Strategy of In Ambulance Thrombolysis Followed by Routine
PCI in Acute Myocardial Infarction
Ajit Mullasari.
Institute of Cardio-Vascular Diseases Madras Medical Mission, Chennai
Background
Although mortality in patients with STEMI has declined substantially over the past two decades, it is estimated that, up to one-third of eligible patients with STEMI still receive no reperfusion therapy acutely (1). Timely reperfusion of the infarct-related coronary artery using thrombolysis or percutaneous coronary intervention (PCI) is central to optimal STEMI treatment, reducing infarct size, minimizing myocardial damage, preserving left ventricular function, and reducing morbidity & mortality. However, the principal objective of prompt reperfusion has become overshadowed by debate over which approach (mechanical or pharmacologic) is superior (2). In our country vast majority of patients present to centres without PCI facility and undergo thrombolysis. What happens next remains controversial: Should only patients with failed reperfusion be transferred for early PCI? Should high-risk patients be transferred for catheterization at some point beyond 24 hours? Or should high-risk STEMI patients be transferred for routine early PCI after thrombolysis? With the publication of newer trials with more clear data the role of PCI after thrombolysis is being redefined and will be reviewed here.
Reperfusion Strategies: An Overview
Thrombolysis vs. Primary PCI
The current ACC/AHA and ESC STEMI guidelines recommend PCI as the initial approach to management of STEMI, contingent upon treatment at centers with a skilled PCI laboratory and rapid initiation. This is based on multiple randomized clinical trials demonstrating superiority of rapid primary PCI over thrombolysis in STEMI (3,4) . Appropriately selected patients undergoing primary PCI were shown to have lower rates of nonfatal re-infarction, stroke, and short-term mortality than thrombolytic recipients in a meta-analysis of data from 23 randomized trials enrolling thrombolytic-eligible patients with STEMI (5). Primary PCI would likely become the universal “dominant default strategy” for prompt early reperfusion if resource and logistical constraints did not limit its more broad-based adoption.However, for many patients these criteria for primary PCI to be preferred will not be met and it is important to note that the guidelines also state that there is no strong preference between PCI and thrombolysis as the choice of initial reperfusion therapy in patients who present within 3 h after symptom onset. This is based, in part, on the CAPTIM (Comparison of Angioplasty and Pre-hospital Thrombolysis in Acute Myocardial Infarction) and PRAGUE-2 (Primary Angioplasty in Patients Transported From General Community Hospitals to Specialized PTCA Units With or Without Emergency Thrombolysis-2) trials, which suggested that earlier presenting patients (within 2 to 3 h) had similar or lower mortality with thrombolysis than with primary PCI (6, 7).
Results from many studies have demonstrated time dependence of the benefit of PCI versus thrombolysis. An analysis of 21 trials showed that as PCI-related time delay increased, absolute mortality reduction at 4 to 6 weeks favoring primary PCI versus thrombolysis decreased (0.94% decrease per additional 10-min delay; p= 0.006) , with apparent equivalence after a PCI-related time delay of 62 min (8). This is reflected by the STEMI guidelines, which indicate that thrombolysis is generally preferred when there is a delay to implementing an invasive strategy such that door-to-balloon time minus door-to-needle time exceeds 1 h.
Prehospital Thrombolysis
A number of studies have demonstrated that prehospital thrombolytic administration can significantly decrease time from symptom onset to treatment (9-11) .This is reflected by several studies showing improved outcomes, such as mortality (Fig. 1), with prehospital thrombolysis (10,12,13) . In a large meta-analysis, mortality was significantly lower among patients receiving prehospital versus in-hospital thrombolysis (odds ratio 0.83; 95% confidence interval 0.70 to 0.98) (12). Comparison of prehospital thrombolysis with transfer to a hospital for immediate PCI in the CAPTIM trial revealed no statistically significant between-treatment difference regarding the composite primary end point (death, nonfatal reinfarction, and nonfatal disabling stroke within 30 days) or mortality. Clinical trials data support the safety and efficacy of prehospital thrombolysis in the treatment of STEMI (14). The ACC/AHA STEMI guidelines state that “itE-mail: icvddoctors@mmm.org.in
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seems reasonable to expect that if thrombolytic therapy could be started at the time of prehospital evaluation, a greater number of lives could be saved”. Prehospital thrombolysis may also decrease time to treatment in other settings, including rural or congested urban areas where transportation times are long, as well as areas in which primary PCI facilities are not immediately available or where time to mobilize the appropriate team may be excessive.
