Heart Failure Part 3

Question 1

Aldosterone Receptor Antagonists (AA) = MRA

Answer 1

• Aldosterone is elevated in HF, leads to: continued sympathetic activation, parasympathetic inhibition, cardiac and vascular remodeling.
• Spironolactone (nonselective) and eplerenone (selective) block aldosterone effects independent of the effects of ACEIs or ARBs: Decrease K and Mg losses: May protect against arrhythmias, Decrease Na retention: Decrease fluid retention, Deceases sympathetic simulation: numerous effects, Blocks direct fibrotic action on myocardium

Question 2

Aldosterone Receptor Antagonists

Answer 2

• Spironolactone: Non-selective agent, structurally similar to progesterone; Inhibits the effects of dihydrotestosterone at the receptor site and increases the peripheral conversion of testosterone into estradiol; A/E’s: gynecomastia (~10%), impotence, menstrual irregularities
• Eplerenone: Selective agent with a100 -to1000-fold lower affinity for androgen, glucocorticoid, and progesterone receptors than spironolactone; No antiandrogenic effects; Substrate of CYP3A4

Question 3

Dosing/Administration for aldosterone receptor antagonists

Answer 3

• Should be added to ACEI/ARB/ARNI and Beta-blocker therapy
• Avoid: SeCr>2.5 (♂) or >2.0 (♀)mg/dL (or CrCl<30 mL/min)
  and SeK>5 mEq/L; Hx of severe hyperkalemia or recent worsening renal fx
• Concomitant use of K sparing diuretics or supplements should be avoided (unless hypokalemia SeK<4 mEq/L)
• Avoid NSAIDS, triple therapy (ACEI, ARB, MRA) and caution high dose ACEI/ARB

Question 4

Monitoring for aldosterone receptor antagonists

Answer 4

• Mx: renal fx and K: within 3 days-1 wk after any change or addition, diseases, or acute illnesses that may influence potassium concentrations, then every month for 3 months, then every 3-4 months and with increase ACEI or ARB restart
• Counsel patients: Avoidance of salt substitutes; Close questioning for all other sources of potassium

Question 5

Consensus Recommendations for AAs

Answer 5

• Stage B: No recommendations
• Stage C: Patients with NYHA II-IV and HFrEF, and eGFR >30 and K < 5. (Class I); Careful mx of K, renal function and diuretic dosing is essential; Patients taking AAs in which K can’t be maintained < 5.5 should be discontinued to avoid life threatening hyperkalemia

Question 6

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Answer 6

potential mechanisms: improve ventricular loading conditions: diuresis, natruuresis, afterload reductions; myocardial energetics and meabolomics; direct effects on myocardium; TGF and reduction in IGH
* Unclear benefit in heart failure
* Osmotic diuresis and natriuresis
* Decreased arterial pressure and stiffness
* Preload and afterload reduction and associated reduction in hypertrophy and fibrosis: Reduced myocardial remodeling

Question 7

SGLT2 Inhibitors indication

Answer 7

• Indication: Reduce the risk of CV death or hospitalization for HFrEF patients with NYHA Class II-IV
• Dosing: Dapagliflozin and empagliflozin 10 mg once daily
• eGFR: D: eGFR >30 and E: >20 mL/min/1.73 m2
• A/E’s: Volume depletion; KTA in DM, Hypoglycemia, Infection risk (UTI/PN, NFP, Mycotic)

Question 8

SGLT2 Inhibitors recommended for

Answer 8

patients with symptomatic chronic HFrEF w/wo DM to reduce hospitalizations and CV mortality

Question 9

Initiation: ACC/AHA Guidelines

Answer 9

• Titration of GDMT dosing to achieve target doses showed to be efficacious in RCTs is recommended, to reduce cardiovascular mortality and HF hospitalizations, unless not well tolerated
• Titration and optimization of GDMT medications as frequently as every 1 to 2 weeks depending on the patient’s symptoms, vital signs, and laboratory findings can be useful to optimize management.

