Recent advances in the management of unstable angina and non-Q-wave myocardial infarction

Abstract

The ‘acute coronary syndromes’ represent a spectrum of disease, from Q-wave myocardial infarction to unstable angina, in which the common pathogenic feature is the rupture of an atherosclerotic plaque, followed by platelet aggregation and thrombus formation. Q-wave myocardial infarction is most strongly associated with complete arterial occlusion, whereas non-Q wave myocardial infarction and unstable angina involve lesser degrees of occlusion [1]. Immediate clinical outcomes reflect the severity of arterial occlusion, but mortality rates at 1 year are the same in those suffering Q-wave and non-Q wave myocardial infarction [2]. In addition, there is progression within 6 months to acute myocardial infarction in 45% of patients with crescendo angina, 62% of patients with acute rest angina and 25% of patients with subacute angina at rest according to the Braunwald classification based on history alone [3]. However, variations in the diagnostic criteria used for unstable angina in different studies have resulted in a range of rates of progression to acute myocardial infarction and cardiac death [4]. The most recent data would suggest that patients with non-Q wave myocardial infarction and unstable angina based on history, electrocardiogram (ECG) and cardiac enzyme activities still have a high risk of recurrent angina and cardiac death, rising from 3.3% to 14.8% between 6 and 150 days [5]. The heterogeneity of acute coronary syndromes reflects the spectrum of underlying disease but gives rise to two important points. Firstly, care must be taken in comparing data on therapeutic efficacy in trials of unstable angina because of differences in the selection criteria used for patients. Secondly, there is a clinical need to identify the patients at greatest risk amongst those who suffer from non-Q wave myocardial infarction and unstable angina, in order to target more aggressive therapies. Non-Q wave myocardial infarction is defined on the basis of a history of prolonged ischaemic chest pain plus elevation of cardiac enzymes in the absence of Q-waves on the ECG. Unstable angina is a clinical diagnosis based on a history of rest pain in the absence of cardiac enzyme and ECG changes diagnostic of an acute myocardial infarction. ECG changes may predict prognosis in unstable angina, since 11% of patients with >1 mm ST deviation suffer death or recurrent myocardial infarction at 1 year, compared with only 6.8% patients with isolated T-wave inversion. However, such ST deviation and T-wave changes are absent in the majority (63.9%) of patients admitted with unstable angina based on history [6]. Other non-specific variations of the ECG commonly occur in unstable angina, but changes are not universal and may be transient. Cardiac enzymes are not usually raised—by definition, where the creatine phosphokinase (CPK) activity is elevated to twice the upper limit of normal, the diagnosis is acute myocardial infarction and not unstable angina. CPK has limited prognostic power as a marker for minor myocardial cell damage. Enzyme assays may be improved by the use of CPK mass, CK-MB, or by myoglobin estimation but the problem remains that patients are often classified as suffering a myocardial infarction or unstable angina after the event for which treatment is required. Troponin T and I are myofibrillar proteins solely expressed in myocardial cells and released from the myofibrils on disintegration of the contractile apparatus during cell damage. Measurement is relatively easy, since development of bed-side assays compared with more time-consuming and costly ELISA techniques [7]. Troponins were found in 33% of over 4000 patients with acute coronary syndrome, despite no significant change in standard cardiac enzyme estimations [8]. Prospective studies show elevated troponin T levels to be associated with a worse prognosis in unstable angina, whether or not there are changes in other cardiac enzymes [9–11]. The prognostic influence of elevated troponin I levels may have greater sensitivity compared with troponin T [12, 13]. Stratification of patients with symptoms of angina and ST depression on a 12-lead ECG into low, intermediate and high risk groups according to troponin T levels allows detection of patients with a 4.3%, 10.5% and 16.1% risk of myocardial infarction or cardiac death respectively [14]. Troponin I and T are more sensitive markers of myocardial cell necrosis and thus are able to help identify patients who are at high risk of future cardiac events especially when combined with exercise testing [15]. However, although troponin estimation identifies patients with a worse prognosis, there is no evidence that earlier or more intensive treatment solely based on elevated levels will improve outcome. Since troponin may continue to be released for up to 2 weeks following infarction [16], an isolated measurement