To the Editor: Several studies have evaluated the role of combinationmedical therapies administered upstream of primary percutaneousintervention (PCI). As noted in the review of the time to treatmentin PCI, by Nallamothu et al. (Oct. 18 issue),1 these trialshave failed to demonstrate a survival benefit from either full-dosefibrinolysis plus PCI or reduced-dose fibrinolysis in combinationwith glycoprotein IIb/IIIa antagonists plus PCI in patientswith ST-elevation myocardial infarction. However, there is evidenceof improved outcomes with early administration of glycoproteinIIb/IIIa anatagonists as compared with administration in thecatheterization laboratory.2 A Thrombolysis in Myocardial Infarction(TIMI) flow grade of 2 or 3 was significantly more frequentin the group in which glycoprotein IIb/IIIa antagonists wereadministered early than in the late-administration group, andthere was a trend toward a reduction in mortality.2 A TIMI flowgrade of 2 or 3 before PCI is associated with a decrease inadverse events and improved 1-year outcomes.2,3 Other studieshave revealed decreased 30-day mortality and reinfarction rateswith the use of the glycoprotein IIb/IIIa inhibitor abciximab.4Thus, these data support early administration of glycoproteinIIb/IIIa inhibitors to improve outcomes in patients undergoingprimary PCI.
Roger Kapoor, M.D., M.B.A. John R. Kapoor, M.D., Ph.D. Stanford University Stanford, CA 94305
References
Nallamothu BK, Bradley EH, Krumholz HM. Time to treatment in primary percutaneous coronary intervention. N Engl J Med 2007;357:1631-1638. [Free Full Text]
Montalescot G, Borentain M, Payot L, Collet JP, Thomas D. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2004;292:362-366. [Free Full Text]
Mehta RH, Harjai KJ, Cox D, et al. Clinical and angiographic correlates and outcomes of suboptimal coronary flow inpatients with acute myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1739-1746. [Free Full Text]
De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293:1759-1765. [Free Full Text]
To the Editor: In their review of primary PCI, Nallamothu etal. reaffirm the importance of the time to treatment and underscorethe point that the superiority of PCI over thrombolysis is limitedin time, "reaching equipoise between 60 and 120 minutes." Therefore,facilitated PCI by means of pretreatment with tissue plasminogenactivator (t-PA) was seen as a logical option. But as the authorsemphasize, this combination actually increased mortality. Theincompatibility of t-PA with PCI may be related to t-PA's procoagulanteffect and the significant rate of coronary reocclusion.1 Incontrast, prourokinase follows another fibrinolytic paradigm2and has a very different mode of action.3 Indeed, prourokinasecaused no measurable thrombin generation and little reocclusion(1.4%),4 indicating that the above complications should notbe seen as an inevitable accompaniment of all thrombolytic agents.
Therefore, it is surprising that in their discussion of futurechallenges, the authors do not include a thrombolytic agentthat is compatible with PCI. Surely, the optimal reperfusionstrategy would be immediate thrombolysis followed by PCI, therebyalso addressing the critical issue of microvascular perfusion.This possibility may not be beyond reach.
Victor Gurewich, M.D. Beth Israel Deaconess Medical Center Boston, MA 02215 vgurewic{at}bidmc.harvard.edu
References
Fitzgerald DJ, Fitzgerald GA. Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator. Proc Natl Acad Sci U S A 1989;86:7585-7589. [Free Full Text]
Pannell R, Black J, Gurewich V. Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained. J Clin Invest 1988;81:853-859. [ISI][Medline]
Liu JN, Gurewich V. A comparative study of the promotion of tissue plasminogen activator and pro-urokinase-induced plasminogen activation by fragments D and E-2 of fibrin. J Clin Invest 1991;88:2012-2017. [ISI][Medline]
Weaver DA, Hartmann JR, Anderson JL, Reddy PS, Sobolski JC, Sasahara AA. New recombinant glycosylated prourokinase for the treatment of patients with acute myocardial infarction. J Am Coll Cardiol 1994;24:1242-1248. [Abstract]
To the Editor: Nallamothu et al. note that fibrinolytic therapyremains a practical option for many patients with ST-elevationmyocardial infarction when there is no immediate access to acatheterization laboratory. Despite data showing the superiorityof primary PCI over thrombolysis, aspects of prehospital fibrinolysisshould be mentioned. Because the benefit of thrombolysis ismaximal during the first 2 hours after the onset of symptoms,and most patients with ST-elevation myocardial infarction presentto hospitals without on-site PCI facilities, transport delaysmay limit the benefits of PCI ("time is myocardium"). Data fromthe Comparison of Angioplasty and Prehospital Thrombolysis inAcute Myocardial Infarction (CAPTIM) trial showed that in thegroup of patients treated with prehospital thrombolysis whowere randomized less than 2 hours after the onset of symptoms,as compared with the primary-PCI group, there was a trend towardlower 30-day mortality, and cardiogenic shock was less frequent(occurring in 1.3% of patients, vs. 5.3% in the primary-PCIgroup; P=0.032).1 Prehospital thrombolysis is safe, may shortenthe time until reperfusion therapy by about 60 minutes,2 andis associated with a fourfold increase in aborted myocardialinfarction, as compared with in-hospital treatment.3 Patientswith ST-segment myocardial infarction who were treated withfacilitated PCI after prehospital fibrinolysis had improvedtissue perfusion and smaller infarcts, with a trend toward abetter clinical outcome.4
