Solving the Revolving Door - Virginia Pharmacists Association€¦ · •Insulin aspart sliding...

Solving the Revolving DoorManaging Heart Failure at

Transitions of Care and Beyond

Brent N. Reed, PharmD, BCCPAssociate Professor

University of Maryland School of PharmacyATRIUM 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 problems contribute to a significant number of ADHF admissions

• Up to two-thirds are preventable

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.

• 1 in 4 patients is readmitted within 30 days and nearly half are readmitted within 6 months

• Pharmacists can to reduce readmissions by 1/3 to nearly 1/2

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:• Atorvastatin 40 mg daily • Lisinopril 10 mg daily• Metoprolol succinate 100 mg daily • Spironolactone 25 mg once daily • Furosemide 40 mg twice daily • Metformin 1000 mg twice daily • Insulin glargine 25 units subq at night

Vitals: BP 118/78 mmHg, HR 71 bpm

Hemoglobin A1c: 8.5%NT-proBNP 12,800 pg/mLChest x-ray: cardiomegaly, bilateral interstitial/alveolar edema; no effusions

134 98 28182

4.5 26 1.4

EF ejection fraction, EMR electronic medical record, NT-proBNP N-terminal pro-B-type natriuretic peptide

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?


Questions



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:• Atorvastatin 40 mg daily • Lisinopril 10 mg daily• Metoprolol succinate 100 mg daily • Spironolactone 25 mg once daily • Furosemide 40 mg twice daily • Metformin 1000 mg twice daily • Insulin glargine 25 units subq at night


Hemoglobin A1c: 8.5%NT-proBNP 12,800 pg/mLChest x-ray: cardiomegaly, bilateral interstitial/alveolar edema; no effusions

134 98 28182

4.5 26 1.4

EF ejection fraction, EMR electronic medical record, NT-proBNP N-terminal pro-B-type natriuretic peptide

Diabetes

COPD

Chronic kidney disease

Anemia

Depression

Endocrinologist

Pulmonologist

Hematologist

Nephrologist

Psychiatrist

Medication reconciliation can identify drug-related causes of ADHF• Most patients with heart failure have

> 5 comorbidities and take > 6 chronic medications1

• Use of nonprescription medications may be as high as 93%2

• Nonadherence remains a major contributor to decompensation

COPD chronic obstructive pulmonary disease. (1) Am J Med. 2011 Feb;124(2):136–43. (2) J Card Fail. 2009 Sep;15(7):600–6.

Diu

reti

c R

esp

on

se

Diuretic Concentration

Normal

Heart Failure

Lower peak due to delayed absorption

Higher doses required for effect

Diu

reti

c C

on

cen

trat

ion

Time

Diminished maximal response

Left adapted from: Cardiology. 2001;96(3–4):132–43. Right adapted from: Am J Med. 1998 Jun 1;104(6):533–8.

Impaired Diuretic Response

Normal

Heart Failure

Questions




0 5 10 15 30 60

150

100

50

0

mm

Hg

Urine Output

Effects of Furosemide Over Time1

Time (minutes)

20

15

10

mL

Preload

0 200 400 600

12.5

10.0

7.5

5.0

2.5

0

Pro

bab

ility

of

Mo

rtal

ity

Door-to-Furosemide Time2

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.

> 1 hour associated with 3-fold increase in mortality (6.0 vs. 2.3%, p=0.002)

Acute Diuretic Response

308 patients with ADHF randomized

Bolus vs. Infusion

(q12 hour bolus vs. continuous infusion)

High vs. Low-Dose

(1x home dose vs. 2.5x home dose)

Adjust at 48 hours per clinician discretion

Change to oral therapy Continue regimen Intensify regimen

48 hours

24 hours

Assess safety/efficacy outcomes at 72 hour

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

DOSE Trial

High Dose• Greater net fluid loss• Greater weight loss• More symptomatic relief

Low Dose• Less transient worsening of

renal function

• 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.

