CLINICAL STUDY
A union in reperfusion:
The concept of facilitated percutaneous coronary intervention*
C. Michael Gibson, MS, MD, FACCa
a University of California, San Francisco, California, USA
Reprint requests and correspondence: Dr. C. Michael Gibson, Chief of Interventional Cardiology, University of California, San Francisco, 3333 California Street, Suite 430, San Francisco, California 94118
There are four components to the time-dependent "open vasculature" hypothesis. The achievement of 1) early flow, 2) full microvascular flow, 3) full epicardial flow, and 4) sustained flow are all related to improved clinical outcomes in acute myocardial infarction (MI) (1). Pharmacologic strategies may more fully satisfy the first two criteria (they rapidly open epicardial vessels and the microvasculature), but mechanical interventions may better satisfy the latter two criteria (full and sustained reperfusion). Clinical outcomes are related not merely to the attainment of one, but rather to the fulfillment of all four prerequisites of the open vasculature hypothesis (1). Perhaps "open vasculature hypothesis" is now a more appropriate term than "open artery hypothesis" because it has been shown that improved tissue-level perfusion (either on the angiogram [2], the echocardiogram [3], or the electrocardiogram [4]) is related to improved clinical outcomes independent of flow in the epicardial artery. Pharmacologic agents, such as the glycoprotein 2b3a inhibitors, may improve tissue-level reperfusion in acute MI (4). It would therefore be logical to offer the best of two complementary strategies by combining the speed of patency and improved microvascular function provided by a pharmacologic strategy with the speed of flow following more definitive (albeit later) mechanical intervention in what has alternatively been called a "JIMI" (Joint Intervention in Myocardial Infarction)-like approach (1), "prejunctive" therapy (5), or "facilitated PCI" (6).
Despite these intuitive benefits, early randomized trials did not show a clinical benefit of conventional angioplasty when routinely performed immediately following thrombolysis over thrombolysis alone (7–9). This may have been due to a higher risk of intramural hemorrhage in the arterial wall and the ensuing abrupt closure. These trials are now outdated, having preceded the widespread use of stents, thienopyridines, and glycoprotein 2b3a inhibitors. Recently, the PACT study (Primary Angioplasty/Alteplase Compatibility Trial) incorporated these current practice patterns and demonstrated that half-dose tPA can be safely combined with PCI (percutaneous coronary intervention) (5). This trial reaffirmed the time-dependent nature of the open vasculature hypothesis: those patients who had TIMI (Thrombolysis in Myocardial Infarction trial) flow grade 3 restored early, before PCI, had improved ejection fractions (62%) compared with those who had delayed restoration of TIMI flow grade 3 after PCI (58%) (p = 0.001) (5).
Although stand-alone thrombolytic agents restore normal blood flow (TIMI flow grade 3) in approximately 60% of patients, the combination of fibrinolytic agents (which act upon the fibrin component of the clot) with glycoprotein 2b3a inhibitors (which act upon the platelet component of the clot that holds the fibrin together) dramatically improves angiographic efficacy even earlier, by 60 min: normal TIMI flow grade 3 has been observed in 72% of patients treated with combination therapy versus 43% in those patients treated with front-loaded tPA in the TIMI-14 trial (p = 0.002) (10). Combination therapy also allows the use of lower doses of thrombolytic agents, which may in turn potentially reduce the risk of intracranial hemorrhage; and it combats the prothrombotic state induced by thrombolytic agents. Thus, glycoprotein 2b3a inhibitors may be well suited as an adjunct to both thrombolytic and mechanical interventions in acute MI.
To this end, data from the SPEED trial advances these efforts by demonstrating that it is safe and efficacious to perform PCI after either thrombolytic monotherapy or combination therapy (rPA and abciximab) (6). Like so many initial efforts in any field, this is a nonrandomized comparison of early PCI versus no PCI. Considering the momentum of the open vascular hypothesis, a randomized comparison of early PCI versus no PCI has historically been difficult to undertake, because many investigators believe it is unethical to withhold early PCI. Insofar as it is a nonrandomized comparison, the SPEED analysis suffers from the usual limitations of measured (and unmeasured) imbalances between the two groups as acknowledged by the investigators.
