Shunt Safety for Patients with HFpEF

At Alleviant, we believe in following the science to develop treatment options for the millions of people worldwide suffering from heart failure.

Prior clinical trials have taught us a great deal about interatrial shunting and the critical importance of appropriate patient selection.

Heart failure patients are not all alike. Even within categorizations of heart failure with preserved or reduced ejection fraction (HFpEF or HFrEF), additional variables in the heart failure status, as well as right-side compliance (or evidence of right heart dysfunction), make a significant difference in choosing the appropriate treatment.

Interatrial shunting has been shown to relieve shortness of breath, fatigue and weakness in patients with heart failure (HF) when excess pressure is reduced.1

In some patients, shunts may be highly effective. In others, they are neutral and in still others they may worsen their underlying condition.2

Building on the foundation of decades of relevant clinical data, and with particular attention to the insights uncovered in recent years, the science is clear:

For certain patients with HFpEF, an interatrial shunt is likely safe,
and may be highly effective in reducing the clinical burden of the disease.³

Our highly informed ALLAY-HF trial aims to confirm this by evaluating the safety and efficacy of the Alleviant System in patients who match the “responder phenotype,” or patient population most likely to benefit, that has been identified from previous interatrial shunt studies.

  • The Alleviant System enables the creation of a stable therapeutic interatrial shunt, which may reduce elevated left atrial pressure and relieve symptoms for certain patients with HF, without an implant. As a result, there is no implant that may interfere with the cardiac motion of the septum or impact potential follow-on procedures later in the patient’s life.

    During the procedure, an interventionalist inserts the Alleviant System into the patient’s femoral vein and advances it over a guidewire across the interatrial septum. The device is positioned under echocardiography or fluoroscopic guidance, and a precise segment of the interatrial septum is secured within the catheter.

    An internal electrode is used to apply a brief pulse of energy to create the septectomy. The device with the securely captured tissue is removed. The result is a natural communication between the right and left atria to allow pressure relief with no implant left behind.

    The no-implant approach has several clinical advantages and preserves options for additional transseptal procedures patients may require in the future.

  • The primary endpoint for the ALLAY-HF study is a composite outcome of mortality, heart failure event rates and quality of life improvements over a 12-month follow-up period.

    Candidates for ALLAY-HF are chronic heart failure patients with HFpEF with EF ≥ 40% who remain symptomatic despite stable guideline-directed medical therapy.

    Exercise hemodynamic testing is an essential aspect of ALLAY-HF patient selection to identify patients with elevated left atrial pressure or evidence of right heart dysfunction. We believe this trial could be extremely impactful for a population that otherwise faces a substantial gap in both diagnosis and treatment.

    Patients are enrolling at select study sites across the United States, Canada, Europe, Israel, Australia and New Zealand. These leading research institutions include Duke University Hospital (NC, USA), INCLIVA Institute (Valencia, Spain), Hendrick Health (Texas, USA), Ann Arbor VA (Michigan, USA) and others soon offering this trial as listed here.

  • No; grouping all HFpEF patients in this statement is an overgeneralization. Data indicate that shunts may be harmful in certain patients with HFpEF—those with advanced disease and some form of right ventricle/pulmonary arterial (RV/PA) dysfunction. (4,5)

    This same data confirms that it is possible to select the HFpEF population most likely to benefit from shunts: those with symptomatic HFpEF with EF ≥ 40%, NYHA Class II, III or ambulatory IV, with exercise right heart catheterization demonstrating a healthy RV/PA axis. (4)

    There is now 3-year follow-up data in HFpEF patients with the same criteria as ALLAY-HF, who continue to demonstrate benefit. (5)

  • The RELIEVE-HF trial aimed to assess safety and efficacy of the V-Wave Interatrial Shunt System in improving clinical outcomes for patients with HF. This trial enrolled patients across the ejection fraction spectrum (including HFrEF) and did not utilize complete hemodynamic phenotyping. Ultimately, this trial enrolled a patient population which has been shown in previous studies to do poorly with shunting therapy. (6)

    The study failed to meet its primary endpoint for efficacy—in other words, the implantable V-Wave device showed no significant benefit.

    There has been some discussion of an underpowered subgroup of HFpEF patients for which RELIEVE-HF appeared to indicate harm.

    We believe it is critical to be attentive to all data that can inform better clinical decision-making and patient selection, and have closely scrutinized the RELIEVE-HF data.

