Present treatment options for unstable angina and non-Q-wave myocardial infarction

Unstable angina is one of the commonest life‐threatening medical emergencies. Despite enormous advances in the understanding of the pathophysiology of unstable angina, development of newer drugs and modern intervention techniques, there are considerable controversies about its most effective and definitive management. We review the literature to produce an evidence‐based practical guide to a uniform approach to managing unstable angina, including non‐Q‐wave myocardial infarction. Annually, there are likely to be at least 130 000 cases of unstable angina (UA) in the UK, 130 000 in France, 188 000 in Germany, 129 000 in Italy and 80 000 in Spain.1 In 1991, it constituted about 55% of all coronary care unit (CCU) admissions.2 It may result in death or non‐fatal myocardial infarction in up to 20% within 30 days of an ischaemic event.3 Among 9146 patients of UA treated in the Duke University Medical Centre between 1985 and 1992, the highest risk of death was found within the first 48 h.4 Because of the uncertain outcome, patients of UA have priority over the stable myocardial infarction (MI) for admission in a CCU bed. As the clinical differentiation between UA and non‐Q‐wave myocardial infarction (NQMI) is usually difficult initially, the two conditions are usually treated in a similar way, under the term ‘acute coronary syndrome‘.4,5 Despite its common prevalence and high morbidity and mortality, the treatment strategy of UA is not clearly defined. We address the controversies and present the treatment options currently available for UA/NQMI. The presence of one or more of the following may define UA:1,4 (i) angina at rest; (ii) angina that increases in severity or duration or frequency; (iii) new‐onset angina at least Canadian Cardiovascular Society Grade III severity. Non‐Q‐wave MI may be defined as an increase in cardiac enzymes in the absence of Q‐wave in the ECG.1 Subendocardial MI or Non‐ST‐elevation MI are other terms usually used synonymously with NQMI. Braunwald's classification of UA published in 19896 is not only clinically useful but also has been validated by prospective trials. UA class: Class I, new‐onset or accelerated angina; Class II, angina at rest during the preceding 1 month but not within the previous 48 h; Class III, Angina at rest within the preceding 48 h. Clinical circumstances: secondary UA (e.g. exacerbated by anaemia, thyrotoxicosis etc.); primary UA; post‐infarction UA (within 2 weeks of a documented MI). Among such unstable patients, there are high‐risk groups with poorer outcomes. Indicators of high risk in unstable angina are:7,8 raised troponin concentration (troponin I>1.0 mcg/l; troponin T>0.1 mcg/l); ST segment depression in ECG. Usually a fissure or rupture of a coronary atherosclerotic plaque triggers new thrombus formation with increased platelet adhesiveness and aggregation.9,10 This progresses to partial occlusion of the coronary lumen. Rapid thrombosis and subtotal coronary occlusion remains the main cause of the ACS despite the recognition of other causative factors, e.g. inflammation.11 Since 1983, the main target of UA treatment has therefore been the platelets. Aspirin reduced the risk of cardiac ischaemic events by about 35%.12,13 Lately, newer and more potent anti‐platelet agents with different mechanisms of action have been added to the armamentarium of the medical treatment of UA/NQMI (Figure 1). The addition of heparin to aspirin for the treatment of UA helped reduce the cardiovascular risk by another 25%.12,13 Further improvement of the outcome of the treatment of UA resulted from the use of low‐molecular‐weight heparin (LMWH) in place of unfractionated heparin (UFH).11,14–16 Combined therapy with aspirin and heparin was until recently considered the ‘gold standard’ of UA treatment.17 Different anti‐platelet agents with different mechanisms of action. The use of anti‐anginal drugs is usually a part of treatment of UA. However, whether a particular drug reduces mortality or MI is still unclear. In an overview of four randomized controlled trials including 2346 UA patients, intravenous beta‐blocker therapy given within 12 h of onset of symptoms was found to reduce the odds of development of MI by one sixth (p=0.04).18 There is no clear evidence that nitrate and calcium channel