （P < 0.008）]。

双盲RCT（n=6545)）RELAX-AHF-2¹²⁵试验发现，安慰剂组和serelaxin组的前5天心衰恶化率（约7%）和180天死亡率（约11%）相似。

如此多的AHF短期干预措施相关研究的失败可能反映了这一治疗理念的失败、干预措施的无效或试验设计存在问题。有关AHF的RCT很难实施，尤其是在双盲的情况下。

事实上，还有一项GALACTIC研究使用硝酸盐和氢丙嗪进行个性化、早期强化和持续血管舒张治疗的试验也未能显示出益处，这让人对血管舒张药用于急性心力衰竭常规治疗的做法产生了质疑¹²⁶。许多病人在半夜出现严重的呼吸困难，但是很难让研究人员全天候24小时待命。存在感情因素的研究人员也可能不愿意入选那些最容易出现不良结果的体弱老年患者。

此外，呼吸困难通常在数小时内就可对氧气和利尿剂产生反应¹²⁷，特别是对收缩压为≥125mmHg的患者，而这却是serelaxin相关试验的要求之一。另一方面，广泛的外周水肿²⁶、肾功能不全和低血压的患者往往不是急诊病例常见表现，但是预后差，需要更有效的干预措施，包括药物或装置^127,128。

干细胞疗法

心肌内注射干细胞不能帮助进行左心室辅助装置的脱机¹³⁰。

癌症患者的心脏衰竭

对心脏肿瘤学的关注反映了癌症生存率的提高，对已诊断的和新发的癌症治疗相关的CV毒性认识的增强，以及对化疗前的个性化风险评估的认识。与心肌病相关的基因突变的患者在接受化疗后可能更容易出现心室功能障碍（7.5% vs. 1.1%）¹³¹。

高入侵HER2þve早期乳腺癌患者中断曲妥珠单抗会导致癌症复发的风险增加，其中大约60%的中段用药都是由于心脏毒性¹³²。

一项观察性研究显示，在30名接受靶向治疗的LVEF为40-49%并前瞻性地使用β受体阻滞剂和血管紧张素转换酶抑制剂的女性中，只有3名女性最终发展为严重的心力衰竭或LVEF <35%¹³³；心功能在治疗结束后几乎不会恢复正常，这对曲妥珠单抗相关的左室功能障碍通常是可逆的观点提出了挑战。

最近的一项研究报告显示，在接受强效蛋白酶体抑制剂（如carfilzomib和bortezomib）治疗的多发性骨髓瘤患者中，CV事件，特别是心力衰竭的发生率很高¹³⁴，导致生存率的减低。发生CV事件的危险因素包括治疗前NT-proBNP升高或治疗期间这一指标的升高。

对预防性使用肾素-血管紧张素-醛固酮拮抗剂和β受体阻滞剂的系统回顾发现了22个相关的随机对照试验，其中最大的仅有206例患者^135,136，但没有发现有说服力的临床疗效证据。

实施治疗

对英国基层医疗机构管理数据的分析表明，在过去的十年中，尽管许多患者的剂量仍低于目标剂量，但现在有72％的患者接受了β受体阻滞剂的治疗，这已大大改善了治疗现状⁶。

在威尔士和英格兰，患有HFrEF的患者中有89％在出院时都接受β-受体阻滞剂治疗，这与在ESC-EURO观察性心力衰竭长期注册计划中入选的HFrEF患者中观察到的情况非常相似¹³⁷。

但是，对美国医疗保险受益人的分析发现，只有51％的HFrEF患者在首次或因心力衰竭再次住院治疗后接受β受体阻滞剂治疗，12％的患者接受了1年至少≥50％的目标剂量治疗¹³⁸。这表明HFrEF的护理组织对治疗产生了重要影响，进而影响患者的预后。

但是，一项群组RCT（n=2494）研究旨在改善医院到家庭的医疗过渡，其中包括自我保健教育，结构化的出院摘要，1周内家庭医生的随访以及高风险患者的家庭访视，但这些措施并没有实质性改善患者的健康状况或临床结局¹³⁹。

一项RCT（n=110）表明，定期（每月几次）去社区药房可以改善药物依从性和幸福感¹⁴⁰。

有纳入450例患者的RCT发现，电子医疗干预在开始后的前3个月有益于自我保健行为和改善生活质量¹⁴¹，但此后便没有改善作用，且对住院或死亡率没有影响。

复杂干预的RCT失败的原因有很多，包括干预强度不足，试验设计欠佳，对对照组的护理已经非常完善，工作人员和患者缺乏长期参与动力，接受药物干预的患者群体是无效的（例如HFpEF）。我们还需要更多证据，从过去的经验中学习¹⁴²。

康复

系统回顾表明，以运动为基础的康复治疗可以改善患者的健康状况和运动能力，减少与心力衰竭相关的和所有原因的住院治疗率，但不能降低死亡率，还有可能提高治疗的依从性^143-147。何为最佳和最经济的服务模式是一个需要积极研究的课题^148,149。

姑息治疗

吗啡可缓解慢性肺病患者的慢性呼吸困难症状，但有关心力衰竭的数据却很少。纳入45例患者的RCT未能显示吗啡对HFrEF或NYHA功能III级的HFpEF患者有任何重要临床益处¹⁵⁰。

心功能恢复后停止对心力衰竭的治疗

对于那些心室功能完全恢复的特发性或遗传型扩张型心肌病患者，如果要退出治疗，必须非常谨慎¹⁵¹。虽然LVEF恢复 (HFrcEF)的患者预后可能较好，但也有仍然不佳的可能¹⁵²。需要对围产期和其他特殊类型的心肌病还需要进行进一步的研究。

最近一份来试验报告表明，停用地高辛与因心力衰竭住院的风险增加有关，但对死亡率没有影响¹⁵³。

来自巴西的纳入188例稳定型心衰患者的RCT显示，75%的患者可以至少停用襻利尿剂90天而不至出现症状恶化、需要重新进行利尿剂治疗或血浆NT-proBNP升高¹⁵⁴。

这与英国的一个较小的RCT形成鲜明的对比，在英国这项研究中，停用利尿剂和其他疗法48小时将会导致NTproBNP的血浆浓度增加一倍，左室和左房容积增加，症状恶化¹⁵⁵。

结论

在过去的一年中，关于心力衰竭的认识和治疗取得了很大的进展。新的争论和新的证据对许多旧的观念提出了挑战。一如既往，一些人会抵制进步，而另一些人会拥抱进步。作为读者，你们必须帮助我们的专业人士和患者在鲁莽的热情与诊断和治疗惰性之间找到合适的平衡点。

扫描上方二维码查阅原文

参考文献

1. Torabi A, Rigby AS, Cleland J. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol 2009;55:79–81.

2. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez-Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579–1588.

3. Zhang C, Jiang L, Xu L, Tian J, Liu J, Zhao X, Feng X, Wang D, Zhang Y, Sun K, Xu B, Zhao W, Hui R, Gao R, Yuan J, Song L. Implications of N-terminal pro-B-type natriuretic peptide in patients with three-vessel disease. Eur Heart J 2019;40:3397–3405.

