Zimarino, Marco MD, PhD; Sacchetta, Daniele MD; Renda, Giulia MD, PhD; De Caterina, Raffaele MD, PhD
THE TIME FACTOR IN REPERFUSION THERAPY
The prognosis of patients with acute ST-elevation acute myocardial infarction (STEMI) is highly dependent on the effective and rapid restoration of blood flow in the infarct-related coronary artery and in the microcirculation.1 Both thrombolysis and primary percutaneous coronary intervention (PCI) are validated therapies in the treatment of STEMI. Thrombolysis can be ubiquitously administered, and its use is independent of the underlying anatomy. Primary PCI achieves a higher rate of vessel patency and involves a lower occurrence of reocclusion and bleeding when compared to lysis,2,3 but it can be performed, when anatomy is suitable, only in tertiary referral centers, requiring a complex network organization to be widely effective. In patients admitted to the hospital with a duration of symptoms less than 12 hours, primary PCI is associated with lower 30-day mortality, nonfatal myocardial infarction (MI), and stroke compared with fibrinolysis.2,4 Primary PCI is still more effective than thrombolysis when the patient needs to be transferred to a hospital with cath lab facilities, provided that the transfer time is <90 minutes and the vessel patency is restored within 120 minutes.4,5 Thrombolysis is less effective as time passes, whereas the efficacy of primary PCI, although also dependent on time,6 appears to be less time-dependent than thrombolysis.7 Indeed, the superiority of primary PCI over thrombolysis has clinical relevance for a time interval between 3 and 12 hours after the onset of symptoms because of a greater myocardial preservation.8 Relative benefits of primary PCI versus thrombolysis seem negligible within 2 hours of symptom onset, once the gap between the time needed to start mechanical recanalization (as measured by the door-to-balloon time) and the time needed to start pharmacological recanalization (as measured by the door-to-needle time) exceeds 1 hour.9 Prehospital lysis, which would decrease the time to treatment by moving it outside of the hospital setting, is therefore a tempting option. In the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) trial, patients who received prehospital thrombolysis within 2 hours of symptom onset, with rescue PCI in case of lytic failure, showed a trend toward lower 30-day mortality (P = 0.06) when compared with subjects who underwent systematic primary PCI.10 However, it must be acknowledged that 26% of patients who received prehospital lysis underwent rescue PCI, and 70% underwent PCI by 30 days. Prehospital thrombolysis has not been implemented widely, is rarely used in clinical practice, and is scarcely reported in large-scale surveys,11 with the exception of some urban areas.12 This is probably due to the several logistic needs involved, mainly the training of paramedical personnel and the ability to transmit electrocardiograms (ECGs).
In a recent pooled analysis of randomized trials, primary PCI was associated with significantly lower 30-day mortality relative to lysis, regardless of the treatment delay, even when the primary PCI-related delay was less than 35 minutes.7 Primary PCI is extremely effective in achieving coronary recanalization, but this is not synonymous with myocardial reperfusion. In patients with STEMI, a prolonged ischemic time is associated with impaired myocardial perfusion, larger infarct size, and higher 1-year mortality13; all efforts should therefore be made to shorten the ischemic time and to achieve a better myocardial perfusion to obtain myocardial salvage. Angiographic myocardial blush, which is an index of tissue reperfusion, was a more powerful predictor of prognosis than the sole achievement of Thrombolysis In Myocardial Ischemia (TIMI) grade-3 flow (an index of effective recanalization),14 and is therefore currently used as a proxy of myocardial perfusion.15
RATIONALE FOR ADJUNCTIVE THERAPY IN PRIMARY PCI
The importance of arriving in the cath lab with an infarct-related artery already open has been clearly documented; in-hospital survival and left ventricular ejection fraction are significantly higher in patients arriving with an open artery than in those in whom reperfusion already occurred after PCI.16 De Luca et al17 stratified a large cohort of patients undergoing primary PCI by applying the TIMI risk score (Table 1) and documented that the benefit deriving from arriving in the cath lab with an open artery is most evident in the high-risk subgroup.
