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Interventional Cardiology The efficacy and safety of combination glycoprotein IIbIIIa inhibitors and reduced-dose thrombolytic therapy–facilitated percutaneous coronary intervention for ST-elevation : A meta-analysis of randomized clinical trials Mohamad C.N. Sinno, MD, Sanjaya Khanal, MD, FACC, Mouaz H. Al-Mallah, MD, Muhammad Arida, MD, and W. Douglas Weaver, MD Detroit, MI

Objective We reviewed the literature and performed a meta-analysis comparing the safety and efficacy of adjunctive use of reduced-dose thrombolytics and glycoprotein (Gp) IIbIIIa inhibitors to the sole use of Gp IIbIIIa inhibitors before percutaneous coronary intervention (PCI) in patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Background Early reperfusion in STEMI is associated with improved outcomes. The use of reduced-dose thrombolytic and Gp IIbIIIa inhibitors combination before PCI in the setting of acute STEMI remains controversial. Methods We performed a literature search and identified randomized trials comparing the use of combination therapy–facilitated PCI versus PCI done with Gp IIbIIIa inhibitor alone. Included studies were reviewed to determine in Myocardial Infarction (TIMI)-3 flow at baseline, major , 30-day mortality, TIMI-3 flow after PCI,and 30-day reinfarction. We performed a random-effect model meta-analysis. We quantified heterogeneity between studies with I2. A value N50% represents substantial heterogeneity. Results We identified 4 clinical trials randomizing 725 patients; 424 patients were pretreated with combination therapy before PCI, and 301 patients had Gp IIbIIIa inhibitor alone during PCI. Combination therapy–facilitated PCI was associated with a 2-fold increase in TIMI-3 flow upon arrival to the catheterization laboratory compared with the sole use of upstream Gp IIbIIIa inhibitors (192/390 patients [49%] versus 60/284 [21%]; relative risk [RR], 2.2; P b .00001). However, post-PCI TIMI-3 flow was similar between the 2 groups (279/319 patients [87%] versus 188/212 [88%]; RR, 0.99; P = .85). Major bleeding events significantly increased in the combination therapy group (40/420 patients [9.5%] versus 14/299 [4.7%]; RR, 2.2; P = .007). The 30-day mortality (15/424 patients [3.5%] versus 5/301 [1.7%]; RR, 1.47; P = .46) and 30-day reinfarction rate (5/424 patients [1.1%] versus 3/301 [1.0%]; RR, 0.96; P = .96) were similar in the 2 treatment groups. Conclusions Awaiting the results of the ongoing clinical trials, the current cumulative evidence does not support the routine use of combination of reduced-dose thrombolytic and Gp IIbIIIa inhibitor therapy–facilitated PCI for the treatment of STEMI. (Am J 2007;153:579286.)

The primary goal of therapy for acute ST-segment artery (IRA) blood flow. Irrespective of whether a elevation myocardial infarction (STEMI) is early, rapid, mechanical versus pharmacological strategy is used, complete, and sustained restoration of infarct-related Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the culprit artery within 90 minutes of presentation has been shown to correlate with im- From the Henry Ford Health System, Detroit, MI. proved 30-day1 and long-term2 survival in patients with Submitted June 20, 2006; accepted December 26, 2006. Reprint requests: Sanjaya Khanal, MD, FACC, Heart Center of Antelope Valley, 43807 acute STEMI. North 10th Street West, Lancaster, CA 93536. Primary percutaneous coronary intervention (PCI) is E-mail: [email protected] currently the preferred approach to 0002-8703/$ - see front matter n 2007, Published by Mosby, Inc. when delivered expeditiously in centers with docu- 3 doi:10.1016/j.ahj.2006.12.024 mented expertise and outcomes. Time to treatment, American Heart Journal 580 Sinno et al April 2007

Table I. Summary of characteristics in trials comparing simultaneous use of thrombolytics and glycoprotein IIb/IIIa inhibitors vs glycoprotein IIb/IIIa Inhibitors alone for PCI

No. of females/ Symptom onset No. of Patients Total (%) Mean Age yrs. to drug, mins. Combination IIb/IIIa Combination IIb/IIIa Combination IIb/IIIa Combination IIb/IIIa Inclusion therapy inhibitors therapy inhibitors therapy inhibitors therapy inhibitors Study Criteria group group group group group group group group

