(4/4) Groo Lecture: Pharmacotherapy of Heart Failure with Reduced Ejection Fraction (HF-rEF) Treatment Goals of HF-rEF • Relieve symptoms and improve QoL • Reduce hospitalizations • Improve survival • Slow disease progression • BP Goal < 130/80mmHg (If HT) ACE-Inhibitors

- Place in Therapy: All patients. Cornerstone therapy HF-rEF – Improves overall survival, ßhospitalizations o Stage C/D: Symptomatic HF-rEF [Evidence A, Class 1] o Stage B: Asymptomatic HF-rEF [Evidence A, Class 1] o Stage A: High Risk for HF-rEF [Evidence A]

§ Heart Failure Society Guidelines 2010 - Mechanism: Decreased Preload, Decreased Afterload, Cardiac Remodeling

o Improves overall survival, ß HF symptoms, ßHospitalizations - Dosing: Choices for ACE-I are interchangeable. The Higher doses were

associated with an additional 12% reduction in mortality/hospitalizations vs low dose

ARBs - Place in Therapy: All patients who are intolerant to ACE-I – Improves overall survival, ß hospitalizations,

ßHF symptoms o Stage B, C, D: HF-rEF intolerant to ACE-I [Evidence A, Class 1] o ACE-I Intolerance? Cough, Angioedema (if severe)

- Dosing: Choices for ARBs are also interchangeable, though only 3 have documented evidence for treatment in HF. The HEAAL Study showed that Higher doses of losartan has improved outcomes

- DO NOT COMBINE: Do not use ACE-I with ARB due to increased risk of renal dysfunction and hyperkalemia

ACE-I and ARB Monitoring Both ACE-I and ARBs are ContraX in Preggers

Blood Pressure: Monitor for Symptomatic Hypotension. Normally, in HF pt, addition of ACE-I or ARB does not affect BP if baseline BP is normal. There is a chance these meds ÝBP, due to improving CO Renal Function + K+: Within 1-2 weeks of initiating therapy and after each dose increase. Small fluctuations in creatinine are acceptable, but K should remain stable ADR: ACE-I Cough – should resolve within 2-3w of d/c ace-I ACE-I Angioedema – Can occur at any time – do not expect it on day 1

Beta-Blockers (BB) - Place in Therapy: All patients currently treated with ACE-I – Improves overall survival, ß hospitalizations,

ßHF symptoms, slows the progression of HF, ß risk of sudden death Stage B, C, D: [Evidence A, Class 1] Do not delay, Start early, even before ACE-I is at target dose. Mortality benefits are seen within weeks of initiation. (Study done in FC IV) Warning, BB are negative inotropes: Avoid starting or increasing doses during acute HF exacerbations, this includes cases of fluid overload – may worsen outcomes Start BB therapy in hospital à better future adherence rates

Recall…

InitialCardiacInsult

PrimaryDamageleadstodecreaseO2 Supply

CompensatorymechanismsviaNeurohormones

SecondaryDamageduetoNeurohormones

Didomenico: “Beta-blockers should be in the water for pt with HF”

Beta-Blockers Continued - Mechanism: Decrease Afterload, Prevent Cardiac Remodeling, Block SNS

excess (NE toxicity) - Dosing: Though data is limited, evidence suggests Higher doses are

associated with ßmortality/hospitalizations and Ýejection fraction o Start low due to an initial negative ionotropic effect – allow the

patient to adjust, then titrate Ý q2w as tolerated - Carvedilol: Hits b1, b2, and a

o a - Produces a vasodilatory effect, which is beneficial for HT patients, but can cause AE dizziness o AE: Has been associated with diarrhea

- Metoprolol and Bisoprolol: ‘Cardio-selective’, b1 selective o Selectively may make them effective in treating hypotensive patients and those with reactive airway

disease Beta-Blocker Counseling

Initial Negative Inotrope Effect: BB may initially worsen symptoms If experiencing: More SoB, More weight gain, More swelling in legs – Report it to MD/Office staff ASAP *It takes time for this drug to become effective, do not titrate up too quickly, allow to stabilize

Beta-Blocker Monitoring S/Sx of worsening HF: Such as SoB, Edema. In these cases, augment the dose of the diuretic, and/or slow titration Symptomatic Bradycardia: Lower the dose. If inducing heart block – d/c. It may be required to implant a pacemaker before optimal BB doses can be administered Symptomatic Hypotension: Determine the cause. If due to volume depletion, lower dose of diuretic. May also attempt to separate ACE-I and BB dose. Try changing Carvedilol à metoprolol

