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Invasive versus Conservative Approaches
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Most patients with non–ST-segment elevation (NSTE)-ACS in the United States undergo cardiac catheterization. The evidence for invasive management is based on several randomized trials that showed improvement in MACE, improved symptoms, improved quality of life, and reduction in readmission. Moreover, early definition of coronary anatomy has been shown to be associated with earlier discharge.
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A 2006 meta-analysis of seven trials that randomized 8375 patients153 found that the invasive approach improved mortality (4.9% vs 6.5%; RR, 0.75; 95% CI, 0.63-0.90), nonfatal MI (7.6% vs 9.1%; RR, 0.83; 95% CI, 0.72-0.96), and readmission for unstable angina (RR, 0.69; 95% CI, 0.72-0.96) (Fig. 42–10). Similarly, in a propensity score–matched retrospective study of 19,704 patients, an invasive approach in patients with ACS was associated with reduction in cardiac mortality, all-cause mortality, and readmission.154 The benefits were greater in patients with higher risk (ie, elevated biomarker, ST-segment changes, higher TIMI or GRACE [Global Registry of Acute Coronary Events] risk scores). An updated meta-analysis of 10,150 patients155 found that both men and women with positive biomarkers or ST-segment deviation benefit from an invasive strategy. Interestingly, men with negative biomarkers or ST-segment deviation also had benefit, with reduction in the risk of death, MI, or rehospitalization. On the basis of these randomized trial findings, US guidelines recommend early catheterization, particularly in intermediate- and high-risk NSTE-ACS patients156 (Table 42–3).
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Timing of catheterization has been evaluated in randomized and observational trials. Initially, it was thought that it may be beneficial to “cool off” an ulcerated thrombotic lesion with antiplatelet and anticoagulant agents for a few days. However studies found that earlier intervention is better, particularly in higher risk patients. The TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial randomized 3031 patients with NSTE-ACS to early (< 24 hours) versus delayed (> 36 hours) coronary angiography.157 Early catheterization was performed at a median of 14 hours after randomization and was associated with reduced refractory ischemia (1.3% vs 3.3%; P < .0001), but early catheterization did not improve the primary end point of death or MI (9.6% vs 11.3%). However, 25% of the delayed group crossed over to early catheterization. Also, in high-risk ACS patients, there was a significant reduction in the risk of death, MI, or stroke (14.1% vs 21.6%; P = .008). The ISAR-COOL Intracoronary Stenting With Antithrombotic Regimen Cooling Off) trial randomized 410 intermediate-to-high-risk ACS patients to very early (median time, 2.4 hours) versus delayed (median, 86 hours) catheterization.158 Early catheterization was associated with a reduction in death or large MI at 30 days (5.9% vs 11.6%; P = .04). The ABOARD (Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes) trial randomized 352 high-risk ACS patients to immediate (median, 70 minutes) versus next working day (median, 21 hours) catheterization.159 There were no differences in peak troponin levels or clinical events. Conversely, the RIDDLE-NSTEMI (Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients) trial160 randomized 323 non–ST-segment elevation MI (NSTEMI) patients to immediate (median, 1.4 hours) versus delayed (61 hours) intervention. The immediate strategy was associated with a lower composite of death or new MI at 30 days (4.3% vs 13%; P = .008) and at 1 year (6.8% vs 18.8%; P = .002). Although the LIPSiA-NSTEMI (Leipzig Immediate Versus Early and Late Percutaneous Coronary Intervention) trial161 reported no differences in outcomes in immediate versus early versus selective invasive strategies, 85% of patients in the “selective” arm underwent catheterization. Thus, one would not expect any difference in clinical outcome. In a post hoc analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, which randomized NSTE-ACS patients to different pharmacologic strategies, PCI was performed in 7749 patients.162 Approximately one-third of patients were treated within 8 hours of presentation, one-third between 8 and 24 hours, and the remainder after 24 hours. The two groups in which PCI was done early (< 24 hours) did equally well; however, patients who had PCI after > 24 hours had a significant increase in the individual components of death, MI, and ischemia. These differences were observed in both intermediate- and high-risk patients (Fig. 42–11).
