
==== Front
J Res Med Sci
J Res Med Sci
JRMS
J Res Med Sci
Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences
1735-1995
1735-7136
Wolters Kluwer - Medknow India

JRMS-29-32
10.4103/jrms.jrms_851_23
Original Article
Development of the first Iranian clinical practice guidelines for the diagnosis, treatment, and secondary prevention of acute coronary syndrome
Sarrafzadegan Nizal 12
Bagherikholenjani Fahimeh 1
Shahidi Shahla 1
Ghasemi Golsa 3
Shirvani Ehsan 24
Rajati Fatemeh 5
Najafi Farid 6
Ghaffari Samad 27
Khosravi Alireza 28
Assareh Ahmadreza 29
Adel Seyed Mohammad Hassan 210
Kojuri Javad 211
Samiei Niloufar 212
Masoudkabir Farzad 213
Farshidi Hossein 214
Kermani-Alghoraishi Mohammad 24
Sadeghi Masoumeh 215
Shafei Davood 216
Jorjani Masoumeh 17
Siavash Mansour 18
Khorvash Fariborz 19
Isfahani Mehdi Nasr 20
Fatemi Behzad 21
Davari Majid 21
Moradinia Mitra 22
Hoseinkhani Ramesh 23
Hajhashemi Valiollah 24
Mohammadifard Noushin 25
Mobarhan Majid Ghayour 26
Momeni Ali 27
Mortazavi Mojgan 3
Akbari Mohammad 28
Sattar Fereshteh 29
Noohi Fereidoun 230
Kheiri Maryam 31
Tabatabaeilotfi Mosa 32
Bakhshandeh Sanaz 32
Janjani Parisa 33
Fakhri Sajad 34
Abdi Alireza 35
1 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
2 Iranian Network of Cardiovascular Research, Tehran, Iran
3 Isfahan Kidney Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
4 Interventional Cardiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
5 Department of Health Education and Health Promotion, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
6 Research Center for Environmental Determinants of Health, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
7 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
8 Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
9 Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
10 Department of Cardiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
11 Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
12 Heart Valve Disease Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
13 Cardiac Primary Prevention Research Center, Cardiovascular Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
14 Cardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
15 Cardiac Rehabilitation Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
16 Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
17 Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
18 Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
19 Isfahan Neurosciences Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
20 Department of Emergency Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
21 Department of Pharmacoeconomics and Pharmaceutical Administration, Pharmaceutical Management and Economic Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
22 Physician of Community Health Center, Isfahan University of Medical Sciences, Isfahan, Iran
23 Deputy of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
24 Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
25 Pediatric Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
26 Iranian UNESCO Center of Excellence for Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
27 Department of Internal Medicine, School of Medical Science, Shahrekord University of Medical Sciences, Shahrekord, Iran
28 Department of Mental Health Nursing, Nursing and Midwifery Care Research Center, Faculty of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran
29 Cardiology Department, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
30 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
31 Department of Health, Ministry of Health and Medical Education, Tehran, Iran
32 Department of Treatment, Development of Standard and Clinical Practice Guideline Group, Ministry of Health and Medical Education, Tehran, Iran
33 Cardiovascular Research Center, Health Institute, Imam-Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
34 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
35 Department of Emergency and Critical Care Nursing, Faculty of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran
Address for correspondence: Dr. Farid Najafi, Research Center for Environmental Determinants of Health, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran. E-mail: farid_n32@yahoo.com
2024
11 7 2024
29 3231 12 2023
20 2 2024
04 3 2024
Copyright: © 2024 Journal of Research in Medical Sciences
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

This article introduces the first national guidelines for the management including diagnosis, treatment, and secondary prevention of acute coronary syndrome (ACS) in Iran.

Materials and Methods:

The members of the guideline development group (GDG) were specialists and experts in fields related to ACS and were affiliated with universities of medical sciences or scientific associations in the country. They carefully examined the evidence and clinical concerns related to ACS management and formulated 13 clinical questions that were sent to systematic review group who developed related evidence using Grade method. Finally the GDG developed the recommendations and suggestions of the guideline.

Results:

The first three questions in the guideline focus on providing recommendations for handling a patient who experience chest pain at home, in a health house or center, during ambulance transportation, and upon arrival at the emergency department (ED) as well as the initial diagnostic measures in the ED. Subsequently, the recommendations related to the criteria for categorizing patients into low, intermediate and high-risk groups are presented. The guideline addressed primary treatment measures for ACS patients in hospitals with and without code 247 or having primary percutaneous coronary intervention (PCI) facilities, and the appropriate timing for PCI based on the risk assessment. In addition, the most efficacious antiplatelet medications for ACS patients in the ED as well as its optimal duration of treatment are presented. The guideline details the recommendations for therapeutic interventions in patients with ACS and acute heart failure, cardiogenic shock, myocardial infarction with nonobstructive coronary arteries (MINOCA), multivessel occlusion, as well as the indication for prescribing a combined use of anticoagulants and antiplatelet during hospitalization and upon discharge. Regarding secondary prevention, while emphasizing the referral of these patients to rehabilitation centers, other interventions that include pharmaceutical and nonpharmacological ones are addressed, In addition, necessary recommendations for enhancing lifestyle and posthospital discharge pharmaceutical treatments, including their duration, are provided. There are specific recommendations and suggestions for subgroups, such as patients aged over 75 years and individuals with heart failure, diabetes, and chronic kidney disease.

Conclusion:

Developing guidelines for ACS diagnosis, treatment and secondary prevention according to the local context in Iran can improve the adherence of our health care providers, patients health, and policy makers plans.

Acute coronary syndrome
clinical practice guideline
ST-elevation myocardial infarction
non-ST-elevation myocardial infarction
unstable angina
==== Body
pmcBACKGROUND

Ischemic heart diseases, including acute coronary syndrome (ACS), account for almost half of the deaths related to cardiovascular disease (CVD).[1] ACS is the leading cause of hospitalization for both men and women in the United States. Each year, over 5 million Americans refer to the emergency room for chest pain and other related symptoms, with 10% diagnosed with acute myocardial infarction (AMI) and 50% with unstable angina (UA).[2]

ACS is a condition of myocardial ischemia that usually occurs due to a sudden decrease in coronary blood flow and includes a range of diseases from UA to myocardial infarction (MI) mainly caused by the formation of a thrombus on the atherosclerotic plaque.[3] Patients suffering from MI are divided into two separate groups: MI with ST-elevation (STEMI) and MI with non-ST-elevation (NSTEMI), based on electrocardiogram (ECG) results.[4]

Despite the remarkable advances in the management of ACS patients,[4] ACS remains a major global health issue, with the Middle Eastern countries being one of the areas of concern worldwide.[5] In Iran, CVD is the most common cause of death, accounting for approximately 46% of deaths. The prevalence of these diseases is experiencing an upward trend.[6] The results of a study by Ahmadi et al. in 31 provinces of Iran showed that the incidence of death per 1000 persons/year in followed up patients with STEMI and NSTEMI patients was 3698.4 and 4573.3 per 1000 persons/year, respectively. Moreover, the predominant type of stroke in Iranian patients is MI with ST-segment elevation.[7] On the other hand, ischemic heart disease ranked as the second priority in a study by the national network of CVD research in 2022.[8]

Therefore, accurate and prompt diagnosis followed by precise early intervention, which includes administering emergency care, is crucial in reducing complications and mortality in ACS. The multiple components of emergency care should be viewed as an interconnected system that complements each other, encompassing home-based prehospital care, transfer to the hospital, and in-hospital care.[9]

Clinical practice guidelines (CPG) are essential tools for optimizing the care and treatment of patients, including CVD patients. Guidelines consist of clinical recommendations founded on systematic, up-to-date, and credible research evidence to assess the effectiveness and safety of interventions.[10] Their goal is to enhance the efficiency of interventions, promote equitable access to services, and aid health policymakers, physicians, health-care providers, and patients in making informed decisions.[11]

Different countries have created distinct clinical guidelines for preventing, managing, and treating ACS.[101213141516] These guidelines differ in their scope (e.g. prevention, diagnosis, and treatment), the user group within the field, and the specific target population. Few guidelines cover all levels of service provision and different areas and take into account dealing with the patients from the onset of the pain until reaching the emergency room and then hospitalization in general or specialized hospitals. In general, developing guidelines for ACS is more challenging than developing guidelines for other diseases. This difficulty primarily arises from encompassing three conditions within ACS, including STEMI, NSTEMI, and UA. In addition, the complexity of managing and treating ACS patients involves navigating various levels of care, further contributing to the challenge.

Due to the lack of Iranian guidelines for managing ACS, most physicians rely on American or European guidelines. However, these guidelines may not always be applicable or feasible within Iran’s health-care system and local context. As a result, it is imperative to provide recommendations tailored to each level of the health-care system and considering the socioeconomic situation and patients’ beliefs in Iran.

