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Selecting a Treatment Modality in Acute Coronary Syndrome
Introduction
Acute coronary syndrome (ACS) is one of the manifestations of ischemic heart disease.[1][2] The term is used to describe any constellation of symptoms that suggests that acute myocardial ischemia is occurring.[1] ACS encompasses the following clinical entities: unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). The most common mechanism for acute myocardial ischemia represents coronary artery plaque rupture that results in thrombosis and leads to either partial or complete occlusion of the coronary artery.[3] Other mechanisms of acute myocardial ischemia requiring acknowledgment in the current era where effective medical therapy significantly decreased the risk of plaque rupture are plaque erosion, microvascular disease, vasospasm, and restenosis after stenting.[4] 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. STEMI refers to acute coronary syndrome accompanied with ST elevations in the electrocardiogram (ECG) with concomitant or subsequent appearance of biomarkers of myocardial injury.[5] The estimated prevalence of coronary artery disease in the United States of America (USA), including myocardial infarction (MI), is around 6% of the population.[6] In 2008, a report stated the incidence rate of STEMI in the USA was about 50 per 100000 and showing a decreasing trend when compared to earlier years.[7] The national registry of MI reported 2.5 million cases of MI between 1990 and 2006 and additionally demonstrated an increase in the proportion of the cases caused by NSTEMI from 14.2% to 59.1% during the registry timeframe.[8] Numerous factors influence the mortality of patients with STEMI, but the details of these epidemiologic characteristics are beyond the scope of this document. Certain angiography registries report 1-year mortality in STEMI patients to be generally around 10%.[9][10] Some studies demonstrate that short-term mortality in patients with NSTEMI is lower than patients with STEMI, but as the follow-up extends to 2 years, mortality rates become comparable.[11]
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The pharmacologic treatment of ACS can be broken down into several groups of medications that improve survival, decrease recurrent ischemic events, and provide symptomatic relief. Choosing an adequate treatment modality in ACS involves several critical decisions. It is essential to distinguish STEMI patients from those who are experiencing NSTEMI or UA. This distinction further impacts the priorities, timing, and selection of pharmacotherapy used in different patients with ACS.
First is a review of the choice of treatment modalities in patients with STEMI. In this group of patients, the most important objective is to provide timely reperfusion modality with the goal of ischemic time being less than 120 minutes. Ischemic time refers to the time from onset of symptoms to the administration of reperfusion therapy. Reperfusion therapy can be a fibrinolytic agent or a form of percutaneous coronary intervention (PCI). The choice of the reperfusion strategy will depend on the estimation of the time that will be necessary for the administration of reperfusion therapy. In the case of fibrinolysis, that time is referred to as door-to-needle, while in the case of PCI, it is door-to-balloon time. PCI is the preferred reperfusion strategy in all patients with STEMI presenting within 12 hours of symptom onset with the condition that it must be done 120 minutes from STEMI diagnosis.[7] Apart from promptly restoring the coronary flow by reopening the culprit artery, it also provides definitive diagnostic modality for a comprehensive assessment of coronary anatomy, hemodynamic data, determines the need for coronary artery bypass surgery (CABG), 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.[12] PCI should also be considered in patients presenting with symptoms that last more than 12 hours, which also have clinical evidence of ongoing ischemia, hemodynamic instability, malignant arrhythmias, or heart failure. The detailed discussion about the choice of vascular access, revascularization technique, and the optimal type of stent, along with the approach to non-culprit lesions, is out of the scope of this review. Briefly, 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.[7]
Fibrinolysis should be a consideration if the patient first presents to a non-PCI capable facility and the anticipated time from first medical contact to the performance of primary PCI exceeds 120 minutes (this 120-minute duration usually accounts for a 30-minute door in-door out time (DIDO) time goal at the non-PCI capable facility). Upon deciding about whether or not to use fibrinolysis, it should preferably occur within the first 30 minutes of the first medical contact. This strategy can be achieved either as prehospital fibrinolysis by the emergency medical service (EMS) provider or within 30 minutes of arriving at a non-PCI capable facility (door to needle time). Contraindications to fibrinolysis require prompt review if this strategy is an option. 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.