Solving the Revolving Door Managing Heart Failure at Transitions of Care and Beyond Brent N

Solving the Revolving Door Managing Heart Failure at Transitions of Care and Beyond Brent N. Reed, PharmD, BCCP Associate Professor University of Maryland School of Pharmacy ATRIUM Cardiology Collaborative

@brentnreed or @ATRIUMRx Disclosures

I have no relevant personal or financial relationships to disclose. Learning Objectives

1. Design a strategy for relieving ADHF symptoms and managing GDMT being taken prior to admission. 2. Given a patient failing to meet decongestion goals, determine etiologies of diuretic resistance and design a modified strategy. 3. Given a patient preparing for discharge, design a strategy for reducing risk of readmission, including initiation/titration of GDMT. 4. Given a patient with chronic heart failure and a history of hospitalization, list strategies for optimizing GDMT.

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy Transitions: Scope of the Problem

• Medication-related • 1 in 4 patients is problems contribute readmitted within 30 to a significant days and nearly half number of ADHF are readmitted within admissions 6 months • Up to two-thirds are • Pharmacists can to preventable reduce readmissions by 1/3 to nearly 1/2

ADHF acute decompensated heart failure. Ann Pharmacother. 2002 Sep;36(9):1331–6. Circulation. 2017 Mar 7;135(10):e146–603. Arch Intern Med. 2008 Apr 14;168(7):687–94. CB is a 62 year-old white woman with nonischemic cardiomyopathy (EF 25%), diabetes mellitus, and osteoarthritis who presents to the emergency department with fatigue, shortness of breath, and abdominal discomfort of several weeks’ duration. She reports her heart failure always seems to get worse after her arthritis acts up. Her breathing effort is labored and she has bilateral crackles over two-thirds the height of the lung fields. Other findings include 2+ lower extremity edema and 10-kg weight gain. She is warm and well-perfused. Medications Listed in EMR: Vitals: BP 118/78 mmHg, HR 71 bpm • Atorvastatin 40 mg daily • Lisinopril 10 mg daily 134 98 28 182 • Metoprolol succinate 100 mg daily 4.5 26 1.4 • Spironolactone 25 mg once daily • Furosemide 40 mg twice daily Hemoglobin A1c: 8.5% • Metformin 1000 mg twice daily NT-proBNP 12,800 pg/mL • Insulin glargine 25 units subq at night Chest x-ray: cardiomegaly, bilateral interstitial/alveolar edema; no effusions EF ejection fraction, EMR electronic medical record, NT- proBNP N-terminal pro-B-type natriuretic peptide Questions

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy Questions

1. What factor(s) may have precipitated her ADHF?

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy CB is a 62 year-old white woman with nonischemic cardiomyopathy (EF 25%), diabetes mellitus, and osteoarthritis who presents to the emergency department with fatigue, shortness of breath, and abdominal discomfort of several weeks’ duration. She reports her heart failure always seems to get worse after her arthritis acts up. Her breathing effort is labored and she has bilateral crackles over two-thirds the height of the lung fields. Other findings include 2+ lower extremity edema and 10-kg weight gain. She is warm and well-perfused. Medications Listed in EMR: Vitals: BP 118/78 mmHg, HR 71 bpm • Atorvastatin 40 mg daily • Lisinopril 10 mg daily 134 98 28 182 • Metoprolol succinate 100 mg daily 4.5 26 1.4 • Spironolactone 25 mg once daily • Furosemide 40 mg twice daily Hemoglobin A1c: 8.5% • Metformin 1000 mg twice daily NT-proBNP 12,800 pg/mL • Insulin glargine 25 units subq at night Chest x-ray: cardiomegaly, bilateral interstitial/alveolar edema; no effusions EF ejection fraction, EMR electronic medical record, NT- proBNP N-terminal pro-B-type natriuretic peptide Endocrinologist

Diabetes Pulmonologist Medication reconciliation

COPD can identify drug-related causes of ADHF • Most patients with heart failure have > 5 comorbidities and take > 6 Psychiatrist Depression chronic medications1 • Use of nonprescription medications 2 Chronic may be as high as 93% kidney disease • Nonadherence remains a major Nephrologist contributor to decompensation Anemia

COPD chronic obstructive pulmonary disease. (1) Am J Med. 2011 Feb;124(2):136–43. (2) J Hematologist Card Fail. 2009 Sep;15(7):600–6. Left adaptedfrom: Diuretic Response Impaired Diuretic Response Diuretic Concentration Cardiology Heart FailureHeart Normal . . 2001;96(3 maximal response required foreffect Higher doses Diminished – 4):132 – 43. Right adaptedfrom: 43. Am J Am Med Diuretic Concentration . . Jun19981;104(6):533 delayed absorption Lower peak due to Heart FailureHeart Normal – 8. Time Questions

1. What factor(s) may have precipitated her ADHF? 2. How should her congestive symptoms be managed? (Provide recommendations regarding drug, dose, and frequency).

