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Compared with fibrinolysis alone, fibrinolysis followed by immediate percutaneous coronary intervention (PCI) reduced clinical events in the Combined Angioplasty and Pharmacological Intervention versus Thrombolysis ALone in Acute Myocardial Infarction (CAPITAL AMI) study. It is unclear whether the benefits go beyond achieving epicardial reperfusion.
To determine the differences in ST segment resolution (STR) among patients treated with tenecteplase (TNK)-facilitated PCI compared with patients treated with TNK alone.
A formal ST segment analysis was conducted on the 170 patients with ST elevation myocardial infarction in the CAPITAL AMI trial: 86 patients treated with TNK-facilitated PCI were compared with 84 patients who were treated with TNK alone. Epicardial flow measured by percentage with Thrombolysis In Myocardial Infarction (TIMI) 3 flow improved from 52% (pre-PCI) to 89% (post-PCI) in those assigned to facilitated PCI. ST segment resolution was stratified by complete (70% or greater), partial (less than 70% to 30%) or no (less than 30% to 0%) resolution. The baseline mean ST segment elevation was 11.3±7.5 mm in the facilitated PCI patients and 11.8±7.1 mm in patients with TNK alone (P=0.66). Complete STR in the facilitated PCI patients versus the TNK-alone patients was present in 55.6% versus 54.6%, respectively (P=0.58) at 180 min and 62.0% versus 55.3% (P=0.64), respectively at day 1. The mean STR at 180 min and day 1 were similar in patients who experienced death, reinfarction, recurrent unstable ischemia or stroke at six months compared with patients who remained event free: 56.3% versus 64.6% at 180 min (P=0.40); and 67.7% versus 67.6% at day 1 (P=0.99), respectively.
TNK-facilitated PCI did not demonstrate differences in ST segment resolution compared with TNK alone, despite improvement in epicardial flow after PCI. Further studies are required to clarify these findings.
Par rapport à la fibrinolyse seule, la fibrinolyse suivie d’une intervention coronaire percutanée (ICP) immédiate réduisait les événements cliniques dans le cadre de l’essai CAPITAL AMI sur l’angioplastie combinée et l’intervention pharmacologique par rapport à la thrombolyse seule en cas d’infarctus aigu du myocarde. On ne sait pas si les bienfaits vont au-delà d’une reperfusion épicardique.
Déterminer les différences de résolution du segment ST (RST) chez les patients traités au moyen d’une ICP facilitée par le ténectéplase (TNK) par rapport à ceux traités au moyen de TNK seul.
On a effectué une analyse officielle du segment ST auprès de 170 patients ayant eu un infarctus du myocarde avec élévation du segment ST dans le cadre de l’essai CAPITAL AMI : les 86 patients traités par ICP facilitée par le TNK ont été comparés aux 84 patients traités par TNK seul. Le débit épicardique mesuré en pourcentage au moyen de la thrombolyse dans l’infarctus du myocarde à triple flux est passé de 52 % (avant l’ICP) à 89 % (après l’ICP) chez les patients faisant partie de l’ICP facilitée. La résolution du segment ST était stratifiée selon la résolution complète (70 % ou plus), partielle (moins de 70 % à 30 %) ou inexistante (moins de 30 % à 0 %). L’élévation moyenne du segment ST de départ était de 11,3±7,5 mm chez les patients ayant eu une ICP facilitée et de 11,8±7,1 mm chez ceux prenant seulement le TNK (P=0,66). On constatait une RST complète chez 55,6 % des patients ayant eu une ICP facilitée par rapport à 54,6 % de ceux prenant seulement le TNK (P=0,58) au bout de 180 minutes et de 62 % par rapport à 55,3 % (P=0,64), respectivement, le jour 1. La RST moyenne à 180 minutes et le jour 1 était similaire chez les patients qui sont décédés ou ont eu un nouvel infarctus, une ischémie instable récurrente ou un accident vasculaire cérébral au bout de six mois par rapport à ceux qui n’en avaient pas subi, soit 56,3 % par rapport à 64,6 % à 180 minutes (P=0,40) et 67,7 % par rapport à 67,6 % le jour 1 (P=0,99), respectivement.
L’ICP facilitée par le TNK n’entraînait pas de différence entre la RST et le TNK seul, malgré une amélioration du débit épicardique après l’ICP. D’autres études s’imposent pour clarifier ces constatations.
