https://meditropics.com/acs/

  Ranjit K. Nath, Director Professor & Head of Cardiology, ABVIMS & Dr. RML Hospital, New Delhi.

Acute coronary syndrome (ACS) is one of the manifestations of ischemic heart disease and is characterized by a sudden reduction in blood supply to the heart. Despite tremendous achievements in its management, ACS remains a leading cause of mortality worldwide(1). To further improve outcomes following ACS, it is paramount for physicians dealing with such patients to implement in clinical practice the latest findings from large RCTs and guidelines.

ACS includes ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina (UA). The most common mechanism for acute myocardial ischemia represents coronary artery plaque rupture (type I MI) that results in thrombosis and leads to either partial or complete occlusion of the coronary artery(2). Other mechanisms of acute myocardial ischemia are due to other illness or process causing an oxygen supply and demand mismatch (type 2 MI) in the myocardium such as microvascular disease, vasospasm, respiratory distress, hypotension/shock and coronary artery dissection. STEMI refers to ACS accompanied with ST elevations in the electrocardiogram (ECG) with concomitant or subsequent appearance of biomarkers of myocardial injury while NSTEMI does not have the typical ST segment elevation. The basis for UA and NSTEMI differentiation is the presence of biomarkers of myocardial damage (cardiac-specific troponins) in the blood sample of patients with NSTEMI and the lack of those in patients with UA.

Chest discomfort at rest is the most common presenting symptom of ACS and affects approximately 79% of men and 74% of women presenting with ACS, although approximately 40% of men and 48% of women present with nonspecific symptoms, such as dyspnea, either in isolation or, more commonly, in combination with chest pain(3)(4). For patients presenting with possible ACS, electrocardiography should be performed immediately (within 10 minutes of presentation) and can distinguish between STEMI and non–ST-segment elevation ACS (NSTE-ACS). STEMI is caused by complete coronary artery occlusion and accounts for approximately 30% of ACS. ACS without significant ST-segment elevation on electrocardiography, termed NSTE-ACS, account for approximately 70% of ACS, are caused by partial or intermittent occlusion of the artery and are associated with ST-segment depressions (approximately 31%), T-wave inversions (approximately 12%), ST-segment depressions combined with T-wave inversions (16%), or neither (approximately 41%)(4).

A cardiac troponin elevation is a factor for differentiating an ACS from unstable angina and other causes of chest pain. It is also a component of the risk stratification of an ACS. Use of high-sensitivity (Hs) troponin assays has been growing consistently over the past decade. It allows for a more rapid detection of troponin elevation even within an hour of the event and with more sensitivity and specificity. Hs-cTn is a continuous variable and its concentration increases over time. Early (i.e., within 1 h or 2 h) absolute changes have shown to be a surrogate of later (within 3 h or 6 h) changes. ESC guidelines recommended its use for rapidly ruling-out and ruling-in protocols using validated thresholds for both baseline and variation (i.e., Δhs-cTn) levels of hs-cTn. It is particularly helpful in ruling out an ACS.

Choosing an adequate treatment modality in ACS involves several critical decisions. First step is to distinguish patients of STEMI from those who present with an NSTEMI or UA. This distinction is most important as it impacts the selection of pharmacotherapy to be used, the timing of action and the priority to be accorded to the patient. We will first briefly look upon the choice of treatment modalities in patients with STEMI. In these patients, the most important goal of management is to timely re-perfuse the culprit vessel and all efforts should be guided to reduce the ischemic time to less than 120 minutes. Ischemic time is the time from onset of symptoms to the institution of reperfusion therapy which can either be a fibrinolytic agent or a percutaneous coronary intervention (PCI). The choice of the strategy for reperfusion depends on the estimated time which will be necessary for the institution of reperfusion therapy. In the case of fibrinolysis, that time is door-to-needle time, while in PCI, it is door-to-balloon time. PCI is the preferred reperfusion strategy in all patients with STEMI who present within 12 hours of symptom onset. The only condition is that PCI must be done within 120 minutes of diagnosing a STEMI. PCI promptly restores the coronary flow by reopening the culprit artery and also definitively assesses coronary anatomy, hemodynamic data and provides prognostic data related to short-term and long-term mortality by calculating the thrombolysis in myocardial infarction (TIMI) flow grade or TIMI frame count. Rapid reperfusion with PCI within 120 minutes reduces mortality from 9% to 7%(4). Mortality reduction has been shown to be greatest in the first 2 to 3 hours although the time of muscle salvation may be modified by presence of functioning collateral coronary arteries, any ischemic preconditioning and reduced myocardial oxygen demands. Mortality reduction in patients with STEMI who are undergoing fibrinolysis is the highest within the first 4 hours, being around 80% after 2 hours and less than 20% after 4 hours of symptom onset(6). 51% increase in mortality is seen if call-to-balloon time is >150 min vs ≤90 min. Apart from this PCI is considered in patients who present more than 12 hours after symptom onset but have clinical evidence of ongoing ischemia, hemodynamic instability, malignant arrhythmias, or heart failure. In brief, European guidelines from 2017 indicate that the stent deployment should be into the culprit artery and a drug-eluting stent (DES) is preferable to a bare-metal stent (BMS) for primary PCI. Also, radial access may be preferred over femoral access when performed by an experienced operator(5). If PCI within 120 minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase should be administered (or streptokinase if cost is a consideration), followed by transfer of the patient to an advanced facility with a goal of definitive PCI within the next 24 hours of admission.. Absolute contraindications are any previous intracranial hemorrhage, ischemic stroke in the past 3 months, central nervous system neoplasm or arteriovenous malformation, major head trauma or surgery within the past month, known active bleeding or bleeding diathesis (with the exception of menses), suspected aortic dissection, severe uncontrolled hypertension unresponsive to emergent medical therapy and use of streptokinase in the last 6 months which may require prompt review of this strategy as an option. Upon deciding for a fibrinolytic strategy, agents that are fibrin-specific and given as a bolus (such as tenecteplase and reteplase) are preferred to other agents due to demonstrated lower risk of intracerebral bleeding and are more convenient to use(7).

