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January/February 2010
PCI Strategies After Fibrinolytic Therapy
How to choose the appropriate reperfusion strategy.
Survival in patients presenting with ST-segment elevation myocardial infarction (STEMI) depends on early, complete, and sustained reperfusion of the infarct-related artery.1-3 Pharmacological therapy with the use of fibrinolytic agents can achieve early reperfusion, but complete flow is restored at best in only 60% of patients.4 Mechanical reperfusion with primary percutaneous coronary intervention (PCI) can restore complete flow in up to 95% of patients and is associated with a lower rate of reocclusion.4 However, unlike fibrinolytic therapy, which is widely available, primary PCI can only be performed in centers equipped with a catheterization facility. An overview of 23 randomized trials comparing the two strategies reported an absolute 2% survival benefit with primary PCI.5 In this study, intracranial hemorrhage occurred in 1% of patients treated with fibrinolytic therapy but was virtually eliminated with primary PCI.
Primary PCI holds a survival advantage only if it can be performed in a timely fashion. The principle that “time is myocardium” applies to both fibrinolysis (door-to-needle) 1 and primary PCI (door-to-balloon).6 Hence, guidelines have been developed to help physicians choose the appropriate reperfusion strategy for patients with STEMI.7 Although pharmacological and catheter-based strategies may be viewed as separate and competing options in some situations, the coupling of these two strategies is now believed to play a key role in regional STEMI systems in which primary PCI is not applicable.
FACILITATED PCI
The term facilitated PCI denotes a strategy of planned
immediate PCI after an initial pharmacological regimen (ie,
full-dose fibrinolysis or a platelet glycoprotein IIb/IIIa
inhibitor, or a combination of reduced-dose fibrinolytic
therapy and a platelet glycoprotein IIb/IIIa inhibitor).
Because of the inherent limitations of fibrinolytic therapy
and primary PCI, it was suggested that combining the two
therapies could provide the speed of pharmacological
reperfusion with the more complete and sustained reperfusion
provided by PCI. To address the merits of full-dose fibrinolytic-
facilitated PCI, the ASSENT-4 trial8 was designed to
compare tenecteplase-facilitated PCI with primary PCI. The
primary endpoint in this study was a composite of death,
congestive heart failure, or shock within 90 days of randomization.
The trial was stopped early, after enrolling 1,667
patients, because of higher in-hospital mortality in the facilitated
group than in the standard PCI group. At 90 days, the
primary endpoint was measured in 19% of patients assigned
to facilitated PCI versus 13% of those assigned to primary
PCI (P = .005). In light of these results, the updated 2007. American College of Cardiology/American Heart
Association STEMI guidelines gave a class III recommendation
for a full-dose fibrinolytic-facilitated PCI strategy.9
RESCUE PCI
Rescue PCI is defined as PCI performed for failure of fibrinolytic
therapy. Accordingly, patients are reassessed 60 to 90
minutes after initiating fibrinolytic therapy to determine if
reperfusion has occurred. A repeat electrocardiogram is
used to assess reperfusion: a criterion of < 50% resolution in
the lead with previous maximal ST-segment elevation suggests
absence of reperfusion. This strategy was recently evaluated
in the REACT trial.10 The primary endpoint in this
trial, a composite of death, recurrent myocardial infarction,
cerebrovascular event, or severe heart failure at 6 months,
was significantly less in patients treated with rescue PCI
(5.3% vs 29.8.% among those treated with conservative therapy
vs 31% among those treated with repeat fibrinolysis)
(P < .01).
PHARMACOINVASIVE STRATEGY
Although primary PCI has become the treatment of
choice in many urban centers where catheterization facilities
are usually available, fibrinolysis remains the treatment of
choice in most rural community hospitals because quick
access to PCI-capable centers is not usually available.
However, fibrinolysis followed by watchful waiting and noninvasive
assessment is limited by incomplete reperfusion
and reocclusion of the infarct-related artery.2,11,12
A strategy of coupling fibrinolytic therapy and early cardiac catheterization was tested several years ago during the era of balloon angioplasty.13-15 This approach was found to be complicated by increased bleeding, with no apparent clinical benefit compared with fibrinolysis alone, and was then abandoned. Technological advances in coronary angioplasty with the introduction of stents prompted investigators to design trials to re-evaluate the merits of coupling fibrinolysis with an early invasive approach. Seven randomized trials conducted during the era of coronary stenting have reported on the outcomes of combining a pharmacological reperfusion strategy with an early invasive strategy compared to a pharmacological reperfusion strategy followed by either watchful waiting or a late invasive strategy.16-23 Table 1 describes the pharmacological approach used for each of these trials and their respective primary outcome. The combination strategy used in these trials has led to the term pharmacoinvasive, which is now defined as a strategy in which full-dose fibrinolysis, or a combination of reduceddose fibrinolytic therapy and a platelet glycoprotein IIb/IIIa inhibitor, is given for reperfusion with the intention of performing early (< 24 hours) cardiac catheterization/PCI.
It is important to understand the difference between a pharmacoinvasive strategy and a facilitated PCI strategy. The plan with facilitated PCI is to proceed immediately with intervention after the initiation of pharmacological agents, with the focus on drugs helping with the mechanical intervention. The pharmacoinvasive approach, as currently defined, does not mandate immediate intervention after the initiation of pharmacological reperfusion therapy, and the focus is on the PCI helping the outcomes of the pharmaceutical approach. Among some of the contemporary randomized trials that assessed the pharmacoinvasive approach, the time from administration of drug to catheterization or balloon inflation in the early invasive arm of the study was relatively short, and patients in these trials could be construed as having had facilitated PCI. However, the comparator arm in these trials was not primary PCI, as was the case in the ASSENT-4 trial, but was usual care or delayed intervention after administration of fibrinolytic agents.