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Thus, in intermediate-to-high risk or unstable NSTE-ACS patients, it appears that earlier catheterization is better, whereas in low-risk, stable patients, catheterization may be delayed. Immediate angiography is recommended for hemodynamic instability, congestive heart failure, ongoing or recurrent ischemia, dynamic ECG changes, ventricular arrhythmias, or mechanical complications such as mitral regurgitation or ventricular septal defect (Table 42–4). In other ACS patients, catheterization is often performed the next working day.
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Findings of Catheterization in the Patient With Non–ST-Segment Elevation Acute Coronary Syndrome and How It Influences Treatment
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Unlike STEMI, the cause of NSTE-ACS is often a “nonocclusive” ruptured plaque. When the plaque is further analyzed, it may contain platelet thrombi, not fibrin-laden clots. Thus, thrombolytic therapy is not beneficial and, in fact, may be harmful and is not recommended. In our clinical and trial experience, single-vessel disease is found in the majority of STEMI patients, and PPCI is performed in approximately 90%. Conversely, in the NSTE-ACS patient,163 single-vessel disease is present in only 30% of cases; multivessel disease is present in 40% to 50%, left main disease in 4% to 10%, and nonsignificant disease in 10% to 20%. Thus, catheterization (or coronary computed tomography angiography in low-risk patients) is essential to determine the most appropriate treatment strategy. Even in the 10% to 20% of patients with nonsignificant disease, defining the coronary anatomy has been shown to reduce readmissions.
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To date, only one trial randomized patients with unstable angina to PCI versus coronary artery bypass grafting (CABG).164 In this trial of 454 high-risk patients, there was no difference in mortality at 36 months, but more angina and revascularization in the PCI group. Other trials of both stable and unstable angina comparing PCI and CABG in patients with multivessel disease had similar findings. Thus, the choice of PCI or CABG often depends on the presence of factors that influence survival (diabetes, SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] score) but not on the presence of NSTE-ACS. The use of CABG varies widely based on patient risk and hospital center; publications from early randomized trials reported CABG rates of 16% to 50% in NSTE-ACS patients. A more recent publication reported that CABG was performed in 10% of NSTE-ACS patients.165
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Thrombectomy for Non–ST-Segment Elevation Acute Coronary Syndrome
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Although angiographic evidence of thrombus may be present in up to 40% of ACS cases, it is usually not flow occlusive. A single study randomized 440 patients with ACS to adjunctive thrombectomy versus PCI alone.166 There was no difference in microvascular obstruction as assessed by cardiac magnetic resonance imaging. Thus, routine thrombectomy is not recommended for patients with NSTE-ACS undergoing PCI.
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Radial Access for Non–ST-Segment Elevation Acute Coronary Syndrome
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One of the most common complications of the invasive strategy for NSTE-ACS is a vascular access complication, including bleeding. Although bleeding avoidance strategies include cautious dosing of antithrombotics, radial access has emerged as a valuable approach. Several trials and registries have reported reduction in bleeding using radial compared to femoral access. Valgimigli et al167 randomized 8404 patients with ACS to radial versus femoral approach and found reductions in MACE and major bleeding as well as improved survival (1.6% vs 2.2%; RR, 0.72; 95% CI, 0.53-0.99; P = .045) in the radial group. The improvement in survival occurred predominantly in the NSTE-ACS group. A meta-analysis of nine studies with 220,126 NSTE-ACS patients168 found reduction in major bleeding (OR, 0.52; 95% CI, 0.36-0.73; P = .0002), transfusions (OR, 0.61; 95% CI, 0.41-0.91; P = .02), and 1-year mortality (OR, 0.72; 95% CI, 0.55-0.95; P = .02). These data suggest that radial access should be the preferred approach for NSTE-ACS patients undergoing an invasive strategy.
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Pharmacotherapy for Patients Presenting for Percutaneous Coronary Intervention During Non–ST-Segment Elevation Acute Coronary Syndrome
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The primary goal of pharmacotherapy for NSTE-ACS is to alleviate ischemia using antiplatelets, antithrombotics, and adjunctive therapies to reduce myocardial oxygen demand. Pharmacotherapy in NSTE-ACS is crucial for management, because a substantial portion of patients will not immediately undergo coronary angiography and/or revascularization. Here, we summarize these therapies and translate their use into clinical practice.
