HFPEF的多样特征给治疗和研究带来挑战

曾经备受期待的TOPCAT试验在去年11月发布了令人失望的结果：螺内酯在左室射血分数保留的心力衰竭(HFPEF)患者中未能显示出对主要终点(死亡或心力衰竭住院)的显著益处。不过这一中性结果还是比另一项试验的失败结果更有意义。

TOPCAT试验的结果还凸显了HFPEF患者的异质性，这是该综合征的一种特征性表现。异质性被认为在TOPCAT和其他多项HFPEF试验的不成功之中起着重要作用。


Gregg C. Fonarow医生

尽管HFPEF被定义为有明确心力衰竭临床症状而左室射血分数(LVEF)≥45%(近来改为≥50%)，但随着中性试验结果的累积越来越清楚的是，HFPEF是一种综合征。与单一疾病大不相同的是，HFPEF可有不同的病因和表现出不同的亚型。

明尼苏达州梅奥医院的Barry A. Borlaug医生在接受采访时指出：“HFPEF并不是只涉及舒张功能障碍和心室硬化的单纯疾病，而是一种涉及心血管和外周储备的非常复杂、高度融合的多系统衰竭。我们中的很多人发现，HFPEF有多种亚表型，每种都具有独特的机制和临床轨迹，因而很可能需要特定的治疗。”

哈佛医学院内科学教授、布里格姆妇女医院心内科主任Scott D. Solomon医生指出：“这是一种极具异质性、病因多样的综合征，有的患者存在明显的心室肥大，有的患者存在舒张功能障碍，有的患者症状轻微但运动时症状明显，有的患者处于代偿、稳定状态，还有一些患者则失代偿。这种疾病谱系相当宽泛，可能包含多种疾病。”

去年，有2篇述评明确提出了HFPEF谱系疾病的概念。在其中一篇述评中，西北大学心脏病学家Sanjiv J. Shah医生提出了3种特征性的HFPEF患者亚型(J. Am. Coll. Cardiol. 2013;62:1339-42)：运动诱发性舒张功能障碍而静息时无症状，仅有轻微液体潴留，从未因心力衰竭住院，但长期患有高血压和运动不耐受；容量过载和水肿，近期因心力衰竭住院，伴劳力性呼吸困难，有中重度心力衰竭症状；最差的一种亚型是已因HFPEF引起肺高压和右心室衰竭，目前频繁因心力衰竭住院。不过，HFPEF患者未必会从其中某种亚型进展为另一种亚型。


John R. Teerlink医生

“患者在这个疾病谱系中既可能加重也可能减轻，还可能维持在某种亚型。这种综合征具有很强的异质性，不仅在于临床表现，也在于病因和病理生理。HFPEF的自然史、发展过程以及患者变化轨迹仍有很多值得探索的地方。”

第二篇述评描述了数种相对常见的HFPEF表型，这些表型既可单独出现也可混合出现，包括充盈受限、射血受限、心动加速和血管调节(Eur. Heart J. 2013;34:1393-5)。

异质性带来的风险

除了提供有关HFPEF病因与后果的更好的知识框架之外，将HFPEF视为一种异质性的综合征还有助于解释，为何10年前的CHARM Preserved(Lancet 2003;362:777-81)、I-PRESERVE(N. Engl. J. Med. 2008;359:2456-67)和近期的TOPCAT等针对HFPEF的关键干预试验均未能在主要终点方面显示出统计学获益。

“异质性会妨碍我们寻找有效治疗手段，我推测这是HFPEF试验结果不理想的主要原因。”


John G.F. Cleland医生

加州大学洛杉矶分校内科学教授Gregg C. Fonarow医生指出：“现在回过头去看，包括CHARM Preserved和TOPCAT在内的很多试验实际上招募了一些非HFPEF患者。”Shah医生表示：“未来临床试验的关键将是如何更好地对HFPEF进行分类，并更好地将HFPEF患者与治疗相匹配。”

奥地利格拉茨医科大学心脏病学系主任Burkert M. Pieske医生指出：“在这些大型试验中，部分患者所患的并非HFPEF而是存在其他障碍，例如去适应和肥胖，而针对心脏的治疗对这些障碍并无益处。我们需要识别出将会对治疗产生应答的患者。”

