Disclosures Update on Heart Failure with Honoraria (consulting): - - PDF document

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Update on Heart Failure with Reduced and Preserved Ejection Fraction

Van N Selby, MD UCSF Advanced Heart Failure and Heart Transplant Program May 20, 2019

Disclosures

Honoraria (consulting): Alnylam Pharmaceuticals, Akcea Therapeutics

Objectives

Understand the role of new therapies in the management of chronic heart failure with both reduced (HFrEF) and preserved ejection fraction (HFpEF): § Angiotensin-Neprilysin Inhibitors § Ivabradine § SGLT2 inhibitors § Remote hemodynamic monitoring § Mineralocorticoid receptor antagonists for HFpEF

Medical Therapy for HFrEF: 2013

§ACE Inhibitors (Class Ia)

• ARB as an alternative (Class Ia)

§Beta-blockers (Class Ia) §Mineralocorticoid receptor antagonists (Class Ia) §Hydralazine/Isosorbide for African-Americans (Class Ia) §Other: Diuretics, digoxin, etc

Yancy CW et al, Circulation 2013

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Sacubitril-valsartan: HF pathways

Sauer AJ et al, Heart Failure Reviews. Mar 2019, 24(2); 167–176

PARADIGM-HF

§ 8442 patients with NYHA class II, III, or IV chronic heart failure

• LVEF < 35-40%
• SBP ≥ 95, GFR ≥ 30, K ≤ 5.4
• Tolerated enalapril 10 mg daily or equivalent for ≥ 4 weeks

§ Randomized to enalapril 20 mg daily vs sacubitril-valsartan 400 mg daily § Primary outcome was a composite of cardiovascular death or HF hospitalization

McMurray JJV et al, N Engl J Med 2014 McMurray JJV et al, N Engl J Med 2014

Enalapril Cumulative Probability 1.0 0.4 0.6 0.5 0.3 0.2 0.1 0.0 180 360 540 900 720 1080 1260 Days since Randomization Primary End Point Hazard ratio, 0.80 (95% CI, 0.73–0.87) P<0.001 LCZ696

McMurray JJV et al, N Engl J Med 2014

PARADIGM-HF:

Primary endpoint: CV Death or Hospitalization

2016 Heart Failure Guideline Update

Yancy, CW et al. Circulation 2016

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the rare complication of angioedema (30). 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 (31, 32). Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to

2016 Guideline Update

Yancy, CW et al. Circulation 2016

Compared to enalapril, sacubitril-valsartan is also associated with improvements in:

• CV Death
• HF Hospitalization
• All-cause mortality
• Coronary outcomes
• Clinical progression of HF
• Functional mitral regurgitation
• Physical and social activities
• Attenuation of diabetic nephropathy
• Markers of myocardial fibrosis

PARADIGM-HF: Secondary analyses

McMurray JJV et al, N Engl J Med 2014. Kang DH, et al. Circulation. 2018 Smith KR et al, Pharmacotherapy 2018

PIONEER-HF: Sacubitril/Valsartan for hospitalized patients

§ 881 patients hospitalized for acute HF

• 52.1% were not previously treated with ACEi/ARB

§ Randomized to enalapril vs sacubitril/valsartan § All patients were hemodynamically stable prior to randomization

• No IV vasodilators or diuretics in the previous 6 hours
• No inotropes in the previous 24 hours

§ The primary outcome of reduction in NT-proBNP was significantly greater in patients receiving sacubitril/valsartan § Rehospitalization for HF was lower in sacubitril/valsartan group § No significant differences in hypotension or worsening renal function

Velazquez EJ et al, NEJM 2018.