Therefore, taking into account, the previously mentioned concerns and considering the Iranian patients’ level of awareness like their misconceptions about heart pain, social and economic conditions, as well as the structure and environment of providing health services in Iran like the existence of a favorable structure of the health and treatment system and the possibility of referral and follow-up of patients, we decided to develop the first Iranian guidelines for the management and treatment of ACS.

MATERIALS AND METHODS

Participating groups in the development of guidelines

Steering Committee (SC)

This committee included the project executive, officials of the Office of Health Technology Assessment, Standardization, and Tariff of the Ministry of Health who officially requested the development of the CPG, and members of the guidelines development and updating unit in the Cardiovascular Research Institute (a WHO collaborating center) affiliated to the Isfahan University of Medical Sciences. This group was in charge of selecting the experts who would develop the guidelines at a national level. The SC was responsible to monitor the schedule of the whole process until finalizing the guideline development.

Guideline development group (GDG)

This group consisted of 26 members mainly from the national network of CVD, experts, and specialists from different universities of medical sciences at a national level including but not limited to Tehran, Isfahan, Tabriz, Mashhad, Shiraz, Hormozgan, Shahrekord, and Ahvaz, research institutes, and scientific associations related to the fields of cardiology. The group included specialists in the following fields (intervention cardiology, cardiac surgery, heart failure and cardiac transplant, emergency medicine, family physicians, endocrinologists, neurologists, nephrologists, pharmacologists, and health economists). In addition, there were nurses and staff working in related organizations like the deputy of health and treatment of universities and cardiac patients.

Systematic review group (SRG)

The members of this group were independent pundits and were experts in the field of systematic review and meta-analysis who were interested in this subject. None of the members in this group belonged to the guideline development group.

Declaration of conflicts of interest

To identify the types of conflicts of interest (e.g., finance, work, research, and consultancy), the standard conflict of interest approved by the Ministry of Health of Iran was completed and signed by all members of the GDG, SC, and systematic review group (SRG). There were no cases of conflict of interest in the completed forms; however, according to prior planning, it was decided if any conflict of interest was identified while maintaining the confidentiality of information, the cases would be managed by the SC members and decisions like exclusion from participation in the group or restriction of participation in meetings or discussions would be adopted.

Scope of guidelines and questions

The scope defined the main axes of the clinical questions, included the functional area, the target groups, and the outcomes obtained from the guideline. The scope of the guideline, according to the GDG members, was determined to be management, which involved diagnosis, treatment, and secondary prevention (pharmacological and nonpharmacological therapies after discharge). The target group includes all male and female adults who are aged 18 years and older and have ACS events.

However, the GDG considered some subgroups such as patients aged over 75 years, women, and those with post coronary artery bypass graft (CABG), chronic kidney disease, diabetes mellitus, heart failure, COVID-19, and ACS with angiographically normal coronary arteries. No relevant evidence was found for subgroups of women and COVID-19 patients. Therefore, there are no specific recommendations or suggestions related to them.

To determine and rank the outcomes, the members of the SC prepared an initial list of outcomes related to the diagnosis, management, and treatment of ACS. The GDG members were asked to submit their suggested outcomes electronically through a provided form. Some similar outcomes were merged following discussions and the sharing of perspectives among the GDG members. Then, the GDG members were asked to rank each outcome based on its relative importance using a scale of one to nine.[17]

Having received the opinions of the GDG, the average score for each outcome was determined. Accordingly, an average score of 7–9 signified that the outcome was critical, while 4–7 denoted it was important, and 1–3 indicated that it was not important.[17] Finally, only critical outcomes [Table 1] were included in the design of Population, Intervention, Comparison, and Outcomes (PICO) questions.

Table 1 The expected critical outcomes of the ACS guideline include

All-cause mortality	
Cardiovascular mortality (30 days, 1 year, and at >1 year)	
30-day and 1-year re-infarction	
30-day and 1-year readmission for cardiovascular reasons	
Stroke	
MACE	
Bleeding outcomes	
MACE=Major adverse cardiac events

In the next step, clinical questions were extracted in the form of PICO questions. At the beginning of this process, the GDG was asked to categorize their initial questions regarding ACS-related problems according to the residency place like rural or urban, the Iranian health infrastructure and facilities available in health houses in rural or urban health centers or general and referral specialized hospitals. Therefore, dealing with patient with ACS whether at home or during transfer and in hospitals was addressed. Later, following an initial review and discussions between GDG members with the assistance of the methodologist 130 questions were evaluated. Any ambiguous, inappropriate, or repetitive questions were deleted, while similar questions were combined, resulting in 24 and ultimately 13 questions. Questions 5 and 6 were merged later because they were completely related, as supported by similar evidence.

At the next step, an analytical framework was created [Figure 1] that showed the impact of interventions on outcomes and specified the order of the 13 PICO questions to better visualize and integrate them along the patient management pathway.

Figure 1 Analytical Framework of ACS

To identify the values and preferences of patients with ACS, a session of focus group discussion was held with the participation of 12 patients having anyone of ACS events such as STEMI, NSTEMI, and UA. During this session, the participants’ preferences for diagnosis measures, nonpharmacologic therapy including healthy lifestyle behaviors, and medical therapy at different levels of service delivery and follow-ups were extracted and taken into account in the design of PICO questions.

Search for evidence

This process was carried out by the SRG members who were selected by the SC. The SRG members were primarily researchers working at the Center for Systematic Review and Meta-analysis Studies of the Kermanshah University of Medical Sciences. Several coordination meetings were held with this group, and neither the SC nor the GDG members were engaged with the SRG and their work process of extracting the evidence.

For each PICO question, a systematic search was conducted in PubMed, Embase, and Cochrane databases by the SRG without a time limit to extract all available and related reviews and scientific evidence. The evidence for each PICO question was analyzed based on specified outcomes and population subgroups, and the findings were likewise presented in a similar manner. Initially, a review of all systematic reviews or a review of reviews was conducted based on the Cochrane Review (Umbrella Systematic Review). This approach involved identifying the most recent data from new systematic reviews. If there were no new systematic reviews available for any of the questions, it was intended to carry out a systematic review using primary studies. The systematic reviews found were evaluated in terms of their up-to-datedness, the degree of compliance with the PICO questions, the assessment of their methodology by the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) tool, the provision of sufficient information to assess the certainty of the evidence, and reporting evidence for each outcome and the subgroups; subsequently, the most appropriate ones were selected.

Then, the evidence was rated using the standard Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach suggesting the assessment of the certainty and quality of the evidence, the risk of bias, and inconsistency.[17] The SRG incorporated as many reviews as needed to address all aspects of PICOs. Most of the reviews included exhibited high confidence levels on evaluation using the AMSTAR tool.[18]

Compilation of recommendations and suggestions

To compile the recommendations, the decision-making criteria, evidence-to-decision tables, and the methods for employing the gathered evidence to develop recommendations were explained by the methodologist to the members of the GDG. During these meetings, a review of the most recent related guidelines published in the past 5 years was shared with the GDG.

After that, the evidence found for each PICO was presented in the form of the GRADE evidence profile. The members of the GDG group completed the evidence-to-decision tables by reviewing the evidence while considering the following indicators: patients’ values and preferences, the overall certainty of the evidence, health benefits and harms, resources, costs, acceptability by the health-care providers, the feasibility of implementing the recommendations according to the different levels of health services in Iran, and health equity. Finally, 89 recommendations and suggestions that consist of 71 recommendations and 18 suggestions were developed.

The strength of a recommendation reflected the GDG’s confidence in the extent to which the desirable effects of the recommendations (e.g. beneficial health outcomes) outweighed the potential undesirable effects (e.g. side effects). The recommendations in this guideline were categorized into two groups based on the strength of the evidence as follows:

Strong recommendation: It was based on moderate-to-high quality evidence and had beneficial health outcomes, and the GDG was confident that the favorable effects of adhering to them would outweigh their adverse effects

Suggestion or conditional recommendation: There was greater uncertainty regarding the quality of evidence, the balance between benefits and harms, values and preferences, and the use of resources; however, the GDG concluded that the positive effects of adhering to it would probably outweigh its negative effects.

Updating time

The GDG decided that the update time for this guideline to be set at 2 years.

Funding institution

The Deputy of Treatment of the Ministry of Health and Medical Education provided the funds for developing this guideline.

Recommendations and suggestions

Based on the preceding discussions, the extracted recommendations and suggestions for the PICO questions on the management, diagnosis, treatment, and secondary prevention of ACS are outlined as follows. The documents and evidence of all the recommendations and suggestions are presented in the final report.

