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

Disclosures Update on Heart Failure with Honoraria (consulting): Alnylam Pharmaceuticals, Akcea Therapeutics Reduced and Preserved Ejection Fraction Van N Selby, MD UCSF Advanced Heart Failure and Heart Transplant Program May 20, 2019 Objectives Medical Therapy for HFrEF: 2013 Understand the role of new therapies in the management of chronic § ACE Inhibitors (Class Ia) heart failure with both reduced (HFrEF) and preserved ejection o ARB as an alternative (Class Ia) fraction (HFpEF): § Beta-blockers (Class Ia) § Mineralocorticoid receptor antagonists (Class Ia) § Angiotensin-Neprilysin Inhibitors § Ivabradine § Hydralazine/Isosorbide for African-Americans (Class Ia) § SGLT2 inhibitors § Other: Diuretics, digoxin, etc § Remote hemodynamic monitoring § Mineralocorticoid receptor antagonists for HFpEF Yancy CW et al, Circulation 2013 1 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Sacubitril-valsartan: HF pathways PARADIGM-HF § 8442 patients with NYHA class II, III, or IV chronic heart failure o LVEF < 35-40% o SBP ≥ 95, GFR ≥ 30, K ≤ 5.4 o 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 Sauer AJ et al, Heart Failure Reviews. Mar 2019, 24(2); 167–176 McMurray JJV et al, N Engl J Med 2014 PARADIGM-HF: 2016 Heart Failure Guideline Update Primary endpoint: CV Death or Hospitalization Primary End Point 1.0 Hazard ratio, 0.80 (95% CI, 0.73–0.87) P<0.001 Cumulative Probability 0.6 0.5 0.4 Enalapril 0.3 LCZ696 0.2 0.1 0.0 0 180 360 540 720 900 1080 1260 Days since Randomization Yancy, CW et al. Circulation 2016 McMurray JJV et al, N Engl J Med 2014 2 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

PARADIGM-HF: Secondary analyses 2016 Guideline Update Compared to enalapril, sacubitril-valsartan is also associated with improvements in: o CV Death the rare complication of angioedema (30). III: ARNI should not be administered concomitantly with ACE inhibitors or o HF Hospitalization B-R Harm 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 o All-cause mortality o Coronary outcomes o Clinical progression of HF o Functional mitral regurgitation o Physical and social activities o Attenuation of diabetic nephropathy o Markers of myocardial fibrosis Yancy, CW et al. Circulation 2016 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 Sacubitril/Valsartan hospitalized patients § Can be used to replace ACEi or ARB in patients with chronic HFrEF or as initial therapy § 881 patients hospitalized for acute HF • 36 hour washout period for patients previously treated with • 52.1% were not previously treated with ACEi/ARB ACE-I § Randomized to enalapril vs sacubitril/valsartan • For patients hospitalized with acute heart failure, start Entresto § All patients were hemodynamically stable prior to randomization after at least 6 hours of hemodynamic stability, and no inotropes for at least 24 hours • No IV vasodilators or diuretics in the previous 6 hours § Starting dose is 49/51 mg BID • No inotropes in the previous 24 hours o Start with a reduced dose of 24/26 mg for those not previously § The primary outcome of reduction in NT-proBNP was significantly taking ACE/ARB, or those on a low dose greater in patients receiving sacubitril/valsartan § Double the dose every 2-4 weeks to a target dose of 97/103 mg § Rehospitalization for HF was lower in sacubitril/valsartan group § May need to reduce diuretic dose § No significant differences in hypotension or worsening renal function Velazquez EJ et al, NEJM 2018. 3 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

SHIFT: HF Death or Hospitalization Ivabradine: The SHIFT Trial 40 Placebo (937 events) Ivabradine (793 events) HR 0·82 (95% CI 0·75 – 0·90), p<0·0001 § Heart rate is an independent predictor of mortality in heart failure Patients with primary composite endpoint (%) Patients with first hospital admission § Ivabradine is an inhibitor of the I f current in the SA node 30 § The SHIFT trial enrolled 6558 patients: o Symptomatic HFrEF (LVEF ≤ 35%) 20 o HR ≥70 in sinus rhythm o At least one HF hospitalization in the past year o On background HF therapy including beta-blockers if tolerated 10 § Randomized to ivabradine (titrated to a max of 7.5 mg BID) vs placebo 0 0 6 12 18 24 30 Months Number at risk Swedberg K et al, Lancet 2010 Swedberg K et al, Lancet 2010 Sep 11;376(9744):875-85. 2016 Guideline Update Recommendation for Ivabradine COR LOE Recommendation Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HF r EF (LVEF ≤ 35%) who IIa B-R 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 I f current in Therapies for heart failure with preserved ejection § No patients enrolled from the US fraction (HFpEF) § Only 23% were on target dose beta-blocker o There was no significant improvement in the primary outcome among patients taking at least 50% target dose beta-blocker at randomization o With true target doses of beta-blockers, the heart rate will usually fall below 70 Yancy, CW et al. Circulation 2016 4 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Spironolactone for HFpEF: Background TOPCAT: Spironolactone for HFpEF § No medical therapy has been proven to improve outcomes for HFpEF § The TOPCAT trial randomized patients with HFpEF to spironolactone vs placebo § Mineralocorticoid receptor antagonists (MRA) improve § A negative trial overall: No significant difference in the primary outcomes in HFrEF and post-MI with LV dysfunction composite outcome of cardiovascular death, aborted cardiac arrest, or HF hospitalization § Small studies suggested MRAs may improve diastolic function as well § 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 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 HR 0.82 HR 0.74 § 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. Pfeffer MA et al, Circulation 2015 Jan 6;131(1):34-42. 5 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Cardiac amyloidosis in HFpEF 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure Cardiac amyloidosis, especially transthyretin (TTR), is now recognized as an overlooked cause of HFpEF • TTR identified in 13% of patients > 60 years hospitalized for HFpEF 1 • TTR found in 25% of patients > 85 years at autopsy 2 • TTR identified in approximately 1 in 7 patients undergoing TAVR 3 1 González-López E et al, Eur Heart J 2015; 36:2585-2594. 2 T anskanen M et al, Ann Md 2008; 40:232-239. 3 Castaño A et al, Eur Heart J, Volume 38, Issue 38, 7 Oct 2017, 2879–2887. Yancy, CW et al. Circulation 2017 When to suspect cardiac amyloidosis When to suspect cardiac amyloidosis § Echocardiography: § Echocardiography: • Thick LV with low ECG volts • Thick LV with low ECG volts • Thickened RV free wall, valves • Thickened RV free wall, valves § New hypertrophic cardiomyopathy § New hypertrophic cardiomyopathy with an alternative explanation with an alternative explanation § Intolerance of beta-blockers/ACEi § Intolerance of beta-blockers/ACEi § Low or normal BP in a previously hypertensive patient § Low or normal BP in a previously hypertensive patient § Bilateral carpal tunnel syndrome § Bilateral carpal tunnel syndrome § Peripheral or autonomic neuropathy, orthostatic hypotension § Peripheral or autonomic neuropathy, orthostatic hypotension § Family history (hATTR), African American > 60 years § Family history (hATTR), African American > 60 years 6 5/20/19 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]