 

Along with the decision regarding reperfusion strategy, it is of utmost importance to administer appropriate antiplatelet therapy and anticoagulation treatment in these ACS patients. All patients should receive aspirin as early as possible with an oral loading dose of 162 to 325 mg. The reperfusion strategy which has been decided for the patient further influences the choice of the second antiplatelet agent. In patients undergoing primary PCI, ESC guidelines recommend the use of ticagrelor (loading dose of 180mg and maintenance dose of 90 mg twice daily) or prasugrel (loading dose of 60 mg and maintenance dose of 10 mg daily) or in the case of unavailability of these drugs, Clopidogrel (600 mg loading dose with subsequent dosing of 150 mg in the first week and 75 mg daily). Contraindications to prasugrel include a history of ischemic stroke and/or transient ischemic attack. Apart from these oral drugs, intravenous P2Y12 inhibitor cangrelor is an option when quick on and off action of platelet inhibition is required and especially in patients who have not been pretreated with oral adenosine-diphosphate (ADP) antagonists or in situations where patients cannot absorb orally. With  regard to the timing of the initial dose of the second antiplatelet drug, in patients undergoing PCI, current guidelines support a loading dose with the diagnosis of STEMI. While due to accumulating evidence demonstrating the lack of benefit in term of ischemic prevention and a consistent increase of the risk of bleeding complications associated with pretreatment, the 2020 ESC NSTEMI guidelines have recommended against the routine administration of P2Y12 inhibitors in patients in whom coronary artery anatomy is not known and an early invasive management is planned. GpIIb/IIIa inhibitors are useful in certain clinical scenarios and its adjunctive use at the time of PCI can be considered on a case-to-case basis. These are mostly helpful for patients with a large thrombus burden or in situations with an inadequate P2Y12 antagonist loading. In those patients who have received bivalirudin, the routine adjunctive use of GP IIb/IIIa inhibitors is not recommended, except for “bail-out” therapy in selected cases. In patients undergoing fibrinolysis, Clopidogrel is the recommended P2Y12 inhibitor. Based on trials that evaluated the use of Clopidogrel in this clinical setting, the loading dose in this scenario is 300 mg, administered as soon as possible, followed by maintenance of 75 mg daily.

 

Anticoagulation in patients with STEMI undergoing primary PCI can be done by unfractionated heparin (UFH), low molecular weight heparin (LMWH), and bivalirudin. A meta-analysis by Hai-Long et al. in 2018demonstrated a reduced incidence of MI and death in patients with STEMI treated with enoxaparin compared to UFH, without a difference in major bleeding(8). At present, the latest European Society guidelines for STEMI recommend UFH as the preferred agent, but enoxaparin remains a reasonably safe and alternate consideration. Although initial  studies which studied bivalirudin in patients with STEMI undergoing PCI demonstrated a higher incidence of stent thrombosis, subgroup analysis the of large observational SWEDEHEART study demonstrated similar rates of early stent thrombosis, with patients who were treated with UFH had an increased mortality. Currently, bivalirudin use mostly remains in patients with heparin-induced thrombocytopenia. For patients with STEMI who are undergoing fibrinolysis, an anticoagulant is necessary until revascularization occurs. If there is no planned revascularization, it should be administered at least 48 hours, up to 8 days(5).It seems reasonable to prefer enoxaparin over UFH in patients with STEMI undergoing fibrinolysis, although guidelines suggest class I recommendation for both agents(5).

