Thrombolysis Followed by Coronary Angiography Versus Primary Percutaneous Coronary Intervention in Non-Anterior ST-Elevation Myocardial Infarction

Abstract: Background. Previous studies demonstrated the superiority of primary percutaneous coronary intervention (PCI) over thrombolysis for treatment of ST-elevation myocardial infarction (STEMI); however, this advantage is less evident in low-risk populations. The aim of this study was to assess whether a strategy of thrombolysis followed by routine coronary angiography in patients with non-anterior STEMI is non-inferior to primary PCI. Methods. Consecutive patients with non-anterior STEMI presenting within 6 hours of symptom onset who received reperfusion treatment were included. Mortality, infarct size, and in-hospital and long-term major adverse events were compared between patients treated with primary PCI to those who received thrombolysis followed by coronary angiography and intervention as needed. Results. A total of 300 patients were included: 180 who received thrombolysis and 120 treated with primary PCI. No significant differences were found in mortality, infarct size, or long-term adverse events between groups. Higher rates of in-hospital recurrent ischemic events and longer hospitalization were noted in the thrombolysis group. Conclusions. The strategy of thrombolysis followed by routine coronary angiography in non-anterior STEMI patients results in major outcomes similar to primary PCI. Thrombolysis serves as a viable approach for patients presenting with non-anterior STEMI to hospitals without catheterization facilities. The optimal time between thrombolysis and coronary angiography should be within 2 days to avoid recurrent ischemia. 

J INVASIVE CARDIOL 2013;25:632–636

Key words: ST-elevation MI, primary PCI, thrombolysis

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Early reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) has been shown to limit myocardial damage and improve clinical outcomes.¹ Previous studies have shown that treatment with primary percutaneous intervention (PCI) improves clinical outcomes when compared with intravenous thrombolysis.^2-7 However, the efficacy of treatment with PCI is time dependent, and any delay in treatment leads to a significant decline in myocardial salvage and loss of the relative superiority of this treatment over thrombolysis.^8-10 This time dependency, along with a shortage of catheterization labs, has limited the use of primary PCI to less than 50% of patients worldwide.^11-13

Appropriate treatment of STEMI patients presenting to centers lacking the ability to perform primary PCI remains controversial. Recent studies have shown that a strategy of acutely transferring patients for primary PCI is superior to thrombolytic therapy, provided that the patients can be transferred and treated with PCI in no more than 2 hours.¹⁴ However, patients treated with thrombolysis in these studies did not undergo routine coronary angiography and revascularization,^4,14,15 as is currently recommended. On the other hand, another study showed that performing thrombolysis in centers lacking catheterization facilities followed by transfer for PCI is as safe as primary PCI in preserving cardiac function and provides earlier and more effective coronary perfusion.¹⁶

The superiority of PCI over thrombolysis has been shown mostly in high-risk patients (patients with large anterior MI or who are in shock), but is less evident in low-risk patients.^5,17,18 Nevertheless, the current guidelines do not differentiate between high- and low-risk STEMI patients with regard to the recommended treatment, even in centers lacking catheterization facilities. Only three studies have directly compared thrombolysis to primary PCI in low-risk patients.^19-21 Two of these studies demonstrated a benefit of PCI over thrombolysis; however, angiography was performed routinely after thrombolysis in only one study. A meta-analysis published recently by de Boer et al has shown that primary PCI is consistently associated with a relative reduction in 30-day mortality irrespective of patient baseline risk; however, the benefit was relatively small in low-risk patients and the authors concluded that thrombolysis remains a legitimate option in low-risk patients because of the small absolute risk reduction achievable by primary PCI.²²

Our institution comprises two hospitals, a tertiary center with catheterization facility in which all STEMI patients undergo primary PCI, and a primary-care hospital without a catheterization laboratory in which patients requiring coronary angiography are transferred to the PCI center. Since door-to-balloon time for STEMI patients arriving to the primary hospital is greater than 90 minutes in many cases due to transfer delays, the treatment policy of STEMI patients in this hospital was to transfer high-risk patients (anterior MI and unstable patients) and late arrivals (>6 hours from symptom onset) to the tertiary center for primary PCI, whereas stable patients with non-anterior STEMI were treated with thrombolysis. The objective of this study was to assess whether a reperfusion strategy of immediate thrombolysis followed by routine transfer for catheterization in the following days is non-inferior to primary PCI in stable non-anterior STEMI patients. 