DOSE In Detail

BONUS Question

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


What About HFpEF? (ROPA-DOP1)

Outcome at 72 hours Intermittent Bolus(n=43)

Continuous Infusion(n=47)

p

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

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

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

Questions



3. What should be done with her other GDMT?• Lisinopril 10 mg daily• Metoprolol succinate 100 mg daily • Spironolactone 25 mg once daily


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

ACE inhibitor

ACE angiotensin-converting enzyme, RAAS renin-angiotensin-aldosterone systemCardiology. 2017;137(2):121–5.

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

RAAS Inhibitors

0 15 30 45 60 75 90

25

20

15

10

5

0

Mo

rtal

ity

rate

(%

)

WithdrawnNot treatedContinuedNewly started

Beta Blocker Treatment Groups

(p < 0.001)

Days Since Discharge

• In OPTIMIZE-HF, beta blocker continuation was associated with lower risk of death (HR 0.60, 95% CI 0.37-0.99, p=0.044)1

• Confirmed in B-CONVINCED, which showed no worsening of ADHF with continuation during hospitalization2

(1) J Am Coll Cardiol 2008; 52:190–9. (2) Eur Heart J 2009; 30: 2186-92.

Beta Blockers

Considerations for Discontinuing GDMT

Drug or Drug Class Scenarios in Which Discontinuation May Be Considered

ACE inhibitors, ARBs, or ARNI

Worsening SCr due to recent initiation or titration, symptomatic hypotension, severe hyperkalemia (> 5.5 mEq/L)

Beta blockers ADHF due to recent initiation or titration, worsening low output orcardiogenic 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:• Beta blocker held (over weekend, before

you could intervene)• Furosemide 120 mg IV BID• Insulin aspart sliding scale ACHS• Metformin being held


130 94 24118

3.8 28 1.4

134 98 28182

4.5 26 1.4

Admission Values (For Reference)

BP 118/78, HR 71 bpm

ACHS prior to meals and at bedtime, BID twice daily

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.

Questions


Decreased gut absorption and/or renal perfusion

Compensatory sodium reabsorption

Remodeling of the nephron

Neurohormonal activation

Arginine vasopressin

Renin-angiotensin-aldosterone system

Loop of Henle

Proximal convoluted

tubule

Distal convoluted tubule

Collecting duct

Glomerulus

Common Mechanisms of Diuretic Resistance

Questions


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?

Diu

reti

c R

esp

on

se

Diuretic Concentration

Cardiology. 2001;96(3–4):132–43. N Engl J Med. 2011 Mar 3;364(9):797–805.

Augmenting Diuretics: Increasing DoseDiuretic threshold: concentration that must be achieved to elicit a response

Ceiling dose:Higher doses do not elicit an additional response

Normal

Heart Failure

• Optimize dose before increasing frequency

• Safe and efficacious per DOSE trial

Diuretic threshold

Diu

reti

c C

on

cen

trat

ion

Time

Bolus doses at initiation and with

dose increases Continuous infusion

Transition to Continuous Infusion

J Card Fail. 2010 Jul;16(7):541–7.

Trials other than DOSE:• Increased total and net UOP• No differences in ADRs• Shorter length of stay?

Continuous Infusions

Advantages• Can achieve higher total daily

doses than boluses

• Avoids off-diuretic periods

• May be advantageous in specific populations (e.g., preload-dependent conditions, delayed transcapillary refill)

Disadvantages• May encourage “set it and forget

it” mentality

• Overnight urination (fall risk, decreased sleep quality)

• Drug mismanagement (omitting boluses, “titrate” orders)

Add a Thiazide-Type Diuretic

Agent Metolazone Chlorothiazide Hydrochlorothiazide

Oral bioavailability 40-65% N/A 65-75%

Usual dose (max/day)

2.5–5 mg qday(20 mg)

500–1000 mg qday to bid (2000 mg)

25–50 mg qday to bid (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

Pre-thiazide Post-thiazide

3500

3000

2500

2000

1500

1000

500

0

Net

Uri

ne

Ou

tpu

t (m

L)

711

2030

877

2275

Metolazone

Chlorothiazide

Metolazone vs. Chlorothiazide1

(p=0.026 for non-inferiority)Summary of Studies in ADHF1-3

• HCTZ < chlorothiazide• Chlorothiazide ≈ metolazone

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.

