ST elevation myocardial infarction facilitated percutaneous coronary intervention

Myocardial infarction
ICD-10	I21-I22
ICD-9	410
DiseasesDB	8664
MedlinePlus	000195
eMedicine	med/1567  emerg/327 ped/2520

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Vijayalakshmi Kunadian MBBS MD MRCP [2]

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Facilitated PCI

Facilitated PCI is defined as the intent to perform a PCI (either conventional balloon angioplasty or coronary stent placement) in the setting of STEMI following treatment with either a full dose or half dose of a fibrinolytic agent. This approach is also termed a pharmaco-invasive strategy. This strategy differs from rescue or adjunctive PCI in that the intent of facilitated PCI is to perform PCI, and the administration of a fibrinolytic agent is intended to improve the PCI results. Facilitated PCI is the subject of this chapter.

Strategies that Facilitated PCI should be distinguished from include:

Primary PCI

Primary PCI is defined as the performance of percutaneous coronary intervention (PCI) (either conventional balloon angioplasty or coronary stent placement) in the setting of ST elevation MI (STEMI) without antecedent treatment with a fibrinolytic agent. The chapter on Primary PCI can be found here.

Rescue PCI

Stated simply, this is performance of a PCI in a closed artery following fibrinolytic therapy. Rescue PCI is defined as the intent to administer a fibrinolytic agent in the setting of STEMI, and the performance of PCI for failure of the fibrinolytic agents is unintended. If there are clinical signs and symptoms of failure of the fibrinolytic agent to achieve reperfusion, then rescue PCI is performed to open the totally occluded artery. The strategy differs from facilitated PCI, a strategy in which the intent is to administer a fibrinolytic agent, and routinely perform PCI in the majority of patients even in the presence of or irrespective of signs and symptoms of successful fibrinolytic reperfusion. The chapter on Rescue PCI can be found here.

Adjunctive PCI

Stated simply, this is performance of a PCI in an open artery following fibrinolytic therapy. Adjunctive PCI is defined as the intent to administer fibrinolytic agent in the setting of STEMI, and the performance of PCI for partial success of the fibrinolytic agent is unintended. If there are clinical signs and symptoms of incomplete reperfusion, then adjunctive PCI is performed to further open a patent artery (one with TIMI grade 2 or 3 flow). The strategy differs from facilitated PCI in that the intent is to administer a fibrinolytic agent, and the performance of PCI is intended to improve the fibrinolytic results.

Introduction

This approach to reperfusion therapy has also been labeled a pharmacoinvasive approach. This treatment strategy refers to the pre-PCI administration of pharmacologic reperfusion followed by planned diagnostic catheterization and immediate Percutaneous Coronary Intervention. The goal of facilitated PCI is to improve coronary patency before the procedure for the treatment of ST elevation myocardial infarction. Examples of pharmacotherapies administered before PCI as part of a facilitated PCI approach are:

1. Full dose or reduced dose fibrinolytic drug administration + PCI
2. The combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent (e.g., administration of fibrinolytic drug’s typically reduced to half dose) + PCI
3. Some consider the administration of glycoprotein IIbIIIa inhibitors followed by PCI a facilitated PCI strategy while others consider this part of a traditional Primary PCI strategy

Limitations of Fibrinolysis

Fibrinolysis has been the main stay of treatment for patients with acute ST segment elevation myocardial infarction over 30 years. It still continues to be used as the primary reperfusion treatment in a number of countries where primary PCI facilities are not imminently available. For patients who present within 2 hours of symptom onset, a previous study demonstrated that there was no significant difference in the in-hospital mortality between fibrinolysis and PPCI treatment groups (5.1% vs. 7.8%, p=0.37). Another study demonstrated a trend towards reduction in 30-day mortality with fibrinolysis when initiated within 2 hours of symptom onset compared to PPCI (2.2% vs. 5.7%, P=0.058) . It is well known that fibrinolysis however is associated with a number of limitations. These include the inability of fibrinolysis to restore normal TIMI flow grade 3 in 50-60% of patients, the occurrence of intracerebral hemorrhage in 0.9% of cases and recurrent ischemia and reinfarction in 3-5% cases.

