abchf abchf ABC Heart Fail Cardiomyop ABC Heart Fail Cardiomyop 2764-3107 Sociedade Brasileira de Cardiologia - SBC abchf.20220013 10.36660/abchf.20220013 Viewpoint SGLT2 Inhibitors and Sacubitril-Valsartan: How Trial Results will Revolutionize the Treatment of Heart Failure with Mildly Reduced Ejection Fraction 0000-0002-0095-9049 Fernandes-Silva Miguel Morita 1 2 Universidade Federal do Paraná Curitiba PR Brazil Universidade Federal do Paraná, Curitiba, PR – Brazil Quanta Diagnóstico por Imagem Curitiba PR Brazil Quanta Diagnóstico por Imagem, Curitiba, PR – Brazil Mailing Address: Miguel Morita Fernandes da Silva • Departamento de Clínica Médica - Hospital de Clínicas da Universidade Federal do Paraná, 181 General Carneiro street, 10th floor. Postal Code 80060-900, Curitiba, PR - Brazil E-mail: miguelmorita@ufpr.br

Author Contributions

Writing of the manuscript and Critical revision of the manuscript for intellectual content: Fernandes-Silva MM.

Potential Conflict of Interest

Received consulting and speaking fees from Novartis.

 12 04 2022 Jan-Mar 2022 2 1 67 71 30 01 2022 01 02 2022 16 02 2022 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Heart Failure Ejection Fraction Angiotensin-converting Enzyme Inhibitor Angiotensin receptor-neprylisin Inhibitor Beta-blocker Mineralocorticoid Receptor Antagonist Sodium-glucose Cotransporter 2 Inhibitor

Left ventricular ejection fraction (EF) is a key parameter in the management of heart failure (HF) and a crucial biomarker for prognostic evaluation and therapeutic decision.1 Patients with HF are classified into different categories according to EF. Although the concept of “normal” EF was introduced four decades ago, the cutoff values for normal and abnormal EF have considerably varied over time. In 2016, the European Society of Cardiology HF guidelines defined HF with reduced EF (HFrEF) as patients with EF below 40%, while HF with preserved EF (HFpEF) was the category for patients with EF equal to 50% or above.2 To fill in the gap between the two categories, the term HF with mid-range EF was introduced. More recently, the guidelines considered more appropriate to rename this category to HF with mildly reduced EF (HFmrEF).3 , 4 Why has the EF-based classification changed in recent years and how may this affect HF treatment?

In the 1980s, the first HF trials used in their design EF cutoffs to select patients with worse prognosis as an enrichment strategy, ie, they included patients based on a biomarker that improves design efficiency. Because patients with lower EF have worse prognosis and, therefore, higher rates of events, a relatively smaller sample size would be required to detect an effect. These trials used cutoff values for EF that ranged from < 45% to < 25% ( Table ) and were highly successful in finding effective therapies. In general, trials using a cutoff EF of < 40% consistently found drugs and devices for the treatment of HF that improved outcomes.

– Ejection fraction inclusion criteria for key phase III drug trials in heart failure
Treatment HFrEF HFpEF
Trial EF cutoff (%) Trial EF cutoff (%)
ACEi

SOLVD19

≤ 35

PEP-CHF20

≥ 40
ARB

CHARM-Alternative21

≤ 40

CHARM-Preserved22

I-PRESERVED23

> 40

≥ 45
Beta-blocker

MERIT-HF24

CIBIS-II25

U.S. Carvedilol26

COPERNICUS27

≤ 40

≤ 35

≤ 35

≤ 25

J-DHF28

> 40
MRA

RALES29

EMPHASIS-HF30

≤ 35

≤ 35

TOPCAT31

SPIRRIT-HFpEF32

SPIRIT-HF33

FINEARTS-HF34

≥ 45

≥ 40

≥ 40

≥ 40
ARNi

PARADIGM-HF35

≤ 40

PARAGON-HF11

≥ 45
SGLT2i

DAPA-HF37

EMPEROR-Reduced38

≤ 40

≤ 40

DELIVER39

EMPEROR-Preserved40

>40

>40

ACEi: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker; MRA: mineralocorticoid receptor antagonist; ARNi: angiotensin receptor-neprylisin inhibitor; CHARM: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity; CIBIS-II: The Cardiac Insufficiency Bisoprolol Study II; COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival Trial; DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER: Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMPEROR-Preserved: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; EMPEROR-Reduced: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; EMPHASIS-HF: Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; FINEARTS-HF: Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure; I-PRESERVED: Irbesartan in Heart Failure with Preserved Ejection Fraction Study; MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial; PARAGON-HF: Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction; PEP-CHF: Perindopril for Elderly People With Chronic Heart Failure Study; RALES: Randomized Aldactone Evaluation Study; SLGT2: sodium-glucose cotransporter 2 inhibitor; SOLVD: Studies of Left Ventricular Dysfunction; SPIRIT-HF: Spironolactone In The Treatment of Heart Failure; SPIRRIT-HFpEF: Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.