Recent studies have tried to define the role of new reperfusion strategies for patients with ST elevation myocardial infarction (STEMI) (1–7). These trials and subsequent qualitative reviews have provided insights into the three primary modalities: primary percutaneous coronary intervention (PCI), fibrinolysis-facilitated PCI and fibrinolysis alone (8,9). Primary PCI performed in a timely fashion has been shown to be superior to facilitated PCI and fibrinolysis (2,6,10). Lack of on-site catheterization or long transfer delays may make primary PCI unrealistic (11). The options then include fibrinolysis with a wait-and-see approach or immediate transfer for PCI after initiating fibrinolysis. Contemporary randomized trials comparing fibrinolysis-facilitated PCI and fibrinolysis alone demonstrated that early systematic PCI after fibrinolysis decreased adverse outcomes (1,3–5,7,8). This benefit may be due to earlier and more complete restoration of an ‘open artery’, and consequently, increased myocardial salvage (12). The basis of this rationale has not been fully elucidated and the advantages provided with early epicardial reperfusion have not been confirmed to improve microvascular perfusion (13).
Analysis of ST segment resolution (STR) on electrocardiograms (ECGs) provides a simple means to document the success of epicardial reperfusion, and predict the short- and long-term prognosis of patients after STEMI (14–23). Resolution of ST segment elevation has also been used as a tool to evaluate microvascular- and tissue-level perfusion (24–26). Persistent elevation of ST segments after restoration of epicardial flow may be indicative of incomplete myocardial reperfusion and confers a poorer prognosis (27,28).
The Combined Angioplasty and Pharmacological Intervention versus Thrombolysis ALone in Acute Myocardial Infarction (CAPITAL AMI) trial provided the opportunity to compare STR in patients treated with facilitated PCI and fibrinolysis alone. The trial randomly assigned 170 high-risk patients with STEMI to a strategy of tenecteplase (TNK)-facilitated PCI or TNK alone. The primary end point was a composite of death, reinfarction, recurrent unstable ischemia or stroke at six months. All patients received full-dose TNK with weight-adjusted unfractionated heparin. Patients in the TNK-alone arm were brought for acute cardiac catheterization if persistent ST segment elevation existed after 90 min or more, or if there was hemodynamic deterioration. The rate of rescue for patients treated with fibrinolysis alone was 9.5%. The results of the CAPITAL AMI trial demonstrated a reduction in the primary end point from 24.4% in the fibrinolysis-alone arm to 11.6% in the facilitated PCI arm.
The aim of the present substudy of CAPITAL AMI was to evaluate the differences in STR in patients receiving TNK-facilitated PCI compared with those receiving TNK alone. Improved STR in patients receiving TNK-facilitated PCI may infer better epicardial and microvascular reperfusion. Analysis of STR may also provide insights into the long-term prognosis of patients receiving fibrinolysis-facilitated PCI.
All patients enrolled in the CAPITAL AMI trial were reviewed and only patients with a complete set of ECGs (ie, baseline, within 4 h of reperfusion therapy, and day 1) were included. ECGs with features confounding proper ST segment evaluation, such as left bundle branch block, accelerated idioventricular rhythm and missing leads, were excluded from the analysis. Two investigators blinded to the clinical outcomes analyzed all available ECGs. ST segment analysis was conducted according to previously validated criteria (20,21). ST segments were measured 20 ms after the end of the QRS complex and the TP segment was used as the isoelectric reference baseline. The sum of ST segment elevation was measured for anterior STEMI (V1 to V6, I and aVL) and inferior STEMI (II, III, aVF, V5 and V6) (22). For measurement of total ST segment deviation, leads with 1 mm or greater depression were added to the sum of ST segment elevation for anterior STEMI (leads II, III and aVF) and inferior STEMI (leads V1 to V4). ST elevation in the single lead with the highest ST elevation was also measured. Measurement of the corrected Thrombolysis In Myocardial Infarction frame count (CTFC) was performed as described by Gibson et al (29).
The protocols of the CAPITAL AMI trial and the present substudy were approved by the institutional review boards of each hospital involved in the study. Informed consent was obtained from all patients.
As per previous studies, the extent of STR was calculated by comparison with the baseline ECG (20,22). The results were divided into three prognostic groups. Complete STR was defined as 70% or greater; partial STR as less than 70% to 30%; and no resolution as less than 30% to 0% or greater. For the 180 min ECG, a time window of 120 min to 240 min was allowed, as per previous studies (20,22). The day 1 ECG was the first ECG recorded more than 24 h and less than 48 h after random assignment.
The CTFC was divided into two groups based on a previous analysis (30) demonstrating a correlation with left ventricular recovery and long-term outcomes after myocardial infarction. Patients with a CTFC of 27 or less were defined as low CTFC, while those with a CTFC of greater than 27 were defined as high CTFC (30).
