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(Circulation. 2001;104:624.)
© 2001 American Heart Association, Inc.

Editorial

Importance of TIMI 3 Flow

Christopher P. Cannon, MD

From the Cardiovascular Division and TIMI Study Group, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Christopher P. Cannon, MD, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail cpcannon{at}partners.org www.timi.org

Key Words: Editorials • angioplasty • catheterization • myocardial infarction • platelet aggregation inhibitors • stents • thrombolysis

Since the advent of reperfusion therapy for acute ST elevation myocardial infarction, the "open artery hypothesis" proposed that benefit is achieved from early reperfusion of the occluded coronary artery, which limits the size of infarction, reduces the degree of left ventricular dysfunction, and improves survival.¹ After numerous studies confirmed the benefit of a patent infarct-related artery, more careful examination of the degree of reperfusion was performed using the Thrombolysis in Myocardial Infarction (TIMI) flow grading system devised in the TIMI 1 trial.² When differentiating apparently normal TIMI grade 3 flow from more delayed TIMI grade 2 flow in patent arteries, greater myocardial salvage and improved survival were observed in patients who achieved TIMI grade 3 flow.^3,4 There is a nearly linear correlation between higher rates of early TIMI grade 3 flow and improved survival, regardless of whether reperfusion is achieved with thrombolysis or primary percutaneous coronary intervention (PCI).⁴

See p 636

The open artery hypothesis became the "open artery theory"⁵ after the results of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I trial.^6,7 This trial demonstrated that a more aggressive thrombolytic regimen (using tissue plasminogen activator [t-PA]) that could improve the achievement of early TIMI grade 3 flow could also reduce mortality.^6,7 Thus, an active treatment that increased TIMI grade 3 flow led to improved survival.

The importance of time to achieving reperfusion has also been emphasized by several types of studies, including observational studies of time to treatment versus mortality.^4,8 Trials of prehospital thrombolysis, which saved between 30 and 120 minutes, demonstrated a 19% reduction in mortality.⁹ In GUSTO I, treatment with t-PA resulted in higher rates of TIMI grade 3 flow at 60 and 90 minutes compared with streptokinase, but by 180 minutes, rates were similar.⁷ Thus, the benefit of t-PA on improved early left ventricular function and mortality was attributed to the earlier achievement of TIMI grade 3 flow. In primary PCI, shorter door-to-balloon times were associated with lower mortality.¹⁰ Finally, a similar analysis in >80 000 patients treated with thrombolytic therapy showed that increases in the door-to-drug time of just 30 minutes can lead to significant increases in mortality.¹¹ Thus, these various lines of evidence point to the need to shorten the time to achieving reperfusion to any extent possible, even if by just 30 minutes.

The outstanding analysis by Stone et al¹² sheds more light on the importance of TIMI 3 flow. After combining data from >2500 patients in the 4 Primary Angioplasty in Myocardial Infarction (PAMI) trials, they compared patients who achieved TIMI grade 3 flow spontaneously on the angiogram before primary PCI, who comprised 16% of the population, with those who had TIMI 0 to 2 flow.¹² Despite relatively similar baseline characteristics, those with spontaneous TIMI grade 3 flow had improved left ventricular function, lower rates of congestive heart failure, and lower mortality. In addition, they observed that procedural success was higher in patients with baseline TIMI 3 flow. Their observations add new data to the existing body of evidence supporting the benefits of rapid reperfusion.

This analysis thus fuels enthusiasm for the strategy of "facilitated PCI" for ST elevation myocardial infarction, in which pharmacological treatment is initiated while patients are being transported to the cardiac catheterization laboratory for primary PCI. This strategy is designed to achieve the earliest possible reperfusion, while maintaining the benefits of primary PCI (ie, complete reperfusion, relief of coronary obstruction, and prevention of arterial remodeling with primary stenting). These benefits have also translated into lower rates of death, reinfarction, and stroke (especially intracranial hemorrhage) when compared with thrombolysis.¹³ Primary PCI is especially efficacious when combined with glycoprotein IIb/IIIa inhibition.¹⁴

Institutional experience, as gauged by volume of procedures, has been shown to influence mortality after primary PCI,¹⁰ and thus there was initial concern that the benefits of primary PCI seen in clinical trials could not be achieved in the "real world." However, with advances in interventional cardiology, this issue has been overcome, as was demonstrated in a recent analysis from the National Registry of Myocardial Infarction, which stratified hospitals by their volume of primary PCI procedures.¹⁵ In this setting, there was a significantly lower mortality with primary PCI versus thrombolysis in the 75% of patients treated at the intermediate and high-volume centers and equivalent mortality at low-volume centers. However, in all volume strata, there was a significantly lower rate of nonfatal stroke with primary PCI versus thrombolysis, even at these low-volume hospitals (0.4% versus 1.1% for high versus low volume; P<0.001). Thus, in the current era, primary PCI appears to be the reperfusion strategy of choice.

