therapy in st-elevation myocardial infarction: reperfusion strategies, pharmacology and stent...

Curr Treat Options Cardio Med (2014) 16:302DOI 10.1007/s11936-014-0302-9

Coronary Artery Disease (D Feldman, Section Editor)

Therapy in ST-elevationmyocardial infarction:reperfusion strategies,pharmacology and stentselectionVikas Singh, MDMauricio G. Cohen, MD*

Address*Cardiovascular Division, and the Elaine and Sydney Sussman CardiacCatheterization Laboratory, University of Miami Hospital, Miller Schoolof Medicine, 1400 N.W. 12th Avenue, Suite 1179, Miami, FL 33136, USAEmail: [email protected]

Published online: 26 March 2014* Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Coronary Artery Disease

Keywords Myocardial infarction I Thrombolytic therapy I Primary percutaneous coronary intervention I Coronarystents

Opinion statement

The estimated annual incidence of new and recurrent myocardial infarction (MI) in the U.S. is715,000 events. Primary percutaneous coronary intervention (PCI) is the reperfusion strategyof choice in most patients with acute ST-elevation myocardial infarction (STEMI). Recent ad-vances in percutaneous techniques and devices, including manual aspiration catheters andnewer generation drug eluting stents and pharmacologic therapies, such as novel antiplateletsand anticoagulants have led to significant improvements in the acute and long-termoutcomesfor these patients. Implementation of community-wide systems directed to shorten treatmenttimes tied to closely monitored quality improvement processes have led to further advances inSTEMI care. Recent data suggests that transradial access for primary PCI is associated withimproved outcomes. This contemporary review discusses the strategies for reperfusion, phar-macological therapy and stent selection process involved in STEMI.

IntroductionThe past decade has witnessed a marked decline in theincidence of STEMI (from 133 to 50 cases per 100,000person-years) [1]. The estimated annual incidence of

new and recurrent myocardial infarctions (MI) in theU.S. is 525,000 and 190,000 events, respectively [2].Approximately 15 % of patients who experience a

MI in a given year in the US die of it [2]. Treatment ofST-segment elevation myocardial infarction (STEMI)has recently seen numerous advances in techniqueand adjunctive therapies. The door-to-balloon timeseems to have reached a threshold where further re-duction may not significantly improve mortality,and, therefore, the paramount importance of pre-hos-pital STEMI care in reducing total ischemic time andimproved outcomes has now been realized [3•]. Focushas now shifted to reducing pre-hospital delays by ed-ucating the general public about STEMI symptoms toimprove the interval from time of symptom onset tofirst medical contact (FMC), improvement in EMS tri-age, establishment of STEMI networks and use ofcommunitywide resources for regional systems ofcare.

Current management relies on a system-based ap-proach with activation of a regional STEMI networkand administration of evidence-based therapies and/or procedures with a primary goal of reperfusion.The strategy includes pre-hospital diagnosis of STEMIcombined with field triage of patients directly to per-cutaneous coronary intervention (PCI) centers. Me-chanical reperfusion of the culprit epicardialcoronary artery is the treatment of choice as it in-

creases vessel patency, reduces risk of reinfarction, di-minishes stroke risk, and boosts survival, althoughthere remains a role for thrombolytic therapy. Theconcept of “door-to-balloon time” or “door-to-needletime” has been replaced with the concept of “FMC-to-device time” which underlines the primary intentionof triaging and treating the patient as soon as possibleand the fact that balloon dilatation may no longer bethe initial approach chosen by the operators in pa-tients undergoing primary PCI.

The mortality rates associated with STEMI have alsoseen a significant downward trend in part due to re-cent advances in pharmacologic therapies and the in-ception of drug-eluting stents (DES). There is now abetter understanding of the critical balance betweenanti-ischemic effects and bleeding risks associated withantithrombotic agents. The new STEMI guidelines in-clude specific recommendations regarding newerP2Y12 inhibitors. Direct thrombin inhibitors have al-so assumed a significant role in the management ofSTEMI with improved outcomes over the combinationof heparin and GPIIb/IIIa inhibitors (GPI).This reviewdiscusses the reperfusion strategies, pharmacologicaltherapy and the stent selection process involved incontemporary management of STEMI.

Reperfusion strategies

Rapid restoration of normal blood flow in the infarct-related artery iscrucial to maximize myocardial salvage and improve survival in patientswith STEMI [4]. Reperfusion therapy should be administered to all eli-gible STEMI patients with symptom onset within the prior 12 hours [5].A treatment strategy with either primary PCI or thrombolytics must bechosen promptly when the amount of salvageable myocardium isgreatest. Several randomized trials have compared primary PCI withthrombolytic therapy for acute STEMI [6-8]. A large meta-analysis in-cluding 23 such trials and 7,739 patients demonstrated the short- termand long-term mortality benefit from primary PCI [9].

PCI versus thrombolytic therapyPatients who present ≤3 hours from symptom onset provide an opportunityfor substantial myocardial salvage and mortality reduction. The randomizedSTREAM (Strategic Reperfusion Early after Myocardial Infarction) study in-cluding 1,892 patients who presented within three hours of symptom onsetprobably provides the best evidence comparing PCI to thrombolytic therapyin this setting [10•]. For patients who could not undergo PCI within one

302, of 20 Curr Treat Options Cardio Med (2014) 16:302

hour of FMC, pre-hospital thrombolytic therapy with timely coronary angi-ography resulted in effective reperfusion; however, it was associated with aslightly increased risk of intracranial bleeding [10•]. Patients who presentedbetween 3-12 hours of symptoms onset (approximately 50 % of STEMI pa-tients) are better served with primary PCI due to greater efficacy and reducedrisk of stroke when compared to thrombolytic therapy [11]. Limited evidenceexists for benefit of primary PCI beyond 12 hours of symptom onset as mostof these patients were excluded from the trials. However, it is generally ac-cepted that the presence of symptoms and ST elevation are indications forreperfusion therapy regardless of time of symptom onset.

Primary PCI, if available, is the reperfusion strategy of choice in all pa-tients [9]. Independent triage by paramedics and transport to a PCI capablehospital is, therefore, the recommended strategy with an ideal FMC-to-devicetime system goal of G90 minutes [12, 13•, 14•]. However, when a patientpresents to a facility that does not offer primary PCI, immediate transfer to aPCI-capable hospital is recommended with an FMC-to-device time system goalofG120 minutes (Fig.1) [13•, 15, 16]. If this target cannot be achieved, ad-ministration of thrombolytic therapy within 30 minutes of arrival providestherapeutic advantage and is the reperfusion therapy of choice [17-19]. TheAmerican College of Cardiology/American Heart Association (ACC/AHA)and the European Society of Cardiology (ESC) guidelines recommendtransfer-for-PCI in patients with STEMI and absolute contraindications tothrombolytic therapy or in those at high risk of intracranial hemorrhage[13•]. Strong consideration should be given to transferring high-risk patientsfor primary PCI presenting with heart failure and/or pulmonary edema, highTIMI (Thrombolysis in Myocardial Infarction) risk score and in those withcardiogenic shock [20, 21].

Increased treatment delays are associated with less favorable outcomes forboth thrombolytic therapy and primary PCI. For patients presenting to anon–PCI-capable hospital, a rapid decision about administration of throm-bolytic therapy must be made based on the assessment of several factorsincluding the time of symptoms onset, complications risk related to STEMI,bleeding risk, and the time required for transfer to a PCI-capable hospital.This is because as PCI related delays (difference between the door-to-needletime and the door-to-balloon time) increase, the benefit from primary PCIcompared to thrombolytic therapy declines [22, 23]. A meta-regressionanalysis of 23 randomized trials (RCTs) including 7,739 patients demon-strated no survival advantage of primary PCI over thrombolytic therapy whenthe PCI-related delay was more than 62 minutes [24]. Another study in-cluding 19,000 propensity-score matched patients enrolled in the NationalRegistry of Myocardial Infarction (NRMI) demonstrated delays of990 minutes in 68 % of patients who were transferred for primary PCI [25].The National Cardiovascular Data Registry (NCDR) ACTION–GWTG registryreported a median door-in-door-out time of 68 minutes in a subset of14,821 patients with STEMI [26•]. Multivariable analysis found no mortalityadvantage for primary PCI over thrombolytic therapy in patients with a PCI-related delay longer than approximately 120 minutes. For patients with PCIdelays of G60 and 60 to 90 minutes, the in-hospital mortality was lower with

Curr Treat Options Cardio Med (2014) 16:302 of 20, 302

PCI (2.7 % vs.7.4 % and 3.6 % vs.5.5 %, respectively), whereas among pa-tients with PCI delay of 990 minutes, mortality rates were similar in bothgroups (5.7 % vs. 6.1 %) [25, 27•].

