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Failed thrombolysis in myocardial infarction
International Journal of Cardiology 75 (2000) 5–14 www.elsevier.com / locate / ijcard
Review
Failed thrombolysis in myocardial infarction a, b a A. Qasim *, A. Chauhan , R.S. More a
b
St. Mary’ s Hospital, Milton Road, Portsmouth, PO3 6 AD, UK Blackpool Victoria Hospital, Whinney Heys Road, Blackpool, FY3 8 NR, UK
Received 18 October 1999; received in revised form 3 April 2000; accepted 8 April 2000
Abstract Prompt treatment with thrombolytic therapy in acute myocardial infarction has been proven to reduce infarct size and mortality. However, reperfusion fails to occur in 30–50% of patients, either due to impaired epicardial artery flow or microvascular occlusion, with these patients experiencing a higher morbidity and mortality. We review the diagnosis and management of failed thrombolysis in acute myocardial infarction. 2000 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction The management of acute myocardial infarction is geared towards early use of thrombolytic therapy to secure epicardial artery patency and reduce infarct size, the benefits of this approach having been proven in large randomised controlled trials [1]. However, reperfusion fails to occur in 30–50% of patients [2], either due to impaired epicardial artery flow or microvascular occlusion, with these patients experiencing a markedly higher morbidity and mortality. At present in the UK limited measures are routinely taken to detect this high-risk population [3], besides which the optimal management for failed thrombolysis remains unclear. Angiographic sub-studies following thrombolytic therapy use show that not only epicardial artery patency, but unimpaired flow are required to reduce mortality. The Thrombolysis in Myocardial Infarction (TIMI) investigators (Table 1) demonstrated that patients with angiographic occlusion (TIMI grades 0 *Corresponding author. Tel.: 144-1705-286-000; fax: 144-1705-866967. E-mail address: [email protected] (A. Qasim).
and 1) and impaired flow (TIMI grade 2) had double the mortality of those with unimpaired flow (TIMI grade 3) [4]. TIMI 3 flow in the infarct-related epicardial artery is regarded as the standard for successful coronary thrombolysis. Although this is achieved in 31% of patients with streptokinase compared to 54% with tissue plasminogen activator (tPA) [5], streptokinase remains the thrombolytic agent of choice for most patients in 90% of British centres [3]. This practice may give sub-optimal results, but Table 1 The Thrombolysis in myocardial infarction study group angiographic classification of coronary artery flow [4]. Flow grade
Angiographic definition
TIMI 0
No perfusion. No anterograde flow of contrast medium is detected beyond the point of occlusion. Penetration without perfusion. Contrast medium passes through the point of obstruction but anterograde flows fails to opacify the distal portion of the vessel at any time. Partial perfusion. Contrast material penetrates through the point of obstruction but enters the distal vessel at a rate slower than for unobstructed arteries in the same patient. Complete perfusion. Anterograde flow into the distal coronary bed is rapid and complete.
TIMI 1
TIMI 2
TIMI 3
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00282-5
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further discussions on the choice of thrombolytic agent, and associated financial and cost-benefit implications are beyond the scope of this review.
2. Pathogenesis Thrombolysis may fail to restore myocardial perfusion because of occlusion or impaired flow in the epicardial artery, or because of distal microvascular occlusion. Structural factors play an important role at the site of epicardial artery occlusion. Where plaque expansion sub-acutely has contributed more than acute thrombosis on the plaque surface to occlusion, thrombolysis is of limited value, and TIMI 3 angiographic flow is less likely [6]. Post mortem examination suggests that complex plaques, with an irregular fissured surface, and haemorrhage into the plaque are more likely to be associated with thrombolytic failure [7,8]. This may relate to ongoing plaque fissuring and thrombogenesis in such lesions in spite of fibrinolytic therapy. The presence of anti-streptokinase antibodies, either because of past infection with b-haemolytic streptococci or previous treatment with streptokinase, is sited as a reason to avoid streptokinase, or for its failure. Most individuals have low titres of these antibodies, and enough streptokinase must be infused to neutralise them. A study of 40 patients treated with streptokinase for their first acute myocardial infarction [9] found that in most anti-streptokinase antibodies were not detectable prior to treatment, but all had developed high titres 10 days after administration. High levels were still detected in 75% 2 years later, and serum from these patients inhibited in vitro fibrin plate lysis by streptokinase. This suggests further treatment with streptokinase for myocardial infarction would be ineffective during this period. The evidence that streptokinase fails because of antibody neutralisation in those who have not been treated with it previously is less convincing [10]. Raised levels of thrombin–anti-thrombin III complexes and persistently elevated fibrinogen levels in patients treated with streptokinase are associated with ongoing thrombogenesis and failure of thrombolysis [11]. This may reflect either inadequate dosing or efficacy of agents, and is associated with a poorer
outcome. Fibrinolysis leads to a rise in fibrin degradation products (FDPs), and raised levels of crosslinked FDPs or D-dimers may be used as markers of active thrombolysis, as levels are raised from fibrinolysis solid-state thrombus-related fibrin rather than soluble fibrin breakdown [12,13]. Myocardial ischaemia may continue despite thrombolysis restoring TIMI 3 flow in the infarct-related epicardial artery. This ‘no-reflow’ is due to microvascular occlusion or micro-circulatory failure. Platelet micro-thrombi are released from arterial thrombus by fibrinolysis and the distal microvascular occlusion they cause results in ‘early no-reflow’ [14,15]. These microthrombi are resistant to lytic agents. In fact fibrinolytic agents cause an increase in thrombin activity, and platelet reactivity and aggregation. In addition endothelial and myocardial oedema contribute to microcirculatory failure termed ‘late no-reflow’ [8]. This mechanism is likely to determine whether a treatment delay will still lead to successful thrombolysis, as even if arterial patency is restored late no-reflow will to lead to further ischaemia and infarction, yet the patient is still exposed to the risks and haemorrhagic complications of lytic therapy.
3. Reocclusion There is a risk that after thrombolytic therapy has restored infarct-related artery patency, reocclusion may occur [16]. By angiographic definition reocclusion requires three angiograms: one demonstrating the occluded artery, the next following restoration of flow, and the third showing reocclusion. Twentyeight studies of reocclusion after thrombolysis [17] performed in this way found mean reocclusion rates of 16%, with a standard deviation of 10%. Most studies of reocclusion, however, use two angiograms: one with the patent artery after treatment and one with the reoccluded infarct-related artery. Thirtythree studies of this kind demonstrated a mean reocclusion rate of 10%, with standard deviation of 8%. The lower rates in this type of study are likely to reflect the inclusion of patients whose infarct-related artery was not completely occluded at the time of thrombolysis, who would have been excluded from studies utilising three angiograms. In total, the 61
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reocclusion studies comprised 6061 patients [17], and the median time between presentation and the final angiogram was 16 days (range 0.1–365). Reocclusion is most likely to occur within the first 2 weeks, and is more likely if TIMI 3 flow is not restored by thrombolysis. The clinical course of patients with reocclusion is more complicated, and they tend to have reduced left ventricular systolic function. A combination of mechanisms are likely to be involved in the process of reocclusion, but it is clear that platelet activation plays a crucial role. Thrombin– anti-thrombin complex levels are lower in patients with reocclusion after successful thrombolysis for acute myocardial infarction than in those without, suggesting reduced thrombin generation. In contrast platelet aggregation is increased [18], and it is possible that strategies to reduce platelet activity may lower reocclusion rates. Early studies with the direct thrombin inhibitors hirudin and hirulog as adjuvants to thrombolytic therapy have not shown a reduction in re-infarction or mortality [19]. Inhibition of platelet activity using glycoprotein IIb / IIIa antagonists such as abcixmab may prove to be beneficial in this area.