 

Other general pharmacologic therapy that needs to be chosen and considered in all patients with ACS includes nitrates, analgesics, beta-blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS). Analgesic therapy is useful to relieve chest pain and anxiety which can in turn reduce tachycardia and resultant reduce the myocardial oxygen demand. Nitrate is used for the treatment of chest pain due to ischemia. It is also indicated for the treatment of acute hypertension and can also be utilized as a vasodilator for treatment of acute LV failure. Contraindications for the use of nitrates include the use of phosphodiesterase inhibitors in the past 48 hours, marked hypotension, and if right ventricular (RV) infarction is suspected. The recommended agent for analgesic therapy is intravenous morphine, although it should not be used routinely. It may be beneficial inpatients with severe chest pain who do not respond to nitrates and patients whose presentation is complicated by acute pulmonary edema. Side effects of morphine include bradycardia and hypotension. Oxygen therapy is to be given only in patients with oxygen saturation less than 90% or arterial blood partial pressure of oxygen less than 60 mmHg. All patients with ACS should receive beta-blockers due the subsequent mortality benefit it provides in the short as well as the long term. Absolute contraindications for beta-blockers include the presence of hypotension, acute heart failure, atrioventricular (AV) node block and severe bradycardia. Early beta-blocker institution is generally favored due to the observed reduction of acute malignant ventricular arrhythmias. Metoprolol is the commonly used agent in patients undergoing fibrinolysis or primary PCI. However based on the CAPRICORN trial, patients with left ventricular (LV) dysfunction after STEMI should preferably receive carvedilol(9). RAAS inhibitors, specifically angiotensin-converting enzyme (ACE) inhibitors should be considered in all patients and unequivocally given to the ones with LV dysfunction, diabetes, or hypertension. Angiotensin receptor blockers (ARB) are be the alternative In patients who cannot tolerate ACE inhibitors. They are usually started within 24 hours of hospital admission and are to be continued indefinitely in most patients. Mineralocorticoid receptor antagonists (MRA) have a well-established indication in patients with ACS who have LV dysfunction and are already on a RAAS inhibitor and a beta-blocker. Contraindications of the use of MRAs include acute kidney injury chronic kidney disease with creatinine more 2.5 mg/dL, and the presence of hyperkalemia. In addition, lipid-lowering agents are to be administered in these patients with high-intensity statin. The goal of treatment is a reduction in low-density lipoprotein (LDL) by more than 50% from baseline. Based on data from the IMPROVE-IT trial, ezetimibe should be a given in patients with intolerance or contraindication to statin treatment.

 

The first decision in an NSTEMI/ UA patient is to make is whether the patient requires a coronary angiography or that his condition permits to use non-invasive functional testing (such as myocardial perfusion imaging or stress echocardiography) for assessing the requirement of reperfusion. Patients with UA/NSTEMI can either have an early invasive strategy or an ischemia-guided (i.e., selective invasive) approach. In the early invasive strategy, coronary angiography is performed within 48 hours of presentation, and subsequent decision is taken to manage the patient with either by PCI, CABG, or he/ she can be left on medical therapy alone, depending on the characteristics of coronary anatomy. The ischemia-guided approach uses medical management as a base therapy for all, while coronary angiography is done in patients exhibiting clinical signs and symptoms of ischemia (e.g., non-resolving chest pain, arrhythmic events, etc.), hemodynamic instability or has positive non-invasive testing. While this initial modality choice is made, it should be kept in mind that early invasive strategy is not recommended in two scenarios: 1) patients who have extensive, severe comorbidities, where the risk of revascularization outweighs the benefit, and 2) patients who have chest pain, but a low clinical likelihood of ACS with negative cardiac biomarkers. Studies have suggested that early invasive strategy provides improved mortality with reduction in non-fatal MI and is also associated with a reduction in death from 6.5% to 4.9%(10). Upon making the decision for an early invasive strategy, it is critical to identify certain higher-risk features of the patient that would warrant a coronary angiography sooner rather than later. These include cardiogenic shock, recurrent or ongoing chest pain refractory to medical treatment, mechanical complications of MI, acute heart failure, prior CABG, prior PCI within six months of presentation with the clinical suspicion of in-stent restenosis or patients with a GRACE score greater than 140(11).

 

 

 

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