Failure of reperfusion by thrombolytic therapy, defined as lack of resolu-tion of ST elevation by at least 50 % in the lead displaying the highestmagnitude of ST elevation at 60-90 minutes, should prompt transfer to a PCIcapable facility for rescue PCI, as lack of ST resolution is associated with in-creased mortality and reinfarction (Table 1) [28, 29]. Severe or worseningchest pain, absence of reperfusion arrhythmias at two hours, hemodynamicinstability or worsening heart failure are other markers for failed reperfusion.In the REACT (Rapid Early Action for Coronary Treatment) study, 427 pa-tients who failed to demonstrate evidence of reperfusion at 90 minutes byECG criteria were randomized to rescue PCI, conservative care, or repeatthrombolytic therapy. The primary endpoint, a composite of death,reinfarction, stroke, or severe HF at six months, was significantly loweramong patients randomized to rescue PCI (HR 0.47, 95 % CI, 0.28 to 0.79;P=0.004 for rescue PCI vs. conservative therapy and HR 0.43, 95 % CI, 0.26to 0.72; P=0.001 for rescue PCI vs. repeat thrombolysis) [30]. The SHOCK(Should We Emergently Revascularize Occluded Coronaries for CardiogenicShock) trial demonstrated the benefit of emergent revascularization (witheither PCI or CABG) compared with immediate medical stabilization anddelayed revascularization in patients with STEMI or new LBBB MI and car-diogenic shock [31]. One-year survival was 46.7 % for patients in the earlyrevascularization group compared with 33.6 % in the medical stabilizationgroup (absolute difference in survival, 13.2 %; 95 % CI, 2.2 %-24.1 %; PG0.03). For patients with cardiogenic shock, the benefit of emergency revas-cularization was apparent across a wide time window, extending up to

Fig. 1. Decision making, timeline and reperfusion strategy in patients with STEMI.


54 hours after MI and 18 hours after shock onset [31]. Immediate transfer toa PCI-capable hospital is, therefore, recommended for patients who developcardiogenic shock irrespective of the time from STEMI onset because of thedownward spiral clinical deterioration associated with shock [31].

The term pharmacoinvasive strategy refers to immediate transfer to a PCI-capa-ble hospital after administration of thrombolytic therapy either in the pre-hospital setting or at a non–PCI-capable hospital (Table 1). This strategy appliesto clinically stable STEMI patients who are treated with thrombolysis and haveshown clinical evidence of reperfusion. The rationale for this approach is basedon the fact that the parameters defining a successful reperfusion with throm-bolytic therapy are ambiguous and pose a dilemma to the physician treating thepatient. Therefore, angiographic assessment of patency of the infarct relatedartery may further identify failed reperfusion. In fact, vessel reocclusion aftersuccessful reperfusion can occur in up to 13 % of cases and is usually clinicallysilent. Vessel reocclusion is associated with larger ventricular volumes, lowerejection fractions, a more complicated hospital course, and increased mortality[32, 33].Whenapplying the pharmacoinvasive approach, coronary angiographyshould ideally be performed between three and 24 hours after thrombolytictherapy to avoid excess bleeding risk [34-36]. The TRANSFER-AMI (Trial ofRoutine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion inAcute Myocardial Infarction) study was the largest RCT in this context (n=1,059) [35]. This study evaluated transfer-for-PCI among high-risk patients afterthrombolytic therapy and showed a significant reduction in the combined pri-mary end point of death, recurrent MI, recurrent ischemia, new or worseningheart failure, or shock at 30 days with immediate transfer for the angiographygroup compared with conservative care (11% vs.17.2%, RR 0.64; 95%CI, 0.47-0.87; P=0.004) [35]. A meta-analysis consisting of seven RCTs and 2,961 pa-tients evaluated for early routine PCI after successful thrombolytic therapy vs.standard therapy, and limiting PCI only to patients without evidence of reper-fusion (rescue PCI), found that the former strategy was associated with a sta-

Table 1. Reperfusion strategies and their level of evidence according to AHA/ACC and ESC guidelines13

ReperfusionTherapy

Definition ACC/AHA Recommen-dation Class and Lev-el of Evidence

ESC Class and Recom-mendation Class andLevel of Evidence

Primary PCI Coronary angioplasty/stenting without prioradministration of thrombolytic therapy or GPI.

COR: ILOE: A

COR: ILOE: A

Rescue PCI PCI performed after failure of reperfusion bythrombolytic therapy.

COR:IILOE: B

COR: ILOE: A

Facilitated PCI Systematic administration of thrombolytictherapy and/or GPI followed by PCI in a PCI-capable hospital

COR:IILOE: B

COR: ILOE: A

PharmacoinvasiveTherapy

Administration of thrombolytic therapy either inthe pre-hospital setting or at a non-PCI-capa-ble hospital, followed by immediate transfer toa PCI-capable hospital for early coronary an-giography and PCI when appropriate.

COR:IILOE: B

COR: ILOE: A

PCI: percutaneous coronary intervention; COR: class of recommendation; LOE: level of evidence


tistically significant reduction in the incidence of death or MI at 30 days (OR:0.65, 95%CI: 0.49-0.88; P=0.004) and at 1 year (OR: 0.71, 95%CI: 0.52-0.97;P=0.03), without an increase in the risk of major bleeding [34].

A potential limitation of PCI related to the procedure itself is distal em-bolization of debris after dilating a thrombotic lesion, leading to microvas-cular obstruction. Aspiration thrombectomy prior to PCI appears to be anappealing strategy to reduce distal embolization and improve microvascularreperfusion [37]. The current ACC/AHA guidelines include a class IIa rec-ommendation for the use of routine manual aspiration thrombectomy dur-ing primary PCI. This recommendation is largely based on the TAPAS(Thrombus Aspiration during Percutanous coronary intervention in Acutemyocardial infarction study) trial 13, 38]. This single center study including1,071 patients demonstrated the benefit of routine use of manual aspirationwith primary PCI compared to PCI alone by reducing mortality by 52 % at1 year follow-up [38]. However, these finding could not be replicated inother studies. The INFUSE-AMI trial randomized 452 patients using a 2x2factorial design to aspiration thrombectomy versus usual care andintracoronary versus intravenous abciximab [39•]. Of note, TIMI 3 epicardialpatency rates and myocardial blush were similar with and without aspira-tion. Moreover, infarct size as assessed with cardiac magnetic resonance wasapproximately 17 % in both groups [39•]. The recently published TASTE(Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia)trial involving 7,244 participants from the national comprehensive SwedishCoronary Angiography and Angioplasty Registry (SCAAR) found no signifi-cant difference in mortality by routine aspiration thrombectomy with PCIwhen compared to PCI alone [40•]. The ongoing TOTAL (Routine aspirationThrOmbecTomy with PCI versus PCI Alone) trial comparing routine aspi-ration versus conventional PCI has recruited 6,080 patients at 73 centers in18 countries as of August 2013. The study primary endpoint is a compositeof cardiovascular death, recurrent myocardial infarction, cardiogenic shock ornew or worsening heart failure up to 180 days [41]. The results of this studymay shed light on the definitive role for systematic use of manual aspirationthrombectomy in PCI and potentially identify patient subgroups that maybenefit the most from this strategy.

Interventional strategies

Nearly 40-65 % of the patients with STEMI present with multivessel CADand are known to have adverse outcomes when compared to those withsingle vessel disease [42, 43]. Treatment of non-culprit significant lesionswith TIMI 3 flow at the time of primary PCI in hemodynamically stablepatients is controversial. Current ACC/AHA guidelines recommendagainst this practice (Class III: Harm) [13•]. However, there is greatvariability in practice with some patients undergoing immediate pre-ventive PCI of the non-culprit vessel, some undergoing staged PCI andothers being conservatively managed with “no preventive PCI”. Studiescomparing these strategies have been either non-randomized or under-powered. A large meta-analyses including 40,280 patients from fourprospective and 14 retrospective studies showed superiority of staged PCIover both “immediate preventive PCI” (OR: 5.31, 95 % CI: 2.31 to 12.21,pG0.0001) and “no preventive PCI” group (OR: 3.03, 95 % CI: 1.41 to


6.51, p=0.005) [44]. Additionally, the “no preventive PCI” groupwitnessed lower mortality when compared to the immediate PCI group(OR: 0.66, 95 % CI: 0.48 to 0.89, p=0.007) [44]. The recently publishedPRAMI (Preventive Angioplasty in Acute Myocardial Infarction) trialshowed that “immediate preventive PCI” is superior to “no preventivePCI” strategy [45•]. This study randomized 465 patients with STEMI whohad multivessel CAD to “preventive PCI” vs. “no preventive PCI” in theUnited Kingdom and demonstrated an absolute risk reduction of 14 %in the composite of cardiac death, nonfatal MI, or refractory angina) inthe preventive-PCI group(HR: 0.35; 95 % CI,0.21 to 0.58; PG0.001)[45•]. This study, however, did not address the question of “immediatepreventive PCI” versus “staged PCI”. Future studies regarding benefit andtiming of PCI to non-infarct arteries in STEMI patients with multivesseldisease may, therefore, significantly impact the current guidelines.