4. Detection of failed thrombolysis In the UK a large proportion (approximately 45%) of cardiologists do not routinely search for evidence of reperfusion, and many units have no established practice for the management of failed thrombolysis [3]. Early coronary angiography to determine epicardial artery flow, together with nuclear medicine perfusion imaging to try to detect no-reflow is probably the ideal combination to assess the success of thrombolysis. These measures are not practical for routine clinical use, and reliable non-invasive markers of reperfusion have not been established.
5. Symptoms The time from the onset of chest pain to treatment with streptokinase, and age are independent predictors of TIMI 3 flow in the infarct-related artery. Many patients experience a dramatic improvement in their symptoms soon after thrombolytic therapy is
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initiated, but this is also affected by the administration of oxygen and analgesics. In up to 50% of patients chest pain is abruptly stopped by thrombolysis and this is approximately 70% sensitive for reperfusion [20,21]. Ongoing ischaemic chest pain after thrombolysis may be useful indicator of reperfusion when used in conjunction with other markers. However, symptoms lack adequate sensitivity and specificity in themselves to be of value as indicators of failed reperfusion. Clearly patients who develop cardiogenic shock have suffered marked myocardial injury which has not responded to thrombolytic therapy. The prognosis in this group is very poor with 3-month mortality over 90%, and these patients may benefit most from any improvement in perfusion.
6. Electrocardiography The ECG at presentation holds some predictive value as to whether thrombolysis will be successful [22]. TIMI 3 flow is more likely with streptokinase if Q waves are absent (55%) than present (35%), and if there is no T wave inversion (50%) than if T waves are inverted (30%). The magnitude of ST elevation at presentation does not predict the likelihood of successfully achieving TIMI 3 flow with thrombolysis, but does predict clinical outcome [23]. This disparity between infarct-related arterial flow and ST resolution as a marker of morbidity and mortality after thrombolysis may reflect a larger area of ischaemic myocardium and higher rates of no reflow in those with greater ST elevation. The degree of resolution of ST elevation after thrombolysis does appear to be related to outcome, with the predictive value increasing as the time from the start of thrombolysis to repeat ECG lengthens [24]. In the INJECT trial [25] mortality was related to the degree of ST resolution 3 h after the start of thrombolysis. In 1398 German patients, the 35-day mortality was 17.5% with less than 30% resolution of ST segment elevation, 4% with 30–70% resolution and 2.5% with greater than 70% resolution. ST elevation did not resolve in over half the patients in the Zwolle primary angioplasty study [26] in whom TIMI 3 flow was restored in the infarct-related epicardial artery, presumably reflecting higher rates of no-reflow. However, the degree of ST resolution
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was highly predictive of 3-year mortality, with the residual ECG abnormalities reflecting the extent of myocardial injury. The degree of ST segment resolution is a powerful tool in detecting failed thrombolysis, although it is not possible to determine whether the failure has been in the epicardial artery or the microvasculature. And although both the rates of TIMI 3 flow and ST segment resolution relate to prognosis, the relation between the two in an individual patient is difficult to predict. Studies to assess this relationship have used a 25–50% resolution of ST segment elevation in all the leads or the single worst lead together with postthrombolytic coronary angiography [8]. The sensitivity and specificity of ST resolution is increased with longer sampling times, but this leaves less time for actions to salvage viable myocardium. GUSTO I [27] included the largest study of ST segment monitoring in patients with acute myocardial infarction treated with thrombolysis. In 373 patients who had assessment of ST resolution there was up to 82% predictive value for patency and up to 64% for artery occlusion. The predictive value was greatest in those with more than 4 mm of ST elevation, and these patients had the worst prognosis. Although this approach might allow more directed strategies of revascularisation in this high risk group it is still worthy of note that over one-third of those patients with ongoing ST elevation had already achieved unimpaired infarct-related epicardial artery flow, and thus might undergo unnecessary cardiac catheterisation. Clearly there are also significant implications if non-invasive strategies for the management of failed thrombolysis are to be used, as pharmacological treatment aimed at restoring epicardial artery patency may exacerbate myocardial damage in those patients with no-reflow. GUSTO I in addition reinforced the observation that ECG resolution may occur where epicardial artery occlusion persists, and this was evident in approximately a quarter of those with ST resolution. This group of patients may have restoration of myocardial perfusion by recruitment of a collateral circulation, and thus reduced cellular injury. They have a relatively good prognosis and outcome in terms of mortality and left ventricular ejection fraction, and there is no evidence to date that a late restoration of arterial flow by angioplasty in this group improves outcome [8].
Computerised continuous ECG monitoring allows automatic assessment of ST segment changes, but in view of the cyclical ECG changes in evolving myocardial infarction and associated with thrombolysis, it is not clear whether this is superior to ECG recordings at specific times after initiating thrombolysis. The timing of ECGs is a compromise between sensitivity to detect failed thrombolysis and early assessment to allow myocardial salvage to be maximised. A repeat ECG 60–120 min after the start of thrombolysis is a reasonable compromise in view of the current data.
7. Echocardiography Echocardiography can be used to detect regional wall movement abnormalities in acute myocardial infarction, and successful thrombolysis reduces the degree of abnormal wall movement. However, there is little evidence that two-dimensional echocardiography has a place in detecting reperfusion in the period immediately after thrombolysis. Perfusion contrast echocardiography has demonstrated that myocardial reperfusion is absent in over one-third of patients with TIMI 3 flow after thrombolysis [28], reflecting no-reflow. Positron emission tomography has provided similar evidence for microvascular occlusion. Both these techniques are valuable when used in conjunction with coronary angiography, but neither is yet widely available.
8. Biochemical markers Biochemical tests to detect failed thrombolysis fall into two broad groups: those which reflect the degree of myocardial damage, and those relating to thrombus formation or breakdown. Troponin I and T, creatine kinase (CK) isoenzymes, fatty acid binding proteins, and myoglobin all show an early peak concentration when thrombolysis has been successful, limiting the extent of myocardial ischaemia [29–32]. At early angiography, patients with TIMI 3 flow after thrombolysis had a significantly higher CK-MB levels than those with impaired flow or occluded infarct-related artery. These markers do show a high sensitivity and spe-
A. Qasim et al. / International Journal of Cardiology 75 (2000) 5 – 14
cificity, but multiple tests are required and in some cases results have to be incorporated into complex mathematical models. Myoglobin levels show early change, and when studied in conjunction with clinical variables, provide a reliable guide to successful thrombolysis and epicardial artery flow. Bedside tests for troponin and myoglobin are becoming increasingly available. Levels of serum fibrinogen and fibrin are elevated at presentation with acute myocardial infarction, and a fall in serum fibrinogen after initiating treatment reflects systemic fibrinolysis [33]. Lower fibrinogen levels are associated with a higher rate of TIMI 3 flow 90 min after initiating thrombolyis. Fibrin degradation products (FDPs) rise because of lysis of soluble, circulating and solid-state fibrinogen and fibrin. Fibrinolysis in myocardial infarction is used to try to break down solid fibrin which is an integral part of coronary artery thrombosis. Fibrin-specific tag ELISA of cross-linked FDPs or D-dimers provides evidence of solid-state fibrin clot lysis, rather than lysis of circulating soluble fibrin [34,35]. It is also of note that raised D-dimer levels are associated with a higher rate of haemorrhagic complications. Thrombolytic agents act by direct or indirect activation of plasminogen to plasmin, and plasminogen consumption can be measured but levels do not correlate with the success of thrombolysis. Thrombin activity can also be measured by urine levels of fibrinopeptide A, and increased levels predict adverse outcome. However, as with measurements of thrombin–anti-thrombin complexes the relation with reperfusion is less clear. Activation of the system does not reflect artery patency, but may be useful in predicting which patients with other evidence of failed thrombolysis might benefit from further anti-thrombotic therapy. Inter-cellular adhesion molecules play a crucial role in thrombogenesis, including activation of platelets, leucocytes and endothelial cells, allowing cell adhesion. Levels of selectins and integrins are raised in acute coronary syndromes. In a sub-study of 23 patients in GUSTO III raised levels of P-selectin and platelet-endothelial cellular adhesion molecule were observed in five patients with failed thrombolysis [36]. These markers do hold promise as predictors of ongoing thrombogenesis and artery patency, although it is possible that early no-reflow
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due to platelet microthrombi may also raise selectin levels. There are a number of promising non-invasive markers that might be used in conjunction with serial ECGs to determine whether thrombolysis has failed. A combination of tests which could evaluate both infarct-related artery patency and myocardial perfusion would be the ideal, but further studies are needed to evaluate these relationships. It is possible that repeat ECGs 60–120 min after the start of thrombolysis, coupled with bedside testing for Ddimers and myoglobin will provide a reliable combination which is feasible for use in all units.
