Guest Column | August 29, 2019

Novartis' Entresto Failure Highlights Need For New HFpEF Trial Designs

By Dominika Rudnicka-Noulin, Ph.D., Decision Resources Group

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Heart failure with preserved ejection fraction (HFpEF) remains one of the greatest and most challenging unmet needs in cardiovascular (CV) medicine. In contrast to the significant advances being made in the treatment of heart failure with reduced ejection fraction (HFrEF), little has changed in the approach to treating HFpEF in decades.

HFpEF affects over 20 million people worldwide, approximately half of all those living with heart failure (HF). This number is constantly growing, driven by population aging, the increasing prevalence of risk factors for HFpEF, such as obesity, hypertension, and type 2 diabetes (T2D), as well as improvements in diagnosis. Those living with HFpEF experience frequent hospitalizations and high mortality rates. Nevertheless, there are currently no approved disease-modifying therapies for HFpEF. The lack of effective treatment options is not due to the lack of pipeline activity in this indication but rather due to the 100 percent failure rate of late-stage clinical trials.

HFpEF Trial Failures

Novartis’ Entresto became the most recent casualty in the effort to bring the first effective therapy to the HFpEF market. In July 2019 the company announced that the Phase 3 PARAGON-HF trial “narrowly missed statistical significance” in reducing CV death and total HF hospitalizations in HFpEF patients.1 The disappointment caused by this announcement was significant given the high expectations fueled by positive Phase 2 data and Entresto’s impressive performance in HFrEF, where it outperformed standard-of-care treatment in reducing the risk of death and HF hospitalization.2

Entresto joins a number of other therapies that have failed in the task of improving outcomes in HFpEF. Previous negative Phase 3 trials include the TOPCAT trial evaluating spironolactone, the I-Preserve trial of irbesartan, and the CHARM-Preserved trial of candesartan, to name just a few. All these therapies were initially proven to improve clinical outcomes in HFrEF patients, but this did not translate into benefit for the HFpEF population.

Challenges Facing HFpEF Drug Development

Why is it so difficult to develop an effective treatment for HFpEF? Part of the answer is in the pathophysiology of the disease. HFpEF is not a uniform condition; it is a syndrome with multiple etiologies and phenotypes. Furthermore, the majority of patients suffer from a number of comorbidities, which further adds to the heterogeneity of this population. Therefore, a one-size-fits-all approach to the treatment of HFpEF might not be valid.

The predominant feature of HFpEF is the presence of signs and symptoms of HF in the context of preserved left ventricular ejection fraction (LVEF). However, the clinical picture is complicated by the fact that the ejection fraction threshold distinguishing HFrEF from HFpEF is not clearly defined. HFpEF is typically considered with an ejection fraction of ≥ 50 percent, but some clinical trials for HFpEF recruit patients with LVEF as low as 40 percent. In an effort to target a broader patient pool, drug developers are adding to the heterogeneity of the studied population. Using more strict inclusion criteria might significantly reduce the target patient pool but at the same time increase the chances of a successful study. This is an important consideration given the fact that only a small minority of all HFpEF patents are typically eligible for clinical trials. It has been estimated that using strict internationally accepted criteria for diagnosing HFpEF could lead to less than 1 percent of patients admitted to hospital for HF being eligible for participation in a clinical trial.3

Another consideration is making a correct diagnosis of HFpEF. This is not a trivial task given the complexity of the diagnostic process, which is largely based on excluding other conditions often presenting with similar symptoms. The validity of this point was demonstrated in the analysis of the TOPCAT trial, where it was revealed that a proportion of patients recruited in Russia and Georgia did not suffer from HFpEF. Inclusion of these patients in the trial likely negatively affected its outcomes and potentially prevented millions of HFpEF patients from benefiting from the use of a cheap, generically available drug.

Considerations For Designing Future Clinical Trials

What is the recipe for designing HFpEF trials with the best chance of success? There are several important considerations.

Drug developers need to carefully consider their target patient population. Inclusion criteria for HFpEF trials should be refined and the EF cutoff adjusted to the preferred HFpEF phenotype.4 Using a more stringent LVEF cutoff of ≥ 50 percent can reduce the chance of recruiting patients that might have underlying HFrEF but have recovered their EF.

