ST elevation myocardial infarction primary percutaneous coronary intervention

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Associate Editor-In-Chief: Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

Definitions of C. Michael Gibson, M.S., M.D.

Primary PCI
Primary PCI is defined as the performance of percutaneous coronary intervention (PCI) (either conventional balloon angioplasty or coronary stent placement) in the setting of ST elevation MI (STEMI) without antecedent treatment with a fibrinolytic agent. Primary PCI is the subject of this chapter.

Facilitated PCI
Facilitated PCI is defined as the intent to perform a PCI (either conventional balloon angioplasty or coronary stent placement) in the setting of STEMI following treatment with either a full dose or half dose of a fibrinolytic agent. This approach is also termed a pharmaco-invasive strategy. This strategy differs from rescue or adjunctive PCI in that the intent of facilitated PCI is to perform PCI, and the administration of a fibrinolytic agent is intended to improve the PCI results. The strategy differs from facilitated PCI, a strategy in which the intent is to administer a fibrinolytic agent, and routinely perform PCI in the majority of patients even in the presence of or irrespective of signs and symptoms of successful fibrinolytic reperfusion. The chapter on Facilitated PCI can be found here.

Rescue PCI
Stated simply, this is performance of a PCI in a closed artery following fibrinolytic therapy. Rescue PCI is defined as the intent to administer a fibrinolytic agent in the setting of STEMI, and the performance of PCI for failure of the fibrinolytic agents is unintended. If there are clinical signs and symptoms of failure of the fibrinolytic agent to achieve reperfusion, then rescue PCI is performed to open the totally occluded artery. The strategy differs from facilitated PCI, a strategy in which the intent is to administer a fibrinolytic agent, and routinely perform PCI in the majority of patients even in the presence of or irrespective of signs and symptoms of successful fibrinolytic reperfusion. The chapter on Rescue PCI can be found here.

Adjunctive PCI
Stated simply, this is performance of a PCI in an open artery following fibrinolytic therapy. Adjunctive PCI is defined as the intent to administer fibrinolytic agent in the setting of STEMI, and the performance of PCI for partial success of the fibrinolytic agent is unintended. If there are clinical signs and symptoms of incomplete reperfusion, then adjunctive PCI is performed to further open a patent artery (one with TIMI grade 2 or 3 flow). The strategy differs from facilitated PCI in that the intent is to administer a fibrinolytic agent, and the performance of PCI is intended to improve the fibrinolytic results. The chapter on Adjunctive PCI can be found here.

Overview
If it can be implemented in a timely fashion (a door-to-balloon time of < 90 minutes), primary PCI is now the recommended treatment strategy for the management of patients with acute ST elevation myocardial infarction (STEMI).

Historical overview of Primary PCI
Based upon an autopsy series of 500 patients, Davies and co-workers reported in 1976 that plaque rupture and coronary thrombosis led to coronary artery occlusion and that this was the basis of ST elevation myocardial infarction. In STEMI, coronary artery occlusion results in chest pain and electrocardiographic changes in the leads corresponding to the infarcted segments. A time dependent wavefront of necrosis of the myocardium ensues starting from the endocardium to the epicardium eventually resulting in full thickness or transmural infarction depending on the duration of occlusion.

Since the introduction of pharmacologic reperfusion therapy in the seventies, the main goal of reperfusion treatment has been to restore early, full and sustained patency of the infarct related artery. In the seventies and in the eighties, fibrinolytic therapy was the primary reperfusion strategy that was available for the management of patients with acute ST elevation myocardial infarction (STEMI). An initial analysis consisting of 9 clinical trials by the Fibrinolysis Therapy Trialists (FTT) group demonstrated that there was a significant reduction in the mortality associated with the administration of fibrinolytic therapy compared to control subjects who did not receive fibrinolytic therapy (9.6% vs. 11.5%, p<0.00001).