PICO1 – Necessary measures in dealing with a patient with chest pain at home, health house, and health center/comprehensive health center

It is recommended that when confronting a patient with chest pain, individuals at home and community health workers in the health house, while creating a calm environment and providing rest to the patient, immediately contact the emergency medical services (115)

It is recommended that when facing a patient experiencing chest pain, individuals at home or community health workers at the health house facility should administer a 325 mg aspirin tablet to the patient until the ambulance arrives. Preferably, the patient should chew the tablet

It is recommended that when facing a patient with chest pain visiting healthcare centers, a nitrate sublingual tablet and a 325 mg aspirin tablet (if not contraindicated) preferably in chewable form should be prescribed by a physician. In addition, an intravenous line should be established, and if there is respiratory distress or oxygen saturation of < 93%, oxygen should be administered, and the patient should be transported to the hospital as soon as possible

It is recommended that when dealing with a patient experiencing chest pain in healthcare facilities, the physician, after conducting initial interventions as aforementioned, should proceed to gather a comprehensive medical history, examine and monitor vital signs (e.g. pulse rate and blood pressure), and if possible, perform an electrocardiogram (ECG) on the patient and promptly send all the information to a cardiologist at the hospital [Figure 2].

Figure 2 Dealing with a patient with chest pain (patient suspected of acute coronary syndrome)

Evidence and rationale

The process of saving patients with ACS begins even before they arrive at medical centers. The measures adopted by ambulance staff play a crucial role in decreasing the mortality rate of these patients. Thus, it is crucial for the patient’s family member to promptly reach out emergency medical center (dial 115) when the patient experiences chest pain or other symptoms of ischemia.[1920]

Based on the findings from a randomized controlled trial (RCT), the implementation of advanced life support (ALS) has been instrumental in reducing the in-hospital mortality rate (death before hospital discharge) among patients with ACS, particularly those with STEMI. ALS involves establishing an effective airway and administering essential medications, including aspirin and sublingual nitroglycerin, for effective treatment.[21]

PICO2 – Necessary measures during the transfer of suspected acute coronary syndrome patients in the ambulance and upon arrival to the emergency department

It is recommended that the transfer of a patient suspected of ACS to the hospital be carried out by an ambulance equipped with a telemonitoring system

It is recommended that during the transfer of a patient suspected of ACS, vital patient information, including vital signs and the results of the ECG, be sent to a cardiologist, and the therapeutic interventions inside the ambulance be administered based on the cardiologist’s prescription

It is recommended that during the transfer of a patient suspected of ACS in the ambulance, thrombolytics, sublingual or intravenous nitrates, and antiplatelet agents be prescribed according to the opinion of a cardiologist

It is suggested that a patient suspected of ACS, after being transferred to the hospital and upon arrival, be admitted to the emergency cardiac triage

It is recommended that on admission of patients diagnosed with STEMI to the hospital, with the confirmation of a cardiologist, code 247 should be activated.

Evidence and rationale

The commencement of diagnostic and therapeutic interventions for ACS patients before their arrival at the hospital will decrease patient mortality rates.[22] Continuous cardiac monitoring and informing the destination hospital during patient transfer have been proven to be beneficial in reducing the mortality of ACS patients. The results of a review study (2022) showed that for patients with symptoms of STEMI being transported to the hospital, the performance of a 12-lead ECG in the ambulance in route to the hospital and promptly informing the receiving hospital on the patient’s arrival were associated with a significant reduction in short-term mortality.[23]

The results of a cohort study in Japan demonstrated that employing a helicopter could diminish the duration required to reach the medical facility in comparison to an ambulance. Nonetheless, this approach did not influence achieving the guideline-recommended goal of 120 min for emergency percutaneous coronary intervention (PCI) in these patients.[23]

Performing a physical examination, conducting an ECG, and sometimes administering thrombolytics, vasodilators, antiarrhythmic medications, and intravenous fluids have been shown to be beneficial. In addition, in instances of ventricular-origin arrhythmias, defibrillators are utilized for treatment.[24] A review study by Cochrane highlighted that prehospital thrombolytic therapy in STEMI patients can lower all-cause mortality (risk ratio: 0.73, 95% confidence interval: 0.37–1.41).[25]

It is highly crucial that suspected ACS patients entering the hospital be transferred with code 247 to provide intervention facilities in advance and hospitalize them for code 247 under the supervision of a cardiologist, leading to a reduction in mortality rates.[26]

PICO3 – First-line diagnostic measures in patients suspected of acute coronary syndrome in the emergency department and time intervals of measuring cardiac enzymes and taking ECG

It is recommended that for patients suspected of ACS and referred to the ED, the initial diagnosis be made based on the patient’s history, physical examination, results of an ECG, and examining cardiac enzymes (high sensitivity [HS] troponin)

It is recommended that in patients suspected of ACS, the HS troponin test should be performed immediately on the patient’s admission to the ED (base time), and repeated one and, if necessary, 3 h later

It is suggested that the creatine kinase myocardial band test should be used only if it is not possible to perform a troponin test

It is recommended that a 12-lead ECG be performed within the first 10 min of the patient’s arrival in the emergency room, and if clinical symptoms persist, it should be repeated

It is recommended that if clinical symptoms persist, along with nondiagnostic or negative ECG, leads V3 and V4 be taken for right ventricular infarction and leads V7–V9 for posterior wall infarction in the ECG

It is recommended that in patients suspected of ACS with hemodynamic instability, an echocardiogram should be performed immediately

It is suggested that for all patients suspected of ACS who are referred to the ED, an echocardiogram should be performed

It is recommended that all patients suspected of ACS should undergo cardiac monitoring until reaching a definitive diagnosis

It is suggested that in patients with a low-to-moderate probability of ACS, a computed tomography (CT) angiography should be performed, and if not possible, other diagnostic measures should be taken.

Evidence and rationale

The recommended actions include performing a 12-lead ECG, conducting cardiac enzyme measurements, and cardiac monitoring following a thorough patient history and comprehensive physical examination to assess the progression of the condition.[20] For the diagnosis of these patients, a combination of measures, such as history assessment, physical examination, ECG analysis, cardiac enzyme measurement, and cardiac monitoring is suggested.[2728] Researchers believe that checking cardiac enzymes can alleviate the workload of the treatment facility. This means that low-risk patients can be discharged from the emergency room in less time and there would be no need for additional treatment measures.[29]

The evaluation of HS troponin as one of the cardiac enzymes can have an important effect on the rapid diagnosis of patients suspected of ACS and improving their prognosis.[30] Performing this assessment upon arrival at the emergency room, as well as 1 and 3 h postarrival, along with an ECG, aids in the prompt diagnosis of acute conditions, such as MI, and the assessment of patient mortality rates.[3132]

Coronary imaging is different in patients with the possibility of ACS. To elaborate, coronary angiography is suitable for patients at high risk of AMI, while individuals with low-to-moderate risk of AMI may benefit from alternative diagnostic tests, such as stress echocardiography, stress magnetic resonance imaging, stress perfusion myocardial scanning, and CT angiography.[33]

PICO4 – Criteria for classifying acute coronary syndrome patients into low-risk, intermediate-risk, and high-risk groups

It is recommended that risk assessment in all patients with NSTEMI-ACS be performed based on one of the thrombolysis in MI (TIMI) or Global Registry of Acute Coronary Events (GRACE) tools [Table 2]

It is recommended that patients with ACS be considered in the high-risk group if they obtain a TIMI score of ≥6 or a GRACE score of ˃140, or have any of the following criteria: hemodynamic instability or cardiogenic shock (CS), life-threatening arrhythmias or cardiac arrest, recurrent or sustained chest pain resistant to treatment, mechanical complications of MI, acute heart failure with resistant angina or ST-segment changes, recurrent dynamic ST- or T-wave changes, especially with intermittent ST-segment elevation, an increase and/ or decrease in troponin levels consistent with MI.

It is recommended that ACS patients should be considered in the intermediate-risk group if they obtain a TIMI score of 3–5 or a GRACE score of 109–140, or have the following criteria: diabetes, renal insufficiency (glomerular filtration rate of <60 ml/min/1.73 m2), left ventricle (LV) dysfunction (LV ejection fraction [LVEF] of <40%), early postinfarction angina, previous revascularization of coronary arteries (PCI and CABG).

It is recommended that ACS patients be considered in the low-risk group if they obtain a TIMI score of 0–2 or a GRACE score of ˂109, or if they lack the criteria mentioned in recommendations.