去年11月报告的TOPCAT(采用醛固酮拮抗剂治疗心脏功能保留的心力衰竭)试验结果凸显了患者异质性问题。这项研究从阿根廷、巴西、加拿大、俄罗斯、格鲁吉亚和美国入组3,400多例患者。回顾性分析显示，在安慰剂组患者中，881例西半球患者在随访期间的主要终点(死亡或心力衰竭住院)发生率为12.6次事件/100患者-年，而俄罗斯和格鲁吉亚的842例患者的主要终点发生率仅为2.3次事件/100患者-年，差异达5倍之多。

参与了TOPCAT的Solomon医生指出：“总体而言，俄罗斯和格鲁吉亚的患者具有较低的事件发生率，病情严重程度必然优于其他患者，但他们恐怕仍患有心力衰竭。这种疾病的界定并不容易，如果1例患者出现心力衰竭症状但射血分数不低，你可能不敢确定这些症状是否就是心力衰竭引起的。这可以解释为何很多人认为在临床试验中应当用另一种标准来定义HFPEF，例如某些类型的利钠肽血清浓度升高。”在参加TOPCAT的患者中，72%是由于近期因心力衰竭住院，28%则是由于血清利钠肽超过了阈值。在血清利钠肽超过阈值的亚组患者中，螺内酯治疗在减少主要终点方面有显著益处，而在其余72%的患者中则并不显著优于安慰剂。


Barry A. Borlaug医生

并未参加TOPCAT试验的Pieske医生指出：“TOPCAT遇到了资金问题、招募问题和监测问题。在俄罗斯和格鲁吉亚招募的患者的病情之稳定令人难以置信，事件发生率仅为2.3/100人-年。即使药物有效，也不可能在事件发生率如此之低的情况下显示出效果。”

Pieske医生曾开展了一项规模小得多的螺内酯研究，纳入422例HFPEF患者。这项名为“在舒张性心力衰竭患者中阻断醛固酮受体(Aldo-DHF)”的试验显示，螺内酯在改善舒张功能方面有效而不能改善运动耐力(JAMA 2013;309:781-91)。

Pieske医生在接受采访时表示：“假如你把TOPCAT和Aldo-DHF放在一起，并问螺内酯是否有效，那么答案是‘对于正确的患者有效’，所谓正确的患者是指有心脏功能异常和利钠肽水平升高的明确证据，或者因心力衰竭住院。螺内酯在这些患者中显然是有效的，但是这些临床试验存在很大争议，因而螺内酯将难以进入治疗指南。”

Shah医生指出：“螺内酯在容量过载和/或右心衰患者中益处最大，这些也是最可能出现利钠肽水平升高的那部分患者。螺内酯对于早期HFPEF的疗效似乎不那么明显。”


Scott D. Solomon医生

数位专家警告称，由于TOPCAT未能在主要终点方面显示出统计学显著获益，要从其结果得出任何其他结论都必须非常谨慎。还有一些专家表示想要查看全部结果，因为2月下旬发表的只是部分结果。他们还指出，很多(很可能占多数)HFPEF患者并无血清利钠肽水平升高。

HFPEF治疗现状如何

关于HFPEF针对性治疗的循证指南很简单，因为目前根本不存在这样的治疗。

去年10月份发布的美国心脏协会(AHA)/美国心脏病学会(ACC)心力衰竭管理指南没有提出任何疾病针对性治疗建议(J. Amer. Coll. Cardiol. 2013;62:e147-e239)。他们呼吁对需要干预的患者根据流行的标准控制高血压，采用利尿剂治疗容量过载的患者，在有冠心病的情况下进行冠脉血管重建，以及在有房颤的情况下加以治疗。2012年发布的欧洲心脏病学会(ESC)指南的说法几乎完全一样(Eur. J. Cardiol. 2012;33:1787-1847)，除了增加以下陈述：迄今尚无任何治疗能令人信服地降低HFPEF患者的并发症发病率和死亡率。

