Current management of non-ST-segment-elevation acute coronary syndrome: reconciling the results of randomized controlled trials1

Abhiram Prasad, Verghese Mathew, David R Holmes, Jr. and Bernard J Gersh*

Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

* Address for reprints: Bernard J. Gersh, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA

Received 16 October 2002; revised 8 January 2003; accepted 20 March 2003

Abstract

Aims Patients presenting with non-ST-segment-elevation acute coronary syndrome represent a heterogeneous group with regard to the severity of coronary atherosclerosis and prognosis. The conventional approach to their treatment has involved admission to the hospital for pharmacologic stabilization, subsequent mobilization, and management by either a conservative or an invasive strategy. The choice of one approach over another is guided largely by local practice patterns and the availability of invasive facilities.

Methods and results However, recent randomized trials comparing the strategies have demonstrated a superiority of the invasive strategy, particularly in patients at higher risk. Furthermore, randomized trials have provided information on refining risk stratification. On the basis of these data, we outline criteria for assessing risk and recommend that stratification be conducted at presentation using clinical features, the electrocardiogram, and biomarkers.

Conclusion Higher-risk patients should be admitted for pharmacologic stabilization and assessed by coronary angiography within 48h with the aim of early revascularization, provided the risk of periprocedural complications is not prohibitive. Glycoprotein IIb/IIIa receptor inhibitors are indicated, particularly in patients requiring percutaneous coronary intervention. The conservative strategy remains appropriate for patients admitted to hospitals without invasive facilities. Patients not at highrisk may be observed in a facility with cardiac monitoring such as a chest pain unit and undergo subsequent stress testing. The adoption of such an early risk stratification and revascularization-based approach is likely to result in a reduction in recurrent myocardial infarction and ischaemia, duration of hospitalization, repeat hospitalization, and mortality.

Key Words: Myocardial infarction • Unstable angina • Risk

List of Abbreviations: ACS, acute coronary syndrome • ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Event • FRAXIS, Fraxiparin in Ischemic Syndromes • FRIC, Fragmin in Unstable Coronary Artery Disease • FRISC, Fragmin During Instability in Coronary Artery Disease • FRISC II, Fragmin and Fast Revascularization During Instability in Coronary Artery Disease • GUSTO IIb, Global Use of Strategies to Open Occluded Coronary Arteries IIb • LMWH, low molecular weight heparin • MATE, Medicine Versus Angiography in Thrombolytic Exclusion trial • NQMI, non-Q-wave myocardial infarction; • NSTEMI, non-ST-segment elevation myocardial infarction • OASIS, Organisation to Assess Strategies for Ischaemic Syndromes • PRISM, Platelet Receptor Inhibition for Ischemia Syndrome Management • PRISM-PLUS, Platelet Receptor Inhibition for Ischemia Syndrome Management in Patients Limited by Unstable Signs and Symptoms • PURSUIT, Platelet IIb/IIa in Unstable Angina Receptor Suppression Using Integrilin Therapy • TACTICS, Treat Angina With Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy • TIMI, Thrombolysis in Myocardial Ischemia • VANQWISH, Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital

1. Introduction

Non-ST-segment-elevation acute coronary syndrome (ACS) represents a continuum from unstable angina to non-ST-segment elevation myocardial infarction (NSTEMI). NSTEMI has become the preferred diagnostic term for nontransmural myocardial infarction. Previous terminology of non–Q-wave myocardial infarction (NQMI) was based on late electrocardiographic criteria that correlated poorly with the pathology and did not aid in the management decisions during the acute presentation. In this review we use the new terminology, except while reviewing the older literature, because the terms are not strictly interchangeable. Unstable angina and NSTEMI share a common anatomic substrate consisting of atherosclerotic plaque rupture or erosion with variable amounts of thrombus formation and distal embolization with compromised blood flow to viable myocardium. Consequently, patients with unstable angina and NSTEMI present with similar clinical features, but NSTEMI is characterized by an increase in the biochemical markers of myocardial injury. Recent major advances in themanagement of non-ST-segment-elevation ACS have emphasized the importance of earlier identification of higher-risk patients among whom aggressive approaches to revascularization might improve outcome. This has prompted the publication of comprehensive guidelines by the European Society of Cardiology, the American College of Cardiology, and the American HeartAssociation.1,2In the context of these guidelines, this review focuses on the latest randomized trials, and from their findings we provide a succinct management strategy.