Access site selection for primary PCI in STEMI

Since the introduction of radial access more than two decades ago, ex-tensive data have accumulated confirming the benefit of this techniqueover the femoral approach in reducing vascular complications, accesssite-related bleeding, and costs [46]. In the RadIal Vs femorAL access forcoronary intervention (RIVAL) trial including 7,021 patients, a subgroupanalysis of 1,958 STEMI patients, radial access was associated with a re-duction in the primary endpoint (death, MI, stroke, and non–CABG-re-lated major bleeding) (3.1 % vs 5.2 %, p=0.026) [47]. Interestingly, all-cause mortality was significantly reduced with radial access (1.26 % vs.3.19 %, p=0.006) [47, 48•]. Subsequently, the RIFLE-STEACS (RadialVersus Femoral Randomized Investigation in ST-Elevation Acute Coro-nary Syndrome) trial including 1,001 STEMI patients showed significantreduction in net adverse clinical events (defined as a composite of cardiacdeath, stroke, myocardial infarction, target lesion revascularization andbleeding) in the radial arm (13.6 %) compared to femoral (21 %) [49•].Again, radial access was associated with a significant reduction in cardiacmortality(5.2 % vs. 9.2 %, p=0.020), however this striking mortalitydifference may have been the result of the play of chance because thecause of death was mostly heart failure, hardly influenced by choice ofvascular access [49•]. An analysis of 90,879 patients (Radial access, n=6,159 and femoral access, n=84,720) undergoing immediate primaryPCI for STEMI from the NCDR, noted a significant growth in the use ofradial access from 0.9 % to 6.4 % (pG0.0001) when compared to femoralaccess from 2007 through 2011 [50•]. Radial access was associated withfewer vascular complications (0.13 % vs. 0.49 %; pG0.001), lower risk ofbleeding (OR: 0.62; 95 % CI: 0.53 to 0.72) and lower risk of in-hospitalmortality (OR: 0.76; 95 % CI: 0.57 to 0.99) [50•]. However, the mediandoor-to-device time was four minutes shorter in the femoral group (74vs. 78 min; pG0.0001) [50•]. A systematic review including 21 ran-domized, case-control, and cohort studies involving 8,534 patients withSTEMI showed significant reductions in major adverse cardiac events(OR 0.56, 95 % CI 0.44-0.72, pG0.001), mortality (OR 0.55, 95 % CI0.42-0.72, pG0.001) and major bleeding (OR 0.32, 95 % CI 0.22-0.48,pG0.001) with radial access [51]. Radial access was also associated with


shorter hospital length of stay with a mean difference of 2.2 days (95 %CI 3.32–1.14, pG0.001) [51]. There were no differences in door-to-bal-loon and procedure times between the two routes [51]. Current ACC/AHA PCI guidelines recommend transradial access whenever feasible toreduce vascular complications [46, 52]. The ESC guidelines provide morespecific procedural recommendations for primary PCI and endorse theuse of transradial access over femoral access, if performed by an experi-enced radial operator [14•].

Thrombolytic therapyThrombolytic agents are broadly divided into two categories of fibrin-specificagents (i.e., alteplase, reteplase and tenecteplase) and non-fibrin specificagents (i.e., streptokinase). Streptokinase is the most commonly used fibri-nolytic agent worldwide, due to its relatively low cost as well as a reasonableefficacy-to-safety ratio; however, it is no longer marketed in the US. Alteplaseimproves survival when compared to streptokinase based on the results ofthe GUSTO-I (Global Utilization of Streptokinase and Tissue PlasminogenActivator for Occluded Coronary Arteries) trial which showed 1 % absolutereduction in 30-day mortality with alteplase [53]. A definite advantage ofbolus thrombolytic therapy is ease of administration and reduced medica-tion errors when compared with more complicated regimens. A simple bolusadministration may facilitate more rapid treatment and shorten the timebetween onset of pain and treatment [53, 54]. Reteplase, administered astwo bolus 30 minutes apart, has been shown to be non-inferior comparedto alteplase (GUSTO III) and tenecteplase, administered as a single weight-adjusted bolus has been shown to be equivalent to alteplase while havinglower rates of non-cerebral bleeding events [55]. Currently, tenecteplase isused as a first line fibrinolytic agent in North America and WesternEurope.

Pharmacology

Rupture of an atherosclerotic plaque is the usual initiating event in an acutecoronary syndrome and persistent thrombotic occlusion of an epicardialcoronary artery results in STEMI. Antithrombotic strategies, therefore, play avital role in management of STEMI.

Antiplatelet therapy with fibrinolysis

Aspirin blocks the enzyme cyclooxygenase that mediates the first step inthe biosynthesis of prostaglandins and thromboxanes from arachidonicacid. Aspirin at a loading dose of 162 to 325 mg should be given as soonas possible to any patient presenting with STEMI. Thereafter, low-doseaspirin (75-100 mg) should be continued indefinitely for secondaryprevention. The Clopidogrel and Aspirin Optimal Dose Usage to ReduceRecurrent Events−Seventh Organization to Assess Strategies in IschemicSyndromes (CURRENT–OASIS 7) trial including 25,086 ACS patientsdid not show any significant difference in cardiovascular outcomes withlow-dose (75-100 mg daily) compared with high-dose aspirin (325 mg


daily) [56]. A higher dose of aspirin may also lead to increased gastricirritation.Platelet P2Y12 receptor antagonists block the binding of ADP to theplatelet P2Y12receptor, thereby causing upstream inhibition of plateletaggregation [57]. The antiplatelet effects of these agents are additive tothose of aspirin, irrespective of whether the patient receives thrombolytictherapy, primary PCI, or no reperfusion. In the Clopidogrel as AdjunctiveReperfusion Therapy (CLARITY)– Thrombolysis in Myocardial Infarction(TIMI) 28 trial, 3,491 patients with age ≤75 years (within 12 hours afterthe onset of STEMI) who received thrombolytic therapy, unfractionatedheparin (UFH) or low molecular weight heparin (LMWH) and aspirinwere randomly assigned to either clopidogrel or placebo [58].Clopidogrel significantly reduced the primary endpoint of occluded in-farct-related artery or death or recurrent MI by 36 % without an associ-ated increase in the rates of major bleeding or intracranial hemorrhage[58]. In the ClOpidogrel and Metoprolol in Myocardial Infarction Trial(COMMIT) trial, 45,852 patients (93 % with STEMI) were randomlyassigned to clopidogrel (75 mg/day) or placebo within 24 hours ofsuspected acute MI. One-half of patients received thrombolytic therapyand all patients were treated with aspirin. At 16 days the primary end-points of death and the composite of death, repeat MI, or stroke weresignificantly lower in the patients who received clopidogrel [59]. Otherplatelet P2Y12 receptor blockers (Ticagrelor and Prasugrel) have notbeen studied as adjuncts to fibrinolysis and, therefore, should not beused due to concerns for excess bleeding.

Antiplatelet therapy with primary PCI

Aspirin at an empiric dose of 325 mg should be given as early as possiblebefore PCI and a maintenance dose of 75-100 mg continued indefinitelythereafter [13•, 60]. A loading dose of clopidogrel 600 mg or prasugrel60 mg or ticagrelor 180 mg must be administered along with aspirin [61–63]. The efficacy of prasugrel was compared to clopidogrel in the Trial toAssess Improvement in Therapeutic Outcomes by Optimizing Platelet In-hibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI 38 trial). This study randomly assigned 13,608 moderate-to-high-riskACS patients undergoing PCI, 3,534 with STEMI, to receive prasugrel(60 mg loading dose followed by 10 mg daily maintenance dose) orclopidogrel (300 mg loading dose followed by 75-mg daily maintenancedose), for six to 15 months [64]. Of note, in this study prasugrel was ad-ministered after coronary angiography when it was certain that the patientwas a candidate for PCI. The primary efficacy endpoint of cardiovasculardeath, nonfatal MI, or nonfatal stroke occurred significantly less often inpatients treatedwithprasugrel at 15month follow-up (10.0%vs 12.4%; p=0.0221) [64]. Additionally, the rate of stent thrombosis was also signifi-cantly reduced in the prasugrel group (1.6 % vs 2.8 %, p=0.023) [64]. Aseries of subgroup analyses in the TRITON-TIMI 38 trial showed threespecific groups that did not experience a favorable net clinical benefit [64].These included patients who had a previous stroke or transient ischemicattack (net harm:HR, 1.54; 95%CI, 1.02 - 2.32;P=0.04), patients≥75 yearsof age (no net benefit HR, 0.99; 95 % CI, 0.81 -1.21; P=0.92), and patients


weighingG60 kg (no net benefit HR, 1.03; 95 % CI, 0.69 to 1.53; P=0.89)[64]. Based on these results, the prasugrel FDA label includes a black boxwarning against its use in patients with history of stroke or TIA. Ticagrelorwas compared to clopidogrel in 18,624 ACS patients in the PLATelet inhi-bition and patientOutcomes (PLATO) trial, 38%ofwhomhad STEMIwithintended PCI [65]. In contrast with the TRITON trial, the design of thePLATO trial mandated ticagrelor administration prior to coronary angiog-raphy. The primary endpoint (MI, stroke, or cardiovascular death) occurredless often with ticagrelor (9.4 % versus 10.8 %; P=0.07) with no significantdifference in major bleeding (P=0.76) [63, 65].Even thoughnewP2Y12 should be considered first line agents, the choice ofagent should be ultimately individualized based on economic factors, pa-tient ability to comply, bleeding risk, type of stent, and the complexity of theintervention performed. Regardless of the choice of P2Y12 inhibitor, dualantiplatelet therapy (DAPT) should be maintained for 12 months [13•].