    What stands out is that the HFpEF patients in RELIEVE-HF appear extremely similar to the non-responders from a previous interatrial shunt study, REDUCE LAP-HF II. (4)

    With data from these two trials, we are even more confident that we have identified a group of HFpEF patients who are most likely to benefit from our no-implant interatrial shunt, the Alleviant System.

  • No. We already understood that it is essential to consider factors including elevated left atrial pressure, PVR during exercise, and evidence of right heart dysfunction when considering an interatrial shunt.

    Heart failure patients with poor right ventricular function, poor pulmonary arterial compliance and right-sided valvular dysfunction appear to do poorly with an interatrial shunt. (3)

    This all fits into our understanding of how and why interatrial shunts work, and RELIEVE-HF provided additional validation from insights gleaned from previous clinical trials.

Frequently Asked Questions

Timeline

Key Takeaway:
A growing evidence base informs our understanding of intertribal shunting for a range of patient populations. REDUCE LAP-HF II and RELIEVE-HF ran concurrently with similar HFpEF patient groups, even though they reported results years apart. As a result, we weren’t surprised that outcomes for many of those patients were similar.

At Alleviant, we remain grateful to all patients and physicians who participate in clinical testing and add to the knowledge base that informs our current study, ALLAY-HF, which we designed with insights from REDUCE LAP-HF II and further validated by RELIEVE-HF.

Heart failure (HF) is one of the most widely diagnosed conditions globally. With more than 26 million people suffering worldwide7 and another 3.6 million diagnosed annually8, these patients need and deserve effective treatment options.

About Heart Failure

Depending on the type of HF, those treatment options can vary widely—leaving many patients with few or no choices to help them live longer, healthier lives.

The two most common types of HF are reduced left ventricular ejection fraction (HFrEF), in which the heart’s ability to contract is impaired, and preserved left ventricular ejection fraction (HFpEF) in which the heart’s ability to fill or eject blood is impaired.

Patients with HFpEF have few therapeutic options and no device treatments available today, despite representing more than half of all HF cases9,10 disproportionately including women11 and frequently accompanied by significant quality of life challenges.12

Alleviant Medical remains committed to developing a safe, effective no-implant treatment option to potentially help these millions of patients live a longer, healthier life.

Additional Resources

1 Emani S, Burkhoff D, Lilly SM. Interatrial shunt devices for the treatment of heart failure. Trends Cardiovasc Med. 2021;31:427–432.

2 O’Riordan, M. (2024, April 10). Interatrial Shunt Falls Short in Sham-Controlled RELIEVE-HF. TCTMD.com. https://www.tctmd.com/news/interatrial-shunt-falls-short-sham-controlled-relieve-hf

3 Borlaug, B. A., John E.A. Blair, Bergmann, M., Bugger, H., Burkhoff, D., Bruch, L., Celermajer, D. S., Claggett, B., John G.F. Cleland, Cutlip, D. E., Dauber, I., Eicher, J.-C., Gao, Q., Gorter, T. M., Gustafsson, F., Hayward, C. S., Van, J., Hasenfuss, G., Hummel, S. L., & Kaye, D. M. (2022). Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure. 145(21), 1592–1604. https://doi.org/10.1161/circulationaha.122.059486

4 Shah, S. (2024, April 6-8). RELIEVE-HF Trial: Discussant. American College of Cardiology 2024, Atlanta, GA, United States.

5 Shah, S. (2024, March 4-6). Patient Selection Considerations for Trials of Interatrial Shunts. Technology and Heart Failure Therapeutics 2024. Boston, MA, United States.

6 Unpublished RELIEVE-HF results presented at ACC 2024. Data on file at V-Wave Medical.

7 Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017 Apr;3(1):7-11. doi: 10.15420/cfr.2016:25:2. PMID: 28785469; PMCID: PMC5494150.

8 Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding. Cells. 2020 Jan 18;9(1):242. doi: 10.3390/cells9010242. PMID: 31963679; PMCID: PMC7016826.

9 Owan, T.E., Hodge, D.O., Herges, R.M., Jacobsen, S.J., Roger, V.L. and Redfield, M.M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. The New England journal of medicine, [online] 355(3), pp.251–9. doi:https://doi.org/10.1056/NEJMoa052256.

10 Tsao, C. W., Lyass, A., Enserro, D., Larson, M. G., Ho, J. E., Kizer, J. R., Gottdiener, J. S., Psaty, B. M., & Vasan, R. S. (2018). Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JACC: Heart Failure, 6(8), 678–685. https://doi.org/10.1016/j.jchf.2018.03.006

11 Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM. Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction. Circulation. (2018) 138:198–205. 10.1161/CIRCULATIONAHA.118.034271 

12 Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451-1461.