Analysis was performed according to an intention-to-treat principle. Categorical variables are reported as percentages using a Fisher’s exact test or χ2 test. For continuous variables, a Student’s t test was used for normally distributed variables and Wilcoxon’s rank-sum test was used for non-normal data. ST segment resolution was considered categorical (complete, partial and no resolution) as well as continuous. All significant tests were two-sided with statistical significance predefined as P<0.05. Statistical analysis was conducted using Systat 11.0 (Systat Software Inc, USA).
In patients randomly assigned to the TNK-facilitated PCI group, epicardial flow was assessed using Thombolysis In Myocardial Infarction (TIMI) flow grades. At baseline angiography, the rate of patency (TIMI 2 or 3) was 84% and the TIMI 3 flow was 52%. After PCI, the rate of patency improved to 97%, with 89% achieving TIMI 3 flow. A complete ECG data set was available for analysis in 169 of the 170 randomized patients. One patient was excluded because of an underlying left bundle branch block. The two treatment groups were well matched in baseline ECG parameters (Table 1).
Using the sum of ST segment elevation criteria at 180 min, the distribution of STR (complete, partial and no resolution, respectively) was 54.6%, 32.5% and 13.0% in the facilitated PCI group, and 55.6%, 26.4% and 18.1% in the TNK-alone group (P=0.58). Similarly, at day 1, STR distributions were 55.3%, 29.4% and 15.3%, respectively, in the facilitated group, and 62.0%, 26.6% and 11.4%, respectively, in the TNK-alone group (P=0.64). Table 2 summarizes the differences in achieving complete STR using several validated ECG criteria between the facilitated PCI group and the TNK-alone group. Quantile plots of STR of ST elevation further demonstrate no discrepancy in the distribution of STR between the two treatment groups (Figure 1).
Among patients in the facilitated PCI group, 71 had complete data for the analysis of both CTFC and STR. Of this group, 30 patients (42.3%) had a CTFC of greater than 27 (high CTFC), versus 41 (57.7%) with a CTFC of 27 or less (low CTFC). Analysis of STR at 180 min demonstrated that patients with a low CTFC had a higher mean STR than those with a high CTFC (Figure 2).
By sum of ST elevation, the average STR at 180 min was 56.3% in patients with a primary end point and 64.6% in those without a primary end point (P=0.40). The day 1 ECG also revealed no differences in STR between those with and without primary end points (67.7% versus 67.6%, respectively; P=0.99). At 30 days, eight patients in the TNK-facilitated PCI group suffered a primary outcome, compared with 15 in the TNK-alone group. The distribution of STR within the group was 42.9%, 42.9% and 14.3% for complete, partial and no STR, respectively, at 180 min (P=0.27).
The present study was the first to compare STR in patients treated with fibrinolysis-facilitated PCI versus fibrinolysis alone. Despite improvements in TIMI flow grades in patients who underwent TNK-facilitated PCI, we found no difference in early STR between patients with STEMI who were treated with TNK-facilitated PCI compared with TNK alone. These results suggest that the reduction in clinical ischemic events in the CAPITAL AMI study was not related to STR.
The extent of STR is a powerful tool in the evaluation of reperfusion therapy in patients with STEMI (23). In both fibrinolytic therapy and primary PCI trials, complete STR after the procedure has been correlated with decreased mortality (20,23,27,31). Epicardial flow, as measured by TIMI flow grade, has been demonstrated to correlate with STR (32). Furthermore, STR has been demonstrated to predict perfusion at a microvascular level (23). Studies have also shown that STR correlates with higher myocardial salvage and a better left ventricular ejection fraction (23,33).
The expected outcome of the present study would be that STR improved in patients assigned to TNK-facilitated PCI because better epicardial flows were achieved after PCI. The lack of differences in STR between the two randomized groups warrants further explanation. A likely possibility may be an ongoing compromise in microvascular reperfusion. This is further supported by the absence of a difference in left ventricular ejection fraction improvement at 30 days between the two groups (1). In the TIMI-14 study, patients with persistent ST segment elevation were at increased risk despite a patent infarct-related artery; the investigators attributed this finding to impaired microvascular perfusion and tissue damage (32). The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) study (16) included patients with glycoprotein IIb/IIIa-facilitated PCI. Despite achievement of TIMI 3 flow in 96.1% of patients in the trial, only 17.4% of patients had normal myocardial perfusion as assessed by blush grade (34).
Corrected TIMI frame count has also been correlated with microvascular reperfusion and myocardial salvage (30,35,36). Because of the CAPITAL AMI study design, CTFC was not possible in patients randomly assigned to the TNK-alone arm. Analysis of the CTFC in patients receiving facilitated PCI demonstrated that those with a low CTFC had a better percentage STR. Because CTFC is an alternate measure of microvascular flow and myocardial recovery, this observed correlation of low CTFC with improved STR would support the hypothesis of ongoing microvascular impairment in patients with TNK-facilitated PCI.
