Metoprolol: 20-Year Journey Down the Memory Lane

Introduction (1-2)

Over the past two decades, metoprolol has established its position in managing cardiovascular diseases. As a beta-1 selective adrenergic receptor blocker, it effectively treats and improves outcomes in hypertension, angina pectoris, chronic heart failure, and post-myocardial infarction. In India, where cardiovascular diseases lead to significant morbidity and mortality, the contribution of metoprolol is significant. This article reflects on metoprolol's journey in India over the last 20 years.

Metoprolol's Mechanism of Action and Clinical Benefits (1-2)

Metoprolol selectively blocks beta-1 adrenergic receptors in the heart, reducing heart rate, cardiac output, and myocardial oxygen demand. Its cardio-selectivity minimizes the impact on beta-2 receptors in the lungs and peripheral blood vessels, reducing bronchoconstriction and peripheral vasoconstriction. Metoprolol's ability to reduce heart rate, decrease myocardial oxygen demand, and lower blood pressure without significantly affecting peripheral resistance or bronchial tone underscores its tailored design for cardiovascular therapy.

The Indian Cardiovascular Landscape (3-4)

India is seeing a rise in cardiovascular diseases due to urbanization, lifestyle changes, and genetic predisposition. Cardiovascular diseases are the leading cause of death in India, accounting for over 28% of all deaths, highlighting the need for practical, affordable therapeutic options. Indians are affected by CAD almost 5–10 years before, of which 25% occur before age 40, in contrast to other communities. The incidence of CAD in young Indians is 12%–16%, whereas it is only 5% in the West.

Metoprolol's Adoption in India

Metoprolol is widely used in India for its efficacy and safety. (5) Hypertension, often undiagnosed, untreated, or treated but uncontrolled hypertension is pervasive in India.(6) Metoprolol provides consistent blood pressure control with a favourable side effect profile, making it a preferred choice among Indian physicians. A cross-sectional, observational survey among Indian healthcare professionals conducted by Jadhav et al revealed that metoprolol was the preferred beta-blocker by almost two-thirds of healthcare professionals participating in the survey. (7) Another pan-India survey also reported that metoprolol was the preferred beta blocker by 86.0% of Indian clinicians for managing hypertension with ischemic heart disease. Metoprolol helps to treat arrhythmias and myocardial infarction in acute settings by reducing heart rate and myocardial oxygen consumption; and improving long-term CV outcomes and mortality. (2)

Metoprolol: Cost-Effectiveness and Accessibility (8)

Metoprolol's cost-effectiveness drives its widespread use in India. Affordable medication is crucial for broad access to treatment in an economically diverse country. Generic formulations of metoprolol offer cost-effective options without compromising efficacy or safety, making them accessible to more people, especially in rural areas and economically disadvantaged societies.

Metoprolol: Clinical Studies and Real-World Evidence (9-14)

Numerous Indian clinical studies highlight metoprolol's benefits in various cardiovascular conditions. For example, the Indian Heart Journal reported significant reductions in blood pressure and heart rate in patients with hypertension and angina using metoprolol. Another study showed improvements in exercise tolerance and reduced hospitalization needs in chronic heart failure patients. Real-world evidence from Indian clinical practice supports metoprolol's effectiveness. Data from hospital databases and patient registries indicate reduced cardiovascular events and improved survival rates among Indian patients, consistent with global clinical trial evidence.

MERIT-HF Trial: This trial evaluated metoprolol succinate in chronic heart failure patients, showing a 34% reduction in mortality and a 38% reduction in hospitalizations. Patients also had improved functional capacity and quality of life. Metoprolol succinate reduced mortality and hospitalizations by improving left ventricular function and reducing chronic sympathetic stimulation, enhancing patients' quality of life.

Post-Myocardial Infarction Care: Studies show that metoprolol reduces the risk of subsequent cardiac events, improves survival rates, and decreases sudden cardiac death (SCD) incidence in post-MI patients.