Early PCI was planned in this trial and was performed in 61% of patients. This is similar to the 61.7% rate of PCI we observed in the TIMI-14 trial when PCI was not necessarily encouraged but was performed at operator discretion (10). If PCI was encouraged in all patients, yet was not performed in 39% of cases, one must search for reasons why PCI was not performed. One obvious explanation is that the no-early-PCI patients had successful thrombolysis with either TIMI flow grade 3 or, alternatively, a minimal lesion (11) at the time of angiography. Indeed, more of the patients not treated with early PCI paradoxically received combination therapy, which has been associated with higher rates of TIMI flow grade 3 (10). We have recently shown that patients with minimal lesions following thrombolysis have very favorable outcomes, and this probably does not account for the poor outcomes in the no early PCI group (11).
It is possible that operators planned to perform PCI not early, but at a delayed time, perhaps because of lingering concerns regarding the advisability of this approach or because of bleeding at the time of initial angiography. Indeed, there was a higher rate of bleeding and transfusion in the no-early-PCI group. It is somewhat counterintuitive that patients in the no-early-PCI group should have had more bleeding. Procedure times should have been shorter, catheter sheath sizes should have been smaller, and heparin and thienopyridines should have been used less often in the no-early-PCI patients. Again, patients not treated with early PCI were more likely to receive combination therapy than were early PCI patients, and this may account in part for some of the increased bleeding. Perhaps operators that did not perform PCI were also less likely to use closure devices and had higher bleeding rates. Or perhaps the bleeding occurred not at the time of the initial angiography, but later in the hospital course, when a patient not treated with early PCI subsequently developed reocclusion and required reinstrumentation and aggressive anticoagulation.
Another important reason why patients may not have undergone early PCI is that early angiography may have identified surgical disease (left main or three-vessel disease) requiring coronary artery bypass grafting (CABG). Bleeding associated with CABG would also account for the higher rates of transfusion in the no-early-PCI arm.
Finally, the no-early-PCI group may have died or sustained adverse outcomes before having the opportunity to undertake PCI, and this may account in part for why the angiographic sample sizes are lower in this study arm (136 patients with angiographic infarct artery location data, whereas 162 patients were in this arm).
The baseline characteristics show that there were more right coronary arteries in the early-PCI arm, and this may have contributed to the favorable outcomes in this arm, which was enriched with inferior MIs. There is no description of disease extent (single-, double-, triple-vessel disease), lesion complexity (type A, B, C), lesion location (ostial or bifurcation), lesion length, hemodynamic perturbations (tachycardia or low blood pressure) to permit a comparison of the two groups. These angiographic and clinical features greatly influence operator choices in either performing or not performing early PCI. Unfortunately, no multivariate model was developed to correct for these potential imbalances in baseline characteristics.
A total of 43 patients underwent PCI outside the "early" 60-to-90-min window and were excluded from this analysis. It is difficult to capture or quantitate why a patient undergoes delayed PCI. Some of these patients may have undergone delayed PCI for reocclusion, and if they had been included among the no-early-PCI group, the results might have been even less favorable for this cohort. Conversely, if these delayed PCIs were performed electively as part of a conservative strategy and had good outcomes, this would have favorably influenced the results reported for the no-early-PCI group.
While previous analyses have segregated the approaches of rescue PCI (artery closed before the procedure) and adjunctive PCI (artery open before the procedure), this analysis lumps the two categories together in the primary analysis. The investigators do substantiate what has been reported in the past: flow is better if PCI is performed on open arteries (adjunctive PCI) than on closed arteries (rescue PCI) after thrombolysis (12,13). Although the overall strategy of early PCI may have "facilitated" better clinical outcomes in this nonrandomized analysis, no pharmacologic regimen was associated with facilitated or improved epicardial flow at the completion of the PCI. However, it is important to note that there may have been improvements in microvascular flow that were not measured. Indeed, we have demonstrated that combination therapy does improve microvascular perfusion both before and after PCI with improved ST segment resolution (14). The advantage of a "facilitated PCI" approach may not be the flow following the intervention, but rather the fact that flow was restored prior to the intervention in many cases. Certainly, the PACT trial has documented that early restoration of flow prior to intervention is related to improved ejection fractions (5).