Add a Thiazide-Type Diuretic

What Maybe Works?Strategies to consider in select patients.

• Increased venous capacitance

• Decongests kidneys

VenousVasodilation

• Improved renal blood flow due to reduced arterial impedance

ArterialVasodilation

NitroprussideNitroglycerin*Nitroprusside

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

Theoretical Benefits of Adding Vasodilators

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

Placebo(n=3444)

Nesiritide(n=3416)

706050403020100102030405060

Pati

ents

(%

) At least moderately better

Worse

No change

ASCEND (Nesiritide)1

Dyspnea at 6 hours(p = NS)

6 24 48 72 120

150

120

90

60

30

0

In-H

osp

ital

Eve

nts

Ularitide

Placebo

TRUE-AHF (Ularitide)2

Persistent Heart Failure(p = 0.63)

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

Time (hours)

Actual Benefits of Adding Vasodilators?*

Minimally better

*Assessed congestive symptoms, not urine output.

Heterogeneity in Recent Vasodilator Trials

Trial Year Agent Patients Mean EFPatients with HFpEF

ASCEND-HF1 2011 Nesiritide 7147 NR 19.9%

RELAX-AHF2 2012 Serelaxin 1161 38.7% 45.0%

ROSE-AHF3 2013Dopamine / nesiritide

360 31.6% 24.4%

TRUE-AHF4 2017 Ularitide 2157 NR 34.8%

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.

Reasonable to consider in HFrEF with refractory congestion (despite optimizing diuretics) and normal to elevated blood pressures.

Placebo Tolvaptan

25%

20%

15%

10%

5%

0%

Pati

ents

(%

)

16%20%

TACTICS-HF (Tolvaptan)1

Dyspnea Improvement at 24 h(p=0.32)

(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.

• Improved weight and fluid loss but not symptoms

• Increased risk of transient WRF• 48 hours of therapy: $1200• Alternative cost-effective options for

hyponatremia exist (furosemide plus hypertonic saline)2-4

Adding Tolvaptan

24 h 48 h 72 h 96 h 7 d 30 d 60 d

0.3

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

Mea

n C

han

ge f

rom

Bas

elin

e (m

g/d

L)

Ultrafiltration

Pharmacologic

CARRESS-HF1

Changes in Serum Creatinine

Time

Primary : change at 96 hours-0.04 vs. +0.23 (p=0.003)

(1) J Am Coll Cardiol 2007;49(6):675-683. (2) N Engl J Med 2012;367(24):2296-2304.

Ultrafiltration Standard care

7654321

Wei

ght

Loss

(kg

)

UNLOAD1

Weight Loss and Dyspnea Scores6543210

Dys

pn

ea S

core

5.0 vs. 3.1 kg(p=0.001)

6.4 vs. 6.1 (p=0.35)

Adding or Substituting Ultrafiltration

(Also reduced rehospitalizations at 90 days, p = 0.022)

(More serious adverse events in ultrafiltration group, p = 0.03)

Why the discrepancy?

Home Dose Furosemide Starting Dose

< 80 mg 40 mg IVB, then 5 mg/h

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

If patient fails to meet urine output goals:1. At 24 hours, advance diuretics2. At 48 hours, Step 1 and consider vasodilators/inotropes3. At 72-96 hours, Step 1-2 and consider hemodynamic guided-

therapy ± MCS

CARRESS-HF Design

Patients with ADHF and renal impairment randomized

Ultrafiltration 200 mL/h for 96 hours

or

ADHF acute decompensated heart failure, IVB intravenous bolus, MCS mechanical circulatory support, MTZ metolazoneJAMA. 2013 Dec 18;310(23):2533-43.