9. Management of failed thrombolysis Given the frequency and clinical significance of failed thrombolysis, the evidence for effective management is very limited. In the UK practice varies amongst those who have an active management plan following failed thrombolysis [3]. About half proceed to urgent coronary angiography, of the remainder most repeat thrombolysis with a different agent, and a small number re-administer the same thrombolytic agent. The aim has been to restore epicardial artery patency and flow, but those with failed perfusion because of no-reflow need alternative strategies, possibly with adjuvant therapy to disperse platelet microthrombi (Fig. 1). The TIMI 14 trial [37] has shown the potential benefits of adding a potent antiplatelet agent, the glycoprotein IIb / IIIa inhibitor abciximab, to a thrombolytic agent in acute myocardial infarction. The large GUSTO IV and SPEED studies [38] are further investigating adjuvant anitplatelet therapy use in conjunction with thrombolysis.
10. Rescue angioplasty Rescue refers to angioplasty performed soon after thrombolysis which has failed to restore TIMI 3 flow in the infarct-related artery, aiming to secure myocardial reperfusion. In contrast primary angioplasty is performed immediately in lieu of thrombolysis, and deferred angioplasty is performed late after the acute infarction. There are three randomised trials of rescue PTCA,
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Fig. 1. Thrombogenesis and thrombolysis. Coronary artery thrombus results from the combination of fibrinogen activated to fibrin by the coagulation cascade, and platelet activation, on the surface of fissured atherosclerotic plaques. Thrombolytic drugs act directly or indirectly on plasminogen, activating the endogenous fibrinolytic system. Direct thrombin inhibitors reduce fibrin formation, and anti-platelet agents act to reduce platelet aggregation.
and it is of note that patients with cardiogenic shock are excluded from these as it was felt unethical to withhold angioplasty. Data from GUSTO 1 and other studies involving patients with cardiogenic shock do suggest possible benefit for rescue angioplasty in this setting [39,40]. The RESCUE study [41] randomised 150 patients with failed thrombolysis for their first anterior myocardial infarction to PTCA or conservative management with aspirin, heparin and coronary vasodilators. The 30-day rates for the combined end points of severe heart failure and death were 6 and 17% (P, 0.05) in the PTCA and conservative management groups, respectively. There was a significant difference in exercise ejection fractions, with 43% in the PTCA group and 38% in the conservative group, but no difference in the resting ejection fractions. The TAMI-5 [42,43] study included 295 patients in whom thrombolysis had failed to restore TIMI 3 flow who were randomised to either rescue PTCA or predischarge PTCA. There was no mortality difference, but rescue PTCA gave improved ejection fraction and a reduction in a composite end-point of adverse outcomes compared to pre-discharge PTCA. Meta-
analysis [44] of these two studies and the Belenkie study [45] of 28 patients demonstrates no mortality benefit for rescue PTCA. However, the overall patient numbers are small, and so a potential mortality benefit for rescue PTCA cannot be excluded. There have been problems recruiting patients into randomised trials of rescue PTCA, and some suggestions that participating centres have been reluctant to randomise more ill patients. RESCUE randomised only 150 patients in 20 centres in the USA in 3 years, and the inclusion criteria did not include evidence of ongoing ischaemic chest pain or failure of ST segment resolution. Directing coronary angiography and angioplasty to these selected groups of higher risk patients with evidence of failed reperfusion and ongoing ischaemia may demonstrate a mortality benefit for rescue PTCA. The evidence for rescue PTCA with coronary stenting is limited to case report series [45], and the routine use of glycoprotein IIb / IIIa antagonist platelet aggregation inhibitors is likely to improve outcome in this setting [46]. Laser optical thrombolysis has been used in conjunction with rescue PTCA [47] but its availability is very limited. A retrospective study of emergency surgical revascu-
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larisation after urgent angiography for acute myocardial infarction of 54 patients in Japan suggests a mortality benefit if there is evidence of failed reperfusion following angioplasty, with ongoing ischaemia [48], No randomised studies have evaluated this approach. Intra-aortic balloon pump (IABP) counterpulsation to improve diastolic flow has been used as an adjunct to rescue PTCA, with improvements in infarct-related epicardial artery patency and flow, and left ventricular ejection fraction [49]. A randomised trial of 45 patients with failed alteplase thrombolysis and TIMI 0, 1 or 2 flow in the infarct-related artery, demonstrated a better outcome with IABP without rescue PTCA compared to drug therapy alone [50]. IABP counterpulsation was operated for 48 h, and the rate of TIMI 3 flow at 3 weeks was 74% compared to 32% in the control group. There is good evidence that IABP usage does improve patency rates, but most cardiologists, having demonstrated coronary artery stenosis, in this context, feel obliged to proceed to PTCA, and in current practice IABP counterpulsation is used mainly as an adjunct in complicated cases with hypotension.
11. Repeat thrombolysis The only randomised trial of repeat thrombolysis is of 37 patients who had less than 25% ST resolution in the most elevated lead, 90 min after initiation of streptokinase thrombolysis [51]. Patients were randomised to repeat lysis with tissue type plasminogen activator (rtPA) or placebo, with 43 patients with ST resolution after streptokinase as controls. Rescue thrombolysis gave an ejection fraction of 44% compared to 34% with placebo, but only in those patients with a serum fibrinogen level greater than 1 g / l after streptokinase. This suggests impaired efficacy of the initial treatment with streptokinase, which may be due to structural factors, or raised levels of antistreptokinase antibodies. There is no direct evidence from studies of repeat thrombolysis for failed reperfusion regarding the increased risk of haemorrhage, but this can be estimated from GUSTO-1 [2], in which the co-administration of streptokinase and tPA to patients with acute myocardial infarction raised their risk of intra-cranial haemorrhage to 0.94% from
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0.49% with streptokinase alone, without any demonstrable mortality benefit. For rescue thrombolysis to be most effective it would have to be targetted at patients who had evidence of failed reperfusion and ongoing ischaemia due to epicardial artery obstruction, rather than microvascular no-reflow, as in the latter situation platelet and thrombin activation associated with thrombolytic agents might exacerbate microcirculation injury. Persistently elevated serum fibrinogen levels do suggest ongoing thrombogenesis, but as an acute phase reactant it is not specific enough to be used alone. If used together with other biochemical markers such as low D-dimers and raised levels of selectins and integrins, it may be possible to develop a relatively simple model to establish which patients may benefit most from rescue thrombolysis.
