What Next? Impact of Medical Therapy in Heart Failure w/ Reduced - - PDF document

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Management of Heart Failure with Reduced Ejection Fraction

What Does the Evidence Show Us?

James C. Fang, MD University of Utah Health Sciences Salt Lake City, UT

65 yr WM presents for followup of HFrEF.

– NYHA II-III, HFH 6 mo ago. Prior CABG, DM and HTN. LVEF 30%. – Meds: lisinopril 10 mg, carvedilol 12.5 mg bid, spironolactone 25 mg, furosemide 40 mg, metformin 500 mg, aspirin, atorvastatin 40 mg. – BP 122/75, HR 73, BMI 28, NAD, no JVD, HS normal, sternal scar, lungs clear, no edema. – EKG SR anterior Qs, NT-proBNP 1500, Cr 1.2, Hgb A1c 8.2%.

What Next?

• A. No changes
• B. Ivabradine
• C. Sacubitril/valsartan
• D. Empagliflozin

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

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What Next?

• A. No changes
• B. Ivabradine
• C. Sacubitril/valsartan
• D. Empagliflozin

Heart Rate, Mortality, and HFrEF

BEAUTIFUL Trial

Fox K, et al. Lancet 2008 HR

HR for CV Death Ivabradine Inhibition of hyperpolarization-activated cyclic nucleotide– gated (HCN) channels.

Psotka and Teerlink Circ 2016

• NYHA II – IV
• Admitted to hospital within 12 months
• LVEF <35%
• Normal sinus rhythm
• Heart rates >70 bpm

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HF hosp HF, MI hosp

SHIFT Outcomes

Driven by reduction in HF hosp

Swedberg K, et al. Lancet 2010

Beta Blockers Use in SHIFT

Swedberg K, et al. Lancet 2010

Ivabradine Placebo

SHIFT and Beta blocker Trials

Apples and oranges?

Teerlink JR. Lancet 2010

Ivabradine

2016 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 cost 24,920 per QALY <$1.00 per pill

Kansal AR, et al. JAHA 2016

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What Next?

• A. No changes
• B. Ivabradine
• C. Sacubitril/valsartan
• D. Empagliflozin

Angiotensin Receptor – Neprilysin Inhibitor

Vardney O et al. JACC-HF 2014

• NYHA II – IV
• BNP >150 pg/ml (>100 if 12m HFH)
• NT-proBNP >600 pg/ml (>400 if 12m HFH)
• LVEF <35%
• ACEi or ARB
• BP >100 mmHg
• eGFR >30 cc/min/1.73m2

Run-In Trial Design

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Off Target Risks?

Other ARNI Benefits

• 21% in worsening HF death, 80% in SCD

– 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

• Benefit consistent regardless of background Rx

– CircHF 2016;9:e003212

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Angiotensin Receptor Neprilysin Inhibitor

2016 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)

Unanswered Questions

• New onset HFrEF
• Advanced HF
• Acute Decompensated HF
• Chronic Kidney Disease
• Post-MI
• HFpEF

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

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California’s Perspective

• California Technology Assessment Forum

concluded that sacubitril/valsartan had intermediate to high long-term care value.

• But felt at current price, value was low due to the

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

What Next?

• A. No changes
• B. Ivabradine
• C. Sacubitril/valsartan
• D. Empagliflozin

Drugs for Type II Diabetes Mellitus

• Sulfonylureas (glipizide, glyburide)
• Biguanides (metformin)
• Meglitinides (‘-glinides’)
• Thiazolidinediones (‘-glitazones’)
• DPP-4 inhibitors (‘-gliptins’)
• SGLT2 inhibitors (‘-gliflozin’)
• Alpha-glucosidase inhibitors (acarbose)

Sodium Glucose Co-Transporters

Glucosuria and Natriuresis

Bailey and Day Brit J Fam Med 2014 Empagliflozin

X

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• Type II DM
• HgbA1c 7.0 – 10.0%
• Established CVD
• eGFR >30 cc/min/m2
• BMI <40 kg/m2
• Age

63

• HgbA1c

8.0%

• CAD

76%

• HF

10%

• eGFR

74 cc/min/m2

• Metformin 74%

EMPA REG OUTCOME Trial

Zinman B, et al. NEJM 2015

SGLT2 decreases HF in DMII

The EMPA REG Trial

Fitchett D, et al. European Heart Journal 2015

SGLT2 inhibitor and Weight Loss

EMPA 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

• f HF and DM

Heart Rate, Mortality, and HFrEF

Bohm M, et al. Lancet 2010

Omecamtiv Mecarbil

Selective Cardiac Myosin Activator

Malik FI, et al. Science 2011

Mechanochemical Cycle of Myosin

Force produc1on OM increases the rate of myosin into a slightly-bound, force-producing state with actin (“More hands pulling on the rope”)

Increases duration of systole Increases stroke volume No increase in myocyte calcium No change in dP/dtmax No increase in MVO2

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Vasodilation

Relaxin Receptor LGR7

• NO, cGMP effectors
• Induction of NOS II/III
• Upregulation of endothelial endothelin type B

receptor, which mediate vasodilation

• Preferential dilation of pre-

constricted vessels

• Natriuretic
• Anti-inflammatory
• Down-modulation
• f

inflammatory cytokines linked to outcome in HF (TNF-α, TGF-β)

• Anti-ischemic
• Anti-apoptotic
• Anti-fibrotic

Relaxin

Mechanisms of Action

Teichman SL, et al. HF Rev 2009; Dschietzig T, et al. Pharm Therap 2006

Cost Effective?

Gaziano TA, et al. JAMA 2016