Heart Failure Part 2

Question 1

Neurohormonal Blockers

Answer 1

• RAS Inhibitors: Angiotensin Receptor Neprilysin Inhibitors (ARNI); Angiotensin Converting Enzyme Inhibitors (ACEI); Angiotensin Receptor Blockers (ARB)
• Beta-blockers (BB)
• SGLT2 Inhibitors
• Mineralocorticoid Receptor Antagonists (MRA)
• Hydralazine/ISDN

Question 2

RAS inhibitors

Answer 2

decrease BP + perfusion; causes system to be activated; we want to block this system b/c it enhances hypertrophy of the cardiac cells, cell death, fibrosis, arrhythmias

Question 3

ACE Inhibitors

Answer 3

• Cornerstone agent
• Numerous studies suggest that ACE Inhibitors: Reduce symptoms, improve NYHA, improve clinical status, decrease hospitalizations (~30% RRR), improve exercise tolerance and QOL; Reduce mortality (~25-50 % RRR) and slow progression of HF
• Benefit occurs regardless of etiology or severity of disease, must be used in all without contraindications
• Additional benefits in IHD, CKD, post-MI, DM

Question 4

ACE Inhibitors: Rationale and Mechanism

Answer 4

inhibition of angiotensin II formation - block conversion of angiotensin 1 –> angiotensin II; enhancement of bradykinin

Question 5

Mechanism of ACE Inhibitor Benefit in Heart Failure

Answer 5

improved endothelial function, decreased NE, inhibition of cardiac hypertrophy (reduction in remodeling in myocardium), improved cardiac hemodynamics, decreased endothelin-1, reduced vasoconstriction, reduced aldosterone, decreased arginine vasopressin, reduced Na and water retention

Question 6

ACEi used in HF

Answer 6

enalapril, captopril, lisinopril, quinapril, ramipril, fosinopril, trandolapril, benazopril, moexipril, perindopril

Question 7

Dosing of ACE Inhibitors

Answer 7

• What are the proper doses of ACE Inhibitors?: Clinical trial dosing vs. dosing to response; Why are these doses so important; Are lower doses as effective? Or do they maintain some efficacy? - ATLAS trial suggests higher doses may have greater benefit
• Why are ACE Inhibitors underdosed and underused?: CKD: Lower doses; Hypotension: Symptomatic vs Low blood pressure

Question 8

Clinical Dosing of ACEi

Answer 8

• Dosages: titrate slowly to the target dose used in clinical trials: Start low and double dose every 1-4 weeks; Some improvement may be evident in several
  weeks; Caution if: Volume depleted, SBP<80; K>5, SeCr >3 - Lower doses and more monitoring are required with serum creatinine > 3.0 and/or ClCr < 30 mL/min.

Question 9

Absolute Contraindications of ACEi

Answer 9

• Pregnancy or intending to become pregnant
• History of angioedema (<1%) or hypersensitivity
• Bilateral renal artery stenosis
• History of WELL-DOCUMENTED intolerance due to symptomatic hypotension, decline in renal function, hyperkalemia or cough.

Question 10

Monitoring of ACEi

Answer 10

• Volume status (normalize prior to initiation)
• Regular Mx of renal function and K, esp in high risk: Prior to therapy, 1-2 weeks after each increase in dose and at 3-6 months intervals; When other treatments are added that may decrease renal function; In patients with a history of renal dysfunction; SeCr may rise after initiation (<30 % acceptable)
• Blood pressure: Avoid symptomatic hypotension
• Other adverse effects

Question 11

Adverse Effects ACEi

Answer 11

• Hypotension
• Functional renal insufficiency
• Hyperkalemia
• Skin rash and dysgeusia (captopril)
• Cough (~20%)
• Angioedema (~1%)

Question 12

Angiotensin II Receptor Antagonists

Answer 12

more blockade of AT1 receptor: prevents an increase in myocardial fibrosis, NE, vasoconstriction, and PAI/endothelin
directly antagonize angiotensin II receptor

Question 13

Angiotensin II Receptor Antagonists used in HF

Answer 13

losartan, valsartan, candesartan
never use with ACEi

Question 14

ARBs vs. ACEIs

Answer 14

• Place in Therapy: Not superior to ACEi; Alternative if: ARB for another reason; Unable to take ACEi due to cough; ACEi-induced angioedema (with caution and close follow-up)
• Monitoring: See ACE inhibitor (except cough) discussion

Question 15

Angiotensin Receptor Neprilysin Inhibitors

Answer 15

dual mechanism of action: NP system and RAAS
inhibits degradation of BNP to promote vasodilation and blocks AT1 receptor to inhibit vasoconstriction

Question 16

ARNI

Answer 16

sacubitril/valsartan - inhibits degradation of BNP, blocks AT1-receptor

Question 17

Sacubitril/Valsartan

Answer 17

• Sacubitril: Metabolite inhibits Neprilysin…increase natriuretic peptides
• Valsartan: ARB
• Indication: Reduce the risk of CV death/hospitalization
  for HFrEF patients with NYHA Class II-IV
• Sacubitril (24, 49, 97 mg): Valsartan (26, 51, 103 mg) ; Valsartan equivalents: 26=40; 51=80; 103=160 mg