2. Natural history

In untreated patients, unstable angina has 5% to 10% mortality and 10% to 20% nonfatal MI rate within the first few days to weeks after the onset of symptoms. Aspirin and heparin therapy has resulted in important reductions (50% to 70%) in the incidence of in-hospital death or MI.3–7However, despite modern therapy there remains a short-term incidence of MI (5% to 10%) and refractory angina (10% to 20%).8–11Typically, unstable angina progresses to NSTEMI rather than ST-segment-elevation MI.

The majority of cases of NSTEMI do not develop Q waves on the electrocardiogram and have previously been termed ‘NQMI’. A minority progress to full-thickness infarction with Q waves (Q-wave MI). There are major differences in the natural history of the lesions in patients with and without ST-segment-elevation MI. These in turn dictate to some extent the subsequent course of events. In ST-elevation MI, initial complete occlusion is the rule and may progress to subtotal occlusion due to spontaneous lysis. In the setting of NSTEMI, the initial lesion is usually characterized by subtotal occlusion, which is subject to progressive thrombosis and total occlusion.12A subset of patients with NSTEMI have total occlusion, most often involving the circumflex artery, with transmural infarction. In both syndromes, the extent of myocardial jeopardy and ultimate necrosis are subject to modification by the extent of the collateral circulation.

An early study by Hutter and colleagues13demonstrated a lower hospital mortality with ‘nontransmural’ vs ‘transmural’ MI. However, long-term outcomes were similar because of a higher rate of subsequent recurrent MI in patients with nontransmural infarction. Similar findings in regard to long-term mortality were reported from a large Israeli registry and a retrospective Swedish study that included follow-up to 10 years.14,15Patients with Q-wave infarctions with presumably larger initial infarcts have a higher rate of subsequent congestive heart failure, whereas those with NQMI experience a higher rate of recurrent ischaemic events, specifically unstable angina. The GUSTO IIb randomized trial demonstrated a 30-day mortality of 3.8% in patients with NQMI vs 6.1% in patients with Q-wave MI, but mortality rates at 1 year were similar in the 2 groups (8.8% vs 9.6%).9

2.1. Changing natural history
The prevalence and consequently the natural history of NQMI and perhaps of unstable angina appears to be changing. The Worcester Heart Attack Study documented an increasing incidence of non–Q-wave MI over a 22-year period.16An Israeli registry also reported an increasing incidence, but this has been accompanied by a reduction in early and late mortality.17Similarly, in a large recent analysis of Medicare patients age ≥65 years in the Cooperative Cardiovascular Project database, the survival curves of patients with non–Q-wave and Q-wave MI were identical over a 2-year period, without any evidence of the higher late attrition rate after NQMI noted in the earlier series.18

Explanations for the apparent change in the natural history are speculative and likely multifactorial but probably relate, in part, to advances in therapy, including beta-adrenergic receptor blockers, aspirin, risk factor reduction, and appropriate coronary revascularization. Moreover, recent trials of glycoprotein IIb/IIIa receptor inhibitors and low molecular weight heparin (LMWH) have identified additional subsets of patients with non-ST-segment-elevation ACS among whom favourable effects on mortality and recurrent infarctions have beenobserved.19,20In addition, the patient population has changed; a greater proportion have had prior coronary revascularization. Finally, the diagnosis in recent years is more frequently based on increased concentrations of serum markers as opposed to diffuse electrocardiographic changes.21Irrespective of the mechanisms, it is possible that the current population with non-ST-segment-elevation ACS is at lower risk and includes patients with an ‘aborted’ ST-elevation MI as a result of prior therapy with aspirin and beta-adrenergic receptor blockers, patients with reduced myocardial jeopardy due to prior coronary revascularization, and a higher proportion with single-vessel disease, based on a diagnosis determined by increased concentrations of serum markers as opposed to electrocardiographic changes. To some extent, this may be offset by increasing prevalence of certain high-risk patients, such as the elderly and diabetic patients.

Although definitive proof of a changing anatomic substrate is not available, trends in natural history suggest that it is an opportune time to re-examine the strategies for managing non-ST-segment-elevation ACS. In this context it is relevant to review the results of randomized trials done in the last decade comparing novel drug therapies and aggressive vs conservative approaches.