Diuretics - Place in Therapy: Add-on Therapy for the management of fluid overload in Stage C,D. There is no data

suggesting that diuretics improve outcomes. They are used for symptomatic improvement only o Stage C, D: Evidence C, Class 1 o Stage A or B patients treated with diuretics are receiving it for

HT tx, not HF - Drug of Choice: Most patients will require Loop diuretics due to the

degree of fluid overload. Patients who are candidates for HT treatment and only have mild fluid overload may be better treated with Thiazides

- Mechanism: Decrease Preload by combating Na+ and H2O retention - Dosing: Initial Dose > Maintenance Dose

o Once fluid overload is properly treated, lower the dose and use as a preventative measure.

o Bioavailability: Furosemide bioavailability is poor (50%) and can be worsened by fluid-filled bellies. Bumetanide and torsemide are more available (80%+) so can be used instead

- Diuretic Resistance: Declining/No response to diuretic despite increasing dose. Check patient’s meds and labs o May be due to: NSAIDs, Excess dietary Na+, declining renal function o If confirmed resistanceà Combine Loop + Thiazide/Metolazone - synergistic effect (+close monitoring)

Diuretic Monitoring Efficacy: Should decrease Sx of HF. Monitor body weight daily. If lose 2-3 pounds overnight or 5 pounds in a week, report to MD and make sure to stay hydrated Safety: BMP, Electrolytes, and renal function tests should be performed 1-2weeks after dose change. Monitor for excess changes in blood pressure and warn about orthostatic hypotension. Ototoxicity may occur with loops at high doses Signs of Excess Diuresis: Dizzy, Thirst/dry mouth, Orthostatic hypotension, rising BUN/Cr, BUN:Cr > 20:1

Aldosterone Receptor Antagonists (ARA) - Place in Therapy: Add-on Therapy for management of neurohormonal toxicity in FC II-IV, Stage C/D [A,1]

o Recommended therapy for (Post-MI, EF < 40, HF Sx or DM) in Stage B/C [B,1] o Benefits: ßhospitalizations, ßmortality, improve symptoms, decrease fibrosis/remodeling

- Mechanism: Decrease Preload, Prevent cardiac remodeling o Left untreated, excess aldosterone will lead to fibrosis in the heart, which further decreases CO and may

lead to arrhythmias. While ARA will not produce significant diuresis, we are using it for its neurohormonal mechanism

Aldosterone Receptor Antagonists Continued [K: 3.5-5.2] - Dosing: Dosing of ARA is dependent on the potassium response.

o High end of normal: Start with low dose o Low end of normal: Start with full dose day 1 o Avoid Initiation: K ³ 5mEq/L, SCr ³ 2.5mg/dL, CrCl < 30mL/min

- After initiating therapy, CrCl plummets. – Do not remove the ARA unless they are also hyperkalemic ARA Monitoring

Renal Function and K+: Check renal fxn and K within 3 days of initiation and at 1 week after initiation. Follow them monthly for the first 3 months. Patient is already on ACE-I/ARB and is at risk for hyperkalemia, monitor [K] closely. Patient should be educated on low-potassium diets . Hyperkalemia [K ³ 5.5mmol/L]: Advise pt to avoid high-K foods, NSAIDs, and ‘No-Salt’

- Severe elevations (>6) may be treated with potassium binders, such as Kayexelate - If new onset bradycardia, check with ECG

Hydralazine/Isosorbide - Place in Therapy: Add-on Therapy to optimized Anti-RAAS + BB regimens in Class III-IV AA patients [B,1]

o Benefits: ßMortality, ßhospitalizations for HF, Improved QoL. Hydralazine/Isosorbide are used as combination therapy for HF. The patients who benefit the most from this combo are sicker patients, AA

o May also be used as Alternate Therapy in patients unable to take ACE-I/ARB due to intolerance [B,2] § This is most often for potassium sensitive patients unable to use the RAAS-I

- Mechanism: Nitric Oxide (NO) is a beneficial neurohormone. o Isosorbide Dinitrate: Venous dilator (Decreased preload), acting as a Nitric oxide donor o Hydralazine: Arterial dilator (Decreased afterload), acting as an antioxidant, inhibiting NO breakdown

- Dosing: The combination drug is BiDil (ISDN 20mg/Hydralazine 37.5mg) taken TID. However, this product is almost never covered and therefore must be administered is individual components

o Initial Tx: Hydr 25-50mg + ISDN 20-30mg TID/QID o Target Tx: Hydr 300mg + ISDN 120mg in divided doses

