PROGRESS AT LAST?: REVIEWING RECENTLY UPDATED ACCF/AHA HEART FAILURE GUIDELINES

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1 PROGRESS AT LAST?: REVIEWING RECENTLY UPDATED ACCF/AHA HEART FAILURE GUIDELINES Jon Linder, Pharm.D. PGY1 Pharmacy Resident Iowa City VA Health Care System Objectives for Pharmacists Summarize the burden of heart failure on hospitals and healthcare costs Explain the pathophysiology of heart failure using the neurohormonal model Recommend sacubitril/ and ivabradine appropriately for patients in the context of other guidelinedirected medication therapy and patient characteristics Outline how to appropriately switch from an ACE-inhibitor or ARB to sacubitril/ Counsel patients on the potential side effects of ivabradine and sacubitril/ Objectives for Technicians Distinguish between the four ACCF/AHA Stages of Heart Failure Identify drugs recommended in the 2013 ACCF/AHA guidelines for Stage C Heart Failure with Reduced Ejection Fraction (HFrEF) Summarize how ivabradine affects heart rate Explain how to appropriately transition from an ACEinhibitor or ARB to sacubitril/ Epidemiology of Heart Failure (HF) United States: Lifetime risk for HF is 2 ~5.7 million Americans have HF Prognosis: ~5 mortality rate at 5 years post-diagnosis Roughly 1 in 9 deaths list HF as contributing factor Incidence = around 650,000 new cases/year Incidence increases with age ~20/1000 people years old >80/1000 people >85 years old Loehr et al. Am J Cardiol Mozzafarian et al. Circulation Heart Failure Hospital Burden Primary diagnosis in over 1 million hospitalizations each year in the United States Those hospitalized with HF symptoms are at high risk for re-hospitalization 25% of patients are readmitted to the hospital within 1 month of HF hospitalization Total cost of HF care is >$30 billion annually 5 consists of hospital costs Mean cost of one HF hospitalization was $23,077 in 2013 Go, et al. Ciculation Circ Cardiovasc Qual Outcomes Description of Heart Failure Structural or functional damage Impairs ventricular filling or ejection of blood from heart Typical symptoms include dyspnea, fatigue, and edema Heart failure with reduced ejection fraction (HFrEF): Patients with an ejection fraction (EF) 4 Most drug trials only enroll patients with HFrEF Heart failure with preserved ejection fraction (HFpEF): Generally, EF of at least 5 Subcategories: Borderline: EF = 41-49% Improved: Previously had HFrEF, but now has EF above ACCF/AHA HF guidelines. Circulation. 1

2 Classifications of Heart Failure ACCF/AHA Stages of Heart Failure A B C D High risk for HF, but no structural heart disease or symptoms Structural heart disease but no signs or symptoms of HF NYHA Functional Classification N/A I No symptoms of HF, even with moderate physical activity Structural heart disease, with symptoms of HF currently or in the past II Slight limitation; Symptoms of HF with moderate physical activity Refractory HF III IV Marked limitation; Symptoms of HF w/ mild physical activity Symptoms with any physical activity, or at rest Adapted from: 2013 ACCF/AHA HF guidelines. Circulation. Causes of Structural Change Tissue death Coronary artery disease (myocardial infarction) Certain chemotherapy (anthracyclines, trastuzumab) Tachycardia Atrial fibrillation Pressure overload Hypertension Aortic stenosis Goldberg. Ann Intern Med ACCF/AHA HF guidelines. Circulation. Pathophysiology of Heart Failure Neurohormonal Model (Theoretical) Bio-active molecules have toxic effects on heart/circulatory system, which worsens heart failure Toxicity from bio-active molecules leads to more left ventricle dysfunction and hemodynamic instability Release of bio-active molecules to promote hemodynamic stability Neurohormones (Bio-active molecules) Angiotensin II Aldosterone Norepinephrine Endothelin Neprilysin (Natriuretic peptides) Current drugs and their targets: Sympathetic nervous system (Beta-blockers) Renin-Angiotensin-Aldosterone System or RAAS (ACE-inhibitors/ARBs and aldosterone antagonists) Natriuretic peptides (neprilysin inhibitors) Mann. Circulation Mann. Circulation ACCF/AHA Practice Guideline 2013 ACCF/AHA Guideline for the Management of Heart Failure Comprehensive guidelines published October 15, 2013 in Circulation Jointly produced by the American College of Cardiology Foundation and the American Heart Association since 1980 Recommendations based on committee s perpetual literature review Cost is a factor, but secondary to efficacy and outcomes Application of Recommendations Size of Treatment Effect: Class I Class IIa Class IIb Class III Benefit clearly outweighs risk; Treatment SHOULD be prescribed Level of Evidence: Benefit outweighs risk, more focused studies needed REASONABLE to prescribe Benefit Risk MAY CONSIDER prescribing Level A Level B Level C Based on multiple randomized clinical trials or meta-analysis Based on single randomized trial or several non-randomized studies No benefit and/or possible harm DO NOT prescribe Based on consensus expert opinion, case studies, or standard of care Adapted from 2013 ACCF/AHA HF guidelines. Circulation. 2