Table 2 Risk assessment in patients with ACS

Risk assessment method	Groups	
Low risk	Intermediate risk	High risk	
TIMI	Score 0–2	Score 3–5	A score ≥6	
GRACE	Score <109	Score 109–140	Score >140	
Assessment of diseases	No comorbidities or side effects	Existence of any of the following criteria: Diabetes,
renal failure (GFR <60 mL/min/1.73 m2), LV dysfunction (LVEF <40%), early
postinfarction angina, previous coronary revascularization (PCI, CABG)	The presence of any of the following criteria: Hemodynamic
instability or cardiogenic shock, life-threatening arrhythmias or cardiac arrest, recurrent
or persistent or refractory chest pain, mechanical complications of MI, acute heart
failure with refractory angina or ST-segment elevation, frequent changes ST segment or
T wave dynamics, especially with intermittent ST elevation, increased and/or
decreased troponin levels consistent with MI	
ACS=Acute coronary syndrome; TIMI=Thrombolysis in myocardial infarction; GRACE=Global registry of acute coronary events; PCI=Percutaneous coronary intervention; CABG=Coronary artery bypass graft; GFR=Glomerular filtration rate; LVEF=Left ventricular ejection fraction; LV=Left ventricle, MI=Myocardial infarction

Evidence and rationale

ACS risk assessment is crucial for making proper decisions.[34] On admission, the risk score is utilized to predict the risk of short-term or in-hospital mortality or bleeding and to influence subsequent management, including the timing of coronary angiography. Before hospital discharge, individual risk of death, MI, or bleeding may be reevaluated to determine the best ambulatory treatment approach. In the months or years after ACS, risk scores are employed to assess the risk of bleeding and ischemia, enabling the optimal management of future cardiovascular events.[35]

Using GRACE as a risk assessment tool is superior to other risk assessment models.[363738]

PICOs 5 and 6 – First-line treatments in acute coronary syndrome patients in the hospital with and without code 247 facilities, and the proper time to perform percutaneous coronary intervention after performing the risk assessment

It is recommended that patients with STEMI should be transferred to hospitals with code 247 or equipped with facilities required for performing PCI. In hospitals with code 247, primary PCI should be performed in less than 90 minutes. If the transfer to the hospital with code 247 takes less than 120 minutes, the patient should be transferred to more equipped centers for primary PCI.

It is recommended that in patients with STEMI who have not undergone primary PCI if symptoms persist or occur, they should immediately undergo angiography to determine PCI eligibility and receive PCI treatment as soon as possible

It is recommended that in cases where it is impossible to transfer STEMI patients to a hospital with code 247 to perform primary PCI within 2 hours, patients should receive treatment with fibrinolytics. Regardless of the treatment outcome, they should be promptly transferred to a hospital with code 247 or equipped with PCI facilities

It is recommended that patients with UA/NSTEMI who are classified in the high-risk group according to the initial risk assessment be transferred to hospitals with 24-h PCI facilities and receive PCI treatment within the earliest possible time (immediate) up to 2 h after admission to the hospital, and at most within 24 h

It is recommended that patients with UA/NSTEMI at moderate risk be transferred to hospitals with 24-h PCI facilities and receive PCI treatment within a maximum of 72 h after admission to the hospital

It is recommended that low-risk patients with UA/NSTEMI should be referred to the hospital for diagnostic tests (noninvasive and, if necessary, invasive)

It is recommended that in a patient with ACS and multi vessel disease(MVD) without CS or hemodynamic complications, complete revascularization should be performed simultaneously with the infarct-related artery (IRA)-PCI

It is recommended that emergency CABG surgery be administered in ACS patients with active (or persistent) ischemia and at high myocardial risk who lack appropriate anatomy for PCI or have had unsuccessful PCI.

Evidence and rationale

After transferring patients with STEMI to either hospitals equipped with code 247 or those without, they may undergo PCI or receive medical treatment without invasive procedures, second group should be followed by a delayed PCI procedure. PCI is the preferred treatment for STEMI patients.[39] However, in medical centers lacking PCI equipment, fibrinolytic therapy should be administered within 2 h following the onset of symptoms. Subsequently, within 2–24 h, the patient should be transferred to a PCI-equipped hospital for further treatment.[4041]

CABG can be effective in some ACS patients, especially patients with ACS who are at high risk of myocardial damage. Patients who have failed PCI and have appropriate coronary anatomy for CABG can also benefit from CABG. A meta-analysis encompassing 9 studies and 9299 in non-ST-elevation-ACS patients with multivessel coronary disease (MVD) and/or unprotected left main coronary artery disease (CAD) revealed that CABG led to greater reductions in major adverse cardiac events (MACE), MI, and the necessity for revascularization over a long-term follow-up period of 3–5 years compared to PCI.[42]

PICO7 – The efficient and economical antiplatelet medications for patients with acute coronary syndrome in the emergency room and the optimal duration for antiplatelet treatment

It is recommended that all patients with ACS in the ED receive an initial loading dose of nonenteric aspirin or chewable aspirin at a dose of 325 mg and continue with a dose of 80–100 mg for 1 year

It is recommended that in patients with ACS referred for PCI, dual antiplatelet therapy (DAPT) including aspirin along with one of the P2Y12 inhibitors (prasugrel or ticagrelor, and if unavailable, clopidogrel) be used for a minimum of 3 months, and if there is no risk of bleeding, it should continue for 12 months

It is recommended that in patients with ACS (as defined in recommendation 2) who will receive one of the P2Y12 inhibitors before PCI, if clopidogrel is prescribed, a 600 mg loading dose and 75 mg/day for maintenance treatment should be administered. If prasugrel is prescribed, a 60 mg loading dose and a 10 mg/day maintenance treatment should be administered, and if ticagrelor is prescribed, a 180 mg loading dose and a 90 mg twice daily maintenance treatment should be used

It is recommended that in patients with ACS, glycoprotein IIb/IIIa inhibitors should be used during PCI when there is a presence of a large thrombus or no reflow

It is recommended that in patients with ACS who are sensitive to aspirin or have aspirin-sensitive asthma, ticagrelor should be administered, and if unavailable, clopidogrel should be given

It is recommended that in all patients with ACS referred for PCI who are at high risk of bleeding, the DAPT regimen (clopidogrel with aspirin) should be continued for up to 3 months, and after three months monotherapy with one of the P2Y12 inhibitors should be done

It is recommended that in patients with ACS who are not referred for PCI and lack a high risk of bleeding, ticagrelor should be prescribed with aspirin for 3 months (except for patients who have recently received thrombolytic), and if there is a high risk of bleeding, clopidogrel should be prescribed with aspirin

It is suggested that in ACS patients over 75 years of age who are referred for PCI, after assessing the risk of bleeding and ischemia, clopidogrel or ticagrelor (or prasugrel with reduced dose) should be administered along with aspirin

It is suggested that in patients with ACS who have been subjected to PCI, after 3 months of using P2Y12 inhibitors as DAPT, they should undergo de-escalation.

Evidence and rationale

The combination of aspirin as an antiplatelet drug with one of the P2Y12 inhibitor family drugs for greater effect is recommended.[43] Clopidogrel is a preferred option alongside aspirin for patients at a high risk of bleeding.[4445] Regarding the duration of treatment with DAPT, a review of 12 RCTs (involving 12,696 patients) showed that there was no significant difference between short-term (3–6 months) treatment with DAPT post-PCI and long-term (12–24 months) DAPT treatment in terms of causing MI, bleeding, stent thrombosis, and mortality.[46]

Based on a meta-analysis conducted on 50,722patients with ACS, DAPT with ticagrelor or prasugrel compared to DAPT with clopidogrel decreased mortality and recurrent MI, and was not associated with a higher risk of bleeding.[47]

Glycoprotein IIb/IIIa inhibitors family drugs are not commonly prescribed, and their usage is typically determined by the physician on a case-by-case basis, usually in particular circumstances [Figure 3].[48]

Figure 3 Flowchart of ACS treatment

PICO8 – Individual or combined therapeutic interventions in acute coronary syndrome patients with acute heart failure or cardiogenic shock

It is recommended that emergency echocardiography should be performed in individuals with ACS who have symptoms of heart failure or CS

It is recommended that emergency angiography and PCI be performed for individuals with ACS and CS, regardless of the time delay from the onset of symptoms

It is recommended that for individuals with ACS and CS without mechanical complications, PCI should only be performed for the culprit lesion and not simultaneously for other vessels. Instead, staged PCI should be conducted for other vessels in subsequent procedures

It is suggested that in patients with ACS and CS undergoing primary PCI, the transradial approach should be implemented, and in some cases, the transfemoral approach may be used based on the physician’s diagnosis

It is recommended that in patients with STEMI and CS if primary PCI is not possible, fibrinolytic drugs should be administered within 2 h of STEMI diagnosis. In the absence of mechanical complications, the use of fibrinolytic drugs should be taken into account

It is recommended that in patients with ACS and CS, emergency CABG should be discussed and decided upon by the Heart Team in the presence of mechanical complications or other indications for CABG

It is recommended that in patients with STEMI and CS having mechanical disorders, support devices should be utilized before invasive interventions, depending on the center’s facilities

It is suggested that in patients with ACS and CS who have intra-aortic balloon pump, venoarterial extracorporeal membrane oxygenation, or Impella implanted that cannot be removed, left ventricular support devices should be used

It is recommended that for patients with ACS and CS if hypoxia is present, inotropic or vasoconstrictor drugs should be administered, and for patients with ACS accompanied by heart failure, intravenous nitroglycerin, inotropic drugs, or vasoconstrictors (norepinephrine, dopamine, and dobutamine) and oxygen should be used

It is recommended that for ACS patients with symptomatic heart failure or LVEF of <40%, beta-blockers, and angiotensin‐converting enzyme (ACE) inhibitors or ARB in case of intolerance to ACE inhibitors should be administered. In addition, mineralocorticoid receptor antagonists (in the absence of hyperkalemia and renal failure), diuretics (in the presence of signs and symptoms of congestion), and sodium-glucose cotransporter 2 inhibitors should be administered [Figure 4].