An approach combining the possibility of quickly starting a widely available and everywhere feasible clot-dissolving medication to promptly restore at least some myocardial blood flow with a subsequent more complete restoration of a widely open epicardial coronary artery lumen as achievable with PCI of the culprit lesion has therefore gained considerable recent interest.18,19 The concept of “facilitated” PCI is based on the premise that pretreatment with a drug potentially affecting the coronary thrombus and thereby permitting some recanalization and/or some reperfusion (thrombolytic drugs and/or glycoprotein GP-IIb-IIIa inhibitors mostly) would improve myocardial salvage, decrease the thrombus burden, and reduce the occurrence of distal embolization that frequently occurs during primary PCI. Thrombus reduction would also “facilitate” PCI (making it literally easier) by allowing an easier passage of the guidewire and permitting the visualization of an angiographic roadmap otherwise often absent when the infarct-related artery is occluded, all advantages that would ultimately translate into an improved clinical outcome. A combined approach with a quickly started clot-dissolving drug (thrombolysis and/or GP-IIb-IIIa inhibition) followed by later PCI of the culprit lesion (lyse now, stent later),20 has therefore gained considerable interest in the recent past.
We deliberately elect here to avoid the term “pharmaco-invasive approach,” which has been sometimes used as a synonym of facilitated PCI and sometimes designates the combined use of drugs and PCI independent of the intention to perform either a PCI with the aim of salvaging myocardium (primary PCI) or to perform a later PCI.
The choice of the best pharmacological strategy for the facilitation of PCI is complex, with several logical candidates, including not only fibrinolytic drugs in either full or reduced dose and GP-IIb-IIIa inhibitors alone or in combination with thrombolytics, but also other antiplatelet agents, unfractionated heparin, low-molecular weight heparins, and direct thrombin inhibitors,1 as well as drugs affecting the microcirculatory vasoreactivity, such as adenosine.21,22 While many currently used drugs (including heparins, aspirin, and clopidogrel) appear to reduce the thrombus burden and should therefore semantically be discussed in this context, such drugs have been implemented in the clinical practice of both thrombolysis alone and of primary PCI. This somewhat justifies the current restriction of the discussion to a much shorter list of drugs, essentially GP-IIb-IIIa antagonists and lytics, or their combination.
The administration of GP-IIb-IIIa antagonists alone, which only tackle the platelet component of the thrombus, is unable to consistently restore vessel patency because a 90-minute TIMI 3 grade flow was documented in less than one third of STEMI patients when abciximab was administered less than 6 hours from symptom onset.23,24 However abciximab,25 tirofiban,26 and eptifibatide27 have been variously shown to reduce thrombus burden and improve myocardial perfusion in the setting of primary PCI.
Conversely, thrombolytic agents alone restore myocardial TIMI 3 grade flow in about two thirds of cases.23 Thrombolytics act by targeting the fibrin mesh component of the thrombus, involving a much larger quantitative proportion of the red thrombus occurring in STEMI, but their use is associated with both heightened thrombin activity and platelet activation. Resistance to fibrinolysis is related to a reduction of both binding to fibrin of the plasminogen activator (PA) used, and to a reduction in the speed of lysis, mainly evident in platelet-rich areas.
The combined use of GP-IIb-IIIa inhibitors and thrombolytic drugs facilitate the rate and the extent of fibrinolysis by primarily improving the rate of PA binding to fibrin and, as a consequence, the rate of lysis.28 However, in order to be clinically effective, the asset of a combined pharmacologic and interventional strategy should outweigh the excess of bleeding deriving from this approach.
COMPLETED TRIALS ATTEMPTING PRIMARY PCI FACILITATION
We reviewed published reports in English from January 2000 to August 2006 using the PubMed database and personal communication with experts in the field. We used the keywords “facilitated angioplasty” and “facilitated PCI.” We also searched through the references of all the studies found from such sources to locate additional references that might be useful for the purpose.
The TIMI-14 trial23 was the first study testing the hypothesis that GP-IIb-IIIa inhibition could be a safe and effective adjunctive to thrombolysis. The study was designed with a dose-finding phase and a dose-confirmation phase, but it showed an unacceptable (10%) rate of major bleeding. In the dose-confirmation phase, the optimal 90-minute TIMI 3 flow rate was achieved with the half-dose (50 mg) alteplase plus abciximab strategy in 77% of cases, significantly more than in the half-dose alteplase-only group (62%; P < 0.02). The safety and effectiveness of a strategy of early primary PCI facilitated by a combination of abciximab and reduced-dose (5 U double bolus) reteplase were then tested in a substudy of the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial, otherwise known as the Global Use of Strategies To Open Occluded coronary arteries (GUSTO) pilot study.29
In the past 5 years, a series of trials have stemmed from these early experiences. They have used clinical and/or angiographic end points for the identification of the “optimal” pharmacologic facilitating strategy. Table 2 summarizes already published large-scale trials that randomized patients to a treatment with lytics and/or GP-IIb-IIIa inhibitors in the setting of primary PCI for STEMI. In a recent meta-analysis of 17 randomized published and unpublished controlled trials comparing facilitated and primary PCI in STEMI, Keeley et al showed that, despite a 2-fold higher initial TIMI grade 3 flow, the facilitated strategy did not result in better clinical outcomes than primary PCI.30 Most of the trials analyzed were underpowered to detect clinical outcomes. The negative results were mainly driven by the largest of these trials, the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) trial,31 which randomized patients with STEMI of less than 6-hour duration to either PCI or PCI preceded by full-dose tenecteplase. This study was halted after enrolling less than half the anticipated number of patients because of a higher in-hospital mortality in the facilitated group (6% versus 3%, P = 0.01). Compared with patients assigned to primary PCI, facilitated PCI showed more strokes (1.8% versus 0%, P < 0.001) and reinfarctions (6% versus 4%, P < 0.05). Several reasons have been advocated to explain the worse clinical outcome of patients receiving tenecteplase in this study.