blockers improve survival in UA patients.19 Nicorandil, a potassium channel opener, when given in addition to other anti‐anginal drugs, reduced transient myocardial ischaemia and non‐sustained ventricular and supraventricular arrhythmias compared to placebo.20 The introduction of a newer anti‐platelet drug, platelet glycoprotein (GP) IIb/IIIa receptor antagonist may revolutionize the medical treatment of UA/NQMI. The integrin glycoprotein is the final pathway of platelet aggregation. It binds circulating macromolecules such as fibrinogen and von Willebrand factor, and cross‐links platelets thus promoting propagation of thrombus formation.4 There are published data of at least 10 medium large clinical trials (each including >1000 patients) using GP IIb/IIIa receptor antagonists in ACS.21 Of the 10 trials, six used GP receptor antagonism as an adjunct to percutaneous coronary revascularization and showed improved outcome with such adjunctive therapy. The EPIC study,22 the EPILOG study,23 the CAPTURE study,24 the IMPACT II study25 and RESTORE26 all showed significant reduction in death, MI or urgent revascularization in high‐risk patients receiving platelet GP IIb/IIIa receptor antagonist as an adjunct to percutaneous coronary interventions (PCI). The rest used the GP IIb/IIIa receptor antagonists as a part of conservative therapy of ACS. The PARAGON trial27 assigned 2282 patients of UA and NQMI and at the end of 6 months, low dose intravenous lamifiban (a platelet GP IIb/IIIa receptor antagonist) plus heparin and aspirin significantly reduced death or non‐fatal MI compared to treatment with conventional heparin plus aspirin therapy (12.6% in lamifiban plus heparin and aspirin group vs. 17.9% in the heparin plus aspirin only group with a risk reduction of 30%). The PRISM Plus trial28 enrolled 1915 patients with high‐risk UA and NQMI. It was a three‐pronged trial in which one group of patients received intravenous tirofiban, a platelet GP IIb/IIIa receptor antagonist alone, second group received heparin alone and the third both, all within 12 h of onset of symptoms. All groups received aspirin if not contraindicated. The tirofiban monotherapy was discontinued in the middle of the trial because of high mortality. In the tirofiban plus heparin group, there was significant reduction of death or non‐fatal MI or refractory ischaemia or readmission at 2 days (p=0.01), at 7 days (p=0.004) and at 30 days (p=0.03) in comparison to the heparin therapy alone, without significant increase in intracranial haemorrhage. The risk reduction for the primary end points was 32% at the end of 7 days. This means that for every 1000 patients treated, 50 ischaemic events could be avoided at the end of 7 days. The composite end point was reduced by 19% at the end of 6 months (p=0.024). However if only death or MI were considered as primary end points at 6 months, then there was only 23% risk reduction (15.3% vs. 12.3%; p=0.063). The risk reduction of MI appeared within 48 h of the start of treatment of tirofiban plus heparin and aspirin and persisted up to 6 months without significant reduction of death. The number needed to treat (NNT) to avoid one MI/death within 30 days was 31. In the subgroup analysis of the PRISM Plus trial results, there were significant reduction of the composite end point in patients of UA with ST segment depression and those with NQMI treated with tirofiban and heparin as opposed to the heparin therapy. In the PURSUIT trial29 with 10 948 patients, eptifibatide (another platelet GP IIb/IIIa receptor antagonist) when given intravenously with heparin within the first 24 h of onset of chest pain was more effective than heparin therapy in patients with ACS (14.2% death or MI in eptifibatide‐treated group vs. 15.7% in heparin‐treated group, p=0.04). The benefit appeared at 4 days of treatment and persisted up to 30 days. However, bleeding complications were more common in the eptifibatide group, although there was no significant increase in intracranial bleeding. The NNT to avoid one MI/death within 30 days was 67. The PRISM trial30 assigned 3232 patients to heparin or tirofiban. There was significant reduction of death, MI or refractory ischaemia in the initial 48 h on the tirofiban group, although the combined endpoint did not remain significant at the end of one month. In a recent trial of 2222 patients of UA7 with