对于合并高血压的HFPEFT患者而言，OPCAT试验的结果进一步巩固了螺内酯作为一种相当安全的降压药物的地位。 控制高血压对于HFPEF患者非常必要，因为高血压被认为与绝大多数患者的HFPEF有关。旧金山退伍军人事务部医疗中心的John R. Teerlink医生指出：“高血压是最常见的HFPEF潜在病因。”


Sanjiv J. Shah医生

Borlaug医生认为，基于现有证据，在HFPEF患者的降压治疗方面，“除非存在禁忌证，否则螺内酯应当是最先尝试的药物之一，但是我并不确定它是否就是最优先选择”。

对于液体过载的HFPEF患者，利尿剂是一种显而易见的降压药物。PEP-CHF试验结果提示，ACE抑制剂培哚普利对老年患者有益(Eur. Heart J. 2006;27:2338-45)。PEP-CHF是又一项大型HFPEF治疗试验，其结果显示培哚普利不能改善主要终点，但在一些次要终点方面得出了阳性结果。

Teerlink医生在接受采访时表示：“患者服用这些药物是为了治疗高血压，但我们认为这些药物对心力衰竭也有好处。我和同事已经在经常使用螺内酯治疗高血压了，TOPCAT结果不会改变我们的做法。我并不打算对患者说，根据TOPCAT结果，他/她应当使用一种醛固酮拮抗剂。”

英国赫尔大学的John G.F. Cleland医生指出：“ACEI很可能是有效的；如果诊断正确的话，螺内酯很可能也有效；我们对β受体阻断剂不太清楚；有一些关于使用地高辛的证据。利尿剂如果能被明智地使用，也是高血压的良好治疗药物。”

Borlaug医生表示：“我对于β受体阻断剂很谨慎，我治疗的一些患者在使用此类药物方面有不好的经历。一些HFPEF患者没有心搏量，没有心脏舒张，只剩下心率，假如你把心率也带走了，那么患者就没有心输出量了。”

除了控制血压之外，专家们还建议良好地管理其他共病，例如冠心病、房颤、糖尿病、睡眠障碍性呼吸和肾病。Shah医生强调：“临床医生应当确保没有漏诊重度冠状动脉疾病、浸润性心肌病、缩窄性心包炎或其他具有针对性治疗的HFPEF病因。”一些药物已在早期研究中显示出了良好前景，例如伊伐布雷定和脑啡肽酶，但是还需要Ⅲ期研究的支持。Fonarow医生说：“在管理HFPEF患者方面，我的建议是尽可能将其招募到随机临床试验中。”


Burkert M. Pieske医生

另一个关键是作出诊断，理想情况下可以避免不可逆性心血管损伤的发生。Borlaug医生指出：“HFPEF的确诊难度较大，除非通过心导管术检测充盈压，但是在早期HFPEF患者中，即使采取侵入性血液动力学检查，结果看上去也相当正常。”另一种方法是运动超声心动图检查，这种方法无创且能够识别出负荷诱导性舒张功能障碍，但这种方法的敏感性和特异性尚不明确。利钠肽水平升高在部分患者中有助于确定HFPEF诊断，但很多其他患者的利钠肽水平仍在正常范围。

为了找出HFPEF患者，Borlaug医生建议提高警惕，寻找呼吸急促、功能容量减少、充血、肺部啰音、超声心动图、肺动脉高压和左心房增大的征象。

Pieske医生指出：“找出患者的难度颇大。HFPEF患者倾向于为老年人、女性和肥胖者，易合并高血压和/或糖尿病。他们主诉呼吸困难和疲乏，很多医生不会考虑到在这些症状和主诉背后隐藏着真实的诊断，尤其是在患者的左心室射血分数保留、利钠肽水平正常的情况下。”舒张期运动负荷试验和超声心动图检查有可能识别出稳定的早期舒张功能障碍患者，但还有待证实。

HFPEF是心力衰竭的主要类型却缺乏良好的治疗手段

专家们指出，由于HFPEF不仅发病率高而且比射血分数下降型心力衰竭(HFREF)增加地更快，所以临床医生在诊断和管理HFPEF方面所承担的责任将出现实质性增加。新加坡国立大学心脏中心的Carolyn S.P. Lam医生去年11月在美国心脏协会(AHA)年会上指出，1997~2006期间发表的13项以社区为基础的研究结果显示，HFPEF在所有心力衰竭病例中平均占55%。