12. Alternative pharmacological approaches Adjuvant therapy to reduce the effects of thrombin released from within a fibrin clot by thrombolytic agents with the direct anti-thrombin agents hirudin, hirulog and similar synthetic compounds has proven promising. The HERO study [52] randomised patients to heparin, low- or high-dose hirulog in addition to standard therapy with aspirin and streptokinase in 412 patients with acute myocardial infarction. Low-dose hirulog gave TIMI 3 flow at 90 min in 46%, compared to 35% with heparin, and hirulog had a markedly lower rate of haemorrhagic complications. The OASIS-2 study [53] found similar benefits in 10 141 patients with unstable angina or myocardial infarction without ST elevation using hirudin, and further studies by the HIT investigators have tried to optimise dosing [19]. GUSTO IIb [54] concluded that hirudin was of benefit as an adjunct to streptokinase, but not with tPA. The place of these direct thrombin inhibitors in failed thrombolysis has not been investigated, but they may improve outcome in those patients with evidence of failed reperfusion and arterial occlusion with biochemical evidence of active thrombogenesis. Anti-platelet therapy with glycoprotein IIb / IIIa inhibitors is now well established in reducing subacute reocclusion after coronary artery stenting in addition to aspirin. Abciximab, the Fab fragment of
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monoclonal antibody to glycoprotein IIb / IIIa, was used in the TIMI 14 trial [37] with various combinations of thrombolytics. TIMI 3 flow rates at 60 min with rtPA were 43%, but increased to 72% with abciximab and rtPA; and 62 and 77%, respectively, at 90 min. There was a small benefit in patency rates using abciximab with streptokinase, but this was offset by a higher rate of haemorrhagic complications. Cost limitations have prevented abcixmab from entering routine clinical practice. Further research is needed to establish whether it has a place in the treatment of failed thrombolysis due to early noreflow caused by platelet micro-thrombi. Oral glycoprotein IIb / IIIa inhibitors including clopidogrel and ticlopidine have no proven benefit in acute myocardial infarction, but further studies are required to evaluate these agents in combination with thrombolysis and in the management of failed reperfusion due to microvascular occlusion.
13. Conclusion At present in the UK we take only limited measures to detect failed thrombolysis for acute myocardial infarction. Unfortunately, at present there are no readily available, easy to use methods for detecting the occurrence and mode of thrombolytic failure, and it has become clear that as well as unimpaired flow in the infarct-related epicardial artery, the microcirculation in the myocardium subtended by that vessel must be in tact to allow reperfusion. Further work is needed to develop reliable indicators for failed thrombolysis which can be utilised widely. Methods for treating failed thrombolysis are unresolved. The roles of angioplasty, stenting, repeat thrombolysis and adjuvant therapy with anti-platelet and anti-thrombin agents have not yet been defined. However, further studies will be required in this area to establish the most effective therapy for those patients with acute myocardial infarction who have not achieved adequate reperfusion with thrombolysis, and consequently have a markedly higher morbidity and mortality. Studies including the REACT trial are ongoing which are exploring the most beneficial strategy for this patient group. The REACT trial will study patients who fail to achieve 50% resolution of ST elevation following thrombolysis for acute myocar-
dial infarction, and they will be randomised to conservative therapy with heparin, or repeat thrombolysis, or coronary angiography, and if appropriate angioplasty, at the local interventional centre. A suggested policy on the basis of the limited data available currently would advocate routine use of a repeat ECG 60–90 min after the initiation of thrombolysis to assess ST resolution. In those with failure of ST segment elevation to resolve by 25%, particularly in the context of an anterior, right ventricular, or second myocardial infarction at a site different from the first, an urgent measurement of serum fibrinogen should be carried out. If the fibrinogen level is greater than 1 g / l then accelerated regime tissue plasminogen activator thrombolysis should be administered. For those with fibrinogen levels less than 1 g / l either intra-aortic balloon pump support or an intra-venous glycoprotein IIb / IIIa antagonist, such as abciximab, should be administered. In those patients with less than TIMI 3 flow in the infarctrelated artery after failed thrombolysis, 48 h of IABP counterpulsation may be of benefit. Although the evidence is limited at present, in interventional centres, we would advise early angiography and PTCA in those who fail to show ST segment resolution.
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patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimes: a substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. J Am Coll Cardiol 1995;26:1657–67. Van’t Hof AWJ, Liem A, de Boer M. Zwolle myocardial infarction study group: clinical value of 12-lead electrocardiogram after successful reperfusion therapy for myocardial infarction. Lancet 1997;350:615–9. Klootwwijk P, Langer A, Meij S et al. Non-invasive prediction of reperfusion and coronary artery patency by continuous ST segment monitoring in the GUSTO-1 trial. Eur Heart J 1996;17:689–98. Ito H, Okamura A, Iwakura K et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation 1996;93:1993–9. Lavin F, Kane M, Forde A et al. Comparison of five cardiac markers in the detection of reperfusion after thrombolysis in acute myocardial infarction. Br Heart K 1995;73:422–7. Ishii J, Nomura M, Ando T et al. Early detection of successful coronary reperfusion based on serum myoglobin concentration: comparison with creatine kinase isoenzyme MB activity. Am Heart J 1994;128:641–8. Apple FS, Henry TD, Berger CR, Landt YA. Early monitoring of serum cardiac troponin I for assessment of coronary reperfusion following thrombolytic therapy. Am J Clin Pathol 1996;105:6–10. Laperche T, Steg P, Benessiano J et al. Patterns of myoglobin and MM creatine kinase isoforms release early after intravenous thrombolysis or direct percutaneous transluminal coronary angioplasty for acute myocardial infarction, and implications for the early noninvasive diagnosis of reperfusion. Am J Cardiol 1992;70:1129–34. Boisclair MD, Lane DA, Wilde JT et al. A comparative evaluation of assays for markers of activated coagulation and / or fibrinolysis: thrombin-antithrombin complex, D-dimer, and fibrinogen / fibrin fragment E antigen. Br J Haematol 1990;74:471–9. Ho CH, Wang SP. Serial thrombolysis-related changes after thrombolytic therapy with TPA in patients with acute myocardial infarction. Thromb Res 1990;58:331–41. Cushman M, Lemaitre RN, Kuller LH et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999;19:493–8. Gurbel PA, Serebruany VL, Shustov AR et al. Increased baseline levels of platelet P-selectin, and platelet-endothelial adhesion molecule-1 in patients with acute myocardial infarction as predictors of unsuccessful thrombolysis. Coron Artery Dis 1998;9:451–6. Antman EM, Giugliano RP, Gibson CM et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 investigators. Circulation 1999;99:2720–32. Califf RM. Glycoprotein IIb / IIIa blockade and thrombolysis: early lessons from the SPEED and GUSTO IV trials. Am Heart J 1999;138:S12–15. SHOCK Registry Investigators, Hochman JS, Boland J, Sleeper LA et al. Cuurent spectrum of cardiogenic shock and effect of early revascularisation on mortality: results of an international registry. Circulation 1995;91:873–81. Berger PB, Holmes Jr. DR, Stebbins AL et al. Impact of aggressive invasive catheterisation and revascularisation strategy on mortality in patients with cardiogenic shock in the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) trial: an observational study. Circulation 1997;96:122–7.
