Tissue perfusion

The ideal method of diagnosing failure of thrombolytic treatment would be some test of myocardial perfusion. Possibilities include positron emission tomography and contrast echocardiography. Although they have been used to demonstrate the inadequacies of thrombolysis as well as its angiographic analysis, they have not been used prospectively in studies of diagnostic power. In addition, they require equipment or training that is not commonly available.

Angiographic flow

Although angiography has been considered by many to be the gold standard for diagnosis, it has major limitations. The act of angiography itself can influence the efficacy of thrombolytic agents, opening up some occluded vessels.10 Although the TIMI flow rate is the established method of analysis, this does not actually measure tissue perfusion. However, until techniques for measuring the latter are perfected, this will probably remain the methodology used for analysing new reperfusion strategies.

Electrocardiographic techniques

Many ECG criteria have been examined. These include the ratio of the height of maximum ST elevation before and after treatment (usually measured 80 ms after the J point), the ratio of sums of ST segment elevation and/or depression, and the height of the T wave. There are few prospective studies where the ECG has been analysed at predetermined times following thrombolytic treatment with respect to the results of angiography. The criterion that appears to be most established is failure of the elevated ST segment (measured 80 ms after the J point in the lead of the 12 lead ECG with maximal ST elevation at baseline) to fall by 50% or more (figs 1 and 2). If measured two hours after the start of thrombolysis the diagnostic accuracy is about 80–85% for failure to achieve TIMI 3 flow.10 This means that 15% of patients will, however, be wrongly classified. Some patients will have a fall in ST elevation but the vessel remains occluded (false negative for failed thrombolysis). It has been demonstrated, however, that those who have early ST falls are in a good prognostic group, and so it is possible that those who fail to achieve patency are protected in some way (possibly by collaterals). If the 12 lead ECG is used, an ECG recorded at 60 minutes after onset of thrombolysis identifies a high risk group with as much accuracy as one recorded at 90 and 180 minutes.9

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

ECG diagnosis of successful thrombolysis. The baseline ECG before thrombolytic treatment shows significant ST elevation in the anterior leads, with maximal ST elevation of 7 mm in lead V3 80 ms after the J point (A). Two hours after the start of thrombolysis with streptokinase, the ST segments have reduced (B). Although the ST elevation in C3 is 2–3 mm, the fall in ST elevation from baseline is greater than 50% of the initial elevation. The patient was shown at angiography to have TIMI 3 flow in the left anterior descending artery (the infarct related vessel).        

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

ECG diagnosis of failed thrombolysis. The pre-thrombolysis ECG shows significant ST elevation, maximal at just over 4 mm in lead V3 (A). Two hours after the start of thrombolysis, there is no change in the ST elevation in this lead (B). The patient was shown to have an occluded left anterior descending artery at angiography just after the ECG was taken.

 Continuous ST monitoring using a varying number of ECG leads has been studied by several groups. This technique has revealed the very dynamic nature of the reperfusion process. ST segment monitoring is attractive in concept as this provides a means of assessing peak ST elevation, rather than its baseline level just before treatment starts. This could improve accuracy, but additional equipment is necessary and results must be available on-line for meaningful clinical use. ST segment and QRS vector analysis are other methods under evaluation but are not in routine clinical use.

Reperfusion arrhythmias are well recognised but are very insensitive for prediction of reperfusion. The early and frequent appearance of automatic idioventricular rhythm is perhaps the most useful marker of reperfusion and the absence of this rhythm can be incorporated as one of several criteria to help make the diagnosis of failed reperfusion.10

Biochemical markers

Measurement of cardiac enzyme release has become an integral part of the retrospective diagnosis of myocardial infarction, and the peak concentrations are useful in the process of risk stratification. In general, though, they have not proved very useful for immediate decision making in the management of acute myocardial infarction. Although enzyme concentrations can now be measured rapidly, a single measurement is not useful and even sequential measurements are difficult to interpret as the shape of the release curve relates to the time from onset of infarction (which is very variable) and, of course, to the thrombolytic agent used.