Some of the readership may interpret the 86% rate of TIMI flow grade 3 at the completion of the PCI as unimpressive compared with that reported in other interventional trials (15,16). However, we have shown that when the standard definition of TIMI flow grade 3 is used, this is about 10 percentage points lower than if a "3 heart beat definition" for dye to traverse the artery for TIMI flow grade 3 is used in interventional trials (15,16). Thus, to be put on a par with the results of interventional trials, the post-PCI 86% rate reported by Hermann et al. (6) would translate into an approximate 96% rate reported for interventional trials using a "3 heart beat" definition of TIMI flow grade 3 (15,16).
Percutaneous coronary intervention was encouraged in all cases, and perhaps we should evaluate the results of the entire trial on an "intent to treat" basis, or "intent to perform early PCI" basis. In this case, 17 of 485 (3.5%) of the patients in which there was the intent to perform facilitated PCI died. This is significantly lower (p = 0.028) than the pooled mortality among all patients treated with either thrombolysis alone (68/1,055 or 6.5%) or primary percutaneous transluminal coronary angioplasty (PTCA) (47/1,038 or 4.5%) in all randomized trials of primary PTCA versus thrombolysis (1,17). Thus, the intent to perform facilitated PCI, or the strategy as a whole, had a lower mortality than did prior randomized trials of either thrombolytic monotherapy or primary PTCA. If facilitated PCI is viewed as the totality of modern therapies (early PCI, stents, glycoprotein 2b3a inhibitors), then these modern strategies tend to improve outcomes over older strategies.
TNK is more fibrin specific than either tPA or rPA; it tended to reduce intracranial hemorrhage in those >75 years of age (1.72% vs. 2.62%, p = 0.18) and significantly reduced bleeding complications and the need for transfusion, compared with tPA in the ASSENT-2 trial (18). The safety profile of this single-bolus thrombolytic agent may also allow it to be very efficacious in combination with glycoprotein 2b3a antagonists and interventional strategies. Indeed, we have reported that weight optimizing the dose of TNK significantly improves flow both before and after interventions and as such "facilitated" post-PCI flow in the TIMI-10B trial (19). Several combination therapy trials of reduced-dose TNK in conjunction with glycoprotein 2b3a inhibitors are now under way: low-dose TNK in conjunction with abciximab/enoxaparin in ENTIRE and ASSENT-3; in conjunction with eptifibatide in INTEGRITI; and in conjunction with tirofiban in FASTER.
Although the data from the SPEED trial demonstrates that PCI is both safe and effective after either rPA alone or in combination with abciximab, a dedicated randomized trial of PCI versus no PCI is necessary to examine the benefits combining these approaches. Finally, though the risk of intracranial hemorrhage does not appear to be increased with combination therapy in the TIMI-14 and SPEED trials (10), this preliminary observation requires further substantiation in much larger trials such as GUSTO-4 involving approximately 8,000 patients per study arm before combination therapy can be universally advocated. Finally, "time is myocardium": we have recently demonstrated in over 27,000 primary PTCA patients that delays in door-to-balloon time for primary PCI are associated with higher mortality (20), and facilitated PCI may further improve upon outcomes by speeding the time to vessel patency (5).
