What is a negative inotrope (inotropic agent)?

From the Guidelines

Beta-blockers, such as carvedilol, metoprolol, and bisoprolol, are the most effective negative inotropes for reducing morbidity and mortality in patients with heart failure, as evidenced by a 34% reduction in mortality in the metoprolol arm of the MERIT-HF trial 1.

Key Points

• Negative inotropes, including beta-blockers, calcium channel blockers, and antiarrhythmic medications, decrease the contractility of cardiac muscle, reducing the heart's ability to pump blood.
• Beta-blockers, such as carvedilol, metoprolol, and bisoprolol, are recommended for the long-term management of patients with hypertension-related LV systolic dysfunction, due to their ability to lower BP and alleviate ischemia and angina 1.
• The CarvedilOl ProspEctive RaNdomIzed CU-mulative Survival (COPERNICUS) trial demonstrated a 38% reduction in mortality risk at 12 months with carvedilol compared to placebo 1.
• The Multicenter Oral Carvedilol Heart failure Assessment (MOCHA) trial showed a dose-related effect of carvedilol, with higher doses of 25 mg twice daily showing greater LV functional and clinical superiority than placebo 1.
• When prescribing negative inotropes, dosing must be carefully considered, especially in patients with existing heart failure or conduction disorders, as excessive negative inotropy can worsen cardiac output.

Important Considerations

• Side effects of negative inotropes may include fatigue, bradycardia, hypotension, and in some cases, worsening heart failure symptoms.
• Negative inotropes are contraindicated in cardiogenic shock and must be used cautiously in patients with bradycardia or heart block.
• The Carvedilol or Metoprolol European Trial (COMET) demonstrated a 17% greater mortality reduction in favor of carvedilol compared to metoprolol XL, with mean daily doses of 85 and 42 mg/d, respectively 1.

From the FDA Drug Label

Ivabradine does not have negative inotropic effects. Ivabradine causes a dose-dependent reduction in heart rate, with no effects on myocardial contractility. The key points are:

• No negative inotropic effects
• Reduces heart rate
• No effects on myocardial contractility 2 2

From the Research

Definition and Effects of Negative Inotrope

• A negative inotrope is a substance that decreases the contractility of the heart muscle, leading to a decrease in cardiac output 3.
• Beta-blockers are an example of negative inotropes, which were once considered contraindicated in patients with chronic heart failure due to their negative inotropic action 4.

Therapeutic Use of Beta-Blockers

• Despite their negative inotropic effects, beta-blockers have become an established treatment for chronic heart failure, as they have been shown to reduce mortality and morbidity in patients with impaired systolic function [(3,4,5)].
• The benefits of beta-blockers in heart failure patients include a decrease in heart rate, a decrease in energy consumption, antifibrillatory effects, protection against adrenergic overactivation, and inhibition of myocardial cell necrosis 3.

Initiation and Titration of Beta-Blocker Therapy

• Beta-blocker therapy should be started in stable patients with a very low initial dosage and then up-titrated to the maximal tolerated dosage [(3,5)].
• The target dose should be the maximum tolerated for adequate bradycardia, and treatment benefit appears proportional to the magnitude of heart rate reduction 5.

Comparison of Different Beta-Blockers

• Different beta-blockers, such as bisoprolol, carvedilol, and metoprolol, have been shown to have similar benefits in reducing morbidity and mortality in patients with heart failure [(3,6)].
• However, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes, and additional studies are needed to fully understand the advantages and disadvantages of selective versus nonselective adrenergic blockade 6.