HEART FAILURE TREATMENT RECENT ADVANCES 2024

HEART FAILURE TREATMENT

1. Heart Failure Buzz : F antastic 4, Fabulous 5 and Flight of 6 HF, heart failure. Dr Awadhesh Sharma, DM, FACC, FSCAI, FISC, FICCM Associate Professor of Cardiology LPS Institute Of Cardiology GSVM Medical College, Kanpur, UP

2. Disease Progression Cardiac Function & QoL Hospitalisations for ADHF HF – A Chronic condition interspersed with acute Episodes Truby LK, Rogers JG. Advanced Heart Failure: Epidemiology, Diagnosis, and Therapeutic Approaches. JACC Heart Fail. 2020 Jul;8(7):523-536. Chronic Decline

3. The incidence of HF is soaring in India, but it may be underestimated HF, heart failure. Ref.: Savarese G and Lund LH. Card Fail Rev. 2017 Apr;3(1):7-11. Portugal USA 1–2 1.5–1.9 China 1.3 Japan 1 India 0.12–0.44 Malaysia 6.7 Singapore 4.5 South America 1 Australia 1–2 0.1–0.2 0.1–0.2 0.9 0.05–0.17 0.2 Spain 2.1 Germany 1.6–1.8 Sweden 1.8–2.2 Italy 1.44 UK 0.39–0.44 0.39 0.27 Netherlands 0.38 0.31–0.39 0.5 0.4 0.3 0.2 0.1 1 2 3 4 5 Prevalence(%) Incidence (%)

4. 1 out of every 3 patients readmitted at least once over 1 year Hospital readmissions at 1 year HF, heart failure; HFrEF , heart failure with reduced ejection fraction; HFpEF , heart failure with preserved ejection fraction. Ref.: Harikrishnan S, et al. Am Heart J. 2017 Jul;189:193-199. 30.2% 1-year hospital readmission rate 24.4% Readmitted once 5.8% Readmitted more than once Similar across gender Men (30.3%), Women (30.9%) Similar irrespective of ejection fraction HFrEF (30.1%), HFpEF (31.6%) India witnesses a huge HF hospitalization burden

5. Increasing mortality in HF patients across the HF spectrum in India HF, heart failure; HFrEF , heart failure with reduced ejection fraction; HFpEF , heart failure with preserved ejection fraction. Ref.: Harikrishnan S, et al. Am Heart J. 2017 Jul;189:193-199. HF patients die within 1 year during their productive life years Mortality rate per 100 person years of follow-up 1/3 HFrEF-43.8% HFpEF-35.7%

6. Current available therapies for heart failure- Fantastic Four

7. ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist. Ref.: Sindone A. How to welcome the fantastic four. Available [online] URL: https://www.csanz.edu.au/wp-content/uploads/2023/09/CSANZ_Speaker_Series_Heart_Failure.pdf As accessed on 4th Jan 2024. In 2013, there were 3 main pillars of heart failure therapy ACEi or ARB Beta-blocker MRA

8. ARNI changed the face of HF treatment In 2014, Sacubitril/Valsartan, a new class of drug comprising an angiotensin receptor- neprilysin inhibitor (ARNI) was tested against Enalapril in HFrEF patients New evidence for HF treatment with ARNI after a decade HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ARNI, angiotensin receptor-neprilysin inhibitor; PARADGIM-HF, Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure. Ref.: Marcondes-Braga. ABC Heart Fail Cardiomyop . 2022;2(1):31-5. PARADIGM-HF

9. PARADIGM-HF: The largest clinical trial in HFrEF CV death/HF hospitalization, primary composite outcome. HF, heart failure; CV, cardiovascular; CI, confidence interval; HR, hazard ratio; HFrEF, heart failure with reduced ejection fraction; PARADGIM-HF, Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure. Ref.: McMurray JJV, et al. N Engl J Med. 2014 Sep 11;371(11):993-1004. Sacubitril/valsartan keeps HFrEF patients out of hospital, helps them live longer HR 0.80 ( 95% Cl, 0.71-0.89) HR 0.79 ( 95% Cl, 0.71-0.89) HR 0.80 ( 95% Cl, 0.73-0.87) 20% reduction P<0.001 P<0.001 P<0.001 20% reduction 21% reduction

10. ESC, European Society of Cardiology; ACEi , angiotensin converting enzyme inhibitor; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFA, Heart Failure Association; HFSA, Heart Failure Society of America; MRA, mineralocorticoid receptor antagonist; ARNI, angiotensin receptor–neprilysin inhibitor; ACC, American College of Cardiology; AHA, American Heart Association; ARB, angiotensin receptor blocker; CV, cardiovascular; ACCF, American College of Cardiology Foundation; NYHA, New York Heart Association. Ref.: 1. Ponikowski P, et al. Kardiol Pol. 2016;74(10):1037-1147; 2. Yancy CW, et al. Circulation. 2016 Sep 27;134(13):e282-93. Change in guidelines after decades

11. ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitors. Ref.: Sindone A. How to welcome the fantastic four. Available [online] URL: https://www.csanz.edu.au/wp-content/uploads/2023/09/CSANZ_Speaker_Series_Heart_Failure.pdf As accessed on 4th Jan 2024. Now, in 2024, there are 4 main pillars of heart failure therapy ARNI Beta-blocker MRA SGLT2i The Fantastic Four