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy Acute Diuretic Response Effects of Furosemide Over Time1 Door-to-Furosemide Time2 20 12.5 > 1 hour associated with 3-fold increase Preload in mortality (6.0 vs. 2.3%, p=0.002) 15

mmHg 10.0 10 7.5

150 5.0 100

Urine Output mL 50 Mortality of Probability 2.5 0 0 5 10 15 30 60 0 0 200 400 600 Time (minutes) Time (minutes)

(1) N Engl J Med. 1973 May 24;288(21):1087–90. (2) J Am Coll Cardiol. 2017 Jun 27;69(25):3042–51. DOSE Trial

308 patients with ADHF randomized

48 hours High vs. Low-Dose Bolus vs. Infusion (1x home dose vs. 2.5x home dose) (q12 hour bolus vs. continuous infusion)

Adjust at 48 hours per clinician discretion

24 hours Change to oral therapy Continue regimen Intensify regimen

Assess safety/efficacy outcomes at 72 hour

ADHF acute decompensated heart failure, IV intravenous, WRF worsening renal function N Engl J Med. 2011 Mar 3;364(9):797–805. DOSE In Detail

High Dose Low Dose • Greater net fluid loss • Less transient worsening of • Greater weight loss renal function • More symptomatic relief

• Low-dose less likely to be transitioned to oral diuretics and more likely to require a dose increase at 48 hours1 • Transient worsening of renal function in ADHF no worse than no change2

ADHF acute decompensated heart failure (1) N Engl J Med. 2011 Mar 3;364(9):797–805. (2) J Card Fail. 2010 Jul;16(7):541–7. DOSE In Detail

Intravenous Bolus Continuous Infusion

• Continuous infusion arm did not receive an initial bolus • Bolus arm twice as likely to receive a dose increase and/or thiazide-type diuretic1 • Prior trials have shown greater fluid and weight loss with continuous infusions2 • Did not include patients with diuretic resistance

(1) N Engl J Med. 2011 Mar 3;364(9):797–805. (2) J Card Fail. 2010 Mar;16(3):188–93. BONUS Question

Would your recommendations for the management of congestion change if this patient had HFpEF rather than HFrEF? Why or why not?

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy What About HFpEF? (ROPA-DOP1)

Outcome at 72 hours Intermittent Bolus Continuous Infusion p (n=43) (n=47) Percent increase in SCr (%) 4.6% (-1.2 to 10.4) 16.0% (8.6% to 23.5%) 0.02 Worsening renal function 5 (11.6%) 17 (36.2%) 0.01 Urine output (L) 10.3 (9.2 to 11.4) 10.7 (9.3 to 12.2) 0.13 Weight loss (kg) -3.3 (-4.4 to -2.2) -4.2 (-6.4 to -2.0) 0.46

No information provided on initial doses, dose changes, or other volume management strategies (all left to clinician discretion)2

SCr serum creatinine (1) JACC Heart Fail 2018;6(10):859-870. (2) JACC Heart Fail 2018;6(12):1049-1050. Questions

1. What factor(s) may have precipitated her ADHF? 2. How should her congestive symptoms be managed? (Provide recommendations regarding drug, dose, and frequency). 3. What should be done with her other GDMT? • Lisinopril 10 mg daily • Metoprolol succinate 100 mg daily • Spironolactone 25 mg once daily

ADHF acute decompensated heart failure, GDMT guideline-directed medical therapy RAAS Inhibitors

ACE inhibitor RAAS Activation • Increased vasoconstriction • Increased volume retention • Increased hypertrophy • Increased fibrosis

Holding ACE inhibitor may increase length of stay (5.5 vs. 3.0 days, p=0.009)?

ACE angiotensin-converting enzyme, RAAS renin-angiotensin-aldosterone system Cardiology. 2017;137(2):121–5. Beta Blockers • In OPTIMIZE-HF, beta blocker Beta Blocker 25 Treatment Groups continuation was associated with (p < 0.001) lower risk of death (HR 0.60, 95% CI 20 1 Withdrawn 0.37-0.99, p=0.044) • 15 Not treated Confirmed in B-CONVINCED, which Continued showed no worsening of ADHF with Newly started 2

10 continuation during hospitalization Mortality rate (%) rate Mortality 5

0 0 15 30 45 60 75 90 Days Since Discharge (1) J Am Coll Cardiol 2008; 52:190–9. (2) Eur Heart J 2009; 30: 2186-92. Considerations for Discontinuing GDMT

Drug or Drug Class Scenarios in Which Discontinuation May Be Considered ACE inhibitors, ARBs, or Worsening SCr due to recent initiation or titration, symptomatic ARNI hypotension, severe hyperkalemia (> 5.5 mEq/L) Beta blockers ADHF due to recent initiation or titration, worsening low output or cardiogenic shock, symptomatic hypotension or bradycardia Aldosterone antagonists Worsening SCr, severe hyperkalemia (> 5.5 mEq/L) Nitrates/hydralazine Symptomatic hypotension Ivabradine Contraindicated in ADHF per labeling Digoxin Symptomatic bradycardia, life-threatening arrhythmias, elevated serum concentration (>> 1.0 ng/mL), signs/symptoms of toxicity