Carolyn S.P. Lam医生

近期2篇基于美国数据的报告显示，HFPEF患病率的增加速度比HFREF快1%/年，主要原因是美国人口老龄化(老年是HFPEF的一个危险因素)和可促进HFPEF发病的共病患病率上升。其中一篇报告推测，至2020年时，大约65%的心力衰竭住院患者的左心室射血分数将≥40%，其中绝大多数是HFPEF患者(Curr. Heart Fail. Rep. 2013;10:401-10)。

目前，HFPEF的患病率至少不低于HFREF。不论共病情况如何，HFPEF都很致命。HFPEF的患病率增长快于HFREF，而二者的治疗有效性却恰恰相反。为何事态会发展成这样？

Fonarow医生指出：“对HFPEF的研究比HFREF晚了10年。20年以前流行的观点是，HFPEF只占很少部分，而且结局比HFREF好得多。”后来有了注册数据和以社区为基础的研究，心脏病医生们才意识到，HFPEF的结局和HFREF一样差。临床试验招募的HFPEF患者中有一些其实并未患HFPEF，而且这一宽泛疾病谱系的患者对治疗的反应不一致，这些都进一步妨碍了对HFPEF的研究。“在对HFPEF病理生理学的认识方面存在很大空白，而且我们在寻找潜在治疗靶点方面投入太少。”

Teerlink对于HFPEF困境的总结是“我们还不清楚该治疗什么”。

Borlaug医生是葛兰素史克、默克、安进、CardioKinetix和DC设备等公司的顾问，接受了Atcor提供的研究支持。Solomon医生是诺华和另外十多家公司的顾问并获得其提供的研究支持。Pieske医生接受了拜耳、勃林格殷格翰、施维雅、美敦力、百时美施贵宝、Menarini和诺华提供的酬金，并获得了诺华和美敦力提供的研究支持。Shah医生是诺华、拜耳先灵和肺高压协会的顾问。Fonarow医生是美敦力、诺华和辉瑞的顾问。Teerlink医生是诺华的顾问并获得了诺华提供的研究支持。Cleland医生接受了诺华提供的酬金和辉瑞提供的研究资助。Lam医生是拜耳、诺华和DC设备的顾问，并接受了波士顿科学、美敦力和ViforPharma提供的研究支持。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

When the highly-anticipated results from the TOPCAT trial reported last November failed to show a statistically significant efficacy benefit from spironolactone treatment in patients with heart failure and preserved left ventricular ejection fraction for the study’s primary endpoint of death or heart failure hospitalization, the neutral result represented more than another failed treatment trial in this rapidly expanding patient population that remains bereft of treatments with proven efficacy.

TOPCAT’s results also underscored the heterogeneity of patients diagnosed with heart failure with preserved ejection fraction (HFPEF), a signature feature of the syndrome. Heterogeneity is believed to have played a large role in the lack of success in TOPCAT as well as in several other major HFPEF trials.

Although HFPEF is defined as patients who exhibit clear clinical symptoms of heart failure but with a LVEF of at least 45%, and more recently at least 50%, what’s become increasingly clear as neutral trial results accumulate is that HFPEF is a syndrome. Far from a single pathologic entity, it can have different etiologies and present as different subtypes in a spectrum of abnormalities and severities.

HFPEF "is not just a simple disease of diastolic function and a stiff ventricle. It’s a very complicated, highly integrated, multisystem failure of cardiovascular and peripheral reserve," said Dr. Barry A. Borlaug, a cardiologist at the Mayo Clinic in Rochester, Minn. "A lot of us are coming to the conclusion that there are different subphenotypes of HFPEF, each with unique mechanisms and clinical trajectories that probably need unique treatment," he said in an interview.

"This is a very heterogeneous syndrome with no one etiology and a wide range of patients, some with marked ventricular hypertrophy, some with diastolic dysfunction, some who are fairly asymptomatic but become symptomatic with exercise, some who are compensated and stable, and others who are uncompensated. The spectrum of disease is very broad, and it may be many diseases," said Dr. Scott D. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, Boston.