GP IIb/IIIa receptor inhibitors

Most trials comparing GPI to placebo were conducted before the routineuse of P2Y12 inhibitors became established. The ADMIRAL (Abciximabbefore Direct Angioplastyand Stenting in Myocardial Infarction Regard-ing Acute and Long-Term Follow-up) study randomly assigned 300STEMI patients to abciximab plus stenting (149 patients) or placebo plusstenting (151 patients) before coronary angiography [66]. Abciximabwas associated with a significant reduction in the composite of death,reinfarction or urgent target vessel revascularization (TVR) at 30 days(6 % vs 14.6 %, p=0.01) and six months (7.4 % vs 15.9 %, p=0.02) [66].The CADILLAC (Controlled Abciximab and Device Investigation toLower Late Angioplasty Complications) trial examined the efficacy andsafety of abciximab and coronary stenting in primary PCI for acute MI in2,082 patients [67]. Abciximab treatment was associated with a signifi-cant reduction in the composite of death, MI, ischemia-driven target-vessel revascularization, or disabling stroke at 30 days (4.6 % vs. 7.0 %;relative risk, 0.65; 95 % CI, 0.46 to 0.93; P=0.01) but not at 12 months(18.4 % for controls versus 16.9 % for abciximab-treated patients; rela-tive risk, 0.92; 95 % CI, 0.76 to 1.10; P=0.29) [68].Two trials, On-TIME 2 (Ongoing Tirofiban In Myocardial infarctionEvaluation 2) and BRAVE-3(Bavarian Reperfusion Alternatives Evalua-tion-3), compared intravenous GPI (tirofiban and abciximab, respec-tively) to placebo in patients pretreated with P2Y12 receptor blockersand aspirin [69, 70]. The former trial suggested benefit while the latterdid not. A meta-analysis has recently suggested significant mortality re-duction with “upstream” abciximab administration before primary PCI(20 % vs. 24.6 %; HR 0.65, 95 % CI=0.65 (0.42-0.98) P=0.02) [71]. Ithas been previously hypothesized that intracoronary administration ofGPI may yield superior outcomes. In the Infuse AMI trial, patients treatedwith intracoronary abciximab had a significant reduction in infarct sizewhen compared to patients treated without abciximab (15.1 % vs 17.9 %of the total myocardial mass, p=0.03) [39•]. However, in the AIDASTEMI trial (The Abciximab Intracoronary versus intravenous Drug Ap-plication in ST-Elevation Myocardial Infarction), which randomly


assigned 2,065 STEMI patients to intracoronary or intravenousabciximab, there were no differences in a combined endpoint of death,MI, or new CHF [72].The Harmonizing Outcomes with Revascularization and Stents in AcuteMyocardial Infarction (HORIZONS-AMI) Trial randomly assigned 3,602STEMI patients treated with primary PCI to heparin plus a GPI orbivalirudin alone [73]. The study found that anticoagulation withbivalirudin alone, as compared with heparin plus GPI, resulted in a re-duced 30-day rate of net adverse clinical events (9.2 % vs. 12.1 %; rela-tive risk, 0.76; 95 % CI 0.63 to 0.92; p=0.005), owing to a lower rate ofmajor bleeding (4.9 % vs. 8.3 %; relative risk, 0.60; 95 % CI,0.46 to 0.77;pG0.001) [73]. Interestingly, the study also found a significant increasein acute stent thrombosis (1.3 % versus 0.3 %, pG0.001) but a significantreduction in 30-day mortality in the bivalirudin arm (2.1 % versus 3.1 %,p=0.047). Additionally, approximately 65 % of the patients had receivedUFH before being randomized to the bivalirudin arm. The use of UFHbefore randomization was associated with a significant reduction inacute stent thrombosis among patients assigned to bivalirudin withoutsignificantly increasing major bleeding [73]. At 3-year follow-up, patientsin the bivalirudin arm had lower all-cause mortality (5.9 %vs 7.7 %,p=0.03), cardiac mortality (2.9%vs 5.1 %, p=0.001), reinfarction (6.2% vs 8.2 %, p=0.04) and major non-CABG bleeding rates (6.9 % vs10.5 %, p=0.0001). There were no significant differences in ischemia-driven TVR, stent thrombosis, or composite adverse events [74].In light of the results of the HORIZONS-AMI trial, the use of GPI hastrended down and bivalirudin has gained more acceptance as the anti-coagulant of choice to support primary PCI [75].

Anticoagulant therapy in fibrinolysis

Three classes of anticoagulants have been evaluated in acute coronarysyndromes. Indirect thrombin inhibitors including UFH and LMWH,direct thrombin inhibitors (eg:hirudin, bivalirudin and lepirudin) andselective factor Xa inhibitors (e.g., Fondaparinux), A number of trialshave compared the relative efficacy of UFH and LMWH in the setting offibinolysis. The ExTRACT TIMI 25 study (Enoxaparin and ThrombolysisReperfusion for Acute Myocardial Infarction Treatment - Thrombolysis inMyocardial Infarction) compared enoxaparin to UFH in 20,506 STEMIpatients who were scheduled to undergo fibrinolysis [76]. Treatmentwith enoxaparin was associated with a 17 % relative risk reduction indeath or non-fatal MI (pG0.001), however the enoxaparin group expe-rienced a higher rate of major bleeding (2.1 % vs. 1.4 %, pG0.001) [76].A meta-analysis of trials comparing UFH to enoxaparin in over 27,000STEMI patients receiving fibrinolytic therapy showed significantly re-duced death, MI, or major bleed at 30 days in patients receivingenoxaparin [77]. Bivalirudin was compared to UFH in the Hirulog andEarly Reperfusion or Occlusion (HERO)-2 randomized trial of 17,073STEMI patients treated with streptokinase. The study showed no mor-tality differences at 30 days between the two groups [78]. The efficacy offondaparinux in STEMI was evaluated in the OASIS-6 (Organization forthe Assessment of Strategies for Ischemic Syndromes) trial of over 12,000


patients who were randomly assigned to fondaparinux (2.5 mg oncedaily) or placebo for up to eight days [79]. This trial showed a significantreduction in mortality without increase in bleeding and stroke withfondaparinux, particularly in patients not undergoing primary PCI.In summary, the current evidence for STEMI patients treated with fibri-nolytic therapy supports the use of anticoagulant therapy with LMWH orfondaparinux for a minimum of 48 hours, and preferably for the dura-tion of the index hospitalization, up to eight days or until revasculari-zation if performed [76].

Anticoagulant therapy in primary PCI

Historically, UFH has been the most commonly used antithrombinagent for PCI. It has several advantages including feasibility of bed-side monitoring with activated clotting time (ACT) and reversibility.LMWH have a more reliable antithrombin effect than UFH however,bedside monitoring is not widely available. The ATOLL (Acute STEMITreated with Primary PCI and IV Enoxaparin or UFH to Lower Is-chemic and Bleeding Events at Short- and Long-term Follow-up) trialcomparing intravenous enoxaparin with UFH for primary PCI failedto meet its primary composite endpoint [80]. Two recent meta-analyses have concluded that the use of LMWH compared to UFHleads to lower rates of mortality and major bleeding [81, 82]. Theefficacy of bivalirudin in primary PCI and the results of HORIZONSAMI have been discussed above under the section “GP IIb/IIIa re-ceptor inhibitors”. The role of other direct thrombin inhibitors, i.e.,argatroban or lepirudin in STEMI has not been studied extensively.Fondaparinux acts upstream from thrombin, which makes it an at-tractive anticoagulant for PCI. In the OASIS-6, patients undergoingPCI had higher rates of guiding catheter thrombosis (0 vs. 22;pG .001) and more coronary complications (225 vs. 270; p =0.04)with fondaparinux [79]. The most current guidelines, therefore ,rec-ommend the addition of agents with activity against factor IIa duringPCI in patients treated with fondaparinux [79].

