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Game Changers in Heart FailureNovel Medical Therapies

James C. Fang, MD

University of Utah Health Sciences

Salt Lake City, UT

Overview

• Ivabradine

• Angiotensin Receptor Neprilysin Inhibitors (ARNis)– Sacubitril/Valsartan

• Sodium Glucose CoTransporter Inhibitors (SGLT2i)– Empagliflozin

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Impact of Medical Therapy in Heart Failure w/ Reduced Ejection Fraction

Therapy RR Red Mortality (%)

NNT (36 mo) RR Red Hosp (%)

ACEI or ARB 17 26 31

Beta Blocker 34 9 41

Aldo antagonist 30 6 35

Hydralazine/Isordil 43 7 33

Yancy C, et al. 2013 ACC AHA HF Guidelines

Heart Rate, Mortality, and HFrEF

Bohm M, et al. Lancet 2010

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Ivabradine Inhibition of hyperpolarization-activated cyclic nucleotide–gated (HCN) channels.

Psotka and Teerlink Circ 2016

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HF hosp

HF, MI hosp

SHIFT OutcomesDriven by reduction in HF hosp

Swedberg K, et al. Lancet 2010

Beta blockers Use in SHIFT

Swedberg K, et al. Lancet 2010

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SHIFT and Beta blocker TrialsApples and oranges?

Teerlink JR. Lancet 2010

Ivabradine2016 HF guidelines – Class IIa

• Ivabradine can be beneficial to reduce HF hosp for pts w/ NYHA II-III stable chronic HFrEF who are receiving GEM, including a BB at maximum tolerated dose, and who are in SR with a HR of 70 bpm or greater at rest.

Cost effective? Wholesale cost24,920 per QALY <$1.00 per pill

Kansal AR, et al. JAHA 2016

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Mechanism of Action of an ARNI

Vardney O et al. JACC‐HF 2014

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Run-In Trial Design

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Off Target Risks?

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Other Benefits

• 21% reduction in worsening HF death, 80% reduction in sudden death – Eur Heart J 2015;36:1990-1997

• Reduction HF hosp apparent in first 30d– Circulation 2015;131:54-61

• Absolute benefit across spectrum of patient risk– JACC 2015;66:2059-2071

Angiotensin Receptor Neprilysin Inhibitor2016 HF guidelines – Class I

• In pts w/ chronic HFrEF NYHA II or III who tolerate an ACEi or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.

• Inhibition of RAS w/ ACEi, or ARBs, or ARNI in conjunction with evidence-based BBs and AldoAnt in selected pts is recommended for pts w/ chronic HFrEF to reduce morbidity and morbidity.

• (…but not w/ ACEi, w/in 36h of ACEi or angioedema)

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Unanswered Questions

• New onset HFrEF

• Advanced HF

• Acute Decompensated HF

• Chronic Kidney Disease

• Post-MI

• HFpEF

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Cost Effective?

• Wholesale acquistion cost: $4560– Lisinopril: $32

– Enalapril: $480

– Valsartan: $628

• Cost per QALY = $50,915– Assuming 0.57 QALY gained

– Greater than $100K/QALY if effect <3y

• U.S. health system budget impact $3 billion/year– To avoid exceeding economic growth, estimated WAC

would be $4168

Olendorf DA, Sandhu AT, Pearson SD. JAMA Internal Medicine 2015

Cost Effective?California’s perspective

• California Technology Assessment Forum felt that sacubitril/valsartan had intermediate to high long-term care value.

• But felt at current price, value was low due to short term impact on budget => ‘preferred’ tier on fomularies.

• Recommended:– Restricting prescribing to cardiologists

– Younger patients for tolerability

– Patients with worsening disease

Olendorf DA, Sandhu AT, Pearcould D. JAMA Internal Medicine 2015

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Sodium Glucose Co-TransportersGlucosuria and Natriuresis

Bailey and Day Brit J Fam Med 2014

EMPA REG OUTCOME Trial

Zinman B, et al. NEJM 2015

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SGLT2 decreases HF in DMIIThe EMPA REG Trial

Fitchett D, et al. European Heart Journal 2015

SGLT2 inhibitor and Weight LossEMPA REG Renal

Barnett AH, et al. Lancet Diab Endo 2014

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Summary

• Ivabradine decreases HFH but doesn’t appear to impact mortality

• Sacubitril/valsartan represents significant advance to pharmacologic treatment of HF

• SGLT2 inhibitors may have a significant impact on the intersection of HF and DM