HF trials started including patients with EF above 40% in the early 2000s, covering the full EF range. Eligibility criteria for these trials varied from EF ≥ 40% to ≥ 50% ( Table ). Although the term “preserved EF” was used for these cutoff points, they differed from the cutoff values for normal EF established in the recommendations from echocardiographic reporting guidelines, which were based on the mean and 2 standard deviations for a healthy population: 52 to 72% for men and 54 to 74% for women.5 , 6

Current guidelines recommend treating all symptomatic patients with HFrEF with an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor-neprylisin inhibitor (ARNi), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 inhibitor (SGLT2i) based on well-established evidence of their effect on reducing mortality. The success of these drugs in HFrEF was attempted to be reproduced in patients with HFpEF. ACEi, angiotensin receptor blocker (ARB), MRA, and ARNi have all been tested in HFpEF but have failed to show overall superiority for the primary endpoint ( Table ). This discrepancy suggests that HF is rather a heterogeneous disease with different mechanisms of progression depending on the phenotype.

Because no interventional trial was specifically dedicated to patients with HFmrEF, treatment of HFmrEF has been based on subanalysis of HFpEF trials, whose EF cutoff points included patients in this category. An analysis of the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) program, combining the CHARM-added, CHARM- alternative and CHARM-preserved trials, showed that the benefit of candesartan on reducing the primary endpoint was observed in the EF range between 40 and 50%, but not above 50%.7 A similar pattern was observed with spironolactone in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial,8 with beta-blockers in patients in sinus rhythm in a meta-analysis,9 and with sacubitril-valsartan.10 In a subgroup analysis of the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial, sacubitril-valsartan reduced the primary endpoint in the EF equal or below median (≤ 57%) but not above this cutoff point.11 In a combined analysis of the PARADIGM-HF and PARAGON-HF trials across the continuum of EF, the treatment effect favoring sacubitril/valsartan appeared to extend to higher EF values ( Figure ).10 In the past two years, regulatory agencies, including the United States Food and Drug Administration and the Brazilian National Health Surveillance Agency, have expanded the indication of sacubitril-valsartan for patients with HF, stating that the benefit is more clearly evident when EF is below normal.

– Treatment effect estimates of disease-modifying medications in heart failure across the spectrum of ejection fraction. Bar colors represent the reported estimated hazard ratios (HR) for each intervention according to ejection fraction. HR were extracted from respective published subanalysis from clinical trials: Candesartan: Lund et al.7 Spironolactone: Pitt et al.29 and Solomon et al.8 Beta-blockers: Cleland et al.9 Sacubitril-valsartan: Solomon et al.10 Empagliflozin: Butler et al.17

Collectively, these data suggest that not only sacubitril-valsartan but also renin–angiotensin–aldosterone system and sympathetic nervous system inhibitors have beneficial effects for HF in the “intermediate” EF range of 41 to 49%. These analyses provide insights that go beyond the treatment effect by indicating a role of these systems on disease progression in this category and helping understand part of the EF-related heterogeneity in HF. For instance, the contribution of noncardiac comorbidities on mortality is proportionally higher with increasing values of EF, particularly in the normal range.12 , 13 This may explain why an intervention targeting the cardiovascular system is less likely to change the course of the disease in patients with normal EF. Patients with HFmrEF have intermediate features between HFrEF and HFpEF, but analyses from registries and clinical trials have shown that they display clinical characteristics that share more similarities with HFrEF than with HFpEF.14 Accordingly, the recently published universal definition and classification of HF properly renamed the old “mid-range EF” category to “mildly reduced EF.”15

Finally, the novel sodium-glucose cotransporter 2 (SGLT2) inhibitors have proven to be successful in HFrEF and paved the way for a new treatment target in HF. The question of whether this new drug class would also benefit patients with HFmrEF and HFpEF remained until the publication of the highly expected Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-preserved) trial in August 2021.16 The EMPEROR-preserved trial included patients with HF and EF above 40% and showed that empagliflozin significantly reduced the primary outcome of cardiovascular death or HF hospitalization. Although this was mostly driven by a reduction in HF hospitalization, it was the first time that a HFpEF trial showed positive results for the primary outcome. A further analysis with data from the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-reduced) and EMPEROR-preserved trials was performed to evaluate whether the treatment effect differs across the EF categories. Similarly, the treatment effect of empagliflozin appeared to attenuate with higher EF values, but it remained consistent in patients with EF below 65%.17 The results of the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, which tested the SGLT2 inhibitor dapagliflozin and is expected to be presented soon, will help understand whether there is a class effect. A trial of a slightly different class, the SGLT2-SGLT1 inhibitor sotagliflozin, included patients with diabetes and worsening HF and showed a significant reduction in the primary endpoint of cardiovascular death, hospitalization, and urgent visits for HF across all spectrum of EF.18