Largely as a result of these limitations, previous studies including a meta-analysis of 23 randomized trials suggest that primary PCI (PPCI) is the optimal treatment strategy for patients with acute ST elevation myocardial infarction with a significant reduction in the short term (4-6 weeks) combined endpoints of death, non fatal reinfarction and stroke compared to fibrinolytic therapy (8% vs. 14% p<0.0001) . These benefits were demonstrated not only in the short term outcomes, but also in the long term outcomes (at 6-18 months). In centers where primary PCI is available, a door-to-balloon time of <90 minutes is associated with improved outcomes .

Limitations of Primary PCI

However, primary PCI is not without its limitations. An analysis from the US-NRMI (National Registry of Myocardial Infarction) study demonstrated that only 4.2% of patients achieve a door-to-balloon time of <90 minutes and in around 15% of cases it is achieved within 120 minutes .

Bringing the best of Fibrinolysis and Primary PCI Together: Rationale for Facilitated PCI

Given the delays associated with implementing a primary PCI in the real world, it has been hypothesized that administration of agents to open the culprit artery prior to PCI would be of benefit. It should alos be kept in mind that there are numerous centers where PPCI is not available, and it has been hypothesized that a strategy of initial fibrinolysis and or administration of glycoprotein IIb/IIIa inhibitor before transport to a PPCI center for mechanical revascularization would be of benefit. Initial studies suggested that facilitated PCI was associated with an increase in the rate of patency or TIMI grade 2/3 flow on arrival to the cardiac catheterization laboratory when compared to groups that had not received a fibrinolytic agent prior to intervention . It was hoped that restoration of early patency using pharmacotherapy prior to PCI would result in reduced infarct size, thrombus burden and improved clinical outcomes.

Clinical trials of Facilitated PCI

These trials tested the hypothesis that pre-PCI administration of a pharmacotherapy would improve clinical outcomes. To be included as a facilitated PCI trial, all patients had to undergo PCI; the only variable that changed was whether the patients did or did not receive pharmacotherapy prior to PCI.

The facilitated PCI strategy has been evaluated in small and large randomized and non-randomized studies. These studies are broadly classified into 3 categories depending upon the agent/agents used to facilitate PCI:

(1) Facilitated PCI using fibrinolysis alone,

(2) Facilitated PCI using glycoprotein IIb/IIIa inhibitor only and

(3) Facilitated PCI using a combination of reduced dose fibrinolytic agent and glycoprotein IIb/IIIa inhibitor (Table 1).

Facilitated PCI Utilizing Pre-PCI Fibrinolysis Alone

PACT

The PACT (Plasminogen-activator Angioplasty Compatibility Trial) trial determined the safety and efficacy of the administration of reduced dose recombinant tissue plasminogen activator (rtPA) compared to placebo followed as soon as possible by coronary angiography . Administration of rtPA was associated with imporved pre-PCI patency of the infarct related artery on initial angiography compared to the placebo group (TFG 2/3 61% vs. 34%, p=0.001). Among patients with initial patent arteries on arrival to the cardiac catheterization laboratory, the ejection fraction was significantly improved at 5-7 days follow-up. There was no difference in the occurrence of adverse events.

PRAGUE

The PRAGUE trial (PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency fibrinolysis) primarily tested the safety of transport of patients with STEMI to a PCI center but consisted of a group of patients who received fibrinolysis (using streptokinase) and were transported for PCI . This study consisted of STEMI patients who presented within 6 hours of symptom onset. In total, 99 patients received fibrinolysis alone, 100 patients received fibrinolysis and were transported for primary angioplasty (this is the facilitated arm) and 101 patients underwent primary angioplasty without fibrinolysis. In the PRAGUE study, primary angioplasty was superior in terms of reductions in death, reinfarction and stroke compared to the fibrinolysis group and fibrinolysis and transport group (8% vs. 23% vs. 15%, p<0.02 respectively). The incidence of reinfarction was reduced using the transport strategy compared to fibrinolysis alone (1% in the primary PCI group vs. 7% in the fibrinolysis + PCI or FPCI group, vs. 10% in fibrinolysis alone group, p<0.03). PRAGUE suggests that the transport of STEMI patients is feasible, and that primary PCI is a superior strategy to Facilitated PCI or fibrinolysis alone.