3 HFrEF Stage C Treatment: Review of 2013 Treatment Recommendations (Stage C HFrEF) Volume overloaded, NYHA class II-IV patients ACE-inhibitor or ARB AND a Beta-Blocker* Persistently symptomatic African-American patients, NYHA Class III-IV All NYHA class II-IV patients, (CrCl >30mL/min and K+ <5mEq/dL) Loop Diuretic Class I, LOE C *Carvedilol, bisoprolol, and metoprolol succinate are the only 3 approved for HF Hydralazine- Nitrates Aldosterone Antagonist Adapted from 2013 ACCF/AHA HF guidelines. Circulation. Other Medications Digoxin no mortality benefit; option for patients optimized on guideline based therapy to reduce hospitalizations (Class IIa; LOE B) Which of the following medications have not been shown to reduce mortality in heart failure? Anticoagulation not recommended for heart failure in the absence of other indication (Class III; LOE B) Statins no benefit for heart failure alone (Class III; LOE A) Avoid antiarrythmics, NSAIDs, thiazolidinediones, and calcium channel blockers (Class III; LOE B) A. Carvedilol B. Propranolol C. Digoxin D. Furosemide 2013 ACCF/AHA HF guidelines. Circulation Focused Update on New Pharmacotherapy (Stage C HFrEF) (Corlanor ) 3

4 Basics of the Sinoatrial (SA) Node Natural pacemaker Other heart cells are stable during diastole; SA node cells intrinsically depolarize during diastole until reaching the threshold for another action potential Depolarization likely due to the I f current Very slow onset and offset Activated by hyperpolarization Mechanism of Action Inhibits hyperpolarization-activated cyclic nucleotide gated channels (f-channels) Disrupts the I f current (funny current) Increases length of diastole (slowing heart rate), without lowering firing threshold for an action potential Only binds to channel during depolarization phase Permeable to sodium and potassium Nawarskas. Cardiology in Review Nawarskas. Cardiology in Review and Outcomes in Chronic Heart Failure Karl Swedberg, et al. Lancet 2010; 376: ,558 patients w/ symptomatic heart failure and EF 35%, in sinus rhythm, with heart rate 70bpm Randomized, double-blind, placebo-controlled, parallel-group Composite Endpoint: CV Mortality or HF Hospitalization 3 2 HR 0.82 p< NNT=24 24% 29% Intervention Primary endpoint 1 ivabradine titrated to max 7.5mg twice daily vs placebo composite of CV death or heart failure hospitalization Swedberg. Lancet Swedberg. Lancet

5 3 2 1 HF Hospitalization HR 0.74 p< NNT=22 16% 21% CV Mortality HR 0.91 p=0.128 NNT=84 14% 15% Adverse Effect (%) (%) p value All serious adverse effects Symptomatic bradycardia 5 1 < Asymptomatic bradycardia 6 1 < Atrial fibrillation Phosphenes 3 1 < Swedberg. Lancet Swedberg. Lancet Pharmacodynamics Heart rate reduction with ivabradine is use-dependent Effects more pronounced at higher heart rates Heart rate reduction limited to 18-2 of baseline Using recommended doses between 2.5 to 7.5mg twice daily Average reduction of 10 bpm at rest and during activity No significant effects on contractility Berdeaux. Drugs European Medicines Agency Pharmacokinetics Absorption 4 bioavailable (first pass elimination) Exposure 20-4 greater when taken with food Metabolism CYP3A4 extensively metabolized to equipotent active metabolite (metabolite also metabolized by CYP3A4) Avoid concomitant use with potent CYP3A4 inducers/inhibitors Elimination 4% unchanged renally Effective half life = 6 hours Corlanor product information Contraindications Acute decompensated heart failure Strong CYP3A4 inhibitors Patients dependent on pacemaker Heart rate <60 bpm before treatment Severe hepatic impairment (Child Pugh Class C) Profound hypotension (<90/50mmHg) Sick sinus syndrome, sinoatrial block, third-degree atrioventricular block Corlanor product information Counseling and Monitoring Typical dose is 5mg twice daily; Always take with food Side effects: bradycardia, atrial fibrillation, visual changes Avoid driving until patient has adjusted to ivabradine Avoid during pregnancy At 2 weeks, adjust based on heart rate Resting rate >60bpm: by 2.5mg twice daily (MAX 7.5mg twice daily) Resting rate <50bpm: by 2.5mg twice daily Patients >75 years old: start at 2.5mg twice daily Corlanor product information