ADVANCE-MI STEMI b6hrs. 74 74 24/148 (16) 28/148 (19) 58 55 - -

SPEED STEMI b12hrs. 191 63 49/254 (19) 21/254 (8) 59 57 153 138

BRAVE STEMI b12hrs. 125 128 28/253 (11) 33/253 (13) 63.1 62.3 160 164

APAMIT STEMI b6hrs. 34 36 8/70 (11) 6/70 (9) 55 56 205 259

however, remains an important determinant of clinical PCI, the range of initial pharmacotherapy encompasses outcome in patients with acute STEMI. thrombolytic and glycoprotein (Gp) IIbIIIa inhibitors. Despite the better outcomes, primary PCI has not The use of Gp IIbIIIa inhibitors has been shown to become the treatment of choice for most patients with improve short-term outcomes in most studies of primary STEMI because of logistical issues and the limited PCI.8,9 However, full-dose -facilitated PCI has availability of institutions that can offer this treatment recently been shown to result in worse outcome than modality in a timely and efficient manner. In the current primary PCI alone.10 The results with combination of US practice, only 4.2% of transferred patients with acute reduced-dose thrombolytic and Gp IIbIIIa inhibitors STEMI were treated within 90 minutes in the National before PCI in patients with MI are however not clear. A Registry of Myocardial Infarction 3/4 registry.4 The idea recent meta-analysis comparing primary and multiple of prehospital ambulance triage of patients with STEMI regimens of thrombolytic-facilitated PCI for STEMI to PCI hospitals has been suggested to decrease inherent showed a higher TIMI grade 3 flow on initial angiogra- time delay that ensues when these patients are seen in phy, but this translated into higher major bleeding non-PCI hospitals. Nallamothu et al5 obtained PCI status events, increased mortality, nonfatal reinfarction, urgent of hospitals from the American Hospital Association target , and stroke11 compared with annual survey and established the location of the primary PCI alone. This study, however, does not population from the 2000 US census and found that 79% provide guidance about the common practice of the use of the adult population lived within 60 minutes of a PCI of reduced-dose fibrinolytic and Gp IIbIIIa inhibitors hospital. Among those with non-PCI hospitals as the before PCI in patients with acute STEMI. We performed closest facility, the additional time to arrive to a PCI a meta-analysis of randomized clinical trials12-15 testing hospital was 30 minutes.5,6 However, with the variability the safety and efficacy of combination therapy (reduced- of the emergency medical system in the United States, dose thrombolytic + Gp IIbIIIa inhibitors)–facilitated PCI getting electrocardiograms in the ambulance for patients versus PCI performed only with Gp IIbIIIa inhibitors. with chest pain and training paramedics to interpret these electrocardiograms is the major issue. Pharmaco- Methods logical therapy, however, can be carried out expedi- tiously and without site-specific variations in outcome in Study objectives and design patients with STEMI.7 Therefore, it is logical to think that Our primary aim was to compare simultaneous administra- tion of Gp IIbIIIa inhibitors and reduced-dose fibrinolytics initial early pharmacological therapy followed by PCI before PCI to primary PCI done with Gp IIbIIIa inhibitors in may deliver both expediency and efficacy that is desired patients with STEMI. ST-segment elevation myocardial infarc- in treating myocardial infarction (MI) patients. tion was defined according to the inclusion criteria of the In fact, many institutions have current policies of trials concerned. providing initial primary PCI alone, thrombolytic thera- py alone, or combination therapy followed by PCI based Search strategy on estimated time to treatment. In addition to standard All randomized, controlled trials comparing facilitated PCI to therapy of , , during primary primary were identified using a 2-level search American Heart Journal Sinno et al 581 Volume 153, Number 4

trials were also excluded. Outcome data had to be available on culprit artery patency evaluated on admission by TIMI flow grades, bleeding, and mortality. Two authors (M.S., M.M.) independently reviewed abstracts or complete articles. Only Combined 4 nonoverlapping studies met the inclusion criteria. Two Clinical End reviewers performed independent data extraction; all discrep- Trial Angiographic Point (Time to ancies were identified and resolved by consensus or, as Agents eight % End Points Follow up) needed, with a third investigator and confirmed by consensus.