The designs of the pharmacoinvasive trials differ. In SIAM III, all patients in the conservative arm were required to undergo coronary angiography before hospital discharge, with intention to perform PCI at that time if needed. In CAPITAL AMI, patients randomized to the pharmacoinvasive arm were taken to the catheterization laboratory immediately and had the shortest time to balloon among the trials (95 minutes). This is in contrast to GRACIA-1, in which the time to angiography was 16.7 hours. The optimal time window for early PCI after fibrinolysis remains to be determined. Also, in GRACIA-1, predischarge revascularization in the conservative group was analyzed as a secondary endpoint because only postdischarge revascularization was regarded as part of the primary endpoint. The only trial that used reduced fibrinolytic therapy plus abciximab as initial pharmacological treatment was the CARESS-in-AMI study. The protocol in TRANSFER AMI and in NORDISTEMI recommended concomitant treatment with clopidogrel at the time of fibrinolysis, which may have improved outcomes in both the pharmacoinvasive and the conservative arms of these trials. Earlier initiation of fibrinolysis could have an impact on events as well; fibrinolysis was initiated in the prehospital setting in 41% of the patients in the WEST trial and in 57% of the patients in the NORDISTEMI trial. Finally, in the NORDISTEMI study, the median transfer distance to PCI was the longest at 158 km (98 miles), and the results provide support for the application of a regional pharmacoinvasive approach for patients living at a far distance from a PCI center.
As depicted in Figure 1, most of the randomized trials evaluating the pharmacoinvasive approach found a significant benefit for patients assigned to the pharmacoinvasive strategy. In the NORDISTEMI trial, the primary endpoint did not reach statistical significance, but the composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive group compared with the conservative group (6% vs 16%; P = .01). Two meta-analyses that evaluated randomized pharmacoinvasive trials have reported that an early invasive strategy after fibrinolytic therapy is associated with significant reductions in mortality and reinfarction.24,25 These two studies were published before the publication of the results of TRANSFER-AMI and CARESS-in-AMI, which also showed that the pharmacoinvasive strategy reduced ischemic events compared to a conservative approach. The risk of major bleeding was noted to be slightly higher with a pharmacoinvasive strategy in some of the trials, but this did not reach statistical significance in any of these trials (Figure 2). Pooling the data from these trials may help further define the risk of bleeding with early angiography after fibrinolytic therapy.
The 2008 European guidelines have recommended that coronary angiography be performed in patients with evidence of reperfusion within 3 to 24 hours after initiation of fibrinolytic therapy regardless of symptoms (grade IIa).23 The 2009 focus update American College of Cardiology/American Heart Association guidelines on STEMI suggest that it is reasonable for high-risk patients who receive fibrinolytic therapy as primary reperfusion therapy at a non- PCI–capable facility to be transferred as soon as possible to a PCI-capable facility where PCI can be performed either when needed or as a pharmacoinvasive strategy (grade IIa).26 Of note, the 2009 appropriateness criteria for coronary revascularization do not recommend immediate revascularization with either fibrinolytic therapy or primary PCI in patients with STEMI presenting > 12 hours from symptom onset without ongoing symptoms of ischemia or clinical instability. 27 The results of the Occluded Artery Trial (OAT) showed that PCI performed 3 to 28 days after myocardial infarction with occlusion of the infarct-related artery did not reduce the occurrence of death, reinfarction, or heart failure in stable patients.28 In fact, PCI was associated with a trend toward excess reinfarction during 4 years of follow- up. The results of OAT also suggest that in some patients, delays in performing coronary angiography early after initiating fibrinolytic therapy may compromise the clinical benefits associated with intervention, as demonstrated in the pharmacoinvasive trials.
THE OTTAWA STEMI SYSTEM
There has been increasing interest in
developing regional systems that provide
optimal reperfusion for STEMI patients.
The University of Ottawa Heart Institute
is the central cardiac catheterization
facility that provides access for PCI for
the entire Ottawa region, which has a
population greater than 1.2 million. The
Ottawa STEMI program has defined two strategic zones
based on the likelihood of achieving a door-to-balloon time
of < 90 minutes (Figure 3). Patients seen within the inner
zone are treated with primary PCI, and patients seen in the
outer zone are treated with the pharmacoinvasive
approach. This STEMI system has been fully operational
since May 2009 and continues to provide for all 16 hospitals
within the region.
SUMMARY
Primary PCI is now recognized as the treatment of choice
for patients presenting with STEMI when the delay to bal-loon is < 90 minutes. When this is not possible, a pharmacoinvasive
strategy allows patients to receive an initial therapy
with fibrinolytic agents and ensures complete and sustained
reperfusion by coupling this therapy with an early
invasive approach. STEMI systems are now incorporating
these two strategies into practice.
Michel R. Le May, MD, is Professor and Director of the Coronary Care Unit, Director of the STEMI program, University of Ottawa Heart Institute in Ottawa, Ontario. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Le May may be reached at (613) 761-4223; mlemay@ottawaheart.ca.
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