4. Cleland JGF, Pellicori P, Clark AL. Prevention or procrastination for heart failure? Why we need a universal definition of heart failure. J Am Coll Cardiol 2019;73:2398–2400.

5. Conrad N, Judge A, Canoy D, Tran J, Pinho-Gomes AC, Millett ERC, Salimi-Khorshidi G, Cleland JG, McMurray JJV, Rahimi K. Temporal trends and patterns in mortality after incident heart failure: a longitudinal analysis of 86000 individuals. JAMA Cardiol 2019;4:1102.

6. Conrad N, Judge A, Canoy D, Tran J, O’Donnell J, Nazarzadeh M, Salimi-Khorshidi G, Hobbs FDR, Cleland JG, McMurray JJV, Rahimi K. Diagnostic tests, drug prescriptions, and follow-up patterns after incident heart failure: a cohort study of 93,000 UK patients. PLoS Med 2019;16:e1002805.

7. Bottle A, Kim D, Aylin P, Cowie MR, Majeed A, Hayhoe B. Routes to diagnosis of heart failure: observational study using linked data in England. Heart 2018;104:600–605.

8. Kim D, Hayhoe B, Aylin P, Majeed A, Cowie MR, Bottle A. Route to heart failure diagnosis in English primary care: a retrospective cohort study of variation. Br J Gen Pract 2019;69:e697–e705.

9. Filippatos G, Angermann CE, Cleland JGF, Lam CSP, Dahlstro¨m U, Dickstein K, Ertl G, Hassanein M, Hart KW, Hu D, Lindsell CJ, Perrone SV, Guerin T, Ghadanfar M, Schweizer A, Obergfell A, Collins SP. Global differences in acute heart failure patient characteristics, precipitants, point of hospital entry and in-patient management: an analysis from REPORT-HF, a worldwide, prospective heart failure disease registry. JAMA Cardiol 2019;in press.

10. Dokainish H, Teo K, Zhu J, Roy A, AlHabib KF, ElSayed A, Palileo-Villaneuva L, Lopez-Jaramillo P, Karaye K, Yusoff K, Orlandini A, Sliwa K, Mondo C, Lanas F, Prabhakaran D, Badr A, Elmaghawry M, Damasceno A, Tibazarwa K, Belley-Cote E, Balasubramanian K, Islam S, Yacoub MH, Huffman MD, Harkness K, Grinvalds A, McKelvie R, Bangdiwala SI, Yusuf S; INTER-CHF Investigators. Global mortality variations in patients with heart failure: results from the International Congestive Heart Failure (INTER-CHF) prospective cohort study. Lancet Glob Health 2017;5:e665–e672.

11. Dewan P, Rorth R, Jhund PS, Ferreira JP, Zannad F, Shen L, Kober L, Abraham WT, Desai AS, Dickstein K, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, McMurray J. Income inequality and outcomes in heart failure: a global between-country analysis. JACC Heart Fail 2019;7:336–346.

12. Dewan P, Jhund PS, Shen L, Petrie MC, Abraham WT, Atif AM, Chen CH, Desai AS, Dickstein K, Huang J, Kiatchoosakun S, Kim KS, Kober L, Lai WT, Liao Y, Mogensen UM, Oh BH, Packer M, Rouleau JL, Shi V, Sibulo AS Jr, Solomon SD, Sritara P, Swedberg K, Tsutsui H, Zile MR, McMurray J. Heart failure with reduced ejection fraction: comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe and the Americas. Eur J Heart Fail 2019;21:577–587.

13. Ferreira JP, Rossello X, Eschalier R, McMurray JJV, Pocock S, Girerd N, Rossignol P, Pitt B, Zannad F. MRAs in elderly HF patients: individual patient-data meta-analysis of RALES, EMPAHSIS-HF, and TOPCAT. JACC Heart Fail 2019;7:1012–1021.

14. Ferreira JP, Rossignol P, Pizard A, Machu JL, Collier T, Girerd N, Huby AC, Gonzalez A, Diez J, Lopez B, Sattar N, Cleland JG, Sever PS, Zannad F. Potential spironolactone effects on collagen metabolism biomarkers in patients with uncontrolled blood pressure. Heart 2019;105:307–314.

15. Pellicori P, Ferreira JP, Mariottoni B, Brunner-La Rocca H-P, Ahmed FZ, Verdonschot J, Collier T, Cuthbert JJ, Petutschnigg J, Mujaj B, Girerd N, Gonza ´lez A, Clark AL, Cosmi F, Staessen JA, Heymans S, Latini R, Rossignol P, Zannad F, Cleland JGF. Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure: rationale, design and baseline characteristics of a proof-of-concept, randomised, precision-medicine, preven-tion trial. The Heart OMics in AGing (HOMAGE) trial. Eur J Heart Failure 2019; in press.

16. Larsson SC, Back M, Rees JMB, Mason AM, Burgess S. Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. Eur Heart J 2019;doi: 10.1093/eurheartj/ehz388.

17. Sillars A, Celis-Morales CA, Ho FK, Petermann F, Welsh P, Iliodromiti S, Ferguson LD, Lyall DM, Anderson J, Mackay DF, Pellicori P, Cleland J, Pell JP, Gill JMR, Gray SR, Sattar N. Association of fitness and grip strength with heart failure: findings from the UK biobank population-based study. Mayo Clin Proc 2019;94:2230–2240.

18. Jamaly S, Carlsson L, Peltonen M, Jacobson P, Karason K. Surgical obesity treatment and the risk of heart failure. Eur Heart J 2019;40:2131–2138.

19. Zhang J, Begley A, Jackson R, Harrison M, Pellicori P, Clark AL, Cleland J. Body mass index and all-cause mortality in heart failure patients with normal and reduced ventricular ejection fraction: a dose-response meta-analysis. Clin Res Cardiol 2019;108:119–132.

20. Kytomaa S, Hegde S, Claggett B, Udell JA, Rosamond W, Temte J, Nichol K, Wright JD, Solomon SD, Vardeny O. Association of influenza-like illness activity with hospitalizations for heart failure: the atherosclerosis risk in communities study. JAMA Cardiol 2019;4:363–369.

21. Loeb M, Dokainish H, Dans A, Palileo-Villanueva LM, Roy A, Karaye K, Zhu J, Liang Y, Goma F, Damasceno A, AlHabib KF, Yonga G, Mondo C, Almahmeed W, Al MA, Yusuf S. Randomized controlled trial of influenza vaccine in patients with heart failure to reduce adverse vascular events (IVVE): rationale and design. Am Heart J 2019;212:36–44.

22. Liu L, Klein L, Eaton C, Panjrath G, Martin LW, Chae CU, Greenland P, Lloyd-Jones DM, Wactawski-Wende J, Manson JE. Menopausal hormone therapy and risks of first hospitalized heart failure and its subtypes during the intervention and extended postintervention follow-up of the women’s health initiative randomized trials. J Card Fail 2019;doi: 10.1016/j.cardfail.2019.09.006.

23. Pieske B, Tschope C, de Boer RA, Fraser AG, Anker SD, Donal E, Edelmann F, Fu M, Guazzi M, Lam CSP, Lancellotti P, Melenovsky V, Morris DA, Nagel E, Pieske-Kraigher E, Ponikowski P, Solomon SD, Vasan RS, Rutten FH, Voors AA, Ruschitzka F, Paulus WJ, Seferovic P, Filippatos G. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2019;40:3297–3317.

