Author + information
- ↵∗Reprint requests and correspondence:
Dr. Mihai Gheorghiade, Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 1006, Chicago, Illinois 60611.
Heart failure with preserved ejection fraction (HFpEF) is now recognized as a major public health problem, accounting for approximately 50% of all patients with HF (1), and morbidity and mortality rates in HFpEF approximate those of HF with reduced EF (HFrEF) (2). Aside from supervised exercise training programs (3), evidence-based treatments are unfortunately lacking in HFpEF. Challenges in the design and conduct of Phase II clinical trials may explain why finding evidence-based therapies for HFpEF remains an elusive challenge. The lack of a robust definition of HFpEF for enrollment into trials, not matching HFpEF subtypes to the mechanism of a given experimental therapy, and suboptimal evaluation metrics and endpoints, all plague Phase II clinical trials in HFpEF. Thus, to effectively improve management in HFpEF, we need optimal Phase II trials that truly inform subsequent Phase III studies.
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HFpEF is a heterogeneous clinical syndrome, with several underlying etiologies and pathophysiologies, including diastolic dysfunction. Abnormal cardiomyocyte sodium and calcium handling has been proposed as a potential mechanism that contributes to diastolic dysfunction (4). Mechanistically, the late inward sodium current (which is enhanced in diseased myocytes), results in diastolic calcium overload via increased sodium-calcium exchange within myocytes. Ranolazine, a potent inhibitor of the late inward sodium channel, was originally approved for use for the indication of refractory stable angina in Europe and the United States. Theoretically, inhibition of this sodium channel in HFpEF with ranolazine may reduce intracellular calcium levels and augment diastolic relaxation (5).
In this issue of JACC: Heart Failure, Maier et al. (6) describe the results of RALI-DHF (RAnoLazIne for the Treatment of Diastolic Heart Failure), a novel Phase IIa proof-of-concept study of the acute effects of ranolazine on hemodynamics and diastolic function in outpatients with chronic HFpEF. In this small pilot study, the investigators randomized 20 patients to either ranolazine or placebo. Therapy involved 24 hours of intravenous infusion of the study drug followed by 2 weeks of oral therapy. Short-term intravenous ranolazine therapy was associated with modest reductions in invasively measured left ventricular (LV) filling pressures and pulmonary artery pressures, without concomitant changes in relaxation kinetics or pulmonary or systemic vascular resistance. Unfortunately, cardiac output also decreased with ranolazine, presumably due to reduced LV filling pressure. After completion of the 2-week oral regimen, no significant changes in exercise capacity and noninvasive indexes of diastolic function, measured by cardiopulmonary exercise testing and echocardiography, respectively, were demonstrated (6).
RALI-DHF provides an excellent early opportunity to evaluate the potential challenges faced by Phase II trials. The study appropriately employed strict inclusion criteria in defining HFpEF, consistent with a consensus report from the European Society of Cardiology (7). The investigators used an agent with known effects on diastolic function and appropriately measured its short-term effects on various LV relaxation parameters. In terms of evaluation and endpoint analysis, Maier et al. (6) utilized invasive hemodynamic testing, echocardiography, and cardiopulmonary exercise testing to monitor drug efficacy in their patient sample. However, RALI-DHF was limited by its small sample size, which resulted in an underpowered study. In addition, the study could have benefited from exercise testing instead of pacing to increase heart rate during the invasive hemodynamic procedure, thereby allowing for a more realistic and physiological assessment of the effects of ranolazine during increases in heart rates. Finally, echocardiographic evaluation after only 2 weeks of oral therapy was too early and likely prevented the investigators from identifying potential longer-term effects of ranolazine in HFpEF.
