Clinical implications of ST-segment non-resolution after thrombolysis for myocardial infarction

Abstract

Failed reperfusion after thrombolytic therapy for acute myocardial infarction is common and signifies a poor prognosis. We investigated the clinical consequences of non-resolution of the ST segment after thrombolytic therapy for acute ST-elevation myocardial infarction, in 85 consecutive patients admitted to a coronary care unit lacking rapid access to angioplasty. Failed thrombolysis was defined as <50% ST-segment resolution 180 minutes after the start of thrombolytic treatment. Outcomes were measured in terms of in-hospital adverse events, length of hospital stay, and mortality at 6 weeks and 1 year.

Thrombolysis was successful, in terms of ST-segment resolution, in 45 patients (53%). After adjustment for other factors, ST resolution was the only independent predictor of an uncomplicated recovery in hospital (odds ratio 6.8, 95% confidence interval 2.3 to 19.9; P<0.001). At 6 weeks and 1 year, overall mortality was lower in the ST resolution group, though these differences became non-significant on multivariate analysis. In patients who survived to hospital discharge, median length of stay was greater in successfully thrombolysed patients (9 days versus 8 days) despite their lower rate of complications.

ST-segment resolution is a useful marker of successful thrombolysis and relates to clinical outcome. If assessed routinely it might assist, along with other clinical markers, in the identification of low-risk patients who can be discharged early.

INTRODUCTION

Thrombolytic therapy for acute myocardial infarction reduces case fatality and improves clinical outcomes.^1,2 However, in up to 60% of patients the treatment does not restore perfusion in the myocardium at risk³ and such failure indicates a worse prognosis.⁴ In the past, reperfusion was commonly assessed in terms of coronary blood flow, achievement of TIMI 3 flow being a favourable sign;⁵ however, this angiographic index is not a reliable indicator of myocardial reperfusion, which is prognostically more relevant than coronary reperfusion.^6,7 By contrast, ST-segment resolution 90–180 minutes after thrombolysis is an excellent marker of successful myocardial reperfusion⁸ and a strong predictor of survival and preservation of left ventricular function.^9–11 In the UK this simple bedside tool tends to be neglected as an indicator of prognosis or guide to further management.¹² Decisions on matters such as length of hospital stay and selection for angiography or treadmill investigation are determined mainly by in-hospital clinical events or age.¹³ Currently in the UK, most district general hospitals lack rapid access to angioplasty and must rely solely on thrombolytic therapy in the first instance. In an observational study of unselected patients we investigated the short-term and long-term implications of ST-segment non-resolution after thrombolytic therapy.

METHODS

Patients

In the course of seven months, 104 consecutive patients received thrombolytic therapy for suspected ST-elevation myocardial infarction, in the coronary care unit of a district general hospital that lacked rapid access to coronary angioplasty. All had a history of typical precordial pain at rest lasting >20 minutes as well as ST elevation in two or more contiguous leads on a standard 12-lead electrocardiogram (0.1 mV limb leads, 0.2 mV precordial leads) or left bundle branch block. Conventional contraindications to thrombolysis were observed and streptokinase or alteplase was administered according to local guidelines. Creatine kinase and troponin-I were measured 12 hours after admission and our final analysis was confined to patients who showed an increase in creatine kinase to twice the upper limit of normal and an increase in troponin-I (>99% centile). 13 patients were excluded on this basis.

Electrocardiographic analysis

A baseline 12-lead electrocardiogram was recorded before initiation of thrombolysis and at 90 and 180 minutes thereafter. The lead with maximum ST segment elevation in the initial record was used for comparison. ST segments were measured by caliper at 60 ms beyond the J-point, retrospectively by a single independent observer blinded to clinical outcomes. Anterior infarction was recorded when maximum ST elevation involved leads V1–V4. Successful thrombolysis was taken as >50% resolution of the worst ST segment at 180 minutes. If the 180-minute electrocardiogram was not available (for example, because of earlier death), then the 90-minute record was used (8% of analysed patients). A further 6 patients with left bundle branch block were excluded, leaving 85 patients for the final analysis.

Data collection

Clinical details were recorded prospectively. In-hospital major adverse events were defined as the occurrence of any of the following: death, reinfarction (defined as two out of three of chest pain, further ST elevation or further cardiac enzyme increase), stroke, cardiogenic shock, hypotension (systolic <90 mmHg), Killip class II–IV, recurrent angina or ischaemia, significant arrhythmias or major bleeds. Adverse events were divided according to timing—days 1–3 (i.e. <72 h) and days 4–7. An uncomplicated course was defined as no major adverse event during the entire inpatient stay.