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[41] Ellis SG, da Silva ER, Heyndickx G et al. Randomised comparison of rescue angioplasty and conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994;90:2280–4. [42] Califf RM, Topol EJ, Slack RS et al. Evaluation of combination thrombolytic therapy and timing of cardiac catheterisation in acute myocardial infarction: results of thrombolysis and angioplasty in myocardial infarction-phase 5 randomised trial. The TAMI study group. Circulation 1991;83:1543–56. [43] Belenkie I, Traboulsi M, Hall CA et al. Rescue angioplasty during myocardial infarction has a beneficial effect on mortality: a tenable hypothesis. Can J Cardiol 1992;8:357–62. [44] Michels KB, Yusuf S. Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomised clinical trials. Circulation 1995;91:476–85. [45] Steinhubl SR, Topol EJ. Stenting for acute myocardial infarction. Lancet 1997;350:532–3. [46] Brener SJ, Baur LA, Burcheval JE et al. Randomised placebocontrolled trial of platelet glycoprotein IIb / IIa blockade with primary angioplasty for acute myocardial infarction. Reopro and Primary PTCA Organisation and Randomised Trial (RAPPORT) Investigators. Circulation 1998;98:734–41. [47] Topaz O, Vetrovec G. Laser optical thrombolysis and facilitation of balloon angioplasty in acute myocardial infarction following failed thrombolysis. Catheterisation and Cardiovascular Diagnosis 1995;36:38–42. [48] Tanaka N, Mukai K, Ade W et al. Emergency myocardial revascularisation for myocardial infarction evolving outside the hospital. A
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feasible option when thrombolysis and coronary angioplasty have failed. J Cardiovasc Surg 1993;34:215–20. Kono T, Morita H, Nishina T et al. Aortic counterpulsation may improve late patency of the occluded artery in patients with early failure of thrombolytic therapy. J Am Coll Cardiol 1996;28:876–81. Ishihara M, Sato H, Tateishi H et al. Intra-aortic balloon pumping as adjunctive therapy to rescue angioplasty after failed thrombolysis in anterior wall myocardial infarction. Am J Cardiol 1995;76:73–5. Mounsey JP, Skinner JS, Hawkins T et al. Rescue thrombolysis: alteplase as adjuvant treatment after streptokinase in acute myocardial infarction. Br Heart J 1995;74:348–53. White HD, Aylward PE, Frey MJ et al. Randomised, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO)Hirulog Early Reperfusion / Occlusion (HERO) Trial Investigators. Circulation 1997;96:2155–61. Organisation to Assess Strategies for Ischaemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet 1999;353:429–38. Metz BK, White HD, Granger CB et al. Randomised comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators. J Am Coll Cardiol 1998;31:1493–8.
Review
Failed thrombolysis in myocardial infarction a, b a A. Qasim *, A. Chauhan , R.S. More a
b
St. Mary’ s Hospital, Milton Road, Portsmouth, PO3 6 AD, UK Blackpool Victoria Hospital, Whinney Heys Road, Blackpool, FY3 8 NR, UK
Received 18 October 1999; received in revised form 3 April 2000; accepted 8 April 2000
Abstract Prompt treatment with thrombolytic therapy in acute myocardial infarction has been proven to reduce infarct size and mortality. However, reperfusion fails to occur in 30–50% of patients, either due to impaired epicardial artery flow or microvascular occlusion, with these patients experiencing a higher morbidity and mortality. We review the diagnosis and management of failed thrombolysis in acute myocardial infarction. 2000 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction The management of acute myocardial infarction is geared towards early use of thrombolytic therapy to secure epicardial artery patency and reduce infarct size, the benefits of this approach having been proven in large randomised controlled trials [1]. However, reperfusion fails to occur in 30–50% of patients [2], either due to impaired epicardial artery flow or microvascular occlusion, with these patients experiencing a markedly higher morbidity and mortality. At present in the UK limited measures are routinely taken to detect this high-risk population [3], besides which the optimal management for failed thrombolysis remains unclear. Angiographic sub-studies following thrombolytic therapy use show that not only epicardial artery patency, but unimpaired flow are required to reduce mortality. The Thrombolysis in Myocardial Infarction (TIMI) investigators (Table 1) demonstrated that patients with angiographic occlusion (TIMI grades 0 *Corresponding author. Tel.: 144-1705-286-000; fax: 144-1705-866967. E-mail address: [email protected] (A. Qasim).
and 1) and impaired flow (TIMI grade 2) had double the mortality of those with unimpaired flow (TIMI grade 3) [4]. TIMI 3 flow in the infarct-related epicardial artery is regarded as the standard for successful coronary thrombolysis. Although this is achieved in 31% of patients with streptokinase compared to 54% with tissue plasminogen activator (tPA) [5], streptokinase remains the thrombolytic agent of choice for most patients in 90% of British centres [3]. This practice may give sub-optimal results, but Table 1 The Thrombolysis in myocardial infarction study group angiographic classification of coronary artery flow [4]. Flow grade
Angiographic definition
TIMI 0
No perfusion. No anterograde flow of contrast medium is detected beyond the point of occlusion. Penetration without perfusion. Contrast medium passes through the point of obstruction but anterograde flows fails to opacify the distal portion of the vessel at any time. Partial perfusion. Contrast material penetrates through the point of obstruction but enters the distal vessel at a rate slower than for unobstructed arteries in the same patient. Complete perfusion. Anterograde flow into the distal coronary bed is rapid and complete.
TIMI 1
TIMI 2
TIMI 3
0167-5273 / 00 / $ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 00 )00282-5
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further discussions on the choice of thrombolytic agent, and associated financial and cost-benefit implications are beyond the scope of this review.
2. Pathogenesis Thrombolysis may fail to restore myocardial perfusion because of occlusion or impaired flow in the epicardial artery, or because of distal microvascular occlusion. Structural factors play an important role at the site of epicardial artery occlusion. Where plaque expansion sub-acutely has contributed more than acute thrombosis on the plaque surface to occlusion, thrombolysis is of limited value, and TIMI 3 angiographic flow is less likely [6]. Post mortem examination suggests that complex plaques, with an irregular fissured surface, and haemorrhage into the plaque are more likely to be associated with thrombolytic failure [7,8]. This may relate to ongoing plaque fissuring and thrombogenesis in such lesions in spite of fibrinolytic therapy. The presence of anti-streptokinase antibodies, either because of past infection with b-haemolytic streptococci or previous treatment with streptokinase, is sited as a reason to avoid streptokinase, or for its failure. Most individuals have low titres of these antibodies, and enough streptokinase must be infused to neutralise them. A study of 40 patients treated with streptokinase for their first acute myocardial infarction [9] found that in most anti-streptokinase antibodies were not detectable prior to treatment, but all had developed high titres 10 days after administration. High levels were still detected in 75% 2 years later, and serum from these patients inhibited in vitro fibrin plate lysis by streptokinase. This suggests further treatment with streptokinase for myocardial infarction would be ineffective during this period. The evidence that streptokinase fails because of antibody neutralisation in those who have not been treated with it previously is less convincing [10]. Raised levels of thrombin–anti-thrombin III complexes and persistently elevated fibrinogen levels in patients treated with streptokinase are associated with ongoing thrombogenesis and failure of thrombolysis [11]. This may reflect either inadequate dosing or efficacy of agents, and is associated with a poorer
outcome. Fibrinolysis leads to a rise in fibrin degradation products (FDPs), and raised levels of crosslinked FDPs or D-dimers may be used as markers of active thrombolysis, as levels are raised from fibrinolysis solid-state thrombus-related fibrin rather than soluble fibrin breakdown [12,13]. Myocardial ischaemia may continue despite thrombolysis restoring TIMI 3 flow in the infarct-related epicardial artery. This ‘no-reflow’ is due to microvascular occlusion or micro-circulatory failure. Platelet micro-thrombi are released from arterial thrombus by fibrinolysis and the distal microvascular occlusion they cause results in ‘early no-reflow’ [14,15]. These microthrombi are resistant to lytic agents. In fact fibrinolytic agents cause an increase in thrombin activity, and platelet reactivity and aggregation. In addition endothelial and myocardial oedema contribute to microcirculatory failure termed ‘late no-reflow’ [8]. This mechanism is likely to determine whether a treatment delay will still lead to successful thrombolysis, as even if arterial patency is restored late no-reflow will to lead to further ischaemia and infarction, yet the patient is still exposed to the risks and haemorrhagic complications of lytic therapy.