[7] Some relative contraindications include a history of chronic poorly controlled hypertension, surgery in the last 3 months, ischemic stroke more than 3 months ago, traumatic or prolonged cardiopulmonary resuscitation (CPR), and any other unspecified intracranial pathology. Some factors merit consideration when considering fibrinolysis based on the available evidence from the recent clinical studies. 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.[13] Patients with developed collateral circulation may have more significant benefits beyond the 2-hour timeframe when compared to patients without collateral circulation. The CAPTIM trial compared prehospital fibrinolysis with PCI in patients with STEMI and found that patients who received treatment with pre-hospital fibrinolysis within 2 hours of symptoms onset had better survival when compared to PCI strategy.[14] Based on the STREAM trial, prehospital fibrinolysis provides similar efficacy when compared to PCI in patients with STEMI who presented within 3 hours and were unable to get PCI within 1 hour but with a higher rate of intracranial bleeding.[15][16] An overview of nine randomized trials published by the Fibrinolytic Therapy Trialist collaborative group suggests that characteristics of patients who derive the least benefit from fibrinolysis are those with a delayed presentation (over 13 to 24 hours of symptom onset), elderly (age greater than 75 years), inferior ST elevations, and uncontrolled hypertension (systolic blood pressure (BP) more than 175 mmHg).[17] Thus, as a general framework, it seems that patients who present with early onset of symptoms but with a significant anticipated delay in transportation to a PCI-capable facility should get fibrinolytic treatment in the absence of absolute contraindications. While on the other hand, patients who present with onset of symptoms longer than 12 hours and absence of hemodynamic instability and evidence of ongoing ischemia of a large amount of myocardium should not receive fibrinolysis due to a likely lack of significant benefit. Other cases require evaluation on a case-by-case basis with careful consideration of risks and benefits. 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.[18][19]
Concomitantly with the decision of reperfusion strategy, it is of paramount importance to institute appropriate antiplatelet and anticoagulation treatment in patients with STEMI. Differences in approach exist depending on the selected reperfusion strategy. In all patients, regardless if they are undergoing PCI or fibrinolysis, aspirin should be administered as early as possible.[20][21][22] The aspirin loading dose should be oral 162 to 325 mg. The already chosen reperfusion strategy influences the choice of the second antiplatelet agent. In patients undergoing primary PCI, current evidence supports the use of oral ticagrelor with a loading dose of 180mg and maintenance dose of 90 mg twice daily or oral prasugrel with a loading dose of 60 mg and maintenance dose of 10 mg daily or clopidogrel with a 600 mg loading dose with subsequent dosing of 75 mg daily.[22][23][24][25] Contraindications to prasugrel include a history of ischemic stroke and/or transient ischemic attack.[25][26] The intravenous formulation of P2Y12 cangrelor could be an option in situations where 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,[27][28] or in situations where patients cannot absorb orally. In regards to the timing of the initial dose of P2Y12 in patients with STEMI undergoing PCI, current guidelines support a loading dose with the diagnosis of STEMI, although there exists a substantial variation in practice. Namely, giving the initial loading dose during PCI, after delineation of the coronary anatomy. Finally, GpIIb/IIIa inhibitors are useful in certain patients. Evidence to support the use of intravenous GP IIb/IIIa receptor antagonists in STEMI was largely established before the use of oral dual antiplatelet therapy. Although prior several studies have failed to show a significant benefit of “upstream” GP IIb/IIIa receptor antagonists use before primary PCI in the setting of dual antiplatelet therapy with either intravenous heparin or bivalirudin, its role is restricted to the use of abciximab based on a meta-analysis which suggested that adjunctive abciximab may be useful in this setting. The adjunctive use of GP IIb/IIIa agents at the time of PCI can be considered in selective situations and on a case-to-case basis, especially for patients with a large thrombus burden or inadequate P2Y12 antagonist loading. In those receiving bivalirudin, the routine adjunctive use of GP IIb/IIIa inhibitors is not recommended, except for “bail-out” therapy in selected cases.[29][30][31]
In patients with STEMI who are undergoing fibrinolysis, clopidogrel is the recommended P2Y12 inhibitor.[32][33] 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. In patients who are older than 75 years, only 75 mg of clopidogrel is the recommended loading dose. Ticagrelor and prasugrel have not been sufficiently investigated in these patients and are not recommended as adjunctive loading therapy, as there might be an increased bleeding risk given the higher potency of these agents. TREAT trial suggests that ticagrelor may be potentially safe in patients with ACS pretreated with clopidogrel who underwent fibrinolytic therapy when administered around 12 hours after the clopidogrel dose.[34] The use of GpIIb/IIIa inhibitors in patients with STEMI who are undergoing fibrinolysis is not recommended.[7]
