The aim of this study was to assess the efficacy and safety of an early invasive strategy post-fibrinolysis in relation to time from symptom onset to fibrinolysis in patients with ST-elevation myocardial infarction (STEMI). The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomized 1,059 patients receiving fibrinolysis for STEMI to an early invasive strategy versus standard therapy. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock at 30 days. In this post hoc subgroup analysis, we examined the effect of an early invasive strategy on efficacy and safety outcomes after stratification by time from symptom onset to fibrinolysis (<2 or ≥2 hours). Of 1,059 patients in TRANSFER-AMI, 557 (53%) received fibrinolysis <2 hours and 502 (47%) ≥2 hours after symptom onset. Compared to patients who received fibrinolysis within 2 hours of symptoms, patients who received fibrinolysis ≥2 hours after symptom onset had higher Global Registry of Acute Coronary Events risk scores (median 127 vs 122, p = 0.004). The effect of an early invasive strategy did not differ between symptom-to-fibrinolysis time strata for the primary efficacy end point (p-heterogeneity = 0.67), 30-day mortality, the composite of death or reinfarction at 30 days, 6 months, or 1 year, or bleeding (all p-heterogeneity >0.40). In conclusion, the efficacy and safety of an early invasive strategy in patients undergoing fibrinolysis for STEMI do not vary in relation to time (<2 or ≥2 hours) from symptom onset to fibrinolysis.
The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) demonstrated the clinical benefits of a routine early invasive strategy in patients undergoing fibrinolysis for ST-elevation myocardial infarction (STEMI) when timely access to primary percutaneous coronary intervention (PCI) is not available. The efficacy of fibrinolysis has been shown to be highly dependent on the interval between symptom onset and treatment administration, with decreasing efficacy as this time interval lengthens. Because of the time-sensitive nature of fibrinolytic therapy, it is conceivable that the interval between symptom onset and treatment administration may also be of clinical relevance in STEMI treatment strategies that include fibrinolysis, such as prehospital fibrinolysis and routine early invasive strategy. Accordingly, we sought to determine whether the efficacy and safety of a routine early invasive strategy depend on the time interval from symptom onset to fibrinolysis in TRANSFER-AMI.
Methods
The design and primary results of the TRANSFER-AMI trial have been previously published. In brief, TRANSFER-AMI randomized 1,059 patients who underwent fibrinolysis for STEMI to an early invasive strategy, consisting of routine transfer for coronary angiography and PCI if needed within 6 hours of fibrinolysis, or standard therapy ( http://www.clinicaltrials.gov/ct2/show/NCT00164190 , NCT00164190 ).
Patients receiving tenecteplase for STEMI at non-PCI-capable hospitals who presented within 12 hours of symptom onset were screened for eligibility. Participants met inclusion criteria if they had an anterior STEMI or an inferior STEMI with at least one of the following high-risk features: systolic blood pressure <100 mmHg, heart rate >100 beats/min, Killip class II or III, ≥2 mm of ST depression in anterior leads, or right ventricular involvement as evidenced by ≥1 mm of ST elevation in right-sided lead V4. Exclusion criteria included cardiogenic shock before randomization, PCI within the previous month, previous coronary artery bypass surgery, and availability of timely primary PCI (i.e., anticipated door-to-balloon time <60 minutes). All participants received standard dose tenecteplase, aspirin, and unfractionated heparin or enoxaparin in the emergency department. Patients in the standard arm with persistent ST-segment elevation and chest pain or with hemodynamic instability were transferred to a PCI-capable center for rescue PCI. Otherwise, patients in the standard arm remained at their presenting hospital for at least 24 hours. The trial protocol recommended that all patients in the standard arm undergo cardiac catheterization within 2 weeks of randomization and was amended in April 2005 to strongly recommend the use of clopidogrel during fibrinolysis.