3. Randomized trials

3.1. Glycoprotein IIb/IIIa inhibitors
Platelet glycoprotein IIb/IIIa receptor inhibitors are a novel class of potent antiplatelet agents that block the final common pathway in platelet aggregation. Six randomized controlled trials have investigated the efficacy of tirofiban, eptifibatide, lamifiban, and abciximab in patients with non-ST-segment-elevation ACS. Together, these trials have investigated more than 30 000 patients. Trials with tirofiban and eptifibatide have shown modest efficacy while those with lamifiban and abciximab have not.10,11,22–25The benefits have to be balanced by the potential of these agents to promote adverse outcomes, possibly as a result of paradoxical platelet activation due to suboptimal inhibition.26Overall, a recent meta-analysis reported that the treatment with glycoprotein IIb/IIIa receptor inhibitors produces a 1% absolute and 9% relative reduction in the composite end point of death and nonfatal MI at 30 days that is associated with a 1% absolute increase in the risk of major bleeding.27The benefit is the result of fewer recurrent MIs without a reduction in mortality and is seen predominantly among patients treated with percutaneous revascularization, with a much smaller effect in those treated medically.

Subanalyses of these studies suggested that certain high-risk subsets of patients derive greater benefit. In the Platelet Receptor Inhibition for Ischemia Syndrome Management (PRISM) study, a beneficial effect was observed only in subjects with an increased troponin value.19In the Platelet Receptor Inhibition for Ischemia SyndromeManagement in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, diabetic patients had a greater improvement in outcome with tirofiban.11In the PRISM and the Platelet IIb/IIIa in Unstable anginaReceptor Suppression Using Integrilin Therapy (PURSUIT) trials, greater benefit was observed (5% vs 1% to 2% absolute risk reduction) in patients undergoing elective percutaneous coronary intervention.10

Consequently, these studies lead us to recommend small molecule glycoprotein IIb/IIIa receptor inhibitor (eptifibatide: 180µg/kg bolus followed by infusion of 2.0µg/kg per min or tirofiban: 0.4µg/kg per min for 30min followed by infusion of 0.1µg/kg per min) therapy for 24h for patients undergoing percutaneous coronary revascularization based on an early invasive strategy and should be strongly considered for high-risk patients in whom an invasive strategy is not planned. Abciximab (0.25mg/kg bolus followed by an infusion of 0.125µg/kg per min [maximum 10 µg/min] for 12 h) may be used if therapy needs to be initiated in the catheterization laboratory.

3.2. Low Molecular Weight Heparin
Recently, LMWH has been introduced because it offers several theoretical advantages over unfractionated heparin, including a more predictable dose-response relationship, greater bioavailability, lack of need for laboratory monitoring, and lower rates of thrombocytopenia. LMWH can be administered subcutaneously and continued long-term on an outpatient basis. Furthermore, LMWH possesses greater anti-Xa activity relative to anti-IIa (antithrombin) activity compared to unfractionated heparin. This may be of therapeutic benefit because factor Xa generation occurs several steps earlier in the coagulation cascade than thrombin generation, and inhibition of Xa has a profound effect on thrombin synthesis.

The Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Event (ESSENCE) and TIMI 11B trials compared enoxaparin with unfractionated heparin in patients with non-ST-segment-elevation ACS.8,28Both studies reported a modest favourable effect (reduction: 3.2% and 2.1%, respectively) of LMWH on the respective primary composite end-points, which included MI, death, recurrent ischaemia, and urgent revascularization. The Fragmin During Instability in Coronary Artery Disease (FRISC) study compared dalteparin to placebo and reported a 3% absolute reduction in death and recurrent MI at 6 days.29The beneficial effect was restricted to patients who had NSTEMI, as detected by an increase in troponin I.20In contrast, the Fraxiparine in Ischemic Syndromes (FRAXIS) and the Fragmin in Unstable Coronary Artery Disease (FRIC) trials found no difference between unfractionated heparin and LMWH.30,31The conflicting results from these trials may be explained partly by differences in study design and pharmacologic differences in the LMWH used in these studies. A meta-analysis of the trials indicated that LMWHs are at least as effective as unfractionated heparin,32whereas data from TIMI 11B and ESSENCE suggest that enoxaparin offers a modest benefit over unfractionated heparin in high-risk patients.33Thus, either LMWHs or unfractionated heparin may be used acutely to treat non-high-risk patients, and enoxaparin may be superior for those at high risk. Heparin therapy may be discontinued after successful percutaneous revascularization in patients managed with an invasive strategy. Among those managed by an early conservative approach, anticoagulation may be stopped after at least 48 h of treatment and the absence of spontaneous ischaemia for 24h. There is no convincing evidence for chronic outpatient therapy. LMWHs should be used with caution in patients with renal insufficiency and avoided in the presence of severe renal failure (creatinine clearance <30ml/min).