Stent selection

Numerous randomized trials have demonstrated the safety and efficacyof coronary stents in the setting of primary PCI during STEMI [67, 83-85]. A meta-analysis consisting of nine RCTs with a total of 4,433 pa-tients showed that bare metal stent (BMS) implantation during primaryPCI decreases the risk for subsequent TVR and possibly the risk forreinfarction, without an associated mortality reduction when comparedwith balloon angioplasty [86]. However, restenosis after BMS implanta-tion, particularly in patients with complex lesion morphology, has raisedconcerns [87]. The inception of DES has significantly reduced restenosisrates, however, the decreased neointimal proliferation and continuedexposure of stent struts may predispose to late stent thrombosis andincrease long-term mortality. This was first noted in 2006 when twometa-analyses demonstrated higher mortality and MI rates in patients


treated with DES compared to BMS [88, 89]. Camenzind et al., showedan increased incidence of mortality and Q-wave MI with the use ofsirolimus-eluting stents: SES (38 % increase) and paclitaxel-eluting stents:PES (16 % increase) when compared with BMS, whereas Nordmann etal., noted an increased risk of non-cardiac mortality (stroke, lung diseaseand cancer) at two-year follow-up with SES versus BMS [88, 89].Whether the risk of very late stent thrombosis is higher with DES re-mains controversial [90-94]. The PASSION trial (Paclitaxel Eluting StentVersus Conventional Stent in ST-segment Elevation Myocardial Infarc-tion) randomly assigned 619 patients with STEMI to receive either a PESor BMS. The composite endpoint of cardiac death, recurrent MI, TVR orstent thrombosis was lower in the PES group compared with the BMSgroup (HR:0.60, CI 0.34-1.09) mainly driven by lower TVR. Angio-graphically proven stent thrombosis was not statistically different be-tween the two groups (2.1 % in the PES group versus 1.4 %; HR 1.48;95 % CI 0.42-5.23) [95]. TYPHOON (Trial to assess the use of the cY-PHer sirolimus-eluting stent in acute myocardial infarction treated withballOON angioplasty) randomized 712 patients with STEMI to receiveeither SES or BMS. At four-year follow-up, the SES group had a signifi-cantly improved rate of freedom from TVR (SES: 92.4 % vs. BMS:85.1 %; p=0.002) with no difference in definite/probable stent throm-bosis (SES: 4.4 % vs. BMS: 4.8 %, p=0.83) [96]. The HORIZONS-AMItrial showed a 2-year cumulative rates of stent thrombosis of 4.4 % withboth DES and BMS (P=0.98) [97]. In the PREMIER study (ProspectiveRegistry Evaluating Myocardial Infarction: Events and Recovery), the useof DES (compared to BMS) was associated with a higher risk of mor-tality within the first six months in cases of early discontinuation ofDAPT [93]. A recent meta-analysis showed a significant reduction in TVRwith use of DES when compared to BMS at long-term follow-up with nodifference in cumulative mortality [98]. A large registry from Massachu-setts including 7,217 patients demonstrated significant reduction in 2-year mortality (8.5 % vs. 11.6 %, P=0.008) in STEMI patients treatedwith DES when compared to BMS [99].

First generation DES (SES and PES) have been shown to elicit focalendothelium-dependent vasomotor dysfunction in both proximal anddistal non-stented reference coronary segments six to 12 months post-stent implantation [100, 101]. Second generation DES have a metal alloyscaffold coated with a durable polymer impregnated with everolimus(EES) or zotarolimus (ZES). Apart from having different antiproliferativeagents, second generation DES have thinner struts with increased flexi-bility, and more biocompatible polymers than first generation DES [102,103]. Multiple studies have compared clinical outcomes between firstand second generation DES. In the ZEST trial (Comparison of the Effi-cacy and Safety of Zotarolimus-Eluting Stent with Sirolimus-Eluting andPacliTaxel-Eluting Stent for Coronary Lesions), ZES group showed non-inferior rates of MACE compared with the SES group (10.2 % vs. 8.3 %,p=0.01) and significantly fewer major adverse cardiac events than thePES group (10.2 % vs. 14.1 %, p=0.01) [104]. The ZEST-AMI trial ran-domized 328 STEMI patients to receive ZES, SES, or PES and found nodifference in primary endpoint (death, MI, and ischemia-driven target


vessel revascularization) at 12 month follow-up [11.3 %, 8.2 %, and8.2 %, respectively (p=0.834)] [105]. A large meta-analysis comprising ofeight RCTs comparing EES with SES including 11,167 patients found nodifference in risk of MACE (HR 0.91 [0.79-1.04]; p=0.15) and TVR (HR0.86 [0.72-1.04]; p=0.12) [106]. The risk of definite stent thrombosiswas significantly lower in patients receiving EES (HR 0.49 [0.27 to 0.91];p=0.02) [106]. Despite the technological advancements, DES have limi-tations in regards to long-term safety due to very late stent thrombosiswith reported rates of up to 2.4 % and 0.6 % with the use of first andsecond generation DES, respectively [107•]. The lowest rates of stentthrombosis have been reported with cobalt-chromium EES [108•].

The persistence of stent scaffold and polymer beyond their short termfunction has been thought to be the key to the mechanisms for late restenosisand stent thrombosis in second generation DES [103]. The emerging newergeneration of DES (with novel biodegradable polymers, polymer free andfully biodegradable scaffolds) have been developed to overcome these limi-tations and have shown to improve clinical outcomes and reduce stentthrombosis rates [109, 110]. Novel technologies such as the STENTYS self-apposing nitinol coronary stents are currently being studied. These stentsdo not require a balloon for deployment, adapt to a range of vessel diametersand sizes and continue to expand after deployment in the case of vasodila-tion [111]. These stents are currently being studied in the APPOSITION V tri-al based on the hypothesis that appropriate stent sizing would eliminatemalapposition and yield improved long term results [112]. Current guide-lines recommend the use of BMS or DES during primary PCI. The stentchoice should be individualized, with preference to BMS in patients with el-evated bleeding risk, barriers to comply with DAPT or an anticipated non-car-diac surgery within 12 months following PCI. The use of DES in thesesituations is best avoided due to association with increased risk of stentthrombosis [113, 114].

Conclusion

Treatments for STEMI continue to evolve in several fields including tech-niques to achieve and maintain reperfusion. The development ofcardioprotective drugs, more potent antiplatelet and anticoagulant agentsand the evolution of stent technology from BMS to third generation DES andemergence of drug eluting bioabsorbable scaffolds are just a few examples.Consistent and reproducible delivery of optimum treatment after STEMI totranslate short term benefits of STEMI care into years of productive life re-mains a challenge.

Compliance with Ethics Guidelines

Conflict of InterestDr. Vikas Singh and Dr. Mauricio G. Cohen each declare no potential conflicts of interest relevant to this article.


Human and Animal Rights and Informed ConsentThis article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance

1. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, GoAS. Population trends in the incidence and outcomesof acute myocardial infarction. N Engl J Med.2010;362(23):2155–65.

2. Go AS, Mozaffarian D, Roger VL, et al. Heart diseaseand stroke statistics–2013 update: a report from theAmerican Heart Association. Circulation.2013;127(1):e6–245.

3.• Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients under-going primary PCI. N Engl J Med.2013;369(10):901–9.

Important landmark article that demonstrates no further re-ductions in mortality with decreasing door to balloon times.4. Anderson JL, Karagounis LA, Califf RM.Metaanalysis of

five reported studies on the relation of early coronarypatency grades withmortality and outcomes after acutemyocardial infarction. Am J Cardiol. 1996;78(1):1–8.

5. Indications for fibrinolytic therapy in suspected acutemyocardial infarction: collaborative overview of earlymortality and major morbidity results from allrandomised trials of more than 1000 patients. Fi-brinolytic Therapy Trialists' (FTT) CollaborativeGroup. Lancet. Feb 5 1994;343(8893):311-322.

6. O'Neill W, Timmis GC, Bourdillon PD, et al. A pro-spective randomized clinical trial of intracoronarystreptokinase versus coronary angioplasty for acutemyocardial infarction. N Engl J Med.1986;314(13):812–8.

7. Ribeiro EE, Silva LA, Carneiro R, et al. Randomizedtrial of direct coronary angioplasty versus intrave-nous streptokinase in acute myocardial infarction. JAm Coll Cardiol. 1993;22(2):376–80.

8. Zijlstra F, Beukema WP, van’t Hof AW, et al. Ran-domized comparison of primary coronary angio-plasty with thrombolytic therapy in low risk patientswith acute myocardial infarction. J Am Coll Cardiol.1997;29(5):908–12.

9. Keeley EC, Boura JA, Grines CL. Primary angioplastyversus intravenous thrombolytic therapy for acutemyocardial infarction: a quantitative review of 23randomised trials. Lancet. 2003;361(9351):13–20.

10.• Armstrong PW, Gershlick AH, Goldstein P, et al. Fi-brinolysis or primary PCI in ST-segment elevationmyocardial infarction. N Engl J Med.2013;368(15):1379–87.

Important randomized clinical trial.

11. McGinn AP, Rosamond WD, Goff Jr DC, Taylor HA,Miles JS, Chambless L. Trends in prehospital delaytime and use of emergency medical services for acutemyocardial infarction: experience in 4 US commu-nities from 1987-2000. Am Heart J.2005;150(3):392–400.