Last year, the heart failure literature featured two editorials spelling out proposed visions of the HFPEF spectrum. One of these proposed three characteristic types of HFPEF patients (J. Am. Coll. Cardiol. 2013;62:1339-42): those with exercise-induced diastolic dysfunction with no symptoms at rest, minimal fluid retention, and never hospitalized for heart failure but with long-standing hypertension and exercise intolerance; patients with volume overload and edema, recently hospitalized heart failure with dyspnea on exertion, and moderately severe heart failure symptoms; and the worst form, patients who have developed pulmonary hypertension and right ventricular failure as a consequence of their HFPEF and now have frequent heart failure hospitalizations. But patients do not necessarily progress from one severity stage to the next, noted Dr. Sanjiv J. Shah, a cardiologist at Northwestern University, Chicago, who wrote the editorial.

"Patients can progress back and forth across the spectrum" or remain in one stage, he said in an interview. "The syndrome is quite heterogeneous, not only in clinical presentation, but in etiology, and pathophysiology. There is still much to learn about the natural history of HFPEF , how it develops, and the trajectory of patients."

The second editorial described several relatively common HFPEF phenotypes that can appear individually or in combination, including filling limitation, ejection limitation, cardioacceleration, and vasoregulation(Eur. Heart J. 2013;34:1393-5). "Patients with heart failure caused by severe mitral insufficiency or aortic stenosis will clearly behave differently and respond to treatments differently from patients with hypertropic cardiomyopathy, constrictive pericarditis, or high-output heart failure. However, despite this heterogeneity these entities continue currently to be lumped together into the category of HFPEF," Dr. Borlaug wrote in this editorial.

The perils of heterogeneity

In addition to providing a better framework for understanding the causes and consequences of HFPEF, the paradigm of HFPEF as a heterogeneous syndrome also helps explain why the major intervention trials that focused on HFPEF patients, starting a decade ago with studies such as CHARM Preserved (Lancet 2003;362:777-81) and I-PRESERVE (N. Engl. J. Med. 2008;359:2456-67), and continuing through to the recent TOPCAT, have all failed to produce a statistically significant benefit for their primary endpoints.

"Heterogeneity confounds our ability to identify effective treatments. It’s the most likely single explanation" for the neutral HFPEF trials, Dr. Borlaug said. "I don’t think it’s as simple as one thing, but my speculation is that it’s the dominant reason."

"Many trials such as CHARM Preserved and TOPCAT seemed to enroll some patients who in retrospect did not have HFPEF," noted Dr. Gregg C. Fonarow, professor of medicine and associate chief of cardiology at UCLA in Los Angeles. "The key to future clinical trials will be better classification of HFPEF" and better matching of HFPEF patients to their treatment, said Dr. Shah.

"In the neutral megatrials some of the patients did not have HFPEF but had other disorders such as deconditioning and obesity – things that cannot be helped by treatments directed at the heart. We need to identify the patients who will respond to the treatment," said Dr. Burkert M. Pieske, professor and director of cardiology at the Medical University of Graz, Austria.

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) results reported last November exemplified the problem of patient heterogeneity. The study enrolled more than 3,400 patients in six countries: Argentina, Brazil, Canada, Russia, the Republic of Georgia, and the United States. Retrospective analysis showed that among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events/100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events/100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.

"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure. Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFPEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator. By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.

"TOPCAT had funding problems, recruitment problems, and monitoring problems. There was not enough money for good monitoring," said Dr. Pieske, who did not participate in TOPCAT. The patients enrolled in Russia and Georgia were "unbelievably stable," with their 2.3/100 patient-years event rate. "Even if the drug works, it can’t exert an effect if there are no events."

Dr. Pieske ran a much smaller study of spironolactone involving 422 patients with HFPEF, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial, which showed efficacy for the endpoint of improved diastolic function but not for the co-endpoint of improved exercise capacity (JAMA 2013;309:781-91).

"If you look at TOPCAT and Aldo-DHF together and ask, does spironolactone work, the answer is yes if you select the right patients, those with clear evidence of cardiac functional abnormalities and increased natriuretic peptide levels or documented hospitalization for heart failure. The drug clearly works in these patients, but there were enough inconsistencies in these trials so that this will not get into the treatment guidelines," Dr. Pieske said in an interview.

