Non-ST segment elevation acute coronary syndromes: a comprehensive review.

Abstract: As the non-ST segment elevation acute coronary syndromes (NSTEACS) include unstable angina pectoris (UAP) and the non-ST segment elevation myocardial infarction (NSTEMI), acute diagnosis and risk stratification can often prove challenging. This review will cover guidelines and strategies for risk assessment, contemporary approaches to acute patient management as well as recommendations for timing of specialist referral.

Key Words: acute coronary syndromes, non-ST segment elevation myocardial infarction, unstable angina, risk stratification, management.

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Previously considered as separate diagnostic entities, unstable angina pectoris (UAP) and non-ST segment elevation myocardial infarction (NSTEMI) are now regarded as sharing a common pathophysiologic basis as manifestations along a spectrum of severity of the same disease. As a consequence, the term "non-ST segment elevation acute coronary syndromes" (NSTE ACS) is now applied for description of these two closely related cardiovascular syndromes. The main difference between UAP and NSTEMI is that in the setting of NSTEMI, macro or microvascular coronary flow is reduced enough to produce detectable myocardial necrosis. (1)

Etiology and Pathogenesis

The Vulnerable Plaque Concept

Considerable evolution has occurred in the understanding of the etiology of ACS. The previous belief that gradual progression of severe, fixed coronary stenosis was the cause of acute cardiac events has evolved with the recognition that the great majority of ACS follow the disruption of a previously nonsevere atherosclerotic lesion. Indeed, early angiographic studies suggested that many patients with NSTE ACS have mild to moderate disease before plaque disruption, with the culprit lesion in up to 80% of patients being less than 70% in severity. (2) Thus, plaque biology more likely defines risk for rupture; these "vulnerable plaques" (Fig. 1) are typically defined by a large lipid pool, and a high percentage of inflammatory cells, as well as a thin fibrous cap separating the lipid core from the blood pool. In contrast to collagen-rich 'hard plaques,' which may progress in severity and result in stable angina pectoris, the vulnerable 'soft' plaque is more prone to acute rupture and exposure of the potently thrombogenic core to the blood pool, with resultant intracoronary thrombosis. (3)

Platelet-Rich Thrombi and Microvascular Embolization 

Following plaque disruption, a rapid sequence of intense platelet-mediated activity occurs. After exposure of ligands for platelet adhesion, including collagen present in the sub-endothelial basement membranes, platelets begin to localize over the site of plaque rupture. This is followed by platelet activation, a process that may occur by a number of platelet-stimulating compounds, including thrombin (present in clots), adenosine diphosphate and serotonin (present within platelet granules), as well as thromboxane-A2. (4) When quiescent, the normal platelet has between 30,000 to 50,000 copies of the glycoprotein (GP) IIb/IIIa receptor present within cytosolic pools. Exteriorization and conformational modification of these receptors allow for aggregation and cross-linking of platelets. (5) Subsequent fixation of the prothrombinase complex and commencement of the coagulation cascade follows, ultimately leading to a platelet-rich thrombus within the coronary artery, over the disrupted plaque.

[FIGURE 1 OMITTED]

Following NSTEMI, between 60 to 85% of cases demonstrate a patent infarct-related artery, (6,7) yet patients develop symptoms of myocardial ischemia and signs of myocardial necrosis, which reflect the importance not only of epicardial coronary artery occlusion/stenosis in the pathophysiology of acute myocardial ischemia, but also the importance of distal embolization of platelet-rich microaggregates of thrombus, with attendant 'micro-infarction' and independent effects on outcomes, regardless of flow in the epicardial artery. (8)

Diagnosis and Evaluation

Current guidelines recommend obtaining a history, physical examination and laboratory evaluation of the patient with suspected NSTE ACS. Laboratory testing includes an initial 12-lead electrocardiogram (ECG), useful for rapid diagnosis, risk stratification and estimation of prognosis, (9) as well as serum troponin testing.

Risk Stratification

When evaluating patients with suspected ACS it is crucial to assess their risk for failing conventional medical therapy and thus raising the need for urgent referral for revascularization. In general terms, certain patient types require relatively limited thought in terms of stratifying their risk; these include those with cardiogenic shock, severe LV dysfunction, or persistent severe ischemia, despite maximal medical management. For patients whose risk is less defined, the various methods described below are available to assist clinicians in stratifying the risk of patients with NSTE ACS quickly into high or low risk. The flow diagram in Figure 2 provides guideline-oriented recommendations for initial medical management by general internists, and specific clinical settings when patients should be referred to the cardiologist.