GRACIA 2

Fibrinolysis facilitation using a modern fibrin specific agent (tenecteplase) was studied in the GRACIA-2 and ASSENT-4 trials. The GRACIA-2 (Grupo de Ana´lisis de la Cardiopatı ´a Isque´mica Aguda) is a study that tested the benefit of early administration of tenecteplase followed by PCI (n=104) within 3-12 hours of randomization compared to a strategy of PCI with abciximab alone (n=108). The occurrence of post-PCI TFG 3/TIMI Myocardial Perfusion Grade 3 was significantly higher in the fibrinolysis and PCI group compared to PCI alone group (21% vs. 6%, p=0.003). Although there was initial angiographic improvement associated with the facilitated PCI strategy, similar efficacy was demonstrated in terms of infarct size limitation and preservation of left ventricular function in these two groups. This trial was not adequately powered to compare the clinical outcomes using the two strategies.

ASSENT 4

The ASSENT-4 trial (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention) was the largest trial of facilitated PCI using full dose tenecteplase therapy (n=829) compared to primary PCI (n=838) among STEMI patients who presented within 6 hours of symptom onset and an anticipated delay of 1-3 hours in performing the PCI. Although this study initially planned to recruit 4000 patients in total, the study was prematurely completed with 1667 patients due to the increased occurrence of death in the facilitated PCI group (6% vs. 3%, p=0.0105). The primary endpoint which consisted of death, congestive heart failure or shock at 90 days was significantly increased in the facilitated PCI group compared to the standard PCI group (19% vs. 13%, p=0.0045). There was also increase in the incidence of in-hospital stroke (1.8% vs. 0%, p<0.0001), but not major non-cerebral bleed (6% vs. 4%, p=0.3118). At 90 days, there was an increase in reinfarction (6% vs. 4%, p=0.0279) and target vessel revascularization (7% vs. 3%, p=0.0041) with the facilitated PCI strategy .

Several potential explanations have been postulated regarding the negative outcomes of the ASSENT-4 trial. The greater the delay in performing primary PCI, the greater the ptential benefit of a facilitated PCI approach. The door to balloon times were realtively rapid in ASSENT 4, and this may have diminished the potential benefit of the facilitated PCI strategy. This study is also criticized for lack of heparin infusion after bolus administration, no up front clopidogrel use and the use of glycoprotein IIb/IIIa inhibitor was not allowed except in bail out situations. Although the initial ST segment resolution was better in the facilitated group, at 60-180 minutes the ST segments worsened which could have been due to the prothrombotic effects and reocclusion.

Fibrinolysis facilitation vs. fibrinolysis alone

In the CAPITAL AMI trial (Combined Angioplasty versus Pharmacological Intervention versus Fibrinolysis ALone in Acute Myocardial Infarction) , a strategy of facilitated PCI versus fibrinolysis alone was tested. A total of 170 patients were randomized to receive tenecteplase alone (n=84) or tenecteplase followed by percutaneous intervention (n=86). There was a significant reduction in the combined primary endpoints of death, reinfarction, recurrent unstable ischemia and stroke in the intervention group compared to the lytic alone group (11.6% vs. 24.4%, p=0.04). This was mainly driven by the reduction in recurrent unstable ischemia (8.1% vs. 20.7%, p=0.03) and a trend towards reduction in repeat myocardial infarction (5.8% vs. 14.6%, p=0.07) in the PCI group. There was no difference in death, stroke and bleeding rates between the two groups.

Facilitated PCI with a glycoprotein IIb/IIIa inhibitor alone

The glycoprotein IIb/IIIa inhibitors such as the small molecules tirofiban, and eptifibatide as well as the large molecule abciximab have been associated with improved outcomes in Primary PCI trials . The agents have also been evaluated in facilitated PCI trials where early administration of glycoprotein IIb/IIIa inhibitors in the emergency room (ER) has been compared with later administration in the cardiac catheterization laboratory.