Hypertension Management: Clinical trials confirm that metoprolol effectively reduces systolic and diastolic blood pressure. Its beta-1 selectivity makes it suitable for a broad patient population and is widely recommended for hypertension management. A cross-sectional study from India, “BEAT Survey,” performed on 3743 young (18 to 55 years) hypertensives, reported an average resting heart rate of 82.79±10.41 bpm and BP of 146.82±15.46 / 89.08±8.8 mmHg. Heart Rate (HR) had a significant positive correlation with both Systolic Blood Pressure (SBP) (r = 0.247, p<0.01) and Diastolic Blood Pressure (DBP) (r =0.219, p<0.01). The resting HR was elevated in the Indian population, as observed in this study, which can impact CV morbidity and mortality. Beta-blockers could be useful clinical considerations in this patient population.

Combination Therapy in Resistant Hypertension: Research in India showed that combining metoprolol with ACE inhibitors or calcium channel blockers improved blood pressure control and reduced cardiovascular risk in patients with resistant hypertension.

Real-World Evidence: An Indian Heart Journal study confirmed that metoprolol significantly reduces blood pressure and heart rate in patients with hypertension and angina and improves exercise tolerance and quality of life in heart failure patients. As per a recently published 2024 expert opinion from Indian cardiologists; among beta-blockers, metoprolol is the first treatment choice for post-PCI and in heart failure patients.

Registry Data Analysis: Analysis of Indian hospital databases and patient registries indicated high utilization rates of metoprolol for hypertension, post-MI care, and chronic heart failure. Patients experienced fewer cardiovascular events and hospital readmissions.

Metoprolol: Guidelines Recommendations in CVD (15-18)

Based on extensive clinical studies and real-world evidence, the following recommendations are made for metoprolol use in cardiovascular disease management:

Hypertension Management: Beta blockers are recommended as the first-line treatment in the management of hypertension. The 2023 European Society of Hypertension (ESH) guidelines have revived the role of beta-blockers, including metoprolol, in India, particularly for patients with coexisting conditions such as heart failure, post-myocardial infarction, and hypertension with high heart rates (>80 bpm) and high pulse pressure (> 60 mmHg). This endorsement is based on robust evidence supporting beta-blockers efficacy in reducing cardiovascular events and improving patient outcomes in diverse populations, including those in India.

Chronic Heart Failure: MERIT-HF demonstrated the clinical efficacy of metoprolol succinate in reducing cardiovascular death and MACE and improving the quality of life among patients with LV systolic dysfunction.

Angina Pectoris: Beta-blockers, ACE inhibitors, and ARBs are recommended as first-line therapy in the treatment of hypertension in patients with chronic coronary disease (CCD).

Post-Myocardial Infarction Care: In patients with CCD and LVEF ≤40% with or without previous MI, the use of beta-blocker therapy is recommended to reduce the risk of future MACE, including cardiovascular death. In patients with CCD and LVEF <50%, using sustained-release metoprolol succinate with titration to target doses is recommended in preference to other beta blockers.

Key Takeaways

• Over the past 20 years, metoprolol has been pivotal in managing cardiovascular diseases in India. Its efficacy, safety, cost-effectiveness, and accessibility have made it a preferred choice among healthcare providers.
• As cardiovascular diseases continue to rise in India, metoprolol remains a critical component in the therapeutic arsenal, providing significant benefits to patients.
• Reflecting on metoprolol's journey highlights its importance in Indian cardiology practice and underscores the need for continued research and public health efforts to combat cardiovascular diseases.
• Even today in 2024, Indian cardiologists opine that among beta-blockers, metoprolol is the first treatment choice for post-PCI and heart failure patients.

References

1. Kumar A, Sinha N. Cardiovascular disease in India: A 360-degree overview. Med J Armed Forces India. 2020 Jan;76(1):1-3.

2. Jason Morris; Ayoola O. Awosika; Alexis Dunham. Metoprolol. [Updated 2023 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Accessed on 04.05.2024 from https://www.ncbi.nlm.nih.gov/books/NBK532906/.