Anticoagulant agents for consideration in patients with STEMI undergoing primary PCI are unfractionated heparin (UFH), low molecular weight heparin (LMWH), and bivalirudin.[7] Early evidence for the efficacy of UFH in patients with STEMI comes from the pre-fibrinolytic era. With the introduction of fibrinolysis, the publication of ISIS-2, and subsequent introduction of aspirin, the risk and benefit from the addition of UFH to fibrinolytic agents changed, but most of the evidence points out to small, but the significant net benefit of UFH when combined with aspirin versus aspirin alone in patients treated with fibrinolysis.[12] The well-known, small, randomized trial that compared UFH to enoxaparin was the ATOLL trial.[35] Around 900 STEMI patients, who received therapy with aspirin, clopidogrel, and Gp IIb/IIIAa inhibitors (in about 80% of patients) were randomized to UFH versus enoxaparin before primary PCI, and the primary outcome of death, MI complications, procedure failure, or major bleeding showed a non-significant reduction in the enoxaparin group. Data from this trial cannot be extrapolated to patients not treated with GpIIb/IIIa inhibitors and patients treated with ticagrelor or prasugrel. A meta-analysis that took place in 2012, including a large number of trials, demonstrated that enoxaparin was superior to UFH, although the study had limitations due to the inclusion of data from non-randomized trials too. A meta-analysis by Hai-Long et al. in 2018[36][37] demonstrated a reduced incidence of MI and death in patients with STEMI treated with enoxaparin compared to UFH, without a difference in major bleeding. At present, the latest European Society guidelines for STEMI recommend UFH as the preferred agent, but enoxaparin remains a reasonably safe and alternate consideration. The studies which evaluated bivalirudin use in patients with STEMI undergoing PCI demonstrated a higher incidence of stent thrombosis.[38] A subgroup of large observational SWEDEHEART study included STEMI patients treated with UFH compared to bivalirudin and demonstrated similar rates of early stent thrombosis, while patients treated with UFH had increased mortality.[39] Due to limited evidence for routine use of bivalirudin, currently, it remains a safe option to use bivalirudin 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.[12][7] Trials such as ASSENT 3 and ExTRACT-TIMI 25 demonstrated the benefit of enoxaparin when compared to UFH, although the latter study showed increased non-cerebral bleeding complications in patients treated with enoxaparin. The study also included patients with creatinine clearance less than 30 mL/min and patients older than 75 with appropriate dose adjustment.[40][41] It seems reasonable to prefer enoxaparin over UFH in patients with STEMI undergoing fibrinolysis, although guidelines suggest class I recommendation for both agents.[12][7]
Other general pharmacologic therapy that needs to be chosen and considered in all patients with STEMI includes beta-blockers, nitrates, analgesics, and inhibitors of the renin-angiotensin-aldosterone system (RAAS).
All patients with STEMI should receive a beta-blocker in the absence of contraindications.[12][7] Absolute contraindications for beta-blockers in the acute phase include hypotension, acute heart failure, atrioventricular (AV) node block, or severe bradycardia. In the absence of contraindications, the decision comes to whether the patient needs to receive an immediate intravenous beta-blocker or an oral beta-blocker within 24 hours of diagnosis. In patients treated with fibrinolysis, early beta-blocker administration is the favored approach due to the observed reduction of acute malignant ventricular arrhythmias.[42][43][44] In patients undergoing primary PCI, evidence regarding early intravenous administration of beta-blocker and beneficial short and long-term effects is inconsistent; thus, due to the potential for adverse effects, routine use in such a manner is discouraged. Regardless, in every patient with STEMI, early beta-blocker therapy may be considered in hemodynamically stable patients or those with hypertension, ongoing ischemia, or an arrhythmia that would benefit from early beta-blockade.[12][7] A commonly used agent in patients undergoing fibrinolysis or primary PCI is metoprolol. Based on the CAPRICORN trial, patients who have transient or permanent left ventricular (LV) dysfunction after STEMI should preferably receive carvedilol.[45]
Routine use of nitrates in patients with STEMI is not a strong recommendation unless used for angina relief.[7][46] Nitrates should be used in patients with STEMI during the acute phase for the treatment of chest pain due to ischemia, treatment of acute hypertension, or as a vasodilator for treatment of acute LV failure. Contraindications include the use of phosphodiesterase inhibitors in the past 48 hours, marked hypotension with systolic blood pressure less than 90 mmHg, and suspected right ventricular (RV) infarction. The agent used in the acute phase is nitroglycerin. The formulation is usually sublingual, but an intravenous formulation is an option in patients with waxing and waning chest pain and patients with acute LV failure.