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Oral Antiplatelet Agents
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Evidence-based guidelines universally advocate that patients with NSTE-ACS should routinely and indefinitely receive low-dose (75-100 mg) non–enteric-coated aspirin, after an initial loading dose of 300 to 325 mg. Aspirin is routinely given to all patients with CAD, and is assumed to equally benefit those undergoing and not undergoing an invasive management strategy.169,170 Early evidence regarding the benefits of aspirin in the specific context of coronary revascularization arose from ISIS-2, a double-blind, randomized, two-by-two factorial, placebo-controlled trial that evaluated the effect of aspirin as an adjunct to thrombolysis (streptokinase) in the management of AMI. This large study demonstrated that 1 month of aspirin given alone or in combination with revascularization therapy significantly improved outcomes.171 It has subsequently been shown that high-dose and low-dose aspirin have equivalent cardiovascular outcomes; thus, low-dose (<150 mg daily) aspirin would seem most prudent in the absence of a direct comparison.172
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The addition of ticlopidine to aspirin substantially benefited patients with NSTE-ACS and established dual antiplatelet therapy (DAPT) as the standard of care. Clopidogrel was subsequently developed to circumvent the adverse side effect profile of ticlopidine. The efficacy of clopidogrel was initially studied in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which randomized patients in double-blind fashion to receive clopidogrel or placebo.173,174 Clopidogrel reduced the composite end point of cardiovascular death, MI, and TVR within 30 days of PCI, and the reduction in MACE was maintained to 9 months of follow-up without differences in major bleeding. Studies also demonstrated that pretreatment with clopidogrel improves outcomes for invasively managed NSTE-ACS, with only a modest increase in minor bleeding. Several subsequent trials and meta-analyses have clarified the current preferred loading and maintenance doses of clopidogrel (600 mg followed by 75 mg daily).175,176 If PCI is not planned for the same day, a 300-mg loading dose may be used.
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Prasugrel has a more rapid onset of action and reduced response variability compared with clopidogrel. TRITON-TIMI 38 randomized clopidogrel-naïve patients with moderate-to-high risk ACS undergoing PCI to receive either prasugrel or clopidogrel (both in combination with aspirin). Randomization occurred following ascertainment of coronary anatomy, with the exception of patients with STEMI. At 15 months of follow-up, the primary end point (composite of cardiovascular death, nonfatal MI, or stroke) was lower with prasugrel, driven by nonfatal MI and stent thrombosis. These benefits were somewhat offset by a significant risk of major and fatal bleeding in the prasugrel-treated versuss clopidogrel-treated group. Prasugrel increased mortality in patients with a prior stroke, and as such should not be given to patients with a history of transient ischemic attack or stroke.177 Additionally, caution should be used in patients with low body weight (< 60 kg) or those > 75 years of age. It should also be noted that the TRILOGY (Prasugrel Versus Clopidogrel for Acute Coronary Syndromes without Revascularization) trial showed that there was no benefit of prasugrel compared with clopidogrel in ACS patients without ST-segment elevation not undergoing PCI and, as such, it is not recommended in guidelines for NSTE-ACS without PCI.
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Ticagrelor was developed as the first reversible nonthienopyridine in an effort to avoid the variable pharmacokinetics of clopidogrel and the adverse safety profile of prasugrel. The PLATO trial randomized ACS patients to receive ticagrelor or clopidogrel. Patients with moderate-to-high risk ACS received an additional, blinded loading dose of clopidogrel or its placebo. At 12 months, ticagrelor significantly reduced the primary end point (cardiovascular death, nonfatal MI, or stroke), driven by reductions in cardiovascular mortality, nonfatal MI, and stent thrombosis without any difference in overall bleeding. An adenosine-mediated mechanism has been suggested for the survival benefit, and improved endothelial function has been found in separate studies with this agent. Major bleeding was higher in ticagrelor-treated patients, including fatal intracranial hemorrhage, but not all-cause fatal bleeding. Several adverse effects with ticagrelor were observed and were associated with discontinuation of therapy, including acute episodic dyspnea, bradycardia (rarely), and elevated serum creatinine and uric acid.178 Because adverse events may be mediated by adenosine, taking the medication with coffee has been suggested. Lastly, patients taking > 100 mg of aspirin daily had increased bleeding rates with ticagrelor, and as such, aspirin doses < 100 mg are recommended.