3.3. Clopidogrel
The Clopidogrel in Unstable Angina to Prevent Recurrent Ischaemic Events (CURE) trial reported a 2.1% absolute risk reduction in the composite end-point of cardiovascular death, MI, or stroke in patients treated with clopidogrel for a mean duration of 9 months.34There was no significant difference in mortality. At 30 days, there was a 0.9% reduction in death or MI, an effect that is similar in magnitude to that seen with the glycoprotein IIb/IIIa receptor inhibitors.27This was accompanied by a 1% increase in major bleeding. The risk of bleeding is a concern for patients requiring coronary artery bypass grafting.35At our institution, because surgical revascularization is usually performed within 5 days of admission, we defer the initiation of clopidogrel until the need for coronary artery bypass grafting has been excluded. This may not be necessary for many centres where surgery is delayed beyond 5 days. The revised European Society of Cardiology and the American College of Cardiology/American Heart Association guidelines recommend the use of clopidogrel in addition to aspirin. However, the guidelines should be implemented with the knowledge that the efficacy of clopidogrel in patients treated with an early invasive strategy was not tested in the CURE trial because only 23% of patients were revascularized during the initial hospitalization, and the safety and efficacy in patients treated with a glycoprotein IIb/IIIa receptor inhibitor remain uncertain, because only 10% of patients received combined therapy. Therapy should continue for 9 to 12 months in patients managed with medical therapy alone and those requiring percutaneous revascularization.

3.4. Invasive vs noninvasive management
Patients with non-ST-segment-elevation ACS are managed by 1 of 2 treatment strategies. The noninvasive approach consists of initial pharmacologic therapy for clinical stabilization followed by stress testing unless patients have recurrent spontaneous ischaemia. This strategy is effective in controlling symptoms in many patients and avoids the need for revascularization procedures except in the presence of recurrent ischaemia or a strongly positive exercise tolerance test. An early invasive strategy is the alternative approach in which patients are managed routinely with coronary angiography and revascularization after initial stabilization with medical therapy. There is considerable variability in the use of these strategies around the world, with the invasive strategy used most frequently in the United States.36–38Even within the United States, regional variation exists depending on availability of catheterization facilities, physician preferences, and patientexpectations.

3.4.1. Early studies
Early studies suggested that there was no survival advantage to an early invasive strategy. The TIMI IIIB trial randomized 1,473 patients with non-ST-segment-elevation ACS to conservative or invasive treatment.39The primary end point of death, MI, or unsatisfactory exercise stress test at 6 weeks did not differ between the groups (18% vs 16%). However, patients assigned to the invasive strategy had a shorter hospital stay (10.2 days vs 10.9 days, p=0.01) and a reduced readmission rate (7.8% vs 14.1%, p<0.001). A trend toward a reduction in death or MI was observed in patients with NSTEMI.40The only subgroup to benefit included patients age ≥65 years who had a lower incidence of death or MI with the invasive strategy (14.8% vs 7.9%, p=0.02). The absence of an overall beneficial effect may, in part, have been due to a high crossover in the noninvasive arm of the study, resulting in convergent rates of revascularization in the invasive group (61%) and the conservative group (49%).

The Medicine Versus Angiography in Thrombolytic Exclusion (MATE) trial studied 201 patients presenting with an MI who were ineligible for thrombolysis mainly because of an absence of ST-segment elevation or contraindications to thrombolytic therapy.41Randomization was performed immediately on admission to early angiography, and therapy was based on the results of the angiogram or conventional medical therapy. An invasive strategy was associated with a 45% reduction in the primary end point of in-hospital recurrent ischaemic events or death (13% vs 34%, p=0.0002). However, the benefits did not persist after a median follow-up of 21 months.