Analgesic treatment in patients with STEMI is important to reduce pain, which can lead to sympathetic hyperactivity, which further impairs myocardial oxygen demand. The recommended agent is intravenous morphine, and it should not be used routinely, but in those patients with severe chest pain, not responding to nitrates, and patients whose presentation is complicated by acute pulmonary edema. Side effects of bradycardia and hypotension require monitoring after morphine administration.
Oxygen is indicated in patients in patients with hypoxemia evidenced by oxygen saturation less than 90% or arterial blood partial pressure of oxygen less than 60 mmHg.[47]
There is strong evidence that RAAS inhibitors, specifically angiotensin-converting enzyme (ACE) inhibitors, are beneficial in patients with STEMI.[12][7] These agents should be considered in all STEMI patients and unequivocally given to the ones with LV dysfunction, diabetes, or hypertension.[12][7] In patients who cannot tolerate ACE inhibitors, angiotensin receptor blockers (ARB) should be the alternative. These agents are usually started after 24 hours from admission or during index hospitalization and continued indefinitely in most patients. Mineralocorticoid receptor antagonists, such as eplerenone, have a well-established indication in patients with STEMI who have LV dysfunction and are already on a RAAS inhibitor and a beta-blocker.[12][7][48][49][50][51] Contraindications include acute renal failure, chronic renal failure with creatinine above 2.5 mg/dL, and hyperkalemia.
Lipid-lowering agents are indicated in the treatment of STEMI.[12][7] The choice has to be high-intensity statin, with careful risk and benefit assessment in populations with increased risk of side effects (patients with liver failure, elderly above age 75 years, previous side effects). The goal of treatment is a reduction in low-density lipoprotein (LDL) by more than 50% from baseline. Thus it is important to check lipid levels in patients with STEMI on admission. The timing of initiation of statin treatment has been investigated in the SECURE-PCI trial and showed a trend toward a beneficial effect of early initiation of statin treatment in a subset of patients with STEMI, but data demonstrates no strong statistical significance.[52] Given the absence of harm in administering statin therapy early, it is reasonable to administer a statin as soon as possible following the diagnosis of STEMI. Agents preferably used in this setting are atorvastatin or rosuvastatin. Based on data from the IMPROVE-IT trial, ezetimibe should be a consideration in patients with intolerance or contraindication to statin treatment.[53] Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a group of medications that lower LDL. The two largest trials evaluating this group of medications were FOURIER and ODYSSEY trials. Both trials demonstrated a reduction in major adverse cardiovascular events when adding these agents to statin therapy.[53][54] The ODYSSEY trial involved patients who had ACS within 12 months of enrollment into the study. The major limitation of these agents remains cost. Regardless, they should be considered in patients on optimal statin therapy after STEMI, with the inability to achieve adequate reduction in LDL when assessed on outpatient follow-up.
The principal difference in the management of UA/NSTEMI compared to STEMI is that the initial choice of treatment modality focuses on medical management with anti-ischemic, antiplatelet, anticoagulant and analgesic therapy, all with the goal to minimize ischemia and prevent complications while simultaneously deciding on the timing and appropriateness of coronary angiography versus non-invasive testing and the type of revascularization strategy.
