Role of metoprolol tartrate in management of acute myocardial infarction in the present era

It has long been known that among patients with acute myocardial infarction (MI), beta-blocker therapy is beneficial in reducing infarct size and early mortality. (1) However, there is still an ongoing debate regarding which agent to be used and more importantly when to initiate it? What is the ideal patient population for this therapy and does it make a difference in which route (parenteral or oral) is used? And most importantly –do these agents have a benefit in the current primary percutaneous coronary intervention (PCI) era.

The following review aims to provide evidence-based answers to such questions that are encountered by all physicians and cardiologists involved in caring for cardiac patients.

Why beta-blockers are beneficial in acute MI?

Proposed mechanisms by which these agents benefit MI patients are:

• Decreasing the oxygen demand due to the reductions in heart rate, blood pressure, and contractility, and the consequent relief of ischemic chest pain. (2)
• Decreased risk of ventricular fibrillation as suggested by experimental studies demonstrating an increase in the ventricular fibrillation threshold and by clinical trials showing a relative risk reduction in sudden cardiac death. (3,4)

The first mechanism serves to reduce the ongoing ischemic insult to the myocardium and in principle should limit the infarct size (2). The latter mechanism is responsible for improving survival (4).

The journey of beta-blockers: "The story of several ups and down".

Beta-blockers have long been a component of care in patients with acute myocardial infarction because of the mechanisms cited above. Preclinical studies showed reduced infarct size in dogs, particularly when the beta-blockers are administered before coronary artery ligation. (5)

Several clinical studies performed in the pre-reperfusion era have demonstrated beneficial effects of β-blockers in acute myocardial infarction in terms of reduction of infarct size (6) or improved survival. (7)

In the thrombolytic era, randomized studies involving early intravenous administration of beta-blockers showed promising results. In the appropriate post-infarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with reduced myocardial ischemia, risk of re-infarction, and ventricular fibrillation. (8, 9)

So, the overall use of beta-blockers in the acute setting in patients with STEMI may be summarized as predominantly beneficial in the pre-reperfusion era.

METOCARD-CNIC trial: "The game-changer" (10)

In 2013, Ibanez et al published the results of the effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) study that aimed to fill the existing gap in the clinical investigation of intravenous β-blockade administered before primary PCI in patients with STEMI.

This multicenter, prospective, randomized study compared early IV metoprolol tartrate (prior to reperfusion) to no metoprolol prior to reperfusion.

Patients were eligible for enrolment if they presented with an anterior STEMI, if their symptom duration was >30 min, and if reperfusion could be performed within 6 h of symptom onset. Exclusion criteria included Killip class III or IV, PR interval >240 ms, type II or III atrioventricular block, systolic blood pressure <120 mmHg, heart rate <60 bpm persistently, history of prior MI, or currently active beta-blocker therapy.

MRI was performed 5–7 days after infarction in all other patients and infarct size was quantified.

Relative to controls, infarct size was significantly lower (25.6 ± 15.3 vs 32.0 ± 22.2 g; p = .012) in patients treated with IV metoprolol. This difference was greatest in patients with TIMI grade 0–1 flow prior to PCI; in this cohort, infarct size was 26.7 ± 15.0 g in patients treated with IV metoprolol, and 34.4 ± 20.0 g in controls (p = .0024). Additionally, there was no difference in adverse cardiac events between groups in the first 24 h.

Of note, 34.9% of the initial myocardial area at risk was salvaged in the metoprolol group compared with 27.7% in the control group.

The authors concluded that in patients with anterior wall STEMI, intravenous metoprolol before PCI reduced infarct size and improved left ventricular function with no excess of adverse events within the first 24 hours after STEMI. (10)

How to use metoprolol tartrate in acute MI setting: (10,11)

The most accepted and widely used dosing regimen is essentially the same as was used in METOCARD-CNIC trial: intravenous metoprolol received up to three 5-mg boluses of metoprolol tartrate 2 minutes apart.