Sacubitril/Valsartan

§ Can be used to replace ACEi or ARB in patients with chronic HFrEF or as initial therapy

• 36 hour washout period for patients previously treated with

ACE-I

• For patients hospitalized with acute heart failure, start Entresto

after at least 6 hours of hemodynamic stability, and no inotropes for at least 24 hours § Starting dose is 49/51 mg BID

• Start with a reduced dose of 24/26 mg for those not previously

taking ACE/ARB, or those on a low dose § Double the dose every 2-4 weeks to a target dose of 97/103 mg § May need to reduce diuretic dose

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Ivabradine: The SHIFT Trial

§ Heart rate is an independent predictor of mortality in heart failure § Ivabradine is an inhibitor of the If current in the SA node § The SHIFT trial enrolled 6558 patients:

• Symptomatic HFrEF (LVEF ≤ 35%)
• HR ≥70 in sinus rhythm
• At least one HF hospitalization in the past year
• On background HF therapy including beta-blockers if tolerated

§ Randomized to ivabradine (titrated to a max of 7.5 mg BID) vs placebo

Swedberg K et al, Lancet 2010 Sep 11;376(9744):875-85. Number at risk 6 12 18 24 30 Months 10 20 30 40 Patients with primary composite endpoint (%) Placebo (937 events) Ivabradine (793 events) HR 0·82 (95% CI 0·75–0·90), p<0·0001 Patients with first hospital admission Swedberg K et al, Lancet 2010

SHIFT: HF Death or Hospitalization

2016 Guideline Update

Recommendation for Ivabradine COR LOE Recommendation 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 GDEM, 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 (37-40). Ivabradine is a new therapeutic agent that selectively inhibits the If current in Yancy, CW et al. Circulation 2016

§ No patients enrolled from the US § Only 23% were on target dose beta-blocker

• There was no significant improvement in the primary outcome

among patients taking at least 50% target dose beta-blocker at randomization

• With true target doses of beta-blockers, the heart rate will

usually fall below 70

Therapies for heart failure with preserved ejection fraction (HFpEF)

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Spironolactone for HFpEF: Background

§No medical therapy has been proven to improve outcomes for HFpEF §Mineralocorticoid receptor antagonists (MRA) improve

• utcomes in HFrEF and post-MI with LV dysfunction

§Small studies suggested MRAs may improve diastolic function as well

TOPCAT: Spironolactone for HFpEF

§ The TOPCAT trial randomized patients with HFpEF to spironolactone vs placebo § A negative trial overall: No significant difference in the primary composite outcome of cardiovascular death, aborted cardiac arrest,

• r HF hospitalization

§ However, there were significant differences in the patient populations depending on country of enrollment

Pitt B, NEJM 2014 Jul 10;371(2):181-2.

TOPCAT: Americas Sub-Analysis

§ Patients enrolled from the Americas appeared to have much higher-risk baseline characteristics compared to those enrolled from Russia/Georgia § Higher rates of many co-morbidities § More likely to be enrolled based on high BNP level § Among patients randomized to placebo, those from the Americas had much higher event rates than those from Russia/Georgia § Suggesting the patients from the Americas were a sicker population

Pfeffer MA et al, Circulation 2015 Jan 6;131(1):34-42.

TOPCAT: Americas Sub-Analysis

Pfeffer MA et al, Circulation 2015 Jan 6;131(1):34-42. HR 0.82 HR 0.74

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Yancy, CW et al. Circulation 2017

2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure

Cardiac amyloidosis in HFpEF

Cardiac amyloidosis, especially transthyretin (TTR), is now recognized as an overlooked cause of HFpEF

• TTR identified in 13% of patients > 60

years hospitalized for HFpEF1

• TTR found in 25% of patients > 85 years

at autopsy2

• TTR identified in approximately 1 in 7

patients undergoing TAVR3

1González-López E et al, Eur Heart J 2015; 36:2585-2594. 2T

anskanen M et al, Ann Md 2008; 40:232-239.

3Castaño A et al, Eur Heart J, Volume 38, Issue 38, 7 Oct 2017, 2879–2887.