Methods

Population and treatment protocol. Consecutive patients with non-anterior STEMI who presented within 6 hours of symptom onset and were admitted to our hospitals were included in this study. We included in our cohort patients without known contraindications for thrombolytic therapy, Killip class 1 on admission,²³ and no life-threatening arrhythmias. These definitions are based on the policy of the primary-care hospital in which these patients were treated with thrombolysis. All other STEMI patients (ie, anterior wall MI, late comers >6 hours and hemodynamically unstable) are transferred for primary PCI. We applied a simple protocol (Figure 1), avoiding a complicated risk-score assessment in the emergency room in order to enhance rapid decision making regarding the appropriate reperfusion strategy. 

In cases of failed thrombolysis, defined as <50% resolution of ST changes and/or persistent chest pain 60 minutes following initiation of therapy, patients are transferred immediately for rescue PCI. In cases of successful thrombolysis, patients are transferred routinely for semi-elective coronary angiography in the subsequent days. 

In order to assess the efficacy of this treatment policy, we performed an observational cohort study. We compared all consecutive patients who received thrombolytic treatment upon admission (thrombolysis group) to all patients who met the same inclusion criteria for thrombolysis (stable non-anterior STEMI presenting within 6 hours of symptom onset) during the same period of time but who presented directly to the tertiary center and thus underwent primary PCI (PCI group). We evaluated the short- and long-term clinical outcomes in the two groups. 

Management and follow-up of patients in this study were the same as the routine management for all STEMI patients and data collection was done retrospectively, hence Institutional Review Board approval was exempted. 

A loading dose of aspirin 300 mg was administered to all patients upon admission before thrombolysis or PCI. Between thrombolysis and angiography, patients were treated with aspirin 100 mg daily and enoxaparin (1 mg/kg twice daily). Clopidogrel was not routinely used in STEMI patients at the time of the study, which was conducted before it was recommended in the guidelines. Glycoprotein IIb/IIIa antagonists and manual thrombectomy were used during the PCI procedure (primary or delayed) according to operator preference. 

Study endpoints. Endpoints during hospital stay (short-term) were specified as: all-cause mortality; recurrent ischemic event (re-infarction, defined as recurrent ischemic symptoms accompanied by recurrent rise and fall of CPK after the index event or recurrent angina at rest without MI), recurrent urgent coronary intervention; stroke; major bleeding event (symptomatic bleeding in a critical area or organ);²⁴ global left ventricular (LV) systolic function (assessed by echocardiography upon discharge); maximal troponin/CPK levels; and length of hospital stay. 

Endpoints during 1-year (long-term) follow-up were specified as: all-cause mortality; and major adverse cardiac event (MACE) rate, including recurrent ischemic event, death, stroke, or the need for recurrent revascularization. 

Data collection. Demographic and clinical data, including timings, were collected from the institutional computerized patient files. Data regarding PCI were collected from the catheterization laboratory computerized files. Long-term data were collected from institutional computerized patient files, phone questionnaires, and the Israeli Ministry of Health registry. 

Statistical analysis. Quantitative variables between two independent groups were compared using the two-sample t-test as well as the non-parametric Mann-Whitney test. Comparison of quantitative variables between three groups or more was done using the ANOVA procedure. The Chi-square test and Fisher’s exact test were applied for assessing the association between two categorical variables. Two multivariate models were used in the analysis of the data: the logistic regression model for a dichotomous outcome variable and the covariance model for a quantitative outcome variable. Variables included in the multivariate models were those that were significant in the univariate analysis and age. Data are reported as odds ratios with 95% confidence intervals (CIs). All tests applied were two-tailed, and a P-value ≤.05 was considered statistically significant.

Results

Baseline characteristics. During the study period, a total of 180 patients with non-anterior STEMI who met the inclusion criteria were treated with thrombolysis followed by coronary angiography (in all patients) and 120 patients were treated with primary PCI. The two groups were similar in terms of baseline characteristics, except for a higher percentage of patients with diabetes mellitus in the thrombolysis group (Table 1). Since only stable patients were included in the study, there were no differences in baseline heart rate and systolic blood pressure between groups. 