Early peaking of creatine kinase or its isoforms is seen with reperfusion (the “washout” phenomenon), but the time course is such that its identification occurs too late to add a second treatment, and there is considerable overlap with non-reperfused patients. Moreover, its assessment needs multiple blood tests and rapid delivery of laboratory results. More productive research has aimed at investigating the concentrations of enzymes and the rate of change of plasma enzyme concentrations in the first two hours or so, making use of the fact that those patients who reperfuse have a much earlier and a higher peak than those who do not. Early studies investigated creatinine kinase isoforms but predictive accuracy was disappointing. More recently, attention has turned to the use of myoglobin or troponin (T or I) concentrations.4 These proteins can be identified earlier and the hope has been that their measurement would lead to greater accuracy in assessing the efficacy of thrombolysis. This has not yet proved to be the case and they are unlikely to be used on a widespread basis until studies comparing their predictive accuracy with ECG markers are performed.

Repeat thrombolysis

Although further thrombolysis can be offered successfully to those who reinfarct after initial reperfusion, there has been only one study of a strategy of repeat thrombolysis for failure of initial treatment.11 The Newcastle protocol was to record a 12 lead ECG 90 minutes after streptokinase. Failure of the baseline ST elevation to fall by 25% or more in the lead showing the greatest elevation was used to define failed reperfusion. These patients were randomised to receive either standard dose alteplase or placebo. Improved left ventricular function was seen in the treatment group, but only in those with failed fibrinogenolysis, defined as a 60 minute fibrinogen level > 1 g/l. This small study (37 patients) was not powered to look at survival benefits, nor for an adequate analysis of bleeding risks (it should be remembered that the combined thrombolytic arm of GUSTO-I doubled the risk of haemorrhagic cerebral events). At this stage, this study cannot be used to support a widespread use of this strategy.

Rescue angioplasty

The literature on rescue angioplasty is dominated by observational series and the few randomised studies have been on relatively small groups of patients.12-15 Current knowledge of rescue angioplasty can be summarised as follows:

(1)

transferring patients from community hospitals to revascularisation centres in the setting of acute myocardial infarction is associated with an acceptably low risk;

(2)

unless delivered very early after thrombolysis, rescue angioplasty is less likely to achieve patency compared to primary angioplasty (80–90% v 90–95%) and less likely to achieve TIMI-3 flow; moreover, reocclusion rates with standard balloon angioplasty are higher in this setting (15–30%) than after primary angioplasty (5–15%);

(3)

rescue angioplasty is applied later than primary angioplasty (because of the time taken for thrombolytic treatment to be administered and the additional delay until the diagnosis of failed thrombolysis is made);

(4)

by definition, rescue angioplasty is associated with the downside of the thrombolytic agent initially administered (allergy, hypotension, and haemorrhage);

(5)

although patients with successful rescue angioplasty do relatively well (in-hospital mortality between 5–10%), failed rescue is associated with a high mortality (25–40%)—overall, the mortality of the entire cohort undergoing rescue angioplasty is higher than the mortality associated with primary angioplasty (probably because the treatments are offered to patients with different risk profiles, but an early hazard associated with rescue angioplasty cannot be excluded).

The latter possibility is suggested particularly from data obtained in the GUSTO-1 angiographic substudy, in which rescue angioplasty was a prespecified end point. Operators performing angiography at 90 or 180 minutes were permitted but not required to perform rescue angioplasty if the vessel was occluded. The overall mortality for the whole rescue group was actually 11.1% (8.6% for successful rescue, 30% for failed rescue), which was higher than the 7.9% for the lytic failure, no rescue group. Although this may simply have represented a higher risk group, it is suggestive that rescue angioplasty may be associated with early harm in some patients.16

The most favourable data come from the TAMI phase 5 and the RESCUE studies. In both, angioplasty was targeted at those with failed thrombolysis, although randomisation to rescue angioplasty or conservative treatment was performed only in the RESCUE study (fig 4). Other smaller studies have not shown consistent results with some suggesting a worse outcome for patients treated with a strategy of early invasive assessment with a view to rescue angioplasty.

