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Heart Failure with Preserved Ejection Fraction(HFpEF).ptx
Heart failure with preserved ejection fraction (HFpEF) is a significant clinical syndrome characterized by symptoms of heart failure alongside an ejection fraction of 50% or greater, commonly associated with various comorbidities such as obesity and hypertension. The prevalence of HFpEF is increasing, particularly among older adults, affecting nearly 70% of cases in those aged 65 to 84, and it poses major challenges in terms of hospitalization and mortality rates akin to heart failure with reduced ejection fraction (HFrEF). Diagnosis involves evidence of diastolic dysfunction, and management focuses on optimizing fluid balance and treating associated conditions, with emerging therapies like SGLT2 inhibitors showing promise in improving outcomes.
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Heart Failure with Preserved Ejection Fraction(HFpEF).ptx
- 1. Heart Failure withPreserved Ejection Fraction (HFpEF) Sarfraz Saleemi
- 2. Outline • Classification ofheart failure • Definition of HFpEF • Prevalence • Pathophysiology • Clinical presentation • Diagnosis • Treatment
- 3. Heart Failure Classification HeartFailure Ejection fraction Progression Time Course Location HFrEF (EF<50%) HFpEF (EF>50%) HFmrEF(EF 40-49%) (Has features of both rEF and pEF) HFrecEF (EF recovered) Acute Chronic New onset Left sided Transient Right sided Stable Worsening Combined McMurray et al. Eur Heart J 2012;33:1787–847 Dickstein K et al. Eur Heart J 2008;29:2388–442
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- 5. Normal Heart Compliant LVwith active diastolic relaxation HFpEF Stiff LV with loss of active diastolic relaxation and high filling pressure leading to pulmonary congestion
- 6. Definition of HFpEF •Symptoms and signs of HF. • An LVEF ≥50%. • Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures, including raised NPs HFpEF is not a single disease but a clinical syndrome as a result of many different pathologies
- 7. HFpEF Ageing Sleep Apnea DM Metabolic syndrome Obesity CKD Hypertension 2018 Steppanet al. Cureus 10(1): e2072. DOI 10.7759/cureus.2072 Physical inactivity Risk factors & comorbidities for HFpEF Autonomic dysfunction Depression Iron deficiency Chronic lung disease
- 8. First report ofHFpEF 188 patients with CHF - radionuclide ventriculography. Sixty-seven (36%) had a normal ejection fraction (EF) of > 45% And 121 patient had EF <45% Prevalence of HFpEF
- 9. • Around 70%of cases of HF among adults aged 65 to 84 years are classified as HFpEF • 50% of patients with HFpEF will develop pulmonary hypertension Mayo clinic study • 6076 patients with heart failure discharged from 1987 to 2001 • HFrEF 53% • HFpEF 47% JAMA 2003 Jan 8;289(2):194-202 • Cross-sectional study – Doppler Echo of 2042 randomly selected subjects aged >45 year over 3 years • 28.1% of population group had diastolic dysfunction • Mild - 20.8% (95% CI, 19.0%-22.7%) – 10% mortality at 5 years • Moderate - 6.6% (95% CI, 5.5%-7.8%) • Severe - 0.7% (95% CI, 0.3%-1.1%) -23% mortality at 5 years Prevalence of HFpEF
- 10. • Prevalence ofHFpEF among patients with discharge diagnosis of HF increased from 38% to 54% from 1987–2001 • Increasing prevalence - wider recognition, ageing population and increases in hypertension and obesity Patients with preserved ejection fraction (%) 70 60 50 40 30 20 0 1986 1990 1994 1998 2002 r=0.92, p<0.001 HFpEF prevalence trends 1. Owan et al. N Engl J Med 2006;355:251–9 2. Blanche et al. Swiss Med Wkly 2010;140:66–72
- 11. 4.6 5.3 5.57.1 7.5 11 11.5 43 69 73 0 10 20 30 40 50 60 70 80 HOSPITALIZATION Per 1000 patient years HFpEF - major public health problem Outcomes of patients with HFpEF as compared with those in trials of other cardiovascular disease, with similar ages, sex and comorbidities profiles stable angina & hypertension hypertension, very elderly hypertension hypertension diabetes hypertension hypertension HFpEF Campbell J Am Coll Cardiol 2012