Hypothesis 1) Constant ultrafiltration rate likely disrupted renal counter-regulation

Hypothesis 2) Stepped therapy group likely unmasked patients with low output by 48 hours

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 WorkDon’t do these things.

Switching IV Furosemide to IV Bumetanide

Agent Onset Peak DurationDose Equivalence

Usual Bolus Doses (max)

Usual Infusion Doses (max)

Furosemide 5 min 2 h 4-6 h 20-40 mg40-160 mg qdayto tid(200 mg/dose)

5-20 mg/h (40 mg/h)

Bumetanide 2-3 min 1-2 h 4-6 h 1 mg0.5-4 mg qday to tid(5 mg/dose)

0.5-2 mg/h(4 mg/h)

• 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 peptideJAMA Cardiol. 2017 Sep 1;2(9):950–8.

(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.

Low-Dose Dopamine (ROSE)1

Outcome PlaceboDopamin

ep

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

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:• Aspirin 81 mg daily • Atorvastatin 40 mg daily • Isosorbide dinitrate 20 mg TID• 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


138 96 24108

4.3 24 1.3

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


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:• Aspirin 81 mg daily • Atorvastatin 40 mg daily • Isosorbide dinitrate 20 mg TID• 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


138 96 24108

4.3 24 1.3

Transitioning Diuretic Therapy

Outcome < 24 hour(n=61)

> 24 hour (n=62)

p (adjusted)

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

J Card Fail. 2017 Oct;23(10):746-752.

Observing Patients on Oral Diuretics Prior to Discharge

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

Ambulatory IV Diuretic Clinic

CategoryMaintenance Diuretic (mg/day)

IV Bolus (mg)IV Infusion(mg/hr x 3hr)

Optional (Inadequate UOP at 90 mins)

Low dose < 40 20 20 -

Medium dose 41-160Equivalent of maintenance dose

20 -

High dose 161-300 200 20 Extra 200 mg dose

Mega dose > 301 200 20Extra 200 mg dose plus thiazide-type diuretic

IV intravenous, WRF worsening renal function, UOP urine outputJACC Heart Fail. 2016 Jan;4(1):1-8.

• 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

Example Protocol in Patients with Worsening Congestion (n=60)

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• Ejection fraction < 35%• NT-proBNP > 600 pg/mL or > 400 if

hospitalized in the last 12 months• Enalapril equivalent > 10 mg/day

• Symptomatic hypotension• Blood pressure < 100/95 mmHg• GFR < 30 mL/min• Serum potassium > 5.4 mEq/L• 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.

0 180 360 540 720 900 1080 1260

1.0

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Adapted from N Engl J Med. 2014 Sep 11;371(11):993-1004.

Primary Composite Endpoint Death from Cardiovascular Causes Alone

Sacubitril/valsartan

Enalapril

p < 0.001

Days Since Randomization

Cu

mu

lati

ve P

rob

abili

ty

0 180 360 540 720 900 1080 1260

1.0

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Sacubitril/valsartan

Enalapril

p < 0.001

Days Since Randomization

Cu

mu

lati

ve P

rob

abili

ty

NNT = 22 NNT = 32

PARADIGM-HF Results

Safety of sacubitril/valsartan vs. enalapril: higher rates of hypotension but lower rates of acute kidney injury and hyperkalemia

PIONEER-HF: ARNI in ADHF

Inclusions Notable Exclusions

• HFrEF (EF < 40%) with ADHF• BNP > 400 or NT-proBNP > 1600 pg/mL• Signs/symptoms of volume overload• SBP > 100 mmHg for 6 hours• No escalation of diuretics or use of

vasodilators in prior 6 hours, or inotropes in prior 24 hours

• Angioedema with ACEi/ARB• Estimated GFR < 30 mL/min/1.73 m2

• Potassium > 5.2 mEq/L

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.