12. Le May MR, So DY, Dionne R, et al. A citywide pro-tocol for primary PCI in ST-segment elevation myo-cardial infarction. N Engl J Med. 2008;358(3):231–40.

13.• O'Gara PT, Kushner FG, Ascheim DD, et al. 2013ACCF/AHA guideline for the management of ST-el-evation myocardial infarction: a report of the Amer-ican College of Cardiology Foundation/AmericanHeart Association Task Force on Practice Guidelines.Circulation. 2013;127(4):e362–425.

Most recent ACC/AHA STEMI guidelines.14.• Steg PG, James SK, Atar D, et al. ESC Guidelines for

the management of acute myocardial infarction inpatients presenting with ST-segment elevation. EurHeart J. 2012;33(20):2569–619.

Most recent ESC STEMI guidelines.15. Andersen HR, Nielsen TT, Vesterlund T, et al. Danish

multicenter randomized study on fibrinolytic thera-py versus acute coronary angioplasty in acute myo-cardial infarction: rationale and design of theDANish trial in Acute Myocardial Infarction-2(DANAMI-2). Am Heart J. 2003;146(2):234–41.

16. Nielsen PH, Terkelsen CJ, Nielsen TT, et al. Systemdelayand timing of intervention in acute myocardial infarc-tion (from the Danish Acute Myocardial Infarction-2[DANAMI-2] trial). Am J Cardiol. 2011;108(6):776–81.

17. McNamara RL, Herrin J, Wang Y, et al. Impact ofdelay in door-to-needle time on mortality in patientswith ST-segment elevation myocardial infarction. AmJ Cardiol. 2007;100(8):1227–32.

18. Chareonthaitawee P, Gibbons RJ, Roberts RS, Chris-tian TF, Burns R, Yusuf S. The impact of time tothrombolytic treatment on outcome in patients withacute myocardial infarction. For the CORE investi-gators (Collaborative Organisation for RheothRxEvaluation). Heart. 2000;84(2):142–8.

19. Gersh BJ, Stone GW, White HD, Holmes Jr DR.Pharmacological facilitation of primary percutaneouscoronary intervention for acute myocardial infarc-tion: is the slope of the curve the shape of the future?JAMA. 2005;293(8):979–86.


20. Thune JJ, Hoefsten DE, Lindholm MG, et al. Simplerisk stratification at admission to identify patientswith reduced mortality from primary angioplasty.Circulation. 2005;112(13):2017–21.

21. Morrow DA, Antman EM, Charlesworth A, et al. TIMIrisk score for ST-elevation myocardial infarction: Aconvenient, bedside, clinical score for risk assessmentat presentation: An intravenous nPA for treatment ofinfarcting myocardium early II trial substudy. Circu-lation. 2000;102(17):2031–7.

22. Boersma E, Maas AC, Deckers JW, Simoons ML. Earlythrombolytic treatment in acute myocardial infarc-tion: reappraisal of the golden hour. Lancet.1996;348(9030):771–5.

23. Bonnefoy E, Steg PG, Boutitie F, et al. Comparison ofprimary angioplasty and pre-hospital fibrinolysis inacute myocardial infarction (CAPTIM) trial: a 5-yearfollow-up. Eur Heart J. 2009;30(13):1598–606.

24. Nallamothu BK, Bates ER. Percutaneous coronaryintervention versus fibrinolytic therapy in acutemyocardial infarction: is timing (almost) everything?Am J Cardiol. 2003;92(7):824–6.

25. Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospitaldelays in reperfusion for ST-elevation myocardialinfarction: implications when selecting a reperfusionstrategy. Circulation. 2006;114(19):2019–25.

26.• Wang TY, Nallamothu BK, Krumholz HM, et al. As-sociation of door-in to door-out time with reperfu-sion delays and outcomes among patients transferredfor primary percutaneous coronary intervention.JAMA. 2011;305(24):2540–7.

Important observational study highlighting the impor-tance of prompt triage of STEMI patients in facilitieswithout PCI.27.• Pinto DS, Frederick PD, Chakrabarti AK, et al. Benefit

of transferring ST-segment-elevation myocardial in-farction patients for percutaneous coronary inter-vention compared with administration of onsitefibrinolytic declines as delays increase. Circulation.2011;124(23):2512–21.

Important observational study indicating the importanceindicating that PCI is preferrable to fibrinolytic therapy infacilities without onsite PCI, in particularly when delays topresentation are longer.28. Schroder R, Wegscheider K, Schroder K, Dissmann R,

Meyer-Sabellek W. Extent of early ST segment eleva-tion resolution: a strong predictor of outcome inpatients with acute myocardial infarction and a sen-sitive measure to compare thrombolytic regimens. Asubstudy of the International Joint Efficacy Com-parison of Thrombolytics (INJECT) trial. J Am CollCardiol. 1995;26(7):1657–64.

29. Wijeysundera HC, Vijayaraghavan R, Nallamothu BK,et al. Rescue angioplasty or repeat fibrinolysis afterfailed fibrinolytic therapy for ST-segment myocardialinfarction: a meta-analysis of randomized trials. J AmColl Cardiol. 2007;49(4):422–30.

30. Gershlick AH, Stephens-Lloyd A, Hughes S, et al.Rescue angioplasty after failed thrombolytic therapyfor acute myocardial infarction. N Engl J Med.2005;353(26):2758–68.

31. Hochman JS, Sleeper LA, White HD, et al. One-yearsurvival following early revascularization for cardio-genic shock. JAMA. 2001;285(2):190–2.

32. Ohman EM, Califf RM, Topol EJ, et al. Consequencesof reocclusion after successful reperfusion therapy inacute myocardial infarction. TAMI Study Group.Circulation. 1990;82(3):781–91.

33. Nijland F, Kamp O, Verheugt FW, Veen G, Visser CA.Long-term implications of reocclusion on left ven-tricular size and function after successful thrombol-ysis for first anterior myocardial infarction.Circulation. 1997;95(1):111–7.

34. Borgia F, Goodman SG, Halvorsen S, et al. Earlyroutine percutaneous coronary intervention after fi-brinolysis vs. standard therapy in ST-segment eleva-tion myocardial infarction: a meta-analysis. EurHeart J. 2010;31(17):2156–69.

35. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routineearly angioplasty after fibrinolysis for acute myocardialinfarction. N Engl J Med. 2009;360(26):2705–18.

36. Primary versus tenecteplase-facilitated percutaneouscoronary intervention in patients with ST-segmentelevation acute myocardial infarction (ASSENT-4PCI): randomised trial. Lancet. Feb 182006;367(9510):569-578.

37. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombusaspiration during primary percutaneous coronaryintervention. N Engl J Med. 2008;358(6):557–67.

38. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac deathand reinfarction after 1 year in the Thrombus Aspira-tion during Percutaneous coronary intervention inAcute myocardial infarction Study (TAPAS): a 1-yearfollow-up study. Lancet. 2008;371(9628):1915–20.

39.• Stone GW, Maehara A, Witzenbichler B, et al.Intracoronary abciximab and aspirationthrombectomy in patients with large anterior myo-cardial infarction: the INFUSE-AMI randomized trial.JAMA. 2012;307(17):1817–26.

2x2 factorial design randomized clinical trial showing nobenefit of intracoronary abciximab or thrombus aspirationduring primary PCI.40.• Frobert O, Lagerqvist B, Olivecrona GK, et al.

Thrombus Aspiration during ST-Segment ElevationMyocardial Infarction. N Engl J Med.2013;369(17):1587–97.

Important randomized clinical trial showing the benefit ofthrombus aspiration during primary PCI.41. Jolly SS, Cairns J, Yusuf S, et al. Design and rationale

of the TOTAL trial: a randomized trial of routine as-piration ThrOmbecTomy with percutaneous coro-nary intervention (PCI) versus PCI ALone in patientswith ST elevation myocardial infarction undergoingprimary PCI. Am Heart J 2013. In press.


42. Muller DW, Topol EJ, Ellis SG, Sigmon KN, Lee K,Califf RM. Multivessel coronary artery disease: a keypredictor of short-term prognosis after reperfusiontherapy for acute myocardial infarction. Thromboly-sis and Angioplasty in Myocardial Infarction (TAMI)Study Group. Am Heart J. 1991;121(4 Pt 1):1042–9.

43. Jaski BE, Cohen JD, Trausch J, et al. Outcome of ur-gent percutaneous transluminal coronary angioplastyin acute myocardial infarction: comparison of single-vessel versus multivessel coronary artery disease. AmHeart J. 1992;124(6):1427–33.

44. Vlaar PJ, Mahmoud KD, Holmes Jr DR, et al. Culpritvessel only versus multivessel and staged percutane-ous coronary intervention for multivessel disease inpatients presenting with ST-segment elevation myo-cardial infarction: a pairwise and network meta-analysis. J Am Coll Cardiol. 2011;58(7):692–703.