Tenecteplase, 20 TIMI 3 , Reinfarction flow grade or new CHF End points and definitions @ 30 days , 35 TIMI 3 Death, Reinfarction The primary angiographic end point was TIMI flow grade 3 flow grade or urgent on the first angiogram, which defined open culprit artery on Revascularization admission. The TIMI grade 3 flow was also assessed after PCI. @ 30 days Reteplase, 35 TIMI 3 Infarct size by SPECT, The clinical end points were all-cause mortality, reinfarction Abciximab flow grade Death, Reinfarction, rate, and major bleeding events at 30 days follow-up. major Bleeding, and hemorrhagic , 10 TIMI 3 ACE= Death, Statistical analysis Abciximab flow grade Reinfarction, TVR, The meta-analyses were performed by computing relative Stroke and major risks (RRs) using random-effects model. Quantitative analyses Bleeding were performed on an intention-to-treat basis and were confined to data derived from the period of follow-up. Relative risk for all-cause mortality, TIMI-3 flow, and major bleeding strategy. First, we searched public domain databases including were calculated along with 95% confidence intervals (CIs). MEDLINE (from 1966 to December 14, 2005), the Cochrane Between study heterogeneity was analyzed by means of I2 = Central Register of Controlled Trials (second quarter 2005), [( Q À df)/Q] Â 100%, where Q is the v2 statistic, and df is its Database of Abstracts of Reviews of Effects (second quarter degrees of freedom. This describes the percentage of the 2005), Cochrane Database of Systematic Reviews (second variability in effect estimates that is due to heterogeneity rather quarter 2005), EMBASE (from 1980 to 2005 week 6), and BIOSIS than sampling error (chance). A value greater than 50% may be Previews (from 1969 to 2005 week 8). We used the following considered substantial heterogeneity. Publication bias was key words: acute MI; ST elevation; primary angioplasty; assessed graphically using a funnel plot. All analyses were facilitated angioplasty; thrombolytics including the following performed with RevMan Analyses Version 4.2.7 (2004 the individual : , alteplase, r-TPA, and Cochrane Collaboration). TNK; and Gp IIbIIIa inhibitors including the following individual medications: abciximab, , and eptifibatide. In addition, relevant studies were identified through a hand search of secondary sources including references of initially identified Results articles and proceedings from national cardiology meetings at Trial patient characteristics and study design the American Heart Association, American College of Cardiolo- Of the 1427 potentially relevant articles initially gy, European College of Cardiology and Transcatheter Thera- identified, 126 full-text articles were reviewed. Four peutics from 2001 through 2005. The search was performed trials were identified with a design including randomi- without any language restrictions. When an abstract from a meeting and a full article referred to the same trial, only the full zation to combination therapy (reduced-dose thrombo- article was included in the analysis. When there were multiple lytic + Gp IIbIIIa inhibitors) versus upstream Gp IIbIIIa 12-15 reports from the same trial, we used the most complete and/or inhibitors alone for PCI. The trial names, acronyms, recently reported data. patient characteristics, and details of the study groups are shown in Table I. Study selection and data extraction Enrollment criteria of chest pain (b6orb12 hours) with We restricted our meta-analysis to trials that performed a ST elevation or new left bundle-branch block on the randomized comparison between simultaneous administration electrocardiogram were used in all the trials (Table I). of Gp IIbIIIa inhibitors and reduced-dose fibrinolytics and sole Trial design was broadly similar in all studies; however, use of Gp IIbIIIa inhibitor before PCI in STEMI. A randomized there were some differences regarding the type and dose controlled trial was defined according to the National Library of thrombolytic and/or Gp IIbIIIa inhibitors used. The of Medicine criteria (http://www.nlm.nih.gov/mesh/ same-dose regimen was used throughout the 3 trials that pubtypes2001.html). To be included in the meta-analysis, the used abciximab in both arms of the study—0.25 mg/kg IV trials should have randomized patients within 12 hours of bolus followed by 12 hour infusion at 0.125 mg kgÀ1 symptom onset to either Gp IIbIIIa inhibitors or combination À1 therapy (thrombolytic + Gp IIbIIIa inhibitor) followed by min . Eptifibatide was used in the ADdressing the Value preplanned and angioplasty if indicated. We of facilitated ANgioplasty after Combination therapy or excluded trials where postfacilitation angiography was not Eptifibatide monotherapy in acute Myocardial Infarction done. We also excluded trials that compared facilitated PCI (ADVANCE-MI) trial with 2 boluses of 180 mg/kg IV with thrombolytic therapy alone. Symptom-driven angioplasty 10 minutes apart, then 2.0 mg kgÀ1 minÀ1 infusion. American Heart Journal 582 Sinno et al April 2007

Figure 1

Relative risk of TIMI grade 3 flow with combination therapy versus Gp IIbIIIa inhibitors.