24. Ho JE, Zern EK, Wooster L, Bailey CS, Cunningham T, Eisman AS, Hardin KM, Zampierollo GA, Jarolim P, Pappagianopoulos PP, Malhotra R, Nayor M, Lewis GD. Differential clinical profiles, exercise responses, and outcomes associated with existing HFpEF definitions. Circulation 2019;140:353–365.

25. Pellicori P, Shah P, Cuthbert J, Urbinati A, Zhang J, Kallvikbacka-Bennett A, Clark AL, Cleland J. Prevalence, pattern and clinical relevance of ultrasound in-dices of congestion in outpatients with heart failure. Eur J Heart Fail 2019;21:904–916.

26. Shoaib A, Mamas MA, Ahmad QS, McDonagh TM, Hardman SMC, Rashid M, Butler R, Duckett S, Satchithananda D, Nolan J, Dargie HJ, Clark AL, Cleland J. Characteristics and outcome of acute heart failure patients according to the severity of peripheral oedema. Int J Cardiol 2019;285:40–46.

27. Shoaib A, Farag M, Nolan J, Rigby A, Patwala A, Rashid M, Kwok CS, Perveen R, Clark AL, Komajda M, Cleland J. Mode of presentation and mortality amongst patients hospitalized with heart failure? A report from the First Euro Heart Failure Survey. Clin Res Cardiol 2019;108:510–519.

28. Platz E, Solomon SD, McMurray J. Lung ultrasound: monitoring congestion in patients with heart failure. Eur J Heart Fail 2019;doi: 10.1002/ejhf.1636.

29. Platz E, Campbell RT, Claggett B, Lewis EF, Groarke JD, Docherty KF, Lee MMY, Merz AA, Silverman M, Swamy V, Lindner M, Rivero J, Solomon SD, McMurray J. Lung ultrasound in acute heart failure: prevalence of pulmonary congestion and short- and long-term outcomes. JACC Heart Fail 2019;7:849–858.

30. Platz E, Jhund PS, Girerd N, Pivetta E, McMurray JJV, Peacock WF, Masip J, Martin-Sanchez FJ, Miro O, Price S, Cullen L, Maisel AS, Vrints C, Cowie MR, DiSomma S, Bueno H, Mebazaa A, Gualandro DM, Tavares M, Metra M, Coats AJS, Ruschitzka F, Seferovic PM, Mueller C; on behalf of the Study Group on Acute Heart Failure of the Acute Cardiovascular Care Association and the Heart Failure Association of the European Society of Cardiology. Expert consensus document: reporting checklist for quantification of pulmonary congestion by lung ultrasound in heart failure. Eur J Heart Fail 2019;21:844–851.

31. Pivetta E, Goffi A, Nazerian P, Castagno D, Tozzetti C, Tizzani P, Tizzani M, Porrino G, Ferreri E, Busso V, Morello F, Paglieri C, Masoero M, Cassine E, Bovaro F, Grifoni S, Maule MM, Lupia E; on behalf of the Study Group on Lung Ultrasound from the Molinette and Careggi Hospitals. Lung ultrasound integrated with clinical assessment for the diagnosis of acute decompensated heart failure in the emergency department: a randomized controlled trial. Eur J Heart Fail 2019;21:754–766.

32. Rivas-Lasarte M, A´ lvarez-Garcı ´a J, Ferna ´ndez-Martı ´nez J, Maestro A, Lo´pez-Lo´pez L, Sole´-Gonza ´lez E, Pirla MJ, Mesado N, Mirabet S, Fluvia ` P, Brossa V, Sionis A, Roig E, Cinca J. Lung ultrasound-guided treatment in ambulatory patients with heart failure: a randomized controlled clinical trial (LUS-HF study). Eur J Heart Fail 2019;doi: 10.1002/ejhf.1604.

33. Ter Maaten JM, Kremer D, Demissei BG, Struck J, Bergmann A, Anker SD, Ng LL, Dickstein K, Metra M, Samani NJ, Romaine SPR, Cleland J, Girerd N, Lang CC, Van Veldhuisen DJ, Voors AA. Bio-adrenomedullin as a marker of congestion in patients with new-onset and worsening heart failure. Eur J Heart Fail 2019;21:732–743.

34. Abraham J, Bharmi R, Jonsson O, Oliveira GH, Artis A, Valika A, Capodilupo R, Adamson PB, Roberts G, Dalal N, Desai AS, Benza RL. Association of ambulatory hemodynamic monitoring of heart failure with clinical outcomes in a concurrent matched cohort analysis. JAMA Cardiol 2019;4:556–563.

35. Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogne W, Mullens W. Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance. Eur J Heart Fail 2019;21:1415–1422.

36. Jones NR, Roalfe AK, Adoki I, Hobbs FDR, Taylor CJ. Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis. Eur J Heart Fail 2019;21:1306–1325.

37. Kwok CS, Zieroth S, Van Spall HGC, Helliwell T, Clarson L, Mohamed M, Mallen C, Duckett S, Mamas MA. The Hospital Frailty Risk Score and its association with in-hospital mortality, cost, length of stay and discharge location in patients with heart failure short running title: frailty and outcomes in heart failure. Int J Cardiol 2019;doi: 10.1016/j.ijcard.2019.09.064.

38. Savarese G, Dahlstrom U, Vasko P, Pitt B, Lund LH. Association between renin-angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score-matched cohort study. Eur Heart J 2018;39:4257–4265.

39. Stolfo D, Uijl A, Benson L, Schrage B, Fudim M, Asselbergs FW, Koudstaal S, Sinagra G, Dahlstrom U, Rosano G, Savarese G. Association between betablocker use and mortality/morbidity in older patients with heart failure with reduced ejection fraction. A propensity score-matched analysis from the Swedish Heart Failure Registry. Eur J Heart Fail 2019;doi: 10.1002/ejhf.1615.

40. Rush CJ, Campbell RT, Jhund PS, Petrie MC, McMurray J. Association is not causation: treatment effects cannot be estimated from observational data in heart failure. Eur Heart J 2018;39:3417–3438.

41. Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, Backs J, Bauersachs J, Burkhoff D, Bonow RO, Chopra VK, de Boer RA, de WL, Hamdani N, Hasenfuss G, Heymans S, Hulot JS, Konstam M, Lee RT, Linke WA, Lunde IG, Lyon AR, Maack C, Mann DL, Mebazaa A, Mentz RJ, Nihoyannopoulos P, Papp Z, Parissis J, Pedrazzini T, Rosano G, Rouleau J, Seferovic PM, Shah AM, Starling RC, Tocchetti CG, Trochu JN, Thum T, Zannad F, Brutsaert DL, Segers VF, De Keulenaer GW. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J 2019;40:2155–2163.

42. de Boer RA, De KG, Bauersachs J, Brutsaert D, Cleland JG, Diez J, Du XJ, Ford P, Heinzel FR, Lipson KE, McDonagh T, Lopez-Andres N, Lunde IG, Lyon AR, Pollesello P, Prasad SK, Tocchetti CG, Mayr M, Sluijter JPG, Thum T, Tschope C, Zannad F, Zimmermann WH, Ruschitzka F, Filippatos G, Lindsey ML, Maack C, Heymans S. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur J Heart Fail 2019;21:272–285.