3. The changing patterns of cardiovascular diseases and their risk factors in the states of India: The Global Burden of Disease Study 1990–2016. Lancet Glob Health. 2018;6(12)

4. Shetty, Reddy, Patil, Jayaprakash, Sheethal et al. Epidemic of Coronary Artery Disease in Young Indians: Comparative Study of Lipid Indices in Children of Patients with and without Premature Coronary Artery Disease. Journal of Clinical and Preventive Cardiology. 2023;12(1):8-15.

5. Kathiresan M , Saxena A , Tripathy P , Tripathi S , Upendra G. Management of hypertensive patients with ischemic heart disease and the role of a fixed - dose combination of telmisartan and metoprolol: a physician - based research survey. Int J Adv Med 2023 ; 10 : 367 - 76

6. Varghese JS, Venkateshmurthy NS, Sudharsanan N, Jeemon P, Patel SA, Thirumurthy H, Roy A, Tandon N, Narayan KMV, Prabhakaran D, Ali MK. Hypertension Diagnosis, Treatment, and Control in India. JAMA Netw Open. 2023 Oct 2;6(10):e2339098. doi: 10.1001/jamanetworkopen.2023.39098. PMID: 37870834; PMCID: PMC10594142.

7. Jadhav U, Tiwaskar M, Khan A, Kalmath BC, Ponde CK, Sawhney J, Tripathy MP, Hazra PK, Sahoo PK, Routray SN, Chandra S, Alexander T, Chopra VK. Hypertension in Young Adults in India: Perspectives and Therapeutic Options amongst Clinician's in a Cross Sectional Observational Study. J Assoc Physicians India. 2021 Nov;69(11):11-12. PMID: 34781615.

8. Patel RS, Sharma KH, Kamath NA, Patel NH, Thakkar AM. Cost-effectiveness analysis of nebivolol and metoprolol in essential hypertension: a pharmacoeconomic comparison of antihypertensive efficacy of beta blockers. Indian J Pharmacol. 2014;46(5):485-489. doi:10.4103/0253-7613.140577

9. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in congestive heart failure (MERIT-HF). Lancet. 1999;353(9169):2001-7.

10. Reddy S, Bahl A, Talwar KK. Congestive heart failure in Indians: how do we improve diagnosis & management? Indian J Med Res. 2010 Nov;132(5):549-60.

11. Aneja P, Srinivas A, Biswas AD. Comparative clinical study of the efficacy and safety of a S-metoprolol ER tablet versus a racemate metoprolol ER tablet in patients with chronic stable angina. Int J Clin Pharmacol Ther. 2007 May;45(5):253-8.

12. Mittal N, Shafiq N, Reddy S, Malhotra S, Kumari S, Varma S. Evaluation of efficacy of metoprolol in patients having heart failure with preserved ejection fraction: A randomized, double-blind, placebo-controlled pilot trial. Perspect Clin Res. 2017 Jul-Sep;8(3):124-31.

13. Dalal, J., Dasbiswas, A., Sathyamurthy et al. Heart Rate in Hypertension: Review and Expert Opinion. International Journal of Hypertension, 2019(1), 2087064.

14. Kumar, Arram Sreenivas; Kumar, Viveka; Shah, Chetan P; Kasturi, Sridhar; Birla, Ashish; Revankar, Santosh; Yadav, Neeraj Kumar. Hypertension Management in Pre- and Post-Percutaneous Coronary Intervention Patients: An Expert Opinion of Cardiologists from India. Journal of the Practice of Cardiovascular Sciences. 2024;10(1):18-24.

15. Mancia G, Kreutz R, Brunstrom M, et al. The Task Force for the management of arterial hypertension of the European society of hypertension. 2023 ESH guidelines for the management of arterial hypertension. J Hypertens. 2023;41(12):1874–2071.

16. Winchester D, Sun M et al. 2023 Chronic Coronary Disease Guideline-at-a-Glance. J Am Coll Cardiol. 2023 Aug, 82 (9) 956–960.

17. Virani S et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. Aug 2023; 148(9)e9-e119.

18. Satheesh G, Dhurjati R, Balagopalan J et al. Comparison of Indian clinical practice guidelines for the management of hypertension with the World Health Organization, International Society of Hypertension, American, and European guidelines. Indian Heart Journal. 2024 Feb;76(1)6-9.