needs to be interpreted within the clinical context. Troponin estimation may also be of use as an immediate diagnostic test of practical value to enable clinicians to discriminate between patients with acute coronary syndromes and patients who could be discharged directly from the emergency department. The sensitivity of a single whole blood troponin T assay is 85% and the specificity is 92% but a small proportion of patients without elevation of troponin levels may still develop cardiac problems. However, in a series of 773 consecutive emergency room attendants with acute chest pain, no cardiac events occurred within 30 days in patients with negative troponin I tests measured on two occasions at least 4 h apart and no acute ECG changes. The negative predictive value of troponin T and troponin I in patients with a history of ischaemic rest pain within the preceding 48 h was 98.9% and 99.7% respectively for cardiac events within 30 days [17]. Further work may confirm whether troponin testing alone or in combination with other investigations would be sufficiently safe to allow early discharge from hospital emergency departments. These negative tests may place the patient in a good prognostic category but do not exclude the possibility of underlying ischaemic heart disease, which may still require further investigation. Recent evidence suggests that this test, available for use in most hospitals, could be useful in risk stratification of patients with unstable angina. C-reactive protein (CRP) is an acute phase reactant that is a marker for systemic inflammation. Using highly sensitive immunoassays, a CRP level above 3 mg l−1 predicts increased frequency of death, myocardial infarction and coronary intervention in patients with unstable angina with a positive predictive value of 90% [18]. Elevated levels also predict risk of coronary events in patients with stable angina [19, 20]. CRP testing has the advantage over troponin measurement in that therapeutic intervention directed at patients with elevated levels reduces subsequent coronary events [21]. It may be that combination of assays for CRP and troponin T will enable physicians to detect high risk patients with unstable angina more accurately [22], but prospective studies have not yet been carried out to determine the negative predictive value of the tests together in patients presenting to the emergency department with chest pain. Most patients with unstable angina have coronary artery atheroma but develop symptoms following acute plaque disruption, platelet activation and fibrin deposition, leading to the formation of overlying non-occlusive thrombus [23]. Treatments developed for use in unstable angina have targeted both platelet activation and thrombin formation. Aspirin is the standard antiplatelet reference compound for the secondary prevention of complications of coronary artery disease. Four randomized controlled trials clearly document a reduction in risk of death and nonfatal myocardial infarction in unstable angina using doses from 75 mg day−1 and above [24–27]. In the Antiplatelet Triallists Collaborative meta-analysis, aspirin reduced vascular event rates complicating unstable angina from 14% to 9% with a 6 month benefit of 50 out of 1000 events avoided [28]. However, aspirin is not a panacea. It is a relatively weak platelet inhibitor and it affects neither platelet adhesion nor secretion. Aspirin is also less effective if shear stress or ADP are important stimuli of platelet activation. Ticlopidine and clopidogrel are two newer antiplatelet agents which operate by interference with ADP-mediated platelet activation. In theory, the combination of thromboxane-inhibition with aspirin and selective inhibition of ADP-mediated platelet activation with the thienopyridines should be synergistic but the combination has only been tested following percutaneous coronary angioplasty [29]. In unstable angina, ticlopidine reduces mortality from 13.6% to 7.3% and is probably as effective as aspirin in secondary prevention [30]. However, ticlopidine is not widely used because of the frequency and severity of side-effects (diarrhoea, 20%; neutropenia, 2.4%) [31]. The alternative, clopidogrel, may be more effective than aspirin with an equivalent side-effect profile but there are no randomised trial data in unstable angina [32]. Therefore aspirin remains the oral antiplatelet agent of choice in the first line treatment of unstable angina. Intravenous infusion of unfractionated heparin with dose-titration using the activated partial thromboplastin time (APPT) to the therapeutic range (1.5–2.5×normal) is currently the second-line therapy most commonly used in unstable angina. The efficacy of heparin has been studied in a number of trials, although the results have been less concordant than those for aspirin. Four intravenous injections of heparin (10 000 IU) daily for 7 days reduced the incidence of myocardial infarction by 80% in the first