Risk Stratification Methods

The TIMI (Thrombolysis In Myocardial Infarction) risk score (10) is a stratification tool that uses seven variables independently predictive of adverse outcome in patients with UAP or NSTEMI (See Table 1). It may be useful not only for identifying those patients at risk for ischemic complications from their ACS, such as progression to MI or death, but also offers useful information regarding benefit from specific interventions for ACS management (see below).

Certain elements from the TIMI Risk Score such as the ECG and troponins bear specific mention.

The baseline ECG has an important prognostic value for ACS, as the risk of new or reversible ST segment depression greater or equal to 0.5 mm has comparable risks to transient ST elevation or new left bundle branch block: It nearly doubles the risk for death (from 8.2% to 15.8%) (11,12) and it increases the risk for MI or recurrent rest ischemia, as well as failure of medical therapy from three to six-fold. (13) Although specific for identifying those at risk for complications, in the setting of NSTE ACS, the ECG is less sensitive and has poor negative predictive value; thus, a negative ECG does not offer reassurance. Furthermore, in many cases of NSTE ACS, the ECG only demonstrates nonspecific ST and T wave changes or isolated T wave inversions, which have an equivocal relationship to adverse outcome (see Table 2).

The serum troponins are now considered the 'gold standard' for diagnosis of cardiac injury, and are useful for biochemical risk stratification in ACS. The troponins are highly cardiac specific, and more sensitive than previous cardiac markers, notably the MB isoenzyme of creatine phosphokinase. In addition, levels of troponin are correlated in a nearly linear manner with risk for adverse outcomes among patients with NSTE ACS. (14)

[FIGURE 2 OMITTED]

Because detectable levels of troponin are not present in the blood of patients with NSTEMI until 4-6 hours after myocardial injury, serial blood testing should always take place after this period in patients who present with a nondiagnostic ECG but high clinical suspicion for NSTE ACS. A strategy of troponin measurement at baseline, 8, and 16 hours should detect the great majority of those with NSTEMI ACS. (15)

Contemporary Approaches for Managing the Acute Patient with NSTE ACS

Traditional Medical Management

Generally speaking, therapy of the NSTE ACS patient should be directed at stabilizing the hemodynamics, relieving ischemic pain, using antithrombotic therapy to minimize myocardial damage and reducing the risk for recurrent ischemia. Subsequently, risk stratification should be utilized to assess the likelihood for failure of medical therapy and the need for revascularization. It has been estimated that 80% of ACS patients can be stabilized within 48 hours after being started on an intensive medical program for ischemia, while the rest require urgent catheterization and revascularization. (16)

Initial therapy for patients presenting with chest pain has traditionally employed oxygen, aspirin, nitroglycerin and morphine. Exceptions to this general rule exist with regards to the treatment of NSTE ACS. Notably, oxygen therapy, while written into the guidelines, has never been shown to impact the degree of tissue-level ischemia in patients with ACS. Morphine may be useful to achieve analgesia and reduce anxiety; however, morphine is not routinely recommended as an 'up front' therapy for ischemia, as it may mask the clinical response to anti-ischemic treatment. Morphine does have Class I recommendation status in patients with acute pulmonary edema, reflecting its beneficial effects on the pulmonary vasculature. (1)

Anti-ischemic Therapy

Nitrates have not been demonstrated to improve mortality or recurrent myocardial infarction (17); however, they have many mechanisms (reduction in afterload, improvement in the coronary collateral circulation, relief of coronary spasm, etc) through which they can improve symptoms. (18)

Beta Blockers are indicated in all patients with NSTE ACS unless contraindicated (heart rate <60, systolic blood pressure <100, high-Grade AV block). Beta blockers reduce myocardial oxygen demand and ventricular wall tension. They have been shown to decrease the rate of adverse cardiovascular events in patients with ACS, including a 29% relative risk reduction in mortality among high risk individuals with an evolving MI. (19) A later meta-analysis in 1988 showed a 13% decrease in progression to new or recurrent MI. (20)

Current guidelines evolved from these studies and now recommend an IV beta blocker infusion (ie, 5 mg of metoprolol q. 5 min repeated 3 times) in the setting of chest pain, followed by long-term use of oral beta blocker (such as metoprolol 25 mg p.o. q. 6 h) titrated to heart rate 55 to 60 for low to intermediate-risk patients with angina and for all high-risk patients unless contraindicated. (1)

Antithrombotic Therapy

In recognition of the role of intracoronary thrombosis, the use of antithrombotic therapy for the management of NSTE ACS is a mainstay in therapy and stabilization of the patient with ACS.

