HEART FAILURE
Clinical Overview

Pharmacotherapy

 

Adrenergic Blockade: Rationale for Use

  • Increased sympathetic nervous system (SNS) activity is a major compensatory mechanism in heart failure
  • Long-term stimulation of SNS leads to the progression of heart failure
  • Adrenergic blockade could help to alleviate progression of heart failure

Increased sympathetic nervous system activity is an important compensatory mechanism in heart failure. However, evidence suggests that long-term activation of the sympathetic nervous system eventually contributes to disease progression. Long-term sympathetic stimulation may contribute to heart failure progression via direct toxic effects of catecholamines on cardiac tissue and to effects of increased heart rate and blood pressure on myocardial oxygen requirements.30

Although it had previously been cautioned that beta-blockers are contraindicated in heart failure due to their short-term hemodynamic effects (decreased cardiac output and blood pressure), it has now been proposed that chronic adrenergic blockade might be useful in the management of this disease by antagonism of the sympathetic nervous system. When used in low doses, some of these agents have been shown to actually improve symptoms of heart failure.31 Studies have generally initiated therapy with one-tenth to one-twentieth the dose used for hypertension or angina due to the initial adverse effects of beta-blockers on hemodynamics in heart failure patients. A very gradual and careful titration is recommended. Several studies have reported that two or more months of therapy are need to see the apparent favorable hemodynamic effects of beta-blockade in these patients.
 

Properties of carvedilol32

  • alpha1-adrenergic-receptor blocker
  • nonspecific beta-blocker
  • antioxidant
  • possible calcium-channel blocker (high dose)

Indications33

  • slow the clinical progression of heart failure
  • may be give to patients who cannot tolerate an ACE inhibitor

Carvedilol is the first beta-blocker to receive an FDA indication for heart failure treatment; it is FDA approved for the treatment of hypertension as well as mild to moderate (NYHA class II - III) heart failure in conjunction with digoxin, diuretics, and ACE inhibitors. The non-selective beta-blocking properties of this agent inhibit sympathetic activity thus decreasing cardiac workload. The vasodilatory effects of alpha-blockade reduce preload and afterload which offsets the negative inotropic action of the non-selective beta-blockade.32

Studies have shown that not all beta-blockers have a beneficial effect on heart failure symptoms and progression of disease. Discussion of studies involving other beta-blockers in the treatment of heart failure is discussed in the Investigational Pharmacologic Strategies section.

Cautions34

  • nonallergic bronchospasm
  • peripheral vascular disease
  • diabetes
  • thyroid disease

Contraindications33

  • severe decompensated heart failure
  • marked bradycardia
  • sick sinus syndrome
  • partial or complete AV block unless a pacemaker is in place
  • bronchial asthma

Because of blockade of beta2-adrenoreceptors, patients with nonallergic bronchospasm should only use carvedilol at the lowest possible dose and only if they cannot tolerate other heart failure therapies. Carvedilol is contraindicated in patients with bronchial asthma. Cardiovascular conditions in which carvedilol is contraindicated include: severe decompensated heart failure, marked bradycardia, sick sinus syndrome, and partial or complete AV block unless a pacemaker is in place.

So far, studies have not shown any aggravation of diabetes or PVD with carvedilol use. However patients should be warned that signs and symptoms of hypoglycemia and hyperthyroidism, i.e. tachycardia, may be masked by the beta-blocking properties of carvedilol.

Side Effects33

  • edema
  • dizziness
  • bradycardia
  • hypotension
  • nausea
  • diarrhea
  • blurred vision
  • rare: reversible deterioration of renal function, mild hepatocellular injury


Drug Interactions34

digoxin

digoxin concentrations are increased by 15%

rifampin

reduces carvedilol plasma concentrations by 70%

cimetidine

increases carvedilol's AUC

quinidine

may increase carvedilol's vasodilating effects

fluoxetine

paroxetine

propafenone

MAO inhibitors
reserpine

may cause severe hypotension / bradycardia

clonidine

hypotension - taper clonidine slowly if stopping therapy

Dosing34

  • Continue down flow chart as long as patient tolerates
  • If patient does not tolerate a new dose, switch them back to the last tolerated dosage.
  • At the start of each new dosage, the patient should be observed for 1 hour for signs of dizziness or light-headedness.
Trials

The U.S. Carvedilol Heart Failure Study35

This study was one of the major determinants for FDA approval of carvedilol for heart failure. 1094 patients with chronic heart failure were enrolled in this double-blind, placebo-controlled study. The Data and Safety Monitoring board recommended early termination of the study because of the dramatic results. The reduction in risk of overall mortality in the carvedilol group was 65%. There was a 27% reduction in the risk of hospitalization for cardiovascular causes in the carvedilol treatment group.

The Australia and New Zealand Study36

This study supported the finding from the U.S. carvedilol study. Patients with mild to moderate heart failure were treated with carvedilol or placebo. After 18 months or more of treatment, the carvedilol group showed a 26% lower rate of death or hospitalization as compared to the placebo group.

 

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