randomized-controlled trial in unstable angina [33]. This trial was criticized because 46% of randomized patients were excluded from analysis. However, the results were replicated when heparin was given by continuous intravenous infusion (1000 IU h−1 ) over 6 days [26]. In these trials (over 70% and 90% respectively) patients included had recent chest pain associated with acute ECG changes. Subsequently, a lower dose of heparin (10 000 IU 6 hourly for 24 h, then 7500 IU 6 hourly for 4 days) given as intermittent intravenous bolus injections failed to produce benefit [27]. This later trial included more stable patients, since some were recruited on the basis of a positive exercise test prior to discharge. In addition, APTT was not measured, so there may have been periods of inadequate anticoagulation. Continuous heparin infusion adjusted to APTT reduced the number of symptomatic and silent ischaemic episodes on Holter monitoring in patients with unstable angina [34]. Of all the heparin trials, only the RISC [27] study had sufficient power to detect (a 50%) reduction in death and myocardial infarction event rate with heparin. Whilst it is certain that aspirin alone is beneficial and it is probable that heparin alone is beneficial, the next important question is whether the combination of aspirin and heparin is more effective than aspirin alone. In trials directly comparing aspirin against aspirin and heparin, results have shown both additive effects [35–36] and the absence of benefit [26, 27, 37]. A recent meta-analysis of the main trials in unstable angina suggested that combination therapy reduces risk of myocardial infarction or death by 33% compared with those treated with aspirin alone [38]. Results of the comparative trials may have been complicated by three factors. Firstly, one of the negative trials studied intermittent intravenous injection of heparin although this is not as effective as continuous infusion monitored to control APTT [39]. Secondly, the maximum benefit from heparin may accrue from infusion limited to the first 48 h and prolonged treatment may be associated with adverse consequences, yet four out of the five studies gave heparin for longer [40]. Thirdly, because discontinuation of heparin suppresses anti-thrombin III, a rebound hypercoaguable state may cause recurrent ischaemic symptoms. Concomitant use of other anticoagulants reduces this tendency [41]. In order to prevent reactivation, optimum treatment of unstable angina requires adequate anticoagulation over a prolonged period of time. Long-term continuous intravenous infusion of unfractionated heparin is impractical, exposes the patient to risks of thrombocytopenia (and possibly osteoporosis), and may lead to delay in necessary invasive treatment [42]. The development of low molecular weight (LMW) heparins may herald improvements in treatment. LMW heparins have a number of pharmacokinetic advantages. Bioavailability after subcutaneous injection is close to 100%, compared with 30% for standard heparin. Half-life is 2–4 times longer than that of standard heparin and the lower rate of protein binding leads to a more predictable anticoagulant response. This means that adequate and persistent anticoagulation can be achieved with twice daily subcutaneous injections, making these formulations easier to use in the clinical setting. Furthermore, the risk of thrombocytopenia and osteoporosis seems to be substantially lower with the LMW formulation [42]. The disadvantages of LMW heparin include a comparatively high cost, difficulty in monitoring anticoagulant effect, lack of available antidote and variation in the pharmacokinetics of the different LMW fractions available. Potential therapeutic benefits of LMW heparin were reduction in recurrent ischaemia, myocardial infarction and requirement for urgent revascularisation found in the first study, an open-label comparison of aspirin and subcutaneous injections of nadroparin 214 IU kg−1 twice daily with aspirin and monitored intravenous heparin for 5–7 days [43]. In the FRISC study of 1506 patients with unstable angina, aspirin and dalteparin (120 IU kg−1 twice daily for 6 days, then 7500 IU once daily for 35–45 days) were compared with aspirin and placebo injections in a double-blind manner [43]. The primary endpoint of death and myocardial infarction at 6 days was reduced from 4.8% to 1.8% in the aspirin plus dalteparin group. Patients selected for the study were at high risk, since all had new or increased angina in association with ST depression or T-wave inversion. Differences in rates of death persisted at 40 days. Subsequent studies have compared subcutaneous injection of LMW heparin with continuous intravenous infusion of unfractionated heparin titrated according to APTT. The first, an open comparison with dalteparin, found no difference in the combined outcome measure of death, myocardial infarction or recurrent angina [44]. The second was a double-blind trial which