New Winners in the World of Heart Failure Laura Steffens PharmD Candidate 2016 CICU Presentation August 12, 2015
Jessup 2014 Shaking Things Up 2003: FDA approved eplerenone for the treatment of heart failure 2005: FDA approved hydralazine-isosorbide dinitrate No major changes in heart failure treatment in the past DECADE! 2 New Medications Entresto Sacubitril/Valsartan Corlanor Ivabradine
Drug 1 Entresto Sacubitril/Valsartan FDA Approved July 7, 2015
Bavishi 2015, Gu 2010 Mechanism of Action
Trial stopped at 27 months due to significant benefit seen with study drug McMurray 2013 McMurray 2014 Key Trial for Approval PARADIGM-HF Trial Design: Double-blind, active-comparator Population: >18 y/o with NYHA Class II, III, or IV HF and EF <40% Trial Group: Entresto 97/103 mg BID (n=4187) Comparator Group: Enalapril 10 mg BID (n=4212) Outcomes: Death from CV causes or hospitalization for HF Planned duration: 34 months
PARADIGM-HF Trial Results Entresto superior to Enalapril Outcome Entresto Enalapril P value Death from CV Cause 13.3% 16.5% <0.001 Hospitalization for HF 12.8% 15.6% <0.001 Combined 21.8% 26.5% <0.001 New Onset Afib 84 patients 83 patients 0.84 Most Common Adverse Effects Entresto: symptomatic hypotension Enalapril: cough, SCr >2.5 mg/dl, K >6.0 mmol/l McMurray 2014
Entresto Formulation: tablets Renal adjust: -safety and efficacy not estimated in CrCl <30 ml/min -Recommend 24/26 mg BID to start Hepatic Adjust: Not recommended in severe impairment Cost: ~$375 per month 24mg/26 mg 45 mg/51 mg Entresto Package Insert 97 mg/103 mg
Administration and Monitoring Adverse Effects: hypotension, dizziness, hyperkalemia, elevated SCr, cough, RARE: angioedema Administration: orally, with or without food Missed Doses: No recommendation. Consider patient s current state. Overdose: treat hypotension, monitor K and SCr -not removed well by hemodialysis due to high protein binding Entresto Package Insert
Entresto Package Insert Entresto Dosing Key Dosing Strategy Initial dosing is based off whether patient is on an ACE or an ARB prior to starting therapy Dosing titrated every 2-4 weeks to Entresto 97/103 mg BID Important Point Discontinue ACE inhibitors 36 hours prior to starting Entresto therapy due to risk of angioedema
Drug 2 Corlanor Ivabradine FDA Approved April 15, 2015
Mechanism of Action Ivabradine Package Insert Sulfi 2006
Current Review X Ivabradine
Comparison of Therapies SA Node I f channels Effects of Ivabradine Limited receptors Effects of Beta Blockers Many receptors Vision I h Channels
Key Trial for Approval SHIFT Trial Design: randomized, double-blind, placebo-controlled, parallel group Population: symptomatic HF with LVEF <35%, HR >70 bpm Trial Group: ivabradine titrated to 7.5 mg BID (n=3241) Comparator Group: placebo BID (n=3264) Outcomes: Composite for CV death or hospital admission for worseing HF Average duration: 22.9 months Swedberg 2010
SHIFT Trial Results Efficacy Outcome Corlanor Placebo P value Combined 24% 29% <0.001 Hospital Admission for HF 16% 21% <0.001 Afib 8.3% 6.6% --- Safety Most Common Adverse Effects Symptomatic and asymptomatic bradycardia Visual symptoms (3%) Headache Swedberg 2010 Tardif 2005
Corlanor Package Insert Fox 2008, Fox 2009 Corlanor Indication: reduction of hospitalization for worsening HF in patients with resting HR >70 BPM who are on maximum doses of β blockers or cannot tolerate β blockers Formulation: 5 mg, 7.5 mg tablets Renal adjust: No adjustment needed >15 ml/min Hepatic Adjust: Contraindicated in severe hepatic impairment Cost: ~$375 per month
