Disclosures Advances in Chronic Heart Failure Management I have nothing to disclose Van N Selby, MD UCSF Advanced Heart Failure Program May 22, 2017 Goal statement To review recently-approved therapies and updates to practice guidelines for chronic heart failure Overview New pharmacologic therapies for heart failure with reduced ejection fraction (HFrEF) New pharmacologic options for heart failure with preserved ejection fraction (HFpEF) Remote hemodynamic monitoring for heart failure Anemia and iron deficiency as a therapeutic target in chronic heart failure 1
Medical Therapy for HFrEF: 2013 Guidelines Angiotensin-Neprilysin Inhibition ACE Inhibitors (Class Ia) o 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 Vardeny O et al, JACC Heart Failure 2014 PARADIGM-HF 8442 patients with class II, III, or IV chronic heart failure o EF < 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 A Primary End Point Cumulative Probability No. at Risk 0.6 0.4 0.3 0.2 0.1 0.6 0.4 0.3 0.2 0.1 0 180 360 540 900 720 1080 1260 4187 4212 3922 3883 C Hospitalization for Heart Failure Cumulative Probability No. at Risk Hazard ratio, 0.80 (95% CI, 0.73 0.87) P<01 Days since Randomization 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 0 180 360 540 900 720 1080 1260 4187 4212 3922 3883 Days since Randomization 3663 3579 Hazard ratio, 0.79 (95% CI, 0.71 0.89) P<01 3018 2922 2257 2123 1544 1488 896 853 249 236 B Death from Cardiovascular Causes Cumulative Probability No. at Risk Cumulative Probability 0.6 0.4 0.3 0.2 0.1 0.6 0.4 0.3 0.2 0.1 Hazard ratio, 0.80 (95% CI, 0.71 0.89) P<01 0 180 360 540 900 720 1080 1260 4187 4212 4056 4051 D Death from Any Cause No. at Risk Days since Randomization 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 Hazard ratio, 0.84 (95% CI, 0.76 0.93) P<01 0 180 360 540 900 720 1080 1260 4187 4212 4056 4051 Days since Randomization 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 McMurray JJV et al, N Engl J Med 2014 280 279 2
2016 Guideline Update the rare complication of angioedema (30). III: ARNI should not be administered concomitantly with ACE inhibitors or 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 Sacubitril/Valsartan (Entresto TM ) Starting dose is 49/51 mg BID o Start with a reduced dose of 24/26 mg for those not previously taking ACE/ARB, or those on a low dose 36 hour washout period Double the dose after 2-4 weeks to a target dose of 97/103 mg The rate of hypotension was slightly higher than with enalapril, but did not lead to higher rates of study drug discontinuation $4500/year Yancy, CW et al. Circulation 2016 Compared to enalapril, sacubitril/valsartan is: Associated with reduced risk of hyperkalemia when combined with al aldosterone antagonist 1 No more likely to cause severe hypotensive events 2 More cost-effective 3 Ivabradine Heart rate is an independent predictor of mortality in heart failure Ivabradine is an inhibitor of the I f current in the SA node The SHIFT trial randomized 6558 patients: o Symptomatic HF with LVEF 35% o HR 70 in sinus rhythm o HF hospitalization in the past year o On background HF therapy including BB if tolerated Ivabradine (titrated to a max of 7.5 mg BID) vs placebo 1 Desai AS et al, JAMA Cardiology 2016 2 Vardeny O et al, HFSA Scientific Sessions 2016 3 Gaziano TA et al, JAMA Cardiology 2016 Swedberg K et al, Lancet 2010 3
Ivabradine: SHIFT Trial 2016 Guideline Update A B Patients with primary composite endpoint (%) 40 30 20 10 Placebo (937 events) Ivabradine (793 events) HR 0 82 (95% CI 0 75 0 90), p<0 0001 Patients with first hospital admission for worsening heart failure (%) 30 20 10 Placebo (672 events) Ivabradine (514 events) HR 0 74 (95% CI 0 66 0 83), p<0 0001 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 I current in 0 0 6 12 18 24 30 Months Number at risk Placebo group 3264 2868 2489 2061 1089 439 Ivabradine group 3241 2928 2600 2173 1191 447 0 0 3264 3241 6 12 18 24 30 Months 2868 2489 2061 1089 439 2928 2600 2173 1191 447 C Swedberg K et al, Lancet 2010 Yancy, CW et al. Circulation 2016 SHIFT Trial: Considerations No patients enrolled from the US Only 23% were on target dose beta-blocker o Average systolic BP was 122 mmhg at enrollment o There was no significant improvement in the primary outcome among patients taking at least 50% target dose beta-blocker at randomization Spironolactone for HFpEF Approximately 50% of all patients with heart failure have preserved ejection fraction No medical therapy has been proven to improve outcomes for these patients Mineralocorticoid receptor antagonists (MRA) improve outcomes in HFrEF and post-mi with LV dysfunction Small studies suggested MRAs may improve diastolic function 4
TOPCAT: Spironolactone for HFpEF The TOPCAT trial randomized patients with HFpEF to spironolactone vs placebo No significant difference in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or HF hospitalization BUT, there were significant differences in the patient populations depending on country TOPCAT: Americas Sub-Analysis Patients enrolled from the Americas more likely to have elevated BNP Patients enrolled on the basis of elevated BNP or NT- ProBNP did show a reduction in the primary outcome HR 0.82 HR 0.74 Pitt B, NEJM 2014 Pfeffer MA et al, Circulation 2014 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure Remote Hemodynamic Monitoring for HF IPT A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America Yancy, CW et al. Circulation 2017 Adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009. 5