3. Reocclusion There is a risk that after thrombolytic therapy has restored infarct-related artery patency, reocclusion may occur [16]. By angiographic definition reocclusion requires three angiograms: one demonstrating the occluded artery, the next following restoration of flow, and the third showing reocclusion. Twentyeight studies of reocclusion after thrombolysis [17] performed in this way found mean reocclusion rates of 16%, with a standard deviation of 10%. Most studies of reocclusion, however, use two angiograms: one with the patent artery after treatment and one with the reoccluded infarct-related artery. Thirtythree studies of this kind demonstrated a mean reocclusion rate of 10%, with standard deviation of 8%. The lower rates in this type of study are likely to reflect the inclusion of patients whose infarct-related artery was not completely occluded at the time of thrombolysis, who would have been excluded from studies utilising three angiograms. In total, the 61
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reocclusion studies comprised 6061 patients [17], and the median time between presentation and the final angiogram was 16 days (range 0.1–365). Reocclusion is most likely to occur within the first 2 weeks, and is more likely if TIMI 3 flow is not restored by thrombolysis. The clinical course of patients with reocclusion is more complicated, and they tend to have reduced left ventricular systolic function. A combination of mechanisms are likely to be involved in the process of reocclusion, but it is clear that platelet activation plays a crucial role. Thrombin– anti-thrombin complex levels are lower in patients with reocclusion after successful thrombolysis for acute myocardial infarction than in those without, suggesting reduced thrombin generation. In contrast platelet aggregation is increased [18], and it is possible that strategies to reduce platelet activity may lower reocclusion rates. Early studies with the direct thrombin inhibitors hirudin and hirulog as adjuvants to thrombolytic therapy have not shown a reduction in re-infarction or mortality [19]. Inhibition of platelet activity using glycoprotein IIb / IIIa antagonists such as abcixmab may prove to be beneficial in this area.
4. Detection of failed thrombolysis In the UK a large proportion (approximately 45%) of cardiologists do not routinely search for evidence of reperfusion, and many units have no established practice for the management of failed thrombolysis [3]. Early coronary angiography to determine epicardial artery flow, together with nuclear medicine perfusion imaging to try to detect no-reflow is probably the ideal combination to assess the success of thrombolysis. These measures are not practical for routine clinical use, and reliable non-invasive markers of reperfusion have not been established.
5. Symptoms The time from the onset of chest pain to treatment with streptokinase, and age are independent predictors of TIMI 3 flow in the infarct-related artery. Many patients experience a dramatic improvement in their symptoms soon after thrombolytic therapy is
7
initiated, but this is also affected by the administration of oxygen and analgesics. In up to 50% of patients chest pain is abruptly stopped by thrombolysis and this is approximately 70% sensitive for reperfusion [20,21]. Ongoing ischaemic chest pain after thrombolysis may be useful indicator of reperfusion when used in conjunction with other markers. However, symptoms lack adequate sensitivity and specificity in themselves to be of value as indicators of failed reperfusion. Clearly patients who develop cardiogenic shock have suffered marked myocardial injury which has not responded to thrombolytic therapy. The prognosis in this group is very poor with 3-month mortality over 90%, and these patients may benefit most from any improvement in perfusion.
6. Electrocardiography The ECG at presentation holds some predictive value as to whether thrombolysis will be successful [22]. TIMI 3 flow is more likely with streptokinase if Q waves are absent (55%) than present (35%), and if there is no T wave inversion (50%) than if T waves are inverted (30%). The magnitude of ST elevation at presentation does not predict the likelihood of successfully achieving TIMI 3 flow with thrombolysis, but does predict clinical outcome [23]. This disparity between infarct-related arterial flow and ST resolution as a marker of morbidity and mortality after thrombolysis may reflect a larger area of ischaemic myocardium and higher rates of no reflow in those with greater ST elevation. The degree of resolution of ST elevation after thrombolysis does appear to be related to outcome, with the predictive value increasing as the time from the start of thrombolysis to repeat ECG lengthens [24]. In the INJECT trial [25] mortality was related to the degree of ST resolution 3 h after the start of thrombolysis. In 1398 German patients, the 35-day mortality was 17.5% with less than 30% resolution of ST segment elevation, 4% with 30–70% resolution and 2.5% with greater than 70% resolution. ST elevation did not resolve in over half the patients in the Zwolle primary angioplasty study [26] in whom TIMI 3 flow was restored in the infarct-related epicardial artery, presumably reflecting higher rates of no-reflow. However, the degree of ST resolution
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was highly predictive of 3-year mortality, with the residual ECG abnormalities reflecting the extent of myocardial injury. The degree of ST segment resolution is a powerful tool in detecting failed thrombolysis, although it is not possible to determine whether the failure has been in the epicardial artery or the microvasculature. And although both the rates of TIMI 3 flow and ST segment resolution relate to prognosis, the relation between the two in an individual patient is difficult to predict. Studies to assess this relationship have used a 25–50% resolution of ST segment elevation in all the leads or the single worst lead together with postthrombolytic coronary angiography [8]. The sensitivity and specificity of ST resolution is increased with longer sampling times, but this leaves less time for actions to salvage viable myocardium. GUSTO I [27] included the largest study of ST segment monitoring in patients with acute myocardial infarction treated with thrombolysis. In 373 patients who had assessment of ST resolution there was up to 82% predictive value for patency and up to 64% for artery occlusion. The predictive value was greatest in those with more than 4 mm of ST elevation, and these patients had the worst prognosis. Although this approach might allow more directed strategies of revascularisation in this high risk group it is still worthy of note that over one-third of those patients with ongoing ST elevation had already achieved unimpaired infarct-related epicardial artery flow, and thus might undergo unnecessary cardiac catheterisation. Clearly there are also significant implications if non-invasive strategies for the management of failed thrombolysis are to be used, as pharmacological treatment aimed at restoring epicardial artery patency may exacerbate myocardial damage in those patients with no-reflow. GUSTO I in addition reinforced the observation that ECG resolution may occur where epicardial artery occlusion persists, and this was evident in approximately a quarter of those with ST resolution. This group of patients may have restoration of myocardial perfusion by recruitment of a collateral circulation, and thus reduced cellular injury. They have a relatively good prognosis and outcome in terms of mortality and left ventricular ejection fraction, and there is no evidence to date that a late restoration of arterial flow by angioplasty in this group improves outcome [8].