The primary efficacy end point of TRANSFER-AMI was the composite of death, reinfarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock at 30 days. Secondary and safety end points were death or reinfarction at 6 and 12 months and in-hospital bleeding classified using the Thrombolysis In Myocardial Infarction (TIMI) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Artery bleeding scales.
In the present study, we examined the effect of a routine early invasive strategy on efficacy and safety end points after stratification based on time from symptom onset to fibrinolysis. We stratified patients into 2 prespecified symptom onset to fibrinolysis time strata (<2 and ≥2 hours) based on the results of previous studies. For our efficacy end points, we analyzed the primary outcome, death at 30 days, and the composite of death or reinfarction at 30 days, 6 months, and 1 year.
We present continuous variables using medians and interquartile ranges, and categorical variables using percentages or frequencies. We compared continuous variables using the Mann-Whitney U test and categorical variables using the chi-square test (or Fisher’s exact test when appropriate). We provided odds ratios and 95% confidence intervals (CIs) for all end points analyzed and displayed results using Forest plots. We used the Breslow-Day test to examine the homogeneity of odds ratios associated with routine early invasive strategy after stratification by symptom onset to fibrinolysis time.
Because of the previously described interaction between the Global Registry of Acute Coronary Events (GRACE) risk score and the efficacy of an early invasive strategy, we performed a multivariable regression analysis to adjust for baseline differences in GRACE risk score between symptom-to-fibrinolysis time strata. The explanatory variables in our regression model included the randomized treatment assignment, GRACE risk score, symptom-to-fibrinolysis time (<2 or ≥2 hours), and the interaction terms of symptom-to-fibrinolysis time by treatment assignment and GRACE risk score by treatment assignment. Statistical analyses were conducted using SPSS 22.0 (IBM, Armonk, NY). Two-sided p values <0.05 were considered statistically significant.
Results
In the 1,059 patients randomized in TRANSFER-AMI, the median time from symptom onset to fibrinolysis was 1.92 hours (twenty-fifth and seventy-fifth percentiles 1.25 and 3.12). The time from symptom onset to administration of tenecteplase was <2 hours (median 1.25 hours [0.97, 1.58]) in 557 patients (53%) and ≥2 hours (median 3.24 hours [2.43, 4.80]) in 502 patients (47%). Table 1 lists the baseline characteristics of the patient population stratified by time from symptom onset to fibrinolysis. There were significant differences in baseline characteristics between symptom-to-fibrinolysis time strata. Compared with patients who received fibrinolysis ≥2 hours after symptom onset, patients who received fibrinolysis <2 hours from symptom onset were more likely to be men and have a history of myocardial infarction, PCI, and smoking. These patients were also younger, had greater baseline weight and creatinine levels, and lower GRACE risk scores.
| Characteristic | Hours | p value | |
|---|---|---|---|
| <2 (n=557) | ≥2 (n=502) | ||
| Time from symptom onset to administration of tenecteplase (hours) ∗ | 1.25 (0.97,1.58) | 3.24 (2.43,4.80) | |