Following the introduction of conventional percutaneous transluminal coronary balloon angioplasty (PTCA), patients who were treated with fibrinolytic therapy often underwent PTCA to open a persistently occluded culprit artery (Rescue PCI). To understand whether PTCA performed after fibrinolytic therapy improved outcomes, initial studies compared the outcome of patients who were treated with fibrinolytic therapy alone with those patients who had fibrinolytic therapy followed by urgent PTCA. This was an early test of the strategy of facilitated PCI, not primary PCI. These initial studies did not demonstrate a significant benefit of routinely performing urgent conventional balloon angioplasty following fibrinolytic therapy. Indeed, it was felt that it might be harmful to perform conventional balloon angioplasty following fibrinolytic administration given the high rates of abrupt closure following conventional balloon angioplasty in this setting. The high rate of abrupt closure was thought to be due to hemorrhage into the plaque (intramural hemorrhage) following the balloon angioplasty and the pro-thrombotic environment and platelet activation associated with fibrinolytic administration. These intial studies were limited by the fact that they were performed before intracoronary stents were available, before parenteral antiplatelet agents were available, and before the availability of thienopyridines, all of which may have limited the risk of abrupt closure that was seen in these early studies.

Given the failure of antecedent fibrinolytic therapy to improve PTCA outcomes, interest then shifted towards comparisons of primary angioplasty in the absence of preceding fibrinolytic therapy vs fibrinolytic therapy alone. A decade of trials demonstrated that primary angioplasty alone without antecedent fibrinolytic therapy was superior to fibrinolytic therapy. Hence a strategy of primary PTCA alone for patients with acute STEMI was adopted and this strategy offered significant advantage in terms of reduction in mortality, non-fatal reinfarction, major bleeding and intracranial hemorrhage compared to patients who received fibrinolytic therapy.

Since the introduction of primary PTCA, significant advances have been made in the field of interventional cardiology including the availability of intra-coronary stents, thrombus aspiration devices, and improved antiplatelet and antithrombin agents.

If it can be implemented in a timely fashion (a door-to-balloon time of < 90 minutes), primary PCI is now the recommended treatment strategy for the management of patients with acute STEMI.

Contraindications to fibrinolysis
Although the use of fibrinolytic therapy was associated with significant reduction in mortality, it was soon demonstrated to be overcome by a number of limitations. An analysis from the TIMI-9 registry demonstrated that 10.3% of patients have contraindications to fibrinolysis which consisted of prior stroke or transient ischemic attack, recent cardiopulmonary resuscitation, trauma, surgery, recent bleeding, persistent hypertension and significant illness. Its efficacy in the management of patients with cardiogenic shock complicating acute STEMI is not proven. In addition, not all patients who are treated with fibrinolysis undergo coronary angiography. This results in patients with significant coronary stenosis or three vessel disease not receiving the appropriate revascularization therapy.

Timing of fibrinolytic treatment
The benefit of fibrinolytic therapy decreases as time progresses after the onset of symptoms. Pre-hospital administration of fibrinolysis was beneficial if administered within 70 minutes in terms reduction in the composite score of death, stroke, serious bleed and infarct size (p=0.009). Further studies suggest that significant mortality reduction is seen in patients treated with fibrinolytic therapy within the first 2 hours of symptom onset compared to those presenting later.

Cerebrovascular events
Stroke remains a catastrophic complication of fibrinolytic therapy. The FTT collaborators analysis demonstrated that fibrinolysis was associated with an increase in stroke rates compared to control patients (1.2% vs. 0.8%, p<0.00001). An analysis from the GUSTO I (Global Use of Strategies to Open Occluded arteries in Acute Coronary Syndromes) study demonstrated that the overall incidence of stroke after fibrinolytic therapy was 1.4% (95% of stroke occurred within 5 days). Combination treatment with streptokinase (SK) and tissue plasminogen activator (TPA) was associated with significantly more stroke than SK alone (1.64% vs. 1.19%, p<0.007). Of these in 41% of cases the stroke was fatal. Intracranial hemorrhage (ICH) occurred in 0.46% of cases who received SK and 0.88% of cases who received combination therapy (p<0.001). Another analysis demonstrated a slight increase in ICH among patients receiving TPA (0.95%).

Patency of infarct arteries
In addition to the above limitations, early patency of the infarct related arteries is not demonstrated in all patients treated with fibrinolytic therapy. Angiography following fibrinolytic therapy demonstrates that TIMI flow grade 3 is achieved in only ~40-60% of cases. In an analysis from the GUSTO trial, the patency of infarct artery (TIMI flow grade 2/3) at 90 minutes was achieved in 81% of cases in the accelerated TPA group compared to only 54% in the SK group (p<0.001). Normal flow (TFG 3) was achieved in 54% of patients who received TPA compared to 40% among those who received the other treatments (SK + subcutaneous heparin, SK + intravenous heparin, combination SK, TPA and heparin). The mortality at 30 days was significantly increased among those who had reduced flow compared to those who had normal flow (8.9% vs. 4.4%, p=0.009).

