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Strategies to Optimize Heart Failure Treatment: New Insights and Challenges Harleen Singh, Pharm.D.,BCPS-AQ Cardiology, BCACP Clinical Associate Professor OSU/OHSU College of Pharmacy Objectives Examine evidence-based guidelines for the


  1. Strategies to Optimize Heart Failure Treatment: New Insights and Challenges Harleen Singh, Pharm.D.,BCPS-AQ Cardiology, BCACP Clinical Associate Professor OSU/OHSU College of Pharmacy

  2. Objectives • Examine evidence-based guidelines for the management of heart failure with reduced ejection fraction, including the role of newer agents • Recognize the challenges associated with up-titration of HF medications • Design individualized therapy to optimize treatment • Describe the key self-care interventions in the management of HF

  3. Disclosures Presenter of this CE have nothing to disclose

  4. GDTM in the Outpatient Setting J Am Coll Cardiol 2018;72:351–66 )

  5. GDTM in HFrEF J Am Coll Cardiol 2018;72:351–66 )

  6. Classification of Heart Failure Classification EF (%) Description Heart failure with ≤40 • Systolic HF reduced ejection fraction • Randomized clinical trials have mainly enrolled (HF r EF) patients with HF r EF, and it is only in these patients that efficacious therapies have been demonstrated to date Heart failure with ≥50 • Diastolic HF preserved ejection Diagnosis of HF p EF is challenging because it is • fraction (HF p EF) largely one of excluding other potential noncardiac causes of symptoms suggestive of HF • To date, efficacious therapies have not been identified HF p EF, borderline 41 - 49 • These patients’ characteristics, treatment patterns, and outcomes appear similar to those with HF p EF HF p EF, improved >40 • Patients with improved or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF • Further research is needed to better characterize these patients

  7. 10 Principles for Successful Treatment of HF Yancy et al. JACC VOL. 71,NO.2,2018

  8. Key: HFrEF Stage C Treatment Class I recommendation Class II recommendation ACEI/ARB AND Beta blocker with diuretic as needed For patients with resting HR ≥ 70, For patients with For persistently For patients For patients with eGFR ≥ 30 on maximally symptomatic stable on persistent volume tolerated beta mL/min/1.72 m2, African ACEI/ARB, overload, K+ <5.0 mEq/dL blocker dose in Americans, NYHA class II-III NYHA class II-IV NYHA class II-IV sinus rhythm, NYHA class III-IV NYHA class II-III Titrate Add Switch Add Add Hydralazine Aldosterone Ivabradine ARNI Diuretics + Isosorbide Antagonist dinitrate Yancy et al. JACC VOL. 71:2 ,2018

  9. Diuretics Loops: • Furosemide • Torsemide ~5% • Bumetanide Thiazides: • Hydrochlorothizide • Chlorthalidone • Chlorthiazide ~25% • Metolazone Aldosterone Antagonists: • Spironolactone • Eplerenone Other K-Sparing: • Amiloride • Triamterene Nat Rev Cardiol. 2015;12(3):184-92.

  10. Diuretics: Place in Therapy HFrEF Stage C Treatment ACEI/ARBs and beta blockers with diuretic as needed For patients with persistent volume overload, NYHA class II-IV Titrate Diuretics Yancy et al. JACC VOL. 71:2 ,2018

  11. Pharmacologic Properties of Loops Property Furosemide Torsemide Bumetanide Relative potency 1x 2x 40x Bioavailability (%) 10 - 100 80 - 100 80 - 100 Oral/IV dosing 2:1 1:1 1:1 Time to onset (min) 60 60 30 - 60 Oral peak serum concentration (h) 1 1 1 -2 Absorption affected by food Yes No Yes Average half-life (h) 2 3.5 1 - 1.5 Duration of effect (h) 6-8 6- 16 4 -6 Decreased kaliuresis No Yes No Am Heart J 2015;169:323-33

  12. Diuretics: Initiation and Titration Diuretics Select initial loop diuretic dose based on: • Diuretic naïve • Renal function • Titrate doses to response over days to weeks • May reduce diuretic doses in the setting of titrating ACEI, ARBs, or ARNI • Monitor: blood pressure, electrolytes, and renal function both after initiation and titration Patients who have received doses of furosemide equivalent to 120 mg twice daily consider: • Changing to a different loop diuretic • Adding a thiazide-like diuretic • Monitor blood pressure, electrolytes, and renal function both after initiation and titration Yancy et al. JACC VOL. 71:2 ,2018

  13. Dose-Response Relationship Ceiling Dose Normal Decreased max response “Steep” part of Heart Failure dose-response curve Elevated diuretic threshold (resistance) Patients with heart failure require a higher serum diuretic concentration to elicit the same diuretic response (diuretic resistance) and have diminished responses to ceiling doses of loop diuretics. J Card Fail. 2014;20(8):611-22

  14. Mechanisms of loop diuretic resistance Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.215

  15. Metolazone • Metolazone is most commonly prescribed for combination therapy in the U.S. • Retains efficacy in advanced renal failure • However, other thiazides at equipotent doses are likely to have the same synergistic effects Pharmacokinetics Metolazone Hydrochlorothiazide Bioavailability 90 - 95% 65 - 75% Onset of action ~60 min 2 hours Elimination half-life 6- 20 hours 6- 15 hours Duration of action >24 hours 6- 12 hours J Am Coll Cardiol. 2010;56(19):1527-34