Facilitated PCI trials using tirofiban

The trials using tirofiban to facilitate PCI demonstrated significant improvement in the TFG 3 pre PCI but were not powered to demonstrate significant clinical benefit. The benefit of early administration of tirofiban compared to upstream administration was assessed in the TIGER-PA trial (TIrofiban Given in the Emergency Room before Primary Angioplasty). This study consisted of 100 patients who received tirofiban either in the ER or in the cath lab. There was a significant improvement in the initial angiographic parameters such as TIMI flow grade (TFG), corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG). This study was not powered to demonstrate a significant clinical benefit .

Likewise, the investigators from the On-TIME trial (Ongoing Tirofiban in myocardial infarction Evaluation) evaluated a similar strategy of administration of tirofiban approximately one hour before PCI compared to administration of tirofiban in the cath lab . This study also was not powered to demonstrate clinical benefit. However, the angiographic outcome of TFG 3 pre PCI was used as the primary endpoint which was not increased with the use of early tirofiban compared to upstream tirofiban (19% vs. 15%, p=0.22). In addition, an increase in combined TFG 2/3 flow, reduced thrombus burden and improved myocardial perfusion on angiography noted in the early group did not translate into improved angiographic outcome post PCI or on clinical outcomes.

In contrast to the above two studies, another small trial demonstrated that the use of tirofiban in the ER was not associated with a significant difference in the occurrence of TFG 2/3 compared to using tirofiban in the cath lab (39% vs. 27% p >0.2) but a trend towards better ST segment resolution was observed in the ER group (69% vs.77%, p=0.07) .

Facilitated PCI trials using abciximab

A more recent trial studied the benefit with the use of abciximab in the emergency room (ER) compared to upstream administration in the cath lab. The RELax-AMI study (Randomized Early versus Late abciximab in Acute Myocardial Infarction treated with primary coronary intervention) included 210 patients with acute ST segment elevation myocardial infarction. Of these 105 patients received abciximab in the ER and the remaining 105 received it in the cath lab. Similar to the TIGER-PA studies, this study demonstrated significant improvements in the pre-PCI angiographic parameters including TFG (grade 3 24% vs. 10%, p=0.01), corrected TIMI frame count (78±30 vs. 92±21, p=0.001) and myocardial blush grade (MBG 2/3) [15% vs. 6%, p=0.02] in the early abciximab group compared to the upstream group. The post-PCI ST segment resolution (>70%) was greater in the early abciximab group (50% vs. 35%, p=0.03) and the myocardial blush grade was also better (MBG 2/3 79% vs. 58%, p=0.001). The one month ejection fraction was significantly better in the early group .

Similarly, the ERAMI trial (Early Reopro Administration in Myocardial Infarction) demonstrated significant improvements in the post PCI CTFC and increased rate of TMPG 3 among patients who received abciximab in the ER compared to those who received it in the cath lab without any difference in angiographic parameters pre-PCI . Similar to the ERAMI trial, Zorman et al demonstrated that administration of abciximab in the ER 12 hours before the procedure resulted in increased patency rates of the infarct related arteries. In addition there was also better ST segment resolution, and better survival compared to administration of abciximab in the cath lab or PCI without abciximab. Likewise, the ReoPro- BRIDGING study also demonstrated that early administration of abciximab was associated with increased patency of infarct arteries and improved myocardial perfusion . Another study using abciximab in the ER demonstrated not only an increased TFG 3 flow rate and improved TFC/MBG but also left ventricular function recovery compared to using abciximab in the cath lab .

Facilitated PCI using abciximab versus fibrinolysis

The use of enoxaparin in addition to a fibrinolytic and glycoprotein IIb/IIIa inhibitor was examined in another study which determined the safety and efficacy of administration of enoxaparin followed by tenecteplase (n=104) versus enoxaparin followed by abciximab and transfer for PCI (n=101). This study comparing glycoprotein IIb/IIIa facilitated PCI with fibrinolysis in the presence of enoxaparin in both groups did not demonstrate significant difference in ST segment resolution (>50%) at 120 minutes between the two groups (64% vs. 68%, p=NS). The TFG 3 (at 5-7 days after inclusion in the study) was present in 54% of cases in the fibrinolytic group compared to 71% of cases in the invasive group, p=0.04. There was only a trend towards clinical benefit (death, stroke and reinfarction) in the invasive group compared to the lytic group (3% vs. 8%, p=NS) despite the reduced symptom to treatment time in the fibrinolytic group compared to the invasive group (114 minutes vs. 202 minutes) .