Computerised continuous ECG monitoring allows automatic assessment of ST segment changes, but in view of the cyclical ECG changes in evolving myocardial infarction and associated with thrombolysis, it is not clear whether this is superior to ECG recordings at specific times after initiating thrombolysis. The timing of ECGs is a compromise between sensitivity to detect failed thrombolysis and early assessment to allow myocardial salvage to be maximised. A repeat ECG 60–120 min after the start of thrombolysis is a reasonable compromise in view of the current data.
7. Echocardiography Echocardiography can be used to detect regional wall movement abnormalities in acute myocardial infarction, and successful thrombolysis reduces the degree of abnormal wall movement. However, there is little evidence that two-dimensional echocardiography has a place in detecting reperfusion in the period immediately after thrombolysis. Perfusion contrast echocardiography has demonstrated that myocardial reperfusion is absent in over one-third of patients with TIMI 3 flow after thrombolysis [28], reflecting no-reflow. Positron emission tomography has provided similar evidence for microvascular occlusion. Both these techniques are valuable when used in conjunction with coronary angiography, but neither is yet widely available.
8. Biochemical markers Biochemical tests to detect failed thrombolysis fall into two broad groups: those which reflect the degree of myocardial damage, and those relating to thrombus formation or breakdown. Troponin I and T, creatine kinase (CK) isoenzymes, fatty acid binding proteins, and myoglobin all show an early peak concentration when thrombolysis has been successful, limiting the extent of myocardial ischaemia [29–32]. At early angiography, patients with TIMI 3 flow after thrombolysis had a significantly higher CK-MB levels than those with impaired flow or occluded infarct-related artery. These markers do show a high sensitivity and spe-
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cificity, but multiple tests are required and in some cases results have to be incorporated into complex mathematical models. Myoglobin levels show early change, and when studied in conjunction with clinical variables, provide a reliable guide to successful thrombolysis and epicardial artery flow. Bedside tests for troponin and myoglobin are becoming increasingly available. Levels of serum fibrinogen and fibrin are elevated at presentation with acute myocardial infarction, and a fall in serum fibrinogen after initiating treatment reflects systemic fibrinolysis [33]. Lower fibrinogen levels are associated with a higher rate of TIMI 3 flow 90 min after initiating thrombolyis. Fibrin degradation products (FDPs) rise because of lysis of soluble, circulating and solid-state fibrinogen and fibrin. Fibrinolysis in myocardial infarction is used to try to break down solid fibrin which is an integral part of coronary artery thrombosis. Fibrin-specific tag ELISA of cross-linked FDPs or D-dimers provides evidence of solid-state fibrin clot lysis, rather than lysis of circulating soluble fibrin [34,35]. It is also of note that raised D-dimer levels are associated with a higher rate of haemorrhagic complications. Thrombolytic agents act by direct or indirect activation of plasminogen to plasmin, and plasminogen consumption can be measured but levels do not correlate with the success of thrombolysis. Thrombin activity can also be measured by urine levels of fibrinopeptide A, and increased levels predict adverse outcome. However, as with measurements of thrombin–anti-thrombin complexes the relation with reperfusion is less clear. Activation of the system does not reflect artery patency, but may be useful in predicting which patients with other evidence of failed thrombolysis might benefit from further anti-thrombotic therapy. Inter-cellular adhesion molecules play a crucial role in thrombogenesis, including activation of platelets, leucocytes and endothelial cells, allowing cell adhesion. Levels of selectins and integrins are raised in acute coronary syndromes. In a sub-study of 23 patients in GUSTO III raised levels of P-selectin and platelet-endothelial cellular adhesion molecule were observed in five patients with failed thrombolysis [36]. These markers do hold promise as predictors of ongoing thrombogenesis and artery patency, although it is possible that early no-reflow
9
due to platelet microthrombi may also raise selectin levels. There are a number of promising non-invasive markers that might be used in conjunction with serial ECGs to determine whether thrombolysis has failed. A combination of tests which could evaluate both infarct-related artery patency and myocardial perfusion would be the ideal, but further studies are needed to evaluate these relationships. It is possible that repeat ECGs 60–120 min after the start of thrombolysis, coupled with bedside testing for Ddimers and myoglobin will provide a reliable combination which is feasible for use in all units.
9. Management of failed thrombolysis Given the frequency and clinical significance of failed thrombolysis, the evidence for effective management is very limited. In the UK practice varies amongst those who have an active management plan following failed thrombolysis [3]. About half proceed to urgent coronary angiography, of the remainder most repeat thrombolysis with a different agent, and a small number re-administer the same thrombolytic agent. The aim has been to restore epicardial artery patency and flow, but those with failed perfusion because of no-reflow need alternative strategies, possibly with adjuvant therapy to disperse platelet microthrombi (Fig. 1). The TIMI 14 trial [37] has shown the potential benefits of adding a potent antiplatelet agent, the glycoprotein IIb / IIIa inhibitor abciximab, to a thrombolytic agent in acute myocardial infarction. The large GUSTO IV and SPEED studies [38] are further investigating adjuvant anitplatelet therapy use in conjunction with thrombolysis.
10. Rescue angioplasty Rescue refers to angioplasty performed soon after thrombolysis which has failed to restore TIMI 3 flow in the infarct-related artery, aiming to secure myocardial reperfusion. In contrast primary angioplasty is performed immediately in lieu of thrombolysis, and deferred angioplasty is performed late after the acute infarction. There are three randomised trials of rescue PTCA,
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Fig. 1. Thrombogenesis and thrombolysis. Coronary artery thrombus results from the combination of fibrinogen activated to fibrin by the coagulation cascade, and platelet activation, on the surface of fissured atherosclerotic plaques. Thrombolytic drugs act directly or indirectly on plasminogen, activating the endogenous fibrinolytic system. Direct thrombin inhibitors reduce fibrin formation, and anti-platelet agents act to reduce platelet aggregation.