Patients who tolerate this regimen should then receive early oral therapy with Metoprolol Tartrate IR 25-50mg PO BID:

One should start the first dose 15-30 minutes after the last IV dose. The goal is to discharge at HR at approximately 70bpm.

Is one beta-blocker preferable over the other?

Metoprolol is a lipophilic cardioselective beta-1-adrenergic receptor inhibitor that competitively blocks beta1-receptors with minimal or no effects on beta-2 receptors at oral doses of less than 100 mg in adults. (12) Unlike non-selective beta-blockers like propranolol, metoprolol is safer for use in patients with peripheral vascular disease, respiratory conditions, and others. (13)

Cardioprotective benefits of beta-blockers in acute MI settings are not a class effect. While Werf et al, (14) who randomized STEMI patients undergoing thrombolysis to receive pre-thrombolysis atenolol or placebo, did not find any reduction in infarct size by intravenous β-blocker administration; the TEAHAT study found a significant infarct size reduction when using intravenous metoprolol (15).

Clinical takeaways:

• Infarct size is a major determinant of post-infarction mortality, so limiting the extent of myocardial necrosis in STEMI is a major therapeutic target. (16)
• Huge resources have been dedicated to exploring novel therapies that might reduce infarct size but so far with little success.
•  IV Metoprolol tartrate- an inexpensive medication already approved for STEMI treatment can significantly reduce infarct size simply by being administered before reperfusion.
•  Once the acute phase is over, the American College of Cardiology recommends that patients who have had a MI be treated with a beta-blocker like metoprolol indefinitely. (11)

References:

1. Anderson JL, Morrow DA. Acute Myocardial Infarction. N Engl J Med 2017; 376:2053.

2. López-Sendón J, Swedberg K, McMurray J, et al. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J 2004; 25:1341.

3. Rydén L, Ariniego R, Arnman K, et al. A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias. N Engl J Med 1983; 308:614.

4. Friedman LM, Byington RP, Capone RJ, et al. Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia. J Am Coll Cardiol 1986; 7:1.

5. Rasmussen MM, Reimer KA, Kloner RA, Jennings RB. Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation. 1977; 56:794–798.

6. Hjalmarson A, Armitage P, Chamberlain D, et al. Metoprolol in acute myocardial-infarction (MIAMI): a randomized placebo-controlled international trial. Eur Heart J. 1985; 6:199–226.

7. Hjalmarson A, Herlitz J, Malek I, et al. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomised trial. Lancet. 1981; 2:823–827.

8. Roberts R, Rogers WJ, Mueller HS, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) II-B study. Circulation. 1991; 83:422–437.

9. Chen ZM, Pan HC, Chen YP, Peto R, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366:1622–1632.

10. Ibanez R, Macaya C, Sánchez-Brunete V, Pizarro Get al.Effect of early metoprolol on infarct size in ST-segment–elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial.Circulation. 2013; 128:1495–1503.

11. https://www.mahealthcare.com/pdf/practice_guidelines/Beta_Blocker_Use_Post_AMI.pdf

12. Morris J, Dunham A. Metoprolol. [Updated 2021 Jul 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532923/

13. Grassi G. Metoprolol in the treatment of cardiovascular disease: a critical reappraisal. Curr Med Res Opin. 2018 Sep;34(9):1635-1643.

14. Bell R, Beeuwkes R, Bøtker HE, Davidson S et al. Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop.Basic Res Cardiol. 2012; 107:300.

15. Risenfors M, Herlitz J, Berg CH, Dellborg M, Gustavsson G, Gottfridsson C, Lomsky M, Swedberg K, Hjalmarsson A. Early treatment with thrombolysis and beta-blockade in suspected acute myocardial infarction: results from the TEAHAT Study.J Intern Med Suppl. 1991; 734:35–42

16. Bell R, Beeuwkes R, Bøtker HE, Davidson S et al. Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop.Basic Res Cardiol. 2012; 107:300.