ADHF acute decompensated heart failure, ACE angiotensin-converting enzyme, ARB angiotensin II receptor blocker, ARNI angiotensin receptor neprilysin inhibitor, GDMT guideline-directed medical therapy, SCr serum creatinine, CB experiences some minor improvements in congestive symptoms but she fails to meet goal diuresis for two consecutive days (goal 2-3 L net negative per day, but less than 2 L negative total for the past 48 hours). She reports ongoing dyspnea when laying flat as well as abdominal discomfort, which is only partially relieved by antiemetics.

Medication changes from admission: Vitals: BP 112/72 mmHg, HR 74 bpm • Beta blocker held (over weekend, before you could intervene) 130 94 24 118 • Furosemide 120 mg IV BID 3.8 28 1.4 • Insulin aspart sliding scale ACHS • Metformin being held Admission Values (For Reference) BP 118/78, HR 71 bpm 134 98 28 182 4.5 26 1.4

ACHS prior to meals and at bedtime, BID twice daily Questions

5. What mechanisms might explain diuretic resistance? Common Mechanisms of Diuretic Resistance Distal convoluted tubule Glomerulus Remodeling of the nephron Compensatory Decreased gut Proximal convoluted sodium reabsorption absorption and/or tubule renal perfusion Collecting duct Loop of Henle Arginine Neurohormonal vasopressin activation

Renin-angiotensin- aldosterone system Questions

5. What mechanisms might explain diuretic resistance? 6. What should be done to augment diuresis at this time? Provide recommendations regarding drug, dose, and frequency for at least two pharmacologic options. What Works? Cardiology Diuretic Response Augmenting Diuretics: Increasing Dose . . 2001;96(3 be achievedto be a response elicit Diuretic threshold Diuretic Concentration – 4):132 – 43. N EnglJ Med : concentrationthat must . . Mar 20113;364(9):797 additional responseadditional not elicit doses an do Higher Ceiling dose: – 805. 805. Heart FailureHeart Normal • • per DOSE trial per DOSE Safeefficacious and increasingfrequency Optimizebeforedose Transition to Continuous Infusion

Bolus doses at initiation and with dose increases Continuous Trials other than DOSE: infusion • Increased total and net UOP Diuretic threshold • No differences in ADRs

• Shorter length of stay? Diuretic Concentration Diuretic

Time

J Card Fail. 2010 Jul;16(7):541–7. Continuous Infusions

Advantages Disadvantages • Can achieve higher total daily • May encourage “set it and forget doses than boluses it” mentality • Avoids off-diuretic periods • Overnight urination (fall risk, • May be advantageous in specific decreased sleep quality) populations (e.g., preload- • Drug mismanagement (omitting dependent conditions, delayed boluses, “titrate” orders) transcapillary refill) Add a Thiazide-Type Diuretic

Agent Metolazone Chlorothiazide Hydrochlorothiazide Oral bioavailability 40-65% N/A 65-75% Usual dose 2.5–5 mg qday 500–1000 mg qday to 25–50 mg qday to bid (max/day) (20 mg) bid (2000 mg) (100 mg) Onset (peak) 2–3 h (6-8 h) 2 h (3–6 h) 2 h (3–6 h) Duration of action 12–24 h 6–12 h 6–12 h Add a Thiazide-Type Diuretic

3500 Metolazone vs. Chlorothiazide1 1-3 3000 Summary of Studies in ADHF (p=0.026 for non-inferiority) 2500 • HCTZ < chlorothiazide 2000 • Chlorothiazide ≈ metolazone 1500 1000 2275 2030 500 Chlorothiazide Net Urine Output (mL) OutputUrine Net 877 0 711 Metolazone Pre-thiazide Post-thiazide

ADHF acute decompensated heart failure, CTZ chlorothiazide, HCTZ hydrochlorothiazide, MTZ metolazone (1) Pharmacotherapy. 2016 Aug;36(8):852–60. (2) Pharmacotherapy. 2014 Aug;34(8):882–7. (3) Cardiovasc Ther. 2015 Apr;33(2):42–9. What Maybe Works? Strategies to consider in select patients. Theoretical Benefits of Adding Vasodilators

Venous Arterial Vasodilation Vasodilation • Increased venous • Improved renal capacitance blood flow due to • Decongests kidneys reduced arterial impedance Nitroglycerin* Nitroprusside Nitroprusside

Associated with improvements in some but not all congestive symptoms and cardiac filling pressures, but…

*At high-doses (> 100 mcg/min), nitroglycerin exerts venous and arterial dilating effects. JAMA. 2002 Mar 27;287(12):1531–40. Actual Benefits of Adding Vasodilators?*

ASCEND (Nesiritide)1 TRUE-AHF (Ularitide)2 Dyspnea at 6 hours Persistent Heart Failure 70 (p = NS) (p = 0.63) 60 150 50 Ularitide 40 120 30 At least moderately Placebo 20 better 10 90 0 Minimally better 10 60

Patients (%) Patients No change Hospital Events Hospital

20 -

30 Worse In 30 40 50 60 0 Placebo Nesiritide 6 24 48 72 120 (n=3444) (n=3416) Time (hours) *Assessed congestive symptoms, not urine output.