The results of the SPEED analysis add momentum to a growing body of acute MI literature supporting a "union in reperfusion": the use of pharmacologic agents to quickly open both the artery and the microvasculature and the use of adjunctive interventions to further improve flow and keep arteries open.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Gibson CM. Primary angioplasty versus thrombolysis. New issues in the era of glycoprotein 2b3a inhibition and stenting. Ann Intern Med. 1999;130:841–847[Abstract/Free Full Text]
- TIMI Study GroupGibson CM, Cannon CP, Murphy SA, et al. The relationship of the TIMI myocardial perfusion grade to mortality following thrombolytic administration. Circulation. 2000;101:125–130[Abstract/Free Full Text]
- Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699–1705[Abstract/Free Full Text]
- TIMI-14 Investigatorsde Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST elevation myocardial infarction: A TIMI-14 analysis. Circulation. 2000;101:239–243[Abstract/Free Full Text]
- Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. PACT investigators. Plasminogen-activator Angioplasty Compatibility Trial. J Am Coll Cardiol. 1999;34:1954–1962[Abstract/Free Full Text]
- Hermann HC, Moliterno DJ, Ohman EM, et al. Facilitation of early percutaneous coronary intervention after reteplase with or without abciximab in acute myocardial infarction: results from the SPEED (GUSTO-4 pilot) trial. J Am Coll Cardiol. 2000;36:1489–1496[Abstract/Free Full Text]
- Topol EJ, Califf RM, George BS, et al. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med. 1987;317:581–588[Abstract]
- Simoons ML, Col J, Betriu A, et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet. 1988;1:197–203[Medline]
- TIMI Research Group. Immediate versus delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. JAMA. 1988;260:2849–2858[Abstract]
- Thrombolysis in Myocardial Infarction (TIMI)-14 InvestigatorsAntman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and the extent of thrombolysis: results of TIMI-14 trial. Circulation. 1999;99:2720–2732[Abstract/Free Full Text]
- TIMI InvestigatorsLlevadot J, Giugliano RP, McCabe C, et al. Degree of residual stenosis in the culprit artery after thrombolytic administration. Am J Cardiol. 2000;85:1409–1413[CrossRef][Medline]
- TIMI-4 study groupGibson CM, Cannon CP, Greene RM, et al. Rescue angioplasty in the TIMI-4 Trial. Am J Cardiol. 1997;80:21–26[CrossRef][Medline]
- TIMI Study GroupGibson CM, Murphy SA, Menown I, et al. Determinants of coronary blood flow following thrombolytic administration. J Am Coll Cardiol. 1999;34:1403–1412[Abstract/Free Full Text]
- de Lemos JA, Gibson CM, Antman EM, et al. Abciximab improves microvascular function after rescue PCI: a TIMI-14 substudy (abstr). J Am Coll Cardiol. 2000;35(Suppl A):47A
- TIMI Study GroupGibson CM, Ryan K, Sparano A, et al. Methodologic drift in the assessment of TIMI grade 3 flow and its implications with respect to the reporting of angiographic trial results. Am Heart J. 1999;137:1179–1184[CrossRef][Medline]
- PAMI Stent Pilot Trial InvestigatorsStone GW, Brodie BR, Griffin JJ, et al. Prospective, multicenter study of the safety and feasibility of primary stenting in acute myocardial infarction: in-hospital and 30-day results of the PAMI stent pilot trial. J Am Coll Cardiol. 1998;31:23–30[Abstract/Free Full Text]
- Gibson CM. Primary and Rescue Angioplasty in the Setting of Acute Myocardial Infarction in Randomized Trials in Cardiovascular Disease. 1st ed. Philadelphia: Saunders; 1999.
- Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716–722[CrossRef][Medline]
- Gibson CM, Cannon CP, Murphy SA, et al. Weight-adjusted dosing of TNK-tissue plasminogen activator and its relationship to angiographic outcomes in the TIMI-10B trial. Am J Cardiol. 1999;84:976–980[CrossRef][Medline]
- NRMI-2 InvestigatorsCannon CP, Gibson CM, Lambrew CT, et al. Relationship of door-to-balloon time to mortality in patients with acute myocardial infarction treated with primary angioplasty. JAMA. 2000;283:2941–2947[Abstract/Free Full Text]
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References