Revascularization and treatment times. The mean time from symptom onset to arrival was 2.4 ± 2.6 hours in the thrombolysis group and 2.6 ± 3.5 hours in the PCI group (P=.67). The mean time from arrival to reperfusion (door-to-balloon) in the PCI group was 2 ± 2.5 hours, while the median door-to-balloon time was 91 minutes (interquartile range [IQR], 68-119 minutes). The mean time from arrival to thrombolysis initiation (door-to-needle) was 12 minutes (range, 5 to 16 minutes). The median time from admission to coronary angiography in the thrombolysis group was 3.5 days (IQR, 1-5 days). All patients in the primary PCI group underwent PCI with a success rate (TIMI-3 flow post PCI in the culprit vessel) of 93%. In the thrombolysis group, 85% underwent PCI (rescue or delayed), 6% were referred for coronary artery bypass graft surgery, and 9% were treated conservatively.

In-hospital outcomes. In-hospital outcomes are summarized in Table 2. Death rates were low in both groups and no significant differences in infarct size were noted. Recurrent ischemic events were documented in 17 patients (9.4%) in the thrombolysis group, 13 of which were recurrent MIs with modest elevation of CPK, but only 2 had recurrent persistent ST elevation that required urgent intervention (Table 2). In the PCI group, a recurrent MI was noted in 1 patient. Fourteen of the ischemic events in the thrombolysis group occurred between thrombolysis and PCI and 3 occurred after PCI. A history of ischemic heart disease (IHD) was a significant predictor for recurrent ischemia (P=.01); no other variable including age was found to predict recurrent ischemia during hospitalization. In multivariate analysis, after adjustments for confounders, the rate of recurrent ischemic events was still higher in the thrombolysis group as well as in patients with a history of IHD (Table 3). 

The length of hospital stay was significantly longer in the thrombolysis group (8.8 ± 5.3 days) compared to the PCI group (6.2 ± 2.5; P<.01). There was a non-significant trend toward longer hospitalizations for diabetic patients (P=.07) and elderly patients (P=.07).

Long-term outcomes. Long-term follow-up for mortality was available in all patients and for MACE was available for 235 patients (128 in the thrombolysis group and 107 in the PCI group). No significant differences were noted between the two groups at 1-year follow-up. Death rate was 3.4% in the thrombolysis group and 2.5% in the PCI group (P=.75). The occurrence of total MACE was 27.3% in the thrombolysis group and 38.3% in the PCI group (P=.07). 

Failed thrombolysis. Thirty-four patients (18.9%) in the thrombolysis group had no evidence of reperfusion and underwent rescue PCI. We assessed the relationship between patient baseline and clinical characteristics and the need for a rescue PCI, but did not identify any risk factors predictive of failure of thrombolysis.

Clinical outcome was worse in patients with failed thrombolysis; 2 patients (5.9%) died during hospitalization, as opposed to 0 patients in the group who had successful thrombolysis (P=.04). Furthermore, MACE rate at 1 year was higher, and LV function was poorer in patients with failed thrombolysis (Table 4). 

Discussion

Early reperfusion is a major factor in the prognosis of STEMI patients and studies have shown that shortening time delay in primary PCI or thrombolytic therapy improves clinical outcome.^2-7,25 Currently, primary PCI is considered the preferred treatment strategy in STEMI; however, the relative lack of qualified catheterization facilities worldwide undermines the ability to provide fast reperfusion in many cases. An efficient transfer system of patients to PCI centers is not always available and STEMI patients requiring interhospital transfer often have prolonged overall door-to-balloon times as a result of delays (mainly at the referral hospital).²⁶ Consequently, thrombolysis remains a valid reperfusion strategy in many primary-care hospitals. In addition, the superiority of primary PCI over thrombolysis was not clearly shown in several settings such as very old or low-risk patients.^19-22,27 Although it has been extensively investigated, the appropriate management of STEMI patients arriving in peripheral hospitals remains unclear and varies significantly among centers. 