(1) N Engl J Med. 2011 Jul 7;365(1):32–43. (2) N Engl J Med. 2017 18;376(20):1956–64. Heterogeneity in Recent Vasodilator Trials

Patients with Trial Year Agent Patients Mean EF HFpEF ASCEND-HF1 2011 Nesiritide 7147 NR 19.9% RELAX-AHF2 2012 Serelaxin 1161 38.7% 45.0% Dopamine / ROSE-AHF3 2013 360 31.6% 24.4% nesiritide TRUE-AHF4 2017 Ularitide 2157 NR 34.8% Reasonable to consider in HFrEF with refractory congestion (despite optimizing diuretics) and normal to elevated blood pressures.

EF ejection fraction, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, NR not reported (1) N Engl J Med. 2011 Jul 7;365(1):32–43. (2) Lancet. 2013 Jan 5;381(9860):29–39. (3) JAMA . 2013 Nov 18; (4) N Engl J Med. 2017 18;376(20):1956–64. Adding Tolvaptan

TACTICS-HF (Tolvaptan)1 • Improved weight and fluid loss but not Dyspnea Improvement at 24 h symptoms 25% (p=0.32) • Increased risk of transient WRF 20% • 48 hours of therapy: $1200 15% • Alternative cost-effective options for hyponatremia exist (furosemide plus Patients (%) Patients 10% 20% hypertonic saline)2-4 16% 5%

Placebo Tolvaptan

(1) J Am Coll Cardiol. 2017 Mar 21;69(11):1399–406. (2) Eur J Heart Fail. 2000 Sep;2(3):305–13. (3) Am Heart J. 2003 Mar;145(3):459–66. (4) Int J Cardiol. 2013 Jul 15;167(1):34–40. Adding or Substituting Ultrafiltration

UNLOAD1 CARRESS-HF1 Weight Loss and Dyspnea Scores 6 Changes in Serum Creatinine 5 0.3 4 5.0 vs. 3.1 kg Primary : change at 96 hours 3 (p=0.001) 0.2 -0.04 vs. +0.23 (p=0.003) 2 0.1 1

Weight Loss Loss (kg) Weight 0

0 )

dL -0.1 7 6.4 vs. 6.1 (mg/ -0.2 Pharmacologic 6 (p=0.35) 5 -0.3 Ultrafiltration 4 3 (Also reduced rehospitalizations at 90 -0.4 (More serious adverse events in 2 days, p = 0.022) Baseline from Mean Change -0.5 ultrafiltration group, p = 0.03) Dyspnea Score Dyspnea 1 Ultrafiltration Standard care 24 h 48 h 72 h 96 h 7 d 30 d 60 d Time Why the discrepancy?

(1) J Am Coll Cardiol 2007;49(6):675-683. (2) N Engl J Med 2012;367(24):2296-2304. Hypothesis 1) Constant ultrafiltration rate likely disrupted CARRESS-HF Design renal counter-regulation

Ultrafiltration 200 mL/h for 96 hours or Patients with ADHF and renal Home Dose Furosemide Starting Dose impairment < 80 mg 40 mg IVB, then 5 mg/h randomized 81-160 mg 80 mg IVB, then 10 mg/h + MTZ 5 mg 161-240 mg 80 mg IVB, then 20 mg/h + MTZ 5 mg BID > 240 mg 80 mg IVB, then 30 mg/h + MTZ 5 mg BID Hypothesis 2) Stepped therapy group likely If patient fails to meet urine output goals: unmasked patients with low 1. At 24 hours, advance diuretics output by 48 hours 2. At 48 hours, Step 1 and consider vasodilators/inotropes ADHF acute decompensated heart failure, IVB 3. At 72-96 hours, Step 1-2 and consider hemodynamic guided- intravenous bolus, MCS mechanical circulatory support, MTZ metolazone therapy ± MCS JAMA. 2013 Dec 18;310(23):2533-43. If you’re thinking about therapies in the “What Maybe Works” category, it’s probably time to investigate further for low output if you haven’t already. What Doesn’t Work Don’t do these things. Switching IV Furosemide to IV Bumetanide

