Battling Heart Failure- Decoding the Scope of Metoprolol

Heart failure in India: What statistics reveal

Estimates reveal that the yearly incidence of HF in coronary heart disease (CHD) patients in India varies from 0.4% to 2.3% per year, implying that 1,20 000-6,90 000 Indians may acquire symptomatic HF owing to CHD each year. The risk factors of HF are also rising in India, which include an ageing population, uncontrolled hypertension, obesity, and diabetes. (4)

The INDUS study concluded that the prevalence was around 1.2/per 1000 people in India. (5) Once developed, heart failure has a 1-year mortality rate of 7.2% and a 1-year hospitalization rate of 31.9% in patients with chronic heart failure. These rates increase to 17.4% and 43.9% for inpatients hospitalized for acute heart failure. (6)

Understanding the pathophysiology of heart failure:

The renin-angiotensin-aldosterone system and the sympathetic nervous system (SNS) are hyperactivated after a myocardial injury, whether acute (e.g., myocardial infarction or myocarditis) or chronic (e.g., hypertension or mitral valve insufficiency), which leads to left ventricular dysfunction. This increase in catecholamine release causes chronic and sustained activation of myocardial beta-receptors, resulting in dysfunction and negative consequences for a failing heart. Cardiac beta-receptor dysfunction in HFrEF is characterized by a reduced beta 1-receptor density and uncoupling of beta 1- and 2-receptors, resulting in their functional desensitization. (1) These processes have clinical repercussions, such as decreased systolic function and left ventricular ejection fraction, accelerated left ventricular remodelling, and the emergence of life-threatening ventricular arrhythmias. (1)

Heart failure classification:

Heart failure staging can be divided into three categories based on the left-ventricular ejection fraction (LVEF):(6)

• Heart failure with preserved ejection fraction (LVEF 50%),
• Heart failure with midrange ejection fraction (LVEF 41%-49%), and
• Heart failure with reduced ejection fraction (HFrEF, in which the LVEF < 40%)

Heart Failure -Treatment Goals

Heart failure has a substantial socioeconomic cost, requiring emergency pharmacological therapy, multiple hospitalizations, productivity loss, early retirement, eventual surgery, and, in rare cases, heart transplant costs. The therapeutic objective for HF patients is to reduce mortality and morbidity, increase the quality of life, and limit disease progression.

Beta-Blockers: Backbone of Heart Failure Therapy

Because of their ability to counteract the sympathetic over-activity associated with left ventricular failure, in addition to reducing heart rate (HR), contractility, and blood pressure and lowering CHF mortality, beta-blockers remain the backbone of treatment for chronic heart failure (CHF) patients. (2) The modulation of sympathetic-adrenergic activation by chronic beta-blocker therapy, whose effects differ from those of acute administration, has resulted in a promising paradigm for the use of these drugs in HF, representing a significant advancement in its therapeutics. Over the years, ample studies have consistently shown that beta-blockers lower morbidity and death in HF patients. (3)

Beta-Blockers Benefit Across the Spectrum of Heart Failure

While extensive, high-quality evidence supports the use of β-blockers for patients with HFrEF (7,8), their efficacy in managing HFpEF is gaining momentum with studies highlighting that beta blockers, by way of reversing the neurohormonal effects of the sympathetic nervous system, may be beneficial in individuals with HFpEF (8). Along these lines, a meta-analysis of 12 studies undertaken to evaluate the efficacy of beta-blockers on mortality and morbidity in HFpEF patients affirmed that beta-blocker therapy was associated with 19% lower all-cause mortality in HFpEF patients. (8)

Beta Blockers in Patients with Heart Failure and Comorbidities:

Research confirms that beta 1-blockers are beneficial and safe in patients with concurrent HFrEF, chronic obstructive pulmonary disease (COPD), or asthma; and are the drugs of choice in these individuals. In patients with COPD, beta 1-selective agents are recommended since they do not interfere with the therapeutic effects of beta-agonists and are not responsible for exacerbating respiratory symptoms. (1)

Place of Metoprolol in Clinical Practice

Metoprolol is an FDA-approved drug used to treat angina, heart failure, myocardial infarction, atrial fibrillation, and hypertension. Off-label uses include supraventricular tachycardia and thyroid storm. Being a cardio-selective beta-blocker, it blocks beta-1 receptors with minimal effects on beta-2 receptors at oral doses of less than 100 mg. It decreases cardiac output through adverse inotropic and chronotropic effects. (9) This drug has exhibited an impressive reduction in CHF mortality and improved the quality of life (QoL) in these patients. (2)

Study Testimonies: Potential Benefit of Metoprolol Tartrate over Metoprolol Succinate