| Age (years) ∗ | 56 (49,64) | 58.5 (51,68) | 0.001 |
| Women | 17% | 25% | 0.002 |
| Weight (kg) ∗ | 82 (71,91) | 78 (68,90) | 0.001 |
| Heart rate (beats/min) ∗ | 74 (63,88) | 78 (66,90) | 0.01 |
| Hypertension | 33% | 34% | 0.73 |
| Diabetes | 14% | 16% | 0.33 |
| Smoker | 65% | 58% | 0.04 |
| Current smoker | 45% | 40% | 0.15 |
| Dyslipidemia | 29% | 27% | 0.65 |
| Prior angina pectoris | 12% | 12% | 0.82 |
| Prior myocardial infarction | 13% | 8.0% | 0.01 |
| Prior heart failure | 1.4% | 1.2% | 0.73 |
| Prior stroke or transient ischemic attack | 1.8% | 2.2% | 0.64 |
| Prior peripheral arterial disease | 1.4% | 1.0% | 0.52 |
| Prior percutaneous coronary intervention | 6.8% | 3.6% | 0.02 |
| Creatinine (umol/L) ∗ | 94 (82,107) | 87 (75,101) | <0.001 |
| Anterior ST-segment elevation | 54% | 54% | 0.84 |
| Killip class | 0.98 | ||
| I | 91% | 92% | |
| II | 7.2% | 6.6% | |
| III | 0.9% | 1.0% | |
| IV | 0.5% | 0.6% | |
| TIMI risk score ∗ | 2 (1,3) | 2 (1,4) | <0.001 |
| GRACE risk score ∗ | 122 (107,140) | 127 (110,148) | 0.004 |
| Procedures | |||
| Coronary angiography | 95% | 93% | 0.19 |
| Narrowed coronary arteries † | <0.001 | ||
| 0 | 9.7% | 6.0% | |
| 1 | 57% | 51% | |
| 2 | 28% | 32% | |
| 3 | 5.3% | 13% | |
| Percutaneous coronary intervention | 77% | 76% | 0.56 |
| Rescue percutaneous coronary intervention ‡ | 19% | 15% | 0.09 |
| Time from randomization to percutaneous coronary intervention (hours) ∗ | 3.8 (2.8,7.2) | 4.1 (2.9,17.0) | 0.10 |
| Baseline infarct-related artery TIMI flow | 0.63 | ||
| 0 | 19% | 18% | |
| 1 | 10% | 13% | |
| 2 | 16% | 16% | |
| 3 | 55% | 53% | |
| Final infarct-related artery TIMI flow | 0.95 | ||
| 0 | 1.0% | 0.5% | |
| 1 | 1.0% | 0.8% | |
| 2 | 4.8% | 4.9% | |
| 3 | 93% | 94% | |
| Final infarct-related artery TIMI 3 flow | 93% | 94% | 0.79 |
∗ median (25th,75th percentiles).
† Data represent percentage of patients among those who underwent coronary angiography.
‡ Data represent percentage of patients in standard arm only.
Table 2 provides baseline characteristics of the standard and early invasive treatment arms stratified by time from symptom onset to administration of tenecteplase. Baseline characteristics were well balanced between treatment arms within both symptom-to-fibrinolysis time strata, with the exception of a higher prevalence of previous stroke or transient ischemic attack in the early invasive arm compared with the standard arm in the stratum of patients who received fibrinolysis ≥2 hours after symptom onset. Pharmacologic and procedural therapy use stratified by treatment arm and time from symptom onset to fibrinolysis are provided in Table 3 . Compared with the standard arm, patients in the early invasive arm were more likely to receive coronary angiography, PCI, and GP IIb/IIIa inhibitors in both symptom-to-fibrinolysis time strata. The rates of rescue PCI in the standard arm were similar between symptom-to-fibrinolysis time strata. With regard to angiographic variables, there were significant differences in the number of diseased vessels and the final infarct-related artery TIMI flow between the early invasive and standard arms in the stratum of patients who received fibrinolysis ≥2 hours after symptom onset. All other pharmacologic and procedural variables were similar between treatment arms within each symptom-to-fibrinolysis time stratum.