Figure 4 Manage people with ACS and Cardiogenic Shock (CS)

Evidence and rationale

In cases where CS is suspected following ACS, emergency echocardiography alongside prompt PCI intervention is needed to be performed. Initially, PCI should target the culprit lesion in these patients, with consideration for treating other affected vessels at a later stage.[49]

Transradial access is the preferred method for PCI due to lower bleeding, mortality, and vascular access complications compared to transfemoral access.[5051]

When encountering CS with mechanical complications, it is recommended to utilize assist devices before proceeding with PCI, as such devices have been shown to decrease mortality rates in these cases.[52]

Administering inotropic and vasodilator medications is crucial for these individuals. The review study by Cochrane highlighted the significance of using these drug classes in decreasing mortality rates among patients experiencing hemodynamic instability due to CS. While both categories of drugs are effective, no specific drug within either category has shown superiority in reducing mortality compared to others.[53]

PICO9 – Therapeutic interventions in patients with acute coronary syndrome and normal coronary vessels on angiography

It is recommended that in patients with ACS, specific diagnostic assessments be performed for the final diagnosis of MI with nonobstructive coronary arteries (MINOCA)

It is recommended that treatment for patients with ACS and MINOCA should be based on considering the underlying disease

It is recommended that in patients with ACS and MINOCA, after conducting coronary angiography and failure to reach a diagnosis, cardiac magnetic resonance is performed if possible

It is recommended that in patients with ACS and MINOCA, once the final diagnosis is reached, treatment for the underlying disease should be carried out, and if there are symptoms of atherosclerotic diseases, secondary prevention treatment (lifestyle modification and drug therapy) and risk factor control should be implemented

It is suggested that in patients with ACS and MINOCA, if there is chest pain resistant to treatment, nicorandil and ranolazine should be administered [Figure 5].

Figure 5 MINOCA Management Chart

Evidence and rationale

Special diagnostic tests should be conducted for ACS patients who have been diagnosed with MI with nonobstructive coronary arteries (MINOCA). These patients should be given equal consideration as those with MI,[54] and once a definitive diagnosis is made, treatment for the underlying condition must be initiated. For those with atherosclerosis risk factors, secondary prevention involves lifestyle modification, medication therapy, and managing risk factors.[55] The use of beta-blockers, statins, DAPT, and ACE inhibitors/angiotensin receptor blockers does not show a significant reduction in AMI.[56]

In review studies, MINOCA patients sometimes have intractable pain in the chest, for whom nicorandil and nicorandil have been demonstrated to be an effective treatment.[5557]

PICO10 – Indications and appropriate medication regimen in the combined administration of anticoagulants and antiplatelets during hospitalization and after discharge

It is recommended that oral anticoagulants and antiplatelets be administered simultaneously in patients with ACS and atrial fibrillation, LV thrombosis, atrial thrombosis, LV aneurysm, pulmonary thromboembolism/deep vein thrombosis, and a mechanical valve

It is recommended that in patients with ACS, if there is an indication for prescribing oral anticoagulants (as mentioned in recommendation 1), the choice of drug should be based on the risks of ischemic, bleeding, thromboembolic, and patient preference

It is recommended that in patients with ACS who have an indication for long-term anticoagulant therapy and undergo PCI but are at high risk of bleeding, anticoagulant therapy along with an antiplatelet drug (clopidogrel) should be continued for up to 6 months; following that, only anticoagulant therapy should be continued

It is recommended that in ACS patients who have an indication for long-term anticoagulant therapy, undergo PCI, and are at a high risk of ischemia, anticoagulants with DAPT (clopidogrel and aspirin) should be administered for 1 month, and then the anticoagulant drug should be continued with an antiplatelet drug (clopidogrel) for 12 months. After a year, the anticoagulants should be continued alone

It is recommended that in ACS patients who have an indication for long-term anticoagulant therapy, undergo PCI, and lack a high risk of bleeding or ischemia, previous anticoagulant therapy along with clopidogrel should be used for up to 12 months, and then only anticoagulant therapy should be continued

It is recommended that in ACS patients who will undergo PCI and have previously taken an oral anticoagulant, after assessing the risk of bleeding or thromboembolism, clopidogrel along with aspirin should be used for 1–3 months

It is recommended that in ACS patients who undergo PCI, during PCI, in addition to DAPT, unfractionated heparin (UFH; or enoxaparin in case of previous use) should be prescribed, and in case of high risk of thrombosis, glycoprotein IIb/IIIa inhibitors should also be added

It is recommended that in ACS patients who have chronic kidney failure and are candidates for PCI, the dose of UFH should be modified, and in case of previous use of warfarin with an international normalized ratio of > 2.5, anticoagulant drugs should not be prescribed

It is recommended that in ACS patients who have an indication for anticoagulant therapy and are not a candidate for PCI, anticoagulant drugs should be prescribed, and in the absence of bleeding risk, anticoagulant therapy along with aspirin (or clopidogrel if aspirin is contraindicated) should be prescribed for up to 12 months

It is recommended that in ACS patients requiring antiplatelet therapy along with anticoagulants, the preferred drug from the P2Y12 inhibitors group should be clopidogrel

It is suggested that in patients with high-risk STEMI who have an indication for anticoagulant therapy and are going to use fibrinolytic drugs (but PCI is not possible), after assessing the bleeding risk, anticoagulant drugs should be continued in addition to the loading dose of DAPT.

Evidence and rationale

According to the results of a review study involving 4857 patients with ACS, both those who received PCI and those who did not, the simultaneous administration of DAPT alongside direct oral anticoagulants (DOACs) led to a significant decrease in MI, cardiovascular death, and strokes.[58]

Using antiplatelet medications in conjunction with oral anticoagulants has been found to be effective for ACS patients with one of the following conditions: atrial fibrillation, LV thrombosis, atrial thrombosis, LV aneurysm, pulmonary thromboembolism/deep vein thrombosis, or a mechanical valve.[59] Currently, DOACs are commonly prescribed for patients with venous thromboembolism or atrial fibrillation. However, according to recent review studies, the use of these medications in patients with LV thrombosis can be as effective and safe as warfarin.[60] In ACS patients who are treated with an oral anticoagulant and a P2Y12 inhibitor following PCI, the incidence of bleeding is reduced compared to those who combine these agents with aspirin.[61] Given that aspirin can elevate the risk of bleeding, it is advisable to utilize P2Y12 inhibitors along with anticoagulants in ACS patients when antiplatelet therapy is necessary. It is recommended that health-care providers first assess the thrombotic and bleeding risks in ACS patients before initiating and managing treatment.[62]

PICO11 – Therapeutic measures in acute coronary syndrome patients with multi-vessel occlusion

It is recommended that the treatment of a patient with ACS and MVD should be based on the patient’s clinical condition, comorbidities, disease complexity, and available facilities in the country

In ACS patients with MVD and CS, IRA-only PCI is recommended

In ACS patients with MVD and CS, staged PCI for other vessels is suggested.

Evidence and rationale

In cases where MVD is also present in an ACS patient, the selection of the most optimal treatment approach becomes crucial. A recent review analysis (2023) of 15 research studies determined that for individuals with MVD, it is more advantageous to administer comprehensive revascularization in a step-by-step (staged) manner rather than a one-step procedure. The former approach would lower all-cause and cardiovascular mortality without increasing the chances of MI, revascularization, or MACE.[63]

The optimal treatment approach for NSTEMI patients with MVD or left main CAD remains uncertain. In this regard, a review study (2022) comparing PCI and CABG methods in these patients revealed no significant difference between these two methods in the 30-day follow-up. However, in the extended follow-up period post-PCI, there was a heightened risk of MACE.[42]

In ACS patients with CS, it is recommended to perform PCI as culprit-only or IRA-only and staged PCI for other vessels in the next stages.[49]

PICO12 – Necessary recommendations to improve lifestyle in patients with acute coronary syndrome

All patients with ACS should be referred to rehabilitation centers for secondary prevention and rehabilitation both during hospitalization and after discharge (outpatient) to receive nonpharmacological and pharmacological interventions. The nonpharmacological interventions and recommendations are as follows:

In patients with ACS, education on a healthy lifestyle should be provided, including the following:

It is recommended that ACS patients adhere to the following healthy diet and, if possible, be referred to rehabilitation centers, comprehensive health centers, or private nutrition counseling centers to receive a diet tailored to their individual needs

Patients should eliminate the consumption of foods containing transfatty acids as much as possible. They should consume less saturated fatty acids and replace them with unsaturated oils, preferably canola and olive oil

The total salt intake should be <5 g/day. Consumption of salty foods and adding salt during cooking should be limited, and adding salt to food at the table should be avoided

The consumption of sweets and products containing simple sugars should be decreased

The diet should include fruits and vegetables, low-fat dairy products, whole grains, fish, poultry, lean red meat, and plant proteins, such as legumes and nuts

Supplements and vitamins should only be consumed in case of deficiency or other indications.