Question 18

Enalapril 20/day =

Answer 18

captopril 150/day = lisinopril 20-40/day

Question 19

Sacubitril/Valsartan AEs

Answer 19

• A/E’s (remember ARBs and ACEIs): Hypotension (> enalapril); Elevations in SeCr, SeK (< enalapril); Angioedema rare; Pregnancy: Same contraindication
  very expensive

Question 20

Must stop an ACEi within ____ hours of starting an ARNI

Answer 20

36

Question 21

Recommendations for ARNi/ACEi/ARB

Answer 21

• Stage B: ACEi’s: Class I OR ARBs: If intolerant to ACEIs (Class I)
• Stage C: ARNi: Patients with current or previous Sxs; ACEi’s: Patients with current or previous Sxs (Class I) when use of ARNi not feasible; ARBs: If intolerant to ACEIs when ARNi not feasible (Class I) * ARBs are reasonable alternatives as first line agents
  especially if taking an ARB for another indication (Class IIa); ARNi: Patients with current or previous Sxs who tolerate an ACEi or ARB, replacement with ARNi further reduces mortality

Question 22

ARNI should not be administered to patients with a history of

Answer 22

angioedema

Question 23

Summary: ACC/AHA Guidelines

Answer 23

• …inhibition of the RAS with ARNI, ACEI OR ARBs is recommended to reduce M/M.
• ARNIs are preferred and can be used rather than with pre-treatment with ACE/ARBs
• ACEIs/ARBs to reduce M/M is recommended in patients with cannot take ARNIs: ARBs to reduce M/M is recommended in patients with prior or current Sxs who are intolerant to ACE inhibitors because of cough or angioedema

Question 24

Beta-Blockers

Answer 24

• Traditionally contraindicated in the management of HF
• Recent studies (in >20,000 patients, since mid 90s) suggest that some β-blockers provide symptomatic relief, QOL, and reduce hosp (~25%) and mortality (~35%)
• “Reverse remodeling” is proposed as one mechanism of benefit
• Carvedilol (Coreg, Coreg CR), Metoprolol succinate XL (Toprol XL) are approved by the FDA; Bisoprolol (EMEA) for the treatment of heart failure

Question 25

Rationale beta-AR Pathway in Heart Failure

Answer 25

increased cardiac NE –> beta-AR pathway desensitization –> impaired exercise intolerance –> HF
increased cardiac NE –> myocyte toxicity –> myocardial dysfunction –> HF
want to block this

Question 26

Rationale Beta-blockers in Heart Failure

Answer 26

Decrease: ventricular arrythmias, cardiac hypertrophy and cardiac cell death, VC and HR, cardiac remodeling

Question 27

Patient Selection for Beta-Blockers

Answer 27

• STABLE and euvolemic (no marked signs of fluid retention) patients
• Symptomatic patients should receive diuretics also, esp with current or recent history of fluid retention
• Should be considered in patients with bronchospastic disease and asymptomatic bradycardia, but cautiously
• Initiation in hospitalized patients ?
• Do not abruptly discontinue - rebound HTN
  b-blocker withdrawal syndrome: upregulation in # + function of beta-receptors, when you withdraw it, receptors are able to be activated

Question 28

Beta blockers used in HF

Answer 28

bisoprolol, carvedilol, metoprolol XL

Question 29

Carvedilol dose conversion

Answer 29

carvedilol 3.125 mg = coreg CR 10 mg QD
carvedilol 6.25 mg = coreg CR 20 mg QD
carvedilol 12.5 mg = coreg CR 40 mg QD
carvedilol 25 mg = coreg CR 80 mg QD

Question 30

Beta-blockers Monitoring

Answer 30

• BP (and symptomatic hypotension), HR (1-2 weeks): Patients can also diary these numbers daily; symptomatic hypotension, bradycardia and dizziness are uncommon if slow titration (reduce dose ~50% if necessary); If hypotension only…reduce other drugs first
• Goal HR is not defined as in CAD
• Edema and fluid retention (1-2 weeks): Patients can also diary weight daily; Risk is 1-2 % (more than placebo) if stable, euvolemic patients are chosen; Intensify diuretic therapy
• Fatigue or weakness: Risk is 1-2 % (more than placebo); More difficult to address, may resolve on own or may require decrease or D/C

Question 31

Consensus Panel Recommendations for Beta-blockers

Answer 31

• Stage B: In all patients with a recent or remote history of ACS and reduced EF, should
  receive one of the agents shown to reduce mortality (Class I); All other patients should receive one of the agents shown to reduce mortality (Class I)
• Stage C: Use one of agents shown to reduce mortality in all patients, with current or
  previous symptoms unless contraindicated (Class I)