Dose Usual Bolus Usual Infusion Agent Onset Peak Duration Equivalence Doses (max) Doses (max) 40-160 mg qday 5-20 mg/h Furosemide 5 min 2 h 4-6 h 20-40 mg to tid (40 mg/h) (200 mg/dose) 0.5-4 mg 0.5-2 mg/h Bumetanide 2-3 min 1-2 h 4-6 h 1 mg qday to tid (4 mg/h) (5 mg/dose) • No differences in efficacy when used at equivalent doses • Higher risk of ototoxicity with furosemide, higher risk of musculoskeletal toxicity with bumetanide High-Dose Spironolactone (ATHENA-HF)

• Patients with ADHF receiving spironolactone 12.5-25 mg randomized to continuation vs. increasing dose to 100 mg • No differences in congestive endpoints (NT-proBNP or dyspnea scores), urine output, or weight change

ADHF acute decompensated heart failure, NT-proBNP n-terminal pro-brain natriuretic peptide JAMA Cardiol. 2017 Sep 1;2(9):950–8. Low-Dose Dopamine (ROSE)1

Dopamin Outcome Placebo p e Cumulative urine output 8296 8524 0.59 Change in cystatin C 0.11 0.12 0.72 Patient-reported symptoms (AUC) 4704 4553 0.43 Drug discontinued due to tachycardia 0.9% 7.2% < 0.001 Corroborating results from DAD-II and ROPA-DOP suggest that low-dose dopamine (2-3 mcg/kg/min) does not have renoprotective effects.2-3

(1) JAMA. 2013 Dec 18;310(23):2533-43. (2) Int J Cardiol 2014;172(1):15-121. (3) JACC Heart Fail 2018;6(10):859-870. After a week of aggressive decongestion therapies, CB’s symptoms have significantly improved. She has been successfully weaned from non-diuretic therapies and is approaching her baseline weight. The team plans to send her home in the next several days and is preparing a discharge plan. Numerous changes have been made to her medication regimen during the hospitalization.

Current medications: Vitals: BP 114/80 mmHg, HR 78 bpm • Aspirin 81 mg daily • Atorvastatin 40 mg daily 138 96 24 108 • Isosorbide dinitrate 20 mg TID 4.3 24 1.3 • Hydralazine 50 mg TID • Spironolactone 25 mg once daily • Furosemide 80 mg IV once daily • Insulin glargine 40 units subq at night • Insulin aspart sliding scale ACHS Questions

7. What changes to this patient’s medication regimen should be considered as she approaches discharge? 8. What non-pharmacologic strategies might also reduce her risk of readmission? Questions

7. What changes to this patient’s medication regimen should be considered as she approaches discharge? After a week of aggressive decongestion therapies, CB’s symptoms have significantly improved. She has been successfully weaned from non-diuretic therapies and is approaching her baseline weight. The team plans to send her home in the next several days and is preparing a discharge plan. Numerous changes have been made to her medication regimen during the hospitalization.

Outcome < 24 hour > 24 hour p (adjusted) (n=61) (n=62) 30-day heart failure readmission 11 (18%) 2 (3.2%) <0.001 60-day heart failure readmission 18 (29.5%) 6 (9.7%) <0.001 90-day heart failure readmission 23 (37.7%) 12 (19.4%) <0.001 Any heart failure readmission 34 (55.7%) 23 (37.1%) <0.001

Patients were being discharged from cardiology services, questioning the “patients we know well” concept.

J Card Fail. 2017 Oct;23(10):746-752. Ambulatory IV Diuretic Clinic Example Protocol in Patients with Worsening Congestion (n=60) Maintenance IV Infusion Optional (Inadequate Category IV Bolus (mg) Diuretic (mg/day) (mg/hr x 3hr) UOP at 90 mins) Low dose < 40 20 20 - Equivalent of Medium dose 41-160 20 - maintenance dose High dose 161-300 200 20 Extra 200 mg dose Extra 200 mg dose plus Mega dose > 301 200 20 thiazide-type diuretic • Median UOP 1.1 (0.6-1.4) L; only 8.9% transient WRF, 3.5% hypokalemia • Hospitalization “imminent” for 52.8%, but only 31.7% had to be hospitalized

IV intravenous, WRF worsening renal function, UOP urine output JACC Heart Fail. 2016 Jan;4(1):1-8. Isosorbide dinitrate/hydralazine

• Continue combination therapy? • Switch back to lisinopril 10 mg once daily? • Initiate sacubitril/valsartan? PARADIGM-HF: ARNI in Chronic HF

Inclusions Exclusions • NYHA Class II-IV symptoms • Symptomatic hypotension • Ejection fraction < 35% • Blood pressure < 100/95 mmHg • NT-proBNP > 600 pg/mL or > 400 if • GFR < 30 mL/min hospitalized in the last 12 months • Serum potassium > 5.4 mEq/L • Enalapril equivalent > 10 mg/day • Unacceptable side effects

NYHA New York Heart Association, GFR glomerular filtration rate, NT-proBNP n-terminal pro-brain natriuretic peptide. N Engl J Med. 2014 Sep 11;371(11):993–1004. PARADIGM-HF Results