Despite its essential role in the management of HF, EF is an imperfect measure that is influenced by several biological phenomena. Its wide availability in clinical practice is counterbalanced by limitations to accurate measurement of EF. The intra- and interobserver variability of EF measurements using echocardiogram has been reported as 8-21% and 6-13%, respectively, which limits the correct classification in categories with relatively narrow ranges of EF.14 Some studies have evaluated the longitudinal changes of EF, showing considerable variation over time. In a Swedish registry, nearly 1/3 of patients switched to a lower EF category and 1/4 switched to a higher EF category over a median follow up duration of 1.4 years.14 Because of the limitations of EF measurement, alternative methods have been suggested to better address the heterogeneity of HF, such as myocardial tissue characterization with magnetic resonance imaging, global longitudinal strain from speckle-tracking analysis with echocardiogram, multiple biomarker approaches, and proteomic characterization, but their use to guide the clinical management is still limited.14

Well-conducted trials are not only about finding effective therapies. They help understand the pathophysiology of a disease. HF classification has evolved together with the understanding of the disease. Despite the necessary strict and pragmatic criteria adopted in clinical trials, treatment effect of HF drugs has been consistently modified by EF as a continuous measure. Analysis from the latest HF trials of sacubitril-valsartan and SGLT2 inhibitor point to the same direction as those of renin–angiotensin–aldosterone system and sympathetic nervous system inhibitors, grouping together the categories of HF with EF below normal. I look forward to seeing what we will learn from the upcoming trials in HFpEF.

