Recent Progress in Heart Failure. Management. March 9, 2018

Transcription

1 Recent Progress in Heart Failure March 9, 2018 Management Objectives: - Outline practical approaches to HFrEF and HFpEF management - Review major heart failure clinical trials - Discuss recent updates to heart failure guidelines Terrence X. O Brien, MD, FACC Professor of Medicine/Cardiology Medical University of South Carolina

2 Potential Conflicts of Interest: Current Research Grants: NIH-NHLBI Novartis Amgen Boehringer

3 Heart Failure: The Epidemic: HF mortality is increasing despite overall decline in CV deaths, related to Aging population Improved survival of patients with diseases leading to HF ~50% of patients die within 5 years after diagnosis ~35% with severe HF die within 1 year Sudden death accounts for 50% of mortality HF is one of the most frequent causes of hospitalization in patients >65 years

4

5 Cardiomyopathy Etiologies: INFLAMATORY HEART DISEASE SECONDARY CARDIOMYOPATHY Viral myocarditis Endocrine Idiopathic myocarditis Rheumatologic Giant cell myocarditis Nutritional Sarcoidosis Toxic Eosinophilic myocarditis (hypersensitivity) Metabolic Infectious Inherited Lyme disease Neuromuscular disorders HIV X-linked Chagas disease Mitochondrial Peripartum Familial dilated cardiomyopathy EXTRAMYOCARDIAL CARDIOMYOPATHY Storage diseases Coronary artery disease Disorders of cardiac energy metabolism Neoplastic Valvular heart disease Tachycardia-induced cardiomyopathy Amyloidosis Congenital cardiac anomalies Hemochromatosis Hypertension

6 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure Developed in Collaboration With the American Academy of Family Physicians, American College of Chest Physicians, and International Society for Heart and Lung Transplantation

7

8 Recommendations for Pharmacological Therapy for Management of Stage A-B HFrEF:

9 Recommendations for Pharmacological Therapy for Management of Stage C HFrEF:

10 Optimal Dosing of ACE Inhibitors General Guideline: Start low and titrate to the target dose used in the clinical trials or the MAXIMUM TOLERATED DOSE Captopril mg 50 mg BID-TID (SAVE) Enalapril 2.5 mg BID 20 mg BID (SOLVD/X) Ramipril 2.5 mg BID 5 mg BID (AIRE/EX) Lisinopril 10 mg OD mg OD (GISSI 3) Trandolapril 1mg 4 mg (TRACE)

11 β-adrenergic Blocking Agents Titrate to target dose Bisoprolol mg OD Carvedilol mg BID Metoprolol to75 mg /BID If unable to tolerate high dose β-blocker maintain highest tolerated dose Continue indefinitely

12 Recommendations for Pharmacological Therapy for Management of Stage C HFrEF:

13 Biomarkers Biomarkers for Prognosis or Added Risk Stratification COR LOE Recommendations I I A A Measurement of BNP or NTproBNP is useful for establishing prognosis or disease severity in chronic HF. Measurement of baseline levels of natriuretic peptide biomarkers and/or cardiac troponin on admission to the hospital is useful to establish a prognosis in acutely decompensated HF. Comment/ Rationale 2013 recommendation remains current. MODIFIED: Emphasize it is admission levels of natriuretic peptide biomarkers that are useful.

14 Biomarkers Biomarkers Indications for Use COR LOE Recommendation IIa B-R For patients at risk of developing HF, natriuretic peptide biomarker based screening followed by team-based care, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic). Comment/ Rationale NEW: New data suggest that natriuretic peptide biomarker screening and early intervention may prevent HF.

15 Pharmacological Treatment for Stage C HF With Reduced EF Renin-Angiotensin System Inhibition With ACE-Inhibitor or ARB or ARNI COR LOE Recommendations I ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. Comment/ Rationale NEW: New clinical trial data necessitated this recommendation.

16 Neprilysin catalyzes the degradation of B-type natriuretic peptide (BNP) and participates in the breakdown of other vasoactive peptides.

17 PARADIGM-HF: The largest trial ever in patients with HFrEF (N = 8,442): -Prospective comparison of an angiotensin receptor-neprilysin inhibitor sacubitril combined with the ARB valsartan (Entresto) to ACE-inhibitor therapy (enalapril) in patients who had HF with a reduced EF. -Primary endpoint included global mortality and morbidity in heart failure with reduced ejection fraction. -Mechanism: neprilysin inhibition would counter the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling.