documented a reduction in the primary endpoint of death, myocardial infarction and recurrent angina from 19.8% to 16.6% at 14 days with enoxaparin given 100 IU kg−1 twice daily for 2–8 days [45]. This risk reduction was small but fewer patients in the ESSENCE trial had associated ECG changes and the patient population was therefore at lower risk than those in the FRISC study. The implication of these results is that the combination of aspirin and LMW heparin is more effective than aspirin alone and that LMW heparin is at least as effective as unfractionated heparin. Trials using LMW heparin have so far studied composite endpoints and have applied different treatment regimes, such that the optimum dose and duration of therapy is not known. Further studies in progress may provide more evidence (FRISC 2 and TIMI IIb). In trials of both unfractionated and low molecular weight heparin in unstable angina, there is evidence of a rebound increase in events following cessation of therapy. One approach to overcome this problem was tested in the FRISC study, in which injection of LMW heparin was continued for 35–45 days [3]. Differences in the composite endpoint found at 6 days persisted at 40 days, but the trial was hampered by an apparent increase in events in the dalteparin-treated group after a dose reduction at 6 days from twice to once daily injection. It is possible that continued high dose injection of LMW heparin is required to gain the potential benefit of eliminating rebound coronary events. The alternative strategy is to anticoagulate the patient with warfarin. The ATACS trial compared aspirin alone against aspirin, intravenous unfractionated heparin for 3–4 days, followed by warfarin for 12 weeks maintaining the international normalised ratio between 2–3 low risk patients included on the basis of a history of angina alone [35]. A substantial reduction in recurrent angina, myocardial infarction and death (from 25% to 13%) was found at 12 weeks in the group treated with heparin and warfarin. The information on continued warfarin therapy was confounded in this trial by the variable use of heparin and weakened by the use of a combined outcome measure. Aspirin and warfarin were compared with aspirin and placebo in an angiographic trial studying the progression or reocclusion of unstable coronary lesions in patients with unstable angina or acute myocardial infarction [46]. Culprit lesions were less likely to progress (4%vs 33%) and more likely to regress (19%vs 9%) in patients receiving warfarin. The secondary finding was a non-significant reduction in recurrent myocardial infarction with warfarin therapy. Thus, longer term anticoagulation may be beneficial in unstable angina but there is a need for more randomized trials. Platelet adhesion and aggregation are the initial events in thrombus formation. Extension and growth of the clot involves thrombin, which is recruited by means of an autocatalytic feedback loop. In turn, thrombin stimulates fibrin formation. The disadvantage of using heparin in unstable angina is that it is unable to inhibit clot-bound thrombin, since it only activates circulating antithrombin. In addition, heparin is bound or inactivated by plasma proteins and platelet factor four, resulting in an unpredictable anticoagulant effect. The direct thrombin inhibitors, hirudin and hirulog, were developed to overcome these theoretical deficiencies and have been used in the acute coronary syndrome. Initial trials with high dose hirudin (0.6 mg kg−1 bolus followed by 0.2 mg kg−1 h−1 infusion) in acute myocardial infarction and in acute coronary syndromes in general were stopped because of an increase in haemorrhagic stroke [47–48]. Subsequent clinical trials have used lower doses to variable effect. The GUSTO IIb trial compared a 72 h infusion of hirudin (0.1 mg kg−1 bolus followed by 0.1 mg kg−1 h−1 ) with heparin in patients with acute coronary syndrome, including myocardial infarction and unstable angina [49]. A reduction in the overall primary endpoint of death or myocardial infarction at 30 days from 9.8% to 8.9% was seen with hirudin but there was no difference in those patients with unstable angina (all had pain with ST deviation >0.5 mm or T-wave inversion >1 mm). It has been suggested that the lack of effect of direct antithrombins is due to delay in treatment, and that hirudin should been given at an intermediate dose, higher than in GUSTO IIb but lower than GUSTO IIa [50]. These issues were partly addressed in a study of 909 patients with unstable angina, in which infusion of hirudin (0.4 mg kg−1 bolus followed by 0.15 mg kg−1 h−1 ) reduced the composite secondary endpoint of death, myocardial infarction, refractory or severe angina from 15.6% to 9.4% [51]. An initial trial with hirulog has supported a possible beneficial effect in unstable angina [52], but only in reduction of a combined end-point including death, myocardial infarction, ‘clinical deterioration’, and