Figure 2

Relative risk of major bleeding with combination therapy versus Gp IIbIIIa inhibitors.

Alteplase used in the Asia-Pacific Acute Myocardial (BRAVE) trial as well. The 4 trials randomized 725 patients. Infarction Trial (APAMIT) was 15 mg of standard bolus Four hundred twenty-four patients were initially ran- followed by a reduced dose of 35 mg over 60 minutes. The domized to the combination therapy–facilitated PCI ADVANCE-MI study group used half dose of , group, and the rest (301) were randomized to the Gp whereas reteplase was used in the remaining 2 trials. The IIbIIIa inhibitor–facilitated PCI. There were 92% (390/ Strategies for Patency Enhancement in the Emergency 424) assigned to the combination therapy–facilitated PCI Department study group tested multiple doses of rete- group and 94% (284/301) in Gp IIbIIIa inhibitor group plase, but we included the 5 U + 5 U dose regimen in our that had postfacilitation angiography. We decided to analysis because it was associated with a better safety include the APAMIT trial despite being labeled as a rescue profile and was confirmed as the better dose in phase B of angioplasty trial because all the patients in both groups the trial. The same 5 U + 5 U dose of reteplase was used in had angiography and only those patients with TIMI-3 flow the Bavarian Reperfusion Alternatives Evaluation post reduced-dose alteplase did not have angioplasty. In American Heart Journal Sinno et al 583 Volume 153, Number 4

Figure 3

Relative risk of 30-day mortality with combination therapy versus Gp IIbIIIa inhibitors.

Figure 4

Relative risk of reinfarction with combination therapy versus Gp IIbIIIa inhibitors.

the ADVANCE-MI trial, the results were analyzed both in 2 groups in 3 trials (RR, 0.99; 95% CI, 0.86-1.14; P = .85; the bas randomizedQ and bas treatedQ fashion. We included I2 = 81.7%). The postprocedural TIMI-3 flow was not the data from the former group to reduce bias and reported in the ADVANCE-MI trial. maintain an intention-to-treat analysis. The increased original vessel patency (TIMI-3 flow on presentation) was not associated with increased surviv- Clinical outcomes and angiographic end points al. Each of the 4 trials reported all-cause mortality. The All 4 trials reported 30-day mortality, 30-day major 30-day all-cause mortality was the same in patients bleeding events, and TIMI-3 flow upon arrival to the randomized to either treatment group with no hetero- catheterization laboratory. Patients who received com- geneity between the different trials (RR, 1.47; 95% CI, bination therapy more often had patent arteries upon 0.52-4.14; P = .46; I2 = 0). The incidence of 30-day arrival on the catheterization laboratory (RR, 2.18; 95% reinfarction was similar between the 2 groups (RR, 0.96; CI, 1.70-2.81; P b .00001; I2 = 0%). However, that did 95% CI, 0.23- 4.02; P = .96; I2 = 0). not affect the procedural success rate because the The safety of this approach was also assessed. postprocedural TIMI-3 flow rate was similar between the Combination therapy–facilitated PCI was associated American Heart Journal 584 Sinno et al April 2007