- 12. *Readmission rates werecalculated for the 2,339 patients who survived the index admission: 1,493 with HFrEF and 846 with HFpEF 4.5 13.5 4.9 16.1 0 2 4 6 8 10 12 14 16 18 30-day readmission for HF* 1-year readmission for HF* HFpEF HFrEF p=0.66 p=0.09 Percentage of patients HFpEF & HFrEF: hospital readmission rates 1. Bhatia et al. N Engl J Med 2006;355:260–9 2. Fonarow et al. J Am Coll Cardiol 2007;50:768–77 3. Lenzen et al. Eur Heart J 2004;25:1214–20
- 13. HFpEF & HFrEF:mortality Survival 1.0 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 Year HFrEF (LVEF <50%) HFpEF (LVEF ≥50%) p=0.03 1. Owan et al. N Engl J Med 2006;355:251–9 2. Blanche et al. Swiss Med Wkly 2010;140:66–72 3. Meta-analysis (MAGGIC). Eur Heart J 2012;33:1750–7
- 14. Eur Heart J,(33),14,2012 31 studies – 50,991 patients HFpEF & HFrEF: mortality Meta-analysis - Mortality for patients with HF-PEF
- 15. Pathophysiology - Myocardialabnormalities in HFpEF Abnormal untwisting of the heart during diastole leading to elevated LVEDP which ia further exacerbated when heart rate is increased HFpEF Passive myocardial stiffening Impaired diastolic dysfunction • Conditions affecting the extracellular space fibrosis and infiltrative processes • Condonations affecting the cardiomyocyte hypo-phosphorylation of the elastic protein titin Reduced NO resulting in low protein kinase G (PKG) activity
- 16. Proposed mechanisms ofdiastolic dysfunction protein kinase G Ca2+/calmodulin-protein kinase II
- 17. Reduced exercise capacity,neuroendocrine activation, impaired quality of life *P<0.05 vs controls MLHFQ – Minnesota Living Heart Failure Questionnaire HFrEF vs HFpEF – classic domains Domains HFpEF HFrEF Controls Peak VO2 14.2±0.5* 13.1±0.5* 19.9±0.7 Angiotensin 9.1±0.3* 8.7±0.3* 11.5±0.4 Norepinephrine 306±64* 287±62* 169±80 MLHFQ 24.8±4.4 43.8±3.9 - 1. Borlaug BA and Paulus WJ. Eur Heart J 2011;32: 670–679 2. Kitzman DW et al. JAMA 2002; ;288(17):2144-2150
- 18. Pathophysiology of HFpEFand effect on extracardiac organs
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- 20. Drawn image (A)and actual image (B) showing the isovolumic contraction time (IVCT), ejection time (ET), and isovolumic relaxation time (IVRT). Phase 1 Phase 2 Phase 3 Phase 4 Isovolumic relaxation Rapid passive filling E wave Slow filling Diastasis Active filling A wave Phases of Diastole
- 21. Grades of DiastolicDysfunction Mild E/A ratio <0.8 DT >200 ms Abnormal LV relaxation Decreased LV suction usually asymptomatic Grade 1 Grade II Grade III Grade IV Severe E/A ratio >2 DT <160 Restrictive filling Symptoms of advanced heart failure Valsalva change in E/A Reversible restrictive dysfunction Moderate E/A ratio 0.8-2 DT 160–200 ms Elevated LA filling pressure Increased LA size Severe E/A ratio >2 DT <160 Symptoms of Advanced heart failure Valsalva – no E/A change Fixed restrictive dysfunction
- 22. HFpEF Diastolic dysfunction Diastolic Heart Failure Impaired relaxation stiff,non- compliant LV Signs & symptoms of HF with normal systolic function in the presence of diastolic dysfunction HF with impaired diastolic function and multiple systemic comorbidities Clinical grading
- 23. HFrEF 1. Symptoms typicalof HF 2. Signs typical of HF 3. Reduced LVEF HFpEF 1. Symptoms typical of HF 2. Signs typical of HF 3. Normal or only mildly reduced LVEF and LV not dilated 4.Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures, including raised natriuretic peptides McMurray et al. Eur Heart J 2012;33:1787–847 Diagnosis of HFpEF
- 24. Clinical phenotypes ofHFpEF Co-morbidities Environment/diet Genetic susceptibility Vulnerable Heart Vulnerable patient Shah SJ 2013 TYPE I Exercise induced LA Pressure TYPE 3 Pulmonary Hypertension RV failure TYPE 2 Volume overload High BP Younger patients Moderate diastolic dysfunction Near normal proBNP Obese diabetic patients High prevalence of OSA Older patients CKD Myocardial remodeling ERJ Express. Published on December 13, 2018
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- 26. Pretest Probability ofHFpEF High Intermediate Low Age >70 60-70 <60 Obesity/HT//IGT/ DM/Hyperlipidemia >2 1-2 None Previous cardiac intervention Yes No No AF Current Previous No Structural LHD Present No No ECG LBBB/LVH Mild LVH Normal ECHO LA dilation >Grade 2 diastolic dysfunction No LA dilation <Grade 2 diastolic dysfunction No LA dilation E/e′ <13 CMR LA strain or LA/RA >1 No left heart abnormalities ERJ Express. Published on December 13, 2018
