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

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 twice daily with aspirin and monitored intravenous heparin for days In the study of patients with unstable angina, aspirin and IU twice daily for 6 then 7500 IU daily for days) were compared with aspirin and injections in a The of death and myocardial infarction at 6 days was reduced from to in the aspirin plus for the study were at high since all had or increased angina in with ST depression or T-wave inversion. in rates of death at studies have compared subcutaneous injection of LMW heparin with continuous intravenous infusion of unfractionated heparin according to The an comparison with found no in the combined of death, myocardial infarction or recurrent angina The was a trial which a reduction in the of death, myocardial infarction and recurrent angina from to at days with given IU twice daily for days This risk reduction was small but patients in the trial had associated ECG changes and the patient was at lower risk than those in the The 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. using LMW heparin have so studied and have different treatment such that the optimum dose and of therapy is not Further studies in may more evidence 2 and In trials of both unfractionated and low molecular weight heparin in unstable angina, there is evidence of a rebound in events following of to this problem was tested in the study, in which injection of LMW heparin was for days [3]. in the found at 6 days at but the trial was by an in events in the after a dose reduction at 6 days from twice to daily It is that high dose injection of LMW heparin is to the benefit of rebound coronary The is to the patient with The trial compared aspirin alone against intravenous unfractionated heparin for followed by for weeks the between low risk patients included on the basis of a history of angina alone A reduction in recurrent angina, myocardial infarction and death 25% to was found at weeks in the treated with heparin and The on therapy was in this trial by the use of heparin and by the use of a combined Aspirin and were compared with aspirin and in an trial the progression or of unstable coronary in patients with unstable angina or acute myocardial infarction were less to and more to in patients The secondary was a reduction in recurrent myocardial infarction with longer anticoagulation may be beneficial in unstable angina but there is a need for more randomized adhesion and aggregation are the events in thrombus formation. and of the which is recruited by means of an In thrombin fibrin formation. The of using heparin in unstable angina is that it is to since it only In addition, heparin is or by proteins and platelet in an anticoagulant The thrombin and were developed to these and have been used in the acute coronary trials with high dose mg bolus followed by mg h−1 in acute myocardial infarction and in acute coronary syndromes in were because of an in clinical trials have used lower doses to The trial compared a h infusion of mg bolus followed by mg h−1 ) with heparin in patients with acute coronary syndrome, myocardial infarction and unstable angina A reduction in the of death or myocardial infarction at 30 days from to was with but there was no in those patients with unstable angina had pain with ST deviation mm or T-wave >1 It has been suggested that the lack of of is to delay in and that should been given at an intermediate than in but lower than These were in a study of patients with unstable angina, in which infusion of mg bolus followed by mg h−1 ) reduced the secondary of death, myocardial or angina from to trial with has a beneficial in unstable angina but only in reduction of a combined death, myocardial and recurrent angina. the at to be equivalent to heparin but further dose may improve The first in formation is the of to the to the a the vascular but this not of these leads to the of and into a high state are the common for platelet and activation thrombus formation. Recent studies have that of may be useful in unstable angina, although these have use in with The efficacy of platelet in with percutaneous angioplasty was first studied in the in which a bolus dose of was given prior to intervention and for h and patients at risk for were patients with acute or recent myocardial unstable angina pain to heparin and therapy in with ECG or target in patients of or The of death, myocardial infarction or emergency coronary artery or was reduced by at 30 with a reduction in the defined with unstable angina of 62% The use of was by the of the study, in which a bolus dose followed by h infusion was given in with standard or low dose heparin to a lower risk of patients urgent or The of death, myocardial infarction or urgent revascularisation was reduced from to in the given low dose heparin plus although patients with acute myocardial infarction or unstable angina with ECG changes and chest pain in the preceding 24 h were excluded from this trial The trial directly studied the use of in patients with unstable angina pain at rest with ECG changes to therapy with heparin and The inhibitor was for h prior to and for 1 h The of death, myocardial infarction or urgent revascularisation was reduced from to but in addition, the rate of myocardial infarction prior to was reduced from to a for use in unstable angina in the absence of results have been found with the and during percutaneous revascularisation for acute myocardial infarction or within h of unstable angina These trials all suffer from the to use single and most were early after In addition, it would that risk were greatest during the infusion but that benefits with differences in were at 6 months in the patients with unstable angina studied Further studies have the use of in unstable angina. The study patients with unstable angina and non-Q wave myocardial randomized to high dose after a or to low dose 1 after a with or without heparin standard heparin alone was found in death or myocardial infarction at 30 but at 6 a reduction in the combined of death and myocardial infarction occurred in patients treated with and heparin from to However, the high dose patients a in This is to be directly to the inhibitor which have a good profile and is more to have been to the use of heparin. The study compared a 48 h infusion of with continuous heparin in patients with chest pain in the preceding 24 h in with ECG elevation of cardiac or a history of ischaemic disease. In this relatively low risk there was a reduction in the of ischaemia, myocardial infarction and death at 2 days from to This in the was at 7 and 30 despite patients revascularisation in both at risk were studied in the study comparing alone for h, plus heparin, and heparin alone. and patients were included on the basis of chest pain at rest within h in with ST deviation or T-wave or elevated cardiac enzymes The alone was because of an death rate but plus heparin reduced the of recurrent angina, death and myocardial infarction from to at 7 days compared with heparin. This was reduced at 30 days but with a from in those heparin to in those plus heparin. over of patients included in the trial or during the study A of patients to those in the trial was studied in in which was for h with heparin given at the of the A reduction in the of death and myocardial infarction at 30 days from to was although there was no significant in with prolonged to 6 These trials have shown a early benefit in unstable angina but this would to be used in the trials have all been It would that there is a benefit in using in patients early benefits also accrue when used in unstable angina but benefit has not been clearly In addition, patients for unstable angina have revascularisation probably in than would occur in the The advantage of early use may be increased by with oral such as and the period of to later coronary but trial data are not yet available. In patients who have recurrent episodes of myocardial despite intensive or is commonly used to control symptoms and to progression to myocardial infarction. In addition, an aggressive to early invasive of non-Q wave myocardial infarction and unstable angina has in clinical in the is a in to the acute coronary syndromes between the and the with rates of invasive and treatment in the studies of outcomes according to the rates of angioplasty and coronary artery in the and the less aggressive in and have failed to document a The trial was a randomized trial the use of in non-Q wave myocardial infarction and unstable angina based on chest pain at rest in with ECG changes or a history of ischaemic heart disease In addition, the study compared an early invasive of at h to intervention if with or with a was found in in of or although the was inadequate to detect a significant in between the two In addition, of the within 6 weeks and there were no differences between the groups in number of at 30 Further will available intervention in non-Q wave myocardial infarction and unstable angina following the and 3 trials has not been associated with an in mortality and not have a place in the treatment of unstable angina The from both of the is that patients with unstable angina should to be there has been a in the therapeutic available for the of the acute coronary syndromes but the of treatment on evidence should continue to be aspirin and heparin. are that benefits will from use of anticoagulation with LMW heparin or and that may improve mortality aspirin and heparin. These for unstable angina will only if are targeted at high risk patients, since the of a from stratification will an important in the of unstable coronary