The findings of the Veterans Affairs Non-Q-WaveInfarction Strategies in Hospital (VANQWISH) trial were of more concern because the study showed a worse outcome with an invasive approach.42The study randomized 920 patients with NSTEMI to a conservative or an invasive strategy. The conservatively treated group underwent radionucleotide ventriculography at 48 h and exercise thallium scans before dismissal. Revascularization was performed if a patient had at least 1 of the following: recurrent postinfarction angina with electrocardiographic changes, angina with >2-mm ST-segment depression on exercise, greater than 2 redistribution defects, or 1 defect with increased thallium uptake in the lung. At 30 days the primary end point of death or MI was higher in the invasively treated group (5.7% vs 10.4%, p=0.01) because of a high surgical mortality rate of 11.6%. The overall surgical mortality was 7.7% in the study. In comparison, the mortality was 2% in the FRISC II trial and 2.1% in a similar cohort of patients from the Olmsted County database.43,44The high surgical mortality in the study may, in part, have been due to the very high-risk patient profile. No procedural death occurred in patients treated with percutaneous coronary intervention. No subgroup benefited from the invasive approach. The survival curves converge by 3 years of follow-up, raising the possibility that longer follow-up might have led to a different conclusion. The study has several limitations that may have contributed to the negative result. First, the study was not designed to evaluate early treatment, because angiography was performed after 48 h in most patients. Second, revascularization was performed in only 44% of the invasive group vs 33% in the conservative group. Third, there was low use of glycoprotein IIb/IIIa receptor inhibitors, LMWH, and stents because these treatments were introduced during the course of the trial.

3.4.2. Contemporary studies
The Fragmin and Fast Revascularization During Instability and Coronary Artery Disease (FRISC II) trial was the first large randomized trial that demonstrated a significant improvement in cardiovascular end points by using an early invasive strategy. Patients (n=2,457) were randomized to a conservative or an early invasive strategy.43Coronary angiography was performed within the first 7 days in 96% and 10% of the patients, respectively, and revascularization within the first 10 days in 71% and 9% of the patients, respectively. At 6 months, there was a reduction in the primary composite end point of death or MI in the invasive group (12.1% vs 9.4%, p=0.03). The difference was due to a reduction in MI (10.1% vs 7.8%, p=0.045) with no significant difference in mortality. There was also a reduction in the instance of angina and the use of antianginal medications. At 1 year, a reduction in mortality (3.9% vs 2.2%, p=0.016) and MI (11.6% vs 8.6%, p=0.015) was observed in the invasive group.45The study may have underestimated the beneficial effect of an invasive strategy, because coronary angiography was not performed within 48h in most patients.

The Treat Angina with Aggrastat [tirofiban] and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) trial was designed to address timing of coronary angiography and other limitations of previous studies.46Patients (n=2,220) with non-ST-segment-elevation ACS were randomized to conservative or early invasive strategies. All patients received aspirin. Unlike previous studies, all patients received a glycoprotein IIb/IIIa receptor inhibitor (tirofiban) and, among patients in the invasive arm, coronary angiography was performed within 4 to 48h and followed by revascularization as appropriate. The study demonstrated a reduction in the primary composite end point of death, MI, and rehospitalization for ACS in the invasive arm at 30 days (10.5% vs 7.4%, p<0.009) and at 6 months (19.4% vs 15.9%, p=0.025). This benefit was mainly the result of a reduction in MI (5.8% vs 3.1% at 30 days, p=0.002) and rehospitalization (5.5% vs 3.4% at 30 days, p=0.018). A potential bias in favour of the invasive strategy may have occurred due to the higher threshold for creatine kinase-MB used for diagnosing MI in the invasive vs the conservative arm. There was no reduction in mortality. The hospitalization was briefer in the early invasive group (8.3 days vs 7.4 days, p<0.001), but the rate of major bleeding was higher (3.3% vs 5.5%, p=0.01) with the early invasive strategy.

The Value of First Day Angiography/Angioplasty in Evolving Non-ST Segment Elevation Myocardial Infarction: An Open Multicenter Randomized (VINO) trial randomized 131 patients with NSTEMI to an early invasive or a conservative strategy.47In the invasive group, 44% of patients had angioplasty on the first day compared with 3% in the conservative group. At 6 months, 73% vs 39% had been revascularized. There was a significant reduction (6.2% vs 22.3%, p<0.001) in the primary composite end point of death or nonfatal MI at 6 months. Mortality (3.1% vs 13.4%, p<0.03), recurrent MI (3.1% vs 14.9%, p<0.02), and duration of hospitalization were lower in the invasive group. The 30-day outcomes showed similar but statistically nonsignificant trends.