18 Adverse Events during Randomized Treatment: Event LCZ696 Enalapril P Value no. (%) (N = 4187) (N= 4212) Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Systolic BP<90 mm Hg 112 (2.7) 59 (1.4) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) mg/dl 63 (1.5) 83 (2.0) 0.10 Elevated serum potassium >5.5 mmol/liter 674 (16.1) 727 (17.3) 0.15 >6.0 mmol/liter 81 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) <0.001 Angioedema No treatment or use of antihistamines only: 10 (0.2) 5 (0.1) 0.19 Use of catecholamines or glucocorticoids without hospitalization: 6 (0.1) 4 (0.1) 0.52 Hospitalization without airway compromise 3 (0.1) 1 (<0.1) 0.31 Airway compromise 0 0 McMurray et al, NEJM 371:993, 2014

19 PARADIGM-HF Primary Endpoints: McMurray et al, NEJM 371:993, 2014

20 Pharmacological Treatment for Stage C HF With Reduced EF Renin-Angiotensin System Inhibition With ACE-Inhibitor or ARB or ARNI COR LOE Recommendations III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. ARNI should not be administered to III: Harm C-EO patients with a history of angioedema. Comment/ Rationale NEW: Available evidence demonstrates a potential signal of harm for a concomitant use of ACE inhibitors and ARNI. NEW: New clinical trial data.

21 Recommendations for Device Therapy for Management of HFrEF: 2013 ACCF/AHA HF Guidelines

22 Severity of Heart Failure Modes of Death NYHA II CHF NYHA III 64% 12% 24% Other Sudden Death n = % 26% 15% CHF Otherr Sudden Death n = 103 NYHA IV CHF 33% 11% 56% Other Sudden Death n = 27 MERIT-HF Study Group. LANCET.

23 Cardiac Resynchronization Therapy (CRT) Atrial-biventricular stimulation Electrical synchronization narrower QRS Mechanical synchronization reverse remodeling

24 Pharmacological Treatment for Stage C HF With Reduced EF Ivabradine COR LOE Recommendations IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDMT*, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. Comment/ Rationale NEW: New clinical trial data.

25 Ivabradine (Corlanor) Specifically binds the cardiac Funny channel Reduces the slope of diastolic depolarization prolonging diastolic duration Used for when pure heart rate reduction needed Does not alter Ventricular repolarization Myocardial contractility Blood pressure 25

26 SHIFT Trial: Cardiovascular Mortality Swedberg et al, Lancet 2010

27 SHIFT Trial: Heart Failure Admissions Swedberg et al, Lancet 2010

28 Ivabradine: Current Indications Used when pure heart rate reduction needed. It could be used in the following groups Patients with HFrEF who cannot take or tolerate beta-blockers Patients whose heart failure-related tachycardia is not controlled with beta-blockers and whose heart rate is above 70 bpm. 28

29 LVAD/Heart Transplantation: Basic Indications Refractory cardiogenic shock Dependence on IV inotropic support to maintain adequate organ perfusion Peak VO2 < 10 ml / kg / min Severe symptoms of ischemia or ventricular arrhythmias not amenable to therapy Contraindications: age, severe comorbidity

30 Stage D (end-stage) Therapy Meticulous identification and control of fluid retention in refractory end-stage HF. Referral of patients with end-stage HF to a center with expertise in refractory HF and cardiac transplantation. (Ia) Options for end-of-life care should be discussed with the patient and family when severe symptoms from refractory end-stage HF persist despite application of all recommended therapies. (Ic)

31 Heart Failure with Preserved Ejection Fraction (HFpEF)

32 Myofibril Z Titin Z Cardiomyocyte LA RA LV RV Normal HFpEF Actin ECM Myosin

33 Pharmacological Treatment for Stage C HF With Preserved EF COR LOE Recommendations I I B C Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines to prevent morbidity Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. Comment/ Rationale 2013 recommendation remains current recommendation remains current.

34 Pharmacological Treatment for Stage C HF With Preserved EF COR LOE Recommendations IIa IIa IIa C C C Coronary revascularization is reasonable in patients with CAD in whom symptoms (angina) or demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite GDMT. Management of AF according to published clinical practice guidelines in patients with HFpEF is reasonable to improve symptomatic HF. The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF. Comment/ Rationale 2013 recommendation remains current recommendation remains current recommendation remains current.

35 Hypertension Treating Hypertension in Stage C HFpEF COR LOE Recommendations I C-LD Patients with HFpEF and persistent hypertension after management of volume overload should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg. Comment/ Rationale NEW: New target goal blood pressure based on updated interpretation of recent clinical trial data.