5/22/17 CardioMEMS 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 CHAMPION Risk reduction: 36% Risk reduction: 29% Abraham WT et al, Lancet 2011 6
CardioMEMS Inserted via venous catheter, requires selective pulmonary angiogram (10 cc) No batteries or leads FDA approved May 2014 Indication: o Wirelessly measuring and monitoring PA and HR o In patients with functional class III heart failure with at least one hospitalization in the past year o Hemodynamic data are used by physicians with the goal of better HF management and to reduce hospitalization Remote PA Pressure Monitoring: NNT Compared to Other HF Therapies Intervention Trial Mean Duration of Randomized Follow-Up Annualized Reduction in HF Hospitalization Rates NNT per year to Prevent 1 HF Hospitalization Beta-blocker COPERNICUS 10 months 33% 7 Aldosterone antagonist RALES 24 months 36% 7 CRT CARE-HF 29 months 52% 7 Beta-blocker MERIT-HF 12 months 29% 15 ACE inhibitor SOLVD 41 months 30% 15 Aldosterone antagonist EMPHASIS-HF 21 months 38% 16 Digoxin DIG 37 months 24% 17 Angiotensin receptor blocker Val-HeFT 23 months 23% 18 Abraham WT et al, Lancet 2011 Angiotensin receptor blocker PA pressure monitoring CHARM 40 months 27% 19 CHAMPION 17 months 33% 4 CHAMPION According to LVEF Follow-Up (17.6 Months) Ejection Fraction Randomization Group 40% Treatment group (n=62) Control group (n=57) 50% Treatment group (n=35) Control group (n=31) <40% Treatment group (n=208) Control group (n=222) CI indicates confidence interval. No. of Heart Failure Hospitalizations Annualized Rate of Hospitalization for Heart Failure Incidence Rate Ratio (95% CI; P Value) 29 0.43 0 (0.35 0.70; 59 0.86 <001) 13 0.41 0.30 (0.18 0.48; 31 1.39 <001) 153 0.67 0.74 (0.63 0.89; 220 0.90 010) Iron Deficiency: A therapeutic Target in HF Anemia is common in HF Treatment of mild to moderate anemia with Epo agents shows no clear benefit and is associated with increased risk of VTE in HF patients Up to 50% of patients with HF have also have iron deficiency o Defective absorption o Reduced availability of iron recycled in the reticuloendothelial system 7
Iron Deficiency in Heart Failure FAIR-HF Trial 459 patients with chronic HF and NYHA Class II or III symptoms LVEF 40% if class II or 45% if class III Hgb between 9.5 and 13.5 g/dl Iron deficiency: o Ferritin < 100 μg/l, or: o Ferritin 100-299 μg/l if transferrin % sat < 20% Randomized to ferric carboxymaltose vs placebo o 200 mg weekly until iron stores normal, then q 4 weeks Anker SD et al, NEJM 2009 van Veldhuisen, D. J. et al. Nat. Rev. Cardiol 2011 8.0 P<01 P<01 P<01 4.0 2.0 0 4 8 12 16 20 24 FCM 282 291 292 Placebo 146 149 149 50 P<01 P<01 P<01 40 FCM 30 20 Placebo 10 0 10 0 4 8 12 16 20 24 No. of patients 303 284 280 268 Mean 274±6 294±7 312±6 313±7 distance (m) No. of patients 155 144 141 134 Mean 269±9 269±10 272±10 277±10 distance (m) 21±6 37±7 35±8 P<01 P<01 P<01 8.0 4.0 2.0 0 4 8 12 16 20 24 FCM 304 287 294 294 Placebo 155 147 150 150 14 P<01 P<01 P<01 12 10 FCM 8 6 4 Placebo 2 0 2 0 4 8 12 16 20 24 No. of patients 295 274 283 285 Mean 54±1 60±1 62±1 63±1 score No. of patients 152 140 145 146 Mean 54±1 54±2 56±2 57±2 score 6±1 6±2 7±2 CONFIRM-HF Ponikowski P et al. Eur Heart J 2015 8
2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure IPT A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America AC Recommendations for Anemia COR LOE Recommendations Comment/Rationale IIb B-R In patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/ml or 100 to 300 ng/ml NEW: New evidence consistent with See Online Data Supplement D. if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL(173, 174). therapeutic benefit. Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other Targeting Iron Deficiency in Heart Failure No significant difference in adverse events among those receiving IV iron vs placebo o No allergic reactions with newer formulations The benefits are seen regardless of serum hemoglobin High dose oral iron has not shown the same benefit in clinical trials FAIR-HF 2, a larger trial of IV iron in HF, is underway Yancy, CW et al. Circulation 2017 Lewis GD et al, JAMA 2017 Advanced Heart Failure: Know the Signs NYHA Class IIIB/IV symptoms Worsening renal function Systolic BP < 90 mmhg Multiple hospitalizations Inability to tolerate ACE inhibitors or beta-blockers o Need to stop or decrease LV ejection fraction < 25% High diuretic dose (> 100 mg/day of furosemide) Left Ventricular Assist Device Therapy 9
Adult Heart Transplant: Survival by Era All pair-wise comparisons were significant at p < 5. Median survival (years): 1982-1991=8.5; 1992-2001=10.4; 2002-2008=11.9; 2009-6/2014=NA J Heart and Lung Trans 2016 Conclusions New therapies continue to improve outcomes for patients with HFrEF o Sacubitril/valsartan improves HFrEF outcomes compared to ACEi o Ivabradine may be useful in selected HFrEF patients Consider aldosterone antagonists for appropriately selected patients with HFpEF Remote hemodynamic monitoring reduces heart failure rehospitalizations in patients at risk Patients with chronic HF should be screened for iron deficiency and those who meet criteria should be treated with IV iron Prompt referral to a HF center for those with signs of advanced disease Thank you van.selby@ucsf.edu 10