Finally, the third Randomized Intervention Trial of unstable Angina (RITA-3) randomized 1,810 intermediate-risk patients to either a conservative or invasivestrategy.48Median duration to coronary angiography was 2 days. At 4 months, a reduction in the primary composite end point of death, non-fatal MI, or refractory angina was observed in the invasive group (14.5% vs 9.6%, p=0.001). The difference was predominantly due to lower rates of refractory angina without a reduction in mortality or MI.

Thus, although the early trials and the largeOrganisation to Assess Strategies for Ischaemic Syndromes (OASIS) multinational registry36demonstrated a lack of efficacy, four contemporary trials have consistently shown benefits of an invasive strategy on the subsequent rates of refractory angina, death, and MI. Nonetheless, the argument in favour of a routine aggressive strategy in all patients is not persuasive for several reasons. First, access to early angiography is limited in most countries around the world and in many regions of the United States.36–38Second, despite the considerable improvement in the outcomes of patients being revascularized, there remain subgroups (advanced age, peripheral vascular disease, and increased creatinine) at high risk of periprocedural complications.49Finally, the logistic and economic implications of an aggressive strategy for the majority of patients warrant an evaluation of an approach of initial pharmacologic stabilization and risk stratification and a limitation on the use of angiography and revascularization to the most judicious and cost-effective manner. A recent analysis from the FRISC II trial indicated that an invasive strategy in high-risk patients is accompanied by only a modest (13%) increase in cost over 12 months,50but this did not include the potential cost for creating new facilities for angiography.

4. Risk stratification

Major determinants of prognosis in coronary artery disease include the severity of ischaemia, presence of multivessel disease, location of stenosis (proximal left anterior descending and left main), and left ventricular dysfunction. Risk stratification is aimed at detecting the presence of these adverse characteristics and may be performed during the initial evaluation from the history, physical examination, 12-lead electrocardiogram, serum markers of myocardial injury, and echocardiography in some patients to assess left ventricular function. Features in the history that confer increased risk include an age >65 years. Older patients have a higher prevalence of multivessel and advanced coronary artery disease and have multiple comorbidities. The TIMI IIIB and FRISC II trials reported a benefit of an invasive strategy only in patients age >65 years.39,40We confirmed a greater benefit in older patients from an analysis of the Olmsted County Acute Chest Pain database.44Other indicators of multivessel coronary disease and high risk are a history of chronic stable angina, prior MI, left ventricular dysfunction or congestive cardiac failure, and presence of diabetes mellitus. Indicators of increased risk on physical examination are the presence of transient pulmonary oedema, new or worsening mitral regurgitation murmur, third heart sound, hypotension, and ventricular arrhythmia.

The 12-lead electrocardiogram provides important prognostic information. Multiple studies have emphasized the adverse impact of ST-segment depression, both transient and persistent, on long-term mortality and morbidity.51,52Depression of 1 and 2mm in 2 contiguous leads on the baseline electrocardiogram is associated with approximately 6- and 10-fold increase in 1-year mortality, respectively.53In many of the earlier studies that documented the unfavourable natural history of nonocclusive myocardial infarction, the diagnosis was often made because of persistent ST-segment depression as opposed to the more widespread use of serum markers currently. Recurrent and refractory ischaemia with ST-segment depression despite optimal medical therapy is also associated with early mortality and reinfarction.9ST-segment depression is a reflection of diffuse subendocardial ischaemia and, by implication, multivessel disease. T-wave inversions alone are of less value, although the pattern of deep, symmetrical T-wave inversion in the anterior precordial leads is strongly associated with stenosis of the left anterior descending coronary artery and a higher rate of death in MI during subsequent medical therapy.54

Traditionally, an increase in creatine kinase-MB in the absence of ST-segment elevation defined patients with NSTEMI. More recently, an increased cardiac troponin value, even in the absence of an increase in creatine kinase-MB, has been used to define MI, resulting in an apparent increase in the incidence of NSTEMI. An increase in cardiac troponin value confers a worse short- and long-term prognosis independent of the clinical and electrocardiographic risk factors, even in patients with normal creatine kinase-MB concentrations.19,55–57The risk of reinfarction and cardiac death correlates with the magnitude of increase in troponin. Although the adverse effect of the increased serum troponin values on prognosis is undisputed, the explanations for this association have stimulated some controversy. It is unlikely that the ‘microinfarcts’, which the increased serum markers represent, would be the cause of late cardiac death because of the presence of necrosis or re-entrant ventricular arrhythmias. The more plausible explanation is that increased serum markers are surrogates of an unstable plaque and increased thrombus burden, with distal embolization giving rise to recurrent events.58In addition, an angiographic study59demonstrated an association between increased troponin values and more extensive coronary disease and myocardial jeopardy, in addition to saphenous vein graft occlusion and a more severe stenosis of the culprit lesion. These patients appear to have a greater benefit from aggressive medical management with glycoprotein IIb/IIIa receptor inhibitor and LMWH therapy and subsequent early invasive treatment.20,43,60Further refinement of risk stratification may be possible by incorporation of novel cardiac biomarkers such as B-type natriuretic peptide, C-reactive protein, and interleukin-6.61,62