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Pretreatment With Oral Antiplatelet Agents
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Administration of clopidogrel prior to PCI is known to improve outcomes. The PCI-CURE study revealed that patients who received pre-PCI treatment with clopidogrel had reduced cardiovascular death, MI, and stent thrombosis when compared with placebo.174 This can be explained by clopidogrel’s slow onset, which is circumvented by early administration. In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction) trial, pretreatment with prasugrel did not decrease ischemic complications when compared with administration at the time of PCI and was associated with higher risk for major bleeding.179 Prasugrel has a very fast onset, thereby rendering pretreatment unnecessary. Pretreatment with ticagrelor has only been studied in the STEMI PCI patient population, and given its rapid onset of action, pretreatment also did not result in any significant net clinical benefit compared to “on the table” administration.
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Duration and Interruption of Oral Dual Antiplatelet Therapy
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Based on guidelines and available data, we recommend at least 1 year of continuous DAPT in patients with NSTE-ACS and continuation as needed for patients with a low risk of bleeding. For patients with high bleeding risk, lower doses of prasugrel (5 mg daily) and ticagrelor (60 mg twice daily) are available if clinical judgement points to long-term use of a lower dose. Despite these recommendations, “real-world” practice often necessitates DAPT interruption within a year of PCI.180 The context and process of making this decision are important to review; if DAPT is interrupted based on a specific physician-driven decision based on a new clinical development, outcomes were not unfavorable; however, if the DAPT course was disrupted without cardiologist input, then major complications occurred within a week. If DAPT interruption is warranted (eg, for an urgent noncardiac surgery), then clopidogrel is stopped for 5 days, prasugrel for 5 to 7 days, and ticagrelor for 5 days (despite its pharmacokinetic “reversibility”). Individual patient responses may vary, and platelet reactivity testing has been suggested to guide the timing of surgery but without a clinically proven algorithm.
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Intravenous Antiplatelet Agents
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Cangrelor is an IV rapid-onset and rapidly reversible P2Y12 inhibitor, making it a special agent for acutely ill patients who are unable to take or absorb oral medications. It achieves almost complete and immediate inhibition of ADP-induced platelet aggregation when administered as a bolus of 30 μg/kg, and continuous infusion sustains the high degree of inhibition. The plasma half-life is approximately 3 to 5 minutes, normal platelet function is restored within 1 hour after cessation of the infusion, and it has been studied in high-risk patients awaiting CABG.181 The rapid cessation is also beneficial if patients suffer a life-threatening complication. After initial trials showed favorable bleeding profiles, the CHAMPION-PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Patients Who Require PCI) study, a randomized, double-blind, double-dummy trial, was designed to evaluate the efficacy of cangrelor against clopidogrel loading during PCI in patients who had not previously received a P2Y12 antagonist (including patients with stable angina and ACS). A composite end point of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours was lower in the cangrelor group compared with the clopidogrel group, driven by the reduction of acute periprocedural MI and particularly intraprocedure stent thrombosis; there were no differences in adverse events.182 Future studies are needed to determine the optimal way to transition ACS PCI patients from cangrelor to oral P2Y12 inhibitors.