Reinfarction and recurrent ischemia
Fibrinolysis is also limited by frequent occurrence of recurrent ischemia, reocclusion of the infarct artery (reocclusion within 5-7 days occurred in 4.9-6.4% cases in the GUSTO analysis) and reinfarction. Reinfarction occurred in 4.3% of cases following thrombolysis at a median of 3.8 days after fibrinolysis. Gibson et al have reported higher short term and long term mortality associated with reinfarction.

Fibrinolysis versus PTCA
Due to the limitations associated with the fibrinolytic therapy, it became evident in small non-randomized studies that mechanical reperfusion strategy using percutaneous transluminal coronary angioplasty is associated with increased infarct artery patency and reduced mortality. This encouraged randomized trials to directly compare the benefits of primary PTCA with fibrinolytic therapy.

Clinical trials comparing primary PTCA with fibrinolysis
The initial studies compared the efficacy of intracoronary streptokinase administration with primary PTCA among patients with ST elevation myocardial infarction. O’Neill and colleagues randomized a total of 56 patients to either intracoronary streptokinase (SK) or undergo PTCA. There was no difference in the infarct artery patency rates between the two groups (85% SK vs. 83% PTCA, p=NS). However there was significant reduction in the residual stenosis with PTCA compared to fibrinolytic therapy (p<0.001), improvement in global ejection fraction (p<0.001) and regional wall motion abnormality (p=0.05).

Clinical studies with short-term follow-up
Over the following ten years, several small and large randomized clinical studies were performed to assess the benefits of primary PTCA compared with fibrinolysis. In 1995, Michels and Yusuf performed a meta-analysis of 7 clinical trials comparing primary PTCA versus fibrinolytic therapy and 16 clinical trials comparing PTCA after fibrinolysis versus fibrinolytic therapy alone consisting of 8496 patients. There was a significant mortality benefit with primary PTCA compared to fibrinolytic therapy at 6 weeks in addition to benefits in terms of reduction in combined short-term mortality and reinfarction. These benefits were not demonstrated among patients who underwent PTCA after fibrinolysis compared to those who had fibrinolysis alone. This latter finding discouraged PTCA following the administration of fibrinolysis.

In 1997, Weaver and colleagues performed another meta-analysis consisting of 10 single center and multi-center randomized trials consisting of 2606 patients who had primary PTCA and fibrinolytic therapy from January 1985 to March 1996. Streptokinase was used in four of these trials, tissue plasminogen activator (TPA) was used in three trials and the accelerated dose TPA was used in the remaining three trials. There was significant 30-day mortality reduction with primary PTCA (n=1290) compared to fibrinolytic therapy (n=1316) [4.4% vs. 6.5%, p=0.02]. There was also significant reduction in the combined death and reinfarction rates (7.2% vs. 11.9%, p<0.001), total stroke (0.7% vs. 2%, p=0.007) and hemorrhagic stroke rates (0.1% vs. 1.1%, p<0.001).

Clinical trials with long-term follow-up
Although significant benefits have been proven in the short term (4-6 weeks) using the primary PTCA strategy, one of the main limitations of these initials trials is that long term outcome results were not available. Hence subsequent studies including the GUSTO IIb, Zwolle group studies and the PAMI (Primary angioplasty in Acute Myocardial Infarction) trials provided outcome results extending up to 5 years.

GUSTO IIb study
The GUSTO IIb study (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes) demonstrated that benefit in terms of reduction in the composite outcome of death, non fatal reinfarction and non fatal disabling stroke seen at 30 days (9.6% vs. 13.7%, p=0.033) was no longer significant at 6 months (13.3% vs. 15.7 % p=NS) with primary PTCA compared to fibrinolytic therapy using recombinant tissue plasminogen activator among 1138 patients from 57 hospitals. At 30 days there was no difference in the occurrence of death (5.7% vs. 7%, p=0.37), reinfarction (4.5% vs. 6.5%, p=0.13) and stroke (0.2% vs. 0.9%, p=0.11) when analyzed independently.

PAMI trial
In the PAMI trial (Primary angioplasty in Acute Myocardial Infarction), 395 patients were randomized to undergo PTCA (n=195) and fibrinolysis using TPA (n=200) within 12 hours of acute STEMI. In contrast to the GUSTO IIb trial results, the combined death and reinfarction rates at 6 months were significantly reduced in the PTCA group compared to the fibrinolysis group (8.5% vs. 16.8%, p=0.02) with an increase in intracranial hemorrhage with fibrinolysis compared to PTCA (2% vs. 0%, p=0.05).