The first decision to make is whether the patient needs a coronary angiography versus a form of non-invasive functional testing (such as myocardial perfusion imaging or stress echocardiography). Generally, patients with UA/NSTEMI can undergo an early invasive strategy or an ischemia-guided (i.e., selective invasive) approach. The early invasive strategy involves coronary angiography performed within 48 hours of presentation, and subsequent PCI, CABG, or medical therapy alone, depending on the characteristics of coronary anatomy. The ischemia-guided approach puts medical management as a priority, while coronary angiography would be the choice 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. When making this initial modality choice, one should keep in mind that early invasive strategy is not recommended in two groups of patients: 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 [55]. Literature suggests that early invasive strategy provides improved mortality and reduction in non-fatal MI.[56][57][58][59][60] Given the available evidence, clinicians should pursue an early invasive strategy in patients with NSTEMI in the absence of contraindications. 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.[11] 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]
Antiplatelet agents have a well-established benefit in UA/NSTEMI patients.[61][62][63] After the diagnosis of UA/NSTEMI has been made or highly suspected, all patients should receive aspirin and subsequently continued on a daily maintenance dose.[21][64] In addition to aspirin, all patients with UA/NSTEMI should receive therapy with a P2Y12 inhibitor.[65][66][11] The choice and timing of administration of the second antiplatelet agent will depend on whether early invasive strategy or ischemia-guided strategy was the choice and whether PCI, CABG, or medical management is the chosen option. PLATO and TRITON TIMI-38 trials have demonstrated more potent inhibition of platelets by ticagrelor and prasugrel when compared to clopidogrel, respectively. Thus for most patients, ticagrelor or prasugrel are the first choices of the second antiplatelet agents, but bearing in mind certain important caveats. In TRITON TIMI 38 trial, prasugrel has been shown to have less efficacy and increased risk of bleeding in patients who were over 75 years old, had a body weight less than 65 kg or had a history of a transient ischemic attack (TIA) or stroke.[23] These patients should not receive prasugrel. Also, patients who will not undergo PCI after coronary angiography should not receive prasugrel.[11] PRAGUE-18 trial demonstrated no difference in efficacy and safety between prasugrel and clopidogrel in patients with ACS undergoing PCI.[24] It is important to note that the PLATO trial included a subset of patients who were undergoing PCI, CABG, or treated medically.[22] Based on the results of the PLATO trial, it is recommended to use 81 mg aspirin dosing for long-term maintenance when using ticagrelor as the second P2Y12 agent. Higher dosing of aspirin (162 to 325 mg) may attenuate the efficacy of ticagrelor. Clopidogrel should be considered as initial therapy if there is a concern regarding cost and access to ticagrelor or prasugrel, or the patient is at increased risk of bleeding. In the subset of patients who are undergoing ischemia-guided strategy, the initial choice of second antiplatelet agent should be ticagrelor, with clopidogrel considered for the same reason as for patients undergoing early-invasive strategy.[22] Prasugrel should be avoided in this group of patients because the TRILOGY ACS trial demonstrated that prasugrel is associated with a slightly increased risk of bleeding when compared to clopidogrel in patients who are not undergoing primary PCI.[26] This data makes ticagrelor a safer option in patients undergoing an ischemia-guided approach when it is still unknown whether PCI will take place or not. Regardless of the initial strategy, a certain subset of patients with UA/NSTEMI will require CABG as a form of revascularization after defining coronary anatomy. These patients will, by that time, usually receive both aspirin and a P2Y12 inhibitor. The recommendation is that clopidogrel and ticagrelor should be held for five days before surgery, while prasugrel should be held seven days before the surgery.[11][55][67] Aspirin should not be interrupted for CABG.[11][55][67] Consideration to stop aspirin 3 to 5 days preoperatively is an option in patients with a significant risk of bleeding who are refusing blood transfusions.[11] Ultimately, unstable patients with UA/NSTEMI who have anatomy more suitable for CABG, have evidence of ongoing ischemia or hemodynamic instability should be considered for emergent CABG regardless of antiplatelet therapy.
Given the complexities in predicting how the revascularization strategy will change, depending on the clinical scenario and coronary anatomy, the timing of the P2Y12 inhibitor administration has been debated due to concern for potentially delaying CABG if such type of revascularization is needed. Based on the current European and American guidelines, both recommend that the P2Y12 inhibitor is administered as promptly as possible after the diagnosis of UA/NSTEMI.[11][55][67] In real-world practice, it is not unusual that P2Y12 inhibitor administration occurs in selected individuals at the time of coronary angiography with the identification of coronary anatomy and the formulation of a revascularization plan. Although major trials that evaluated the use of ticagrelor, prasugrel, and clopidogrel in ACS patients did include patients where a P2Y12 inhibitor was administered during coronary angiography and sometimes even after, current guidelines do not recommend this practice, and it remains upon the discretion of the interventional cardiologist on a case-by-case basis. It would be reasonable to say that P2Y12 administration may be delayed if the clinical suspicion for underlying multivessel disease and the need for surgical revascularization remains high.