36 Pharmacological Treatment for Stage C HF With Preserved EF COR LOE Recommendations IIb IIb B-R B In appropriately selected patients with HFpEF (with EF 45%, elevated BNP levels or HF admission within 1 year, estimated glomerular filtration rate >30 ml/min, creatinine <2.5 mg/dl, potassium <5.0 meq/l), aldosterone receptor antagonists might be considered to decrease hospitalizations. The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF. Comment/ Rationale NEW: Current recommendation reflects new RCT data recommendation remains current.

37 CHARM-Preserved: Primary outcome CV death or CHF hospitalization % Placebo Candesartan HR 0.89 (95% CI ), p= years Number at risk Candesartan Placebo (24.3%) 333 (22.0%) Lancet. 2003;362:

38 Pharmacological Treatment for Stage C HF With Preserved EF COR LOE Recommendations III: No Benefit III: No Benefit B-R C Routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or QoL in patients with HFpEF is ineffective. Routine use of nutritional supplements is not recommended for patients with HFpEF. Comment/ Rationale NEW: Current recommendation reflects new data from RCTs recommendation remains current.

39 2017 Heart Failure Focused Update Important Comorbidities in HF

40 Anemia COR LOE Recommendations IIb III: No Benefit B-R B-R In patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/ml or 100 to 300 ng/ml if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL. In patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality. Comment/ Rationale NEW: New evidence consistent with therapeutic benefit. NEW: Current recommendation reflects new evidence demonstrating absence of therapeutic benefit.

41 Hypertension Treating Hypertension to Reduce the Incidence of HF COR LOE Recommendations I B-R In patients at increased risk, stage A HF, the optimal blood pressure in those with hypertension should be less than 130/80 mm Hg. Comment/ Rationale NEW: Recommendation reflects new RCT data.

42 Sleep Disorders COR LOE Recommendations IIa IIb III: Harm C-LD B-R B-R In patients with NYHA class II IV HF and suspicion of sleep disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with cardiovascular disease and obstructive sleep apnea, CPAP may be reasonable to improve sleep quality and daytime sleepiness. In patients with NYHA class II IV HFrEF and central sleep apnea, adaptive servo-ventilation causes harm. Comment/ Rationale NEW: Recommendation reflects clinical necessity to distinguish obstructive versus central sleep apnea. NEW: New data demonstrate the limited scope of benefit expected from CPAP for obstructive sleep apnea. NEW: New data demonstrate a signal of harm when adaptive servo-ventilation is used for central sleep apnea.

43 -Diabetes is a major risk factor for CV disease -Prior evidence that glucose lowering reduces rates of CV disease and death are not convincing

44 Meta-analysis of intensive glucose control in T2DM: mortality Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) All-cause mortality (0.90,1.20) CV death (0.84,1.42) Non-CV death (0.89,1.18) Favours more intensive Favours less intensive Meta-analysis of 27,049 participants and 2370 major vascular events from ADVANCE UKPDS ACCORD VADT HR, hazard ratio; CV, cardiovascular Turnbull FM et al. Diabetologia 2009;52:

45 Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) Stroke (0.83, 1.10) Myocardial infarction (0.76, 0.94) Hospitalisation for or death from heart failure (0.86, 1.16) Favours more intensive Favours less intensive Meta-analysis of 27,049 participants and 2370 major vascular events from: ADVANCE UKPDS ACCORD VADT HR, hazard ratio; CV, cardiovascular Turnbull FM et al. Diabetologia 2009;52:

46 Gliflozins: Target SGLT2 receptor Mechanism: selective inhibitor of sodiumglucose cotransporter 2. Increased excretion of glc, Na + and H 2 O Empagliflozin (Jardiance) Canagliflozin (Invokana) Dapagliflozin (Forxiga)

47 EMPA-REG Outcome Study Design Baseline characteristics similar in 2 groups at baseline 99% had established CAD Well treated for HTN and HLD 7028 patients, double blind placebo controlled Randomly assigned 1:1:1 fashion Stratified Hgb A1c(<8.5% or >8.5%) BMI(<30 or >30), max BMI 45 Renal Function(eGFR ml, 60-89mL, >90mL) 4687 pooled empagliflozin group (10mg or 25mg doses) 2333 placebo group Zinman et al., NEJM 373:2117, 2015

48 CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Cumulative incidence function. HR, hazard ratio 48

49 All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p= Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p= HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio 49

50 Hospitalization for heart failure Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p= Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p= Cumulative incidence function. HR, hazard ratio 50