References 1. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart Failure with Mid-range or Mildly Reduced Ejection Fraction. Nat Rev Cardiol. 2022;19(2):100-16. doi: 10.1038/s41569-021-00605-5. Savarese G Stolfo D Sinagra G Lund LH Heart Failure with Mid-range or Mildly Reduced Ejection Fraction Nat Rev Cardiol 2022 19 2 100 116 10.1038/s41569-021-00605-5. 2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC)Developed with the Special Contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. doi: 10.1093/eurheartj/ehw128. Ponikowski P Voors AA Anker SD Bueno H Cleland JGF Coats AJS et al 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC)Developed with the Special Contribution of the Heart Failure Association (HFA) of the ESC Eur Heart J 2016 37 27 2129 2200 10.1093/eurheartj/ehw128. 3. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. Eur Heart J. 2021;42(36):3599-726. doi: 10.1093/eurheartj/ehab368. McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M et al 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure Eur Heart J 2021 42 36 3599 3726 10.1093/eurheartj/ehab368. 4. Marcondes-Braga FG, Moura LAZ, Issa VS, Vieira JL, Rohde LE, Simões MV, et al. Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021. Arq Bras Cardiol. 2021;116(6):1174-212. doi: 10.36660/abc.20210367. Marcondes-Braga FG Moura LAZ Issa VS Vieira JL Rohde LE Simões MV et al Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021 Arq Bras Cardiol 2021 116 6 1174 1212 10.36660/abc.20210367. 5. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-70. doi: 10.1093/ehjci/jev014. Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L et al Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging Eur Heart J Cardiovasc Imaging 2015 16 3 233 270 10.1093/ehjci/jev014. 6. Barberato SH, Romano MMD, Beck ALS, Rodrigues ACT, Almeida ALC, Assunção BMBL, et al. Position Statement on Indications of Echocardiography in Adults - 2019. Arq Bras Cardiol. 2019;113(1):135-81. doi: 10.5935/abc.20190129. Barberato SH Romano MMD Beck ALS Rodrigues ACT Almeida ALC Assunção BMBL et al Position Statement on Indications of Echocardiography in Adults - 2019 Arq Bras Cardiol 2019 113 1 135 181 10.5935/abc.20190129. 7. Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, et al. Heart Failure with Mid-range Ejection Fraction in CHARM: Characteristics, Outcomes and Effect of Candesartan Across the Entire Ejection Fraction Spectrum. Eur J Heart Fail. 2018;20(8):1230-9. doi: 10.1002/ejhf.1149. Lund LH Claggett B Liu J Lam CS Jhund PS Rosano GM et al Heart Failure with Mid-range Ejection Fraction in CHARM: Characteristics, Outcomes and Effect of Candesartan Across the Entire Ejection Fraction Spectrum Eur J Heart Fail 2018 20 8 1230 1239 10.1002/ejhf.1149. 8. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, et al. Influence of Ejection Fraction on Outcomes and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction. Eur Heart J. 2016;37(5):455-62. doi: 10.1093/eurheartj/ehv464. Solomon SD Claggett B Lewis EF Desai A Anand I Sweitzer NK et al Influence of Ejection Fraction on Outcomes and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction Eur Heart J 2016 37 5 455 462 10.1093/eurheartj/ehv464. 9. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-Blockers for Heart Failure with Reduced, Mid-range, and Preserved Ejection Fraction: An Individual Patient-level Analysis of Double-blind Randomized Trials. Eur Heart J. 2018;39(1):26-35. doi: 10.1093/eurheartj/ehx564. Cleland JGF Bunting KV Flather MD Altman DG Holmes J Coats AJS et al Beta-Blockers for Heart Failure with Reduced, Mid-range, and Preserved Ejection Fraction: An Individual Patient-level Analysis of Double-blind Randomized Trials Eur Heart J 2018 39 1 26 35 10.1093/eurheartj/ehx564. 10. Solomon SD, Vaduganathan M, L Claggett B, Packer M, Zile M, Swedberg K, et al. Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure. Circulation. 2020;141(5):352-61. doi: 10.1161/CIRCULATIONAHA.119.044586. Solomon SD Vaduganathan M L Claggett B Packer M Zile M Swedberg K et al Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure Circulation 2020 141 5 352 361 10.1161/CIRCULATIONAHA.119.044586. 11. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-20. doi: 10.1056/NEJMoa1908655. Solomon SD McMurray JJV Anand IS Ge J Lam CSP Maggioni AP et al Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction N Engl J Med 2019 381 17 1609 1620 10.1056/NEJMoa1908655. 12. Rohde LE, Claggett BL, Wolsk E, Packer M, Zile M, Swedberg K, et al. Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights from a Combined PARAGON-HF and PARADIGM-HF Analysis. Circ Heart Fail. 2021;14(3):e008052. doi: 10.1161/CIRCHEARTFAILURE.120.008052. Rohde LE Claggett BL Wolsk E Packer M Zile M Swedberg K et al Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights from a Combined PARAGON-HF and PARADIGM-HF Analysis Circ Heart Fail 2021 14 3 e008052 10.1161/CIRCHEARTFAILURE.120.008052. 13. Wolsk E, Claggett B, Køber L, Pocock S, Yusuf S, Swedberg K, et al. Contribution of Cardiac and Extra-cardiac Disease Burden to Risk of Cardiovascular Outcomes Varies by Ejection Fraction in Heart Failure. Eur J Heart Fail. 2018;20(3):504-10. doi: 10.1002/ejhf.1073. Wolsk E Claggett B Køber L Pocock S Yusuf S Swedberg K et al Contribution of Cardiac and Extra-cardiac Disease Burden to Risk of Cardiovascular Outcomes Varies by Ejection Fraction in Heart Failure Eur J Heart Fail 2018 20 3 504 510 10.1002/ejhf.1073. 14. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart Failure with Mid-range or Mildly Reduced Ejection Fraction. Nat Rev Cardiol. 2022;19(2):100-16. doi: 10.1038/s41569-021-00605-5. Savarese G Stolfo D Sinagra G Lund LH Heart Failure with Mid-range or Mildly Reduced Ejection Fraction Nat Rev Cardiol 2022 19 2 100 116 10.1038/s41569-021-00605-5. 15. Bozkurt B, Coats AJ, Tsutsui H, Abdelhamid M, Adamopoulos S, Albert N, et al. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. 2021:S1071-9164(21)00050-6. doi: 10.1016/j.cardfail.2021.01.022. Bozkurt B Coats AJ Tsutsui H Abdelhamid M Adamopoulos S Albert N et al Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure J Card Fail 2021 S1071-9164 21 00050 00056 10.1016/j.cardfail.2021.01.022. 16. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al. Evaluation of the Effects of Sodium-Glucose Co-Transporter 2 Inhibition with Empagliflozin on Morbidity and Mortality in Patients with Chronic Heart Failure and a Preserved Ejection Fraction: Rationale for and Design of the EMPEROR-Preserved Trial. Eur J Heart Fail. 2019;21(10):1279-87. doi: 10.1002/ejhf.1596. Anker SD Butler J Filippatos GS Jamal W Salsali A Schnee J et al Evaluation of the Effects of Sodium-Glucose Co-Transporter 2 Inhibition with Empagliflozin on Morbidity and Mortality in Patients with Chronic Heart Failure and a Preserved Ejection Fraction: Rationale for and Design of the EMPEROR-Preserved Trial Eur J Heart Fail 2019 21 10 1279 1287 10.1002/ejhf.1596. 17. Butler J, Packer M, Filippatos G, Ferreira JP, Zeller C, Schnee J, et al. Effect of Empagliflozin in Patients with Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction. Eur Heart J. 2022;43(5):416-26. doi: 10.1093/eurheartj/ehab798. Butler J Packer M Filippatos G Ferreira JP Zeller C Schnee J et al Effect of Empagliflozin in Patients with Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction Eur Heart J 2022 43 5 416 426 10.1093/eurheartj/ehab798. 18. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384(2):117-28. doi: 10.1056/NEJMoa2030183. Bhatt DL Szarek M Steg PG Cannon CP Leiter LA McGuire DK et al Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure N Engl J Med 2021 384 2 117 128 10.1056/NEJMoa2030183. 19. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure. N Engl J Med. 1991;325(5):293-302. doi: 10.1056/NEJM199108013250501. Yusuf S Pitt B Davis CE Hood WB Cohn JN Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure N Engl J Med 1991 325 5 293 302 10.1056/NEJM199108013250501. 20. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) Study. Eur Heart J. 2006;27(19):2338-45. doi: 10.1093/eurheartj/ehl250. Cleland JG Tendera M Adamus J Freemantle N Polonski L Taylor J The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) Study Eur Heart J 2006 27 19 2338 2345 10.1093/eurheartj/ehl250. 21. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of Candesartan in Patients with Chronic Heart Failure and Reduced Left-Ventricular Systolic Function Intolerant to Angiotensin-Converting-Enzyme Inhibitors: The CHARM-Alternative Trial. Lancet. 2003;362(9386):772-6. doi: 10.1016/S0140-6736(03)14284-5. Granger CB McMurray JJ Yusuf S Held P Michelson EL Olofsson B et al Effects of Candesartan in Patients with Chronic Heart Failure and Reduced Left-Ventricular Systolic Function Intolerant to Angiotensin-Converting-Enzyme Inhibitors: The CHARM-Alternative Trial Lancet 2003 362 9386 772 776 10.1016/S0140-6736(03)14284-5. 22. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction: The CHARM-Preserved Trial. Lancet. 2003;362(9386):777-81. doi: 10.1016/S0140-6736(03)14285-7. Yusuf S Pfeffer MA Swedberg K Granger CB Held P McMurray JJ et al Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction: The CHARM-Preserved Trial Lancet 2003 362 9386 777 781 10.1016/S0140-6736(03)14285-7. 23. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. N Engl J Med. 2008;359(23):2456-67. doi: 10.1056/NEJMoa0805450. Massie BM Carson PE McMurray JJ Komajda M McKelvie R Zile MR et al Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction N Engl J Med 2008 359 23 2456 2467 10.1056/NEJMoa0805450. 24. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-7. Hjalmarson A Goldstein S Fagerberg B Wedel H Waagstein F Kjekshus J et al Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999 353 9169 2001 2007 25. Dargie HJ, Lechat P. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A Randomised Trial. Lancet. 1999;353(9146):9-13. Dargie HJ Lechat P The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A Randomised Trial Lancet 1999 353 9146 9 13 26. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med. 1996;334(21):1349-55. doi: 10.1056/NEJM199605233342101. Packer M Bristow MR Cohn JN Colucci WS Fowler MB Gilbert EM et al The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure N Engl J Med 1996 334 21 1349 1355 10.1056/NEJM199605233342101. 27. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of Carvedilol on Survival in Severe Chronic Heart Failure. N Engl J Med. 2001;344(22):1651-8. doi: 10.1056/NEJM200105313442201. Packer M Coats AJ Fowler MB Katus HA Krum H Mohacsi P et al Effect of Carvedilol on Survival in Severe Chronic Heart Failure N Engl J Med 2001 344 22 1651 1658 10.1056/NEJM200105313442201. 28. Yamamoto K, Origasa H, Hori M. Effects of Carvedilol on Heart Failure with Preserved Ejection Fraction: The Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. 2013;15(1):110-8. doi: 10.1093/eurjhf/hfs141. Yamamoto K Origasa H Hori M Effects of Carvedilol on Heart Failure with Preserved Ejection Fraction: The Japanese Diastolic Heart Failure Study (J-DHF) Eur J Heart Fail 2013 15 1 110 118 10.1093/eurjhf/hfs141. 29. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-17. doi: 10.1056/NEJM199909023411001. Pitt B Zannad F Remme WJ Cody R Castaigne A Perez A et al The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. Randomized Aldactone Evaluation Study Investigators N Engl J Med 1999 341 10 709 717 10.1056/NEJM199909023411001. 30. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med. 2011;364(1):11-21. doi: 10.1056/NEJMoa1009492. Zannad F McMurray JJ Krum H van Veldhuisen DJ Swedberg K Shi H et al Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms N Engl J Med 2011 364 1 11 21 10.1056/NEJMoa1009492. 31. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2014;370(15):1383-92. doi: 10.1056/NEJMoa1313731. Pitt B Pfeffer MA Assmann SF Boineau R Anand IS Claggett B et al Spironolactone for Heart Failure with Preserved Ejection Fraction N Engl J Med 2014 370 15 1383 1392 10.1056/NEJMoa1313731. 32. Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction [Internet]. Bethesda: ClinicalTrials.gov. 2017 [cited 2022 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT02901184?cond=spirrit+heart+failure&draw=2&rank=1. Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction Internet Bethesda ClinicalTrials.gov 2017 cited 2022 Jan 28 https://clinicaltrials.gov/ct2/show/NCT02901184?cond=spirrit+heart+failure&draw=2&rank=1 33. Clinical Trials Register - Search for Spirit Heart Failure [Internet]. Amsterdam: EU Clinical Trials Register. c2022 [cited 2022 Jan 28]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=spirit+heart+failure. Clinical Trials Register - Search for Spirit Heart Failure Internet Amsterdam EU Clinical Trials Register c2022 cited 2022 Jan 28 https://www.clinicaltrialsregister.eu/ctr-search/search?query=spirit+heart+failure 34. Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants with Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40% [Internet]. Bethesda: ClinicalTrials.gov. 2020 [cited 2022 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT04435626?cond=NCT04435626&draw=2&rank=1. Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants with Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40% Internet Bethesda ClinicalTrials.gov 2020 cited 2022 Jan 28 https://clinicaltrials.gov/ct2/show/NCT04435626?cond=NCT04435626&draw=2&rank=1 35. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-Neprilysin Inhibition Versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077. McMurray JJ Packer M Desai AS Gong J Lefkowitz MP Rizkala AR et al Angiotensin-Neprilysin Inhibition Versus Enalapril in Heart Failure N Engl J Med 2014 371 11 993 1004 10.1056/NEJMoa1409077. 36. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. McMurray JJV Solomon SD Inzucchi SE Køber L Kosiborod MN Martinez FA et al Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction N Engl J Med 2019 381 21 1995 2008 10.1056/NEJMoa1911303. 37. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-24. doi: 10.1056/NEJMoa2022190. Packer M Anker SD Butler J Filippatos G Pocock SJ Carson P et al Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure N Engl J Med 2020 383 15 1413 1424 10.1056/NEJMoa2022190. 38. Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure [Internet]. Bethesda: ClinicalTrials.gov. 2021 [cited 2022 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT03619213?cond=nct03619213&draw=2&rank=1. Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure Internet Bethesda ClinicalTrials.gov 2021 cited 2022 Jan 28 https://clinicaltrials.gov/ct2/show/NCT03619213?cond=nct03619213&draw=2&rank=1 39. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-61. doi: 10.1056/NEJMoa2107038. Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M et al Empagliflozin in Heart Failure with a Preserved Ejection Fraction N Engl J Med 2021 385 16 1451 1461 10.1056/NEJMoa2107038.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of Funding: There were no external funding sources for this study.