First, suboptimal antithrombotic adjunctive therapy has been suggested. The absence of a continuous heparin infusion after the bolus administration coupled with a restrictive use of GP-IIb-IIIa inhibitors might have contributed to an excess of early thrombotic complications, mitigating the benefits of earlier reperfusion by tenecteplase.
Second, the bleeding risk, which became far from negligible, is another explanation. Stroke, major non-cerebral bleedings, and hemorrhagic transformation of the infarcted myocardium all contributed to the increased mortality.
Third, the short time interval between the tenecteplase bolus and primary PCI is yet another explanation. Assuming a delay of about 45 to 60 min between the injection of lytics and the recanalization of the infarct-related vessel, the time gain for reperfusion with the drug was probably not relevant in many patients undergoing subsequent primary PCI. This last hypothesis was corroborated by the reduced mortality occurring with facilitated PCI in the case of patients transported by ambulance compared with patients treated in tertiary centers, and by the findings of 2 recently published studies: the Which Early ST-elevation myocardial infarction Therapy (WEST)32 and the Grupo de Analisis de la Cardiopatıa Isquemica Aguda (GRACIA)-2 trials.33
In the WEST trial, 304 patients were randomized to tenecteplase, tenecteplase and mandatory rescue, routine PCI within 24 hours, or primary PCI. Among patients receiving tenecteplase and usual care, the incidence of 30-day mortality and recurrent MI was 13%, significantly higher than in subjects undergoing primary PCI (4%, P = 0.021). Patients allocated to the arm with tenecteplase and mandatory invasive management less than 24 hours showed a 6.7% 30-day death or recurrent MI rate, slightly higher but nonsignificantly different from primary PCI. The findings of the WEST were complementary to the ASSENT-4 trial, as patients in the facilitated PCI arm underwent PCI early but not immediately after lysis. Interestingly, mortality was lowest and very similar in the 2 groups undergoing intervention: lytic-facilitated PCI and primary PCI (1%), although the small size of the study precludes any serious direct comparison of mortality between strategies.
Therefore, the combination of lytics with interventional treatment seemed feasible when a slightly prolonged time interval occurred between lytics administration and PCI.
This concept was lately reinforced by the GRACIA-2 trial,33 which compared the outcomes of 212 patients randomized to full tenecteplase followed by stent-PCI within 3 to 12 hours of randomization or to undergo primary stenting with abciximab within 3 hours. Both groups were similar as to infarct size, left ventricular function at 6 weeks, major bleedings and 6-month cumulative incidence of death, reinfarction, disabling stroke, or repeat coronary revascularization, suggesting that the time window between fibrinolysis and PCI can be safely widened up to 6 hours after the first medical contact.