and it is of note that patients with cardiogenic shock are excluded from these as it was felt unethical to withhold angioplasty. Data from GUSTO 1 and other studies involving patients with cardiogenic shock do suggest possible benefit for rescue angioplasty in this setting [39,40]. The RESCUE study [41] randomised 150 patients with failed thrombolysis for their first anterior myocardial infarction to PTCA or conservative management with aspirin, heparin and coronary vasodilators. The 30-day rates for the combined end points of severe heart failure and death were 6 and 17% (P, 0.05) in the PTCA and conservative management groups, respectively. There was a significant difference in exercise ejection fractions, with 43% in the PTCA group and 38% in the conservative group, but no difference in the resting ejection fractions. The TAMI-5 [42,43] study included 295 patients in whom thrombolysis had failed to restore TIMI 3 flow who were randomised to either rescue PTCA or predischarge PTCA. There was no mortality difference, but rescue PTCA gave improved ejection fraction and a reduction in a composite end-point of adverse outcomes compared to pre-discharge PTCA. Meta-
analysis [44] of these two studies and the Belenkie study [45] of 28 patients demonstrates no mortality benefit for rescue PTCA. However, the overall patient numbers are small, and so a potential mortality benefit for rescue PTCA cannot be excluded. There have been problems recruiting patients into randomised trials of rescue PTCA, and some suggestions that participating centres have been reluctant to randomise more ill patients. RESCUE randomised only 150 patients in 20 centres in the USA in 3 years, and the inclusion criteria did not include evidence of ongoing ischaemic chest pain or failure of ST segment resolution. Directing coronary angiography and angioplasty to these selected groups of higher risk patients with evidence of failed reperfusion and ongoing ischaemia may demonstrate a mortality benefit for rescue PTCA. The evidence for rescue PTCA with coronary stenting is limited to case report series [45], and the routine use of glycoprotein IIb / IIIa antagonist platelet aggregation inhibitors is likely to improve outcome in this setting [46]. Laser optical thrombolysis has been used in conjunction with rescue PTCA [47] but its availability is very limited. A retrospective study of emergency surgical revascu-
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larisation after urgent angiography for acute myocardial infarction of 54 patients in Japan suggests a mortality benefit if there is evidence of failed reperfusion following angioplasty, with ongoing ischaemia [48], No randomised studies have evaluated this approach. Intra-aortic balloon pump (IABP) counterpulsation to improve diastolic flow has been used as an adjunct to rescue PTCA, with improvements in infarct-related epicardial artery patency and flow, and left ventricular ejection fraction [49]. A randomised trial of 45 patients with failed alteplase thrombolysis and TIMI 0, 1 or 2 flow in the infarct-related artery, demonstrated a better outcome with IABP without rescue PTCA compared to drug therapy alone [50]. IABP counterpulsation was operated for 48 h, and the rate of TIMI 3 flow at 3 weeks was 74% compared to 32% in the control group. There is good evidence that IABP usage does improve patency rates, but most cardiologists, having demonstrated coronary artery stenosis, in this context, feel obliged to proceed to PTCA, and in current practice IABP counterpulsation is used mainly as an adjunct in complicated cases with hypotension.
11. Repeat thrombolysis The only randomised trial of repeat thrombolysis is of 37 patients who had less than 25% ST resolution in the most elevated lead, 90 min after initiation of streptokinase thrombolysis [51]. Patients were randomised to repeat lysis with tissue type plasminogen activator (rtPA) or placebo, with 43 patients with ST resolution after streptokinase as controls. Rescue thrombolysis gave an ejection fraction of 44% compared to 34% with placebo, but only in those patients with a serum fibrinogen level greater than 1 g / l after streptokinase. This suggests impaired efficacy of the initial treatment with streptokinase, which may be due to structural factors, or raised levels of antistreptokinase antibodies. There is no direct evidence from studies of repeat thrombolysis for failed reperfusion regarding the increased risk of haemorrhage, but this can be estimated from GUSTO-1 [2], in which the co-administration of streptokinase and tPA to patients with acute myocardial infarction raised their risk of intra-cranial haemorrhage to 0.94% from
11
0.49% with streptokinase alone, without any demonstrable mortality benefit. For rescue thrombolysis to be most effective it would have to be targetted at patients who had evidence of failed reperfusion and ongoing ischaemia due to epicardial artery obstruction, rather than microvascular no-reflow, as in the latter situation platelet and thrombin activation associated with thrombolytic agents might exacerbate microcirculation injury. Persistently elevated serum fibrinogen levels do suggest ongoing thrombogenesis, but as an acute phase reactant it is not specific enough to be used alone. If used together with other biochemical markers such as low D-dimers and raised levels of selectins and integrins, it may be possible to develop a relatively simple model to establish which patients may benefit most from rescue thrombolysis.
12. Alternative pharmacological approaches Adjuvant therapy to reduce the effects of thrombin released from within a fibrin clot by thrombolytic agents with the direct anti-thrombin agents hirudin, hirulog and similar synthetic compounds has proven promising. The HERO study [52] randomised patients to heparin, low- or high-dose hirulog in addition to standard therapy with aspirin and streptokinase in 412 patients with acute myocardial infarction. Low-dose hirulog gave TIMI 3 flow at 90 min in 46%, compared to 35% with heparin, and hirulog had a markedly lower rate of haemorrhagic complications. The OASIS-2 study [53] found similar benefits in 10 141 patients with unstable angina or myocardial infarction without ST elevation using hirudin, and further studies by the HIT investigators have tried to optimise dosing [19]. GUSTO IIb [54] concluded that hirudin was of benefit as an adjunct to streptokinase, but not with tPA. The place of these direct thrombin inhibitors in failed thrombolysis has not been investigated, but they may improve outcome in those patients with evidence of failed reperfusion and arterial occlusion with biochemical evidence of active thrombogenesis. Anti-platelet therapy with glycoprotein IIb / IIIa inhibitors is now well established in reducing subacute reocclusion after coronary artery stenting in addition to aspirin. Abciximab, the Fab fragment of
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monoclonal antibody to glycoprotein IIb / IIIa, was used in the TIMI 14 trial [37] with various combinations of thrombolytics. TIMI 3 flow rates at 60 min with rtPA were 43%, but increased to 72% with abciximab and rtPA; and 62 and 77%, respectively, at 90 min. There was a small benefit in patency rates using abciximab with streptokinase, but this was offset by a higher rate of haemorrhagic complications. Cost limitations have prevented abcixmab from entering routine clinical practice. Further research is needed to establish whether it has a place in the treatment of failed thrombolysis due to early noreflow caused by platelet micro-thrombi. Oral glycoprotein IIb / IIIa inhibitors including clopidogrel and ticlopidine have no proven benefit in acute myocardial infarction, but further studies are required to evaluate these agents in combination with thrombolysis and in the management of failed reperfusion due to microvascular occlusion.
13. Conclusion At present in the UK we take only limited measures to detect failed thrombolysis for acute myocardial infarction. Unfortunately, at present there are no readily available, easy to use methods for detecting the occurrence and mode of thrombolytic failure, and it has become clear that as well as unimpaired flow in the infarct-related epicardial artery, the microcirculation in the myocardium subtended by that vessel must be in tact to allow reperfusion. Further work is needed to develop reliable indicators for failed thrombolysis which can be utilised widely. Methods for treating failed thrombolysis are unresolved. The roles of angioplasty, stenting, repeat thrombolysis and adjuvant therapy with anti-platelet and anti-thrombin agents have not yet been defined. However, further studies will be required in this area to establish the most effective therapy for those patients with acute myocardial infarction who have not achieved adequate reperfusion with thrombolysis, and consequently have a markedly higher morbidity and mortality. Studies including the REACT trial are ongoing which are exploring the most beneficial strategy for this patient group. The REACT trial will study patients who fail to achieve 50% resolution of ST elevation following thrombolysis for acute myocar-
dial infarction, and they will be randomised to conservative therapy with heparin, or repeat thrombolysis, or coronary angiography, and if appropriate angioplasty, at the local interventional centre. A suggested policy on the basis of the limited data available currently would advocate routine use of a repeat ECG 60–90 min after the initiation of thrombolysis to assess ST resolution. In those with failure of ST segment elevation to resolve by 25%, particularly in the context of an anterior, right ventricular, or second myocardial infarction at a site different from the first, an urgent measurement of serum fibrinogen should be carried out. If the fibrinogen level is greater than 1 g / l then accelerated regime tissue plasminogen activator thrombolysis should be administered. For those with fibrinogen levels less than 1 g / l either intra-aortic balloon pump support or an intra-venous glycoprotein IIb / IIIa antagonist, such as abciximab, should be administered. In those patients with less than TIMI 3 flow in the infarctrelated artery after failed thrombolysis, 48 h of IABP counterpulsation may be of benefit. Although the evidence is limited at present, in interventional centres, we would advise early angiography and PTCA in those who fail to show ST segment resolution.
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