Figure 5

Relative risk of post-PCI TIMI 3 flow with combination therapy versus Gp IIbIIIa inhibitors. with increased major bleeding as reported by all the vessel revascularization compared with primary PCI included trials except in the APAMIT trial (RR, 2.15; 95% alone for patients with STEMI.10 CI, 1.17-3.94; P = .01; I2 = 0). Gp IIbIIIa inhibitors have been shown to reduce event Because small trials are more prone to be affected by rates when used in the setting of primary PCI.8,9,19-24 publication bias, we constructed funnel plots for both Moreover, the early use of Gp IIbIIIa inhibitors improved angiographic and clinical end points that exhibited a outcomes in a recent meta-analysis that included fairly symmetrical distribution and convergence toward 931 STEMI patients.25 Therefore, in addition to aspirin, the pooled effect when the weight of the trials heparin, and clopidogrel, Gp IIbIIIa inhibitors have been increased, suggesting that publication or selection bias considered standard of care during primary PCI. was unlikely (Figures 1-5). Combination of full-dose thrombolysis with full-dose Gp IIbIIIa inhibitors results in prohibitively high risk of bleeding complications.26 A reduced-dose combination Discussion therefore may offer the benefit of earlier reperfusion Time-to-treatment remains an important determinant without increasing bleeding risks. A reduction of recur- of clinical outcome in acute MI care, regardless of the rent MI has been demonstrated in patients treated with methodology used to establish adequate blood flow in half-dose tenecteplase with abciximab when compared the IRAs. Mortality benefit of primary PCI is lost for to full-dose tenecteplase in patients with STEMI.26 patients with door to balloon times exceeding 2 hours Although the mortality rate at 30 days was the same (cannon et al) compared with patients treated with between the 2 groups, the combination therapy group thrombolysis. The attendant delay for primary PCI may experienced fewer recurrent MIs. It is possible that Gp limit its clinical benefit over early use of thrombolysis, IIb/IIIa inhibitors improve flow in the infarct artery and especially when patients present within 3 hours after prevent the prothrombotic milieu that occurs after the the onset of symptoms.16,17 Thrombolysis has been thrombolytic wears off. Because administration of half- compared to primary PCI in multiple studies. These dose thrombolysis may be safer than full-dose in patients investigations demonstrate that PCI-treated patients undergoing primary PCI, many hospitals advocate ad- experience lower short-term mortality rates, less ministration of reduced-dose thrombolytic and Gp IIbIIIa nonfatal reinfarctions, and less hemorrhagic inhibitor during the delay in performing PCI. However, than those treated with fibrinolysis alone when the safety and efficacy of the combination of these 2 performed in a timely and efficient manner.3,18 To take classes of drugs before PCI have not yet been validated in advantage of early therapy of thrombolysis and the a large randomized, blinded, placebo controlled trial. more definite therapy of PCI, a facilitated approach The major finding of our meta-analysis is the demon- has been advocated where patients initially receive stration of a bfacilitatingQ effect of reduced-dose fibrino- thrombolysis while waiting for the definite primary lytic combined with Gp IIbIIIa inhibitors by improving PCI. However, full-dose fibrinolysis-facilitated PCI has preprocedure TIMI-3 flow of the IRA. The TIMI flow on recently been shown to be associated with higher initial angiography has been shown to be a major mortality, nonfatal reinfarctions, and urgent target determinant of survival in primary PCI27 and a valid end American Heart Journal Sinno et al 585 Volume 153, Number 4