Figure 1 Mortality Benefit with Pre-hospital Fibrinolysis versus In-hospital Fibrinolysis
Rescue PCI
The efficacy of lytic therapy is related to many factors and there is still a relatively large group of patients in whom such therapy failed. In such situation shift for invasive approach, called rescue PCI is recommended.
In the Middlesbrough Early Vascularization to Limit Infarction (MERLIN) trial, 307 patients who failed to achieve 50% ECG ST-segment resolution at 60 min following thrombolytic therapy were randomized to either rescue PCI or conservative treatment (without repeat administration of thrombolytic therapy). There was no difference in the mortality at 30 days, but there was lower rate of composite end-point (death/re- nfarction/stroke/subsequent revascularization/ heart failure) in the rescue PCI arm. This difference was mainly driven due to a decrease in subsequent revascularization procedures, and was observed also during 1-year follow-up (15).
The Rescue Angioplasty vs. Conservative Treatment or Repeat Thrombolysis (REACT) trial enrolled 427 patients with, 50% ST-segment
resolution at 90 min and confirmed the important role of rescue PCI showing significant reduction in the composite primary end-point in patients undergoing rescue PCI compared with those randomized to either thrombolytic re-administration or conservative therapy (16).
In the meta-analysis of Wijeysundera et al including 1177 patients from eight trials, rescue PCI was associated with no significant reduction in all cause mortality but showed significant risk reductions in heart failure and re-infarction when compared with conservative treatment (17).
Facilitated PCI
Facilitated PCI is a strategy of planned immediate catheterization after administration of an initial pharmacological regimen that is intended to improve coronary patency before the procedure. These regimens have included high-dose heparin, platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduced-dose thrombolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose thrombolytic agent .Despite potential advantages, clinical trials of facilitated PCI have not demonstrated any benefit in reducing infarct size or improving outcomes and may be harmful. Indeed, the PCI guidelines do not recommend full-dose thrombolytic therapy followed by immediate catheterization, although facilitated PCI regimens using other than full-dose thrombolysis are considered an option in specific high-risk subgroups of patients (large MI or hemodynamic or electrical instability) or when PCI is not immediately available within 90 minutes.
In the Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) trial, patients with STEMI were randomized to full-dose tenecteplase (TNK) followed by primary PCI (n=829) or primary PCI alone (n=838). The trial was to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients since interim analysis showed higher events in TNK + PCI arm. At 90 days, the primary composite endpoint of death, CHF, or shock was higher in the TNK+PCI group (19% vs 13%, p=0.0055) (18).
In Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE ) trial,
patients with STEMI were randomized in a double-blind, double-dummy manner to abciximab with half-dose of the thrombolytic reteplase (n = 828), abciximab alone (n = 818), or placebo (n = 806). Patients then underwent PCI There was no difference in the primary endpoint of death, cardiogenic shock, heart failure, or resuscitated ventricular fibrillation by 90 days between the three groups (9.8% of the combination facilitated PCI arm, 10.5% of the abciximab facilitated PCI arm, and 10.7% of the primary PCI alone arm; p = 0.55) (19) . However, both facilitated PCI strategies were associated with an increased risk of bleeding.
Post Fibrinolytic Optimally Timed PCI – A New Paradigm
Several new studies were conducted to assess safety and benefits of routine angiography/PCI vs. conservative approach in STEMI patients treated with thrombolysis. Based on these studies, particularly after the landmark TRANSFER AMI trial,2008 ESC guidelines have advocated routine angiography and PCI if applicable to all patients after thrombolysis.
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SIAM III TRIAL
In the Southwest German Interventional Study in Acute Myocardial Infarction (SIAM III), a total of 197 patients with STEMI receiving thrombolysis (full-dose reteplase) less than 12 h were randomized either to early coronary angiography/ PCI (within 6 h from thrombolysis) or to elective coronary angiography 2 weeks after thrombolysis with stenting of the infarct-related artery. Strategy of early angiography and immediate stenting (3.5+2.3 h after thrombolysis) was associated with significant reduction of the combined end point of death, re-infarction, target lesion revascularization, and other ischemic events after 30 days (8.5 vs. 30.9%, P , 0.001) and 6 months (25.6 vs. 50.6%, P , 0.001), without significant difference in bleeding risk (20).