It is recommended to maintain a healthy weight (body mass index 18.5–25)

It is recommended to do regular aerobic physical exercise and, with the consent of the treating physician, to have at least 150–300 min of moderate-intensity activity per week (30 min daily and at least 5 times weekly). Inactive individuals should gradually increase their level of activity

It is recommended to abstain from all tobacco products (e.g. hookahs and cigarettes) and alcohol in any amount, and to limit exposure to cigarette smoke. In addition, if prescribed by a physician, patients should seek smoking cessation clinics to quit

It is suggested to avoid using drugs in any amount. In case of previous use, with a physician’s prescription, the patient should be referred to addiction treatment centers

It is recommended to perform psychological interventions for the management of accompanying psychological disorders, and if necessary, pharmacological treatment should be administered as well

It is suggested to avoid exposure to polluted air after discharge from the hospital.

It is recommended to control the risk factors for CVDs in ACS patients

It is recommended to manage and treat all comorbidities related to ACS in these patients

It is suggested to employ telehealth strategies, such as sending text and video messages, educating on the use of mobile applications, and creating electronic health records by physicians and health-care workers for remote health management

It is suggested to educate ACS patients and their families on adherence to medication therapy and lifestyle modifications.

Evidence and rationale

All patients with ACS should engage in a comprehensive cardiac rehabilitation and secondary prevention program immediately following discharge to receive pharmaceutical and nonpharmaceutical interventions. This program, implemented by a multidisciplinary team, focuses on managing and controlling cardiovascular risk factors, healthy lifestyle interventions (e.g. weight control, diet modification, physical activity counseling, and smoking and alcohol cessation counseling), psychological counseling, and education for patients and their families.[6465]

Depression and exposure to tobacco are factors that can elevate the mortality risk associated with CVDs.[666768]

Research has identified a correlation between the eating habits of ACS patients and the risk of mortality.[6970] It has been reported that individuals following a Mediterranean diet exhibit a reduced likelihood of cardiovascular-related mortality.[7172]

Numerous studies have shown the association between prolonged exposure to air pollution and increased risks of CVD, specifically MI.[737475] Employing effective strategies, such as educating patients and their families before discharge, offering distance counseling and training through digital tools (e.g. mobile phones and video clips), and helping to comply with treatment, can potentially prevent up to half of the associated fatalities.[76]

PICO13 – Drug treatments after hospital discharge and their duration in acute coronary syndrome patients

In ACS patients with or without LVEF ≤40% or signs of heart failure after discharge from the hospital:

It is recommended that treatment with aspirin be prescribed

It is recommended that treatment with beta-blockers be prescribed

It is recommended to start high-dose statin therapy as soon as possible. The goal of drug therapy in these patients is to decrease the level of low-density lipoprotein cholesterol (LDL-C) to <55 mg/dl and achieve more than a 50% reduction from the initial LDL-C level

If patients do not reach the treatment goal with the maximum tolerable dose of statin and ezetimibe, combination therapy with a proprotein convertase subtilisin/kexin 9 inhibitor is recommended

It is suggested to use polypill-based therapy to improve adherence to treatment

It is recommended to perform an annual influenza vaccination

It is recommended to prescribe colchicine.

In ACS patients with coronary artery spasm, after discharge from the hospital:

Prescription of long-acting calcium channel blockers is recommended

Prescription of long-acting nitrates is recommended.

In ACS patients with recurrent ischemic attacks after discharge from the hospital:

In addition to the medications mentioned in paragraph one, a prescription of (long-acting) nitrates is recommended if necessary

Prescription of nicorandil is recommended [Figure 6].

Figure 6 Flowchart of Secondary prevention and rehabilitation after ACS treatment

Evidence and rationale

Beta-blockers are the cornerstone of CAD treatment. Their protective effect stems from their negative inotropic and chronotropic properties, as evidenced in numerous RCTs involving patients with MI and stable angina pectoris, leading to a decrease in cardiovascular complications, symptom relief, and myocardial ischemia.[7778]

Multiple RCTs have demonstrated a correlation between decreased LDL-C levels post-ACS and reduced incidence of cardiovascular events.[77]

ACE inhibitors are the first line of treatment for patients with heart failure with preserved left ventricular ejection fraction, with documented efficacy in decreasing mortality and complications.[79]

The utilization of sacubitril/valsartan sodium tablets in the management of AMI patients has been shown to lower the hospitalization rates for heart failure and decrease mortality in individuals with CVDs compared to enalapril.[80]

Patients with a final diagnosis of MINOCA of unknown cause can receive treatment based on secondary prevention guidelines for atherosclerotic disease.[81]

Reducing inflammation with anti-inflammatory medications, such as colchicine, has been validated as a treatment option for secondary prevention in CAD.[82] Maintaining adherence to prescribed medication regimens is crucial in preventing atherosclerotic events. Research indicates that employing a polypill-based strategy enhances treatment adherence for secondary prevention of CVDs.[83]

CONCLUSION

This guideline was developed in a standard method with the cooperation of the steering committee, guideline development and systematic review groups, all of whom were experts in different and related fields from all over the country, as well as patients and their families. Compilation of recommendations and suggestions related to each PICO question was done based on the latest available scientific evidence as well as the structure of the health system and the socio-economic status of the country. Therefore, this guideline will be useful for general and specialist physicians and other service providers in the field of ACS management.

Financial support and sponsorship

This study was funded by Vice-Chancellor for Treatment of Iran’s MOH and Isfahan University of Medical Sciences (Hakami Grant).

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

This project (with number 51120) was prepared based on the request of the ViceChancellor for Treatment of Iran’s MOH. We appreciate the specialists, faculty members, and researchers who contributed to the various stages of project. We also appreciate the patients for participating in the meetings and expressing their values and preferences, and the support team members and IT experts who cooperated with us in holding the meetings.
==== Refs
REFERENCES