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- 28. Management of HFpEF •Optimize fluid balance • Treat the co-morbidities
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- 31. Management of HFpEF SGLT2I Targetsfor treatment of HFpEF
- 32. Management of HFpEF MortalityBenefits HFpEF HFrEF ? Aldosterone antagonists ACE inhibitors ARBs Beta-blockers Vasodilators
- 33. STUDY Study drugPatients Endpoint Outcome Publication CHARM- Preserve Candesartan 3023 CV death or HF hospitalization Primary end-point not met Yusuf S et al Lancet 2003 PEP-CHF Perindopril 850 Death or HF hospitalization Cleland JG et al Eur Heart J 2006 I-Preserve Irbesartan 4128 Death or HF hospitalization Massie BN et al NEJM 2008 McMurray et al. Eur Heart J 2012;33:1787–847 Yusuf S et al. Lancet 2003;362:777 Cleland JG et al. Eur Heart J 2006;27:2338 Massie BM et al. NEJM 2008;359:2456 Management of HFpEF ACE-ARB studies
- 34. Spironolactone in HFpEF NEJM2014:370(15) Composite Hospitalization
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- 36. Beta-blockers in heartfailure with preserved ejection fraction: a meta-analysis Heart Failure Reviews volume 20, pages 193–201 (2015 β-Blockers in HFpEF
- 37. Eur Heart 2012(33) Circulation2013(128)
- 38. NOVEL THERAPIES FORHFpEF
- 39. Study Design MedicationOutcome PARAMOUNT Jhund PS, et al. 2014 Voors AA, et al. 2015 Solomon SD, et al. 2012 Prospective Phase 2, randomized, double-blind, sacubitril/valsartan (Angiotensin-neprilysin inhibitor(ARNI) At 12 weeks, NT-proBNP was significantly reduced in the sacubitril/valsartan group compared with the valsartan group (ratio of change, 0.77; 95% CI, 0.64, 0.92; P = 0.005) PARAGON-HF Solomon SD, et al. 2017 and 2019 Phase 3, randomized, double-blind, sacubitril/valsartan or Valsartan Primary composite outcome was reduced, but failed to reach statistical significance (rate ratio, 0.87; 95% CI, 0.75, 1.01; P = 0.06) DECLARE-TIMI 58 Wiviott SD, et al. 2019 Phase 3, randomized, double-blind, Dapagliflozin 10 mg daily or matching placebo Dapagliflozin was noninferior to placebo in the reduction of MACE (defined as CV death, MI, or ischemic stroke) (P < 0.001 for noninferiority) EMPERORP preserve Phase 3, randomized, double-blind, Empagliflozin 10 mg daily or placebo Reduction in composite primary end point PRESERVED-HF Phase 2 multicenter, randomized dapagliflozin or placebo Met primary end point - heart failure- related health status DELIVER (NCT03619213) Phase 3, international, multicenter, parallel group, event-driven, randomized, placebo controlled, double-blind Dapagliflozin 10 mg daily versus placebo Study start date: 27 August 2018 Results expected second half of 2021
- 40. Angiotensin–Neprilysin Inhibition inHeart Failure with Preserved Ejection Fraction - PARAGON-HF Trial N Engl J Med 2019; 381:1609-1620 Conclusions Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher
- 41. SGLT2 inhibitors inHFpEF Empagliflozin Sotagliflozin Dapagliflozin
- 42. Patients with historyof HF EMPA-REG OUTCOME CANVAS Program DECLARE-TIMI 58 Fixed effects model for history of HF (P = .0002) Patients without history of HF EMPA-REG OUTCOME CANVAS Program DECLARE-TIMI 58 Fixed effects model for no history of HF (P < .0001) Patients with history of HF EMPA-REG OUTCOME CANVAS Program DECLARE-TIMI 58 Fixed effects model for history of HF (P < .001) Patients without history of heart failure EMPA-REG OUTCOME CANVAS Program DECLARE-TIMI 58 Fixed effects model for no history of HF (P < .001) Meta-analysis of SGLT2 Inhibitor CVOTs: HFH or CV Death by Presence of HF Slide credit: clinicaloptions.com 0.35 0.50 1.00 2.50 Favors placebo Favors treatment 0.72 (0.50-1.04) 0.61 (0.46-0.80) 0.79 (0.63-0.99) 0.71 (0.61-0.84) 0.63 (0.51-0.78) 0.87 (0.72-1.06) 0.84 (0.72-0.99) 0.79 (0.71-0.88) 0.75 (0.48-1.19) 0.51 (0.33-0.78) 0.73 (0.55-0.96) 0.68 (0.55-0.83) 0.59 (0.43-0.82) 0.79 (0.57-1.09) 0.73 (0.58-0.92) 0.71 (0.60-0.83) P for interaction = .51 P for interaction = .76 HFH/CV Death HR HR (95% CI) Events/1000 Patient-Yrs Treatment Placebo 63.6 35.4 45.1 15.5 13.6 8.9 85.5 56.8 55.5 24.9 15.2 10.5 40.7 14.1 27.7 6.4 4.3 4.0 52.4 28.1 37.2 10.8 5.7 5.6 HFH Zelniker. Lancet. 2019;393:31.