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

-60

-50

-40

-30

-20

-10

0

10

0 1 2 3 4 5 6 7 8

Ch

ange

in N

T-p

roB

NP

Fro

m B

ase

line

(%

)

Weeks since Randomization

PIONEER-HF Results

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

0 1 2 3 4 5 6 7 8

Me

an S

eru

m

Cre

atin

ine

(m

g/d

L)


3.6

3.8

4.0

4.2

4.4

4.6

4.8

5.0

5.2

0 1 2 3 4 5 6 7 8

Me

an S

eru

m

Po

tass

ium

(m

Eq/L

)


95.0

105.0

115.0

125.0

135.0

145.0

0 1 2 3 4 5 6 7 8

Me

an S

ysto

lic B

loo

d

Pre

ssu

re (

mm

Hg)


p = 0.0047

NT-proBNP (Primary Endpoint) Potassium

Serum Creatinine Systolic Blood Pressure

Sacubitril/valsartan Enalapril

p < 0.001

N Engl J Med. 2018 Nov 11.

Aspirin for Primary Prevention

ASCEND Trial1

(15,480 patients with diabetes)

ASPREE Trial3

(19,114 patients who were aged 70 years or older)

ARRIVE Trial2

(12,546 patients at low to moderate cardiovascular risk)

1.1% reduction in

cardiovascular events(p = 0.01)

0.9% increase in

major bleeding events

(p = 0.003)

0.2% reduction in

cardiovascular events(p = 0.60)

0.5% increase in

gastrointestinal bleeding(p = 0.0007)

0.6 Fewer vascular

events per 1000 PY

(p = NS)

2.4more bleeding

events per 1000 PY(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

Bisoprolol(CIBIS II1)

1.25 mg once dailyIncrease by 1.25 mg every week until 5 mg, then 2.5 mg every 4 weeks

10 mg once daily

Carvedilol(COPERNICUS2, US Carvedilol Trial3)

3.125-6.25 mg twice daily* Double every 2 weeks25 mg twice daily (50 mg if > 85 kg)

Metoprolol succinate(MERIT-HF4)

12.5-25 mg once daily* Double every 2 weeks 200 mg once daily

*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.

Pre-discharge initiation as late as 12 hours prior to departure shown to be safe.5

0 6 12 18 24 30 36 42 48

7

6

5

4

3

2

1

0

Pat

ien

ts w

ith

Eve

nt

(%)

Empagliflozin

Placebo

EMPA-REG OUTCOMEHospitalization for Heart Failure

Months

Hazard ratio 0.65 (95% CI 0.50-0.85)p=0.002

• Empagliflozin also associated with reduction in cardiovascular death (3.7% vs. 5.9%, p<0.001)

• Patients may require reduction in diuretic dose

SGLT2 sodium-glucose cotransporter-2. N Engl J Med 2015;373:2117-28.

SGLT2 Inhibitors in Heart Failure

Questions


8. What non-pharmacologic strategies might also reduce her risk of readmission?

Rx

(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.

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 reduce readmissions significantly

(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.

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

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-fold variability in cost has been observed

• Made more challenging by the fragmented ways in which health care is paid for

• Using pharmacists to improve medication access requires a committed outpatient/retail pharmacy team

The price for 30 days of generic digoxin ranged

from $4 to $306 across the St.

Louis area

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:• Atorvastatin 40 mg daily • Sacubitril/valsartan 49/51 mg twice daily• Metoprolol succinate 50 mg daily • Spironolactone 25 mg once daily • Furosemide 20 mg once daily• Metformin 1000 mg twice daily • Empagliflozin 10 mg once daily• Insulin glargine 10 units subq at night


Hemoglobin A1c: 8.0% (↓8.5%)NT-proBNP: 780 pg/mL (↓12,800)

140 102 1898

4.2 24 1.2

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?

