CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Director – Diabetes and Heart Research Centre, Dhanbad; Editor – CME INDIA.

Black hole of cardiology, the HFpEF gets an efficacious, disease modifying treatment – NNT (Number needed to treat) of 9. Unbelievable!

PRESERVED-HF trial with Dapagliflozin in heart failure with preserved ejection fraction (HFpEF) was presented on September 12th, 2021.

We are aware that HFpEF is a very tedious condition not only for diagnosis but also for management. Heart retains preserved pumping function, but the heart’s relaxation is adversely affected. Many mechanisms like inflammation, fibrosis, and endothelial dysfunction have been found explained. Ultimately it leads to elevated filling pressure. Many patients present with breathlessness and exertional intolerance. It leads to significant physical limitations, poor quality of life, and high risk of hospitalizations and death. We have at present many approved treatments for patients with heart failure with reduced ejection fraction but efficacious treatments for individuals with HFpEF have been sited as distant dream so far. Two new trials have paved a new way to tide over heart failure with preserved ejection failure.

August 27,2021: Remember it

• EMPEROR-Preserved, the first and only successful clinical trial in heart failure with preserved ejection fraction (HFpEF), was presented at the European Society of Cardiology (ESC) Congress.
• Full results were published in the New England Journal of Medicine on August 27.
• It’s “a big day for patients living with HFpEF, a big day for heart failure clinicians,” – Shelley Zieroth commented.
• It is now in history as “First successful trial in heart failure with preserved ejection fraction.”

Empagliflozin emerges as first saviour in HFpEF in landmark trial

• Empagliflozin reduced the risk of a composite of cardiovascular death or hospitalisation for heart failure in both diabetic and non-diabetic patients with HFpEF compared to placebo.
• Prompt changes in clinical practice for HFpEF is on horizon

Fiasco Unlimited

• Till results of EMPEROR-Preserved illuminated, no drug has demonstrated a clear clinical benefit in an HFpEF trials.
• There were limited therapeutic options available and unmet needs.
• In PARAGON-HF trial with sacubitril/valsartan, narrowly missed statistical significance for its composite primary endpoint of reducing cardiovascular death and total heart failure hospitalisations.
• Despite this failure, it was approved for the treatment of HFpEF in February 2021 in the US.
• It indicated the low bar for new drug approvals in HFpEF.
• Worth to remember: In PARAGON-HF trial, sacubitril/valsartan was compared against an active therapy, valsartan while in EMPEROR-Preserved empagliflozin compared against placebo.

Then how EMEROR-Preserved shines!?

• The double-blind, Phase III trial.
• 5,988 symptomatic HFpEF patients (left ventricular ejection fraction over 40%), both with and without type 2 diabetes (T2D).
• Across 23 countries.
• Participants were randomised in a 1:1 ratio to receive either 10mg Jardiance or placebo once daily, in addition to standard of care therapies.
• Median follow-up of 26.2 months.
• 13.8% of Empagliflozin treated patients and 17.1% of placebo-treated patients experienced a primary outcome event, equating to a hazard ratio of 0.79 (P<0.001).
• It translates as 21% relative risk reduction for the composite primary endpoint of cardiovascular death or hospitalization for heart failure, compared with placebo.
• This effect was observed across subgroups, in patients with a left ventricular ejection fraction of less than 50%, 50% to less than 60% or 60% or more.
• The safety profile was generally consistent with the known safety profile of Empagliflozin. A significant 29% reduction in the need for admission to a cardiac care unit or intensive care unit during an HHF.
• A nonsignificant 33% reduction in the need for intravenous vasopressors or positive inotropic drugs during HHF.

EMPEROR-Preserved – A wrench into what had been an unbroken history of renal protection by SGLT2 inhibitors. Points to Ponder:

• This trial witnessed surprising and complicated set of about renal outcomes.
• There were two prespecified secondary outcomes:
  • Total number of HHF – it dropped by a significant 27%, compared with placebo.
  • The mean change in slope of estimated glomerular filtration rate (eGFR) on an annualized basis.
• Empagliflozin regimen reduced the cumulative annual deficit, compared with placebo by an average of 1.36 mL/min per 1.73 m² a significant difference.
• We are well versed that preservation of renal function and a reduction in renal events has become a hallmark property of all agents in the SGLT2 inhibitor class.

• In this trial, composite renal outcome defined as time to first occurrence of chronic dialysis, renal transplantation, a sustained reduction of at least 40% in eGFR, or a sustained drop in eGFR of more than 10 or 15 mL/min per 1.73 m2 from baseline was puzzling as an unexpected neutral finding.

September 9, 2021

• FDA Grants Breakthrough Therapy Designation to Empagliflozin for Heart Failure with Preserved Ejection Fraction.