6 Patient Case 80 yo white M returning to clinic for HF follow up; no new complaints The provider consults you, the pharmacist, and you deduce the patient is inquiring about ivabradine Over the holidays, a friend told him about a new HF pill to lower heart rate (pretty sure it was called Eleanor ) PMH: CAD, HFrEF (NYHA Class II), HTN, GERD, h/o CABG (last echocardiogram was 3 months ago; EF = 33%) Vitals: BP 134/88mmHg, P 86, 88kg PE: chronic SOB (unchanged today), trace edema in legs Meds: omeprazole 20mg daily, furosemide 20mg daily, atorvastatin 40mg daily, losartan 50mg daily, spironolactone 25mg daily, aspirin 81mg daily, carvedilol 3.125mg twice daily (started 1 month ago) What is the most appropriate response? A. Your heart rate is still elevated, so this might be a good time for you to start taking ivabradine. This is a great drug that can help you live longer and frankly everyone should be taking it. B. One of your current drugs is made to lower your heart rate, and we have room to keep increasing the dose. It actually has more benefits than ivabradine and is going to be much more affordable. C. Your heart rate today looks great! We probably don t need to change anything today. Sacubitril and (Entresto ) Natriuretic Peptide System Three peptides: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) ANP, BNP, and CNP activate cgmp as a second messenger Each have cardiorenal protective properties ANP and BNP are not adequately activated in heart failure and hypertension Neprilysin breaks down ANP, BNP, and CNP Mangiafico. Eur Heart J Cardiomyocyte Extracellular Endothelial Cell cgmp-mediated Effects ANP BNP CNP Natriuresis Antihypertrophic Guanylyl cyclase A PDE phosphodiesterase PKG protein kinase G cgmp cyclic guanosine monophosphate cgmp Intracellular Guanylyl cyclase B PDE PKG Adapted from Fig 2, Mangiafico. Eur Heart J Inhibition of renin and aldosterone Anti-apoptosis Lipolysis Vascular regeneration Anti-fibrotic effects Vasodilation Mangiafico. Eur Heart J

7 Angiotensin-Neprilysin Inhibition Versus in Heart Failure 8442 patients w/ class II-IV HF and EF 4; BNP >150pg/mL; stable dose of a beta-blocker and an ACE/ARB; GFR >30mL/min; no history of angioedema or severe hypotension Randomized, double-blind, active comparator, parallel-group McMurray, et al. New England Journal of Medicine Sept 2014; 371: Intervention sacubitril/ 97/103mg BID vs enalapril 10mg BID Primary endpoint CV death or first HF hospitalization Study Design Run-in Run-in Study Switched from current ACE/ARB to single-blind dose of enalapril 10mg twice daily for 2 weeks Switched from enalapril to sacubitril/ for 4-6 weeks Target doses: Sacubitril/ 97/103mg twice daily vs enalapril 10mg twice daily Composite Endpoint: CV Mortality or 1 st HF Hospitalization HR 0.80 p<0.001 NNT= 22 22% Sacubitril/ Sacubitril/ 27% st HF Hospitalization HR 0.79 p<0.001 NNT=36 13% 16% CV Mortality HR 0.80 p<0.001 NNT = 32 13% 17% Adverse Effect Sacubitril/ (%) (%) p value Symptomatic hypotension <0.001 Serum creatinine >2.5mg/dL Serum potassium >6mmol/L Sacubitril/ Sacubitril/ Sacubitril/ Sacubitril/ Cough <0.001 Angioedema