point for mortality in thrombolytic trials.28 However, in facilitated PCIs for STEMI, where the authors grouped all spite of improved preprocedural TIMI-3 flow, postpro- modalities of facilitation (Gp IIbIIIa alone, thrombolytic cedural flow was similar compared with patients therapy alone, and simultaneous Gp IIbIIIa inhibitor undergoing primary PCI alone. Moreover, the combina- with thrombolytic therapy) in one arm and primary PCI tion therapy–facilitated PCI was also associated with in the other; our meta-analysis was dedicated to compare unfavorable trends for mortality and significant increase combination therapy (Gp IIbIIIa inhibitors and throm- in major bleeding events. bolytics) to Gp IIbIIIa inhibitors alone before PCI. The reasons for neutral to worse outcomes in the Besides, in the previous quantitative review, a discrep- facilitated arm despite improved preprocedural TIMI-3 ancy in the definition of primary PCI is to be noted. flow in this analysis may be the same factors that Some patients received no treatment before angiogra- worsen outcomes in patients undergoing facilitation phy, bclassical primary PCI,Q and others received with full-dose thrombolytics. The possible explanations inhibitors of Gp IIbIIIa. Thus, in the final analysis, some may be suboptimal /antiplatelet therapy, patients who received Gp IIbIIIa inhibitors in the treatment delay, and increased bleeding complications primary intervention group were compared with the in the facilitated group compared with patients under- subset of patients who received the same treatment going primary PCI alone. The addition of fibrinolytic modality in the facilitated intervention group. before PCI has been shown to increase nonbleeding In conclusion, similar to the results of thrombolytic- adverse clinical events in spite improved initial TIMI-3 facilitated PCI studies, facilitation of PCI with combina- flow.10 Therefore, whether hemorrhagic transformation tion of reduced-dose thrombolytics and Gp IIbIIIa of the infracted muscle and increased infarct size occurs inhibitors does not result in improved clinical outcome more in the setting of reperfused arteries has to be in spite of better TIMI-3 flow in the infarct artery on entertained. It has been demonstrated that the bleeding presentation. This approach, therefore, cannot be risk is proportionately increased with increasing doses recommended currently except in clinical trial settings. of (heparin and low-molecular-weight heparin). The studies described mostly used standard dose therapy. It is possible that bleeding References may be reduced if lower antithrombin doses are 1. Simes RJ, et al. Link between the angiographic substudy and lowered in the facilitated therapy group. mortality outcomes in a large randomized trial of myocardial The current meta-analysis has a number of limitations, reperfusion. Importance of early and complete infarct artery including inevitable clinical heterogeneity between reperfusion. GUSTO-I Investigators. Circulation 1995;91:1923 -8. 2. Ross AM, et al. Extended mortality benefit of early postinfarction trials and an overall sample size of only 725 patients, reperfusion. GUSTO-I Angiographic Investigators. Global Utiliza- which is statistically adequate to compare TIMI grade 3 tion of Streptokinase and Tissue for Occluded flow (power of 97%) but insufficient for clinical Coronary Arteries Trial. Circulation 1998;97:1549 - 56. outcomes like mortality. Sensitivity analyses were also 3. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus performed, and comparable results were obtained with intravenous thrombolytic therapy for acute myocardial infarction: a random effect model or when the largest study was a quantitative review of 23 randomised trials. Lancet excluded from the meta-analysis. Our analyses were also 2003;361:13 - 20. limited to short-term outcomes, whereas some Gp 4. Shavelle DM, et al. Outcome in patients transferred for percutane- IIbIIIa inhibitor studies have often demonstrated in- ous coronary intervention (a National Registry of Myocardial creased survival benefit with longer follow-up. In spite Infarction 2/3/4 analysis). Am J Cardiol 2005;96:1227 - 32. 5. Nallamothu BK, et al. Driving times and distances to hospitals with of the various limitations, however, the individual trials percutaneous coronary intervention in the United States: implica- were in most cases underpowered, and the combined tions for prehospital triage of patients with ST-elevation myocardial analysis allows more robust conclusions. Whether infarction. Circulation 2006;113:1189 -95. combination of reduced-dose thrombolytic and Gp 6. Rathore SS, et al. Regionalization of ST-segment elevation acute IIbIIIa inhibitor–facilitated PCI will result in better coronary syndromes care: putting a national policy in proper outcomes compared with primary PCI with Gp IIbIIIa perspective. J Am Coll Cardiol 2006;47:1346 - 9. inhibitor only will be finally be determined by ongoing 7. Dauerman HL, Sobel BE. Synergistic treatment of ST-segment randomized studies like the Facilitated Intervention elevation myocardial infarction with pharmacoinvasive recanaliza- with Enhanced reperfusion Speed to Stop Events trial. tion. J Am Coll Cardiol 2003;42:646 -51. Until the results of these studies are available, our 8. Antoniucci D, et al. A randomized trial comparing primary infarct analysis suggests that reduced-dose thrombolytic and artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003;42:1879 - 85. Gp IIb/IIIa inhibitor combination–facilitated PCI does 9. Brener SJ, et al. Randomized, placebo-controlled trial of not offer an advantage over primary PCI done with Gp glycoprotein IIb/IIIa blockade with primary angioplasty for acute IIbIIIa inhibitors only. myocardial infarction. ReoPro and Primary PTCA Organization and Contrary to the previous quantitative review of Randomized Trial (RAPPORT) Investigators. Circulation 11 randomized trials on the comparison of primary and 1998;98:734 - 41. American Heart Journal 586 Sinno et al April 2007