Administration and Monitoring Adverse Effects: Bradycardia, conduction block, visual disturbances, headache, atrial fibrillation (D/C if arrhythmia occurs) Administration: orally with meals Missed Doses: No current recommendations Overdose: severe prolonged bradycardia; may need temporary pacer or beta stimulating agents; ~70% protein bound Corlanor Package Insert
Corlanor Dosing
QUIZ How many hours must you be off an ACE inhibitor, such as lisinopril, prior to initiating therapy with Entresto? 36 hours
QUIZ What are 2 major side effects to monitor for in patients taking Entresto? hypotension, dizziness, hyperkalemia, elevated SCr, cough, RARE: angioedema
QUIZ What are the 2 most common adverse effects of Corlanor? Bradycardia, visual disturbances, headache
References Bavishi C, Messerli FH, Kadosh B, et al. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J 2015. doi: 10.1093/eurheartj/ehv142. Entresto Package Insert. Accessed online 8/2/2015 via: http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807-816. Fox K, Ford I, Steg PG et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the BEAUTIFUL trial. Eur Heart J 2009;30:2337-2345. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNI). J Clin Pharmacol 2010;50:401-414. Jessup M. Neprilysin inhibition: a novel therapy for heart failure. N Eng J Med 2014;371:1062-1064. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062-1073. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:993-1004. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-885. Tardif J-C, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective I f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529-2536. Sulfi S, Timmis AD. Ivabradine-the first selective sinus node I f channel inhibitor in the treatment of stable angina. J Clin Pract 2006;60:222-228.
Image References Amgen Logo. https://www.google.com/search? q=amgen&es_sm=91&source=lnms&tbm=isch&sa=x&ved=0cakq_auoa2ovchmiu86c4oomxwivebqsch2y2qo3 &biw=1408&bih=676&dpr=0.9#imgrc=neczsd4pu-zbnm%3a Beta blocker effects. http://link.springer.com/article/10.1186%2f1742-4933-10-10 Corlanor Bottles. http://www.oneyao.net/article/2015/0418/35330.html Corlanor Mechanism of Action. http://www.corlanorhcp.com/mechanism-of-action.html Corlanor Molecular Structure. http://medlibrary.org/lib/images-rx/corlanor/corlanor-1.jpg Entresto Molecular Structures: https://en.wikipedia.org/wiki/valsartan/sacubitril Eyeball. http://www.4shared.com/photo/zkfoterj/ist2_9076587-blue-eyeball-with.html Phosphenes. https://tignz.wordpress.com/2013/04/07/what-are-the-colors-you-see-when-you-shut-your-eyes/ SA Node: https://quizlet.com/5020277/chapter-20-physiology-cardiac-conduction-system-flash-cards/ SA Node Conduction: http://www.cvphysiology.com/arrhythmias/a004.htm Ventricular Myocyte Action Potential. http://www.cvphysiology.com/arrhythmias/a006.htm
Patients receiving a total daily dose of >10 mg of enalapril Stop ACEi 36 hr before starting Entresto Start Entresto at 49/51 mg BID ACEi ARB Patients receiving a total daily dose of <10 mg of enalapril Patients receiving a total daily dose of >160 mg of valsartan Patient receiving a total daily dose of <160 mg of valsartan Stop ACEi 36 hr before starting Entresto Start Entresto at 24/26 mg BID Start Entresto at 49/51 mg BID Start Entresto at 24/26 mg BID Start Entresto at 24/26 mg BID Double dose after 2-4 weeks to 49/51 mg BID Double dose after 2-4 weeks to 49/51 mg BID Double dose after 2-4 weeks to 49/51 mg BID Double the dose of Entresto after 2-4 weeks, as tolerated to reach target maintenance dose of 97/103 mg BID Not on ACEi or ARB Not currently taking an ACEi or ARB Start Entresto at 24/26 mg BID Double dose after 2-4 weeks to 49/51 mg BID