European Journal of Cardiovascular Medicine

Patients complaining of chest pain is mainly remains the suspects of Acute Myocardial Infarction (AMI) (Karlson et al., 1991)^[14]. The myocardial ischemia can be judged by the severity of chest pain and strongly related with ischemia area in patients (Herlitz et al., 1986)^[16]. Resultant severe myocardial ischemia and AMI brings about sympathetic stimulation which brings about marked increase in circulating catecholamine (Thandroyen et al., 1990)^[17]. Moreover, the density of beta-adrenergic receptors within ischemic myocardial regions increases rapidly, within 30 minutes of coronary artery occlusion (Thandroyen et al., 1990)^[17]. Consequently, damaged heart muscles cells experience heightened sympathic nervous system stimulation during the initial phase of AMI. Treating pain is crucial, not solely for the subjective improvement it provides, but also because the pain itself can trigger systemic circulatory changes such as elevated blood pressure, heart rate and stroke volume (Mannheimer et al., 1985)^[18].

Historically, morphine has been the standard treatment for alleviating chest pain associated with acute myocardial infarction. The recommended protocol typically involves administering an initial intravenous bolus of 2-4 mg, which may be repeated after 5 minutes if necessary (Braunwald et al., 1991)^[19]. However, recent studies have raised concerns about the potential negative effects of morphine in this setting, including increased risk of adverse cardiovascular outcomes. (Boccalandro & Cedeno, 2019)^[21]. This has led to a renewed interest in alternative pain management strategies, such as the use of nitrates, acetaminophen, and non-steroidal anti-inflammatory drugs (Wu et al., 2022)^[28] (Boccalandro & Cedeno, 2019)^[21].

Importantly, early reperfusion of the occluded coronary artery, whether by thrombolytic therapy or primary percutaneous coronary intervention, remains the most effective treatment for limiting myocardial damage and improving patient outcomes (Ahmad & Ali, 2019)^[20] (Kingma, 2020)^[25] (Sayre et al., 2008)^[27] (Iqbal et al., 2022)^[24]. Pain management in AMI is important, as it can mitigate the increased sympathetic activity that results from the ischemic injury (Park & Lucchesi, 1999)^[26] (Fiordelisi et al., 2019)^[22] (Ha & Kim, 2010)^[23]. Another drug isosorbide dinitrate recommended for AMI treatment. Regarding isosorbide dinitrate, the clinical benefits of this agent for pain relief in acute myocardial infarction are not well-established. While isosorbide dinitrate can dilate blood vessels and improve blood flow to the ischemic myocardium, its role in pain management for AMI patients remains unclear (Kingma, 2020) ^[25].

Additional research is needed to fully elucidate the potential benefits and risks of isosorbide dinitrate in this context. In contrast, the benefits of timely reperfusion in acute myocardial infarction are well-documented (Kingma, 2020)^[25] (Iqbal et al., 2022)^[24] (Sayre et al., 2008)^[27]. Early restoration of blood flow to the occluded coronary artery, whether via thrombolytic therapy or primary percutaneous coronary intervention, has been shown to significantly reduce myocardial damage and improve patient outcomes. (Kingma, 2020) ^[25]. Use of metoprolol also been pushforward as potential drug but need detail investigation for AMI patients’ treatment. Metoprolol is a cardio-selective beta-blocker used in the treatment of hypertension and angina, and is also used to reduce mortality due to myocardial infarction. Metoprolol is a selective beta-1 blocker commonly employed as the succinate and tartrate derivatives depending if the formulation is designed to be of immediate release or extended release. (Silberstein et al., 2015)^[1].

In the present study the possible positive outcome of metoprolol intravenous 5mg every 2 minutes up to total dose of 15 mg  followed by 50 mg oral tablet on day1,100mg BD day 2 and onwards on patients suffering from acute myocardial infarction has been put forward once control drug considered as isosorbide dinitrate and diazepam and data was comparatively represented for possible significant changes especially  reduction of chest pain, reduction and limiting the infarct size, reduction and suppression of arrhythmias thereby reduction of  the mortality rate.

The study was carried out as randomized controlled trial with patients suffering from Acute Myocardial Infarction (AMI). The study included sample size of 70 patients equally divided into Control and Treated groups.

Age Distribution of Patients:

 As the patients included in the study are ranging between 31-70 years, its average value of age was found to be around 51-52 years once distribution of patients (male and female) carried out in both sets as shown in table 1.

Table 1: Age and Sex Distribution of Patients

Record of Site of Infarction:

Here, the patients with Anterior wall myocardial infarction (n=25) in each both group. Inferior wall myocardial infarction recorded with (n=10) in each group. Among them metoprolol patients (n=2) having previous infarction history and that of control set having (n=4) patients with history of infarction.