Finally, there is limited use of GpIIb/IIIa inhibitors in patients with UA/NSTEMI.[68][69] These involve patients who are very likely to undergo CABG (e.g., the ones with already known high-risk coronary anatomy, high-risk patients with hemodynamic instability and ongoing ischemia), where GpIIb/IIIa inhibitor can be used before administering P2Y12 inhibitor until defining a clear operative plan. The other group where such therapy should be a consideration includes patients with thrombotic complications during coronary angiography.[68][69][70]
In the absence of absolute contraindication, anticoagulation is indicated in all patients with UA/NSTEMI once the diagnosis is made.[11][55][71] Enoxaparin, UFH, and fondaparinux are listed as class I of recommendation for this purpose.[11][55][67] Enoxaparin and fondaparinux should be avoided in patients with severe renal failure. Data from the SYNERGY trial demonstrated the non-inferiority of enoxaparin when compared to UFH in terms of efficacy, with the expense of a modest increase in bleeding risk.[72][73] On the other hand, a meta-analysis published eight years after the SYNERGY trial reported a superior effect of enoxaparin when compared to UFH in reducing mortality and bleeding outcomes during PCI in patients with ACS.[37] The benefit was observed mostly in patients with STEMI. OASIS-5 study has demonstrated non-inferiority in the efficacy of fondaparinux compared to enoxaparin, with a better bleeding risk profile.[74] An important caveat was an increased risk of catheter-related thrombosis during PCI, which was successfully mitigated by intraprocedural UFH administration.[74][75] Based on these observations, a reasonable approach would be that in patients undergoing early invasive strategy, where PCI is expected, the anticoagulant of choice should be UFH, while enoxaparin could be an option in the absence of bleeding risk and renal failure. Fondaparinux should be considered in patients with higher bleeding risk in the absence of advanced renal failure but would mandate intraprocedural UFH administration to prevent intra-procedural catheter thrombosis. In patients managed by ischemia-guided strategy and PCI is unlikely to happen, fondaparinux offers optimal safety profile, while observations from ESSENCE and TIMI 11B trial suggest that enoxaparin in this clinical scenario should be favored when compared to UFH.[76][77] Bivalirudin is recommended as an anticoagulant agent in patients with UA/NSTEMI who have heparin-induced thrombocytopenia. Otherwise, bivalirudin offers a questionable benefit to a very small group of patients. Those patients would have characteristics that favor a strong inclination to add GpIIb/IIIa inhibitors and, at the same time, would have to be at increased risk of bleeding. In that situation, given non-inferiority in ischemic risk and lower incidence of bleeding with bivalirudin monotherapy compared to LMWH or UFH+GpIIb/IIIa, bivalirudin would be a choice.[68] Anticoagulation in the acute phase of UA/NSTEMI treatment is discontinued after revascularization, or in the case when no revascularization is performed, discontinuation is performed after at least 48 hours.[11][55][71]
Symptomatic therapy with nitrates, morphine, and beta-blockers in the acute phase of UA/NSTEMI, resembles that of patients with STEMI, as described above. High-intensity statin therapy is the recommendation for all patients with UA/NSTEMI and should be initiated as early as possible after admission to the hospital.[11][78][79][80] ACE inhibitors should be started as a long-term therapy after UA/NSTEMI in patients with LV dysfunction, hypertension, or diabetes mellitus type 2, while ARBs should be the choice in the case where ACE inhibitor tolerance is an issue.[81][82][83][84][85] Beta-blockers have well-known, proven efficacy in patients with UA/NSTEMI who have LV dysfunction.[45][86][87][88][89] Even though beta-blockers dosing is a long-term therapy for all patients with UA/NSTEMI, there have been no contemporary randomized controlled trials to assess its use in patients without LV dysfunction.[11] Long-term treatment with mineralocorticoid receptor antagonists (such as eplerenone or spironolactone) is recommended in patients with UA/NSTEMI and LVEF less than 40% and heart failure or diabetes.[48][49][50]
Dual antiplatelet therapy (DAPT) in patients after ACS should ideally be continued for 12 months, regardless if they underwent fibrinolysis, CABG, or PCI and irrespective of what type of stent is placed.[90] If patients on DAPT develop a high bleeding risk or sustain significant bleeding, discontinuation of P2Y12 inhibitor after six months is reasonable, and the recent guidelines support this approach.