If microvascular perfusion was compromised in patients with TNK-facilitated PCI, the mechanisms may be a result of several causes. Mechanical intervention on a ruptured plaque during facilitated PCI may cause microembolization of thrombus into the distal bed, thereby compromising microvascular flow (28,37,38). Restoration of flow may also result in hemorrhagic injury, which may be especially detrimental in patients presenting later after symptom onset (31). Finally, delays from symptom onset to treatment may already have caused irreversible damage, where myocardial salvage is minimal despite restoration of flow in the epicardial vessel (12,39).
Other explanations may contribute to the lack of differences in STR if impaired microvascular reperfusion is not the cause. First, rescue performed in 9.5% of patients in the TNK-alone group may have diminished the actual differences in STR. Previous studies have suggested that STR may worsen in some patients undergoing PCI after fibrinolysis (31). Although this was not observed in the overall cohort in our study, it is conceivable that this phenomenon in a small group of patients may dilute the overall STR effect within the TNK-facilitated arm.
The clinical benefits observed with TNK-facilitated PCI are likely due to an improvement in epicardial patency coupled with prevention of reocclusion in the infarct-related artery. A similar parallel can be drawn from the CADILLAC trial, where primary stenting reduced ischemic events at six months compared with balloon angioplasty alone, despite no significant difference in the rates of TIMI 3 flow and TIMI blush scores (34).
Primary PCI has been definitively proven to be a better strategy if conducted in an expedient manner (2). For geographical regions where fibrinolysis remains the initial modality of treatment, further strategies may be required for high-risk patients who may be receiving a pharmacoinvasive approach. A substudy of TIMI-14 demonstrated that in patients initially treated with fibrinolysis, those who also received abciximab during subsequent facilitated PCI had better STR than those with fibrinolysis-facilitated PCI alone (23,40,41). The recently published Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI) (7) showed half-dose reteplase plus glycoprotein IIb/IIIa (abciximab) with immediate transfer for PCI to be superior to this regimen without immediate PCI. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) (42), however, demonstrated that, when feasible, primary PCI is better than facilitated PCI with glycoprotein IIb/IIIa, or IIb/IIIa in conjunction with fibrinolysis. Thus, the role of glycoprotein IIb/IIIa receptor inhibitors in the presence of fibrinolysis needs further elucidation.
Use of thrombectomy or distal protection devices has been shown to improve STR in smaller preliminary studies (43,44). Previously, these devices have failed to limit infarct size or improve clinical outcomes (45,46). The recently published Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) (28) randomly assigned 1071 patients, and demonstrated clear improvements in STR and blush score with routine aspiration. A one-year follow-up reported mortality reduction in patients who received aspiration during primary PCI. The use of an aspiration device may be a strategy to improve the extent of STR in patients receiving TNK-facilitated PCI.
The improvement in epicardial patency in the facilitated PCI arm coupled with an almost identical degree of STR between the two arms would suggest that even if differences in STR exist, a very large study would be needed to prove the difference. Because of the study design, patients in the TNK-alone group did not receive immediate cardiac catheterization; therefore, comparison of TIMI flow grade or TIMI blush scores relative to the facilitated PCI group was not possible. Because the present study was a randomized trial, the assumption would be that patients receiving TNK alone would have had the same epicardial flow as the pre-PCI flow of those in the facilitated arm. Because the use of STR as a gauge of microvascular perfusion has been validated (23), ongoing impairment in microvascular perfusion would be a possible assumption for the findings of the present study. The correlation of lower CTFC with better STR in patients with facilitated PCI would substantiate this hypothesis. To definitively delineate the status of the microvasculature in patients with TNK-facilitated PCI would require a prospective study that incorporates a modality to measure myocardial perfusion in both arms of the study.
The small sample size and low event rates may be confounding variables for definitive conclusions to be drawn between STR and clinical outcomes in the present study. Also, the primary outcome of CAPITAL AMI was a composite of death, reinfarction, recurrent unstable ischemia or stroke. ST segment resolution may not be reflective of all components within this primary outcome, especially if it is primarily driven by recurrent ischemia. Irrespective of the exact mechanisms behind the lack of differences in STR, our study suggests that new strategies should be considered when treating these high-risk patients.
Percutaneous coronary intervention performed immediately after fibrinolysis did not improve ST segment resolution compared with fibrinolysis alone, despite improvements in epicardial patency after facilitated PCI. Further studies are required to explain these observations.
The parent CAPITAL AMI study was supported by a peer review grant from the Canadian Institutes of Heath Research (CIHR), and a CIHR Industry-Partnered Program with Hoffmann La-Roche Limited Canada and Guidant Corporation Canada.