1. Mendis S Global progress in prevention of cardiovascular disease Cardiovasc Diagn Ther 2017 7 S32 8 28529920
2. Norouzzadeh R Heidari M Predicting the risk of acute coronary syndrome in the elderly based on reported symptoms Feyz J Kashan Univ Med Sci 2013 16
3. Amsterdam EA Wenger NK Brindis RG Casey DE Ganiats TG Holmes DR 2014 AHA/ACC guideline for the management of patients with non – ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association task force on practice guidelines J Am Coll Cardiol 2014 64 e139 e228 25260718
4. Li YH Wang YC Wang YC Liu JC Lee CH Chen CC 2018 Guidelines of the Taiwan Society of Cardiology, Taiwan Society of Emergency Medicine and Taiwan Society of Cardiovascular Interventions for the management of non ST-segment elevation acute coronary syndrome J Formos Med Assoc 2018 117 766 90 30017533
5. Moran AE Forouzanfar MH Roth GA Mensah GA Ezzati M Murray CJ Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: The global burden of disease 2010 study Circulation 2014 129 1483 92 24573352
6. Beyranvand M Kolahi A Ghafelebashi S Charactristics and final diagnosis of patients with primary diagnosis of acute coronary syndrome J Babol Univ Med Sci 2008 10 76 82
7. Ahmadi A Soori H Sajjadi H Modeling of in hospital mortality determinants in myocardial infarction patients, with and without type 2 diabetes, undergoing pharmaco-invasive strategy: The first national report using two approaches in Iran Diabetes Res Clin Pract 2015 108 216 22 25771308
8. Sarrafzadegan N Bagherikholenjani F Noohi F Alikhasi H Mohammadifard N Ghaffari S Priority setting in cardiovascular research in Iran using standard indigenous methods J Res Med Sci 2022 27 91 36685027
9. Safarabadi M Pakniyat A Dervishi A Harorani M The performance of emergency medicine services for patients with suspected acute coronary syndrome, Arak, Iran Clin Res 2016 2 153 7
10. Jneid H Addison D Bhatt DL Fonarow GC Gokak S Grady KL 2017 AHA/ACC clinical performance and quality measures for adults with ST-elevation and non-ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association task force on performance measures Circ Cardiovasc Qual Outcomes 2017 10 e000032 28935817
11. World Health Organization WHO Handbook for Guideline Development World Health Organization 2014
12. Kimura K Kimura T Ishihara M Nakagawa Y Nakao K Miyauchi K JCS 2018 guideline on diagnosis and treatment of acute coronary syndrome Circ J 2019 83 1085 196 30930428
13. National Institute for Health and Care Excellence Acute coronary syndrome Network meta-analysis: Anti-platelets for managing unstable angina or NSTEMI or STEMI, NICE guideline NG185 2020
14. Collet JP Thiele H Barbato E Barthélémy O Bauersachs J Bhatt DL 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Eur Heart J 2021 42 1289 367 32860058
15. Li YH Lee CH Huang WC Wang YC Su CH Sung PH 2020 focused update of the 2012 guidelines of the Taiwan society of cardiology for the management of ST-segment elevation myocardial infarction Acta Cardiol Sin 2020 36 285 307 32675921
16. Chew DP Scott IA Cullen L French JK Briffa TG Tideman PA National heart foundation of Australia and cardiac society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016 Med J Aust 2016 205 128 33 27465769
17. Schünemann H Brożek J Guyatt G Oxman A The GRADE Handbook UK Cochrane Collaboration London 2013
18. Shea BJ Reeves BC Wells G Thuku M Hamel C Moran J AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both BMJ 2017 358 j4008 28935701
19. Hitchcock T Rossouw F McCoubrie D Meek S Observational study of prehospital delays in patients with chest pain Emerg Med J 2003 20 270 3 12748152
20. Papai G Csato G Racz I Szabo G Barany T Racz A The transtelephonic electrocardiogram-based triage is an independent predictor of decreased hospital mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention J Telemed Telecare 2020 26 216 22 30526257
21. Stiell IG Maloney J Dreyer J Munkley D Spaite DW Lyver MB Advanced life support for out-of-hospital chest pain: The OPALS study(†) Prehosp Emerg Care 2022 26 428 36 35191797
22. Alizadeh R Aghsaeifard Z Sadeghi M Hassani P Saberian P Effects of prehospital traige and diagnosis of ST segment elevation myocardial infarction on mortality rate Int J Gen Med 2020 13 569 75 32943908
23. Nakashima T Hashiba K Kikuchi M Yamaguchi J Kojima S Hanada H Impact of prehospital 12-lead electrocardiography and destination hospital notification on mortality in patients with chest pain – A systematic review Circ Rep 2022 4 187 93 35600724
24. Nishigoori S Kobayashi N Shibata Y Shirakabe A Yagi T Takano M Helicopter emergency medical service for patients with acute coronary syndrome: Selection validity and impact on clinical outcomes Heart Vessels 2022 37 1125 35 35032206
25. McCaul M Lourens A Kredo T Pre-hospital versus in-hospital thrombolysis for ST-elevation myocardial infarction Cochrane Database Syst Rev 2014 2014 CD010191 25208209
26. Kroupa J Knot J Ulman J Bednar F Dohnalova A Motovska Z Characteristics and survival determinants in patients after out-of-hospital cardiac arrest in the era of 24/7 coronary intervention facilities Heart Lung Circ 2017 26 799 807 28111177
27. Stoyanov KM Hund H Biener M Gandowitz J Riedle C Löhr J RAPID-CPU: A prospective study on implementation of the ESC 0/1-hour algorithm and safety of discharge after rule-out of myocardial infarction Eur Heart J Acute Cardiovasc Care 2020 9 39 51 31298551
28. Burgos LM Trivi M Costabel JP Performance of the European Society of Cardiology 0/1-hour algorithm in the diagnosis of myocardial infarction with high-sensitivity cardiac troponin: Systematic review and meta-analysis Eur Heart J Acute Cardiovasc Care 2020 10 279 86 32597681
29. Than M Cullen L Reid CM Lim SH Aldous S Ardagh MW A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-pacific region (ASPECT): A prospective observational validation study Lancet 2011 377 1077 84 21435709
30. Eggers KM Aldous S Greenslade JH Johnston N Lindahl B Parsonage WA Two-hour diagnostic algorithms for early assessment of patients with acute chest pain – Implications of lowering the cardiac troponin I cut-off to the 97.5th percentile Clin Chim Acta 2015 445 19 24 25771107
31. Vigen R Diercks DB Hashim IA Pandey A Zhong L Kutscher P Association of a novel protocol for rapid exclusion of myocardial infarction with resource use in a US safety net hospital JAMA Netw Open 2020 3 e203359 32320036
32. Khand A Frost F Grainger R Fisher M Chew P Mullen L Identification of high-risk non-ST elevation myocardial infarction at presentation to emergency department. A prospective observational cohort study in North West England BMJ Open 2020 10 e030128
33. Nestelberger T Wildi K Boeddinghaus J Twerenbold R Reichlin T Giménez MR Characterization of the observe zone of the ESC 2015 high-sensitivity cardiac troponin 0h/1h-algorithm for the early diagnosis of acute myocardial infarction Int J Cardiol 2016 207 238 45 26808985
34. Chang AM Fischman DL Hollander JE Evaluation of chest pain and acute coronary syndromes Cardiol Clin 2018 36 1 12 29173670
35. Chan Pin Yin D Azzahhafi J James S Risk assessment using risk scores in patients with acute coronary syndrome J Clin Med 2020 9 3039 32967247
36. Chew DP Hyun K Morton E Horsfall M Hillis GS Chow CK Objective risk assessment versus standard care for acute coronary syndromes: A randomized clinical trial JAMA Cardiol 2021 6 304 13 33295965
37. Fox KA Fitzgerald G Puymirat E Huang W Carruthers K Simon T Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score BMJ Open 2014 4 e004425
38. D’Ascenzo F Biondi-Zoccai G Moretti C Bollati M Omedè P Sciuto F TIMI, GRACE and alternative risk scores in acute coronary syndromes: A meta-analysis of 40 derivation studies on 216,552 patients and of 42 validation studies on 31,625 patients Contemp Clin Trials 2012 33 507 14 22265976
39. Villablanca PA Olmedo W Weinreich M Gupta T Mohananey D Albuquerque FN Staged percutaneous intervention for concurrent chronic total occlusions in patients with ST-segment-elevation myocardial infarction: A systematic review and meta-analysis J Am Heart Assoc 2018 7 e008415 29654206
40. Fazel R Joseph TI Sankardas MA Pinto DS Yeh RW Kumbhani DJ Comparison of reperfusion strategies for ST-segment-elevation myocardial infarction: A multivariate network meta-analysis J Am Heart Assoc 2020 9 e015186 32500800
41. Yang HT Xiu WJ Zheng YY Liu F Gao Y Ma X Invasive reperfusion after 12 hours of the symptom onset remains beneficial in patients with ST-segment elevation myocardial infarction: Evidence from a meta-analysis of published data Cardiol J 2019 26 333 42 29611165
42. Barssoum K Kumar A Rai D Kharsa A Chowdhury M Thakkar S Meta-analysis comparing percutaneous coronary intervention with coronary artery bypass grafting for non-ST elevation acute coronary syndrome in patients with multivessel or left main disease Curr Probl Cardiol 2022 47 101306 35810843
43. Marques GL Albuquerque AM Romaniello G Bozzi FP da Cunha GP Andraus GS Antithrombotic regimens for the prevention of major adverse cardiac events in chronic coronary syndrome: A systematic review and network meta-analysis Front Cardiovasc Med 2023 10 1040936 37089879
44. Gao CZ Ma QQ Wu J Liu R Wang F Bai J Comparison of the effects of ticagrelor and clopidogrel on inflammatory factors, vascular endothelium functions and short-term prognosis in patients with acute ST-segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention: a pilot study Cellular Physiology and Biochemistry 2018 48 385 96 30016801
45. Li J Wang Q Wu C Qu X Zhang L He X Safety and efficacy of ticagrelor versus clopidogrel in East Asian patients with acute coronary syndrome undergoing percutaneous coronary intervention treated with dual antiplatelet therapy: A meta-analysis of randomized controlled trials Cardiology 2023 148 363 73 37094558