GRACIA I TRIAL
In Grupo de Analisis de la Cardiopatia Isquemica Aguda( GRACIA I) study ,patients were randomized to angiography and intervention (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) if indicated within 24 hours of thrombolysis (n=248), or to an ischemia-guided conservative approach (n=252). In the interventional arm, 80% underwent stenting of the infarct-related artery. CABG was used for revascularization in 2%, and 16% were treated medically. A total of 21% of medical patients underwent angiography, and 19% underwent PCI. The primary endpoint was lower in the interventional arm (9% vs. 21%; risk ratio [RR] 0.44, p=0.0008), with much of the reduction driven by a lower revascularization rate in the intervention arm (4% vs. 12%, RR 0.30, p=0.001), but trends in reduction of death (4% vs. 6%, RR 0.55, p=0.16) and MI (4% vs. 6%, RR 0.60, p=0.22) and there was no increase in bleeding rates (21).
CAPITAL AMI TRIAL
In the Combined Angioplasty and Pharmacological Intervention vs. Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI) study, 170 patients with high-risk STEMI treated with thrombolysis (full-dose tenecteplase) were randomized either to immediate angiography/PCI or conservative approach. Patients received aspirin and clopidogrel loading dose of 300 mg in the cath lab and the median of time from randomization to first balloon inflation was 95 min. The incidence of the primary endpoint (death, re-infarction, recurrent unstable ischemia, or stroke) at 6 months was lower in patients undergoing PCI (11.6 vs. 24.4%, P ¼ 0.04). Observed difference was driven mainly by a reduction in the rate of recurrent unstable ischemia (20.7 vs. 8.1%, P ¼ 0.03). Importantly, there was no difference in frequency of major bleedings (22).
CARESS in AMI TRIAL
The safety and advantages of immediate PCI after combination of reduced dose fibrinolytic and full-dose abciximab have been confirmed by the data of the Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS in AMI) trial. This randomized trial, in fact, has shown that transfer of high-risk STEMI patients (with at least on high risk feature: sum of ST-segment elevation or depression more than 15 mm in 12-lead ECG or new onset complete left bundle-branch block, prior myocardial infarction, Killip class 2 or 3, and left ventricular ejection fraction < 35%) for early routine PCI soon after the administration abciximab and half-dose reteplase reduces the risk of recurrent ischemia and all ischemic complications (death, repeat myocardial infarction, recurrent ischemia; immediate PCI group vs. standard care/rescue PCI group: 4.4 vs. 10.7%, P ¼ 0.004) at 30 days in comparison to conservatively treated patients with ischemia guided PCI (rescue PCI), without a significant increase in major bleeding complications (immediate PCI group vs. standard care/ rescue PCI group( 3.4 vs. 2.3%, P = 0.47), as well as stroke (0.7 vs. 1.3%, P = 0.50). Median of time from thrombolysis initiation to angiography in immediate PCI group was 135 min (23).
TRANSFER AMI : THE LANDMARK TRIAL
In the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) the goal was to evaluate the role of transfer for routine percutaneous coronary intervention (PCI) within 6 hours after fibrinolysis, using contemporary stents and pharmacotherapy, in patients with high-risk ST-elevation myocardial infarction (STEMI) presenting to centers where primary PCI was not feasible in a timely manner
Patients with STEMI were randomized to a pharmacoinvasive strategy (emergent transfer for PCI within 6 hours of fibrinolysis) or to standard treatment after fibrinolysis (which included rescue PCI as required for ongoing chest pain and <50% resolution of ST-elevation at 60-90 minutes, or if patients were hemodynamically unstable). For standard treatment patients who did not require rescue PCI, elective cardiac catheterization within the first 2 weeks was encouraged, but not mandated. All patients received standard-dose tenecteplase (TNK), heparin, and aspirin 160-325 mg.