Facilitated PCI trials using eptifibatide

Comparable to studies using tirofiban and abciximab, in the INTAMI study (INTegrilin in Acute Myocardial Infarction), Zeymer et al demonstrated that administration of eptifibatide in the ER was associated increased TFG 3 pre PCI compared to administration in the cath lab (34% vs. 10%, p=0.01) [22]. But there was no difference in the TFG 3 post-PCI, death, reinfarction, stroke and major bleed up to 30 days.

The TITAN TIMI-34 (Time to Integrilin Therapy in Acute Myocardial Infarction) was a larger trial than the INTAMI trial consisting of a total of 343 STEMI patients of which 180 received eptifibatide in the ER compared to 163 who received the drug in the cath lab. The primary endpoint, pre PCI corrected TIMI frame count was significantly better in the ER group compared to the cath lab group (77.5±32.2 vs. 84.3±30.7, p=0.049). The pre PCI TMPG 3 was more frequently seen in the ER group (24% vs. 14%, p=0.026). However there was no difference in the bleeding events and clinical outcomes between the two groups [23].

Facilitated PCI trials combining low dose fibrinolytic agent and glycoprotein IIb/IIIa inhibitor

Given the discrepancies in the outcomes in facilitated PCI using fibrinolytic alone and glycoprotein IIb/IIIa inhibitor alone, a strategy of combined therapy using low dose fibrinolytic and full dose glycoprotein IIb/IIIa inhibitor was examined. The Strategies for Patency Enhancement in the Emergency Department (SPEED-GUSTO-4 Pilot trial) examined the benefit of administration of fibrinolytic with or without abciximab among patients undergoing early PCI following an acute MI. This non randomized study demonstrated that administration of a half-dose reteplase and abciximab was safe and effective. This strategy was associated with TIMI flow grade 3 in 86% of cases at 90 minutes and the composite end point of death, reinfarction and urgent revascularization occurred in 5.6% of cases in the PCI group compared to 16% in those who did not undergo PCI [7].

The Alteplase and Tirofiban in Acute Myocardial Infarction (ATAMI), a small single centre study demonstrated that there was significantly high rates of TIMI grade 2/3 flow among STEMI patients randomized to combination therapy with 50mg alteplase and tirofiban prior to planned PCI compared to upstream administration of tirofiban in the catheter laboratory (87% vs. 42%, p<0.0001). These groups were compared with a matched control patients who underwent PCI with provisional abciximab in the cath lab (29% of patients had TIMI flow grade 2/3). The 30-day mortality was significantly lower in the combination therapy group compared to upstream tirofiban group and the control group (0.7% vs. 5.5%, p<0.02 vs. 6.3%). There were no differences in the incidence of bleeding events between the three groups [24]. This study has its limitations given the fact that this was a single center study with relatively small number of patients and a lower dose of tirofiban was used (10μg/kg).

Contrary to the SPEED and the ATAMI studies, the BRAVE (Bavarian Reperfusion Alternatives Evaluation) study by Kastrati and coworkers was an open label, randomized multicenter study in which the beneficial effect of the use of half dose reteplase and abciximab on the infarct size using single photon emission tomography (SPECT) was examined. The investigators did not demonstrate any improvement in the final infarct size using the combination therapy (n=125) compared to abciximab alone (n=128) among STEMI patients referred for PCI (mean difference in the infarct size was 1.3% between the two groups). There was no difference in the secondary endpoints such as death, reinfarction or stroke [25]. A similar strategy was examined in APAMIT (Asia Pacific Myocardial Infarction Trial) where all STEMI patients received abciximab and were randomized to either immediate PCI or to PCI sixty minutes later following the administration of alteplase. Like all previous studies this study demonstrated that facilitation with a lytic in addition to abciximab was associated with an increase TFG 3 pre PCI but no difference in the clinical outcomes [26].