Our study found no differences in in-hospital or 1-year major clinical outcomes between patients who received thrombolysis followed by routine transfer for coronary angiography as compared to primary PCI. However, the rate of recurrent ischemia during hospitalization was higher in patients in the thrombolytic group. In general, the MACE rate was fairly low in the study, as expected in this low-risk group. It is important to note that the PCI arm of this study included patients who were admitted directly to a qualified PCI center and underwent primary PCI in a timely fashion and not patients who were transferred for PCI. Despite this, the outcome of thrombolysis was comparable to PCI, suggesting that thrombolysis might be a better treatment approach for stable non-anterior STEMI patients admitted to primary-care hospitals who require transfer to a PCI center. 

Two outcome variables differed between the study subgroups: the rate of recurrent ischemia during hospitalization and the duration of hospital stay. The recurrent ischemic event rate was significantly higher in the thrombolysis group (9.4% vs 0.8%). Most of these events occurred up to 3 days post thrombolysis, while the patients were awaiting coronary angiography. Nevertheless, these events required urgent intervention in only 2 cases and did not affect major outcomes such as infarct size, death, or long-term MACE rate. Shortening the time delay between thrombolysis and PCI should reduce the ischemic event rate and prevent unnecessary urgent transfers and interventions, as shown recently by D’Souza et al.²⁸ On the other hand, performing angiography too close to thrombolysis might increase the risk of procedure-related bleeding.²⁹ The appropriate timing for PCI post thrombolysis remains unclear, but our results suggest that the delay should not exceed 48 hours. This strategy may be especially important in older patients with a history of IHD, who are at increased risk for recurrent ischemia and prolonged hospitalization. 

At the time of the study, patients were treated with aspirin and enoxaparin after thrombolysis, but guidelines have since endorsed the routine use of thienopyridine after thrombolysis.³⁰ Adding clopidogrel to thrombolytic therapy has been shown to improve outcomes,³¹ and it is reasonable to assume that treatment with clopidogrel or other new P2Y12 inhibitors post thrombolysis could further reduce the incidence of ischemic events while these patients are waiting for coronary intervention. 

The major drawback of thrombolysis is that close to 20% of the patients had no evidence of reperfusion and had to undergo rescue PCI. These patients had significantly worse outcomes. In order to minimize the incidence of failed thrombolysis, it is important to define the population of patients who are at an increased risk and transfer them for primary PCI. Unfortunately, we were unable to identify risk factors related to thrombolysis failure. Previous studies have shown that the time between symptom onset and arrival to the hospital is a major predictor for successful thrombolysis.³² Since most of the patients in our study arrived shortly after symptom onset, the symptom-to-door time was not found to be a risk factor in this study. These results might not be applicable to populations in which the symptom-to-door time is longer. A major factor of relevance in patients with failed thrombolysis may be the time delay from admission to rescue PCI. In our group, the mean time to rescue PCI was 3.2 hours, which resulted in delayed reperfusion and worse outcomes. It is possible that taking actions to shorten response time to rescue PCI, such as transferring all patients to a PCI center immediately after thrombolysis, may improve outcomes in this group of patients as shown recently in the STREAM trial.³³

Study limitations. The major limitation of this study is that it was retrospective and non-randomized, and may be affected by selection bias and some inaccuracies in data collection. We tried to minimize those biases by analysis of all consecutive patients that met the inclusion criteria, careful and comprehensive data collection, and adjustments for confounders. Furthermore, baseline characteristics of the study subgroups were similar and the treatment strategy was guided by consistent policy protocols in the different hospitals and not by physician discretion, which further reduced the selection bias. Another limitation is the relatively small sample size to detect differences in outcome variables of low-risk patients; nevertheless, the clear trends found among 300 patients together with the previously published data strengthen our conclusions. 

Conclusion

Our study demonstrates that thrombolysis followed by routine transfer for coronary angiography serves as a viable treatment approach for stable non-anterior STEMI patients who are admitted to hospitals without catheterization facilities. Although recurrent in-hospital ischemia was higher in patients who were treated with thrombolysis, all other major clinical outcomes were similar to primary PCI, particularly for patients with a first coronary event. Dual-antiplatelet treatment post thrombolysis and transfer for coronary angiography within 1-2 days will possibly minimize the incidence of recurrent ischemia and further improve outcome in these patients. 

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