Antiplatelet Therapy

Aspirin irreversibly blocks cyclooxygenase in platelets, rendering them incapable of synthesizing thromboxane A2 for the rest of their circulating lifetime. Aspirin may be associated with up to 50 to 70% reduction in mortality or progression to MI (21) following NSTE ACS.

Clopidogrel, a thienopyridine, inhibits ADP-dependent activation of the GP Ilb/IIIa complex, a necessary step for platelet aggregation, resulting in intense inhibition of platelet function, particularly when clopidogrel is combined with aspirin.

The combination of clopidogrel and aspirin for management of NSTE ACS was evaluated in the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, (22) which examined 12,562 NSTE ACS patients, randomized to receive clopidogrel plus aspirin versus aspirin and placebo for 3 to 12 months, with conservative management mandated unless forced to the cath lab by severe ischemia. The clopidogrel/aspirin group showed a 20% reduction in adverse outcomes particularly due to reduction in new MI. This benefit began within hours of administration and showed lasting benefits for up to 6 to 9 months. Patients brought to the cath lab benefited from clopidogrel treatment as well. Bleeding related to clopidogrel plus aspirin is manageable, related to mucosal hemorrhage, and modulated by an aspirin dose change to 81 mg, without loss of the benefits from treatment together with clopidogrel. (22)

Due to its slow reversibility, concern for the use of clopidogrel has been raised when the possibility of CABG revascularization strategies are indicated and a nonrandomized study (23) showed a 10-fold reoperation need for postoperative bleeding. However, this was not substantiated in the CURE analysis of patients undergoing CABG. (22) A later study confirmed an increase in the rate of bleeding complications after CABG but concluded this risk is lower if it is possible to wait 2 to 3 days to allow the drug to leave the patient's system, and if urgent CABG is needed, it was suggested that the bleeding associated with clopidogrel (which is typically mild) may be an acceptable trade-off given the benefits of this medication. (24)

Current guidelines recommend that if an in-hospital conservative approach or cardiac catheterization and percutaneous coronary intervention (PCI) with a low risk for bleeding are planned, clopidogrel is a Class I recommendation and it should be given as soon as possible to all patients with high-risk ST segment depression or dynamic T-wave inversion in the absence of contraindications. (1)

The value of clopidogrel in the setting of precath lab GP IIb/IIIa inhibitor use has not been thoroughly evaluated, but preliminary data are promising. (25-27)

Glycoprotein (GP) IIb/IIIa Receptor Antagonists include the chimeric monoclonal antibody abciximab, as well as the "small molecule" inhibitors eptifibatide and tirofiban. These IV drugs are potent inhibitors of the platelet GP IIb/IIIa receptor, the "final common pathway" for platelet aggregation.

When used in patients with the NSTE ACS, the small molecule GP IIb/IIIa receptor blockers have been shown to significantly reduce ischemic complications.

Among patients with high risk NSTE ACS (ie, with ST depression on ECG and/or elevated markers of cardiac necrosis), precath lab therapy with either eptifibatide or tirofiban plus unfractionated heparin was associated with a 10 to 20% decrease in death/MI. (28,29) Medical stabilization therapy with abciximab was not associated with significant reductions in adverse ischemic outcomes, (30) emphasizing the optimal use of abciximab as an adjunct to percutaneous revascularization techniques, and begun only just before, or in the cardiac catheterization laboratory.

While the benefits of platelet GP IIb/IIIa receptor blockers appear to be less evident in lower-risk NSTE ACS patients, intermediate and higher-risk patients appear to respond in an incrementally favorable manner to GP IIb/IIIa inhibitors. These include patients with ST segment depression, elevated risk scores, (31,32) elevated serum troponins, (33,34) and diabetes mellitus. (35)

Anticoagulation

Unfractionated heparin (UFH) is a mixture of glycosaminoglycans of varying chain lengths, weighing between 3,000 to 30,000 kDa. UFH binds to antithrombin, enhancing its inhibition of thrombin and factor Xa. (36) In 1996 a metaanalysis showed a 33% reduction in risk of MI or death in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. (37) The use of heparin is limited by a variable dose-response curve and the unpredictable appearance of heparin-induced thrombocytopenia. (38)

Low-molecular weight heparins (LMWH), such as enoxaparin and dalteparin are produced via catalytic degradation of UFH, resulting in a mixture of similar chain lengths. LMWHs have demonstrated relatively more antifactor Xa: antifactor IIa activity compared with UFH, as well as an easier means of administration (SC injection) without the need to monitor activated partial-thromboplastin time, (36) and a lower incidence of thrombocytopenia.