September 12, 2021 – Now PRESERVED-HF with Dapagliflozin shines

• The Effects of Dapagliflozin on Symptoms and Functional Status in Patients with Heart Failure and Preserved Ejection Fraction (PRESERVED-HF).
• “PRESERVED-HF trial demonstrates substantial improvements in symptoms, physical limitations and exercise function with dapagliflozin in individuals with heart failure with preserved ejection fraction (HFpEF).”
• An investigator-initiated, randomized trial.
• Included patients with chronic HFpEF across 26 centers in the United States.
• Randomly assigned treatment with either the SGLT2 inhibitor dapagliflozin, or placebo for 12 weeks.
• The primary endpoint was Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS).
• This score is a well-validated measure of heart failure related symptoms and physical limitations.
• Exercise function was measured by the 6-minute walking distance.
• PRESERVED-HF results:

Wait, DELIVER, trial will further untangle the mystery

• DELIVER Trial is – The Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure.
• It is testing the hypothesis that the SGLT2 inhibitor dapagliflozin will reduce cardiovascular death and heart failure hospitalization in patients with heart failure with a LVEF >40% (HFpEF and HFmrEF).
• It is a Phase III trial.
• It is expected to complete in Q1 2022.
• DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction.

CME INDIA Learning Points

1. Diagnosing HFpEF in PRESERVED-HF

1. Documented diagnosis of symptomatic heart failure (NYHA class II–IV).
2. LVEF >40% and evidence of structural heart disease (i.e. left ventricular hypertrophy or left atrial enlargement) documented by the most recent echocardiogram, and/or cardiac magnetic resonance within the last 12 months prior to enrolment. For patients with prior acute cardiac events or procedures that may reduce LVEF, e.g. as defined in exclusion criterion, qualifying cardiac imaging assessment at least 12 weeks following the procedure/event is required. Structural heart disease will be defined as:
   • LA enlargement with at least one of the following: LA width (diameter) ≥3.8 cm or LA length ≥ 5.0 cm, or LA area ≥20 cm, or LA volume ≥55 mL or LA volume index ≥29 mL/m.
   • Left ventricular hypertrophy with septal thickness or posterior wall thickness ≥ 1.1 cm.
3. NT-proBNP ≥300 pg/mL for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at Visit 1, NT-proBNP must be ≥600 pg/mL.

2. Summary of PRESERVED-HF Trial/Key messages

3. What to expect next?

• Due to the superior results obtained from EMPEROR-Preserved and PRESERVED -HF, SGLT2-inhibitors like empagliflozin and dapagliflozin are  going to achieve a label expansion for HFpEF.
• In the pooled analysis of SCORED and SOLOIST-WHF data with Sotagliflozin, benefits were preserved irrespective of baseline EF (including among patients with HF with preserved EF [HFpEF]) and prior history of HF.
• PRESERVED-HF shows that dapagliflozin can enable individuals with HFpEF to feel better and do more within just 12 weeks.
• SGLT2 inhibitors represent a disease-modifying therapy, and thus appear as an important new treatment option for HFpEF.

CME INDIA Tail Piece

PEFF Scoring System (Reddy YN, et al.Circulation2018,138:861-870)

References

1. FDA Grants Jardiance Breakthrough Therapy designation for heart failure with preserved ejection fraction. News release. Lilly; September 9, 2021. Accessed September 9, 2021. https://investor.lilly.com/news-releases/news-release-details/fda-grants-jardiancer-breakthrough-therapy-designation-heart
2. Packer, M., Zannad, F., Butler, J., Filippatos, G., Ferreira, J.P., Pocock, S.J., Brueckmann, M., Zeller, C., Hauske, S., Anker, S.D. and (2021), Influence of endpoint definitions on the effect of empagliflozin on major renal outcomes in the EMPEROR-Preserved trial. Eur J Heart Fail. https://doi.org/10.1002/ejhf.2334
3. Packer M, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, Carson P, Anand I, Doehner W, Haass M, Komajda M, Miller A, Pehrson S, Teerlink JR, Schnaidt S, Zeller C, Schnee JM, Anker SD; EMPEROR-Preserved Trial Study Group. Effect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-Preserved trial. Circulation 2021, in press.
4. Szarek M, Bhatt DL, Steg PG, et al., on behalf of the SOLOIST-WHF Committees and Investigators. Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure: A Randomized Trial. Ann Intern Med 2021;
5. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.Scott D. Solomon,Rudolf A. de Boer,David DeMets,Adrian F. Hernandez,Silvio E. Inzucchi,Mikhail N. Kosiborod,Carolyn S.P. Lam,Felipe Martinez,Sanjiv J. Shah,Daniel Lindholm,et al.29 May 2021.https://doi.org/10.1002/ejhf.2249

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