recurrent angina. At present, the direct antithrombins appear at best to be equivalent to heparin but further dose refinement may improve their efficacy. The first step in clot formation is the adherence of platelets to the subendothelial surface. Platelets adhering to the vessel wall form a thin monolayer covering the vascular surface but this does not compromise flow. Activation of these platelets leads to the externalisation of glycoprotein IIb/IIIa receptors and transition into a high affinity state promoting aggregation. Gp IIb/IIIa receptors are the final common pathway for platelet aggregation, and activation immediately precedes thrombus formation. Recent studies have indicated that inhibitors of Gp IIb/IIIa receptors may be useful in unstable angina, although these have concentrated upon their use in association with interventional procedures. The efficacy of platelet Gp IIb/IIIa receptor inhibitors in association with percutaneous transluminal angioplasty (PTCA) was first studied in the EPIC trial, in which a bolus dose of abciximab was given immediately prior to intervention and continued for 12 h [53]. Two thousand and ninety-nine patients at ‘high risk for intervention’ were recruited, including patients with acute or recent myocardial infarction, unstable angina (chest pain refractory to heparin and nitrate therapy in association with ECG changes), or complex target lesion morphology in patients of advanced age, female gender, or diabetes mellitus. The composite end-point of death, myocardial infarction or emergency coronary artery bypass grafting (CABG) or PTCA was reduced by 35% at 30 days, with a reduction in the prospectively defined sub-group with unstable angina of 62% [54]. The use of Gp IIb/IIIa inhibitors was extended by the findings of the EPILOG study, in which a bolus dose followed by 12 h infusion was given in association with either standard or low dose heparin to a lower risk group of patients undergoing either urgent or elective PTCA. The composite end-point of death, myocardial infarction or urgent revascularisation was reduced from 11.7% to 5.2% in the group given low dose heparin plus abciximab, although patients with acute myocardial infarction or unstable angina with ECG changes and chest pain in the preceding 24 h were specifically excluded from this trial [55]. The CAPTURE trial directly studied the use of abciximab in patients with refractory unstable angina (chest pain at rest with ECG changes resistant to therapy with heparin and glyceryl trinitrate) undergoing PTCA [56]. The Gp IIb/IIIa inhibitor was infused for 18–24 h prior to PTCA and continued for 1 h thereafter. The primary end-point of death, myocardial infarction or urgent revascularisation was reduced from 15.9% to 11.3% but in addition, the rate of myocardial infarction prior to PTCA was reduced from 2.1% to 0.6%, implying a role for use in unstable angina in the absence of intervention. Equivalent results have been found with the synthetic Gp IIb/IIIa inhibitors, tirofiban and eptifibatide, during percutaneous revascularisation procedures for acute myocardial infarction or within 72 h of unstable angina [57–58]. These trials all suffer from the failure to use single end-points and most were terminated early after achieving predefined efficacy. In addition, it would appear that risk reductions were greatest during the infusion but that benefits declined with time—in CAPTURE, differences in outcome were lost at 6 months in the patients with unstable angina studied [56]. Further studies have examined the use of Gp IIb/IIIa inhibitors in unstable angina. The PARAGON study involved 2300 patients with unstable angina and non-Q wave myocardial infarction, randomized either to high dose lamifiban 5 μg kg−1 min−1 after a 750 μg bolus, or to low dose lamifiban 1 μg kg−1 min−1 after a 300 μg bolus, each with or without heparin vs standard heparin alone [59]. No difference was found in death or myocardial infarction at 30 days, but at 6 months, a reduction in the prespecified combined endpoint of death and myocardial infarction occurred in patients treated with lamifiban and heparin from 17.9% to 12.6%. However, the high dose patients suffered a four-fold increase in bleeding. This latter effect is unlikely to be directly related to the Gp IIb/IIIa inhibitor which have a good safety profile and is more likely to have been related to the concomitant use of heparin. The PRISM study compared a 48 h infusion of tirofiban with continuous heparin in 3232 patients with chest pain in the preceding 24 h either in association with ECG changes, elevation of cardiac enzymes, or a history of ischaemic disease. In this relatively low risk group, there was a reduction in the composite endpoint of refractory ischaemia, myocardial infarction and death at 2 days from 5.6% to 3.8% [60]. This difference in the primary end-point was lost at 7 and 30 days, despite just under 40% patients undergoing revascularisation in