How could primary PCI be enhanced? On the basis of the analysis by Stone et al¹² and the other data listed above, reducing time to achieving reperfusion is one of the most promising avenues. This can be accomplished by implementing a critical pathway, which in one study reduced both door-to-balloon time and mortality.¹⁶ The National Heart Attack Alert Program of the National Institutes of Health has, for the last 10 years, focused attention on the problem and proposed solutions to reduce time delays in the treatment of acute MI (see www.nhlbi.nih.gov/about/nhaap/index.htm).⁸

A second means of reducing time to reperfusion is the facilitated PCI strategy, which combines both medical and interventional approaches. The first test of this strategy actually occurred nearly 15 years ago using full-dose thrombolysis followed by immediate PCI in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 1¹⁷ and TIMI 2A trials.¹⁸ At that time, no benefit was seen with the combined approach. However, interventional techniques and adjunctive antiplatelet therapy have greatly improved since that time; thus, many suspect that outcomes will be improved in the current era. Indeed, a recent analysis from contemporary TIMI angiographic trials of thrombolytic therapy found that outcomes seem to be better for patients who undergo adjunctive PCI after thrombolysis compared with those who do not.¹⁹ This strategy of initial thrombolysis followed by PCI was also revisited in the Plasminogen activator Angioplasty Compatibility Trial (PACT), which found an improvement in early TIMI grade 3 flow with half-dose t-PA administered before PCI (from 15% to 33%).²⁰

A second pharmacological approach that has been tested is glycoprotein IIb/IIIa inhibition. In 4 trials, including TIMI 14,²¹ an improvement to 30% to 35% TIMI grade 3 flow (and 50% patency) has been achieved with the administration of IIb/IIIa inhibitors in the Emergency Department before PCI. The advantage of this approach is that it will enhance reperfusion before PCI, with very low rates of intracranial hemorrhage (<0.1%). The other advantage of using IIb/IIIa inhibition is that it has been shown to improve TIMI myocardial perfusion grade 3, which is an important determinant of mortality, even among patients with TIMI grade 3 (epicardial) flow.^22,23

Stone et al¹² also suggest that early reperfusion could be facilitated by early initiation of another class of antiplatelet agents, thienopyridines. Patients in the 2 PAMI stent trials, in which these drugs were administered in the emergency department, had higher baseline rates of TIMI grade 3 flow (20.7% versus 11.3% in the PAMI 1 and 2 trials, which did not administer ticlopidine before PCI). However, as the authors note, these data should be interpreted cautiously because these rates were also assessed at different core laboratories, which might explain some of the difference. Indeed, it should be noted that the definition of TIMI grade 3 flow in these trials is actually different than the real definition from the TIMI 1 trial. The PAMI definition of TIMI 3 flow, "complete filling of the distal vessel by the third cardiac cycle," when compared with the original definition, which is based on flow compared with the non-infarct-related artery,² actually overestimates the number of patients who are deemed to have TIMI 3 flow by 10%.²⁴ Nonetheless, the data from Stone et al¹² are consistent with the early (eg, within 2 hours) reduction in clinical events seen with clopidogrel in the Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) trial. Further study of this class of agents on early reperfusion for ST elevation myocardial infarction is warranted.

Finally, the use of combination therapy with half-dose thrombolytic therapy plus IIb/IIIa inhibition has been seen as the strategy with the highest potential for improving early reperfusion. TIMI 14 showed that substantial improvements in both early reperfusion and in myocardial perfusion can be achieved with this combination therapy.^21,22 The GUSTO V trial found no difference in early mortality but a significant reduction in death or MI with the combination versus thrombolytic therapy alone (7.4% versus 8.8%; P=0.001).²⁵ Analysis of patients who underwent facilitated PCI in this trial may shed further light on this important new strategy.

Thus, the body of observational evidence, as now expanded by Stone et al,¹² reinforces the central goal of achieving TIMI 3 flow (both epicardial grade 3 flow and myocardial perfusion grade 3) as early as possible in ST elevation myocardial infarction. It is thus time for prospective trials of the various strategies of facilitating PCI as a means of improving outcomes. Pending these trials, we should focus our efforts on reducing time delays in initiating reperfusion therapy, both for thrombolysis and primary PCI. It is hoped that with a multimodality approach to reperfusion therapy, using time reductions and pharmacological and interventional strategies to maximize rates of early TIMI 3 flow, survival and overall clinical outcomes after ST elevation myocardial infarction will be further improved.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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