8 Sacubitril Pharmacodynamics Prodrug: active metabolite is a Neprilysin inhibitor Inhibits the breakdown of vasoactive peptides by neprilysin Blocks breakdown of ANP, BNP, and CNP (cardioprotective) Blocks breakdown of endothelin-1 and angiotensin I (increased RAAS activity and net vasoconstriction) Blocks breakdown of bradykinin (increases angioedema risk) Sacubitril/ Pharmacodynamics Valsartan (angiotensin receptor blocker) added to block the inherent increase in RAAS activity caused by sacubitril ARBs cause less increase of bradykinin than ACE inhibitors, less risk of angioedema in combination w/ sacubitril Sacubitril retains the added benefit of blocking the breakdown of cardio-protective ANP, BNP, and CNP Mangiafico. Eur Heart J Mangiafico. Eur Heart J Sacubitril/ Pharmacokinetics Absorption Valsartan component more bioavailable than other formulations (thus lower dose in the combination pill) Metabolism Sacubitril converted to active metabolite via plasma esterase Valsartan minimal metabolism Elimination Valsartan 13% renal, 86% fecal; half life= 9.9 hours Sacubitril metabolite 6 renal, 4 fecal; effective half life= 11.5h Entresto product information Dosing Starting dose is sacubitril 24mg/ 26mg twice daily for those without prior ACE or ARB (or low doses of either) Starting dose for those with prior ACE or ARB is sacubitril 49mg/ 51mg twice daily Target dose is sacubitril 97mg/ 103mg twice daily, doubling the dose every 2-4 weeks as tolerated CrCl <30mL/min or moderate hepatic impairment = start at lowest dose twice daily Entresto product information Counseling and Monitoring If switching from an ACE inhibitor: Must allow 36-hour washout period before starting sacubitril/ Black Box Warning: avoid in pregnancy (ARB) Side effects: hypotension 18%, hyperkalemia 12%, renal failure 5%, angioedema 0.5% Monitor serum creatinine and potassium after several weeks, periodically thereafter Entresto product information Cost Effectiveness Studies Several analyses conducted based on PARADIGM-HF All found similar results $45,000 to $51,000 per Quality Adjusted Life Year (QALY) Driven by increased average survival Based on wholesale acquisition price of $4,560/year for sacubitril/ Potential for 3000 fewer hospitalizations and deaths per 100,000 patients receiving sacubitril/ over 2 years Reduced HF admissions amount to >$27 million saved Treatment most cost effective in NYHA Class II patients Gaziano. JAMA Cardiol Sandhu. Ann Intern Med

9 Formulary Status HFrEF Stage C Treatment: Typically Tier 3 Preferred Brand Name Drug Most private insurers, including Medicare Part D plans Coinsurance ranges from 30-5 ACE-inhibitor or ARB fdsdfasdf AND a Beta-Blocker Transition from ACE/ARB to Sacubitril/ Class I, LOE B Copays ranging from $ per month Prior Authorization Volume overloaded, NYHA class II-IV patients Persistently symptomatic African-American patients, NYHA Class III-IV All NYHA class II-IV patients, (CrCl >30mL/min and K+ <5mEq/dL) 18 or older, on max tolerated beta-blocker, with no angioedema history Stabilized on ACE/ARB for four weeks prior to starting Prescribed by cardiologist Quantity Limits (60 tablets/month) Entresto Drug Policy. Wellmark Medicare Plan Finder. Medicare.gov. Wellmark BlueRX Complete Formulary Loop Diuretic Class I, LOE C Hydralazine- Nitrates Aldosterone Antagonist Adapted from 2013 ACCF/AHA HF guidelines. Circulation. Case Continued Despite not recommending the use of ivabradine, you encourage the provider to switch from losartan to sacubitril/. You meet with the patient to provide counseling. What counseling points are important to discuss? (select all appropriate answers) A. Take this drug twice daily B. Dose will be titrated every 5 to 7 days C. The most common side effect is low blood pressure D. Stop the losartan and wait 2 days before starting sacubitril/ Updates: Quick Reference Class LOE Recommendation IIa B: RCT can reduce risk of HF hospitalization. Must have heart rate above 70 beats per minute despite maximum-tolerated beta-blocker I B: RCT NYHA Class II or III: patients tolerating ACE inhibitor or ARB should be switched to sacubitril/ to further reduce morbidity and mortality III B: RCT Sacubitril/ should not be used within 36 hours of last dose of an ACE inhibitor III C: Expert Opinion Sacubitril/ should not be started in patients with history of angioedema Summary >$30 billion spent on HF yearly (5 for hospitalizations) RAAS, sympathetic nervous system, and neprilysin all cause HF progression works only at the sinoatrial node to prolong diastole and thus slow heart rate = only if heart rate >70 and on max tolerated beta-blocker Sacubitril adds to mortality benefit by blocking neprilysin s breakdown of cardio-protective natriuretic peptides Guidelines recommend switching ACE/ARB patients to sacubitril/ if no angioedema history (must wait 36 hours to start) Both drugs dosed twice daily and titrated to max tolerated dose LOE = Level of Evidence RCT = Randomized Controlled Trial Focused Updates. Circulation