• Download figure
• Open in new tab
• Download powerpoint

Figure 4

Results from three studies of rescue angioplasty: *TAMI-5¹²; **RESCUE¹³; ***Vermeer et al.14 Combined end points: TAMI-5—death, stroke, reinfarction, reocclusion, heart failure or recurrent ischaemia during hospitalisation (rescue v conservative, p = 0.004); RESCUE—death or congestive failure at 30 days (rescue v conservative, p = 0.05); Vermeer et al—death or recurrent infarction within 42 days (comparison between groups, p = NS).

Considerable gaps in our knowledge concerning rescue angioplasty can be summarised as follows.

• The risk:benefit ratio of rescue strategies for allcomers is still unknown. The overall benefits of this strategy are currently being evaluated in the UK in the REACT and the MERLIN trial. The REACT trial has three arms: (1) thrombolysis with rescue angioplasty being offered to those with ECG evidence of failed thrombolysis; (2) thrombolysis with continuing standard conservative care; and (3) thrombolysis with repeat thrombolysis with reteplase offered to those in whom the first lytic agent fails. The MERLIN study compares a rescue angioplasty arm with a conservative care arm.

• As discussed above, the optimal timing for a diagnosis of “failed reperfusion” after initial thrombolysis is unknown. Current trials may not answer this question.

• The risks and benefits of various adjuncts to rescue angioplasty (stenting, intra-aortic balloon counterpulsation, glycoprotein IIb/IIIa receptor blockers, and embolisation protection devices) are unclear.

• The management of patients with TIMI 3 flow at angiography post-thrombolysis is not clear. We have shown that those with a very tight residual stenosis (> 85%) are highly likely to require urgent re-intervention during the recovery period, suggesting that these patients should be offered early intervention, but that those with residual stenoses < 85% (and certainly those with < 75%) do not need immediate intervention.17

• Patients with TIMI 2 flow at angiography post-thrombolysis present a particularly difficult problem. Some might have reduced flow because of a tight residual stenosis, but many have no significant residual obstructive lesion. The slow-flow phenomenon is probably associated with problems in the distal vasculature. Some of these may subsequently improve to TIMI 3 flow but others may subsequently reocclude. Whether the various factors that contribute to distal problems can be overcome is unknown. Although local vasodilator agents might help, mechanical devices are unlikely to reverse embolisation that has already occurred, and may even lead to further embolisation.

• The duration of follow up needed to demonstrate benefit is unclear. Early risks may be acceptable if the benefits later are evident and sustained. Longer term follow up may be necessary to demonstrate the efficacy of treatment (fig 3). It is possible that any benefit of rescue angioplasty will remain hidden if follow up to only 4–6 weeks or even six months is considered. The timing of crossover from potential harm to potential benefit is unknown.

Coronary artery bypass grafting

There are no randomised trials of surgery in this context, nor are there likely to be. Angioplasty is less risky and easier to deliver. The concept of major surgery in the face of active thrombolysis or combined thrombolytic/antiplatelet treatment is clearly undesirable. Surgery, if indicated, should be delayed as much as possible. Given the lack of knowledge in this setting, the only comments to be made are based on common sense and experience.

In the face of left main stem disease or multivessel disease unsuited to total revascularisation by angioplasty, the culprit artery should be treated where possible, allowing stabilisation and delayed surgery when the risks are much lower. For multivessel disease suited to angioplasty, most operators stabilise the patient by treating the culprit vessel acutely and then deal with other lesions electively at a later date. Where anatomy precludes any attempt at angioplasty, then augmentation of the thrombolytic agent with intra-aortic balloon pumping and possibly with glycoprotein IIb/IIIa agents should be considered and surgery contemplated when bleeding risks have minimised.