Given the small sample size in the above studies, another randomized study, the ADVANCE-MI (ADressing the Value of facilitated Angioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction) study was designed to answer similar questions whether a strategy of combination fibrinolytic and a different glycoprotein IIb/IIIa inhibitor (eptifibatide) compared to eptifibatide + placebo prior to PCI would improve clinical outcomes. Although this study originally planned to recruit 5640 patients, it was prematurely terminated because of slow recruitment. An analysis of a total of 148 patients suggested that combination therapy (reduced dose tenecteplase and eptifibatide) was associated with improved epicardial flow and myocardial tissue perfusion on pre-PCI angiography. This strategy however resulted in a trend towards an increase in adverse outcomes (death, new/worsening heart failure or bleeding) compared to eptifibatide + placebo group [27].

The FINESSE trial (the largest trial on combination therapy) results were presented in the European Society of Cardiology meetings in 2007 (www.escardio.org). The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) study is a 3000-patient, prospective, multicenter, randomized, double-blind, placebo-controlled trial. The study was designed to compare the efficacy and safety of early administration of reduced-dose reteplase and abciximab combination therapy or abciximab alone followed by PCI with abciximab alone administered just before PCI for acute STEMI. Patients were randomized to one of the two facilitated PCI treatments or primary PCI in a 1:1:1 fashion [28]. At 90 days, there were no differences between treatment arms for the primary composite end points of the trial: all-cause mortality, readmission for heart failure, ventricular fibrillation, or cardiogenic shock [10.7% (PCI only group, n=806) vs. 10.5% (abciximab facilitated group, n=818) vs. 9.8% (reteplase and abciximab group, n=828)]. There were also no differences in all-cause mortality (4.5% vs. 5.5% vs. 5.2% respectively), complications of MI (8.9% vs. 7.5% vs. 7.4%), or any of the independent components of the primary composite end point. For safety end points, rates of TIMI major bleeding and minor bleeding were significantly higher for the abciximab/lytic facilitated PCI strategy as compared with primary PCI (14.5% vs. 6.9%, p<0.001). There was also a strong trend toward increased intracranial hemorrhage through discharge or day seven in the combined abciximab/lytic facilitation approach.

More recently, although not truly a facilitated PCI study, the CARESS-in-AMI (Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction) study determined whether early transfer for PCI following pharmacotherapy administration improves outcomes compared to a conservative watchful waiting approach among patients with STEMI with anticipated delay in primary PCI due to their presentation to a non-PCI center [29]. Six hundred patients in this study were pretreated with aspirin, heparin, half dose reteplase and abciximab. Subsequently patients were randomized to either immediate transfer for PCI or transfer only in case of failed reperfusion or clinical deterioration. The investigators demonstrated that there was significant benefit in terms of reduction in 30-day mortality with the immediate transfer strategy (4.4% vs. 10.7%, p=0.004) without any differences in the bleeding events. It is important to note that the CARESS-in-AMI study determines whether early PCI improves pharmacotherapy outcomes. This is in contrast to the facilitated PCI strategy where pharmacotherapy is administered to improve PCI outcomes.

Meta-analysis of facilitated PCI

Three meta-analyses have been performed so far on the facilitated PCI strategy. All three meta-analysis consisted of varying number of clinical trials and patients. But all three analyses suggest that facilitated PCI does not improve clinical outcomes and is associated with adverse outcomes. Keeley and colleagues performed a meta-analysis of 17 randomized trials (consisting of facilitated PCI trials using fibrinolysis alone, glycoprotein IIb/IIIa alone and combination pharmacotherapy) comparing the safety and efficacy of facilitated PCI compared with primary PCI [30]. This study consisted of 2237 patients in the facilitated PCI group and 2267 patients in the PPCI group. Facilitated PCI was associated with an increased rate of TIMI flow grade (TFG) 3 compared to PPCI group prior to PCI (37% vs. 15%). This difference in the TFG 3 was not demonstrated following the completion of the PCI procedure between the two groups (89% vs. 88%). In terms of clinical outcomes, compared to PPCI, facilitated PCI was associated with an increase in death (5% FPCI vs. 3% PPCI), non-fatal reinfarction (3% vs. 2%), urgent target vessel revascularization (4% vs. 1%), major bleed (7% vs. 5%), hemorrhagic strokes (0.7% vs. 0.1%, p=0.0014) and total strokes (1.1% vs. 0.3%, p=0.0008). This study consisted of trials on facilitated PCI since 1990 to September 2005. This study did not include the analysis from the more recent FINESSE trial which was published subsequent to the analysis by Keeley and colleagues.