Zwolle group study
The long term benefit of primary PTCA was assessed by Zijlstra and colleagues. There were 395 STEMI patients who underwent primary PTCA and 201 patients who underwent fibrinolysis. Follow-up results were obtained for 5±2 years in this study. There was once again mortality benefit at 30 days using the primary PTCA strategy compared to fibrinolysis alone (1% vs. 7%, p=0.01) which extended to 5±2 years (13.4% vs. 23.9%, p=0.01). There was also significant difference in the occurrence of combined death and non-fatal reinfarction at 30 days (relative risk 0.13, 95% confidence interval 0.05-0.37) and beyond 30 days (relative risk 0.62, 95% confidence interval 0.43-0.91) with primary PTCA. This study also demonstrated that the estimated cost including initial hospital stay charges, readmission charges, procedural charges, physician charges and medications charges were significantly lower with primary PTCA compared to fibrinolytic therapy ($16090 vs. $16813, p=0.05). Although performed at a later time period than the GUSTO and the PAMI trials, one of the limitations with this study is that intracoronary stents and glycoprotein IIb/IIIa inhibitors were not used.

Meta-analysis of primary angioplasty vs. fibrinolysis
In a meta-analysis in 2003, Keeley and colleagues studied 23 trials of acute myocardial infarction consisting of a total of 7739 patients. Of these, 3867 patients were assigned to fibrinolysis and 3872 were assigned to primary PTCA. Most patients who received fibrinolytic therapy received a fibrin-specific agent (76%). Stents were used in 12 trials and platelet glycoprotein IIb/IIIa inhibitors were used in eight trials. Similar to the previous studies on fibrinolysis versus primary PTCA, this study demonstrated that primary PTCA was better than fibrinolytic therapy in terms of reduction in the overall short-term (4-6 weeks) death (7% vs. 9%; p=0.0002), death excluding the SHOCK trial data (5% vs. 7%; p=0.0003), non-fatal reinfarction (3% vs. 7%; p<0.0001), and stroke (1% vs. 2%; p=0.0004). The combined endpoint of death, non-fatal reinfarction and stroke was significantly reduced in the primary PTCA group (8% vs. 14%; p<0.0001). The benefit of primary PTCA over fibrinolytic therapy was not only seen in the short term but also in the long term (6-18 months) regardless of the type of fibrinolytic agents used and whether or not patients were transferred to another center for primary PTCA.

The issue of reinfarction following primary PTCA was specifically addressed by Kernis and colleagues in an analysis from the PAMI trials [. In this study, reinfarction occurred in 2.1% of cases at one month, lower than that observed in the Keeley analysis. In addition this study demonstrated that the admission Killip class >1, left ventricular ejection fraction <50%, final % coronary stenosis >30%, coronary artery dissection and presence of thrombus were associated with reinfarction. One month reinfarction was associated with an occurrence of death (OR 7.14, 95% CI 3.28 to 15.5) and ischemic target vessel revascularization (OR 15.0, 95% CI 8.68 to 26.0) at 6 months. This study however, may not accurately reflect current practice due to the reduced use of glycoprotein IIb/IIIa inhibitors and stents in the PAMI trials.

Primary PTCA versus pre-hospital thrombolysis
Primary PCI is not only superior to in-hospital thrombolysis but also superior compared with pre-hospital thrombolysis. This was indeed demonstrated in the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) study which consisted of 26 205 patients with ST elevation myocardial infarction. Patients who underwent primary PCI demonstrated clear benefits in terms of reduction in mortality at 30 days (4.9% vs. 7.6% vs. 11.4%) and at one year (7.6% vs. 10.3% vs. 15.9%) compared to those who had pre-hospital thrombolysis and in-hospital thrombolysis. Primary PCI patients had shorter hospital stay and less reinfarction compared to the other two groups.

Advances in PCI
Over the last 15 years there has been significant development in the stent technology and adjunctive pharmacotherapy which further enhances the outcomes of primary angioplasty now commonly referred to as primary percutaneous coronary intervention (PCI).

