Cardiothoracic Division, The James Cook University Hospital, Marton Road, TS4 3BW Middlesbrough, UK
* Corresponding author. Tel.: +44-1642-854620; fax: +44-1642-282408
See doi:10.1016/S1095-668X(02)00525-0for the article to which this editorial refers.
Patients with non ST-segment elevation (STE) acute coronary syndromes (ACS) are subject to a significant risk of adverse cardiac events. The recognition that up to 50% of these patients will experience recurrent ischaemia and 10% will die or reinfarct within 30 days despite optimum medical management has prompted investigation into better pharmacological therapy and the role of invasive procedures.13 However, the timing of intervention is controversial and two different protocols, an early invasive strategy and an early conservative strategy, have been assessed.
The first randomized trials either failed to show an advantage with early intervention (TIMI IIIB)3 or suggested that this approach could potentially be harmful (VANQWISH) compared to an early conservative strategy.4 In the OASIS registry, a large multicentre prospective observational study of an unselected population with non-STE ACS, admission to centres with cardiac catheterization theatres increased the likelihood of revascularization when compared to admission to centres without such facilities.2 However, there was no significant difference in cardiac outcomes at follow-up. Although these studies would argue against a systematic early invasive strategy, the findings have to be interpreted with caution. The high crossover rate to invasive therapy in TIMI IIIB and VANQWISH is an important confounding factor which reduces the statistical power. Although a greater contrast in revascularization rates was achieved in the OASIS registry, the findings are limited by the non-randomized protocol. More fundamentally, since the publication of these early trials significant advances in adjunctive pharmacological therapy with the advent of glycoprotein IIb/IIIa receptor blockers and clopidogrel, as well as surgical and percutaneous techniques with the development of stents and arterial conduits, have improved outcomes following revascularization. These limitations were addressed in FRISC II, where contrasting revascularization rates of 78 and 43% at 1 year in the early intervention and conservative arms were associated with a composite endpoint of death or myocardial infarction in 10.4 and 14.1%, respectively .5 The treatment effects of intervention may have been enhanced by the use of stents in two-thirds of percutaneous procedures and a lower surgical mortality of 2% (compared to 7.7% in VANQWISH). The authors also speculated that the initial period of intense stabilization with medical therapy prior to intervention, which included the use of dalteparin, might have contributed to favourable outcomes by reducing the peri-procedural risk.
Whilst there is little evidence that antithrombotic therapy with low molecular weight heparin is more effective than unfractionated heparin in this setting, a therapeutic role for platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban, lamifiban, eptifibatide or abciximab has been demonstrated in several trials involving over 25 000 participants. Although tirofiban was more effective than heparin in reducing adverse cardiac events after 48h of treatment, statistical significance was lost at 30 days.6 However, in combination with heparin, tirofiban significantly reduced the risk of death, myocardial infarction or refractory ischaemia at 1 week (12.9 vs 17.9%, ) with continuing benefits at 6 months compared to heparin and placebo.7 There were similar findings in the PURSUIT study, where the addition of eptifibatide to heparin lowered the primary endpoint of death and myocardial infarction from 15.7 to 14.2%
at 30 days, compared to heparin.8 In the PARAGON-A study, the event curves for the primary endpoint of death or myocardial infarction only diverged after 30 days with a significant decrease in these adverse outcomes in the group treated with lamifiban and heparin compared to heparin (12.6 vs 17.9,
).9 In contrast, there was no significant treatment effect with abciximab on the primary endpoint of death or myocardial infarction at 30 days in GUSTO IVACS.10 Explanations advanced for this finding included the selection of low-risk populations, inadequate dose and duration of therapy, low rate of intervention, and an under-powered study. On the other hand, abciximab has been consistently shown to reduce thromboticcomplications during percutaneous coronary intervention (PCI)11 and has recently been found to be superior to tirofiban in this setting.12 However, there are no data to support a policy of switching between these agents when patients initially receiving medical therapy subsequently undergo PCI.