0 12 24 36 48 60

100

80

60

40

20

0Pe

rce

nt

Wit

ho

ut

Eve

nt

Time to Death or Hospitalization

0 12 24 36 48 60 72

60

50

40

30

20

10

0

Pe

rce

nt

wit

h E

ven

t

Time to Death or Hospitalization

High-dose lisinopril

Low-dose lisinopril

Low-dose losartan

High-dose losartan

ATLAS Trial1 HEAAL Trial1

HR = 0.90 (95% CI 0.82-0.99)p = 0.027

HR = 0.88 (95% CI 0.82-0.96)p = 0.002

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.

Dose-related differences in hospitalizations but not mortality with ACEi and ARBs:

Increase beta blocker?

0

1

2

3

4

5

6

7

8

Placebo 6.25 mg 12.5 mg 25 mg

Ch

ange

in E

F (%

)

Carvedilol Dose*

Ejection Fraction

0

0.1

0.2

0.3

0.4

Placebo 6.25 mg 12.5 mg 25 mgM

ean

Nu

mb

er

Carvedilol Dose*

Hospitalizations

0%

2%

4%

6%

8%

10%

12%

14%

16%

Placebo 6.25 mg 12.5 mg 25 mg

6-M

on

th M

ort

alit

y

Carvedilol Dose*

Mortality

*Doses listed were administered twice dailyCirculation. 1996 Dec 1;94(11):2807-16.

Dose-related differences in ejection fraction and survival with beta blockers

SHIFT: Initiate Ivabradine?

Inclusions Relevant Exclusions

• Stable heart failure (EF < 35%)• Sinus rhythm• Resting heart rate > 70 bpm• Hospitalization for heart failure

within prior 12 months

• Recent myocardial infarction• Atrial fibrillation or flutter• Symptomatic hypotension

EF ejection fractionLancet. 2010 Sep 11;376(9744):875-85.

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.

0 6 12 18 24 30

35

30

25

20

15

10

5

0

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

Cardiovascular Death or Heart Failure Hospitalization

Ivabradine

Placebo

p < 0.0001

Months

Pat

ien

ts w

ith

an

Eve

nt

(%)

NNT = 50

0 6 12 18 24 30

35

30

25

20

15

10

5

0

Heart Failure Hospitalizations

Ivabradine

Placebo

p < 0.0001Pat

ien

ts w

ith

an

Eve

nt

(%)

NNT = 50

Months

Ivabradine: SHIFT RevisitedPrimary endpoint driven by differences in heart failure hospitalizations (not survival)

SHIFT in Detail

Baseline Characteristic (Select) Placebo(n=3264)

Ivabradine(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(n=3264)

Ivabradine(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• Decreases heart failure

hospitalizations

• Maybe reduces heart failure mortality in certain subgroups

• $400/month

• “Cleaner” for clinicians who would rather not be bothered with monitoring patients

Digoxin• Decreases heart failure

hospitalizations

• Maybe reduces heart failure mortality if SDC < 1 ng/mL

• $15/month

• Requires fulfilling minimum expectations (i.e., monitoring for adverse effects)

SDC serum digoxin concentrationLancet. 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 evidenceJ Am Coll Cardiol. 2013 Oct 15;62(16):e147-239. J Am Coll Cardiol. 2017 Jul 31;70(6):776–803.

Solving the Revolving DoorManaging Heart Failure at

Transitions of Care and Beyond

Brent N. Reed, PharmD, BCCPAssociate Professor

University of Maryland School of PharmacyATRIUM Cardiology Collaborative

@brentnreed or @ATRIUMRx

Solving the Revolving Door - Virginia Pharmacists Association€¦ · •Insulin aspart sliding...

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