A more recent meta-analysis, although a smaller study compared to Keeley and co-workers, demonstrated similar findings that facilitated PCI using half-dose fibrinolytic and glycoprotein IIb/IIIa inhibitor (combination therapy) is not a beneficial strategy in the management of patients with STEMI [31] despite an increase in the initial TFG 3 in the facilitated group (49% vs. 21%, p<0.00001). There was an increase in major bleeding in the facilitated group (9.5% vs. 4.7%, p=0.007) with no difference in 30-day mortality and reinfarction rates. This meta-analysis consisted of the ADVANCE-MI [27], BRAVE [25], SPEED [7] and APAMIT trials [32].

Another meta-analysis evaluated three interventional strategies following STEMI in a total of 5253 patients from 15 randomized trials: (1) rescue PCI vs. no PCI, (2) early (≤24 hours) versus delayed or ischemia guided PCI, and (3) fibrinolysis facilitated PCI versus primary PCI [33]. With respect to fibrinolysis facilitated PCI, this study once again demonstrated no benefit with this strategy compared to primary PCI. Fibrinolysis facilitated PCI was associated with an increase in reinfarction (5% vs. 3%, p=0.013) with no impact on mortality. The PACT trial [8], PRAGUE trial [9], ASSENT-4 [11] and GRACIA-2 [10] were included in this analysis.

Cost-effectiveness of facilitated PCI

The cost-effectiveness of facilitated PCI (specifically combination therapy of low dose fibrinolytic and full dose glycoprotein IIbIIIa inhibtion) were evaluated by Coleman et al in an analysis of STEMI patients who presented from 2000 to 2003 at a single center. Compared to Primary PCI, facilitated PCI was both efficacious and cost effective. The baseline TIMI 3 flow was greater in the facilitated group (49.6% vs. 30.7%, p=0.002) and it was also associated with reductions in in-hospital major adverse cardiac events (5.5% vs. 14.2%, p=0.02). Facilitated PCA was also associated with non-significant reductions in intensive care length of stay and total length of stay (0.8 day and 1 day respectively). The authors estimated that in 94.6% of patients, facilitated PCI was both more effective and less costly [34]. It should be noted that these benefits were observed in a single center. Given the failure of facilitated PCI to demonstrate significant benefits in recent randomized prospective trials, the results of this single center const-effectiveness study may only be of historical interest only, as a facilitated PCI strategy is no longer recommended in routine clinical practice.

Recommendations

Given the failure of facilitated PCI to demonstrate significant benefits in recent randomized prospective trials, the 2007 focused update of the American College of Cardiology/American Heart Association 2004 guidelines for the management of STEMI provides a Class IIb recommendation for the performance of facilitated PCI using regimens other than full dose fibrinolytic agents among high risk patients with low bleeding risks (young age, in the absence of uncontrolled hypertension and normal body weight) and when primary PCI is not available within 90 minutes (Level of evidence C) [35].

Similarly the European Society of Cardiology guidelines for percutaneous coronary intervention indicate that there is no evidence to recommend facilitated PCI [36].

Conclusions

Facilitated PCI is associated with an increase in the restoration of both normal epicardial blood fow (TIMI grade 3 flow) and normal myocardial perfusion (Myocardial Perfusion Grade 3) prior to PCI. However, these improvements in pre PCI flow and perfusion have not translated into improvements in angiographic or clinical outcomes following PCI. Given the failure of facilitated PCI to demonstrate significant benefits in recent randomized prospective trials, facilitated PCI is no longer recommended.