The LMWHs have been compared with UFH for the management of NSTE ACS, enoxaparin in the ESSENCE (39) and TIMI 11B (40) trials and dalteparin in the FRISC trial. In both the ESSENCE and TIMI 11B trials, enoxaparin/aspirin was superior to UFH/aspirin in reducing the composite endpoint of death, MI and urgent revascularization by 20%. (41) The FRISC 1 trial showed a similar reduction of dalteparin/aspirin to UFH/aspirin in the risk for early death or MI. (42)

In general, clinical trials have noted LMWH as superior to UFH and easier to administer. However, the use of LMWH is limited by difficulties with their use in patients managed with angiography who demonstrate a higher risk for hemorrhage than with those treated with UFH. (43) Accordingly, while the superiority of LMWH is clear when used for treatment of medically managed patients, the role of LMWH in those referred for percutaneous revascularization is less well defined.

Lipid-lowering Agents

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is central not only to cholesterol metabolism (via the liver) but also plays a key role in cell signaling in many vascular cells. Through lipid-dependent as well as lipid-independent (so-called pleiotropic) effects, statins have been shown to also have beneficial effects on inflammation, endothelial dysfunction and the coagulation cascade. The PROVE IT-TIMI 22 trial (44) randomized a total of 4,162 patients with ACS to intensive statin therapy (atorvastatin 80 mg) or standard therapy (pravastatin 40 mg). The trial showed that the use of intensive statin therapy improved clinical outcomes over two years in ACS patients versus standard therapy. Differences based on achieved LDL-C could be further discriminated by the achieved C-reactive protein level, suggesting the presence of pleiotropic effects on inflammation. The reductions in events in PROVE-IT were evident early after ACS (45) and sustained to a full year of follow-up. In some contrast, the A to Z trial randomized subjects to receive intermediate dose simvastatin (40 mg) to higher-dose simvastatin (80 mg) following NSTE ACS. In this study, the higher dose of simvastatin was not associated with statistically significant reductions in clinical events relative to the intermediate dose group; however, the achieved LDL cholesterol in the 'intermediate dose' group was much lower than the pravastatin group in PROVE-IT. Thus, in aggregate, these results suggest that ACS patients should be started on high-dose statins in-hospital and continued long term.

Percutaneous/Early Invasive Management of the NSTE ACS

Although early studies such as the TIMI IIIB (46) and VANQWISH (47) trials suggested an increased risk for early invasive management of those patients with ACS, more recent studies, notably the FRISC II (48) and especially the TACTICS TIMI 18 (49) trials, suggested a clear benefit for patients with high-risk NSTE ACS. In contrast, a recent large randomized trial--the ICTUS Study--suggested that an early invasive strategy was not necessarily superior to a selective invasive strategy (angiography/revascularization only with refractory angina despite optimal medical treatment) in patients with NSTEMI ACS. (50) Notably, the differences between the results of TACTICS TIMI 18 and the ICTUS study may rest in the definition of MI in the latter study: in ICTUS, the nonsuperiority of invasive management was driven by the definition of MI in the study. In particular, in ICTUS, post-PCI cardiac biomarker release was not considered differently than spontaneous MI; as such, similar standards were held for both, and led to a higher rate of 'MI' among those undergoing early invasive management. Thus, categorizing post PCI troponin elevation as an MI equivalent (something which is not done as standard of care) no doubt influenced the results of ICTUS.

In most contemporary clinical trials for patients with NSTE ACS, significant reductions in MI and death/MI were observed related to early referral for catheterization with revascularization, when indicated. The benefits of early catheterization with revascularization are particularly noted in those patients with high-risk features, such as high TIMI risk score, ST segment depression or positive cardiac markers.

While the benefits of platelet GP IIb/IIIa blockers are extended to high risk patients irrespective of early invasive management, the clear synergy (51) between GP IIb/IIIa blockers and procedures in the cath lab (which are also indicated in patients at high risk) makes the use of GP IIb/IIIa blockers followed by early invasive catheterization strategies the most logical approach.

Cardiogenic Shock and Intra-aortic Balloon Pump (IABP) Support in NSTE ACS

Although cardiogenic shock (CS) occurs in only 2% of NSTE ACS patients, it is a major cause of death in all types of ACS. (52) The SHOCK registry data suggests that stabilization of CS patients using an intra-aortic balloon pump (IABP) followed by emergency revascularization may be associated with a 20% absolute risk reduction in mortality. (53) Similar findings were echoed in a recent trial from the EuroHeart survey, wherein a nearly 40% reduction in the risk for death was observed in ACS patients receiving IABP support--a benefit independent of ST segment status. (54) Thus, the use of intra-aortic balloon pump counterpulsation among hemody-namically unstable ACS patients, especially those with CS, is firmly recommended. (1)

An Integrative Summary

For the patient with suspected or proven NSTE ACS, the goals for the clinician are to 1) establish a diagnosis, 2) stratify risk, and 3) choose optimal therapeutic interventions, based on the level of risk identified in risk stratification. To achieve the goals of risk assessment, numerous tools are available to the clinician, including history, physical examination, as well as results from ECG or serum troponin testing. A general overview of risk assessment and patient management is provided in Figure 2.