Hydr/ISDN Monitoring Adherence: Adherence is key, the pill burden will be high due to the PK/PD. AE may limit the pt’s adherence due to:

- Headache: pt often quit due to the resulting HA. Just lower the dose or give them APAP ContraX: Patients with Symptomatic Hypotension are contraindicated with Hydr/ISDN

(4/6) Groo Lecture: Pharmacotherapy of Heart Failure with Reduced Ejection Fraction (HF-rEF) Part II Sacubitril/Valsartan (Entresto)

- Place in Therapy: Replacement Therapy for symptomatic HF-rEF pt on ACE-I/ARB [Evidence B-R, Class 1] o Well-run RCT showed Entresto had less hospitalizations and mortality compared to enalapril (Standard) o Benefit: ßhospitalizations, ßCV mortality, Improve QoL o ContraX: Current ACE-I/ARB must be d/c, as Entresto will be replacing it. Patients with any Hx of

angioedema with ACE-I or ARB therapy are contraX with Entresto, due to higher risks of Angioedema - MoA: See ARB for valsartan. Sacubitril inhibits Neprillysin, thereby preventing the breakdown of BNP

o During pressure/volume overload, ventricles of the heart are producing BNP to offset the RAAS system. BNP, a natriuretic peptide, is capable of inducing vasodilation, lowering BP, reducing sympathetic tone, and promoting diuresis. BNP is naturally broken down by the enzyme neprillysin

- Dosing -there are 3 tablet strengths available o Initial dose depends on current ACE-I/ARB dosage o Due to heightened risk for hypotension, we will not immediately jump

from target to target – start conservatively o Target dose is the highest dose: 97/103mg BID. Titrate every 2 weeks to target dose as tolerated o Switching from ACE-I: Will require a 36h washout period due to increased risk of angioedema. Methods

vary from calling pharmacy to d/c the therapy or taking the old ACE-I from the patient - PK/PD + Efficacy: 60% bioavailability that is short-acting and takes quick effect. Steady state in 3 days

o Blood Pressure: Reduces systolic BP by 3mmHg o Sacubitril is a prodrug that is metabolized by esterases to LBQ657. Sacubitril is 50-70% renal-eliminated o No notable drug interactions

Sacubitril/Valsartan Monitoring Hyperkalemia and Renal Fxn: Lower risk in Entresto compared to ACE-I/ARB Hypotension: Higher risk in Entresto, requires caution and monitoring in patients with baseline BP < 100mmHg

Ivabradine (Corlanor) - Place in Therapy: Add-on Therapy for optimized patients with symptomatic HF, FCII-IV, & HR > 70bpm

o Detailed Indication: Patient needs to be in sinus rhythm and on the max tolerated BB dose. This is a good option for tachycardic patients in and out of the hospital, or poorly tolerating BB

o Level of Evidence [B-R, 2a]. The outcomes were not very strong o Laskey WK, et al. JAMA (2015): Showed the association of ÝHR with Ýmorality

§ Trials with ivabradine: ONLY show ßhospitalizations - MoA: Operating specifically in the Sinus Node, ivabradine selectively inhibits the If current of Na+ ions, therefore

reducing the slow diastolic depolarization phase ~ effectively slowing down HR. This helps with poor diastolic filling time in HF patients

o Whereas BB act directly on SNS excess, Ivabradine works indirectly on SNS excess - Dosing: Initial dose is 5mg BID AE: New onset AFib, Luminous phenomena (reversible), Bradycardia

o HR > 60bpm: Increase dose by 2.5mg BID o HR = 50-60bpm: Continue current dose o HR < 50bpm or Symptomatic Bradycardia: Decrease dose by 2.5mg BID, if on 2.5mg à D/C

- PK/PD + Efficacy: Recommended to take ivabradine with food for enhanced bioavailability (60-80%). When taken with food, the peak plasma concentration is delayed from 1 hour to 12 hours.

o Metabolism: Liver, Intestine (3A4 oxidation) o Efficacy: The degree of HR reduction depends on the dose and baseline HR

Ivabradine Monitoring Heart Rate: Check 2 weeks after every dose adjustment, and normally every 4 months. Allows TDM

Digoxin - Place in Therapy: Add-on Therapy for optimized patients with symptomatic HF [B, 2a]

o Benefits: ß hospitalizations. Determined to have no effect on mortality o Digoxin is a very old drug that is infrequently used. It has a nice history, was the mainstay for HF 50ya

- MoA: Digoxin inhibits the Na+/K+-ATPase o à Neurohormonal modulation: ßsympathetic activity, ß[NE], ß[Aldosterone], ß renin activity o à Parasympathetic Activity: In general is increased. ÝVagal tone, ßAV nodal conduction, ßHR o à +Inotrope (weak): Improves contraction