When to suspect cardiac amyloidosis

§ Echocardiography:

• Thick LV with low ECG volts
• Thickened RV free wall, valves

§ New hypertrophic cardiomyopathy with an alternative explanation § Intolerance of beta-blockers/ACEi § Low or normal BP in a previously hypertensive patient § Bilateral carpal tunnel syndrome § Peripheral or autonomic neuropathy, orthostatic hypotension § Family history (hATTR), African American > 60 years

When to suspect cardiac amyloidosis

§ Echocardiography:

• Thick LV with low ECG volts
• Thickened RV free wall, valves

§ New hypertrophic cardiomyopathy with an alternative explanation § Intolerance of beta-blockers/ACEi § Low or normal BP in a previously hypertensive patient § Bilateral carpal tunnel syndrome § Peripheral or autonomic neuropathy, orthostatic hypotension § Family history (hATTR), African American > 60 years

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Tafamidis improves all-cause survival in TTR cardiac amyloidosis

Maurer MS et al, NEJM 2018

Therapies for heart failure with preserved or reduced ejection fraction

Sodium-glucose transporter-2 inhibition

§ Block sodium/glucose uptake in the proximal tubule, inducing glycosuria

• Also induce natriuresis

§ Reduces A1c levels by approximately 1% § SGLT2 inhibitors reduce blood pressure and body weight § In multiple clinical trials of SGLT2 inhibitors, a significant decrease in heart failure hospitalizations was observed

• Osmotic diuresis
• Reduces plasma volume without sympathetic activation
• Decrease vascular stiffness, improve endothelial function

SGLT2 Inhibitors associated with reduction in heart failure hospitalizations

Zelniker TA et al, Lancet 2019; 393.31-19.

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Melanie J. Davies et al. Dia Care 2018;41:2669-2701 Melanie J. Davies et al. Dia Care 2018;41:2669-2701 Melanie J. Davies et al. Dia Care 2018;41:2669-2701

SGLT2 initiation pathway

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SGLT2 Inhibitors: Considerations

§ Possible increased risk of Fournier gangrene

• Now associated with all SGLT2 inhibitors

§ Urinary tract/genital infections, urosepsis § May cause/worsen hypovolemia

Remote Hemodynamic Monitoring for HF

Adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

Remote Hemodynamic Monitoring for HF

Adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

CardioMEMS

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CHAMPION TRIAL

§ NYHA Class III heart failure § Previous HF hospitalization § No ejection fraction criteria § Randomized to a wireless implantable hemodynamic monitoring system vs control § At least 6 months follow-up § Primary outcome: re-hospitalization

Abraham WT et al, Lancet 2011 Feb 19;377(9766):658-66.

CHAMPION

Abraham WT et al, Lancet 2011 Feb 19;377(9766):658-66.

Risk reduction: 36% Risk reduction: 29%

CardioMEMS

§ Inserted via venous catheter, requires selective pulmonary angiogram (10 cc contrast) § No batteries or leads § Indication:

• Wirelessly measuring and monitoring PA and HR
• In patients with functional class III heart failure with at least one

hospitalization in the past year

• Hemodynamic data are used with the goal of better HF

management and to reduce hospitalization

CardioMEMS: Improved survival among patients with HFrEF on GDMT

Givertz MM et al, J Am Coll Cardiol. 2017 Oct 10;70(15):1875-1886.

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CardioMEMS for HFpEF

Ejection Fraction Randomization Group

• No. of Heart

Failure Hospitalizations Annualized Rate

• f Hospitalization

for Heart Failure Incidence Rate Ratio (95% CI; P Value) ≥40% Treatment group (n=62) 29 0.43 0.50 (0.35–0.70; <0.0001) Control group (n=57) 59 0.86 ≥50% Treatment group (n=35) 13 0.41 0.30 (0.18–0.48; <0.0001) Control group (n=31) 31 1.39 <40% Treatment group (n=208) 153 0.67 0.74 (0.63–0.89; 0.0010) Control group (n=222) 220 0.90

Abraham WT et al, Lancet 2011

Conclusions

§ For patients with HFrEF, sacubitril/valsartan is associated with improvements in multiple clinical outcomes compared to ACE inhibitors § Spironolactone is associated with improved outcomes in appropriately selected patients with HFpEF § Do not miss cardiac amyloid in patients with HFpEF! § Consider SGLT2 inhibitors for patients with DM and HF (or atherosclerotic cardiovascular disease) § CardioMEMS remote hemodynamic monitoring reduces hospitalization in chronic HF regardless of EF

Thank you

van.selby@ucsf.edu