Sebastian Szabo, M.D. Thomas Oikonomopoulos, M.D. Hans Martin Hoffmeister, M.D., Ph.D. Städtisches Klinikum Solingen 42653 Solingen, Germany krisztinaszb{at}aol.com
References
Steg PG, Bonnefoy E, Chabaud S, et al. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the CAPTIM randomized clinical trial. Circulation 2003;108:2851-2856. [Free Full Text]
Chittari MS, Ahmad I, Chambers B, Knight F, Scriven A, Pitcher D. Retrospective observational case-control study comparing prehospital thrombolytic therapy for ST-elevation myocardial infarction with in-hospital thrombolytic therapy for patients from same area. Emerg Med J 2005;22:582-585. [Free Full Text]
Lamfers EJ, Hooghoudt TE, Hertzberger DP, Schut A, Stolwijk PW, Verheugt FW. Abortion of acute ST segment elevation myocardial infarction after reperfusion: incidence, patients' characteristics, and prognosis. Heart 2003;89:496-501. [Free Full Text]
Thiele H, Engelmann L, Elsner K, et al. Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction. Eur Heart J 2005;26:1956-1963. [Free Full Text]
The authors reply: Kapoor and Kapoor highlight the potentialrole of glycoprotein IIb/IIIa inhibitors in a "facilitated"approach, when used "upstream" of PCI. We agree that this strategyhas been associated with improvements in TIMI flow grades butnote the inconclusive data in regard to a clinical benefit.1Indeed, the Facilitated Intervention with Enhanced ReperfusionSpeed to Stop Events (FINESSE) trial investigators recentlyreported that upstream administration of abciximab did not providean additional clinical benefit when compared with in-laboratoryadministration.2
Gurewich points out the existing limitations of fibrinolytic-therapydrugs that have been combined with PCI in contemporary trials.His observation that some drugs in this class (e.g., prourokinase)may be better suited for use with PCI because of diminishedprocoagulant effects is provocative, particularly given thehigher rates of reinfarction noted with tenecteplase plus PCIin the Assessment of the Safety and Efficacy of a New TreatmentStrategy for Acute Myocardial Infarction (ASSENT) 4 trial.3However, recent results from the FINESSE and ASSENT-4 trialsmay make it challenging to pursue this area further.
We agree with Szabo and colleagues that prehospital fibrinolytictherapy is safe and effective when delivered within organizedemergency-medical-service (EMS) systems that are capable ofmaking a rapid diagnosis and treating eligible patients outsidethe hospital. However, several barriers — unrelated tothe clinical benefit — continue to prevent the practicalapplication of this strategy in the United States. These includelimited funding and infrastructure within EMS systems in general,as well as concerns about legal liability and reimbursement.4In addition, EMS systems with enough volume to justify dedicatingresources to overcome these barriers are likely to be in urbanareas where there is the potential for rapid access to primaryPCI.5
Brahmajee K. Nallamothu, M.D., M.P.H. Ann Arbor Veterans Affairs Medical Center Ann Arbor, MI 48109
Elizabeth H. Bradley, Ph.D. Harlan M. Krumholz, M.D., S.M. Yale University New Haven, CT 06520 harlan.krumholz{at}yale.edu
References
Montalescot G, Borentain M, Payot L, Collet JP, Thomas D. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2004;292:362-366. [Free Full Text]
Ellis SG. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial. Presented at the European Society of Cardiology Annual Congress, Vienna, September 1–5, 2007.
Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet 2006;367:569-578. [CrossRef][ISI][Medline]
Welsh RC, Ornato J, Armstrong PW. Prehospital management of acute ST-elevation myocardial infarction: a time for reappraisal in North America. Am Heart J 2003;145:1-8. [CrossRef][ISI][Medline]
Nallamothu BK, Bates ER, Wang Y, Bradley EH, Krumholz HM. Driving times and distances to hospitals with percutaneous coronary intervention in the United States: implications for prehospital triage of patients with ST-elevation myocardial infarction. Circulation 2006;113:1189-1195. [Free Full Text]
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