- Dosing: The dosing for digoxin is quite complicated. Dean Bauman + others developed a therapeutic drug monitoring (TDM) nomogram that considers CrCl, BMI, and current serum [digoxin]. The serum level goal is < 1.0 ng/mL. Usual dose is 0.125-.25mg QDaily

- PK/PD + Efficacy: Absorption varies by product, such that Bioavailability (F) is 75-95%. It exhibits a prolonged distribution phase, highly concentrating in tissues dependent on Na+/K+-ATPase activity.

o Metabolism: Hydrolysis in the stomach/liver as well as intestinal colony bacteria metabolism § T1/2 variability depends on renal function, but ranges 29-177h. On average ~38h

o Elimination: Mainly dependent on renal-elimination and PGP Digoxin Monitoring

Potassium and Mag: Patients with low levels are at increased risk of toxicity. Electrolytes need to be maintained Drug Interactions: PGP-inhibitors and other AV nodal blockers may enhance digoxin’s effects leading to toxicity TOXICITY

- Echocardiogram: To see AV block or bradycardia - [Digoxin] > 2ng/mL Leads to N, V, D, and potentially vision changes or confusion

Therapies of Heart Failure and their applicability to Neurohormonal Imbalance

- Inhibit the Bad Hormones: Aldosterone (ARA), Angiotensin II (ACE-I/ARB), Norepinephrine (BB), If (Iva) - Enhance the Good Hormones: BNP (NEP-I, sacubitril), NO (Hydr/ISDN), ANP (not discussed) - Not hormonal, just Symptoms: Diuretics, Digoxin (although, Digoxin has not shown positive outcomes)

Algorithm of HF-rEF Summary - All patients: ACE-I + BB

o If unable to use ACE-I, use either ARB or Hydr/Nitrates (AA) - Volume overload symptoms: Diuretics - Persistently symptomatic (Stage C,D)

o Add Hydr/ISDN: for AA Add ARA: for K < 5.0 and CrCl > 30 o Substitute ARNI: for ACE-I or ARB Add Ivabradine: for HR > 70 and in sinus rhythm o Some randoms will need digoxin

(4/9) Dwyer Lecture: Acute Decompensated Heart Failure and Transitions of Care Acute Decompensated Heart Failure (ADHF)

- Exacerbations of heart failure are associated with increased risk of readmission and mortality. It is most frequently a result of: Ischemia/ACS, Uncontrolled HT, nonadherence to meds, worsening renal function, respiratory infection. ADHF will present as-

- Either: • Rapidly developing symptoms of new-onset heart failure (massive MI, damage) • Gradual worsening of chronic heart failure (this is the majority of patients seen)

- S/Sx: ADHF, depending on its cause, can present as either Wet or Cold Wet: Volume Overload

• This presentation is the result of S/Sx: ÝBNP, Pulmonary/peripheral edema, JVD + HJR, weight gain, cough, worsening orthopnea, PND, anorexia

Cold: Low Cardiac Output • This presentation is the result of low/poor forward flow S/Sx: Tachycardia, cold/clammy extremities, ÝBUN/SCr, decreased urine output, worsening DOE or dyspnea at rest, fatigue, altered mental status

- Dx: Forrester Hemodynamic Subsets of ADHF o The Forrester classifications consider the patient’s fluid status and

cardiac output. The typical patient presenting with ADHF will have class II or IV, both are associated with an increased mortality.

o Class IV: Cardiogenic shock – very concerning diagnosis Once a patient is identified as ADHF, we should establish our goals of treatment

- Initiate/Optimize Guideline-directed medical therapy (GDMT): This goal is most applicable to the pharmacist. ~ensure the patient has their ACE-I/ARB + BB optimized

Guideline-Directed Medical Therapy (GDMT) Continue chronic therapy

- 2013 AHA/ACCF: In the absence of hemodynamic instability or contraX, continue GDMT (Evidence: B) - 2010 HFSA: In ADHF, continue the current BB therapy. D/c is associated with poor outcomes (Evidence: C)

Administered Parenteral Therapy - Loops, Inotropes, Vasodilators

Loop Diuretics (Furosemide, Bumetanide, Torsemide) -THE BACKBONE OF ADHF- - Patients with normal heart function exhibit a proportional increase in stroke volume (SV) with an increased

preload. In HF patients, the ability to compensate for increased preload is lessened, leading to backflow and symptoms of volume overload (‘wet’), such as pulmonary congestion and lower extremity swelling.