Issues of Concern
One of the significant issues in the management of patients who had ACS is the optimal strategy to balance ischemic risk and bleeding risk in patients who require long-term anticoagulation due to another specific indication, as these patients already require antiplatelet therapy post-ACS. This type of treatment has the name triple therapy. In the most recent ACC/AHA guideline on UA/NSTEMI, the recommendation is that patients who had ACS and underwent PCI should receive triple therapy, but with making every effort to minimize the duration to limit the risk of bleeding.[55] Literature reports unequivocally increased risk of bleeding in patients who are on triple therapy when compared to DAPT or single antiplatelet agent.[55][91][92] Several strategies have been proposed to mitigate those risks. These include the use of clinical calculators such as HAS-BLED to assess bleeding risk, evaluating the appropriateness of indication for anticoagulation, targeting the international normalized ratio (INR) to 2 to 2.5 when using warfarin, the use of clopidogrel instead of more potent P2Y12 inhibitors, and the use of proton pump inhibitors in patients with a prior history or at risk of gastrointestinal bleeding.[90] The most recent guidelines for the management of ACS recommend that triple therapy continues for six months following PCI in patients with lower bleeding risk, assessed by HAS-BLED score is equal to or less than 2, followed by an oral anticoagulant (OAC) and clopidogrel or aspirin for the remaining 6 months.[7][11][55] In patients with HAS-BLED score of 3 and above, the recommendation is that triple therapy should be administered for one month, followed by an oral anticoagulant (OAC) and clopidogrel or aspirin for the total duration of 12 months. The choice of OAC involves a vitamin K antagonist (VKA) or a non-VKA novel oral anticoagulant (NOAC), based on the patient's preference and other socioeconomic factors. The decision between aspirin and clopidogrel during the period of treatment with OAC and one antiplatelet agent depends on the balance of ischemic risks such as complex coronary stenting, left main disease, bifurcation lesions, patients with diabetes, and bleeding risks such as a history of major bleeding and predisposition for future bleeding events. After 12 months of the described treatment, the guidelines recommend that OAC should be continued as a monotherapy indefinitely for the original indication.[7][11][55] In patients with ACS who did not undergo revascularization or have undergone CABG, the recommendation is that dual therapy involving OAC and aspirin or clopidogrel should continue for 12 months, and after completing that time, OAC should remain in place. Regardless of the type of revascularization, patients with high ischemic risk may continue OAC and aspirin beyond the 12-month time frame. Several recent trial results have disputed the concept of triple therapy and examined the effect of OAC along with P2Y12 inhibitor in patients with ACS who are undergoing PCI.[93][94][95][96] WOEST, PIONEER-AF, RE-DUAL[96], and AUGUSTUS trials have examined the efficacy and safety of warfarin, rivaroxaban, dabigatran, and apixaban, respectively, in conjunction with clopidogrel for treatment of patients with ACS who underwent PCI, compared to treatment with triple therapy.[93][95][96][97] Based on the reported results, it appears that dual therapy with an anticoagulant agent and P2Y12 inhibitor, when compared to triple therapy, significantly decreases the bleeding risk, while ischemic and thromboembolic risk remains unchanged. Based on these studies, new practice-changing guidelines are warranted, and the data requires interpretation for safe use in clinical practice. The ongoing ENTRUST-PCI study (NCT02866175) will provide data on edoxaban in this type of clinical scenario. It is worth noting that patients receiving anticoagulation for mechanical valve should exclusively be on warfarin, while the antiplatelet regimen strategy is essentially the same as described above.