Out-of-hospital clinical outcomes at 6 weeks were all-cause mortality and morbidity (reinfarction, stroke or cardiac readmission without enzyme rise), determined at routine clinic visit, by review of the case notes or by contact with the general practitioner. At 1 year, only mortality was assessed. Follow-up was complete in all patients included in the final analysis.

Statistical analysis

For statistical analysis we used SPSS 11.5 for Windows. Differences between groups were evaluated by χ² and Fisher's exact test for categorical variables and by unpaired Student's t test for continuous variables. Spearman's rank correlation analysis was used to investigate the relation between non-parametric variables. Multivariate logistic regression was used to test associations between pre-determined variables and outcomes. Values were specified as probability values (P) or odds ratio (OR) with 95% confidence intervals (CI). A P value of <0.05 was taken as significant.

RESULTS

Of the 85 patients included in the analysis, 45 (53%) showed ST-segment resolution. Table 1 summarizes the ST-segment results in relation to baseline characteristics. In a multivariate analysis, the only difference that approached significance was pain to needle time (P=0.06). Age was not an independent predictor of ST-segment non-resolution.

Table 1.

Patient characteristics in relation to ST-segment resolution (success) and non-resolution (failed)

	Success (n=45)	Failed (n=40)	P
Age in years (SD)	62.7 (12.9)	70.3 (12.5)	0.007
Male	31 (69%)	24 (60%)	0.50
Smoker	20 (44%)	14 (35%)	0.51
Diabetes	8 (18%)	12 (30%)	0.21
Hypertension	22 (49%)	19 (42%)	1.0
Hypercholesterolaemia	21 (47%)	14 (35%)	0.38
Peripheral vascular disease	3 (7%)	9 (23%)	0.04
Previous angina	12 (27%)	9 (23%)	0.43
Previous myocardial infarction	7 (16%)	6 (15%)	0.59
Previous revascularization	2 (4%)	4 (10%)	0.28
Median pain to needle time min (25th and 75th percentiles)	163 (105,290)	199 (134,561)	0.04
Anterior infarct	14 (31%)	21 (53%)	0.04
Heart rate/min (SD)	80 (19)	70 (21)	0.80
Systolic pressure mmHg (SD)	144 (27)	146 (30)	0.74
Peak creatine kinase IU/L (SD)	1753 (1180)	1827 (1402)	0.81
Streptokinase administered	27 (50%)	27 (50%)	0.51
Alteplase administered	18 (58%)	13 (42%)	0.50

Figure 1 shows the difference in adverse events between the groups with successful and unsuccessful thrombolysis. The patients with ST-segment non-resolution had more than twice the rate of adverse events during the first 72 hours. The most striking difference was in the proportions of patients who had an uncomplicated in-hospital stay— 62% of the ST-resolution group compared with 17% of the non-resolution group (P<0.001).

Figure 1.

Difference in inpatient adverse event rate between successful and failed ST segment resolution following thrombolysis. □ successful; ▪ failed

Another important finding was that, irrespective of the electrocardiographic outcome of thrombolytic therapy, late (day 4–7) inpatient adverse events were always preceded by early (day 1–3) events; in other words, any patient who did not experience an early adverse event remained event-free throughout his or her in-hospital stay.

In a multivariate analysis including age, pain to needle time, diabetes and previous myocardial infarction, only ST resolution proved to be a significant predictor of an uncomplicated recovery throughout the hospital stay (adjusted OR 6.8, 95% CI 2.3 to 19.9, P<0.001).

Length of stay was calculated only in patients who survived to hospital discharge, and we excluded any inpatient transfers to our tertiary centre. Any 'social' days (i.e. awaiting placements or social work-up) which delayed discharge were also omitted from the analysis. With these exclusions, overall median length of hospital stay was one day greater in the successfully thrombolysed group (9 days versus 8 days).

At 6 weeks, 13 (15%) of the entire cohort had died, 12 of whom were from the failed thrombolysis group. Table 2 shows the predictors of 6-week mortality, of which only pain to needle time was significant on multivariate analysis (adjusted OR 0.996, 95% CI 0.993 to 0.999, P=0.02); ST non-resolution was just short of statistical significance (adjusted OR 0.12, 95% CI 0.12 to 1.28, P=0.07). There was no significant difference in 6-week morbidity after hospital discharge, with 3 (7%) successful compared with 4 (10%) failed cases experiencing the combined endpoint of reinfarction (2), stroke (0) or cardiac readmission (5).

Table 2.

Predictors of 6-week mortality

	Univariate P	Multivariate P
Age	<0.001	0.11
Female gender	0.006	0.36
Anterior infarction	0.026	0.35
Time to treatment	0.003	0.02
ST non-resolution	<0.001	0.07

Overall, the number of deaths at 1 year was 15 (18%), 13 from the ST-non-resolution group. In a multivariate analysis, age was the only significant predictor of 1-year mortality (adjusted OR 0.89, 95% CI 0.80 to 0.99, P=0.03); pain to needle time (P=0.08) and ST resolution (P=0.10) showed only a trend.