- 43. CONCLUSIONS Empagliflozin reduced thecombined risk of cardiovascular death or hospitalization or heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved Trial)
- 44. Sotagliflozin in Patientswith Diabetes and Recent Worsening Heart Failure - SOLOIST-WHF Trial N Engl J Med 2021; 384:117-128
- 45. The SGLT2 inhibitordapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial (PRESERVED-HF) Conclusion: Dapagliflozin treatment significantly improved patient- reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF. 28 October 2021
- 46. Dapagliflozin in heartfailure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial Eur J Heart Fail. 2021 Jul; 23(7): 1217–1225 Study Design Testing scheme for primary and secondary end points PRIMARY END POINT composite: 1. CV death 2. Hospitalization for HF 3. Urgent HF visit
- 47. SGLT2 inhibitors -Caution SGLT2 inhibitors should be avoided in patients with the following conditions •All patients with type 1 diabetes mellitus. •Presence of type 2 diabetes mellitus with prior diabetic ketoacidosis (DKA) or a condition predisposing to DKA (including pancreatic insufficiency, drug or alcohol addiction, prolonged fasting). •Volume depletion or symptomatic hypotension. •GFR <20 , end-stage kidney disease, or rapidly declining renal function. •History of complicated urinary tract infections or genitourinary infections. •Presence of risk factors for foot amputation (neuropathy, foot deformity, vascular disease, and/or history of previous foot ulceration). Patients taking SGLT2 inhibitors should be monitored for signs and symptoms of foot ulceration.
- 48. Recent RCTs inHFpEF TYPE I Exercise induced LA Pressure TYPE 3 Pulmonary Hypertension RV failure TYPE 2 Volume overload High BP REDUCE LAP-HF II (Inhaled / oral Nitrite) PANACHE(adenosine 1 agonist) EMPEROR PRESERVED (Empagliflozin) PARAGON (Sacubitril- Valsartan) VITALITY-HFpEF (Vericiguat) SERENADE (Macitentan) SOUTHPAW (oral Treprostinil) HELP PH (Levosimendan) CADENCE(Sotatercept)
- 49. Pulmonary vasodilator therapiesare of no benefit in pulmonary hypertension due to left heart disease: A meta-analysis Cao, Jacob Y. et al. International Journal of Cardiology 2018; 09.043 • RCT =10 Treated=439 placebo=338 • PDE5I: n = 206; SGCSs: n = 132; ERAs: n = 101 • The risks of all-cause mortality, cardiovascular mortality and worsening heart failure were numerically higher in the treated compared to the control group, although not statistically significant. • Conclusions • The current meta-analysis demonstrated that there is no current evidence to support the widespread use of PAH therapy in PH-LHD. On the basis of a numerically increased risk of clinical harm, these agents should not be prescribed in this setting, unless further evidence of benefit arises in the future.
- 50. Despite recent advancesin the understanding of PAH medications for patients with PH-LHD, uncertainty remains about their utility in distinct subgroups. Nonetheless, PAH pharmacotherapy should generally be avoided for most patients with PH-LHD. PAH medications should not be recommended in two distinct HF populations: 1.patients with HF without definitive PH diagnosis 2.patients with isolated post-capillary PH due to HF.
- 51. Recommendations for thetreatment of patients with HFpEF
- 52. Low dose dopamineand furosemide infusion in Acute heart failure with pEF Conclusions: In HFpEF patients hospitalized with acute heart failure, low- dose dopamine had no significant impact on renal function, and a continuous infusion diuretic strategy was associated with renal impairment.
- 53. Conclusion • HFpEF iscommon in older population with comorbidities. • Pathophysiology, etiology and management of HFpEF is distinct • Treatment is based on symptoms and co-morbidities • Many effective treatments for HFrEF have shown disappointing results when applied to HFpEF patients • Medications used to treat HFpEF lack evidence for mortality benefit • New pharmacological treatment targets such as SGLT2 inhibitors may play a role in optimum management of HFpEF • Further research is needed to better understand HFpEF for improved clinical outcome
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