Treatment delay between the pharmacologic intervention and primary PCI is of utmost relevance. The magnitude of the beneficial drug effect seems to be directly related to the rapidity of drug administration. Montalescot et al analyzed data from 6 trials enrolling STEMI patients treated with abciximab or tirofiban in combination with primary PCI and documented that early drug administration at the point of initial contact (emergency department or ambulance) was associated with a higher TIMI 3 flow grade before primary PCI (20%) and a trend to lower mortality (3.4%) when compared to a late administration in the cath lab (12%, P < 0.001 and 4.7%, P = 0.42, respectively).34 The benefit deriving from GP-IIb-IIIa inhibition seems to be at its maximum when the drug is administered early, as suggested in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL)35 trial, and it tends to wane out when the drug is administered immediately before the primary PCI, as occurred in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) study.36
The additive or synergistic potential of a combination therapy with GP-IIb-IIIa inhibitors and half-dose lytics failed, however, to translate into any benefit in 2 small-scale trials: the ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE-MI)37 and the Bavarian Reperfusion AlternatiVes Evaluation (BRAVE).38 Excess bleeding with combined drug facilitation flawed initial enthusiasms in both studies. These findings were further confirmed in a recent meta-analysis that identified 4 clinical trials by randomizing patients to combination therapy before primary PCI or GP-IIb-IIIa inhibitor alone during primary PCI. Combination therapy with reduced-dose lytics and GP-IIb-IIIa inhibitors was associated with a 2-fold increase in TIMI-3 flow upon arrival to the cath-lab, an increased major bleeding rate, and similar 30-day mortality and reinfarction rate as compared to primary PCI done with GP IIb-IIIa inhibitor alone.39
The American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of STEMI40 currently designate facilitated PCI as a class IIb recommendation with level of evidence B, stating, “Facilitated PCI might be performed as a reperfusion strategy in higher-risk patients when PCI is not immediately available and bleeding risk is low.” The guidelines for PCI of the European Society of Cardiology Task Force are even more restrictive, as they stated, “there is no evidence to recommend facilitated PCI.”8
DOUBTS AND UNCERTAINTIES FROM ONGOING TRIALS
Several ongoing trials are now testing various facilitation strategies before primary PCI. It is remarkable, to the dismay of clinical science, that most such trials will not include an arm of primary PCI without facilitation, something that appears somewhat necessary considering the recent disappointing results of ASSENT-4.31 Most such trials are experiencing recruitment problems, which might preclude their actual completion.
The previously mentioned ADVANCE-MI trial37 has randomized STEMI patients to eptifibatide + half-dose tenecteplase or eptifibatide alone before primary PCI. The study was planned to enroll 5640 STEMI patients to provide 85% power with a 2-sided α = 0.05 to detect a 2.6% absolute reduction in the primary endpoint of death or the occurrence of new/worsening severe heart failure within 30 days with reduced-dose tenecteplase + eptifibatide, assuming an event rate of 13% in the eptifibatide group. The trial has been prematurely stopped for a low recruitment rate after only 149 patients had been enrolled at 30 sites.
The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) study is enrolling STEMI patients in a 3-arm comparison of primary PCI with abciximab administered in the Emergency Department versus abciximab initiated in the cath lab versus abciximab + half-dose reteplase administered in the emergency department.41 The trial has been designed to answer the questions (1) whether an early “upstream” abciximab administration would provide a clinical benefit over a “downstream” use, after the meta-analysis of Montalescot identified only an increase in TIMI flow34 and (2) to unveil the potential benefit of the combination therapy, already unsuccessfully tested in the BRAVE trial.42 Unfortunately a “pure” primary PCI arm has not been included, as the trial does not offer alternatives to abciximab.
In the Combined Abciximab RE-teplase Stent Study in Acute Myocardial Infarction (CARESS in AMI) trial, all patients will receive full-dose abciximab and half-dose reteplase, and will undergo randomization to a conservative strategy with rescue or primary PCI.43
The Randomized Study on Facilitated Angioplasty with Tirofiban or Abciximab (FATA)44 will be the first large-scale independent study to make a direct comparison between 2 GP-IIb-IIIa inhibitors before primary PCI. To test the hypothesis that tirofiban is equivalent to abciximab for facilitating primary PCI, ST segment resolution 90 minutes after opening of the infarct-related artery will be used as the primary endpoint. As of May 2007, 600 of the planned 700 patients have been randomized.
The Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI)45 trial will be performed in a rural area in Canada without cardiac catheterization facilities and will test the safety and efficacy of routine transfer for PCI immediately after thrombolysis. It will randomize 1200 patients, following tenecteplase, to facilitated PCI or a “conservative” approach, with provisional rescue PCI. The primary endpoint will be the composite of death, reinfarction, recurrent ischemia, heart failure, and shock at 30 days.
THE CLOPIDOGREL ISSUE
The ACC/AHA/SCAI guidelines46 define facilitated PCI as “a strategy of planned immediate PCI after an initial pharmacological regimen such as a full dose fibrinolytic, a half-dose fibrinolytic, a GP-IIb-IIIa inhibitor, or a combination of reduced-dose fibrinolytic therapy and a platelet GP-IIb-IIIa inhibitor.” The ESC guidelines8 refer to facilitated PCI as “planned intervention within 12 hours after onset of symptoms, soon after clot-dissolving medication to bridge the delay between first medical contact and primary PCI.” However, there is no a priori reason not to include other antithrombotic treatments that may either prompt recanalization of thrombotic occlusion or reduce reocclusion.
During the planning of most studies, dual oral antiplatelet therapy (adding clopidogrel to aspirin) has become a mainstay of pretreatment before coronary intervention in a broad clinical scenario.