Primary Composite Endpoint Death from Cardiovascular Causes Alone

1.0 1.0 NNT = 22 NNT = 32 0.6 0.6 0.5 0.5 Sacubitril/valsartan Sacubitril/valsartan 0.4 0.4 Enalapril Enalapril 0.3 0.3 0.2 0.2

0.1 p < 0.001 0.1 Cumulative Probability Cumulative Cumulative Probability Cumulative p < 0.001 0.0 0.0 0 180 360 540 720 900 1080 1260 0 180 360 540 720 900 1080 1260 Days Since Randomization Days Since Randomization Safety of sacubitril/valsartan vs. enalapril: higher rates of hypotension but lower rates of acute kidney injury and hyperkalemia Adapted from N Engl J Med. 2014 Sep 11;371(11):993-1004. PIONEER-HF: ARNI in ADHF

Inclusions Notable Exclusions • HFrEF (EF < 40%) with ADHF • Angioedema with ACEi/ARB • BNP > 400 or NT-proBNP > 1600 pg/mL • Estimated GFR < 30 mL/min/1.73 m2 • Signs/symptoms of volume overload • Potassium > 5.2 mEq/L • SBP > 100 mmHg for 6 hours • No escalation of diuretics or use of vasodilators in prior 6 hours, or inotropes in prior 24 hours

SBP 100–119 mmHg: sacubitril/valsartan 24/26 mg or enalapril 2.5 mg twice daily SBP > 120 mmHg: sacubitril/valsartan 49/51 mg or enalapril 5 mg twice daily

ACE angiotensin-converting enzyme, ARB angiotensin II receptor blocker, ADHF acute decompensated heart failure, BNP b-type natriuretic peptide, HFrEF heart failure with reduced ejection fraction, GFR glomerular filtration rate, NT-proBNP n-terminal pro-BNP, SBP systolic blood pressure. N Engl J Med. 2018 Nov 11. PIONEER-HF Results Sacubitril/valsartan Enalapril

10 NT-proBNP (Primary Endpoint) 5.2 Potassium

0 5.0 /L)

-10 4.8

mEq proBNP

- p < 0.001 -20 4.6 4.4 -30 4.2 -40 Serum Mean

4.0 Potassium ( Potassium From Baseline (%) Baseline From -50

Change in NT in Change 3.8 -60 3.6 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Weeks since Randomization Weeks since Randomization

2.0 Serum Creatinine 145.0 Systolic Blood Pressure 1.8 135.0 1.6 p = 0.0047 1.4 125.0 1.2 115.0

Mean Serum Serum Mean 1.0 Creatinine (mg/dL) Creatinine Pressure (mmHg) Pressure 105.0

0.8 Blood Systolic Mean 0.6 95.0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Weeks since Randomization Weeks since Randomization

N Engl J Med. 2018 Nov 11. Aspirin for Primary Prevention

ASCEND Trial1 ARRIVE Trial2 ASPREE Trial3 (15,480 patients with diabetes) (12,546 patients at low to (19,114 patients who were moderate cardiovascular risk) aged 70 years or older)

1.1% 0.9% 0.2% 0.5% 0.6 2.4 reduction in increase in reduction in Fewer vascular increase in more bleeding cardiovascular major bleeding cardiovascular events per gastrointestinal events per events events events 1000 PY (p = 0.01) (p = 0.003) (p = 0.60) bleeding (p = NS) 1000 PY (p = 0.0007) (p < 0.001)

(1) N Engl J Med. 2018 Oct 18;379(16):1529-1539. (2) Lancet. 2018 Sep 22;392(10152):1036-1046. (3) N Engl J Med. 2018 Oct 18;379(16):1509-1518. Other Medication Adjustments

• How to resume beta blocker? • What about diabetes medications? Beta Blocker Initiation

Beta Blocker (Trial) Initial Dose Titration Scheme Target Dose Increase by 1.25 mg every Bisoprolol 1.25 mg once daily week until 5 mg, then 2.5 10 mg once daily (CIBIS II1) mg every 4 weeks Carvedilol 25 mg twice daily (COPERNICUS2, US Carvedilol 3.125-6.25 mg twice daily* Double every 2 weeks Trial3) (50 mg if > 85 kg)

Metoprolol succinate 12.5-25 mg once daily* Double every 2 weeks 200 mg once daily (MERIT-HF4) Pre-discharge initiation as late as 12 hours prior to departure shown to be safe.5

*Lower starting doses used in patients with New York Heart Association III to IV heart failure (1) Lancet. 1999 Jan 2;353(9146):9-13 (2) N Engl J Med. 2001 May 31;344(22):1651-8. (3) N Engl J Med. 1996 May 23;334(21):1349-55. (4) Lancet. 1999 Jun 12;353(9169):2001-7. (5) J Am Coll Cardiol. 2004 May 5;43(9):1534-41. SGLT2 Inhibitors in Heart Failure EMPA-REG OUTCOME Hospitalization for Heart Failure • Empagliflozin also associated 7 with reduction in cardiovascular 6 Hazard ratio 0.65 (95% CI 0.50-0.85) death (3.7% vs. 5.9%, p<0.001) 5 p=0.002 • Patients may require reduction 4 Placebo in diuretic dose 3 2