Invasive hemodynamic testing, a key feature of RALI-DHF, requires further scrutiny. The role of invasive hemodynamic assessment in Phase II HFpEF studies is presently uncertain. Two decades of experience from drug development programs in HFrEF have suggested a lack of correlation between short-term hemodynamic or symptomatic parameters and long-term clinical endpoints. There appears to be a distinct disconnect between successful Phase II programs and subsequent negative Phase III clinical trials in this area. Agents such as inotropes that acutely improve systolic function (but increase cardiac workload) in HFrEF may have neutral or even deleterious effects on long-term safety endpoints. By contrast, established therapies in HFrEF such as beta-blockers that may acutely contribute to decompensation of the failing myocardium have consistently demonstrated longer-term clinical outcome benefit. Additional major drawbacks to invasive investigations are high trial costs and the limited number of enrolled subjects. The investigators of RALI-DHF recognize that small, single-center studies may be underpowered to provide definitive answers, and in a heterogeneous syndrome such as HFpEF, may not be generalizable enough to lay the groundwork for definitive Phase III studies.
Invasive hemodynamic monitoring therefore likely has a limited and specific role in the setting of HFpEF trials. Hemodynamic data may be most useful for: 1) developing a mechanistic understanding of a novel drug’s action, thereby bridging pre-clinical and clinical studies during the exploratory T1 translational phase (8); 2) clarifying optimal dosages in dose-ranging investigations; and 3) identifying specific subgroups that are most likely to benefit in later Phase III trials. In Phase II HFpEF studies, invasive hemodynamic testing is most likely to be helpful if it is comprehensive (i.e., includes pressure–volume analysis and contemporaneous echocardiography) and includes dynamic exercise testing.
Although RALI-DHF represents a small, underpowered, short-term invasive hemodynamic Phase II trial, the recently published PARAMOUNT (Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction) study (9), which evaluated a novel angiotensin-receptor neprilysin inhibitor (LCZ696), represents the other end of the Phase II spectrum, and exemplifies many features of a well-conducted early-phase study in HFpEF. PARAMOUNT collected safety and efficacy data on over 300 patients from 65 centers and 13 different countries. Drug monitoring was achieved using biomarkers and echocardiography during a treatment period spanning 36 weeks (9). PARAMOUNT might serve as the paradigm for the evaluation of upcoming drugs or devices in this area, although its relatively large size and scope for a Phase II trial might prove to be too costly to be the norm. For the majority of agents with established mechanisms of actions, appropriately powered, multicenter Phase II HFpEF studies with sample sizes in the 100 to 200 range, with detailed echocardiography and/or cardiac magnetic resonance imaging, might be the most optimal trial design.
Thus far, the management of patients with HFpEF has revolved around active detection and aggressive treatment of comorbidities (10). Based on available clinical trial data, therapies known to be effective in HFrEF appear to have a limited role in patients with HFpEF. Thus, novel treatment targets and agents are required in HFpEF in the near future to ameliorate the high morbidity and mortality burden. The exploratory RALI-DHF study represents 1 of several ongoing early Phase II studies in HFpEF, an area that is largely uncharted, lacking an effective roadmap. An established paradigm for the routine testing and evaluation of new therapies for patients with HFpEF is therefore sorely needed. Recent advances in cardiac imaging and biomarkers related to HF have expanded the available arsenal clinicians and trialists can use to diagnose, characterize, and monitor treatment response in HFpEF (11). As data begin to accrue in patients with HFpEF, a concrete evaluative framework is required to help guide initial drug development programs. Further understanding of this unique patient population through large registries and trials (12), along with specific recommendations for patient selection and intermediate endpoints (Table 1), provides an initial starting point for this process.
↵∗ Editorials published in JACC Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC Heart Failure or the American College of Cardiology.
Dr. Gheorghiade has received research support or consultation fees from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, sanofi-aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. Dr. Shah has received grants from the National Institutes of Health, American Heart Association, and Gilead Sciences; and has served on an advisory board for Bristol-Myers Squibb. Dr. Vaduganathan has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Steinberg B.A.,
- Zhao X.,
- Heidenreich P.A.,
- et al.
- Kitzman D.W.,
- Brubaker P.H.,
- Morgan T.M.,
- et al.
- Maier L.S.,
- Layug B.,
- Karwatowska-Prokopczuk E.,
- et al.
- Paulus W.J.,
- Tschope C.,
- Sanderson J.E.,
- et al.
- Shah S.J.,
- Heitner J.F.,
- Sweitzer N.K.,
- et al.