45.• Wald DS, Morris JK, Wald NJ, et al. Randomized trialof preventive angioplasty in myocardial infarction. NEngl J Med. 2013;369(12):1115–23.

First study to suggest advantage of non-culprit vessel PCI inSTEMI.46. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et

al. Radial versus femoral approach for percutaneouscoronary diagnostic and interventional procedures;Systematic overview and meta-analysis of random-ized trials. J Am Coll Cardiol. 2004;44(2):349–56.

47. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoralaccess for coronary angiography and intervention inpatients with acute coronary syndromes (RIVAL): arandomised, parallel group, multicentre trial. Lancet.2011;377(9775):1409–20.

48.• Mehta SR, Jolly SS, Cairns J, et al. Effects of radialversus femoral artery access in patients with acutecoronary syndromes with or without ST-segment el-evation. J Am Coll Cardiol. 2012;60(24):2490–9.

Important subgroup analysis of the RIVAL trial demonstrat-ing decreased mortality with use of transradial access forprimary PCI.49.• Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al.

Radial versus femoral randomized investigation inST-segment elevation acute coronary syndrome: theRIFLE-STEACS (Radial Versus Femoral RandomizedInvestigation in ST-Elevation Acute Coronary Syn-drome) study. J Am Coll Cardiol.2012;60(24):2481–9.

Randomized study demonstrated decreased mortality withtransradial access for PCI in a broad population of patientswith ST-elevation acute coronary syndromes.50.• Baklanov DV, Kaltenbach LA, Marso SP, et al. The

prevalence and outcomes of transradial percutaneouscoronary intervention for ST-segment elevationmyocardial infarction: analysis from the NationalCardiovascular Data Registry (2007 to 2011). J AmColl Cardiol. 2013;61(4):420–6.

Large observational study demonstrating improved out-comes with transradial access in patients with STEMI.

51. Jang JS, Jin HY, Seo JS, et al. The transradial versusthe transfemoral approach for primary percutaneouscoronary intervention in patients with acute myo-cardial infarction: a systematic review and meta-analysis. EuroIntervention: J EuroPCR Collab WorkGroup Interv Cardiol Eur Soc Cardiol.2012;8(4):501–10.

52. Rao SV, Ou FS, Wang TY, et al. Trends in theprevalence and outcomes of radial and femoralapproaches to percutaneous coronary intervention:a report from the National Cardiovascular DataRegistry. JACC Cardiovasc Interv. 2008;1(4):379–86.

53. An international randomized trial comparing fourthrombolytic strategies for acute myocardial in-farction. The GUSTO investigators. The New En-gland journal of medicine. Sep 2 1993;329(10):673-682.

54. Effectiveness of intravenous thrombolytic treatmentin acute myocardial infarction. Gruppo Italiano perlo Studio della Streptochinasi nell'Infarto Miocardico(GISSI). Lancet. Feb 22 1986;1(8478):397-402.

55. Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loadedalteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet.1999;354(9180):716–22.

56. Mehta SR, Bassand JP, Chrolavicius S, et al. Dosecomparisons of clopidogrel and aspirin in acutecoronary syndromes. N Engl J Med.2010;363(10):930–42.

57. Foster CJ, Prosser DM, Agans JM, et al. Molecularidentification and characterization of the plateletADP receptor targeted by thienopyridine antithrom-botic drugs. J Clin Investig. 2001;107(12):1591–8.

58. Sabatine MS, Cannon CP, Gibson CM, et al. Additionof clopidogrel to aspirin and fibrinolytic therapy formyocardial infarction with ST-segment elevation.New Engl J Med. 2005;352(12):1179–89.

59. Chen ZM, Jiang LX, Chen YP, et al. Addition ofclopidogrel to aspirin in 45,852 patients with acutemyocardial infarction: randomised placebo-con-trolled trial. Lancet. 2005;366(9497):1607–21.

60. Jolly SS, Pogue J, Haladyn K, et al. Effects of aspirindose on ischaemic events and bleeding after percu-taneous coronary intervention: insights from the PCI-CURE study. Eur Heart J. 2009;30(8):900–7.

61. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-doseversus low-dose aspirin in individuals undergoingpercutaneous coronary intervention for acute coro-nary syndromes (CURRENT-OASIS 7): a randomisedfactorial trial. Lancet. 2010;376(9748):1233–43.

62. Roe MT, Armstrong PW, Fox KA, et al. Prasugrelversus clopidogrel for acute coronary syndromeswithout revascularization. N Engl J Med.2012;367(14):1297–309.


63. Steg PG, James S, Harrington RA, et al. Ticagrelorversus clopidogrel in patients with ST-elevation acutecoronary syndromes intended for reperfusion withprimary percutaneous coronary intervention: APlatelet Inhibition and Patient Outcomes (PLATO)trial subgroup analysis. Circulation.2010;122(21):2131–41.

64. Montalescot G, Wiviott SD, Braunwald E, et al.Prasugrel compared with clopidogrel in patients un-dergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38):double-blind, randomised controlled trial. Lancet.2009;373(9665):723–31.

65. Wallentin L, Becker RC, Budaj A, et al. Ticagrelorversus clopidogrel in patients with acute coronarysyndromes. N Engl J Med. 2009;361(11):1045–57.

66. Montalescot G, Barragan P, Wittenberg O, et al.Platelet glycoprotein IIb/IIIa inhibition with coro-nary stenting for acute myocardial infarction. N EnglJ Med. 2001;344(25):1895–903.

67. Stone GW, Grines CL, Cox DA, et al. Comparison ofangioplasty with stenting, with or withoutabciximab, in acute myocardial infarction. N Engl JMed. 2002;346(13):957–66.

68. Tcheng JE, Kandzari DE, Grines CL, et al. Benefits andrisks of abciximab use in primary angioplasty foracute myocardial infarction: the ControlledAbciximab and Device Investigation to Lower LateAngioplasty Complications (CADILLAC) trial. Cir-culation. 2003;108(11):1316–23.

69. ten Berg JM. van 't Hof AW, Dill T, et al. Effect ofearly, pre-hospital initiation of high bolus dosetirofiban in patients with ST-segment elevationmyocardial infarction on short- and long-term clini-cal outcome. J Am Coll Cardiol. 2010;55(22):2446–55.

70. Mehilli J, Kastrati A, Schulz S, et al. Abciximab inpatients with acute ST-segment-elevation myocardialinfarction undergoing primary percutaneous coro-nary intervention after clopidogrel loading: a ran-domized double-blind trial. Circulation.2009;119(14):1933–40.

71. De Luca G, Bellandi F, Huber K, et al. Early glyco-protein IIb-IIIa inhibitors in primary angioplasty-abciximab long-term results (EGYPT-ALT) coopera-tion: individual patient's data meta-analysis. JThromb Haemost: JTH. 2011;9(12):2361–70.

72. Thiele H, Wohrle J, Hambrecht R, et al.Intracoronary versus intravenous bolus abciximabduring primary percutaneous coronary interven-tion in patients with acute ST-elevation myocar-dial infarction: a randomised trial. Lancet.2012;379(9819):923–31.

73. Stone GW, Witzenbichler B, Guagliumi G, et al.Bivalirudin during primary PCI in acute myocardialinfarction. N Engl J Med. 2008;358(21):2218–30.

74. Stone GW, Witzenbichler B, Guagliumi G, et al.Heparin plus a glycoprotein IIb/IIIa inhibitor versusbivalirudin monotherapy and paclitaxel-elutingstents versus bare-metal stents in acute myocardialinfarction (HORIZONS-AMI): final 3-year resultsfrom a multicentre, randomised controlled trial.Lancet. 2011;377(9784):2193–204.

75. Roe MT, Messenger JC, Weintraub WS, et al. Treat-ments, trends, and outcomes of acute myocardialinfarction and percutaneous coronary intervention. JAm Coll Cardiol. 2010;56(4):254–63.

76. Antman EM, Morrow DA, McCabe CH, et al.Enoxaparin versus unfractionated heparin with fi-brinolysis for ST-elevation myocardial infarction. NEngl J Med. 2006;354(14):1477–88.

77. Murphy SA, Gibson CM, Morrow DA, et al. Effi-cacy and safety of the low-molecular weight hep-arin enoxaparin compared with unfractionatedheparin across the acute coronary syndromespectrum: a meta-analysis. Eur Heart J.2007;28(17):2077–86.

78. White H. Thrombin-specific anticoagulation withbivalirudin versus heparin in patients receiving fi-brinolytic therapy for acute myocardial infarction:the HERO-2 randomised trial. Lancet.2001;358(9296):1855–63.

79. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects offondaparinux on mortality and reinfarction in pa-tients with acute ST-segment elevation myocardialinfarction: the OASIS-6 randomized trial. JAMA.2006;295(13):1519–30.

80. Montalescot G, Zeymer U, Silvain J, et al. Intravenousenoxaparin or unfractionated heparin in primarypercutaneous coronary intervention for ST-elevationmyocardial infarction: the international randomisedopen-label ATOLL trial. Lancet.2011;378(9792):693–703.