Effective antiplatelet therapy with glycoprotein IIb/IIIa receptor blockers in conjunction withaspirin, heparin and anti-ischaemic medication stabilises patients and prevents 1532 adverse cardiovascular events per 1000 patients treated.13 Retrospective analyses of several of these trials, by comparing the patients who underwent early PCI to those who remained on medical therapy, suggest that beneficial effects are mainly realised in patients who subsequently undergo coronaryintervention, with 65 events prevented per 1000 patients treated.13 In the PURSUIT study, combination therapy with eptifibatide and heparin reduced the primary endpoint in patients undergoing PCI from 16.7 to 11.6% but there was no significant difference in outcomes in those managed solely on medical therapy (15.6 to 14.5,
).8 In PRISM-PLUS, the greatest treatment effect of combination therapy with tirofiban and heparin was noted in the patients who subsequently underwent PCI.7 However, these trials were not designed to compare PCI with medical therapy and it is likely that the patients selected for intervention represented either those who were perceived to be at highest risk or patients who had already developed complications. Nevertheless, the interaction between the use of glycoprotein IIb/IIIa receptor blockers and early intervention was tested in a randomized fashion in the TACTICSTIMI 18 study.14 The protocol mandated the treatment of all subjects with aspirin, heparin and tirofiban for at least 48 or 12h post-PCI. During the initial hospitalization, revascularization was performed in 60% of the early invasive arm and 36% of the early conservative arm with stents used in over 80% of PCI in both arms. The primary endpoint of death, myocardial infarction or readmission with an ACS at 6 months was reached in 15.9% of patients in the invasive arm and 19.4% of those in the conservative arm
.
Platelet inhibition with a combination of clopidogrel and aspirin has also been shown to reduce the incidence of the adverse outcomes in non-STE ACS compared to aspirin.15 A substudy investigating the role of clopidogrel in PCI demonstrated that the incidence of the composite endpoint of death or myocardial infarction at 30 days was reduced in the combination therapy group compared to the aspirin group (2.9 vs 4.4%; ).16 This finding, together with the evidence from the glycoprotein IIb/IIIa receptor blocker studies, lends support to a strategy of pre-treatment with effective antiplatelet regimens in order to stabilize patients prior to intervention and protect against the thrombotic complications of invasive procedures. This is illustrated by comparing the event curves in FRISC II and TACTICSTIMI 18. In FRISC II, where glycoprotein IIb/IIIa receptor blockers were used in only 10% of PCI, the long-term advantages of an early invasive strategy were partly offset by an initial excess mortality related to peri-procedural events, and a beneficial effect was only observed after 4 weeks. In contrast, in TACTICSTIMI 18, the event curves in favour of the early invasive arm diverged after 1 week, suggesting that tirofiban may have contributed to the success of this approach by reducing peri-procedural complications.
Patients with the highest risk of adverse complications are most likely to derive the greatest benefit from aggressive therapy. This is supported by several retrospective analyses showing that the release of troponin identifies high-risk patients where the treatment effects of glycoprotein IIb/IIIa receptor blockers were most evident.17,18 Furthermore, subgroup analysis in TACTICSTIMI 18demonstrated that early coronary intervention significantly reduced the primary endpoints in patients with elevated troponin, but those without a troponin release had similar outcomes with either strategy.14 Clinical indicators of poor prognosis include age, previous myocardial infarction, diabetes mellitus and haemodynamic instability. The ECG offers an additional method of risk stratification and includes the admission ECG, continuous ST-segment monitoring and stress testing, the latter being a better indicator of long term rather than short-term outcomes.
In this issue, Hersi et al. evaluate the prognostic value at 6 months of the discharge ECG in addition to the admission ECG in 918 patients presenting with non-STE ACS from the PARAGON-B Troponin substudy.19 Subjects presenting with ST-segment depression had a five-fold greater risk of death compared to those without ST-segment depression. This is consistent with previous studies that have associated ST-segment changes on admission with adverse cardiac outcomes.18,20 Hersi et al. extend these observations by demonstrating that the incidence of death or myocardial infarction was significantly higher in patients with persistent ST-segment depression on discharge compared to those who never developed ST-segment depression (6.0 vs 0.9% and 16.3 vs 7.4%, respectively).19 The presence of Q-waves on discharge also increased the risk of death or myocardial infarction compared to the absence of such changes (4.8 vs 1.9% and 13.8 vs 8.3%, respectively; both ). Although new ST-segment depression at discharge was also an indicator of poor prognosis, the numbers were too small to draw meaningful conclusions. Interestingly, the cardiac outcomes at the end of the study in patients who normalized their ST-segment by discharge were similar to those who never developed ST-segment changes. This offers a potential means to assess therapeutic success in this population.
The current trials do not endorse the systematic early use of glycoprotein IIb/IIIa receptor blockers and angiography in patients with non-STE ACS. However, they do support early treatment in the highest risk patients, which also enhances the cost effectiveness of these strategies. Risk stratification is therefore an essential part of the management of these patients, and in this way low risk patients can avoid needless invasive procedures, and high-risk patients can be steered to interventional centres. Further work is needed to determine the relative merits of one form of risk stratification over another, but as simplicity is important, the most practical methods of assessment are clinical features, ECG changes and biochemical markers of myocardial injury. For units that cannot deliver inpatient angiography, the pre-discharge ECG would appear to provide another useful means of selecting patients for early intervention.
References
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