| Characteristic | Hours | |||||
|---|---|---|---|---|---|---|
| <2 | ≥2 | |||||
| Standard Treatment (n=269) | Early Invasive Treatment (n=288) | p value | Standard Treatment (n=253) | Early Invasive Treatment (n=249) | p value | |
| Age (years) ∗ | 56 (49,64) | 56 (49,65) | 0.73 | 58 (50,68) | 59 (53,67) | 0.49 |
| Women | 15% | 18% | 0.37 | 25% | 24% | 0.68 |
| Hypertension | 34% | 32% | 0.70 | 35% | 33% | 0.59 |
| Diabetes mellitus | 14% | 14% | 0.94 | 17% | 16% | 0.78 |
| Current smoker | 43% | 46% | 0.52 | 39% | 42% | 0.61 |
| Dyslipidemia | 29% | 28% | 0.68 | 28% | 27% | 0.85 |
| Prior angina pectoris | 11% | 12% | 0.61 | 11% | 13% | 0.37 |
| Prior myocardial infarction | 13% | 13% | 0.96 | 6.7% | 9.2% | 0.30 |
| Prior heart failure | 2.2% | 0.7% | 0.16 | 2.0% | 0.4% | 0.22 |
| Prior stroke or transient ischemic attack | 1.1% | 2.4% | 0.34 | 0.8% | 3.6% | 0.03 |
| Prior peripheral vascular disease | 1.9% | 1.0% | 0.49 | 1.2% | 0.8% | >0.99 |
| Prior percutaneous coronary intervention | 5.2% | 8.3% | 0.14 | 3.2% | 4.0% | 0.61 |
| Killip class | 0.20 | 0.80 | ||||
| I | 91% | 91% | 93% | 91% | ||
| II | 8.2% | 6.3% | 5.9% | 7.2% | ||
| III | 0.4% | 1.4% | 1.2% | 0.8% | ||
| IV | 0% | 1.0% | 0.4% | 0.8% | ||
| Hours | ||||||
|---|---|---|---|---|---|---|
| <2 | ≥2 | |||||
| Standard treatment (n=269) | Early Invasive Treatment (n=288) | p value | Standard Treatment (n=253) | Early Invasive Treatment (n=253) | p value | |
| Drug Therapy | ||||||
| Aspirin | 99% | 98% | 0.45 | 97% | 100% | 0.04 |
| Clopidogrel | 91% | 96% | 0.02 | 91% | 97% | 0.01 |
| Beta blocker | 96% | 94% | 0.33 | 95% | 95% | 0.72 |
| ACE inhibitor /Angiotensin receptor blocker | 90% | 85% | 0.14 | 88% | 91% | 0.28 |
| Statin | 96% | 93% | 0.11 | 93% | 93% | 0.96 |
| Glycoprotein IIb/IIIa inhibitor | 58% | 75% | <0.001 | 57% | 72% | 0.001 |
| Procedures | ||||||
| Coronary angiography | 90% | 99% | <0.001 | 87% | 98% | <0.001 |
| Narrowed coronary arteries ∗ | 0.16 | 0.02 | ||||
| 0 | 12% | 7.8% | 9.0% | 3.2% | ||
| 1 | 59% | 55% | 52% | 49% | ||
| 2 | 24% | 32% | 25% | 36% | ||
| 3 | 4.6% | 5.8% | 14% | 12% | ||
| Percutaneous coronary intervention | 70% | 83% | <0.001 | 64% | 87% | <0.001 |
| Baseline infarct-related artery TIMI flow | 0.02 | 0.46 | ||||
| 0 | 20% | 18% | 21% | 17% | ||
| 1 | 7.8% | 12% | 11% | 15% | ||
| 2 | 12% | 20% | 17% | 15% | ||
| 3 | 60% | 51% | 52% | 54% | ||
| Final infarct-related artery TIMI flow | 0.95 | 0.05 | ||||
| 0 | 1.1% | 0.8% | 0.6% | 0.5% | ||
| 1 | 0.6% | 1.3% | 1.3% | 0.5% | ||
| 2 | 5.0% | 4.7% | 1.9% | 7.1% | ||
| 3 | 93% | 93% | 96% | 92% | ||
| Final infarct-related artery TIMI 3 flow | 93% | 93% | 0.96 | 96% | 92% | 0.10 |
| Left ventricular ejection fraction | 0.14 | 0.50 | ||||
| <20% | 0.8% | 3.9% | 0.8% | 2.0% | ||
| 20 to 34% | 16% | 24% | 22% | 21% | ||
| 35 to 50% | 52% | 43% | 50% | 57% | ||
| >50% | 31% | 29% | 27% | 19% | ||
| Coronary-artery bypass grafting | 5.9% | 6.3% | >0.99 | 9.9% | 6.8% | 0.26 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