Table 2: Site of Infarction and Previous Infarction

Record of Chest pain and Associated Symptoms:

As per chest pain record metoprolol treated patients having precordial pain (n=32), chest pain with epigastric pain (n=3) and chest pain associated with sweating (n=30). In a similar pattern, control patients recorded with precordial pain (n=34), chest pain with epigastric pain (n=1) and chest pain associated with sweating (n=28) as shown in table: 3. similarly, in metoprolol treated group, patients associated with vomiting (n=20), chest pain associated with giddiness (n=2) and chest pain associated with dyspnoea (n=3) was recorded. In case of control set, chest pain associated with vomiting (n=22), chest pain associated with giddiness (n=4) and chest pain associated with dyspnoea (n=18) has been recorded as shown in table 3.

Table 3: Type of Chest pain and Associated Symptoms

15 minutes Chest Pain Relief Pattern

Among 70 sample size, the patients of metoprolol and isosorbide dinitrate and diazepam once administrated with drugs within 15 minutes the relief of chest pain was recorded. It has been observed that 10 out of 35 patients in metoprolol and 4 out of 35 patients in isosorbide dinitrate and diazepam (control) recorded with early relief. Among them those one having Anterior wall myocardial infarction found to be predominately got relief (n=7) and (n=3) for metoprolol and control set, respectively and then for inferior infarction patients (n=3) and (n=1) for the same as above as shown in table 4.

Table 4: Number of Patients showing relief of Chestpain within 15 min after Administration of metoprolol

Patients Chest pain duration and Treatment Interval:

Patients visited hospital with varied period of chest pain with as early as 1 hour to maximum of 12 hours. Hence, upon classification of patients for 6 hours distribution, it has been observed that patients are equally distributed in 0-6 and 6-12 hours groups with no significant change (P>0.6919) as shown in table 5.

Table 5: Interval from onset of Chestpain to starting of Treatment

Clinical class of patients based on Killip's Classification:

As per Killip's classification (class I, II, III, IV), patients in both set found to be predominately recorded in class-I with n=32 and n=21 and for class-II with n=3 and n=11 for metoprolol and control group respectively. No patients were found in class IV class shown in table 6.

Table 6: Clinical class according to Killip's Classification

Addiction and Associated History of Disease:

The patients considered in the study were found to be associated with Addiction of Smoking, followed by Type-A personality, hypertension, obesity, history of IHD and lastly Diabetes mellitus in a decreasing order as shown in table 7.

Table 7: Risk Factors

Treatment Effect on Heart rate:

In a control group during treatment Anterior and Inferior MI patients recorded with 83±9.6 and 80±8.2 beats/minutes as heart rate which was found to be non/significant in change (P>1.00). Once compared to post treatment with 83±5.4 and 80±8.2 beats/minutes heart rate.

In contrast, metoprolol treated group recorded with initial value as 82±7.2 and 78±7.4 in Anterior and Inferior MI patients during Pre-treatment which was found to be significantly (P<0.0001) reduced upon treatment as 67±6.2 beats/minutes, respectively showcased better action of metoprolol as shown in table 8-A).

Table 8: A) Heart Rate (Beats/minute)

Treatment effect on Systolic Blood Pressure:

In a control set pre recorded blood pressure of anterior and Inferior MI recorded as 136±8.8 and 132±8.9 mm Hg, respectively which was non-significant (P>0.3424 and P> 0.3478). Once compared to post treatment blood pressure as 134±8.7 and 130±8.8 mm Hg. In contrast, with treated group Anterior and Inferior MI pre values were recorded as 144±9.8 and 142±9.8 respectively which was significantly (P<0.0001) reduced upon treatment as 130±8.6 and 128±8.5 mm Hg indicates better performance of Metoprolol as shown in table 8-B).

Table 8: B) Systolic Blood Pressure (mm of Hg)

Estimation of Infarct size in Anterior Myocardial Infarction patients:

Among infarct size data, total five parameters were recorded and statistically analyzed. Here except ER in anterior MI once compared to metoprolol versus control found to be statistically non-significant (P>0.0529) while all others recorded as precordial mapping in anterior MI, showing NS-T₃₅ numbers of sites showing ST elevation more than 1 mm in Anterior MI and showing number of Q waves in anterior MI found to be statistically significant (P<0.05) as shown in Table 9.

Table 9: Showing Infarct Size Data recording

Electrocardiographic findings in Anterior MI patients:

Upon treatment for patients with metoprolol and control drugs, the significant change (P<0.05) recorded between them for total five parameters of electrocardiographic findings namely EST₆ lead ECG, NS-T₆, ER in 12 lead ECG, and Number of Q waves in 12 lead ECG in Anterior MI patients as shown in table 10

Table 10: Showing Electrocadiographic Findings in Anterior MI Patients

Electrocardiographic findings in Inferior MI patients:

In a similar manner, electrocardiographic findings for inferior MI has been recorded and similar output was recorded for all the five parameters are significant (P<0.005) change was recorded for Interior MI patients as shown in table 11.