Question 10

Initiation: Titration Strategies after 42 days

Answer 10

• Maintenance or additional titration of the four foundational therapies
• Consideration of EP device therapies or transcatheter mitral valve repair
• Consideration of add-on medications or advanced therapies, if refractory
• Manage comorbidities

Question 11

ISDN/Hydralazine

Answer 11

• Combination produces a balanced VD effects, causing reductions in both preload and afterload
• First drug combination with reduction in mortality (VeHeft, 1986)
• Previous studies (VeHeft II, 1991) suggested less effective than ACEI’s in all patients with HF
• BiDil indicated for the treatment of HF in black patients AS AN ADJUNCT TO STANDARD THERAPY (A-Heft 2004)
• Cost: Brand vs. Generic
• AEs are a significant problem and a major limiting factor in
  clinical trials: Headache, nausea, flushing, dizziness, tachycardia, lupus-like syndrome, hypotension, inc HR, myocardial ischemia, fluid retention

Question 12

Consensus Recommendations for ISDN/Hydralazine

Answer 12

• Stage B: No recommendations
• Stage C: Black patients with NYHA III-IV, receiving optimal medical therapy, to improve symptoms and reduce M/M (Class I); Patients with Sxs (or previous Sxs), who can’t receive ARNI, ACEI or ARB (due to drug intolerance, or renal insufficiency) might be considered. (Class IIb)

Question 13

Consider additional therapies once GDMT optimized

Answer 13

NYHA II-III, HFrEF, NSR, heart rate >/= 70 bpm on maximally tolerated beta blocker - ivabradine
NYHA II-IV, LVEF < 45%, recent HFH, or IV diuretics, elevated NP levels - vericiguat
symptomatic HFrEF - digoxin

Question 14

Ivabradine

Answer 14

• Indication: Reduce the risk of hospitalization (worsening HF) for symptomatic HF, EF<35% (HFrEF) in NSR with rHR>70 in max tolerated Beta- blocker or with CI.
• ApprovedbyFDAinApril,2015
• Dosing: 2.5-5 mg BID, adjust q2 weeks based on HR. Max: 7.5 BID, Conduction defects or when bradycardia is a concern: 2.5

Question 15

Ivabradine AEs

Answer 15

• A/E’s: Fetal toxicity; Atrial fibrillation; Bradycardia and conduction disturbances
• CYP3A substrate: KTZ CI, Avoid diltiazem, verapamil, GFJ
• Cost: >$6,000/year

Question 16

Application of US HF Guidelines for Ivabradine

Answer 16

• Reduce HF hospitalization and CV death for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF <35%), treated with a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a HR > 70 bpm at rest

Question 17

Digoxin/Digitalis Glycosides Mechanism of Action

Answer 17

two fold MOA:
inhibits Na+/K+ ATPase –> decrease Na+/K+ ATPase pump –> increase Ca2+ –> increase force
stimulator of PSNS: increase vagal activity –> decrease AV conduction –> decrease rate

Question 18

Digoxin/Digitalis Glycosides

Answer 18

• Cardiac glycosides have been used clinically for nearly 200 years.
• Benefits are due to neurohormonal modulation effects: Increases parasympathetic activity; Vagolytic effects at the AV and SA nodes …reduces HR at rest and slows AVN conduction (Atrial fibrillation tx); Re-sensitization of barorecptors
• Inhibits the Na+/K+ ATPase altering excitation- contraction- coupling: increases intracellular Ca+2, enhancing the force of contraction; Relatively mild positive inotrope

Question 19

Place of Digoxin in HF Treatment

Answer 19

• Efficacy of digoxin in HF with Afib is well established: Role in HF and normal sinus rhythm is controversial.
• DIG trial: digoxin effective in reducing hospitalizations but NOT mortality
• US Guidelines: Consider in patients with symptomatic HFrEF despite (optimized) GDMT, or who can’t tolerate GDMT to decrease hospitalization for HF

Question 20

Digoxin

Answer 20

• Dosing: Most clinicians dose digoxin EMPIRICALLY: 0.125-0.25 mg daily; 0.125 mg be used in the majority of patients with 0.5-0.9 ng/mL being the goal serum digoxin conc (SDC); Lower doses in >70 yrs, impaired renal function, low weight
• Review drug interactions from PK: Amiodarone; Quinidine; Verapamil; Itra/KTZ