  16. Timing of CDT Doses • Pre-dosing of oral metolazone 30-60 min prior to furosemide is common practice – Increased regimen complexity – Inconvenient • No published clinical studies compared pre-dosing to simultaneous dosing • Onset of metolazone is unlikely to be clinically significant with chronic treatment once steady-state is achieved • TD (with longer duration of action) maintains diuresis after short acting LD has worn out J Am Coll Cardiol. 2010;56(19):1527-34

  17. HFrEF: The Building Blocks of Therapy Ivabradine TX Digoxin VAD CRT H-ISDN ICD ARNI Beta blocker MRA ACEI/ARB

  18. Magnitude of Benefits Demonstrated in RCTs NNT for Mortality RR Reduction in RR Reduction in Reduction GDMT HF Mortality (Standardized to Hospitalizations 36 months) ACEI or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone 30% 6 35% antagonist Hydralazine/nitrate 43% 7 33% ARNI 20% 21* 21% *Standardized to 27 months, active comparator (enalapril) vs placebo JACC 2013;62:e147-239

  19. HFrEF – ACEI ACEI Doses Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials Captopril Capoten 6.25mg TID 50mg TID 122.7 mg/day Enalapril Vasotec 2.5mg BID 20mg BID 16.6 mg/day Fosinopril Monopril 5 - 10mg daily 80mg daily N/A Lisinopril Zestril/ 2.5-5mg daily 20mg daily *4.5 mg/day (low dose ATLAS) Prinivil 33.2 mg/day (high dose ATLAS) Quinapril Accupril 5mg BID 80mg daily N/A Ramipril Altace 1.25 - 2.5mg daily 10mg daily N/A Trandolapril Mavik 1mg daily 4mg daily N/A *No difference between mortality between high and low dose groups, but 12% lower risk of death or hospitalization in high dose group vs. low dose group. JACC 2013;62:e147-239

  20. HFrEF – ARB ARB Doses Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials Candesartan Atacand 4 -8 mg daily 32 mg daily 24 mg/day Losartan* Cozaar 12.5 - 25 mg daily 150 mg daily 129 mg/day Valsartan Diovan 40 mg BID 160 mg BID 254 mg/day *Not FDA approved for HF JACC 2013;62:e147-239

  21. ACEI/ARB: Initiation and Titration Barriers to titration ACEI/ARB • Worsening renal function • Hyperkalemia • Bilateral renal artery stenosis • Symptomatic Hypotension Select an initial dose of • Overdiuresis ACEI/ARB • Other medications Monitoring Consider increasing dose every 2 weeks • SCr and K assessed within 1-2 weeks of initiation or dose increase Monitor BP, renal function and potassium Yancy et al. JACC VOL. 71:2 ,2018

  22. What we know about RAASi dose response? Follow- Age, Male, Trial Drug Groups N up, years % months ATLAS 1 Lisinopril LD = 2.5-5.0 mg 1,596/ 64 79 46 daily 1,568 HD = 32.5-35 mg daily HEAAL 2 Losartan LD = 50 mg daily, 1,919/ 66 71 56 HD = 150 mg 1,927 daily 1. Packer M, et al. Circulation 1999;100:2312-2318 2. Konstam MA, et al. Lancet 2009;374:1840-1848

  23. Circulation. 1999;100:2312-2318

  24. Lancet 2009; 374: 1840–48

  25. ACEI/ARB with Renal Impairment Generally considered safe when: • SCr <3.0 mg/dL • Renal impairment (eGFR 30-60 mL/min/1.73m 2 ) Should we stop ACEI/ARB in CKD stage 4 and 5?

  26. Hyperkalemia: Is It Real? Pseudohyperkalemia • Delayed processing – Central vs. local labs – Traumatic draw • Presence/absence of hyperglycemia

  27. Target Serum Potassium Ranges in HF 7 • Heart Failure Hyperkalemia – 4.0-5.0 mEq/L 1,2 6 – 4.5-5.5 mEq/L 3 Serum Potassium (mEq/L) • Expert opinion 5 • Hyperkalemia Normal – 5.0 vs. 5.5 vs. 6.0 mEq/L 4 3 Hypokalemia 2 1. Circulation. 2004,110(5):588-636. 2. Arch Intern Med. 2000;160(16):2429-2436. 3. J Am Coll Cardiol. 2004;43(2):155-161.

  28. Mortality by Prior RAAS Inhibitor Dose 35 30.1 30 27.7 25 22.4 Percent of Patients 20.3 20 13.7 15 13.1 11.0 10.1 9.8 10 8.2 5.0 4.1 5 0 CKD Stage 3-4 Heart Failure Diabetes Total n = 43,288 n = 20,529 n = 79,087 n = 201,655 Maximum Dose Sub-Maximum Dose Discontinued Am J Manag Care. 2015;21:S212-S220.

  29. Clinical Dilemma Continue RAAS Inhibitor Discontinue RAAS Inhibitor Accept Hyperkalemia Sacrifice Mortality Benefit

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