• A study aimed to evaluate the efficacy and tolerance of a selective beta-blocker (ß-1), metoprolol tartrate, in patients with heart failure due to moderate to severe dilated cardiomyopathy, added to the standard care (digitalis, diuretics, angiotensin-conversion enzyme inhibitors or vasodilators, and nitrates). Fifty patients aged 52±14.8 yrs, with functional class II to IV heart failure (HF) and left ventricular ejection fraction (LVEF)< 45%, were evaluated in a retrospective study. Metoprolol tartrate was added to the standard therapy, with a starting dose of 12.5 mg, which was increased weekly to 200 mg/day, according to the patient's tolerance. Results revealed functional class (NYHA) improvement, increased left ventricular ejection fraction, decreased left ventricular-end systolic and diastolic diameter, and reduced HF among patients on metoprolol tartrate. (11)
• Another study (3) aimed to compare the hemodynamic effects of twice-daily metoprolol tartrate (MT) and once-daily metoprolol succinate (MS) in congestive heart failure patients. Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally, and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Results highlighted that long-term therapy with metoprolol was associated with significant functional and exercise improvements. The team concluded that Metoprolol tartrate and metoprolol succinate produce similar hemodynamic and clinical effects acutely and chronically despite the four-fold greater starting dose of MS.
• The Metoprolol in Dilatated Cardiomyopathy (MDC) trial was carried out on 383 patients with idiopathic dilated cardiomyopathy with ejection fraction (EF) below 40%, assigned to a metoprolol or placebo group. Patients in the metoprolol group had 34% fewer primary endpoints (all-cause mortality) than the placebo group. In addition, metoprolol was related to an increase in the ejection fraction (0.13 vs. 0.06, p < 0.0001) and exercise time (p = 0.046) from baseline to 12 months with respect to placebo. (10)

Metoprolol: Dosages Regime:

The immediate-release oral formulation of metoprolol tartrate is to be administered immediately following food intake. As it is a short-acting formulation, metoprolol tartrate is usually prescribed twice daily. (9)

Metoprolol tartare is to be used with caution for patients with a history of noncompliance, as the abrupt cessation of the drug can lead to sudden withdrawal syndromes. (9)

Key pointers-

• Heart failure continues to be a significant health burden in India.
• Because of their potential to counteract the neurohumoral effects of the sympathetic nervous system and hence provide prognostic and symptomatic improvements, Beta-blockers are valuable agents for managing patients with heart failure and diminished ejection fraction. (1)
• Metoprolol is an FDA-approved cardioselective beta 1 blocker used effectively in heart failure.
• A growing body of research highlights the benefits of long-term therapy with metoprolol in HFrEF and HFpEF patients.
• The acute and long-term hemodynamic and clinical effects of metoprolol tartrate and metoprolol succinate are similar, achieved with a four times lower starting dose of metoprolol tartrate.

References

1. Masarone, D.;Martucci, M.L.; Errigo, V.; Pacileo, G. The Use of -Blockers in Heart Failure with Reduced Ejection Fraction. J. Cardiovasc. Dev. Dis. 2021, 8, 101. https://doi.org/10.3390/ jcdd809010

2. Cheng X, Zhu M, Liu Q, Feng Z, Meng Y. Effectiveness of Metoprolol in Improving Cardiac and Motor Functions in Patients with Chronic Heart Failure: A Prospective Study. Drug Des Devel Ther. 2020 Aug 25;14:3485-3494. doi: 10.2147/DDDT.S263026. PMID: 32921985; PMCID: PMC7457782.

3. Kukin, M. L., Mannino, M. M., Freudenberger, R. S., Kalman, J., Buchholz-Varley, C., & Ocampo, O. (2000). Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure. Journal of the American College of Cardiology, 35(1), 45-50.

4. Huffman MD, Prabhakaran D. Heart failure: epidemiology and prevention in India. Natl Med J India. 2010 Sep-Oct;23(5):283-8. PMID: 21250584; PMCID: PMC3913650.

5. Chaturvedi V, Parakh N, Seth S, Bhargava B, Ramakrishnan S, Roy A, et al. Heart failure in India: The INDUS (India Ukieri Study) study. J Pract Cardiovasc Sci2016;2:28-35

6. Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart Failure With Reduced Ejection Fraction: A Review. JAMA. 2020 Aug 4;324(5):488-504. doi: 10.1001/jama.2020.10262. Erratum in: JAMA. 2020 Nov 24;324(20):2107

7. Silverman DN, Plante TB, Infeld M, et al. Association of β-Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients With Heart Failure With a Preserved Ejection Fraction: A Secondary Analysis of the TOPCAT Trial. JAMA Netw Open. 2019;2(12):e1916598. doi:10.1001/jamanetworkopen.2019.16598

8. Bavishi, C., Chatterjee, S., Ather, S., Patel, D., & Messerli, F. H. (2015). Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart failure reviews, 20(2), 193-201

9. Morris J, Dunham A. Metoprolol. [Updated 2022 Jul 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532923/

10. Waagstein, F.; Bristow, M.R.; Swedberg, K.; Camerini, F.; Fowler, M.B.; Silver, M.A.; Gilbert, E.M.; Johnson, M.R.; Goss, F.G.; Hjalmarson, A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993, 342, 1441–1446. [CrossRef]

11.  Figueiredo Neto, J. A. D., Mady, C., & Grupi, C. (2006). Effects of metoprolol tartrate therapy in patients with heart failure. Arquivos Brasileiros de Cardiologia, 87, 329-335.