Strong support for an invasive approach based on risk stratification is provided by the 4 trials that unequivocally demonstrated a benefit for an aggressive vs a conservative strategy. In the FRISC trial, the advantages of the invasive strategy were noted only in the highest-risk patients with rest pain, ST-segment depression, and increased serum troponin or interleukin-6 values.4362,63The pattern was similar in the TACTICS trial, such that the magnitude of benefit was proportional to the overall risk.46The TIMI investigators used clinical, electrocardiographic, and enzymatic variables in the calculation of a risk score and 6-month outcomes. There was an 11.1%, 4.2%, and 1% absolute risk reduction at 6 months in the high-, intermediate-, and low-risk patients, respectively. A marked benefit with invasive treatment was observed in patients with but not those without a troponin T increase and in those with ST-segment depression. The RITA-3 trial also reported a modest benefit in intermediate-risk patients.48The VINO trial as well as a recently published retrospective analysis of the TIMI IIIB data confirmed an improved outcome with an early invasive strategy in high-risk patients.47,64However, a subgroup analysis in women from the FRISC II trial did not show any benefit from an early invasive strategy.65This may have been, in part, due to the fact that women tended to be older and had higher mortality after coronary artery bypass grafting but had less severe coronary atherosclerosis than men. An absence of benefit in women was also reported in the RITA-3 trial but not in the TACTICS trial.46,48Thus, we believe that further prospective evaluation of treatment strategies is warranted in women, but in the meantime we recommend careful risk stratification-based application of invasive management for both men and women.

The clinical, electrocardiographic, and biomarker indices have been integrated into the Agency for Healthcare Policy Research criteria that categorize the patients into low, intermediate, and high risk.66We previously validated these criteria and confirmed that the criteria correlate with the severity of coronary artery disease in patients with non-ST-segment-elevation ACS such that intermediate- and high-risk patients have a high likelihood of angiographically significant coronary disease.67Furthermore, the clinical risk stratification also correlates with the magnitude of ischaemic myocardium, as measured by the myocardial jeopardy score.

From the evidence of recent trials, we have adopted a modified version of the Agency for Health Care Policy Research criteria that divides patients into high- and non-high-risk groups (Fig. 1). High-risk ACS patients can be defined as those with at least 1 of the following: prolonged ongoing chest pain (>20min), age >65 years, diabetes mellitus, chronic stable angina, pulmonary oedema, dynamic 0.05-mV or greater ST-segment depression, hypotension, significant arrhythmia, and increased concentrations of troponin or creatine kinase-MB. These patients are admitted to a coronary care or step-down unit with the aim of stabilization of ischaemia with pharmacologic therapy and subsequent early coronary angiography. At the Mayo Clinic, we aim to perform angiography and, if indicated, percutaneous revascularization within 48h. This is consistent with the European guidelines that also recommend that angiography be performed at least within the hospitalizationperiod.1Medical therapy should include aspirin, beta-adrenergic receptor blockers, unfractionated heparin or LMWH, and a glycoprotein IIb/IIIa receptor inhibitor (Fig. 1). However, a few patients will not stabilize and will require emergency or urgent cardiac catheterization, placement of an intra-aortic counterpulsation balloon pump, and urgent coronary revascularization. Patients suitable for revascularization should undergo either percutaneous coronary intervention or coronary artery bypass grafting, as determined by the coronary anatomy. Those unsuitable for revascularization should receive optimum medical therapy. These recommendations require a change in clinical practice because both the OASIS Registry and our data from the Olmsted County database suggest that coronary angiography and revascularization are performed more frequently in lower-risk patients.32,44



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Fig. 1 Early risk stratification-based management strategy for non-ST-segment-elevation acute coronary syndromes. CABG, coronary artery bypass graft; ECG, electrocardiogram; LMWH, low molecular weight heparin; PCI, percutaneous coronary intervention.