Stent-PAMI study
The safety and efficacy of primary stenting using the Palmaz-Schatz stents for patients with acute ST elevation myocardial infarction was examined in the stent PAMI trials [22;23]. In the pilot trial, 312 patients from 9 centers were included. Of these, 240 (77%) patients underwent stenting which was successful in 98% of the cases. TIMI flow grade 3 was achieved in 96% of cases. Low rates of in-hospital death (0.8%), reinfarction (1.7%), recurrent ischemia (3.8%) and pre discharge target vessel revascularization (1.3%) were demonstrated with the stenting strategy. There were no additional events at 30 days except the occurrence of target vessel revascularization (TVR) in one patient. A subsequent study from the same group demonstrated that at 7.4±2.6 month follow-up, the incidence of death, reinfarction and TVR continued to be low among patients who underwent primary angioplasty using stents. This was also associated with a low rate of restenosis at follow-up (27.5%).

STOP-AMI study
Stenting in combination with glycoprotein IIb/IIIa inhibitor was examined in the STOP-AMI trial (Stent versus Fibrinolysis for Occluded coronary arteries in patients with Acute Myocardial Infarction). One hundred and forty patients were randomized to undergo PCI using stents (n=71) and abciximab or to receive alteplase (n=69). The primary endpoint of this study consisted of the degree of myocardial salvage assessed using Tc 99m sestamibi scans. The median infarct size in the PCI group was significantly reduced compared to the fibrinolytic group (14.3% vs. 19.4%, p=0.02). The salvage index which is calculated by dividing the % of left ventricle salvaged by % of left ventricle compromised by the initial reperfusion defect was also favorable with primary PCI (PPCI) compared to fibrinolysis (0.57 vs. 0.26, p<0.001). The cumulative incidence of death, reinfarction and stroke at 6 months was significantly reduced in the PPCI group (8.5% vs. 23.2%, p=0.02).

Sirolimus-eluting stent studies
Over the last five years, drug eluting stents have played a major role in reducing the incidence of restenosis. The advantages of using drug eluting stents have been examined in the setting of an acute myocardial infarction. In the Trial to assess the use of the cYPHer stent in acute myocardial infarction treated with ballOON angioplasty (TYPHOON), the use of sirolimus eluting stents was associated with a significant reduction in the primary endpoint of target vessel failure at one year which consisted of target vessel failure related death, repeat myocardial infarction and target vessel revascularization (7.3% vs. 14.3%, p=0.004) which was mainly driven by a reduction in the occurrence of target vessel revascularization (5.6% vs. 13.4 %, p<0.001) without a significant reduction in death and repeat myocardial infarction (MI).

Likewise, the SESAMI study (Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction) demonstrated that primary PCI using sirolimus eluting stent compared to bare metal stent was associated with reduction in binary restenosis by 56%, target lesion revascularization by 61%, target vessel revascularization by 62%, adverse events by 59% and target vessel failure by 53% at one year. The Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs. Abciximab and Bare Metal Stent in Myocardial Infarction study (STRATEGY) demonstrated that PPCI using high dose tirofiban and sirolimus eluting stents (n=87) was associated with a significant reduction in the primary endpoint of combined death, non fatal reinfarction, stroke and binary restenosis at 8 months (19% vs. 50%, p<0.001) compared to a strategy of abciximab and bare metal stent implantation (n=88). The binary restenosis was also significantly reduced in the sirolimus group (9% vs. 36%, p=0.002).

Paclitaxel-eluting stent study
On the other hand, in the PASSION trial (Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) using paclitaxel eluting stents, the benefits of using paclitaxel eluting stents following an acute myocardial infarction were not striking. There was a trend towards reduction in death, recurrent myocardial infarction and target vessel revascularization (8.8% vs. 12.8%, p=0.09) with no difference in death, recurrent MI and TVR when assessed independently compared to the bare metal stents.

RAPPORT trial
The use of adjunctive pharmacotherapy using glycoprotein IIb/IIIa inhibitor was assessed in the RAPPORT trial (Reopro And Primary PTCA Organization and Randomized Trial). Patients underwent primary PTCA with (n=241) and without abciximab (n=242). Abciximab significantly reduced the incidence of death, reinfarction and target vessel revascularization at 7 days (3.3% vs. 9.9%, p=0.03), 30 days (5.8% vs. 11.2%, p=0.003) and at 6 months (11.6% vs. 17.8%, p=0.05). The need for bail-out glycoprotein IIb/IIIa inhibitor therapy was reduced in the abciximab group by 42%, p=0.008. However, there was an increased risk of major bleed in the abciximab group (16.6% vs. 9.5%, p=0.02) compared to the placebo group.

