low risk patients should be evaluated on a case by case basis [2,13,14]. An analysis from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY‐ACS) cohort of medically managed ACS patients identified older age, diabetes mellitus, NSTEMI on presentation and lack of angiography to guide strategy, as the most important parameters associated with subsequent spontaneous myocardial infarction [15].
Optimal timing of coronary intervention in NSTE‐ACS should be tailored to the individual patient characteristics. A meta‐analysis of eight randomized controlled trials (n=5,324 patients) found no difference in mortality between an early and a delayed invasive strategy overall; however, mortality was lower with an early invasive strategy in patients with elevated cardiac biomarkers at baseline (hazard ratio [HR] 0.761, 95% CI 0·581‐0·996), diabetes (HR 0·67, 0·45‐0·99), a GRACE risk score more than 140 (HR 0·70, 0·52‐0·95), and aged 75 years older (HR 0·65, 0·46‐0·93), although tests for interaction were inconclusive [16]. The Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography (VERDICT) trial showed that a strategy of very early invasive coronary evaluation (within 12 hours of diagnosis) did not improve overall long‐term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with NSTE‐ACS. However, in the highest risk patients, very early invasive therapy improved long‐term outcomes [17]. Criteria for determining the optimal management strategy and the timing of intervention are summarized in Figure 12.2.
Figure 12.2 Algorithm for managing NSTE‐ACS patients and determining the timing of coronary angiography and coronary revascularization.
CABG, coronary artery bypass grafting; h, hours; PCI, percutaneous coronary intervention.
Revascularization for NSTE‐ACS
Radial access is preferred for NSTE‐ACS patients, if feasible [14]. The Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) trial randomized 8404 patients with ACS to radial vs femoral access and reported lower incidence of major bleeding and mortality at 30 days. In subgroup analysis, NSTE‐ACS patients benefited the most from the intervention while no difference was evident in the STEMI group [18]. In single‐vessel CAD, ad hoc PCI should be performed, while in multivessel CAD (more than 50% of cases) the alternative of coronary artery bypass grafting (CABG) should be considered. For hemodynamically unstable patients with very high‐risk features that have to be revascularized in a timely fashion PCI is usually preferred. On the contrary, stable patients with complex anatomy (high SYNTAX score or left main disease) should be evaluated by a Heart Team before determining the optimal treatment strategy [19]. In this setting, patients undergoing PCI have been shown to be at lower risk for peri‐procedural stroke, MI, major bleeding, or renal injury, higher risk for ischemia driven repeat revascularization, and similar risk of death [20,21]. Regardless of the approach, achievement of complete revascularization (CR) is preferable if technically feasible. A meta‐analysis of 35 studies including 89,883 patients demonstrated an association of CR with lower long‐term morbidity and mortality [22]. Rathod et. al. examined 21 857 NSTEMI patients and reported that CR was associated with higher 5‐year survival, despite higher in‐hospital mortality [23]. According to the results of the Single‐Staged Compared With Multi‐Staged PCI in Multivessel NSTEMI Patients (SMILE) trial, complete 1‐stage revascularization was superior to staged revascularization in reducing the incidence of major adverse cardiovascular and cerebrovascular events (23.2% vs 13.6%; p= 0.004) in 584 NSTE‐ACS patients [24]. Finally, identification of significant lesions may be challenging and could be facilitated by intravascular imaging (especially with optical coherence tomography) to identify the underlying pathology (thrombus, plaque rupture, plaque erosion etc.) and guide management [].
Adjunctive pharmacologic treatment
Adjunctive pharmacologic therapy with anti‐ischemic, antiplatelet and anticoagulant agents is critical for both conservatively and invasively treated patients. During the acute phase general supportive anti‐ischemic measures should be implemented, including supplemental oxygen only when blood oxygen saturation is <90% or the patient is in respiratory distress [28,29], intravenous nitrates for angina control [30], and beta‐blockers in patients who are not at risk of developing cardiogenic shock [31]. In cases with suspected vasospastic angina a combination of calcium channel clockers and nitrates should be administered instead of beta‐blockers [32]. In addition, early aspirin and P2Y12 inhibitor therapy is recommended in conjunction with anticoagulation. In more detail:
Aspirin
Acetylsalicylic acid irreversibly inactivates the cyclooxygenase enzyme exerting antiplatelet as well as anti‐inflammatory actions. In view of its efficacy, low cost, and widespread availability, all NSTE‐ACS patients should receive it, unless they have a contraindication [33]. Both the American and European guidelines give a class I recommendation for early aspirin administration in patients with NSTE‐ACS. Proposed dosing is 81–325 mg (325 mg for all patients if not already on aspirin prior to PCI) for the United States and 150–300 mg (or 80–150 mg I.V.) for Europe [13,14]. After the acute phase, life‐long treatment is recommended.
Oral P2Y12 receptor inhibitors
An oral P2Y12 inhibitor should be administered in addition to aspirin to all NSTE‐ACS patients. Three oral P2Y12 inhibitors are currently being used: clopidogrel, prasugrel, and ticagrelor (ticlopidine is seldom used because of potentially serious hematologic side effects).
The first P2Y12 inhibitor studied was clopidogrel, a prodrug that requires multistep activation in the liver. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, dual antiplatelet therapy (DAPT) was shown to be superior to aspirin monotherapy in reducing the incidence of the composite of cardiovascular death, MI, or stroke (9.3% vs 11.4%; p<0.001) after nine months of follow‐up in NSTE‐ACS [34]. Optimal clopidogrel dosing was studied during the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes 7 (CURRENT–OASIS 7) trial, in which doubling clopidogrel dose early after the procedure was shown to lower the risk of stent thrombosis (1.6% vs 2.3%; p‐value < 0.001) at the cost of increased major bleeding (2.5% vs 2.0%; p = 0.01) while there was no difference in the primary outcome of 30‐day cardiovascular death, MI, or stroke (4.2% vs 4.4%; p = 0.30) [35]. One of the main limitations of clopidogrel is the large number of patients with inadequate response due to CYP 2C19 gene polymorphisms [36]. In the POPular Genetics trial that randomized 2488 STEMI patients undergoing primary PCI to a genotype‐guided strategy for selection of oral P2Y12 inhibitor or with standard therapy with ticagrelor or prasugrel. Approximately 40% were clopidogrel non‐respondents. At 12 months the incidence of death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding was 5.1% in the genotype‐guided group vs 5.9% in the standard‐treatment group P<0.001 for noninferiority), with lower incidence of PLATO major or minor bleeding in the genotype‐guided group [37].
Prasugrel is another prodrug with potent antiplatelet properties but unlike clopidogrel has a very efficient conversion to its active metabolite. In the trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38) 13,608 PCI patients (74% NSTE‐ACS) were randomized to prasugrel or clopidogrel (300 mg loading dose). During a median follow‐up of 14.5 months, compared with clopidogrel, prasugrel reduced the incidence of cardiovascular death, MI, or stroke (9.9%