81. Navarese EP, De Luca G, Castriota F, et al. Low-mo-lecular-weight heparins vs. unfractionated heparin inthe setting of percutaneous coronary interventionfor ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost: JTH.2011;9(10):1902–15.

82. Silvain J, Beygui F, Barthelemy O, et al. Efficacyand safety of enoxaparin versus unfractionatedheparin during percutaneous coronary interven-tion: systematic review and meta-analysis. BMJ.2012;344:e553.

83. Grines CL, Cox DA, Stone GW, et al. Coronary an-gioplasty with or without stent implantation foracute myocardial infarction. Stent Primary Angio-plasty in Myocardial Infarction Study Group. N EnglJ Med. 1999;341(26):1949–56.

84. Randomised placebo-controlled and balloon-angio-plasty-controlled trial to assess safety of coronarystenting with use of platelet glycoprotein-IIb/IIIablockade. Lancet. 1998;352(9122):87-92.


85. De Luca G, Suryapranata H, Stone GW, et al.Coronary stenting versus balloon angioplasty foracute myocardial infarction: a meta-regressionanalysis of randomized trials. Int J Cardiol.2008;126(1):37–44.

86. Nordmann AJ, Hengstler P, Harr T, Young J, BucherHC. Clinical outcomes of primary stenting versusballoon angioplasty in patients with myocardial in-farction: a meta-analysis of randomized controlledtrials. Am J Med. 2004;116(4):253–62.

87. Gibson CM, Karha J, Murphy SA, et al. Early andlong-term clinical outcomes associated withreinfarction following fibrinolytic administration inthe Thrombolysis in Myocardial Infarction trials. JAm Coll Cardiol. 2003;42(1):7–16.

88. Camenzind E SP, Wijns W. A meta-analysis of firstgeneration drug eluting stent programs. Program andAbstracts from the World Congress of Cardiology2006, Barcelona, September 2-5, 2006. Hotline Ses-sion I.

89. Nordmann AJ BM, Bucher HC. Safety of drug-elutingstents: insights from a meta-analysis. Program andAbstracts from the World Congress of Cardiology2006, Barcelona, September 2-5, 2006. Hotline Ses-sion I.

90. Roiron C, Sanchez P, Bouzamondo A, Lechat P,Montalescot G. Drug eluting stents: an updated me-ta-analysis of randomised controlled trials. Heart.2006;92(5):641–9.

91. Stone GW, Ellis SG, Cox DA, et al. A polymer-based,paclitaxel-eluting stent in patients with coronary ar-tery disease. N Engl J Med. 2004;350(3):221–31.

92. Daemen J, Tanimoto S, Garcia-Garcia HM, et al.Comparison of three-year clinical outcome ofsirolimus- and paclitaxel-eluting stents versus baremetal stents in patients with ST-segment elevationmyocardial infarction (from the RESEARCH and T-SEARCH Registries). Am J Cardiol.2007;99(8):1027–32.

93. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence,predictors, and outcomes of premature discontinua-tion of thienopyridine therapy after drug-elutingstent placement: results from the PREMIER registry.Circulation. 2006;113(24):2803–9.

94. Raber L, Wohlwend L, Wigger M, et al. Five-yearclinical and angiographic outcomes of a randomizedcomparison of sirolimus-eluting and paclitaxel-elut-ing stents: results of the Sirolimus-Eluting VersusPaclitaxel-Eluting Stents for Coronary Revasculariza-tion LATE trial. Circulation. Jun 212011;123(24):2819-2828, 2816 p following 2828.

95. Dirksen MT, Vink MA, Suttorp MJ, et al. Two yearfollow-up after primary PCI with a paclitaxel-elutingstent versus a bare-metal stent for acute ST-elevationmyocardial infarction (the PASSION trial): a follow-up study. EuroIntervention: J EuroPCR Collab WorkGroup Interv Cardiol Eur Soc Cardiol. 2008;4(1):64–70.

96. Spaulding C, Teiger E, Commeau P, et al. Four-yearfollow-up of TYPHOON (trial to assess the use of theCYPHer sirolimus-eluting coronary stent in acutemyocardial infarction treated with BallOON angio-plasty). JACC Cardiovasc Interv. 2011;4(1):14–23.

97. Dangas GD, Caixeta A, Mehran R, et al. Frequencyand predictors of stent thrombosis after percutane-ous coronary intervention in acute myocardial in-farction. Circulation. 2011;123(16):1745–56.

98. De Luca G, Dirksen MT, Spaulding C, et al. Drug-eluting vs bare-metal stents in primary angioplasty: apooled patient-level meta-analysis of randomizedtrials. Arch Intern Med. 2012;172(8):611–21.

99. Mauri L, Silbaugh TS, Garg P, et al. Drug-eluting orbare-metal stents for acute myocardial infarction. NEngl J Med. 2008;359(13):1330–42.

100. Obata JE, Kitta Y, Takano H, et al. Sirolimus-elutingstent implantation aggravates endothelial vasomo-tor dysfunction in the infarct-related coronary arteryin patients with acute myocardial infarction. J AmColl Cardiol. 2007;50(14):1305–9.

101. Togni M, Raber L, Cocchia R, et al. Local vasculardysfunction after coronary paclitaxel-elutingstent implantation. Int J Cardiol.2007;120(2):212–20.

102. Garg S, Serruys PW. Coronary stents: looking forward.J Am Coll Cardiol. 2010;56(10 Suppl):S43–78.

103. Sammel AM, Chen D, Jepson N. New generationcoronary stent technology–is the future biodegrad-able? Heart Lung Circ. 2013;22(7):495–506.

104. Park DW, Kim YH, Yun SC, et al. Comparison ofzotarolimus-eluting stents with sirolimus- and pac-litaxel-eluting stents for coronary revascularization:the ZEST (comparison of the efficacy and safety ofzotarolimus-eluting stent with sirolimus-elutingand paclitaxel-eluting stent for coronary lesions)randomized trial. J Am Coll Cardiol.2010;56(15):1187–95.

105. Lee CW, Park DW, Lee SH, et al. Comparison of theefficacy and safety of zotarolimus-, sirolimus-, andpaclitaxel-eluting stents in patients with ST-eleva-tion myocardial infarction. Am J Cardiol.2009;104(10):1370–6.

106. de Waha A, Cassese S, Park DW, et al. Everolimus-eluting versus sirolimus-eluting stents: an updatedmeta-analysis of randomized trials. Clin Res CardiolOff J German Cardiac Soc. 2012;101(6):461–7.

107.• Raber L, Magro M, Stefanini GG, et al. Very latecoronary stent thrombosis of a newer-generationeverolimus-eluting stent compared with early-gen-eration drug-eluting stents: a prospective cohortstudy. Circulation. 2012;125(9):1110–21.

108.• Palmerini T, Biondi-Zoccai G, Della Riva D, et al.Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensivenetwork meta-analysis. Lancet. 2012;379(9824):1393–402.


109. Kimura T, Morimoto T, Kozuma K, et al. Compari-sons of baseline demographics, clinical presenta-tion, and long-term outcome among patients withearly, late, and very late stent thrombosis ofsirolimus-eluting stents: Observations from theRegistry of Stent Thrombosis for Review and Re-evaluation (RESTART). Circulation.2010;122(1):52–61.

110. Navarese EP, Kubica J, Castriota F, et al. Safety andefficacy of biodegradable vs. durable polymer drug-eluting stents: evidence from a meta-analysis ofrandomised trials. EuroIntervention: J EuroPCRCollab Work Group Interv Cardiol Eur Soc Cardiol.2011;7(8):985–94.

111. Koch KT on Behalf of APPOSITION III Investigators.A post- market study to assess the STENTYS self-

expanding coronary stent in acute myocardial in-farction in real life. TCT San Francisco, USA 2011.

112. Stentys Coronary Stent System Clinical Trial in Pa-tients With Acute Myocardial Infarction (APPOSI-TION V). http://clinicaltrials.gov/show/NCT01732341.

113. Park DW, Park SW, Park KH, et al. Frequency of andrisk factors for stent thrombosis after drug-elutingstent implantation during long-term follow-up. AmJ Cardiol. 2006;98(3):352–6.

114. Pfisterer M, Brunner-La Rocca HP, Buser PT, etal. Late clinical events after clopidogrel discon-tinuation may limit the benefit of drug-elutingstents: an observational study of drug-elutingversus bare-metal stents. J Am Coll Cardiol.2006;48(12):2584–91.


http://clinicaltrials.gov/show/NCT01732341

http://clinicaltrials.gov/show/NCT01732341

therapy in st-elevation myocardial infarction: reperfusion strategies, pharmacology and stent...

Documents

theincidence of stemi

primary pci

reperfusion strategies

primary goal of reperfusion

stemi symptoms toimprove

chanical reperfusion

reperfusion strategyof

prehospital delays