43. Packer M. The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction. Eur J Heart Fail 2018;20:1567–1569.

44. Pellicori P, Zhang J, Cuthbert J, Urbinati A, Shah P, Kazmi S, Clark AL, Cleland JGF. High sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes and mode of death. Cardiovasc Res 2020;116:91–100.

45. Tromp J, Ouwerkerk W, Demissei BG, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Metra M, Ng LL, Ponikowski P, Samani NJ, Van Veldhuisen DJ, Zannad F, Zwinderman AH, Voors AA, van der Meer P. Novel endotypes in heart failure: effects on guideline-directed medical therapy. Eur Heart J 2018;39:4269–4276.

46. Kao DP, Lewsey JD, Anand IS, Massie BM, Zile MR, Carson PE, McKelvie RS, Komajda M, McMurray JJ, Lindenfeld J. Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. Eur J Heart Fail 2015;17:925–935.

47. Cao TH, Jones DJL, Voors AA, Quinn PA, Sandhu JK, Chan DCS, Parry HM, Mohan M, Mordi IR, Sama IE, Anker SD, Cleland JG, Dickstein K, Filippatos G, Hillege HL, Metra M, Ponikowski P, Samani NJ, Van Veldhuisen DJ, Zannad F, Lang CC, Ng LL. Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets. Eur J Heart Fail 2019;doi: 10.1002/ejhf.1608.

48. Cleland JGF, Van Veldhuisen DJ, Ponikowski P. The year in cardiology 2018: heart failure. Eur Heart J 2019;40:651–661.

49. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–2200.

50. Wehner GJ, Jing L, Haggerty CM, Suever JD, Leader JB, Hartzel DN, Kirchner HL, Manus JNA, James N, Ayar Z, Gladding P, Good CW, Cleland JGF, Fornwalt BK. Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? Eur Heart J 2019;doi: 10.1093/eurheartj/ehz550.

51. Seferovic PM, Ponikowski P, Anker SD, Bauersachs J, Chioncel O, Cleland JGF, Boer RA, Drexel H, Ben Gal T, Hill L, Jaarsma T, Jankowska EA, Anker MS, Lainscak M, Lewis BS, McDonagh T, Metra M, Milicic D, Mullens W, Piepoli MF, Rosano G, Ruschitzka F, Volterrani M, Voors AA, Filippatos G, Coats AJS. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of The Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:1169–1186.

52. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019;40:689–697.

53. Pellicori P, Urbinati A, Kaur K, Zhang J, Shah P, Kazmi S, Capucci A, Cleland JGF, Clark AL. Prevalence and incidence of atrial fibrillation in ambulatory patients with heart failure. Am J Cardiol 2019;124:1554–1560.

54. Anderson SG, Shoaib A, Myint PK, Cleland JG, Hardman SM, McDonagh TA, Dargie H, Keavney B, Garratt CJ, Mamas MA. Does rhythm matter in acute heart failure? An insight from the British Society for Heart Failure National Audit. Clin Res Cardiol 2019;108:1276–1286.

55. Packer M. Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation. Eur Heart J 2019;40:1873–1879.

56. Chen S, Purerfellner H, Meyer C, Acou WJ, Schratter A, Ling Z, Liu S, Yin Y, Martinek M, Kiuchi MG, Schmidt B, Chun KRJ. Rhythm control for patients with atrial fibrillation complicated with heart failure in the contemporary era of catheter ablation: a stratified pooled analysis of randomized data. Eur Heart J 2019; doi: 10.1093/eurheartj/ehz443.

57. Barra S, Duehmke R, Providencia R, Narayanan K, Reitan C, Roubicek T, Polasek R, Chow A, Defaye P, Fauchier L, Piot O, Deharo JC, Sadoul N, Klug D, Garcia R, Dockrill S, Virdee M, Pettit S, Agarwal S, Borgquist R, Marijon E, Boveda S. Very long-term survival and late sudden cardiac death in cardiac resynchronization therapy patients. Eur Heart J 2019;40:2121–2127.

58. Barra S, Providencia R, Narayanan K, Boveda S, Duehmke R, Garcia R, Leyva F, Roger V, Jouven X, Agarwal S, Levy WC, Marijon E. Time trends in sudden cardiac death risk in heart failure patients with cardiac resynchronization therapy: a systematic review. Eur Heart J 2019;doi: 10.1093/eurheartj/ehz773.

59. Cleland JGF, Hindricks G, Petrie M. The shocking lack of evidence for implantable cardioverter defibrillators for heart failure; with or without cardiac resynchronization. Eur Heart J 2019;40:2128–2130.

60. Halliday BP, Baksi AJ, Gulati A, Ali A, Newsome S, Izgi C, Arzanauskaite M, Lota A, Tayal U, Vassiliou VS, Gregson J, Alpendurada F, Frenneaux MP, Cook SA, Cleland JGF, Pennell DJ, Prasad SK. Outcome in dilated cardiomyopathy related to the extent, location, and pattern of late gadolinium enhancement. JACC Cardiovasc Imaging 2019;12:1645–1655.

61. Rorth R, Dewan P, Kristensen SL, Jhund PS, Petrie MC, Kober L, McMurray J. Efficacy of an implantable cardioverter-defibrillator in patients with diabetes and heart failure and reduced ejection fraction. Clin Res Cardiol 2019;108:868–877.

62. Rossello X, Ariti C, Pocock SJ, Ferreira JP, Girerd N, McMurray JJV, Van Veldhuisen DJ, Pitt B, Zannad F. Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials. Clin Res Cardiol 2019;108:477–486.

63. Nikolaidou T, Johnson MJ, Ghosh JM, Marincowitz C, Shah S, Lammiman MJ, Schilling RJ, Clark AL. Postmortem ICD interrogation in mode of death classification. J Cardiovasc Electrophysiol 2018;29:573–583.

64. Leclercq C, Burri H, Curnis A, Delnoy PP, Rinaldi CA, Sperzel J, Lee K, Calo L, Vicentini A, Concha JF, Thibault B. Cardiac resynchronization therapy nonresponder to responder conversion rate in the more response to cardiac resynchronization therapy with MultiPoint Pacing (MORE-CRT MPP) study: results from Phase I. Eur Heart J 2019;40:2979–2987.

65. Asch FM, Grayburn PA, Siegel RJ, Kar S, Lim DS, Zaroff JG, Mishell JM, Whisenant B, Mack MJ, Lindenfeld J, Abraham WT, Stone GW, Weissman NJ. Echocardiographic outcomes after transcatheter leaflet approximation in patients with secondary mitral regurgitation: the COAPT trial. J Am Coll Cardiol 2019;74:2969–2979.

66. Baron SJ, Wang K, Arnold SV, Magnuson EA, Whisenant B, Brieke A, Rinaldi M, Asgar AW, Lindenfeld J, Abraham WT, Mack MJ, Stone GW, Cohen DJ; On behalf of the COAPT Investigators. Cost-effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation: results from the COAPT trial. Circulation 2019;140:1881–1891.