both groups. Patients at higher risk were studied in the PRISM Plus study comparing tirofiban alone for 72 h, tirofiban plus heparin, and heparin alone. One thousand nine hundred and fifteen patients were included on the basis of chest pain at rest within 12 h in association with ST deviation or T-wave inversion or elevated cardiac enzymes [61]. The tirofiban alone arm was dropped because of an initial higher death rate but tirofiban plus heparin again reduced the primary composite endpoint of recurrent angina, death and myocardial infarction from 17.9% to 12.9% at 7 days compared with heparin. This difference was reduced at 30 days but remained significant, with a fall from 22.3% in those receiving heparin to 18.5% in those receiving tirofiban plus heparin. Just over 50% of patients included in the PRISM-Plus trial underwent CABG or PTCA during the study period. A similar group of patients to those in the PRISM -Plus trial was studied in PURSUIT, in which eptifibatide was infused for 72–96 h with heparin given at the discretion of the investigator [62]. A reduction in the primary end-point of death and myocardial infarction at 30 days from 15.7% to 14.2% was documented, although there was again no significant difference in outcome with prolonged follow-up to 6 months. These trials have shown a consistent early benefit in unstable angina but this would appear to be small. Moreover, primary endpoints used in the trials have all been composite. It would appear that there is a per-procedural benefit in using Gp IIb/IIIa inhibitors in patients undergoing early intervention. Early benefits also accrue when used in unstable angina but longer-term benefit has not been clearly demonstrated. In addition, many patients receiving Gp IIb/IIIa inhibitors for unstable angina have undergone revascularisation procedures, probably in higher numbers than would occur in the United Kingdom. The advantage of early use may be increased by continued dosing with oral agents, such as sabrifiban and xemilofiban, thereby extending the period of protection to cover later coronary instability, but trial data are not yet available. In patients who have recurrent episodes of myocardial ischaemia despite intensive medical therapy, PTCA or CABG is commonly used to control symptoms and to avoid progression to myocardial infarction. In addition, an aggressive approach to early invasive management of non-Q wave myocardial infarction and unstable angina has become entrenched in clinical practice in the United States. There is a marked difference in approach to the acute coronary syndromes between the U.S.A. and the United Kingdom, with far higher rates of invasive investigation and surgical treatment in the former. Comparative studies of outcomes according to the relative rates of angiography, angioplasty and coronary artery surgery in the U.S.A. and the less aggressive management in Canada and have failed to document a difference [63]. The TIMI-IIIB trial was a prospective, randomized trial studying the use of thrombolysis in non-Q wave myocardial infarction and unstable angina based on chest pain at rest in association with ECG changes or a history of documented ischaemic heart disease [64]. In addition, the study compared an early invasive strategy of angiography at 18–48 h proceeding to intervention if possible with PTCA or CABG with a conservative management strategy. No difference was found in outcome in terms of thrombolysis or management strategy, although the sample size was inadequate to detect a significant difference in outcome’ between the two strategies. In addition, 64% of the ‘conservative’ group underwent angiography within 6 weeks and there were no differences between the groups in number of CABG operations performed at 30 days. Further information will become available regarding intervention in non-Q wave myocardial infarction and unstable angina following the VANQWISH and RITA 3 trials [65]. Thrombolysis has not been associated with an improvement in mortality and does not have a place in the treatment of unstable angina [66]. The consensus from both sides of the Atlantic is that patients with unstable angina should to be managed conservatively. Recently, there has been a rapid expansion in the therapeutic options available for the management of the acute coronary syndromes but the mainstay of treatment on current evidence should continue to be aspirin and heparin. There are indications that benefits will arise from longer-term use of anticoagulation with either LMW heparin or warfarin, and that Gp IIb/IIIa inhibitors may improve mortality beyond aspirin and heparin. These new treatments for unstable angina will only reach their full potential if they are targeted at high risk patients, since the combinations of antithrombotic therapies carries a substantial side effect potential from bleeding. Risk stratification will play an increasingly important role in the management of unstable coronary syndromes.