46. Misumida N Abo-Aly M Kim SM Ogunbayo GO Abdel-Latif A Ziada KM Efficacy and safety of short-term dual antiplatelet therapy (≤6 months) after percutaneous coronary intervention for acute coronary syndrome: A systematic review and meta-analysis of randomized controlled trials Clin Cardiol 2018 41 1455 62 30225978
47. Lepone A Castiglione V Gentile F Scalera S Negro F Ridolfi L Comparison of the efficacy and safety between different oral P2Y12 receptor inhibitors in patients with acute coronary syndrome: A systematic review and meta-analysis Europ Heart J 2022 43 Suppl 2 ehac544 1231
48. Verdoia M Khedi E Ceccon C Suryapranata H De Luca G Duration of dual antiplatelet therapy and outcome in patients with acute coronary syndrome undergoing percutaneous revascularization: A meta-analysis of 11 randomized trials Int J Cardiol 2018 264 30 8 29776573
49. Hu MJ Yang YJ Jiang WY Xu J Culprit-only versus multivessel percutaneous coronary intervention among STEMI patients complicated by cardiogenic shock in real-world practice: An updated systematic review and meta-analysis Ann Palliat Med 2021 10 8628 41 34379982
50. Del Rio-Pertuz G Mekraksakit P Ansari MM Meta-analysis comparing vascular access site on mortality in patients undergoing primary percutaneous coronary intervention with ST-elevation myocardial infarction complicated by cardiogenic shock Am J Cardiol 2022 168 173 4 35090699
51. Ahsan MJ Ahmad S Latif A Lateef N Ahsan MZ Abusnina W Transradial versus transfemoral approach for percutaneous coronary intervention in patients with ST-elevation myocardial infarction complicated by cardiogenic shock: A systematic review and meta-analysis Eur Heart J Qual Care Clin Outcomes 2022 8 640 50 35460230
52. Del Rio-Pertuz G Benjanuwattra J Juarez M Mekraksakit P Argueta-Sosa E Ansari MM Efficacy of mechanical circulatory support used before versus after primary percutaneous coronary intervention in patients with cardiogenic shock from ST-elevation myocardial infarction: A systematic review and meta-analysis Cardiovasc Revasc Med 2022 42 74 83 35570152
53. Schumann J Henrich EC Strobl H Prondzinsky R Weiche S Thiele H Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome Cochrane Database Syst Rev 2018 1 CD009669 29376560
54. Pelliccia F Pasceri V Niccoli G Tanzilli G Speciale G Gaudio C Predictors of mortality in myocardial infarction and nonobstructed coronary arteries: A systematic review and meta-regression Am J Med 2020 133 73 83.e4 31260664
55. Alves da Silva P Bucciarelli-Ducci C Sousa A Myocardial infarction with non-obstructive coronary arteries: Etiology, diagnosis, treatment and prognosis Rev Port Cardiol 2023 42 655 66 36905982
56. De Filippo O Russo C Manai R Borzillo I Savoca F Gallone G Impact of secondary prevention medical therapies on outcomes of patients suffering from myocardial infarction with nonobstructive coronary artery disease (MINOCA): A meta-analysis Int J Cardiol 2022 368 1 9 35987312
57. Tamis-Holland JE Jneid H Reynolds HR Agewall S Brilakis ES Brown TM Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: A scientific statement from the American Heart Association Circulation 2019 139 e891 908 30913893
58. Diaz Quintero L Mata A Diaz Espinoza L Fuentes H Taf A Outcomes of dual antiplatelet therapy in combination with direct oral anticoagulants in patients with acute coronary syndrome: A meta-analysis Europ Heart J 2022 43 Supplement_2 ehac544 1379
59. Brunetti ND Tricarico L De Gennaro L Correale M Santoro F Ieva R Meta-analysis study on direct oral anticoagulants versus warfarin therapy in atrial fibrillation and PCI: Dual or triple approach? Int J Cardiol Heart Vasc 2020 29 100569 32637570
60. Cochran JM Jia X Kaczmarek J Staggers KA Rifai MA Hamzeh IR Direct oral anticoagulants in the treatment of left ventricular thrombus: A retrospective, multicenter study and meta-analysis of existing data J Cardiovasc Pharmacol Ther 2021 26 173 8 33078629
61. Colleran R Byrne RA Ndrepepa G Alvarez-Covarrubias HA Mayer K Kuna C Antithrombotic therapy with or without aspirin after percutaneous coronary intervention or acute coronary syndrome in patients taking oral anticoagulation: A meta-analysis and network analysis of randomized controlled trials Cardiovasc Revasc Med 2022 36 99 106 34099410
62. Khan SU Arshad A Riaz IB Talluri S Nasir F Kaluski E Meta-analysis of the safety and efficacy of the oral anticoagulant agents (Apixaban, Rivaroxaban, Dabigatran) in patients with acute coronary syndrome Am J Cardiol 2018 121 301 7 29195825
63. Rawat A Nazly S Kumar J Khan TJ Kaur K Kaur G Comparison of immediate versus staged complete revascularisation in patients presenting with acute coronary syndrome and multivessel disease: A meta-analysis of randomized and non-randomized studies Cureus 2023 15 e43968 37746472
64. Ambrosetti M Abreu A Corrà U Davos CH Hansen D Frederix I Secondary prevention through comprehensive cardiovascular rehabilitation: From knowledge to implementation. 2020 update. A position paper from the secondary prevention and rehabilitation section of the European Association of Preventive Cardiology Eur J Prev Cardiol 2021 28 460 95 33611446
65. Abreu A Frederix I Dendale P Janssen A Doherty P Piepoli MF Standardization and quality improvement of secondary prevention through cardiovascular rehabilitation programmes in Europe: The avenue towards EAPC accreditation programme: A position statement of the secondary prevention and rehabilitation section of the European Association of Preventive Cardiology (EAPC) Eur J Prev Cardiol 2021 28 496 509 33611459
66. Adkins-Hempel M Japuntich SJ Chrastek M Dunsiger S Breault CE Ayenew W Integrated smoking cessation and mood management following acute coronary syndrome: Protocol for the post-acute cardiac event smoking (PACES) trial Addict Sci Clin Pract 2023 18 29 37173792
67. Lichtman JH Froelicher ES Blumenthal JA Carney RM Doering LV Frasure-Smith N Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: Systematic review and recommendations: A scientific statement from the American Heart Association Circulation 2014 129 1350 69 24566200
68. Sweda R Siontis GC Nikolakopoulou A Windecker S Pilgrim T Antidepressant treatment in patients following acute coronary syndromes: A systematic review and Bayesian meta-analysis ESC Heart Fail 2020 7 3610 20 32935927
69. Ravera A Carubelli V Sciatti E Bonadei I Gorga E Cani D Nutrition and cardiovascular disease: Finding the perfect recipe for cardiovascular health Nutrients 2016 8 363 27314382
70. Brandhorst S Longo VD Dietary restrictions and nutrition in the prevention and treatment of cardiovascular disease Circ Res 2019 124 952 65 30870119
71. Becerra-Tomás N Blanco Mejía S Viguiliouk E Khan T Kendall CW Kahleova H Mediterranean diet, cardiovascular disease and mortality in diabetes: A systematic review and meta-analysis of prospective cohort studies and randomized clinical trials Crit Rev Food Sci Nutr 2020 60 1207 27 30676058
72. Minelli P Montinari MR The mediterranean diet and cardioprotection: Historical overview and current research J Multidiscip Healthc 2019 12 805 15 31632049
73. Gakidou E Afshin A Abajobir AA Abate KH Abbafati C Abbas KM Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2016: A systematic analysis for the global burden of disease study 2016 Lancet 2017 390 1345 422 28919119
74. Cramer J Jørgensen JT Hoffmann B Loft S Bräuner EV Prescott E Long-term exposure to air pollution and incidence of myocardial infarction: A Danish nurse cohort study Environ Health Perspect 2020 128 57003 32438827
75. Zhu W Cai J Hu Y Zhang H Han X Zheng H Long-term exposure to fine particulate matter relates with incident myocardial infarction (MI) risks and post-MI mortality: A meta-analysis Chemosphere 2021 267 128903 33213879
76. Şaylık F Çınar T Hayıroğlu Mİ Tekkeşin Aİ Digital health interventions in patient management following acute coronary syndrome: A meta-analysis of the literature Anatol J Cardiol 2023 27 2 9 36680440
77. Martínez-Milla J Raposeiras-Roubín S Pascual-Figal DA Ibáñez B Role of beta-blockers in cardiovascular disease in 2019 Rev Esp Cardiol (Engl Ed) 2019 72 844 52 31402328
78. Dahl Aarvik M Sandven I Dondo TB Gale CP Ruddox V Munkhaugen J Effect of oral β-blocker treatment on mortality in contemporary post-myocardial infarction patients: A systematic review and meta-analysis Eur Heart J Cardiovasc Pharmacother 2019 5 12 20 30192930
79. Yu S Jin J Chen Z Luo X High-intensity statin therapy yields better outcomes in acute coronary syndrome patients: A meta-analysis involving 26,497 patients Lipids Health Dis 2020 19 194 32829708
80. Zhang L Yan K Zhao H Shou Y Chen T Chen J Therapeutic effects and safety of early use of sacubitril/valsartan after acute myocardial infarction: A systematic review and meta-analysis Ann Palliat Med 2022 11 1017 27 35365031
81. Ciliberti G Verdoia M Merlo M Zilio F Vatrano M Bianco F Pharmacological therapy for the prevention of cardiovascular events in patients with myocardial infarction with non-obstructed coronary arteries (MINOCA): Insights from a multicentre national registry Int J Cardiol 2021 327 9 14 33242505
82. Razavi E Ramezani A Kazemi A Attar A Effect of treatment with colchicine after acute coronary syndrome on major cardiovascular events: A systematic review and meta-analysis of clinical trials Cardiovasc Ther 2022 2022 8317011 35495414
83. Rivera A Campos B Ceolin S Godoi A Castanha E Campello Jorge CA Polypill-based strategy versus usual care for secondary prevention of cardiovascular disease: A meta-analysis of randomized controlled trials Eur J Prev Cardiol 2023 30 1828 37 37490769