Clinical Significance
Special attention needs to be devoted to a particular subset of patients with cardiogenic shock following ACS. Cardiogenic shock as a complication of ACS is most commonly the consequence of LV failure, while other causes include mechanical complications such as ventricular septal defect, papillary muscle rupture, and RV failure.[98] In-hospital mortality rates, once cardiogenic shock occurs, are 40 to 60%, and prompt revascularization is one of the interventions that potentially can provide benefit.[98][99] Such patients require immediate attention and rapid institution of inotropes or vasopressors, mechanical circulatory support, and an effective revascularization strategy.[100] Contemporary trials suggest that revascularization should take place as early as possible, and if PCI is the chosen strategy, the culprit vessel should be revascularized as opposed to multivessel PCI.[101][102] Patients with RV infarction can have a clinical presentation of cardiogenic shock. In such patients, special care should be taken to avoid worsening hypotension due to medications such as nitrates, morphine, and diuretics (that may be otherwise routinely used in patients with myocardial infarction and LV dysfunction). Patients with RV infarction benefit from volume expansion that will increase RV preload and subsequent cardiac output.[103]
Other Issues
There are several subgroups of patients with UA/NSTEMI that are at higher risk of adverse outcomes. Those include patients aged 75 or older, women, diabetes mellitus (DM), and chronic kidney disease (CKD).[11] Patients older than 75 years have a higher incidence and prevalence of adverse outcomes, increased risk of bleeding, and are more likely to present with atypical symptoms.[6][104][105][106] Practical suggestions to decrease the risk of bleeding in the elderly include the use of low-dose aspirin, avoidance of prasugrel, consideration for the use of bivalirudin as an anticoagulant, and avoidance of abciximab if there is a need for the use of GpIIb/IIIa inhibitor.[107] It merits noting that in the absence of comorbidities that are a potential contraindication for revascularization, advanced age alone should not determine that the patient does not need early invasive strategy or revascularization.[55] Multiple studies have shown that women, compared to men, present with atypical symptoms, tend to have more comorbidities, and have a lower likelihood of being referred for coronary angiography.[60][105][108] These findings warrant implementation for raising awareness of cardiovascular risk in women and adherence to the guidelines for the treatment of UA/NSTEMI regardless of sex.[109] Given worse outcomes in patients with DM who present with UA/NSTEMI,[110] it is important to note that certain choices in treatment modality must merit consideration. Limited data show the benefit of more potent antiplatelet agents, such as prasugrel [111], along with favoring early invasive strategy in patients with DM, and preference of CABG compared to PCI in diabetic patients with complex coronary artery disease.[11][112] Patients with CKD who present with UA/NSTEMI are at increased risk of recurrent ischemic events, stent thrombosis, and post-PCI ischemic events.[113][114][115] Patients with advanced CKD stage IV or V usually get excluded from most of the clinical studies. A meta-analysis involving UA/NSTEMI patients with CKD has demonstrated favorable outcomes with an early invasive strategy.[59] Data suggest that CABG is the preferred option of revascularization in patients with CKD who have multivessel CAD and acceptable surgical risk, while if PCI is selected, DES is preferable over BMS.[11]
Enhancing Healthcare Team Outcomes
Many interventions and treatments have been proven so far to improve outcomes in patients with ACS. Still, given the emerging new evidence, heterogeneity in the population of patients with ACS, and complexity in optimal decision-making in managing these patients, a robust interprofessional and streamlined system is necessary to keep improving outcomes. The highly coordinated care of patients with ACS, especially those with STEMI, starts early, with the first contact with emergency medical services (EMS) or the first contact with the emergency department. It is crucial that regardless of the type of initial medical contact, an electrocardiogram (ECG) needs to take place in less than 10 minutes, and the initial diagnosis is made.[7][116][117] If a STEMI is suspected, it is necessary to provide ECG monitoring with the capacity of defibrillation.[7][118][119] Given these requirements, success in outcomes will depend on adequate prehospital care resources and prompt access to the healthcare facility. It requires efficient transportation, trained personnel, availability of therapeutics, and optimal communication with the healthcare providers in the corresponding hospital, enabling early activation of the cardiac catheterization lab.[120][121][122][123] Given the proven benefit of timely evaluation of patients with STEMI, avoiding treatment delays is necessary at all costs. There should be a system with meticulous tracking of target times for the institution of quality improvement. It is essential to raise awareness of the symptoms of ACS is raised in the general population for the avoidance of patient-related treatment delays.[124][125][126]
It is essential to create a geographic area of responsibility to transport patients to a PCI-capable center in a timely fashion, where the cardiac catheterization lab is available 24 hours a day, seven days per week, and where healthcare personnel has clear written protocols that facilitate risk stratification and management.[127][128][129][130] In geographic areas where timely transport to a PCI-capable facility is not possible, there is a need for a clear protocol for prehospital or early hospital fibrinolysis.[131][132][133] The care coordination continues upon patient admission in the hospital, and it is necessary that hospitals provide infrastructure in the form of coronary care units (CCU) or intensive care units (ICU), along with the units that have the capability of continuous monitoring and specialized care for patients with ACS.[134] A coordinated discharge of the patient is of paramount importance after the acute phase of treatment, medical stabilization, and optimal hospital stay. Apart from the medication reconciliation and confirmation that the patient will be able to receive the medications, interventions including smoking cessation, nutrition education, weight control, and exercise-based cardiac rehabilitation are strongly advised.[135][136][137] To reduce the gap between the ideal care and the real-world care of patients with ACS,[138][139] establishing quality indicators is recommended with the goal to serve as a foundation for quality improvement interventions.[140]
ACS therapy modality selection requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]
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