10. Primary versus tenecteplase-facilitated percutaneous coronary in- 19. Montalescot G, et al. Platelet glycoprotein IIb/IIIa inhibition with tervention in patients with ST-segment elevation acute myocardial coronary stenting for acute myocardial infarction. N Engl J Med infarction (ASSENT-4 PCI): randomised trial. Lancet 2006; 2001;344:1895 -903. 367:569 -78. 20. Neumann FJ, et al. Effect of glycoprotein IIb/IIIa receptor blockade 11. Keeley EC, Boura JA, Grines CL. Comparison of primary and with abciximab on clinical and angiographic restenosis rate after facilitated percutaneous coronary interventions for ST-elevation the placement of coronary stents following acute myocardial myocardial infarction: quantitative review of randomised trials. infarction. J Am Coll Cardiol 2000;35:915 - 21. Lancet 2006;367:579 - 88. 21. Topol EJ, Neumann FJ, Montalescot G. A preferred reperfusion 12. ADVANCE AMI Investigators. Facilitated percutaneous coronary strategy for acute myocardial infarction. J Am Coll Cardiol intervention for acute ST-segment elevation myocardial infarction: 2003;42:1886 - 9. results from the prematurely terminated ADdressing the Value of 22. van den Merkhof LF, et al. Abciximab in the treatment of acute facilitated ANgioplasty after Combination therapy or Eptifibatide myocardial infarction eligible for primary percutaneous transluminal monotherapy in acute Myocardial Infarction (ADVANCE MI) trial. coronary angioplasty. Results of the Glycoprotein Receptor Antag- Am Heart J 2005;150:116 -22. onist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 13. The SPEED Study Group. Trial of abciximab with and without low- 1999;33:1528 - 32. dose reteplase for acute myocardial infarction. Strategies for 23. Makkar R, et al. Effect of glycoprotein IIb/IIIa inhibition without Patency Enhancement in the Emergency Department (SPEED) thrombolytic therapy on reperfusion in acute myocardial infarction: Group. Circulation 2000;101:2788 -94. results of ReoMI pilot study. Catheter Cardiovasc Interv 14. Wong A, et al. Combined fibrinolysis using reduced-dose alteplase 1999;48:430 -4. plus abciximab with immediate rescue angioplasty versus primary 24. Antman EM, et al. Abciximab facilitates the rate and extent of angioplasty with adjunct use of abciximab for the treatment of thrombolysis: results of the Thrombolysis in Myocardial Infarction acute myocardial infarction: Asia-Pacific Acute Myocardial In- (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 1999;99: farction Trial (APAMIT) pilot study. Catheter Cardiovasc Interv 2720 -32. 2004;62:445 - 52. 25. Montalescot G, et al. Early vs late administration of glycoprotein IIb/ 15. Kastrati A, et al. Early administration of reteplase plus abciximab vs IIIa inhibitors in primary percutaneous coronary intervention of abciximab alone in patients with acute myocardial infarction acute ST-segment elevation myocardial infarction: a meta-analysis. referred for percutaneous coronary intervention: a randomized JAMA 2004;292:362 - 6. controlled trial. JAMA 2004;291:947 -54. 26. Merlini PA, et al. Effect of abciximab on prothrombin activation and 16. Widimsky P, et al. Multicentre randomized trial comparing transport generation in patients with acute myocardial infarction to primary angioplasty vs immediate thrombolysis vs combined also receiving reteplase. Am J Cardiol 2004;93:195 - 8. strategy for patients with acute myocardial infarction presenting to a 27. Stone GW, et al. Normal flow (TIMI-3) before mechanical community hospital without a catheterization laboratory. The reperfusion therapy is an independent determinant of survival PRAGUE study. Eur Heart J 2000;21:823 - 31. in acute myocardial infarction: analysis from the primary 17. Steg PG, et al. Impact of time to treatment on mortality angioplasty in myocardial infarction trials. Circulation 2001; after prehospital fibrinolysis or primary angioplasty: data from the 104:636 - 41. CAPTIM randomized clinical trial. Circulation 2003;108:2851 -6. 28. The effects of tissue plasminogen activator, streptokinase, or both on 18. Weaver WD, et al. Comparison of primary coronary angioplasty coronary-artery patency, ventricular function, and survival after and intravenous thrombolytic therapy for acute myocardial infarc- acute myocardial infarction. The GUSTO Angiographic Investiga- tion: a quantitative review. JAMA 1997;278:2093 - 8. tors. N Engl J Med 1993;329:1615 -22.