67. Arnold SV, Chinnakondepalli KM, Spertus JA, Magnuson EA, Baron SJ, Kar S, Lim DS, Mishell JM, Abraham WT, Lindenfeld JA, Mack MJ, Stone GW, Cohen DJ. Health status after transcatheter mitral-valve repair in heart failure and secondary mitral regurgitation: COAPT trial. J Am Coll Cardiol 2019;73:2123–2132.

68. Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack MJ. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–2318.

69. Iung B, Armoiry X, Vahanian A, Boutitie F, Mewton N, Trochu JN, Lefe`vre T, Messika-Zeitoun D, Guerin P, Cormier B, Brochet E, Thibault H, Himbert D, Thivolet S, Leurent G, Bonnet G, Donal E, Piriou N, Piot C, Habib G, Rouleau F, Carrie´ D, Nejjari M, Ohlmann P, Saint Etienne C, Leroux L, Gilard M, Samson G, Rioufol G, Maucort-Boulch D, Obadia JF, Obadia JF; on behalf of the MITRA-FR Investigators. Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years. Eur J Heart Fail 2019;doi: 10.1002/ejhf.1616.

70. Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRA-FR and COAPT trials. JACC Cardiovasc Imaging 2019;12:353–362.

71. Packer M, Grayburn PA. Contrasting effects of pharmacological, procedural, and surgical interventions on proportionate and disproportionate functional mitral regurgitation in chronic heart failure. Circulation 2019;140:779–789.

72. Witte KK, Lipiecki J, Siminiak T, Meredith IT, Malkin CJ, Goldberg SL, Stark MA, von Bardeleben RS, Cremer PC, Jaber WA, Celermajer DS, Kaye DM, Sievert H. The REDUCE FMR trial: a randomized sham-controlled study of percutaneous mitral annuloplasty in functional mitral regurgitation. JACC Heart Fail 2019;7:945–955.

73. Nickenig G, Weber M, Lurz P, von Bardeleben RS, Sitges M, Sorajja P, Hausleiter J, Denti P, Trochu JN, Nabauer M, Dahou A, Hahn RT. Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation: 6-month outcomes of the TRILUMINATE single-arm study. Lancet 2019;394:2002–2011.

74. Taramasso M, Benfari G, van der Bijl P, Alessandrini H, Attinger-Toller A, Biasco L, Lurz P, Braun D, Brochet E, Connelly KA, de BS, Denti P, Deuschl F, Estevez-Loureiro R, Fam N, Frerker C, Gavazzoni M, Hausleiter JR, Ho E, Juliard JM, Kaple R, Besler C, Kodali S, Kreidel F, Kuck KH, Latib A, Lauten A, Monivas V, Mehr M, Muntane-Carol G, Nazif T, Nickening G, Pedrazzini G, Philippon F, Pozzoli A, Praz F, Puri R, Rodes-Cabau J, Scha FU, Schofer J, Sievert H, Tang GHL, Thiele H, Topilsky Y, Rommel KP, Delgado V, Vahanian A, von Bardeleben RS, Webb JG, Weber M, Windecker S, Winkel M, Zuber M, Leon MB, Hahn RT, Bax JJ, Enriquez-Sarano M, Maisano F. Transcatheter versus medical treatment of symptomatic severe tricuspid regurgitation. J Am Coll Cardiol 2019;74:2998–3008.

75. Branch KR, Probstfield JL, Eikelboom JW, Bosch J, Maggioni AP, Cheng RK, Bhatt DL, Avezum A, Fox KAA, Connolly SJ, Shestakovska O, Yusuf S. Rivaroxaban with or without aspirin in patients with heart failure and chronic coronary or peripheral artery disease: the COMPASS trial. Circulation 2019;140: 529–537.

76. Cleland JGF, Pellicori P. Myocardial dysfunction and coronary artery disease as therapeutic targets in heart failure. Circulation 2019;140:538–541.

77. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

78. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, B? elohla´vek J, Bo¨hm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Duka ´t A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjo¨strand M, Langkilde A-M; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.

79. Greenberg B, Neaton JD, Anker SD, Byra WM, Cleland JGF, Deng H, Fu M, La Police DA, Lam CSP, Mehra MR, Nessel CC, Spiro TE, Van Veldhuisen DJ, Vanden Boom CM, Zannad F. Association of rivaroxaban with thromboembolic events in patients with heart failure, coronary disease, and sinus rhythm: a post hoc analysis of the COMMANDER HF trial. JAMA Cardiol 2019;4:515.

80. Mehra MR, Vaduganathan M, Fu M, Ferreira JP, Anker SD, Cleland JGF, Lam CSP, Van Veldhuisen DJ, Byra WM, Spiro TE, Deng H, Zannad F, Greenberg B. A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial. Eur Heart J 2019;40:3593-3602.

81. Morrow DA, Velazquez EJ, DeVore AD, Prescott MF, Duffy CI, Gurmu Y, McCague K, Rocha R, Braunwald E. Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial. Eur Heart J 2019;40:3345-3352.

82. Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, Fonseca C, Goncalvesova E, Cavusoglu Y, Fernandez A, Chaaban S, Bohmer E, Pouleur AC, Mueller C, Tribouilloy C, Lonn E, Buraiki AL, Gniot J, Mozheiko M, Lelonek M, Noe A, Schwende H, Bao W, Butylin D, Pascual-Figal D. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019;21:998–1007.

83. Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, McCague K, Abbas CA, Rocha R, Mitchell GF. Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2019;doi: 10.1001/jama.2019.12843.

84. Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, Camacho A, Pina IL, Rocha RA, Shah AM, Williamson KM, Solomon SD. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;doi: 10.1001/jama.2019.12821.

85. Kang DH, Park SJ, Shin SH, Hong GR, Lee S, Kim MS, Yun SC, Song JM, Park SW, Kim JJ. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 2019;139:1354-1365.

86. Zile MR, O’Meara E, Claggett B, Prescott MF, Solomon SD, Swedberg K, Packer M, McMurray JJV, Shi V, Lefkowitz M, Rouleau J. Effects of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Coll Cardiol 2019;73:795–806.

87. Krum H, Elsik M, Schneider HG, Ptaszynska A, Black M, Carson PE, Komajda M, Massie BM, McKelvie RS, McMurray JJ, Zile MR, Anand IS. Relation of peripheral collagen markers to death and hospitalization in patients with heart failure and preserved ejection fraction: results of the I-PRESERVE collagen substudy. Circ Heart Fail 2011;4:561–568.

88. Solomon SD, Rizkala AR, Lefkowitz MP, Shi VC, Gong J, Anavekar N, Anker SD, Arango JL, Arenas JL, Atar D, Ben-Gal T, Boytsov SA, Chen CH, Chopra VK, Cleland J, Comin-Colet J, Duengen HD, Echeverria Correa LE, Filippatos G, Flammer AJ, Galinier M, Godoy A, Goncalvesova E, Janssens S, Katova T, Kober L, Lelonek M, Linssen G, Lund LH, O’Meara E, Merkely B, Milicic D, Oh BH, Perrone SV, Ranjith N, Saito Y, Saraiva JF, Shah S, Seferovic PM, Senni M, Sibulo AS Jr, Sim D, Sweitzer NK, Taurio J, Vinereanu D, Vrtovec B, Widimsky J Jr, Yilmaz MB, Zhou J, Zweiker R, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, McMurray JJV. Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial. Circ Heart

Fail 2018;11:e004962.

89. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; on behalf of PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338–2345.

90. Parthasarathy HK, Pieske B, Weisskopf M, Andrews CD, Brunel P, Struthers AD, MacDonald TM. A randomized, double-blind, placebo-controlled study to determine the effects of valsartan on exercise time in patients with symptomatic heart failure with preserved ejection fraction. Eur J Heart Fail 2009;11:980-989.

91. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M,

Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–1620.

92. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-1898.

93. Solomon SD, Vaduganathan M, Claggett BL, Packer M, Zile M, Swedberg K, Rouleau J, Pfeffer MA, Desai A, Lund LH, Koeber L, Anand I, Sweitzer NK, Linssen G, Merkely B, Arango JL, Vinereanu D, Chen CH, Senni M, Sibulo A, Boytsov S, Shi V, Rizkala A, Lefkowitz M, McMurray J. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation 2019;doi:10.1161/CIRCULATIONAHA.119.044586.

94. McMurray JJV, Jackson AM, Lam CSP, Redfield MM, Anand IS, Ge J, Lefkowitz MP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Rizkala AR, Sabarwal SV, Shah AM, Shah SJ, Shi VC, Van Veldhuisen DJ, Zannad F, Zile MR,Cikes M, Goncalvesova E, Katova T, Kosztin A, Lelonek M, Sweitzer NK, Vardeny O, Claggett B, Jhund PS, Solomon SD. Effects of sacubitril-valsartan, versus valsartan, in women compared to men with heart failure and preserved ejection fraction: insights from PARAGON-HF. Circulation 2019;doi:10.1161/CIRCULATIONAHA.119.044491.

95. Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, Milicic D, Arango JL, Packer M, Shi VC, Lefkowitz MP, McMurray JJV, Solomon SD. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol 2019 Nov 6. pii: S0735-1097(19)38299-3. doi: 10.1016/j.jacc.2019.11.003. [Epub ahead ofprint].

96. Dewan P, Rorth R, Jhund PS, Shen L, Raparelli V, Petrie MC, Abraham WT, Desai AS, Dickstein K, Kober L, Mogensen UM, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, McMurray J. Differential impact of heart failure with reduced ejection fraction on men and women. J Am Coll Cardiol 2019;73:29–40.

97. Chandra A, Vaduganathan M, Lewis EF, Claggett BL, Rizkala AR, Wang W, Lefkowitz MP, Shi VC, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, McMurray JJV, Solomon SD. Health-related quality of life in heart failure with preserved ejection fraction: the PARAGON-HF trial. JACC Heart Fail 2019;7:862–874.

98. Santema BT, Ouwerkerk W, Tromp J, Sama IE, Ravera A, Regitz-Zagrosek V, Hillege H, Samani NJ, Zannad F, Dickstein K, Lang CC, Cleland JG, Ter Maaten JM, Metra M, Anker SD, van der Harst P, Ng LL, van der Meer P, van Veldhuisen DJ, Meyer S, Lam CSP, Voors AA, Richards AM, Lam CSP, Anand I, Hung C-L, Ling LH, Liew HB, Narasimhan C, Ngarmukos T, Park SW, Reyes E, Siswanto BB, Shimizu W, Zhang S. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet 2019;394:1254–1263.

99. Merrill M, Sweitzer NK, Lindenfeld J, Kao DP. Sex differences in outcomes and responses to spironolactone in heart failure with preserved ejection fraction: a secondary analysis of TOPCAT trial. JACC Heart Fail 2019;7:228–238.

100. Linde C, Cleland JGF, Gold MR, Claude DJ, Tang ASL, Young JB, Sherfesee L, Abraham WT. The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual-patient data meta-analysis. Eur J Heart Fail 2018;20:780–791.

101. Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Moller M, Jorgensen NR, Faber J, Danser AHJ, Gansevoort RT, Rossing P, Persson F, Heerspink H. Effects of dapagliflozin on volume status when added to reninangiotensin system inhibitors. J Clin Med 2019;8:E779.

102. Dekkers CCJ, Sjostrom CD, Greasley PJ, Cain V, Boulton DW, Heerspink H. Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes. Diabetes Obes Metab 2019;21:2667–2673.

103. Cefalo CMA, Cinti F, Moffa S, Impronta F, Sorice GP, Mezza T, Pontecorvi A, Giaccari A. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol 2019;18:20.

104. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.

105. Yang DY, He X, Liang HW, Zhang SZ, Zhong XB, Luo CF, Du ZM, He JG, Zhuang XD, Liao XX. Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171, 253 participants from 91 randomized controlled trials. Cardiovasc Diabetol 2019;18:47.

106. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major ad-

verse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022–2031.

107. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Kober L, Petrie MC, McMurray J. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–785.

108. Shen L, Rorth R, Cosmi D, Kristensen SL, Petrie MC, Cosmi F, Latini R, Kober L, Anand IS, Carson PE, Granger CB, Komajda M, McKelvie RS, Solomon SD, Staszewsky L, Swedberg K, Huynh T, Zile MR, Jhund PS, McMurray J. Insulin treatment and clinical outcomes in patients with diabetes and heart failure with preserved ejection fraction. Eur J Heart Fail 2019;21:974–984.

109. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–39.

110. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular

outcomes in type 2 diabetes. N Engl J Med 2019;380:347–357.

111. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, Desai AS, Goto S, Johansson PA, Gause-Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528–2536.

112. McMurray JJV, DeMets DL, Inzucchi SE, Kober L, Kosiborod MN, Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, Sjostrand M, Solomon SD; on behalf of the DAPA-HF Committees and Investigators. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail 2019;21:1402–1411.

113. Martinez FA, Serenelli M, Nicolau JC, Petrie MC, Chiang CE, Tereshchenko S, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Ponikowski P, Sabatine MS, DeMets DL, Dutkiewicz-Piasecka M, Bengtsson O, Sjostrand M, Langkilde AM, Jhund PS, McMurray J. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation 2019;doi: 10.1161/CIRCULATIONAHA.119.044133.

114. Kosiborod MN, Jhund P, Docherty KF, Diez M, Petrie MC, Verma S, Nicolau JC, Merkely B, Kitakaze M, DeMets DL, Inzucchi SE, Koeber L, Martinez FA, Ponikowski P, Sabatine MS, Solomon SD, Bengtsson O, Lindholm D, Niklasson A, Sjostrand M, Langkilde AM, McMurray J. Effects of dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation 2019;doi:10.1161/CIRCULATIONAHA.119.044138.

115. Nassif ME, Windsor SL, Tang F, Khariton Y, Husain M, Inzucchi SE, Mc-Guire DK, Pitt B, Scirica BM, Austin B, Drazner MH, Fong MW, Givertz MM, Gordon RA, Jermyn R, Katz SD, Lamba S, Lanfear DE, LaRue SJ, Lindenfeld J, Malone M, Margulies K, Mentz RJ, Mutharasan RK, Pursley M, Umpierrez G, Kosiborod M; On behalf of the DEFINE-HF Investigators. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation 2019;140:1463–1476.

116. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025–1029.

117. Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, Teoh H, Leiter LA, Zinman B, Juni P, Zuo F, Mistry N, Thorpe KE, Goldenberg RM, Yan AT, Connelly KA, Verma S. Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease. Circulation 2019;doi: 10.1161/CIRCULATIONAHA.119.044235.

118. Swedberg K, Young JB, Anand S, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O’Connor CM, Pfeffer MA, Solomon SD, Sun Y, Tendera M, Van Veldhuisen DJ; RED-HF Committees, RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013;368:1210–1219.

119. Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab 2018;20:1361–1366.

120. Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frøkiær J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Bøtker HE, Wiggers H. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 2019;139:2129–2141.

121. Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Juni P, Zinman B, Connelly KA; For the EMPA-HEART CardioLink-6 Investigators. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART cardiolink-6 randomized clinical trial. Circulation 2019;140:1693–1702.

122. Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Zeller C, George J, Brueckmann M, Anker SD, Zannad F; on behalf of the EMPEROR-Reduced Trial Committees and Investigators. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:1270–1278.

123. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Zeller C, George J, Brueckmann M, Zannad F, Packer M; on behalf of the EMPEROR-Preserved Trial Committees and Investigators. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction:rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail 2019;21:1279–1287.

124. Maggioni AP, Lopez-Sendon J, Nielsen OW, Hallen J, Aalamian-Mattheis M, Wang Y, Ertl G. Efficacy and safety of serelaxin when added to standard of care in patients with acute heart failure: results from a PROBE study, RELAX-AHF-EU. Eur J Heart Fail 2019;21:322–333.

125. Metra M, Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Pang PS, Ponikowski P, Voors AA, Adams KF, Anker SD, Arias-Mendoza A, Avendano P, Bacal F, Bohm M, Bortman G, Cleland JGF, Cohen-Solal A, Crespo-Leiro MG, Dorobantu M, Echeverria LE, Ferrari R, Goland S, Goncalvesova E, Goudev A, Kober L, Lema-Osores J, Levy PD, McDonald K, Manga P, Merkely B, Mueller C, Pieske B, Silva-Cardoso J, Spinar J, Squire I, Stepinska J, van MW, von LD, Wikstrom G, Yilmaz MB, Hagner N, Holbro T, Hua TA, Sabarwal SV, Severin T, Szecsody P, Gimpelewicz C; RELAX-AHF-2 Committees Investigators. Effects of serelaxin in patients with acute heart failure. N Engl J Med 2019;381:716–726.

126. Kozhuharov N, Goudev A, Flores D, Maeder MT, Walter J, Shrestha S, Gualandro DM, de Oliveira Junior MT, Sabti Z, Mu¨ller B, Noveanu M, Socrates T, Ziller R, Baye´s-Genı ´s A, Sionis A, Simon P, Michou E, Gujer S, Gori T, Wenzel P, Pfister O, Conen D, Kapos I, Kobza R, Rickli H, Breidthardt T, Mu¨nzel T, Erne P, Mueller C; GALACTIC Investigators. Effect of a strategy of comprehensive vasodilation vs usual care on mortality and heart failure rehospi-talization among patients with acute heart failure: The GALACTIC Randomized Clinical Trial. JAMA 2019;322:2292–2302.

127. Mebazaa A, Pang PS, Tavares M, Collins SP, Storrow AB, Laribi S, Andre S, Courtney DM, Hasa J, Spinar J, Masip J, Peacock WF, Sliwa K, Gayat E, Filippatos G, Cleland JGF, Gheorghiade M. The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study. Eur Heart J 2010;31:832–841.

128. Biegus J, Zymlinski R, Siwolowski P, Testani J, Szachniewicz J, Tyci? nska A, Banasiak W, Halpert A, Levin H, Ponikowski P. Controlled decongestion by reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies. Eur J Heart Fail 2019;21:1079–1087.

129. Keeble TR, Karamasis GV, Rothman MT, Ricksten SE, Ferrari M, Hullin R, Schersten F, Reitan O, Kirking ST, Cleland JGF, Smith EJ. Percutaneous haemodynamic and renal support in patients presenting with decompensated heart failure: a multi-centre efficacy study using the Reitan Catheter Pump (RCP). Int J Cardiol 2019;275:53–58.

130. Yau TM, Pagani FD, Mancini DM, Chang HL, Lala A, Woo YJ, Acker MA, Selzman CH, Soltesz EG, Kern JA, Maltais S, Charbonneau E, Pan S, Marks ME, Moquete EG, O’Sullivan KL, Taddei-Peters WC, McGowan LK, Green C, Rose EA, Jeffries N, Parides MK, Weisel RD, Miller MA, Hung J, O’Gara PT, Moskowitz AJ, Gelijns AC, Bagiella E, Milano CA; for the Cardiothoracic Surgical Trials Network. Intramyocardial injection of mesenchymal precursor cells and successful temporary weaning from left ventricular assist device support in patients with advanced heart failure: a randomized clinical trial. JAMA 2019; 321:1176–1186.

131. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, Ito K, Willcox JA, Arany Z, Li J, Owens AT, Govind R, Nunez B, Mazaika E, Bayes-Genis A, Walsh R, Finkelman B, Lupon J, Whiffin N, Serrano I, Midwinter W, Wilk A, Bardaji A, Ingold N, Buchan R, Tayal U, Pascual-Figal DA, de MA, Ahmad M, Garcia-Pinilla JM, Pantazis A, Dominguez F, John BA, O’Regan DP, Rosen SD, Prasad SK, Lara-Pezzi E, Provencio M, Lyon AR, Alonso-Pulpon L, Cook SA, DePalma SR, Barton PJR, Aplenc R, Seidman JG, Ky B, Ware JS, Seidman CE. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation 2019;140:31–41.

132. Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT, Hudis CA, Dang CT, Steingart RM. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 2015;149:489–495.

133. Lynce F, Barac A, Geng X, Dang C, Yu AF, Smith KL, Gallagher C, Pohlmann PR, Nunes R, Herbolsheimer P, Warren R, Srichai MB, Hofmeyer M, Cunningham A, Timothee P, Asch FM, Shajahan-Haq A, Tan MT, Isaacs C, Swain SM. Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study. Breast Cancer Res Treat 2019;175:595–603.

134. Cornell RF, Ky B, Weiss BM, Dahm CN, Gupta DK, Du L, Carver JR, Cohen AD, Engelhardt BG, Garfall AL, Goodman SA, Harrell SL, Kassim AA, Jadhav T, Jagasia M, Moslehi J, O’Quinn R, Savona MR, Slosky D, Smith A, Stadtmauer EA, Vogl DT, Waxman A, Lenihan D. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J Clin Oncol 2019;37:1946–1955.

135. Abuosa AM, Elshiekh AH, Qureshi K, Abrar MB, Kholeif MA, Kinsara AJ, Andejani A, Ahmed AH, Cleland J. Prophylactic use of carvedilol to prevent ventricular dysfunction in patients with cancer treated with doxorubicin. Indian Heart J 2018;70(Suppl. 3):S96–S100.