References

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36. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W (2005) Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 26:804-847 Table 1: Summary of facilitated PCI trials  »

               Agents used       Number*            TFG pre PCI        Clinical outcomes

Fibrinolysis facilitated PCI

PACT r TPA 302 Better TFG 3 No difference

PRAGUE SK 100 Better TFG 3 PPCI better

CAPITAL-AMI Tenecteplase 86 Better TFG 3 Reduced recurrent ischemia

GRACIA-2 Tenecteplase 104 Better TFG 3 No difference

ASSENT-4 Tenecteplase 829 Better TFG 3 Increased mortality, stroke, shock, reinfarction, TVR

Glycoprotein IIb/IIIa facilitated PCI

TIGER-PA Tirofiban 50 Better TFG 3 Not powered

On-TIME Tirofiban 251 Better TFG 2/3 Not powered

RELax-AMI Abciximab 105 Better TFG 3 Not powered

Svensson et al** Abciximab 101 Better TFG 3 No difference

ERAMI Abciximab 36 No difference No difference/not powered

Zorman et al Abciximab 56 Better TFG 3 Reduced mortality, heart failure

ReoPro BRIDGING Abciximab 28 Better TFG 3 No difference/not powered

Bellandi et al Abciximab 27 Better TFG 3 Not powered

Cutlip et al Tirofiban 28 Not better Not powered

INTAMI Eptifibatide 55 Better TFG 3 No difference in death, stroke, reinfarction, major bleed

TITAN-TIMI 34 Eptifibatide 180 Better TFC No difference

Combination therapy

SPEED Reteplase+abciximab 323 Better TFG 3 No difference

ATAMI Alteplase+tirofiban 151 Better TFG 3 Reduced moratlity

APAMIT Alteplase+abciximab 34 Better TFG 3 No difference

BRAVE Reteplase+abciximab 125 Better TFG 3 No difference

ADVANCE-MI Tenecteplase+eptifibatide 74 Better TFG 3 No difference

FINESSE Reteplase, abciximab 1646*** Better TFG 3 Increased bleeding

Meta-analysis

               No. of trials         No. of pts.           TFG pre PCI        Clinical outcomes

Keeley et al# 17 2237 Better TFG 3 Increased mortality, non fatal reinfarction, TVR and bleeding

Collet et al§ 4 1334 NA Increased reinfarction

Sinno et al¶ 4 424 Better TFG 3 No difference mortality and reinfarction, but increased bleeding

•  » See text for expansion of abbreviations

• *refers to number of patients in the facilitated PCI group

• **TFG at 5-7 days after treatment

• ***Consists of abciximab facilitated group and combined reteplase and abciximab group

• # Includes fibrinolytic trials, glycoprotein IIb/IIIa inhibitor trials and combination therapy trials,

• § Combination therapy trials,

• ¶ Fibrinolysis trials

Mechanism of Benefit

The time-dependent "open vasculature" hypothesis has four components. The achievement of early flow (preprocedural open artery), full epicardial flow (TIMI Grade 3 flow), full myocardial microvasculature flow (TIMI MPG 3) and sustained flow (no abrupt closure or restenosis) have each been shown to improve outcomes in AMI. It is clear that an ideal therapy for acute myocardial infarction would therefore satisfy each of the four components of the "open vasculature" hypothesis with minimal incidence of serious complications. The benefits of reperfusion are time-dependent no matter if epicardial blood flow is restored with percutaneous coronary intervention or thrombolytic administration.

Despite of its economic and application difficulties, the facilitated PCI regimen provides some potential advantages as improved patient stability, earlier time to reperfusion, lower infarct artery thrombus burden, smaller infarct size, higher procedural success rates, higher percentages of TIMI 2 and 3 Flow grades (an open artery), and improved short and long term survival rates. Success during percutaneous intervention is more likely due to a less hectic procedure, and better distal vessel visualization.

Side Effects

Potential risks of facilitated percutaneous coronary interventions include

• Increased minor and major bleeding complications, especially in older patients.
• Additional cost of pharmacotherapy and bleeding complications.

Despite of the potential advantages listed above, performed randomized clinical trials and observational studies of facilitated PCI have not demonstrated any benefit in reducing infarct size or improving outcomes.

Guidelines (Do Not Edit)

Class IIb

1. Facilitated PCI using regimens other than full-dose fibrinolytic therapy might be considered as a reperfusion strategy when all of the following are present:

a. Patients are at high risk,

b. PCI is not immediately available within 90 minutes, and

c. Bleeding risk is low (younger age, absence of poorly controlled hypertension, normal body weight). (Level of Evidence: C)

Class III

1. A planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI may be harmful. (Level of Evidence: B)

References

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