raised troponin I (>1 mcg/l) or troponin T (>0.1mcg/l, Abbott Laboratories), intravenous tirofiban, when given within 24 h of onset of chest pain, significantly reduced the risk of death or MI at the end of 30 days compared with heparin therapy. The benefit was extended to patients who were treated medically but had undergone PCI after 48 h tirofiban infusion. Patients with UA and negative troponin (low‐risk group) should continue to be treated initially with ‘conventional therapy’ with LMWH plus aspirin and anti‐anginal drugs (Figure 2). There is no advantage of GP IIb/IIIa receptor antagonist (tirofiban) over conventional heparin therapy in the treatment of UA with negative troponin.7 During stabilization, LMWH is usually continued for 2 to 8 days.15 A stress test may then be considered pre‐discharge31,39 to stratify further risks. Those patients who do not improve with conservative therapy or who have a positive pre‐discharge stress test should be promptly considered for coronary angiography and PCI or coronary artery bypass graft surgery (CABG). Patients with negative stress test are at low risk of cardiac events and can be followed‐up medically31 (Figures 2 and 3). Patients of UA with raised serum troponin (high‐risk UA) and/or persistent ST segment depression should be treated with intravenous infusion of a platelet GPIIb/IIIa receptor antagonist plus intravenous UFH and aspirin within 12–24 h of onset of symptoms. One third of all UA patients are likely to be at high risk. In the UK, tirofiban and eptifibatide are licensed for the treatment of ACS, and are to be administered under the direct supervision of a specialist.32 The regimen is to be continued for at least 48 h or on average, for 72 h. Those who have improved on this regimen can mobilize and undertake a pre‐discharge stress test. Patients with negative tests are at low risk of cardiac events and can be followed up medically. Patients who do not respond to the initial GP IIb/IIIa antagonist and heparin combination therapy and who have positive pre‐discharge stress test should undergo urgent coronary angiogram and, if necessary PCI/CABG (Figures 2 and 3). More than 80–90% of patients of UA will usually improve with optimal medical therapy.33,34 Where cardiac catheterization and PCI/CABG facilities are available on site or within easy reach, all high‐risk patients should preferably undergo early coronary angiogram and PCI/CABG if necessary. The combination of GP IIb/IIIa antagonist (tirofiban) and LMWH (enoxaparin) was used in a pilot study consisting of 53 patients.35 There was better inhibition of platelet aggregation with this combination in comparison to that of tirofiban and UFH. Minor and major bleeding complications were the same on both sides. Whether LMWH is superior to UFH in this regard requires large clinical trials such as the ACUTE II to determine. There is usually no benefit from thrombolytic therapy in the management of UA, including acute NQMI.1,36 Algorithm for the management of unstable angina (UA) and non‐Q‐wave myocardial infarction (NQMI). *Raised troponin I>1.0 mcg/l; troponin T>0.1 mcg/l. **Stress test positive at low workload, ST depression ≥3 mm, developing hypotension, appearance of transient ST elevation or T wave inversion (severe and prolonged angina with pulmonary oedema with/without persistent hypotension is an indication for urgent coronary angiogram and intervention if necessary). UFH, unfractionated heparin; LMWH, low‐molecular‐weight heparin; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery. Flow chart showing management strategy of UA/NQMI after a coronary angiogram. LV, left ventricle; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery. Conservative and invasive treatments of UA are both effective in reducing the risk of death or MI. There are no convincing data to suggest which is better.1 In the VANQWISH trial37 of 920 patients with NQMI, patients treated non‐invasively initially had significantly reduced death or non fatal MI at the time of discharge, at 1 month and at 1 year. Although CABG mortality at 30 days was higher at 7.7%, even when the low mortality rate of percutaneous coronary interventions (PCI) (1.3%) was compared with that of ischaemia‐guided conservative management, there was no improvement in outcome on the invasive side. The TIMI IIIb trial36 which enrolled 1473 patients with ACS (476 NQMI) did not show a significant reduction in death or MI at the end of 6 weeks among the patients treated invasively early after thrombolysis with tissue plasminogen activator. However, the number of recurrent ischaemias or readmissions was lower in this group. In the OASIS trial,38 there was no benefit from an early invasive approach to treatment of UA and NQMI; in fact, the rates of death or MI and stroke were lower in patients treated conservatively. However, the FRISC II trial,39 for the first time showed a benefit from invasive treatment of UA. This trial enrolled 2457 patients. In the invasive group, coronary angiogram was performed within a few days of enrolment with a view to revascularize either by PCI or CABG within 7 days of the start of the open‐label treatment. Platelet GP IIb/IIIa receptor antagonism with abxicimab was used as an adjunct to the invasive procedures. However, abxicimab was not used on the non‐invasive group. The peri‐CABG mortality was low at 2.1% in comparison to that of VANQWISH (7.7.%). The superiority of the invasive over the non‐invasive approach in the FRISC II trial could have been partly because the rate of myocardial revascularization was higher in FRISC II (78%) compared to only 44% in VANQWISH and 55% in TIMI IIIB, and also because all the patients were initially (first 4–6 days) treated with aspirin and deltaparin.31 Thirdly, Abxicimab was used in 10% of the patients on the invasive side. Routine use of the platelet GPIIb/IIIa antagonist to treat high‐risk unstable angina and NQMI might have improved the outcome of the patients treated non‐invasively. The other trials21 have shown that the new conservative treatment of UA with GP IIb/IIIa receptor antagonism in addition to the conventional heparin and aspirin therapy, has further improved outcome in terms of reduction in death or non‐fatal MI or recurrent ischaemia or re‐admissions. In an ongoing meta‐analysis, pooling 5207 NQMI‐patients randomized to invasive vs. non‐invasive treatment strategies, 7‐day death among the patients treated invasively was significantly higher by 63%, while there was no significant difference in mortality between the two strategies in the long term. Early non‐fatal MI was also higher on the invasive side, while there was a 12% decrease in non‐fatal MI in patients treated invasively in the long term.40 The strategies are complementary rather than competitive. The ischaemia‐guided conservative management of UA/NQMI should certainly be the initial treatment of choice in district general hospitals where there is no invasive facility or it is not within easy reach. The patients unresponsive to the initial medical treatment will anyway be considered for urgent coronary angiogram and intervention if necessary. Further benefits were derived when these patients had to undergo PCI after treatment with a platelet GP IIb/IIIa receptor antagonist.28,29 High‐risk UA and NQMI are indications for early coronary angiogram.31 Risk stratification using troponin level and ST segment deviation in the ECG can help to identify high‐risk patients with unstable angina. Low‐risk UA should be treated with the conventional regimen of LMWH plus aspirin and anti‐anginal drugs. Intravenous platelet GP IIb/IIIa receptor antagonist when given with intravenous unfractionated heparin plus aspirin further improves the outcome of high‐risk UA without increasing intra‐cranial bleeding complications. The ischaemia‐guided conservative approach should remain the initial treatment of choice for UA/NQMI, in the district general hospitals where there is no invasive facility or it is not within easy reach. Patients who are unresponsive to initial medical treatment should be urgently considered for coronary angiogram and further intervention. Early treatment with intravenous GP IIb/IIIa receptor antagonists followed by early coronary angiogram and PCI/CABG if necessary may be considered where readily available. More large randomized controlled trials such as the TACTICS‐TIMI 18 and RITA 3 will provide further information on whether the invasive treatment of all patients of UA or the ischaemia‐guided initial conservative approach is superior, practicable or cost effective. Address correspondence to Dr A.G. Davies, Department of Medicine, Bronglais Hospital, Aberystwyth SY23 1ER

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