136. Li X, Li Y, Zhang T, Xiong X, Liu N, Pang B, Ruan Y, Gao Y, Shang H, Xing Y. Role of cardioprotective agents on chemotherapy-induced heart failure: a systematic review and network meta-analysis of randomized controlled trials. Pharmacol Res 2020;151:104577.

137. Kapelios CJ, Lainscak M, Savarese G, Laroche C, Seferovic P, Ruschitzka F, Coats A, Anker SD, Crespo-Leiro MG, Filippatos G, Piepoli MF, Rosano G, Zanolla L, Aguiar C, Murin J, Leszek P, McDonagh T, Maggioni AP, Lund LH. Sacubitril/valsartan eligibility and outcomes in the ESC-EORP-HFA Heart Failure Long-Term Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM-HF trial, ESC guidelines, and real world. Eur J Heart Fail 2019;21:1383–1397.

138. Loop MS, van Dyke MK, Chen L, Safford MM, Kilgore ML, Brown TM, Durant RW, Levitan EB. Low utilization of beta-blockers among medicare beneficiaries hospitalized for heart failure with reduced ejection fraction. J Card Fail 2019;25:343–351.

139. Van Spall HGC, Lee SF, Xie F, Oz UE, Perez R, Mitoff PR, Maingi M, Tjandrawidjaja MC, Heffernan M, Zia MI, Porepa L, Panju M, Thabane L, Graham ID, Haynes RB, Haughton D, Simek KD, Ko DT, Connolly SJ. Effect of patient-centered transitional care services on clinical outcomes in patients hospitalized for heart failure: the PACT-HF randomized clinical trial. JAMA 2019;321:753–761.

140. Schulz M, Griese-Mammen N, Anker SD, Koehler F, Ihle P, Ruckes C, Schumacher PM, Trenk D, Bo¨hm M, Laufs U; for the PHARM-CHF Investigators. Pharmacy-based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM-CHF randomized controlled trial. Eur J Heart Fail 2019;21:1012–1021.

141. Wagenaar KP, Broekhuizen BDL, Jaarsma T, Kok I, Mosterd A, Willems FF, Linssen GCM, Agema WRP, Anneveldt S, Lucas C, Mannaerts HFJ, Wajon E, Dickstein K, Cramer MJ, Landman MAJ, Hoes AW, Rutten FH. Effectiveness of the European Society of Cardiology/Heart Failure Association website ‘heartfai-lurematters.org’ and an e-health adjusted care pathway in patients with stable heart failure: results of the ‘e-Vita HF’ randomized controlled trial. Eur J Heart Fail 2019;21:238–246.

142. Shanbhag D, Graham ID, Harlos K, Haynes RB, Gabizon I, Connolly SJ, Van Spall H. Effectiveness of implementation interventions in improving physician adherence to guideline recommendations in heart failure: a systematic review. BMJ Open 2018;8:e017765.

143. Taylor RS, Long L, Mordi IR, Madsen MT, Davies EJ, Dalal H, Rees K, Singh SJ, Gluud C, Zwisler AD. Exercise-based rehabilitation for heart failure: cochrane systematic review, meta-analysis, and trial sequential analysis. JACC Heart Fail 2019;7:691–705.

144. Taylor RS, Walker S, Smart NA, Piepoli MF, Warren FC, Ciani O, Whellan D, O’Connor C, Keteyian SJ, Coats A, Davos CH, Dalal HM, Dracup K, Evangelista LS, Jolly K, Myers J, Nilsson BB, Passino C, Witham MD, Yeh GY. Impact of exercise rehabilitation on exercise capacity and quality-of-life in heart failure: individual participant meta-analysis. J Am Coll Cardiol 2019;73:1430–1443.

145. Taylor RS, Walker S, Smart NA, Piepoli MF, Warren FC, Ciani O, O’Connor C, Whellan D, Keteyian SJ, Coats A, Davos CH, Dalal HM, Dracup K, Evangelista L, Jolly K, Myers J, McKelvie RS, Nilsson BB, Passino C, Witham MD, Yeh GY, Zwisler AO; on behalf of the ExTraMATCH II Collaboration. Impact of exercise-based cardiac rehabilitation in patients with heart failure (ExTraMATCH II) on mortality and hospitalisation: an in-dividual patient data meta-analysis of randomised trials. Eur J Heart Fail 2018;20:1735–1743.

146. Long L, Mordi IR, Bridges C, Sagar VA, Davies EJ, Coats AJ, Dalal H, Rees K, Singh SJ, Taylor RS. Exercise-based cardiac rehabilitation for adults with heart failure. Cochrane Database Syst Rev 2019;1:CD003331.

147. Takeda A, Martin N, Taylor RS, Taylor SJ. Disease management interventions for heart failure. Cochrane Database Syst Rev 2019;1:CD002752.

148. Taylor RS, Sadler S, Dalal HM, Warren FC, Jolly K, Davis RC, Doherty P, Miles J, Greaves C, Wingham J, Hillsdon M, Abraham C, Frost J, Singh S, Hayward C, Eyre V, Paul K, Lang CC, Smith K. The cost effectiveness of REACH-HF and home-based cardiac rehabilitation compared with the usual medical care for heart failure with reduced ejection fraction: a decision model-based analysis. Eur J Prev Cardiol 2019;26:1252–1261.

149. Wingham J, Frost J, Britten N, Greaves C, Abraham C, Warren FC, Jolly K, Miles J, Paul K, Doherty PJ, Singh S, Davies R, Noonan M, Dalal H, Taylor RS. Caregiver outcomes of the REACH-HF multicentre randomized controlled trial of home-based rehabilitation for heart failure with reduced ejection fraction. Eur J Cardiovasc Nurs 2019;18:611–620.

150. Johnson MJ, Cockayne S, Currow DC, Bell K, Hicks K, Fairhurst C, Gabe R, Torgerson D, Jefferson L, Oxberry S, Ghosh J, Hogg KJ, Murphy J, Allgar V, Cleland JGF, Clark AL. Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo-controlled trial. ESC Heart Fail 2019;doi: 10.1002/ehf2.12498.

151. Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ, Rosen SD, Cowie MR, Cleland JGF, Prasad SK. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019;393:61–73.

152. Ghimire A, Fine N, Ezekowitz JA, Howlett J, Youngson E, McAlister FA. Frequency, predictors, and prognosis of ejection fraction improvement in heart failure: an echocardiogram-based registry study. Eur Heart J 2019;40:2110–2117.

153. Aguirre DL, Weber K, Bavendiek U, Bauersachs J, Wittes J, Yusuf S, Koch A. Digoxin-mortality: randomized vs. observational comparison in the DIG trial. Eur Heart J 2019;40:3336–3341.

154. Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simoes MV, Silvestre OM, Ribeiro ALP, Moura LZ, Beck-da-Silva L, Prado D, Sant’Anna RT, Bridi LH, Zimerman A, Raupp da RP, Biolo A. Short-term diuretic with-drawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. Eur Heart J 2019;40:3605–3612.

155. Dovancescu S, Pellicori P, Mabote T, Torabi A, Clark AL, Cleland J. The effects of short-term omission of daily medication on the pathophysiology of heart failure. Eur J Heart Fail 2017;19:643–649.