For low-risk NSTE ACS patients (low TIMI risk score, negative troponins, no ST depression on ECG), the optimal therapeutic interventions would include the use of standard medical therapies, including beta adrenergic blockade, aspirin, and an antithrombotic, such as heparin or LMWH. As the use of clopidogrel was associated with significant benefits in such low-risk patients in the CURE study, (22) the addition of clopidogrel to such patients' regimen seems logical. Use of GP IIb/IIIa receptor blockade or early invasive management would be indicated in such patients only if recurrent ischemia were to occur, or if the patient failed noninvasive stress testing before discharge.

For intermediate-risk patients, the treatment should be the same as above, with special considerations given to those patients with a high probability for adverse outcomes, such as patients with diabetes. Based on individual risk, the choice of platelet GP IIb/IIIa receptor blockade and early catheterization might be a reasonable option.

For high-risk NSTE ACS patients (ie, those with high TIMI risk scores, ST segment depression on ECG, or elevated serum troponins), the urgency is to move toward revascularization in a timely fashion. Accordingly, standard medical therapies, including beta blockade and aspirin are indicated. Either UFH or LMWH should be employed. A platelet GP IIb/IIIa receptor blocker should be added, and the patient should be brought directly for percutaneous revascularization, with the 'intent to stent.' If on-site catheterization facilities are not available, initiation of a 'small molecule' GP IIb/IIIa receptor blocker such as eptifibatide or tirofiban should be commenced, followed by timely transfer. This concept of 'drip and ship' has been demonstrated to be feasible, and is associated with favorable outcomes. (55) While the risk of major CABG-related bleeding appears less significant than originally described, (24) the individual choice in each institution regarding the use of clopidogrel in such subjects must be made based on the preferences of the local cardiac surgical services.

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Abelardo Martinez-Rumayor, MD and James L. Januzzi, Jr, MD

From the Department of Medicine and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston MA.

Reprint requests to James L. Januzzi, Jr, MD, FACC, Massachusetts General Hospital, Yawkey 5984, 55 Fruit Street, Boston, MA 02114. Email: [e-mail]

RELATED ARTICLE: Key Points

* Non-ST segment elevation acute coronary syndromes are varying manifestations of the same disease process along a spectrum of disease severity.

* Non-ST segment elevation acute coronary syndromes are most commonly caused by disruption of vulnerable plaques.

* The goal of risk stratification is to identify who will fail medical management and who will need urgent referral for revascularization.

* Eighty percent of patients with acute coronary syndrome can be stabilized within 48 hours after being started on an intensive medical program for ischemia.

Table 1. TIMI Risk Score variables

Characteristic                                          Point

History
  Age [greater than or equal to] 65 years                1
  Presence of at least 3 risk factors for CHD            1
  Prior coronary stenosis of equal or greater than 50%   1
  Use of aspirin in prior seven days                     1
Presentation
  At least two anginal episodes in previous 24 hours     1
  Presence of ST segment elevation on admission ECG      1
  Elevated serum markers                                 1
Risk score total                                        (0-7)

CHD, cardiovascular heart disease; ECG, electrocardiogram.

Table 2. Advantages and disadvantages of ECG use for risk stratification

Pros                               Cons

Rapidly and widely available: may  Wide inter-observer variability:
  be performed in the field          sensitivity dependent on skill of
                                     the physician interpreting the ECG
Highly specific when positive,     Wide differential for chest pain with
  and may identify culprit vessel    false positive ECG: pericarditis,
                                     myocarditis, subdiaphragmatic
                                     irritation, other
Offers strong PPV for outcomes in  NPV less robust, especially if
  the non-STE ACS: ST segment        patient is "pain free" at the time
  depression: up to 17% mortality    ECG is obtained. Recheck early and
  which may exceed that of ST        often (5-10 mins), ECG tracings
  elevation MI                       often change within a period of 30
                                     seconds

ECG, electrocardiogram; PPV, positive predictive value; NPV, negative
predictive value; non-STE ACS, non-ST segment elevation acute coronary
syndrome; MI, myocardial infarction.