All unsuccessful trials to date had broad inclusion criteria, indiscriminately recruiting patients with different etiologies contributing to diastolic dysfunction. Given the heterogeneity of the HFpEF population, clinical trials might be optimized by focusing on highly phenotyped, relatively uniform, and therefore better-defined patient subsets, such as patients with common comorbidities driving their HFpEF pathophysiology. This is not a straightforward approach, as it is inevitably going to reduce target patient population sizes. Nevertheless, given the heterogeneous pathophysiology of HFpEF, this approach may significantly increase the likelihood of trial success.

It has also been suggested that innovative approaches to designing clinical trials, currently employed in oncology, could be a way to go also in HF.5 The concept involves enrichment trials, adaptive trials, umbrella trials, and even basket trials that could be the answer to the challenges of performing clinical studies in a very heterogeneous HFpEF population. The idea of personalized medicine in the context of HFpEF is also gaining traction. Combining different “omics” approaches with deep phenotyping can help in classifying HFpEF patients into more homogenous subtypes.6

The Emerging Therapy Landscape

Regardless of the significant number of HFpEF trial failures to date, there are still several agents in the pipeline. In particular, two SGLT-2 inhibitors, Jardiance and Farxiga, are currently being evaluated in large Phase 3 trials in HFpEF. These agents are currently marketed for diabetes and are indicated to improve glycemic control. Recently, they have also received approval to reduce the risk of CV death in adult patients with T2D and established CV disease. The DELIVER trial of Farxiga and the EMPERIAL-Preserved trial of Jardiance have broad inclusion criteria, similar to the PARAGON-HF trial of Entresto. Both DELIVER and EMPERIAL-Preserved trials recruit patients with EF ≥ 40 percent, extending the inclusion criteria further than the PARAGON-HF trial, where the cutoff was EF ≥ 45 percent. It will be interesting to see whether these drugs demonstrate a different level of benefit in patients with and without comorbid T2D. If the drugs prove to be more beneficial in patients with comorbid T2D, this would suggest that going down the route of targeting specific patient subsets based on their comorbidities may be beneficial in designing future HFpEF trials. Separately, the SOLOIST-WHF trial evaluating the SGLT-1/2 inhibitor Zynquista in the general HF population (including both HFrEF and HFpEF patients) focuses only on patients with comorbid T2D. Select agents in earlier phases of development are already being investigated in clearly defined subsets of HFpEF patients. Levosimendan is being evaluated in HFpEF patients with comorbid pulmonary hypertension, while macitentan is being investigated in HFpEF patients with pulmonary vascular disease.

Challenges And Opportunities Remain

Despite the fact that HFpEF drug development has only seen failures thus far, a significant market opportunity in this indication remains. High rates of mortality and morbidity among HFpEF patients, combined with the high – and still growing – prevalence of the disease, contribute to a high unmet need but also indicate that commercial success is possible should improved outcomes be demonstrated. However, drug developers should consider the notion that a one-size-fits-all approach might not be the right way to design successful clinical trials in HFpEF. The shift toward personalized medicine that is increasingly shaping drug development strategies could be the key to unlocking clinical and commercial success for emerging therapies for HFpEF.


  1. Novartis, press release, July 29, 2019
  2. McMurray JJ, et al., Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
  3. Patel HC, et al., Heart failure with preserved ejection fraction: the impact of stricter definitions. Eur J Heart Fail. 2014 Jul;16(7):767-71.
  4. Kelly JP, et al. Patient Selection in Heart Failure With Preserved Ejection Fraction Clinical Trials. J Am Coll Cardiol. 2015 Apr 28; 65(16): 1668–1682.
  5. Shah SJ. Innovative Clinical Trial Designs for Precision Medicine in Heart Failure with Preserved Ejection Fraction. J Cardiovasc Transl Res. 2017 Jun; 10(3): 322–336.
  6. Shah SJ., et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015 Jan 20;131(3):269-79.

About The Author:

Dominika Rudnicka-Noulin, Ph.D., MSc, is a senior business insights analyst in the Cardiovascular, Metabolic and Renal division at Decision Resources Group. She specializes in cardiovascular and metabolic indications. Her main areas of expertise include heart failure, acute coronary syndrome, and NASH. Prior to joining DRG, Rudnicka-Noulin was an associate editor at Nature Communications, working across a variety of therapy areas. She also worked for three years as a postdoctoral research associate on a joint project between Imperial College London and MedImmune. Rudnicka-Noulin gained her Ph.D. from the Institut Pasteur in Paris. You can reach her at, connect with her on LinkedIn, or follow her on Twitter.