 Ponto de Vista Inibidores do SGLT2 e Sacubitril-Valsartana: Como os Resultados de Estudos Clínicos Revolucionarão o Tratamento da IC com Fração de Ejeção Levemente Reduzida 0000-0002-0095-9049 Fernandes-Silva Miguel Morita 1 2 Brasil Universidade Federal do Paraná, Curitiba, PR – Brasil Brasil Quanta Diagnóstico por Imagem, Curitiba, PR – Brasil Correspondência: Miguel Morita Fernandes da Silva • Departamento de Clínica Médica – Hospital de Clínicas da Universidade Federal do Paraná – Rua General Carneiro, 181, 10º andar. CEP 80060-900, Alto da Glória, Curitiba, PR - Brasil E-mail: miguelmorita@ufpr.br

Contribuição dos autores

Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Fernandes-Silva MM.

Potencial conflito de interesse

Recebeu honorários de consultoria e palestras da Novartis.

 Insuficiência Cardíaca Fração de Ejeção Inibidor da Enzima Conversora de Angiotensina Inibidor dos Receptores de Angiotensina-neprilisina Betabloqueador Antagonista do Receptor Mineralocorticoide Inibidor do Cotransportador de Sódio-glicose 2

A fração de ejeção (FE) do ventrículo esquerdo é um parâmetro central no manejo da insuficiência cardíaca (IC), sendo um biomarcador crucial de avaliação prognóstica e decisão terapêutica.1 Os pacientes com IC são classificados em diferentes categorias de acordo com a FE. Apesar de o conceito de FE “normal” ter sido introduzido há quatro décadas, os valores de corte para FE normal e anormal têm sofrido variações consideráveis ao longo do tempo. Em 2016, as diretrizes de IC da European Society of Cardiology definiram IC com FE reduzida (ICFER) como pacientes com valores de FE abaixo de 40%, enquanto a IC com FE preservada (ICFEP) foi definida como FE igual ou acima de 50%.2 Para preencher a lacuna entre as duas categorias, foi introduzido o termo IC com FE intermediária. Mais recentemente, as diretrizes consideraram mais apropriado renomear essa categoria para IC com FE levemente reduzida (ICFELR).3 , 4 Por que a classificação baseada na FE mudou consideravelmente nos últimos anos e como isso pode afetar o tratamento da IC?

Na década de 1980, os desenhos dos primeiros estudos de IC utilizavam os pontos de corte da FE para selecionar pacientes com pior prognóstico como uma estratégia de enriquecimento, isto é, selecionavam pacientes com base em um biomarcador que melhora a eficiência do desenho. Visto que pacientes com FE mais baixa apresentam pior prognóstico e, portanto, taxas mais altas de eventos, um tamanho amostral relativamente pequeno seria suficiente para detectar um efeito. Esses estudos utilizavam pontos de corte da FE que variavam de < 45 a < 25% ( Tabela 1 ) e eram extremamente bem-sucedidos na identificação de terapias eficazes. Em geral, os estudos que utilizavam pontos de corte da FE < 40% consistentemente identificavam medicamentos e dispositivos para o tratamento de IC que melhoravam os desfechos.