51 Empagliflozin and progression of kidney disease in type 2 diabetes. -Wanner et al., N Engl J Med 375: , 2016

52 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes Liraglutide (victoza) is an FDA-approved, injectable, long-acting GLP-1 receptor agonist that lowers glucose, reduces BP, and promotes weight loss. Glucagon-like peptide-1 (GLP-1) is a satiety peptide known to stimulate insulin release in the context of elevated glucose levels, reduce prandial glucagon, and delay gastric emptying. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial randomized 9,340 patients with type 2 diabetes and high CV risk to receive liraglutide or placebo. After a median follow-up of 3.8 years, liraglutide was associated with: -Significant reduction in CV mortality, nonfatal MI, or nonfatal stroke (13.0% vs. 14.9%, P<0.001) -Reduction in all-cause mortality (8.2% vs. 9.6%, P=0.02). Marso SP, et al. New England J Med 375(4): , 2016

53

54

55 Dilated Cardiomyopathy Disease Genes Burke, M.A. et al. J Am Coll Cardiol. 2016;68(25):

56

57 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction 1. Initiate and Switch: -Initiate angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARBs), betablockers, and diuretics. -When stable on ACEI/ARBs, switch to angiotensin receptor-neprilysin inhibitors (ARNI) in those with stable blood pressure and EGFR>30 ml/min/1.73 m 2. -Add aldosterone antagonist, and/or hydralazine/isosorbide dinitrate (in African Americans) or ivabradine, as indicated if no contraindications. 2. Titrate: -Titrate diuretic dose over days to weeks to release congestion. -Consider increasing ACEI/ARB/ARNI/aldosterone antagonist/hyd-isdn every 2 weeks until maximum tolerated or target dose. 3. Referral to HF Specialist: Acronym I-NEED-HELP. I: Intravenous inotropes N: New York Heart Association (NYHA) class IIIB/IV or persistently elevated natriuretic peptides E: End-organ dysfunction E: EF 35% D: Defibrillator shocks H: Hospitalizations >1 E: Edema despite escalating diuretics L: Low systolic BP 90, high heart rate P: Progressive intolerance or down-titration of guideline-directed medical therapy [GDMT]) 4. Care Coordination: -More than 50% of the HF patients have four or more noncardiovascular comorbidities and more than 25% have six or more ACC Expert Consensus Decision Pathway J Am Coll Cardiol 2017;Dec 22

58 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction 5. Adherence: Understanding reasons for nonadherence. Capitalizing on opportunities to improve adherence: simplifying regimens, communicating with other clinicians, costs, access, caregivers, and specific patient interventions. 6. Specific Patient Cohorts: Tailor therapy for African Americans, the frail, and the elderly. African Americans: The risk of angioedema is higher 0.5% with ACEI and 2.4% with ARNI; Consider HYD/ISDN in patients with low systolic BP, rather than ARNI. Elderly: The upper range for clinical trials with GDMT has been 75 ± 5 years. There is a higher risk of adverse events. Frailty: At least 20% of those over age of 80 years are frail. The response to GDMT is uncertain. 7. Cost of care: The cost of cardiovascular medications is15.6% of direct costs ACC Expert Consensus Decision Pathway J Am Coll Cardiol 2017;Dec 22

59 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction 8. Managing Increasing Complexity of HF: -Assign top priority to factors that limit GDMT (such as worsening azotemia, hyperkalemia, hypotension), -Optimal sympathetic nervous system modulation (use target doses of beta-blockers and lower doses of renin-angiotensin-aldosterone system blockade when limited by hypotension), -Consider device therapy (implantable cardioverter-defibrillator and cardiac resynchronization therapy) after optimal doses of medications for 3-6 months, -Symptomatic congestion should be treated with diuretics irrespective of other therapies, -Discussions should occur at time of major referrals/interventions such as left ventricular assist devices and heart transplantations. 9. Managing Comorbidities: -Cardiovascular morbidities: coronary artery disease, atrial fibrillation/flutter, mitral regurgitation, aortic stenosis, hypertension, dyslipidemia, peripheral vascular disease, and cerebrovascular disease -Noncardiovascular comorbidities: obesity, chronic lung disease, diabetes mellitus, chronic renal disease, anemia, iron deficiency, hypo- or hyper-thyroid disorder, and sleep-disordered breathing. 10. Palliative/Hospice Care: -Soliciting goals of care and focusing on quality of life throughout the clinical course of HF is important. -Palliative care consultation can be helpful in ameliorating refractory symptoms such as fatigue, dyspnea, pain, and in managing complex decisions ACC Expert Consensus Decision Pathway J Am Coll Cardiol 2017;Dec 22

60 THANK YOU!