12. SGLT2, Sodium-glucose cotransporter-2. Ref.: Packer M, et al. Eur J Heart Fail. 2021;23:882-894. New guidelines focus is on adding drugs rapidly Rapid Evidence-Based Sequencing of Foundational Drugs for HFrEF Conventional Sequencing Rapid Sequencing Step 1 ACE inhibitor or angiotensin receptor blocker Beta-blocker Mineralocorticoid receptor antagonist Angiotensin receptor neprilysin inhibitor SGLT2 inhibitor Step 2 Step 3 Step 4 Step 5 Up titration to target doses at each step Typically requires 6 months or more Beta-blocker SGLT2 inhibitor Angiotensin receptor neprilysin inhibitor All 3 step achieved within 4 weeks Up titration to target doses thereafter Step 1 Step 2 Step 3 Mineralocorticoid receptor antagonist

13. ACEi , angiotensin-converting enzyme inhibitor; ARB, angiotensin ii receptor blocker; ARNi , angiotensin-receptor- neprilysin inhibitor; BB, beta-blocker; CV, cardiovascular; HF, heart failure; HFrEF , heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium glucose cotransporter 2 inhibitor. Ref.: Vaduganathan M, et al. Lancet. 2020 Jul 11;396(10244):121-128. (including supplementary appendix) Risk reduction and expected lifetime benefit of comprehensive disease-modifying therapy in chronic HFrEF Comprehensive therapy (ARNI + BB + MRA + SGLT2i) CV death + HF hospitalization 62% 47% 44% 50% CV death All-cause mortality 68% HF hospitalization V/S Conventional therapy ( ACEi /ARB + BB) Projected event-free survival at age 55 years 8.3 additional years of event-free survival

14. HF, heart failure. Ref.: Fatima K , et al. European Journal of Heart Failure (2023) 25, 1477–1480. doi:10.1002/ejhf.3005 While there has been considerable success in the past two decades in developing HF therapies, there remain significant unmet needs for improved implementation to address the substantial residual risk

15. Fabulous 5-Vericiguat HF, heart failure.

16. 16 HR=0.93 (0.81–1.06)* HR=0.90 (0.81–1.00)* p=0.048 HR=0.91 (0.84–0.99)* p=0.02 # HR=0.90 (0.83–0.98)* p=0.02 # HR=0.95 (0.84–1.07)* p=0.38 # ‡ ARR=4.2 HR=0.90 (0.82–0.98)* p=0.02 Worsening symptoms requiring hospitalization or IV diuretic use in the outpatient setting. For patients with multiple events, only the first event contributing to the composite endpoint is counted. *HR (vericiguat over placebo) and 95% CI from Cox proportional hazard model controlling for stratification factors (defined by region and race). # From log rank test stratified by the stratification factors defined by region and race. ‡ Patients could have been hospitalized more than once. Based on data up to the primary completion date (18 June 2019). ARR, absolute rate reduction; CI, confidence interval; CV, cardiovascular; HFH, heart failure hospitalization; HR, hazard ratio; IV, intravenous; PY, patient-years. 1. Armstrong PW et al. N Engl J Med. 2020;382:1883–1893. The primary composite outcome, total HFH and the composite of HFH or all-cause mortality were significantly reduced with vericiguat vs placebo ARR=1.0 ARR=3.2 ARR=4.1 ARR=4.2 Vericiguat improved both primary and secondary outcomes in patients with chronic and worsening HF in VICTORIA

17. Vericiguat is recommended for patients with HFrEF following a worsening HF event 1–3 17 * Level of evidence B from a randomized trial. # A conditional recommendation is provided because vericiguat has not yet been approved for this indication in Canada. ACC, American College of Cardiology; ACEi, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARNi, angiotensin receptor–neprilysin inhibitor; CCS, Canadian Cardiovascular Society; CHFS, Canadian Heart Failure Society; CV, cardiovascular; ESC, European Society of Cardiology; GDMT, guideline-directed medical therapy; HF, heart failure; HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; HFSA, Heart Failure Society of America; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; sGC , soluble guanylate cyclase. References: 1. McDonald M et al. Can J Cardiol 2021;37:531–546 ; 2. Heidenreich PA et al. Circulation 2022; https://doi.org/ 10.1016/j.jacc.2021.12.012 ; 3. McDonagh TA et al. Eur Heart J 2021;42:3599–3726. Recommendation Class of recommendation Level of evidence AHA/ACC/HFSA 2022 guidelines 2 In selected high-risk patients with HFrEF and recent worsening of HF already on GDMT, an oral sGC stimulator (vericiguat) may be considered to reduce HFH and CV death 2b B – R * ESC 2021 guidelines 3 Vericiguat may be considered in patients in NYHA class II–IV who have had worsening HF despite treatment with an ACEi (or ARNi), a beta blocker and an MRA to reduce the risk of CV mortality or HFH IIb B CCS/CHFS 2021 guidelines 1 We recommend that vericiguat, an oral sGC stimulator, be considered in addition to optimal HF therapies for HFrEF patients with worsening symptoms and HFH in the past 6 months, to reduce the risk of subsequent HFH Conditional # Moderate quality

18. Flight of 6- Intravenous Iron therapy HF, heart failure.

19. Iron deficiency Iron deficiency is an emerging problem in chronic HF, affecting half of the patients. A decreased iron status is associated with disease severity (as assessed by  NYHA  functional class and NT- proBNP level), the presence of anemia and female sex. Iron Deficiency is a strong and independent predictor of outcome. Inclusion of Iron Deficiency provides additive prognostic value when added to a prediction model with established risk factors.

20. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

21. Conclusion Quadruple medical therapy (ARNI, BB, MRA, SGLT2 inhibitor), titrated to maximally tolerated or target doses, is foundational therapy. Rapid sequence or simultaneous initiation of quadruple medical therapy is an evidence-based strategy. Early upfront use of vericiguat should be considered among patient with WHF. Intravenous iron should be administered to patients with iron deficiency.

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