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Glycoprotein IIb/IIIa Inhibitors
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A large number of trials before the era of DAPT showed that patients undergoing angioplasty (greatest benefit) or stent experienced lower ischemic events, mainly driven by reduction in MI, when receiving adequately dosed GP IIb/IIIa inhibitors (GPIs) combined with UFH instead of UFH alone. In a head-to-head trial, abciximab was found to be superior to tirofiban during PCI.183 Currently, GPIs (particularly eptifibatide and tirofiban) are indicated at the time of PCI in high-risk patients, whether or not they have been pretreated with a P2Y12 inhibitor. GPI use has been limited as a result of high bleeding with GPIs because of the long post-PCI infusion and their delayed reversibility in case of an acute bleed (only by platelet transfusions with abciximab and with a 4- to 6-hour half-life for tirofiban and eptifibatide). GPIs are infrequently used as pretreatment in NSTE-ACS patients who receive DAPT and have intermediate- or high-risk features, as both the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) and ACUITY-Timing (Acute Catheterization and Urgent Intervention Triage Strategy Timing) studies showed no benefit to upstream GPI use in all ACS patients versus “on the table” administration only in those patients undergoing PCI.184,185 If a patient has high-risk features, ongoing ischemia, and a long time to PCI (eg, patient awaiting transfer to a PCI-capable center), it is reasonable to initiate GPI therapy while awaiting PCI. Renal dose adjustment is important for eptifibatide and tirofiban safety because these and other agents are often incorrectly dosed in patients with renal dysfunction.186
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Antithrombotic Agents
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Anticoagulation is recommended for all NSTE-ACS patients undergoing PCI at the time of diagnosis (class I practice guideline).170 This is typically administered in the ED or in the cardiology unit as an IV infusion of UFH or a subcutaneous injection of low-molecular-weight heparin; the former requires dose adjustment to target an activated partial thromboplastin time of 50 to 70 seconds but may be more flexible (faster elimination) if an interruption is necessary. The latter does not require monitoring, but a dose reduction according to the renal function is pertinent, and the elimination half-life is many hours.
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Parenteral anticoagulants used in patients with NSTE-ACS undergoing PCI include UFH (most commonly, 50 U/kg bolus followed by an infusion for partial thromboplastin time of 50-70 seconds), low-molecular-weight heparin (usually enoxaparin 0.3 mg/kg IV bolus or 1 mg/kg every 12 hours in the absence of renal failure), bivalirudin (with PCI, 0.75 mg/kg bolus followed by 1.75 mg/kg/h infusion; with dose reduction in renal failure), and fondaparinux (typically used without PCI). Heparin and bivalirudin are the agents of choice in the United States for patients undergoing an invasive approach because of their rather short half-lives in comparison to the longer elimination time of other agents, which may complicate arterial sheath removal timing after PCI.187 In a recent meta-analysis of available trials comparing bivalirudin and heparin, the use of bivalirudin was associated with increased risk of stent thrombosis (mostly in STEMI patients, within a few hours of PPCI) but was associated with significantly less bleeding than heparin; however, the risk of bleeding was attenuated with transradial access rather than femoral access and when potent oral P2Y12 inhibitors rather than GPIs were used.188
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A recent large trial in ACS patients treated with a mostly radial approach for PCI (which has been shown to lower access site–related bleeding) has shown similar composite cardiovascular outcomes between heparin and bivalirudin during PCI, lower bleeding, and lower total mortality. A post-PCI bivalirudin infusion appeared to limit acute stent thrombosis with this agent in STEMI.189
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Other Adjunctive Therapies
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In addition to antiplatelets and antithrombotics, adjunctive therapy with oxygen is empirically administered in all patients, and especially for patients with oxygen saturation < 90%. If patients are experiencing ischemic chest discomfort, sublingual or IV nitroglycerin can be used. β-Blockade should be initiated within 24 hours to reduce heart rate, contractility, and blood pressure, as long as patients are not experiencing heart failure or low output, are at increased risk of cardiogenic shock, or have other contraindications to β-blockade.190 Nondihydropyridine calcium channel blockers can be administered to reduce myocardial oxygen demand if β-blockers are contraindicated (eg, as a result of bradycardia or wheezing). Lastly, high-intensity statin therapy with either atorvastatin 80 mg or rosuvastatin 40 mg should be administered as soon as possible in patients presenting with NSTE-ACS. The PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) TIMI 22 trial revealed that patients who are treated with a high-intensity statin have reduced rates of recurrent MI, coronary heart disease mortality, need for revascularization, and stroke than patients treated with a moderate- or low-intensity statin.191