– Critérios de inclusão da FE nos principais estudos de medicamentos de fase III na insuficiência cardíaca
Tratamento ICFER ICFEP
Estudo Ponto de corte da FE (%) Estudo Ponto de corte da FE (%)
iECA

SOLVD19

≤ 35

PEP-CHF20

≥ 40
BRA

CHARM-Alternative21

≤ 40

CHARM-Preserved22

I-PRESERVED23

> 40

≥ 45
Betabloqueador

MERIT-HF24

CIBIS-II25

U.S. Carvedilol26

COPERNICUS27

≤ 40

≤ 35

≤ 35

≤ 25

J-DHF28

> 40
ARM

RALES29

EMPHASIS-HF30

≤ 35

≤ 35

TOPCAT31

SPIRRIT-HFpEF32

SPIRIT-HF33

FINEARTS-HF34

≥ 45

≥ 40

≥ 40

≥ 40
ARNi

PARADIGM-HF35

≤ 40

PARAGON-HF11

≥ 45
iSGLT2

DAPA-HF37

EMPEROR-Reduced38

≤ 40

≤ 40

DELIVER39

EMPEROR-Preserved40

> 40

> 40

ARM: antagonista dos receptores mineralocorticoides; ARNi: inibidor de neprilisina e do receptor da angiotensina; BRA: bloqueador dos receptores de angiotensina; CHARM: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity; CIBIS-II: The Cardiac Insufficiency Bisoprolol Study II; COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival Trial; DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER: Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMPEROR-Preserved: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; EMPEROR-Reduced: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; EMPHASIS-HF: Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; FINEARTS-HF: Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure; iECA: inibidor da enzima conversora de angiotensina; I-PRESERVED: Irbesartan in Heart Failure with Preserved Ejection Fraction Study; MERIT-HF: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial; PARAGON-HF: Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction; PEP-CHF: Perindopril for Elderly People With Chronic Heart Failure Study; RALES: Randomized Aldactone Evaluation Study; SLGT2: inibidor do cotransportador de sódio-glicose 2; SOLVD: Studies of Left Ventricular Dysfunction; SPIRIT-HF: Spironolactone In The Treatment of Heart Failure; SPIRRIT-HFpEF: Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.

No início da década de 2000, os estudos de IC começaram a incluir pacientes com FE acima de 40%, abordando todo o espectro da FE. Os critérios de elegibilidade desses estudos variavam de FE ≥ 40 a ≥ 50% ( Tabela 1 ). Embora fosse utilizado o termo “FE preservada” para esses pontos de corte, eles diferiam dos valores de corte para FE normal estabelecidos pelas recomendações de diretrizes de laudos ecocardiográficos, que eram baseados na média e nos dois desvios padrões de uma população saudável: 52 a 72% para homens e 54 a 74% para mulheres.5 , 6

As diretrizes atuais recomendam que todos os pacientes sintomáticos com ICFER sejam tratados com um inibidor da enzima conversora de angiotensina/inibidor dos receptores de angiotensina-neprilisina (iECA/ARNi), um betabloqueador, um antagonista do receptor mineralocorticoide (ARM) e um inibidor do cotransportador de sódio-glicose 2 (iSGLT2), com base em evidências bem estabelecidas do efeito desses medicamentos na redução da mortalidade. O sucesso desses medicamentos na ICFER tentou ser reproduzido em pacientes com ICFEP. Os iECAs, BRAs, ARMs e ARNis foram todos testados em pacientes com ICFEP, mas não foram capazes de demonstrar superioridade geral no desfecho primário ( Tabela 1 ). Essa discrepância sugere que a IC é uma doença um tanto heterogênea, com diferentes mecanismos de progressão, os quais dependem do fenótipo.

Visto que não há nenhum estudo de intervenção especificamente dedicado a pacientes com ICFELR, o tratamento dessa condição tem sido baseado em subanálises de estudos “ICFEP”, nos quais os pontos de corte da FE incluem pacientes com ICFELR. Uma análise do programa Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM), que combina os estudos CHARM-Added, CHARM-Alternative e CHARM-Preserved, identificou um efeito benéfico da candesartana na redução do desfecho primário em pacientes com FE entre 40 e 50%, mas não acima de 50%.7 Um padrão semelhante foi observado com a espironolactona no estudo Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT),8 com betabloqueadores em pacientes em ritmo sinusal9 e com sacubitril-valsartana.10 Na análise dos subgrupos do estudo Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF), o sacubitril-valsartana reduziu o desfecho primário em pacientes com FE igual ou abaixo da mediana (≤ 57%), mas não acima desse ponto de corte.11 Em uma análise combinada dos estudos PARADIGM-HF e PARAGON-HF através do contínuo da FE, o efeito do tratamento favorecendo sacubitril-valsartana pareceu estender-se a valores de FE mais elevados ( Figura 1 ).10 Nos últimos 2 anos, agências reguladoras, incluindo a Food and Drug Administration dos Estados Unidos e a Agência Nacional de Vigilância Sanitária, estenderam a indicação de sacubitril-valsartana para pacientes com IC, incluindo que o benefício é mais evidente quando a FE está abaixo do normal.