Table 11: Showing Electrocardiographic Findings in Inferior MI Patients

Serum CPK-MB value:

As per Serum CPK-MB value recorded for metoprolol and control drug treated patients, it has been observed that in both Inferior and Anterior MI patients, significant reduction (P<0.0001) in Serum CPK-MB value recorded in the Metoprolol group (75.53±37.37 and 109.12±33.30) once compared to control drug (124.80±47.85 and 133.80±31.19) indicates better performance of metoprolol as shown in table 12.

Table 12: SERUM CPK -MB VALUE:

Arrhythmia:

Incidence of arrhythmia in metoprolol and control drug group has been recorded. Here, upon treatment in metoprolol group defined control in all parameters here recorded once compared to control drug. Metoprolol reduced the incidence of post-infarction arrhythmias, suppressed VPCs and SVPCs in 22.8 % of treated cases. In a control drug set defined mortality, change in V. fibrillation, circulatory arrest, use of lidocaine, SA block, AV block, CHB and reinfarction recorded indicated better control by metoprolol than control drug as shown in table 13.

Table 13: Incidence of Arrhythmia

Long Term Mortality: 

It is interesting to note that all 35 patients in treated group with metoprolol found to be survived unto 365 days of recording indicated its better potential in patient survival. In contrast, control drug based mortality was recorded about 14% within 15 days, 34% up to 3 months and 37% up to one year as shown in table 14.

Table 14

Figure 1

In the study patients with Acute Myocardial Infarction ranging with age group 31-70 yrs found to be positive for anterior and inferior infarction treated successfully with metoprolol as experimental drug along with control drug isosorbide dinitrate and diazepam. Here it has been observed that metoprolol found to be effective in reducing the chest pain once given in acute phase of definite myocardial infarction as compared to isosorbide dinitrate and diazepam.  In a similar kind of study (Herlitz et al.,1984)^[3] reported earlier that metoprolol is promising to reduce chest pain in AMI patient once they have tested with 1395 patients ranging between 40 to 74 yrs with 15mg dose given intravenously and once given as soon as patients got admitted. (Everts et al., 1999)^[5] also reported that the use of metoprolol- morphine during Memo-study found to be reducing chest pain within 80 minutes after start of double blind treatment. As a side effect they recorded nausea up to 24 hrs of treatment. It is said that management of chest pain in patients mainly during early hours after myocardial infarction is important. Once recorded for short term therapy or long term output (Herlitz et al., 1989)^[6]. The use of high doses of intravenous metoprolol found to be reducing chestpain once studied with myocardial ischemia and especially for those without Q-wave infarction (Everts et al., 1999)^[5] described the effect of intravenous metoprolol on the intensity of chest pain before patient getting hospitalized. They put forward that metoprolol treatment efficiently reduced chestpain by 3.0±1.9 arbitrary units (AU) from before and after IV compared to 2.6±2.1 AU for placebo.

In the present study treatment of metoprolol significantly controlled the heart rate from initial (82±7.3 and 78±7.4) in anterior and inferior MI patients to receive final heart rate as 67±5.4 and 64±6.2 beats/min. Evidence of better heart rate controlling ability confirmed with IV metoprolol IV 50mg to once a daily dose of metoprolol CR/XL once taken 3 times daily as noted by Andersson et al., (2001)^[9].

The treatment of metoprolol also found to be promising in, efficient in reducing systolic blood pressure. According to Bengtsson et al., (1975)^[10] metoprolol with 80mg dose in the morning able to reduce systolic blood pressure where diastolic blood pressure remains statistically non-significantly. They reported lowest systolic pressure as 160±8 to 140±4 mm Hg which is in agreement to the present study also. Present study showcased that metoprolol treated patients recorded with reduced level of Serum CPK-MB value (75.53±37.37 and 109.12±33.30). The similar result published by Boyle et al., (1983)^[11] where patients received metoprolol within 6 hours of myocardial infarction recorded some clinical problem related to early intravenous metoprolol. The metoprolol therapy of AMI patient found to be effective in reducing the mortality as till 365 days we have not recorded any mortality but in case of isosorbide dinitrate and diazepam therapy maximum 37% mortality was recorded. The promising effect of metoprolol once compared to thiazide diuretics once noted for mortality with coronary heart disease and stroke. In contrast to Li et al., (2017)^[13] reported that metoprolol and carvedilol both found to be lesser in significant for cardiovascular death, revascularisation and rehospitalisation. Rather they put forward better evidences for carvedilol as compared to metoprolol as suggested further study also.

In accordance to many published data our study also showcasing significant reduction in early chest pain with relief, better and controlled heart rate, promising improvement with controlled systolic blood pressure, reduction and limitation of infarct size, reduction of nonfatal reinfarction, reduction of mortality, morbidity and significant reduction of cardiac deaths, especially sudden cardiac deaths. The patients those were followed up to 365 days found to be better in health with reduced side effects and mainly 100% survival rate up to 365 days with metoprolol as compared to 37% mortality with isosorbide dinitrate and diazepam, makes the study valuable to study further.

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