Question 21

Digoxin Adverse Effects and S/Sof toxicity

Answer 21

• Noncardiac (Mainly CNS): Anorexia, nausea, vomiting, abdominal pain; Visual disturbances: halos, photophobia, altered color perception; fatigue, weakness, dizziness, headache, neuralgias, confusion, delirium, psychosis
• Cardiac: Ventricular : PVCs, bigeminy, trigeminy, VT, VF; AV block: First, second (Mobitz type I) and third degree; AV junctional escape rhythms, junctional tachycardia; Atrial arrhythmias with slowed AV conduction or AV block; Sinus bradycardia

Question 22

Vericiguat

Answer 22

• Soluble guanylate cyclase stimulator
• Reduces CV death/hospitalization [HR: 0.90 (0.82-0.98)]: Symptomatic (mainly II and III) HFrEF on standard therapy; 2.5 mg once daily → 10 mg once daily
• Verquvo approved in US in early 2021
• Safety: CI in pregnancy; Hypotension and anemia most common AE’s (both similar to placebo)
• US Guidelines: Consider in selected high-risk patients with recent worsening with symptomatic HFrEF despite (optimized) GDMT, to decrease hospitalization for HF and CV death

Question 23

• Omega-3 polyunsaturated fatty acids (PUFA)

Answer 23

Several studies suggest reduced the risk in HF (II-IV) patients; Reasonable as ADJUNCTIVE therapy

Question 24

Antiplatelets

Answer 24

Long term therapy with aspirin (75-81 mg/day) is recommended
in patients with HF and IHD/CAD/ASCVD; Otherwise aspirin in not recommended for routine use; If contraindicated/not tolerated, consider alternatives.

Question 25

Anticoagulants

Answer 25

Recc in HF if Atrial Fib with one additional R/F: Reasonable if no additional R/F; Patients with other indications (ie. Hx of systemic or pulmonary embolism); Routine anticoagulation is not recommended

Question 26

Calcium channel antagonists

Answer 26

Diltiazem, verapamil and nifedipine should not be routinely used; Felodipine and amlodipine may be useful in managing angina/HTN if not effectively managed with HF therapies

Question 27

Non-Pharmacologic Therapies

Answer 27

• Implantation of ICD: LVEF < 35 %, at least 40 days post-MI, NYHA II-III ! LVEF < 30 %, at least 40 days post-MI, NYHA I
• Cardiac resynchronization therapy: NYHA II-III-IV pts on optimal medical therapy; QRS duration ≥150 milliseconds and LVEF ≤35%; New data show impressive benefits in patients with NYHA I-III

Question 28

Other Therapies
with Conflicting or No Benefit

Answer 28

• Nutritional therapies with Conflicting Data: Coenzyme Q10 - Recent investigation suggests 50 % reduction in mortality.
• Nutritional therapies with No Data: Carnitine, taurine, antioxidants; Pharmacists should inquire about their use!
• Hormonal therapies with No Data: HGH, thyroid (unless supplementation needed)

Question 29

Summary of Treatment of HFpEF

Answer 29

• SBP/DBP should be controlled in patients with HFpEF in based on current practice
• Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF, no mortality benefits.
• Management of AF according to published clinical practice guidelines in patients with HFpEF can improve symptomatic HF
• SGLT2i may reduce hospitalizations and CV mortality
• The use of ARBs, ARNIs, MRAs, and ACEIs may be considered to decrease hospitalizations for selected patients with HFpEF, esp at lower end of LVEF

Question 30

Summary of Treatment of HFpEF cont.

Answer 30

• ACEIs and ARBs have not been shown to reduce mortality: ACEIs improve exercise tolerance and reduce hospitalizations; ARBs may reduce hospitalizations
• MRAs may improve diastolic function and reduce remodeling: May be used to reduce hospitalization (See HFrEF for appropriate
  patients); Less convincing than HFrEF
• Digoxin has no affect on mortality or hospitalizations
• Nitrates should be limited to use in patients with HFpEF who may need treatment for symptomatic CAD
• CCBs maybe useful to treat other conditions (HTN)