– Estimativas do efeito do tratamento com medicamentos modificadores de doença na insuficiência cardíaca em todo o espectro da fração de ejeção. As cores das barras representam as razões de risco (HRs) estimadas relatadas para cada intervenção de acordo com a fração de ejeção. As HRs foram extraídas das respectivas subanálises publicadas de ensaios clínicos: Candesartana: Lund LH et al.7 Espironolactona: Pitt et al.29 e Solomon SD et al.8 Betabloqueadores: Cleland JGF et al.9 Sacubitril-valsartana: Solomon SD et al.10 Empagliflozina: Butler J et al.17

Em conjunto, esses dados sugerem que não apenas o sacubitril-valsartana, mas também o sistema renina-angiotensina-aldosterona e os inibidores do sistema nervoso simpático apresentam efeitos benéficos para a IC na faixa de FE “intermediária” de 41 a 49%. Essas análises fornecem informações além do efeito do tratamento, indicando um papel desses sistemas na progressão da IC nessa categoria e ajudando a compreender parte da heterogeneidade relacionada à FE na IC. Por exemplo, a contribuição de comorbidades não cardíacas na mortalidade aumenta proporcionalmente ao aumento dos valores de FE, principalmente na faixa normal.12 , 13 Isso pode explicar por que uma intervenção direcionada ao sistema cardiovascular apresenta menos probabilidade de alterar o curso da doença em pacientes com FE normal. Pacientes com ICFELR apresentam características intermediárias entre ICFER e ICFEP, mas análises de registros e estudos clínicos demonstraram que essas características compartilham mais semelhanças com a ICFER do que a ICFEP.14 Assim, a definição e classificação universais da IC, publicadas há pouco tempo, devidamente renomearam a antiga categoria de “FE intermediária” para “FE levemente reduzida”.15

Por fim, os novos iSGLT2 se demonstraram bem-sucedidos na ICFER e pavimentaram o caminho para um novo tratamento-alvo na IC. A dúvida se essa nova classe de medicamentos também beneficiaria pacientes com ICFELR e ICFEP permaneceu até a publicação do tão esperado estudo Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) em agosto de 2021.16 O EMPEROR-Preserved incluiu pacientes com IC e FE acima de 40% e demonstrou que a empagliflozina reduziu significativamente o desfecho primário de morte cardiovascular ou hospitalização por IC. Embora isso se deva principalmente à redução de hospitalizações por IC, foi a primeira vez que um estudo de ICFEP apresentou resultados positivos para o desfecho primário. Uma outra análise, que reuniu os estudos Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) e EMPEROR-Preserved, foi realizada para avaliar se o efeito do tratamento difere entre as categorias de FE. De modo semelhante, o efeito do tratamento com empagliflozina pareceu atenuado em valores mais altos da FE, mas permaneceu consistente em pacientes com FE abaixo de 65%.17 Os resultados do estudo Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER), que testou o iSGLT2 dapagliflozina e deve ser apresentado em breve, ajudarão a entender se há um efeito de classe. Um estudo com uma classe ligeiramente diferente, o inibidor do SGLT2-SGLT1 sotagliflozina, foi realizado em pacientes com diabetes e piora da IC. Foi demonstrada uma redução significativa do desfecho primário de morte cardiovascular, hospitalização e consultas urgentes por IC em todo o espectro da FE.18

Apesar do seu papel essencial no manejo da IC, a FE é uma medida imperfeita que sofre influência de diversos fenômenos biológicos. Sua ampla disponibilidade na prática clínica é contrabalançada por limitações na medição precisa da FE. As variabilidades inter e intraobservador das medidas de FE com ecocardiograma foram relatadas em 8-21% e 6-13%, respectivamente, o que limita a classificação correta em categorias com uma menor gama de valores de FE.14 Alguns estudos avaliaram as alterações longitudinais da FE, demonstrando variação considerável ao longo do tempo. Em um registro da Suécia, aproximadamente 1/3 dos pacientes mudou para uma categoria mais baixa e 1/4 mudou para uma categoria mais alta de FE durante um acompanhamento médio de 1,4 ano.14 Devido às limitações na medição da FE, métodos alternativos têm sido sugeridos para uma melhor abordagem da heterogeneidade na IC, como caracterização do tecido miocárdico com ressonância magnética, avaliação do strain longitudinal global a partir da análise de speckle-tracking do ecocardiograma, múltiplas abordagens com biomarcadores e caracterização proteômica. No entanto, o uso dessas alternativas na orientação do manejo clínico ainda é limitado.14

Estudos bem realizados não objetivam apenas encontrar terapias eficazes, mas também auxiliam a compreender a fisiopatologia de uma doença. A classificação da IC evoluiu paralelamente ao avanço da compreensão da doença. Apesar dos critérios rigorosos e pragmáticos necessários adotados em estudos clínicos, o efeito do tratamento com medicamentos para IC tem sido consistentemente modificado pela FE como uma medida contínua. Análises dos estudos mais recentes de IC com sacubitril-valsartana e iSGLT2 apontam para a mesma direção daqueles com inibidores do sistema renina-angiotensina-aldosterona e do sistema nervoso simpático, agrupando as categorias de IC com FE abaixo do normal. Estou ansioso para ver o que aprenderemos com os próximos estudos de ICFEP.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.