Improve vessel patency with new lytic regimens

A number of approaches are under evaluation. New thrombolytics (reteplase, saruplase, TNK-tissue plasminogen activator, and lanoteplase) have either been introduced into the clinical arena or are under investigation. Results to date, however, do not show a clear advantage over the most commonly used agents. Combinations of different thrombolytics, or combinations of lytics with antithrombotic treatments, have also been studied, but the most promising results have been seen with low dose thrombolytics and glycoprotein IIb/IIIa inhibitors.18 Further trials are underway. The efficacy of thrombolytics can also be enhanced by intra-aortic balloon pumping, but it is not clear whether this could be easily utilised as a routine in all coronary care units.19

Early thrombolysis and angiography for all, with selected rescue angioplasty

In the past, immediate balloon angioplasty for all patients treated with thrombolytics was not shown to be beneficial and there was a suggestion of early harm. However, these studies can be criticised in a number of ways. First, angioplasty was sometimes delivered relatively late after the onset of chest pain. Some patients did not receive antiplatelet treatment in the early stages. Stenting and glycoprotein IIb/IIIa inhibitors were not available, and there was minimal use of intra-aortic balloon pumping. Angioplasty was also performed on patients with patent vessels and good flow, a group who, in retrospect, almost certainly did not benefit from the strategy. However, this approach is currently undergoing reappraisal with earlier (pre-hospital) thrombolysis, early angiography, and rescue angioplasty only where necessary but not as a routine.20 ,21 Early results of this approach are encouraging and suggest that a combination of thrombolysis and appropriate rescue angioplasty may achieve a reduction in mortality after myocardial infarction close to that achievable with primary angioplasty, and clearly offers the potential of increasing the number of patients who might achieve successful reperfusion without having to increase dramatically the facilities for angioplasty. Randomised trials of this strategy versus primary angioplasty are warranted.

Current management

A number of guidelines are suggested to aid the management of patients in whom thrombolytic treatment is deemed unsuccessful.

(1)

Make the diagnosis only if it will alter management. You cannot be criticised for considering no action with the current state of knowledge, but there probably is some benefit for rescue angioplasty if offered early enough, especially for first time anterior infarction.

(2)

Have a policy concerning the timing of the diagnosis. This may need to change as new information becomes available. Treatment considered and offered on an ad hoc basis is not likely to offer patients a good deal.

(3)

If rescue angioplasty is chosen, ensure that the management protocol is shared by both those administering the thrombolytic agents as well as those providing angioplasty.

(4)

If repeat thrombolysis is considered, monitor the results. More information is needed about the efficacy of this strategy and its associated bleeding risks. It is probably NOT appropriate to use repeat thrombolysis and then to ask for rescue angioplasty when that fails. As further time will have passed and with less myocardium to salvage, rescue angioplasty will probably not carry much benefit. Choose repeat thrombolysis or rescue angioplasty—but not both.

(5)

If rescue angioplasty is considered, accept its limitations and the uncertainties outlined above. If used, measures should be taken to minimise time of transfer and “door-to-balloon” times—measurement of both should be monitored in an audit process. Transfer for rescue angioplasty from one hospital to another is associated with an acceptably low risk.

(6)

Patients who are more than 8–12 hours into an infarct are unlikely to gain much benefit from a rescue strategy. It is likely (but not proved) that efficacy and cost efficacy of a rescue angioplasty service will be greatest if the rescue angioplasty is offered early.

(7)

Enroll patients into trials whenever possible as further information on this common but difficult question is urgently needed.

(8)

Widening the scope for intervention in acute myocardial infarction will certainly increase the number of patients achieving TIMI 3 flow. It is likely, but not yet proved, that this will reduce mortality.