DISCUSSION

This study highlights the poor clinical outcome of patients with ST-segment non-resolution after thrombolytic treatment, indicated by simple evaluation of the post-thrombolysis electrocardiogram. In this series from a district general hospital, ST resolution was the only independent predictor of an event-free recovery in hospital. Although previous studies have demonstrated that older age, female gender and cardiac risk factors such as diabetes and hypertension are associated with an increase in inpatient cardiac events after a myocardial infarction,^14,15 these studies did not incorporate differences in ST-segment resolution after thrombolysis.

The average length of stay in our hospital for all patients was 8 days, which is comparable with the UK national average of 9 days.¹⁶ However, an unexpected finding was that patients with successful thrombolysis spent one day longer in hospital compared to failed cases, which is well over the current European Society of Cardiology recommendations of 4 to 5 days¹⁷ for patients with uncomplicated infarction. We did not investigate the reasons for the discrepant finding in our series, but it could have been related to lack of senior staff on certain days or weekends to sanction early discharge.¹⁸

Some limitations of the study should be mentioned here. First, the ST segment after acute myocardial infarction is dynamic, and our use of static measurements could have led to errors in labelling of patients as successful or failed reperfusion. Our aim, however, was to obtain results relevant to typical coronary care units across the UK, few of which can monitor the ST segment continuously in every patient. Secondly, the small size of our sample increases the likelihood of type 1 or 2 errors. Moreover, the results do not translate to patients with bundle branch block or other electrocardiographic features where ST segment resolution cannot be determined.

What are the practical implications of our findings? The most obvious is the potential utility of ST-segment resolution for deciding which patients can safely be discharged early. Not only did the patients with ST resolution have a 3 to 4-fold greater rate of uncomplicated recovery than those with non-resolution; we also observed that, irrespective of ST-resolution outcome, patients who did not experience an adverse event in the first 72 hours after admission remained event-free subsequently while in hospital. Previous workers have likewise shown that most of the adverse events after myocardial infarction occur in the first 48–72 hours.¹⁹ Combination of these observations— ST resolution as a predictor of clinical outcome, coupled with freedom from complications early in the hospital stay—might allow safe discharge as early as 3–4 days.²⁰ In our study, exactly one-third of the patients would have come into this category, potentially translating into large savings in cost and bed space, to say nothing of improved patient satisfaction. However, this strategy should ideally be assessed in a large prospective trial.

What can be said of the patients in whom thrombolysis fails to restore myocardial reperfusion? The current management options are repeat thrombolysis, rescue angioplasty and stenting, and use of glycoprotein IIb/IIIa inhibitors. Regarding repeat thrombolysis, we are short of evidence. In 37 patients with ST-segment non-resolution 90 minutes after streptokinase, Mounsey et al.²¹ compared alteplase with placebo and found it better in terms of infarct sizes and left ventricular function; however, benefit was seen only in patients who had failed to reach a lytic state with high plasma fibrinogen levels after initial streptokinase. In patients with failed thrombolysis and cardiogenic shock, there is substantial evidence in favour of rescue percutaneous coronary intervention.^22,23 It is the more clinically stable group, with failed thrombolysis but no ongoing ischaemic symptoms, in whom subsequent management is more debatable. In older trials a rescue strategy seemed no better than conservative treatment in terms of subsequent death.²⁴ Hopes were then pinned on stents and glycoprotein IIb/IIIa inhibitors, but the recently published MERLIN trial,²⁵ in which 307 patients with failed thrombolysis (based on ST non-resolution) were randomized to percutaneous coronary intervention or conservative treatment, showed no advantage for the rescue therapy in terms of either 30-day mortality or left ventricular function. Furthermore, rescue therapy was associated with more strokes and major haemorrhage; the only benefit was a reduction in subsequent revascularization. Therefore, rescue percutaneous coronary intervention cannot be recommended as routine treatment after failed thrombolysis. Regarding glycoprotein IIb/IIIa inhibitors, the major drawback of these agents is the risk of bleeding complications.^26,27 Although in combination with thrombolytics they give better reperfusion than thrombolytics alone,²⁸ this does not seem to translate into mortality benefit.^29,30 Thus at present there is no obvious way to improve clinical outcomes after failed thrombolysis.

From this study we conclude that routine evaluation of ST-segment resolution after thrombolysis for myocardial infarction, coupled with other clinical markers, might facilitate selection of patients who can safely be discharged early.