In patients with acute coronary syndromes without ST-segment elevation (NSTEMI) undergoing PCI, adding 300 mg of clopidogrel to standard aspirin therapy reduced the risk of cardiovascular death or myocardial infarction.47 In NSTEMI patients with elevated troponin levels undergoing PCI, the benefit of adjunctive GP-IIb-IIIa inhibition is still evident; even on top of optimal clopidogrel pretreatment (600 mg), abciximab reduced the risk of 30-day death or MI.42 Recently, the documented efficacy of adjunctive clopidogrel therapy has been extended to STEMI patients. In a wide range of patients enrolled in the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), adding 75 mg of clopidogrel daily to aspirin and other standard treatments (fibrinolytic therapy in about 50% of cases) produced a reduction of early death without excessive bleeding.48 In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28,49 the addition of clopidogrel reduced the combined endpoint of an occluded infarct-related artery (TIMI flow grade 0 or 1), in-hospital death, or recurrent MI among patients who received aspirin and a standard fibrinolytic regimens. The reduction in cardiovascular death, MI, or stroke obtained with clopidogrel pretreatment was also consistent also among those patients who underwent PCI within 8 days of the admission.50 However, it appears more likely that clopidogrel improves clinical outcomes by maintaining late coronary patency and preventing reocclusion of open arteries rather than by facilitating early reperfusion. This speculation stemmed from a subanalysis of a cohort of CLARITY-TIMI 28 patients in ST-segment resolution (an early noninvasive marker of coronary reperfusion) was analyzed at 90 and 180 minutes after randomization51; when patients were stratified according to ST-segment resolution category, clopidogrel administration was associated with a significant reduction in the odds of an in-hospital death or MI in patients who achieved partial (OR, 0.30; P = 0.003) or complete ST-segment resolution at 90 min (OR, 0.49; P = 0.056), whereas clinical benefit was not apparent in patients who had no ST-segment resolution.
On the basis of the present knowledge, clopidogrel is de facto a way to facilitate primary PCI and will be extensively used in all STEMI patients. It will be quite hard, therefore, to comment on the results of any trial conducted without clopidogrel pretreatment; the adjunctive benefit of other pharmacological facilitation (lytics and/or GP-IIb-IIIa) should be clearly documented without excessive risk of bleeding on top of an optimum upfront oral antiplatelet therapy.
Primary PCI remains the first treatment of choice among STEMI patients, and everybody should ensure the shortest possible time from first medical contact to PCI. However, in areas without easy access to primary PCI, the suggested strategy must take into account the anticipated time delay to PCI.8,40
An algorithm for patient management is given in Figure 1.
The time issue remains crucial. While we are spending resources in the experimentation of expensive and potentially harmful therapeutic additional strategies, an understanding of the interplay between clinical events and the organizational context in which they occur is particularly in need of further development. Here the lessons from approaches used in hospitals that have achieved notable improvements in their door-to-balloon times52,53 should be learned by all, possibly more than focusing on new trials of drug combinations.
Prompt reperfusion is essential for patients with STEMI. Compared with thrombolysis and all other variables being equal, primary PCI achieves a better myocardial reperfusion, but its efficacy is hindered by transportation delay. A combined approach with a quickly started clot-dissolving drug (thrombolysis and/or GP-IIb-IIIa inhibition) followed by later PCI of the culprit lesion (lyse now, stent later)20 has therefore considerable attractiveness. “Facilitated” primary PCI could achieve some early recanalization as well as reduce thrombus burden and distal embolization. However, the translation of such theoretical benefits into clinical practice is complex, depending on the delicate balance between perfusion advantages and the risk of excess bleeding.
Theoretically, patients with a high risk of major cardiovascular events and a low bleeding risk (eg, the younger) who present very early (eg, within 60 to 90 min from symptom onset) and in whom a more than 2-hour delay to primary PCI is anticipated (eg, a prolonged inter-hospital transfer) are the best candidates to benefit from GP-IIb-IIIa inhibition (abciximab likely better than other drugs of this category) initiated at the time of initial contact.
Thrombolytic therapy should now be discouraged in patients intended to be also promptly treated with PCI, but it might remain an option for time intervals substantially longer than 90 min.
Investigators should propose genuine trials and try to be as independent as possible from the marketing interests of pharmaceutical companies, testing head-to-head alternative strategies for primary PCI facilitation and still including an arm of primary PCI without facilitation, which is the current benchmark for STEMI. Trials should also still aim at identifying which delay to primary PCI is acceptable before administering thrombolytic therapy.
Systematic internal analyses to monitor specific hospital performances in terms of time delays, which are likely to vary from place to place and may influence decision strategies, should also be developed.
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