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Figure 2 TRANSFER AMI Study Design
Either unfractionated heparin (UFH) or enoxaparin was used based on institutions' standard practice, using weight-adjusted dosing consistent with published STEMI guidelines. Clopidogrel loading (300 mg for patients ≤75 years of age, and 75 mg if >75 years of age) was strongly encouraged in all study patients. Glycoprotein IIb/IIIa inhibitors were used at the interventional centers (not at the site of fibrinolysis), as per the discretion of the operator. PCI of the culprit lesion was performed if ≥70% stenosis, or high-risk features were present (i.e., thrombus, ulceration, dissection). Stents were used whenever technically feasible (bare-metal: 79.3%).A total of 1,059 patients were randomized, 537 to the pharmacoinvasive arm, and 522 to the standard treatment arm. About 54% of patients had anterior ST elevations on the electrocardiogram. Cardiac catheterization was performed in 98.5% of patients in the pharmacoinvasive arm, and 88.7% of patients in the standard treatment arm. The median time to administration of TNK from onset of symptoms was about 2 hours in both arms, whereas the median time from TNK to catheterization was 2.8 hours in the pharmacoinvasive arm, and 32.5 hours in the standard treatment
The incidence of the primary endpoint of death, MI, heart failure, severe recurrent ischemia, or shock was significantly lower in the pharmacoinvasive arm (11.0%) compared with the standard management arm (17.2%) (Hazard ratio 0.64, 95% confidence interval 0.47-0.87, p = 0.004). The incidence of mortality, reinfarction, recurrent ischemia, heart failure, and cardiogenic shock was 4.5% and 3.4% (p = 0.39), 3.4% and 5.7% (p = 0.06), 0.2% and 2.1% (p = 0.003), 3.0% and 5.6% (p = 0.04), and 4.5% and 3.1% (p = 0.23) in the pharmacoinvasive and conventional treatment arms, respectively. Death or MI was similar between the two arms at 6 months (8.9% vs. 10.6%, p = 0.36). Any bleeding tended to be higher in the pharmacoinvasive arm (20.5% vs. 16.1%, p = 0.06). The incidence of TIMI or GUSTO major bleeding was 7.4% and 9.0%, respectively (p = 0.36). The rates of transfusion were similar (24).
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Figure 3.TRANSFER AMI: Primary Endpoints
The results of this large randomized clinical trial indicate that in patients presenting with STEMI to centers without timely access to a catheterization lab, a pharmacoinvasive approach consisting of full-dose thrombolytics, followed by emergent transfer for cardiac catheterization within 6 hours, is safe and efficacious compared to treatment with thrombolytics and transfer for rescue PCI only. This suggests that transfer to PCI centers should be initiated immediately after thrombolysis without waiting to see whether reperfusion is successful or not.
GRACIA II TRIAL
In the GRACIA-2 study, 212 STEMI patients were randomized to full dose tenecteplase followed by stenting within 3–12 h of randomization (early routine post-thrombolysis angioplasty), or to undergo primary stenting with abciximab within 3 h of randomization. The time median between randomization and angiography was longer in early routine post-thrombolysis angioplasty group (4.6 h) than in primary PCI group (1 h). Despite this delay, early routine post-thrombolysis angioplasty resulted in higher frequency of complete epicardial and myocardial reperfusion (TIMI 3 epicardial flow and TIMI 3 myocardial perfusion and resolution of the initial sum of ST-segment elevation >70%) and similar infarct size and preserving left ventricular function. GRACIA-2 results showed that PCI may be safely performed 3–12 h later after lytic administration and that this strategy allows obtaining better myocardial reperfusion in comparison to primary angioplasty (25).
Post Fibrinolytic PCI: What is the Optimal Time Window
The question which is still open for debate is when the optimal time to perform angiography/PCI after lytic administration is. Published trials showed different strategy from about 2 h in CARESS in AMI to almost 17 h in GRACIA-1.The mean time to PCI was 3.5 hours in SIAM III study, 3 hours in TRANSFER AMI trial and 4.6 hours in GRACIA II study (26).
It is now inferred that outcomes in previous facilitated trials like ASSENT-4 PCI were harmful due increased peri-procedural ischemic events and bleeding rates because the mean time to PCI was between 90 to 103 minutes which coincided with post thrombolytic pro-thrombotic phase and due sub optimal use of anti platelet therapy.
Since most of the reocclusion and reinfarction occur in the initial 24 hours, the guidelines (ESC) now recommend routine post thrombolytic PCI between 3 and 24 hours (27)
This approach of pharmaco invasive strategy increases the speed of myocardial reperfusion by pharmacologically opening the infarct-related artery rapidly, followed by PCI to ensure sustained and more complete reperfusion thus resulting in less myocardial damage and consequently a decrease in clinical events (28.29).
Figure 4 Current Guidelines Based Reperfusion strategies. The thick arrow indicates the preferred strategy
Figure 4 Current Guidelines Based Reperfusion strategies. The thick arrow indicates the preferred strategy
Conclusions
Majority of STEMI patients should be treated with primary PCI and all efforts should be made to shorten transfer delays and to increase primary PCI availability. However, because of logistic constraints most patients will be treated by thrombolysis and time delay to it can be minimized by the adoption of pre hospital (in ambulance) thrombolysis. Newer trials have clearly shown that although early thrombolysis stabilizes the first bite, prevention of second bite in the form of reocclusion needs routine post thrombolytic PCI which should be optimally timed between 3 and 24 hours.
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