"Spironolactone provides most benefit in patients who are volume overloaded, have right-heart failure, or both. These are also the patients most likely to have elevated natriuretic peptide. Spironolactone does not seem to benefit as much early-stage HFPEF," noted Dr. Shah.

Several experts cautioned that because the TOPCAT results failed to produce a statistically significant benefit for the study’s primary endpoint, any other conclusions from the results must be made very cautiously, and several also said that they wanted to see the full, published results which had not appeared as of late February. They also noted that many patients with HFPEF, most likely a majority, do not have elevated blood levels of natriuretic peptide.

Where HFPEF management stands now

Evidence-based guidelines for the specific treatment of HFPEF are simple. There aren’t any.

The American Heart Association/American College of Cardiology heart failure management guidelines released last October made no disease-specific treatment recommendations (J. Amer. Coll. Cardiol. 2013;62:e147-e239). They call for controlling hypertension in patients who need intervention by prevailing standards, treatment with a diuretic in patients with volume overload, coronary revascularization if coronary disease is present, and management of atrial fibrillation if that’s present. The European Society of Cardiology’s guidelines issued in 2012 say pretty much the same (Eur. J. Cardiol. 2012;33:1787-1847), except they add this statement: "No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFPEF."

If nothing else, TOPCAT’s results further solidified spironolactone’s role as a reasonably safe drug for blood pressure lowering in HFPEF patients who are also hypertensive. Hypertension control is a must for patients with HFPEF as it’s believed to significantly contribute to HFPEF in most patients. “Hypertension is the most common underlying cause of HFPEF,” said Dr. John R. Teerlink, professor of medicine and director of the heart failure program at the San Francisco Veterans Affairs Medical Center.

When it comes to treating hypertension in HFPEF patients, "unless there is a contraindication, spironolactone should be one of the first drugs to try, but I’m not sure you can say it’s the first choice" based on current evidence, Dr. Borlaug said.

A diuretic is an obvious antihypertensive for HFPEF patients with fluid overload. And there were suggestions of benefit from the ACE inhibitor perindopril in elderly patients in the PEP-CHF trial (Eur. Heart J. 2006;27:2338-45), another large HFPEF-treatment trial that failed to show significant benefit for the primary endpoint with perindopril treatment but had positive results in some secondary endpoints.

Patients "get these drugs to treat their hypertension, but we believe they may also help their heart failure. It’s a belief system. My colleagues and I already use a lot of spironolactone to treat hypertension, and the TOPCAT results won’t change my practice. I’m not comfortable telling people that you should use an aldosterone antagonist because of TOPCAT," Dr. Teerlink said in an interview.

"An angiotensin-converting enzyme inhibitor will probably work; spironolactone probably works if you get the diagnosis right; we don’t know about beta-blockers; and there is some evidence for using digoxin," said Dr. John G.F. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England. "There must also be good treatment of hypertension, and judicious use of diuretics."

"I’m careful with beta-blockers; I’ve had some patients who felt miserable on them," said Dr. Borlaug. "Some HFPEF patients don’t have a stroke volume, they don’t have diastole, all they have is heart rate, and if you take that away they are left with no cardiac output."

Aside from controlling blood pressure, experts advise good management of other comorbidities such as coronary disease, atrial fibrillation, diabetes, sleep disordered breathing, and renal disease. "Clinicians should make sure that they are not missing severe coronary artery disease, infiltrative cardiomyopathy, constrictive pericarditis, or other causes of HFPEF that have specific treatments," said Dr. Shah. Some drugs have shown promise in early-phase studies – such as ivabradine and neprilysin – but phase III trials are needed. "My advice on how to manage patients with HFPEF is to make every effort to enroll them in a randomized clinical trial," said Dr. Fonarow.

Another key is making the diagnosis, ideally to prevent development of irreversible cardiovascular damage. "HFPEF is difficult to diagnose with certainty unless you do a cardiac catheterization to measure filling pressures, but in patients with early-stage HFPEF, even their invasive hemodynamics look pretty normal," said Dr. Borlaug. Another approach is an exercise echo, which is noninvasive and can identify stress-induced diastolic dysfunction, but the sensitivity and specificity of this approach remains uncertain, he said. And an elevated natriuretic peptide level can help nail the HFPEF diagnosis in some patients but many other patients have levels within the normal range.

