Heart Failure Part 3 Flashcards
Aldosterone Receptor Antagonists (AA) = MRA
- 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
Aldosterone Receptor Antagonists
- 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
Dosing/Administration for aldosterone receptor antagonists
- 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
Monitoring for aldosterone receptor antagonists
- 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
Consensus Recommendations for AAs
- 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
Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors
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
SGLT2 Inhibitors indication
- 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)
SGLT2 Inhibitors recommended for
patients with symptomatic chronic HFrEF w/wo DM to reduce hospitalizations and CV mortality
Initiation: ACC/AHA Guidelines
- 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.
Initiation: Titration Strategies after 42 days
- 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
ISDN/Hydralazine
- 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
Consensus Recommendations for ISDN/Hydralazine
- 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)
Consider additional therapies once GDMT optimized
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
Ivabradine
- 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
Ivabradine AEs
- A/E’s: Fetal toxicity; Atrial fibrillation; Bradycardia and conduction disturbances
- CYP3A substrate: KTZ CI, Avoid diltiazem, verapamil, GFJ
- Cost: >$6,000/year
Application of US HF Guidelines for Ivabradine
- 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
Digoxin/Digitalis Glycosides Mechanism of Action
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
Digoxin/Digitalis Glycosides
- 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
Place of Digoxin in HF Treatment
- 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
Digoxin
- 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
Digoxin Adverse Effects and S/Sof toxicity
- 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
Vericiguat
- 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
- Omega-3 polyunsaturated fatty acids (PUFA)
Several studies suggest reduced the risk in HF (II-IV) patients; Reasonable as ADJUNCTIVE therapy
Antiplatelets
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.
Anticoagulants
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
Calcium channel antagonists
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
Non-Pharmacologic Therapies
- 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
Other Therapies
with Conflicting or No Benefit
- 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)
Summary of Treatment of HFpEF
- 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
Summary of Treatment of HFpEF cont.
- 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)