1 Empagliflozin Patients with Event (%) Event with Patients 0 0 6 12 18 24 30 36 42 48 Months SGLT2 sodium-glucose cotransporter-2. N Engl J Med 2015;373:2117-28. Questions

7. What changes to this patient’s medication regimen should be considered as she approaches discharge? 8. What non-pharmacologic strategies might also reduce her risk of readmission? Pharmacist Education

• Pharmacist-provided patient education associated with > 40% reduction in readmissions across several trials1,2 • Largest trial (PILL-CVD) did not impact readmissions but compared individualized to standardized education3 • A single session at discharge unlikely to Rx reduce readmissions significantly

(1) Farm Hosp Organo Of Expresion Cient. 2006 Dec;30(6):328–42. (2) Am J Health-Syst Pharm. 1999 Jul 1;56(13):1339–42. (3) Ann Intern Med. 2012 Jul 3;157(1):1–10. Improving Medication Adherence

• Medication adherence remains a major contributor to readmissions • Pharmacists improve adherence rates, which have been associated with reductions in readmission of 19-43%1-3 • Benefits greatest with longitudinal programs vs. single intervention

(1) Arch Intern Med. 1998 May 25;158(10):1067–72. (2) Prog Cardiovasc Dis. 2017 Aug 18. pii: S0033- 0620(17)30113-5. (3) Ann Intern Med. 2007 May 15;146(10):714–25. Example Adherence-Improvement Strategies

• Simplifying complex regimens (e.g., less frequently dosed medications, reducing unnecessary polypharmacy) • Individualized education (e.g., adjusting diuretic based on weight) • Improving medication-taking behavior (e.g., pillboxes, alerts, integrating medications into daily routines) • Referral to pharmacist-managed bridge clinic1 • Improving access by identifying lower cost alternatives

(1) Ann Pharmacother. 2017 Jul;51(7):555–62. Improving Access

• Financial limitations remain a major barrier

• Even within the same geographic area, 75- The price for 30 fold variability in cost has been observed days of generic • digoxin ranged Made more challenging by the fragmented from $4 to $306 ways in which health care is paid for across the St. • Using pharmacists to improve medication Louis area access requires a committed outpatient/retail pharmacy team

JAMA Intern Med. 2017 Jan 1;177(1):126–8. Transitions of Care Clinics

• Many of these interventions are best implemented longitudinally rather than one-and-done at hospital discharge • A growing number of heart failure clinics are integrating pharmacists, where reductions in readmissions of 20-78% have been observed

(1) Arch Intern Med. 1998 May 25;158(10):1067–72. (2) Arch Intern Med. 1999 Sep 13;159(16):1939–45. (3) Ann Intern Med. 2007 May 15;146(10):714–25. CB presents to your clinic for 4-week follow-up after being initially seen in bridge clinic one week after discharge. She reports being able to complete her activities of daily living without becoming fatigued or short of breath, but she does have to stop and catch her breath when carrying laundry from the basement to her bedroom on the second floor. She has trace to 1+ lower extremity edema and her weight is down approximately 2 kg since discharge. She brought all of her medication bottles as instructed. Current medications: Vitals: BP 126/82 mmHg, HR 74 bpm • Atorvastatin 40 mg daily • 140 102 18 Sacubitril/valsartan 49/51 mg twice daily 98 • Metoprolol succinate 50 mg daily 4.2 24 1.2 • Spironolactone 25 mg once daily • Furosemide 20 mg once daily Hemoglobin A1c: 8.0% (↓8.5%) • Metformin 1000 mg twice daily NT-proBNP: 780 pg/mL (↓12,800) • Empagliflozin 10 mg once daily • Insulin glargine 10 units subq at night

NT-proBNP N-terminal pro-B-type natriuretic peptide Questions

9. What additional changes to her GDMT should be made to improve her outcomes related to heart failure?

More specifically: • Should we increase ARNI, beta blocker, or both? • Should we add ivabradine or digoxin?

ARNI angiotensin receptor neprilysin inhibitor, GDMT guideline-directed medical therapy Increase sacubitril/valsartan? Dose-related differences in hospitalizations but not mortality with ACEi and ARBs:

ATLAS Trial1 HEAAL Trial1 100 60 Low-dose HR = 0.88 (95% CI 0.82-0.96) 50 80 p = 0.002 losartan 60 40 High-dose 30 High-dose 40 lisinopril 20 losartan 20 Low-dose HR = 0.90 (95% CI 0.82-0.99) Percent with Event with Percent 10 lisinopril p = 0.027 Percent WithoutEvent Percent 0 0 0 12 24 36 48 60 0 12 24 36 48 60 72 Time to Death or Hospitalization Time to Death or Hospitalization

ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, CI confidence interval, HR hazard ratio (1) Circulation. 1999 Dec 7;100(23):2312-8. (2) Lancet. 2009 Nov 28;374(9704):1840-8. Increase beta blocker? Dose-related differences in ejection fraction and survival with beta blockers

Ejection Fraction Hospitalizations Mortality

8 0.4 16% 7 14% 6 0.3 12% 5 10% 4 0.2 8% 3 6%

2 0.1 4% Mean Number Mean

1 Mortality Month 2%

- Change in EF (%) EF in Change 0 0 6 0% Placebo 6.25 mg 12.5 mg 25 mg Placebo 6.25 mg 12.5 mg 25 mg Placebo 6.25 mg 12.5 mg 25 mg Carvedilol Dose* Carvedilol Dose* Carvedilol Dose*

*Doses listed were administered twice daily Circulation. 1996 Dec 1;94(11):2807-16. SHIFT: Initiate Ivabradine?

Inclusions Relevant Exclusions • Stable heart failure (EF < 35%) • Recent myocardial infarction • Sinus rhythm • Atrial fibrillation or flutter • Resting heart rate > 70 bpm • Symptomatic hypotension • Hospitalization for heart failure within prior 12 months

Therapy was titrated every two weeks to a maximum of 7.5 mg twice daily to achieve a resting heart rate of 60-70 bpm.

EF ejection fraction Lancet. 2010 Sep 11;376(9744):875-85. Ivabradine: SHIFT Revisited Primary endpoint driven by differences in heart failure hospitalizations (not survival)

Cardiovascular Death or Heart Heart Failure Hospitalizations 35 Failure Hospitalization 35 30 30 25 25 Placebo Placebo 20 Ivabradine 20 15 15 Ivabradine 10 10 5 NNT = 50 5 NNT = 50

p < 0.0001 p < 0.0001 Patients with an Event (%) Event an with Patients

Patients with an Event (%) Event an with Patients 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Months Months

CI confidence interval, HR hazard ratio, NNT number needed-to-treat Adapted from Lancet. 2010 Sep 11;376(9744):875-85. SHIFT in Detail

Baseline Characteristic (Select) Placebo Ivabradine (n=3264) (n=3241) Heart rate (bpm) 80.1 ± 9.8 79.7 ± 9.5 Systolic blood pressure(mmHg) 121.4 ± 15.9 122.0 ± 16.1 Patients receiving a beta blocker (%) 2923 (90%) 2897 (89%) Patients at target dose of beta blocker 745 (26%) 743 (26%) Patients at > 50% target dose beta blocker 1600 (56%) 1581 (56%)

Lancet. 2010 Sep 11;376(9744):875-85. SHIFT in Detail

Baseline Characteristic (Select) Placebo Ivabradine (n=3264) (n=3241) Failure to reach target - hypotension 952 (45%) 933 (44%) Failure to reach target - fatigue 670 (32%) 676 (32%) Failure to reach target - dizziness/bradycardia 370 (26%) 284 (14%) Reason for no beta blocker - COPD 109 (32%) 126 (37%) Reason for no beta blocker - hypotension 68 (20%) 59 (17%) Reason for no beta blocker - dizziness/bradycardia 17 (5%) 24 (7%)

Lancet. 2010 Sep 11;376(9744):875-85. Ivabradine vs. Digoxin

Ivabradine Digoxin • Decreases heart failure • Decreases heart failure hospitalizations hospitalizations • Maybe reduces heart failure • Maybe reduces heart failure mortality in certain subgroups mortality if SDC < 1 ng/mL • $400/month • $15/month • “Cleaner” for clinicians who • Requires fulfilling minimum would rather not be bothered expectations (i.e., monitoring for with monitoring patients adverse effects)

SDC serum digoxin concentration Lancet. 2010 Sep 11;376(9744):875-85. JAMA. 2003 Feb 19;289(7):871-8. Am J Cardiol. 2007 Jul 15;100(2):280-4. BONUS Question #2

What GDMT would be helpful if this patient had HFpEF?

GDMT guideline-directed medical therapy, HFpEF heart failure with preserved ejection fraction HFpEF Guideline-Directed Medical Therapy

• ACE inhibitor, ARB, or beta blocker for blood pressure (IIa, LOE C) • ARB to reduce risk of hospitalization (IIb, LOE B) • Spironolactone in select patients to reduce risk of hospitalization (IIb, LOE B) • PARAGON trial (sacubitril/valsartan in HFpEF) ongoing

ACE angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, GDMT guideline-directed medical therapy, HFpEF heart failure with preserved ejection fraction, LOE level of evidence J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239. J Am Coll Cardiol. 2017 Jul 31;70(6):776–803. Solving the Revolving Door Managing Heart Failure at Transitions of Care and Beyond Brent N. Reed, PharmD, BCCP Associate Professor University of Maryland School of Pharmacy ATRIUM Cardiology Collaborative

@brentnreed or @ATRIUMRx