 
In patients not at high risk, a randomized trial from Olmsted County demonstrated the utility of admission to a chest pain unit followed by hospital admission in patients with recurrent pain, ventricular arrhythmias, increased serum markers, or a positive stress test within 24h and hospital dismissal in patients without any of the above features.68Heparin therapy is indicated for intermediate-risk patients. Intermediate risk may be defined as at least one of the following and no high-risk features: rest angina for >20min and resolved; rest angina for less than 20min relieved spontaneously, with rest, or with nitroglycerin; new onset of Canadian Cardiovascular Society class III or IV angina in the past 2 weeks; and presence of Q waves or dynamic T-wave inversion >0.2mV.

A stress test should be performed in those who have a normal electrocardiogram and cardiac markers at 6 to 9h after the onset of symptoms in an attempt to diagnose coronary artery disease and to further stratify thepatient’s risk. The choice of the stress test is determined by the resting electrocardiogram, ability to performexercise, and local availability and expertise. Standard treadmill exercise is adequate in most patients except those who have baseline ST-segment abnormality on their electrocardiogram, left ventricular hypertrophy, intraventricular conduction defect, paced rhythm, pre-excitation, and digoxin therapy, in whom an imaging modality should be included. Physical exercise is the preferred form of stress, although a pharmacologic stress test with imaging may be performed in patients who are unable to exercise or those with left bundle branch block. Features on a stress test that are markers of adverse outcome include a Duke treadmill score of –11 or less,69extensive ischaemia on imaging, stress-induced left ventricular dilation or severe dysfunction (ejection fraction <35%), and increased lung uptake (thallium-201). Patients who have a high-risk stress test or those who develop recurrent chest pain or abnormal electrocardiographic features or cardiac markers during the observation period should also be admitted as inpatients and undergo early coronary angiography. The remainder of the patients can be dismissed with early outpatient follow-up.

5. Conclusions

Patients with non-ST-segment elevation ACS have a heterogeneous risk profile for short-term adverse outcomes and require a tailored approach. The increasing prevalence of coronary artery disease as a result of the aging population and rising incidence of NSTEMI in an era of expensive health care require that observations from well-conducted trials are integrated into practice to develop the most cost-effective management strategies. Early risk stratification based on clinical, electrocardiographic, and serum biomarker indices is the key (Fig. 1). Current evidence suggests that the use of an invasive approach together with glycoprotein IIb/IIIa receptor inhibition should be targeted at higher-risk patients. However, this evidence is largely derived from post hoc analysis of randomized trials and warrants prospective evaluation. Patients deemed not to be at high risk may be observed in a facility with cardiac monitoring such as a chest pain unit. A stress test should be performed in those who have normal serial electrocardiograms and cardiac markers. Patients who have a strongly positive stress test or those who develop recurrent chest pain or abnormal electrocardiogram or cardiac markers during the observation period should also undergo early coronary angiography. The conventional strategy of pharmacologic stabilization, mobilization, and risk stratification remains appropriate for patients admitted to hospitals without invasive facilities. Those with ejection fraction of less than 40% or inducible ischaemia at low or moderate workloads should be referred for early coronary angiography. However, an important caveat of this approach is that the negative predictive value for recurrent events of a low-risk exercise test is reduced in patients with unstable angina compared with stable angina.70

Similar to the recommendations of the European Society of Cardiology,1our approach directs patients down two clinical pathways. Those at low risk are dismissed within 24h (some of whom may in retrospect have experienced noncardiac chest pain) and a second group (approximately 60% to 75% of all patients) undergoes angiography. In the majority of the latter patients, the aggressive strategy is determined by the initial risk stratification. In the remainder, the indications for angiography are determined by the subsequent clinical course after admission to a chest pain unit—for example, recurrent pain, increased serum biomarkers, new electrocardiogram changes, or a positive stress test. This algorithm, based on the role of early risk stratification, eliminates the prolonged hospital stay to stabilize and subsequently identify patients who will need coronary angiography.

On dismissal from the hospital, secondary prevention is achieved by aggressive treatment of risk factors such as diabetes, hypercholesterolaemia, tobacco use, and hypertension and by initiation of therapy with aspirin, beta-adrenergic receptor blockers, and angiotensin-converting enzyme inhibitors.

Footnotes

1 © Copyright 2003 Mayo Foundation. Back

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