To find HFPEF patients, apply a low index of suspicion and look for breathlessness, loss of functional capacity, signs of congestion, lung crackles, echocardiographic signs, pulmonary artery hypertension, and an enlarged left atrium, he suggested.

"Finding patients is a big challenge," said Dr. Pieske. HFPEF patients tend to be elderly, women, and people who are obese who have hypertension and perhaps diabetes. "They complain of dyspnea and fatigue and many physicians think this is just how it is. They will not consider that there is a true diagnosis behind these symptoms and complaints," especially if the patient has preserved left ventricular ejection fraction and a normal natriuretic peptide level." A diastolic stress test using exercise and an echo exam may identify stable patients with early-stage diastolic dysfunction but this requires confirmation, he said.

HFPEF dominates heart failure, lacks good treatment

Experts say the onus on physicians to diagnose and manage HFPEF will grow substantially, since HFPEF is not only highly prevalent but also increasing faster than heart failure with reduced ejection fraction (HFREF). Results from 13 community-based studies published during 1997-2006 showed that HFPEF represented an average of 55% of all heart failure cases, Dr. Carolyn S.P. Lam said last November during a talk at the American Heart Association’s scientific sessions.

Two recent reports of U.S. data documented that the increasing prevalence of HFPEF is outpacing that of HFREF by 1% per year, driven by the aging of the American population (older age is a risk factor for HFPEF) and by the increasing prevalence of comorbidities that contribute to HFPEF. One of the reports, based on U.S. national data collected by the Get With the Guidelines Program, extrapolated that by the end of this decade about 65% of all patients hospitalized for heart failure will have a left ventricular ejection fraction of 40% or greater, the vast majority with HFPEF (Curr. Heart Fail. Rep. 2013;10:401-10). What’s coming is a HFPEF "epidemic," said Dr. Lam, a cardiologist at the National University Heart Centre in Singapore.

The fact that HFPEF is now at least as prevalent as HFREF, that it is about as lethal independent of what comorbidities might contribute, and that it is growing more prevalent than HFREF sharply contrasts with the absence of treatments with proven efficacy. How did that happen?

"Research into HFPEF is decades behind research into HFREF," said Dr. Fonarow. "HFPEF was largely ignored because the prevailing wisdom [20 or so years ago] was that it represented only a small proportion of cases and that outcomes were much better compared with HFREF." Only with registry data and community-based studies run more recently did cardiologists realize that outcomes from HFPEF were as bad as from HFREF. Progress was further hampered by enrollment of patients who did not have HFPEF or a broad spectrum of patients unable to respond equally well to the treatment under study.

"There are large gaps in knowledge of the pathophysiology of HFPEF and little investment has been made to identify potential therapeutic targets. This creates cascading levels of challenges for developing effective treatments despite the massive unmet need," said Dr. Fonarow.

"We don’t know what to treat yet," was Dr. Teerlink’s summation of the HFPEF dilemma.

Dr. Borlaug said that he has been a consultant to GlaxoSmithKline, Merck, Amgen, CardioKinetix, and DC Devices and has received research support from Atcor. Dr. Solomon said he has been a consultant to and received research support from Novartis and more than 10 other drug and device companies. Dr. Pieske said that he has received honoraria from Bayer, BoehringerIngelheim, Servier, Medtronic, Bristol-Myers Squibb, Menarini, and Novartis and received research support from Bayer and Medtronic. Dr. Shah said that he has been a consultant to Novartis, Bayer Schering, and the Pulmonary Hypertension Association. Dr. Fonarow said that he has been a consultant to Medtronic, Novartis, and Pfizer. Dr. Teerlink said that he has been an adviser to and received research support from Novartis. Dr. Cleland said that he has received honoraria from Novartis and research funding from Pfizer. Dr. Lam said that she has been a consultant to Bayer, Novartis, and DC Devices and has received research support from Boston Scientific, Medtronic, and ViforPharma.