ADMIRAL study
The ADMIRAL study (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term follow-up) determined the benefit of administration of abciximab in patients undergoing primary angioplasty with stenting (149 patients received stents and abciximab, 151 patients received stents and placebo). Abciximab administration was associated with an increase in pre-PCI (16.8% vs. 5.4%, p=0.01) and post-PCI (95.1% vs. 86.7%, p=0.04) TIMI flow grade 3. There was a significant reduction in the incidence of combined death, reinfarction and target vessel revascularization in the abciximab group compared to the placebo group at 30 days (6% vs. 14.6%, p=0.01) and at 6 months (7.4% vs. 15.9%, p=0.02) without an increase in major bleed (0.7% vs. 0%). The six-moth left ventricular ejection fraction was also significantly better in the abciximab group compared to the placebo group (61.1±10.6 vs. 57±11.1, p=0.05).

Intracoronary pharmacotherapy during primary angioplasty
One of the problems encountered during PPCI is the occurrence of no-reflow phenomenon despite the lack of obvious epicardial obstruction which is as a result of microvascular dysfunction. Piana et al demonstrated that no-reflow occurred in 11.5% of cases undergoing PTCA following an acute myocardial infarction compared to those who had PTCA in the non-infarct setting (1.5%, p<0.001).

Mechanisms of no-flow phenomenon
Several mechanisms have been postulated for the development of microvascular dysfunction and no-reflow phenomenon including α-adrenergic mediated macro and microvascular constriction. Endothelial dysfunction detected by elevated levels of different factors is noted among patients with coronary slow-flow phenomenon. A number of previous studies have demonstrated elevated levels of plasma endothelin-1, asymmetric dimethylarginine (ADMA), plasma adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin)], homocysteine, C-reactive protein (CRP), interleukin-6, noradrenaline and decreased levels of plasma nitric oxide in the setting of coronary slow-flow phenomenon    . Several pharmacological and mechanical therapies have been suggested for the management of no-reflow . Intracoronary (IC) pharmacotherapy used to treat no-reflow during PCI following an acute myocardial infarction is discussed in this section.

Intracoronary verapamil
Taniyama and colleagues determined the benefit of intracoronary administration of verapamil among forty patients with acute ST elevation myocardial infarction during primary PTCA. Of these 20 patients received intracoronary verapamil and the remaining 20 were control patients. All patients underwent myocardial contrast echocardiography (MCE) with intracoronary injection of sonicated microbubbles. Following the administration of verapamil the low reflow zone reduced from 0.39±0.23 to 0.29±0.17 (p<0.05) and the peak intensity increased from 6±5 to 12±6. The administration of intracoronary verapamil was also associated with greater reduction in the wall motion score from day 1 to day 24 compared to the control group (0.7±0.8 vs. 0.2±1.3 (p<0.05).

Intracoronary nicorandil
A study by Ota et al demonstrated that combined intravenous and intracoronary administration of nicorandil reduces reperfusion injury during PCI and improves the corrected TFC and ST segment resolution in acute myocardial infarction, and appears to be preferable to intracoronary administration alone. In their study, 0.5 mg per dose (1–2 mg in total) of nicorandil was administered into the coronary artery 1–2 times before and after percutaneous coronary intervention (PCI) balloon inflation. For intravenous administration, 4mg of nicorandil was injected, followed by a continuous drip infusion of 6ml/h (≈6mg/h).

Intracoronary adenosine
More recently, Stoel and colleagues have demonstrated that high dose adenosine (60mg) administered into the coronary arteries during PCI (all patients received stents and abciximab) following an acute myocardial infarction resulted in better mean ST segment resolution (35.4% vs. 23% placebo, p<0.05), improved TIMI frame count (15.7 vs. 30.2, p<0.005), improved myocardial blush grades (2.7 vs. 2, p<0.05) and coronary resistance index (0.7 vs. 1.31 mm Hg per ml/min, p<0.005).

Intracoronary glycoprotein IIb/IIIa inhibitors
It has been postulated that local administration of abciximab would enhance the diffusion of antibodies to platelets inside the thrombus within the coronary arteries as a result of an increase in the concentration of abciximab during local delivery than during IV administration [280:1 (minimal washout) vs. 1:1 (normal flow)]. High local concentration might also enhance the anti-inflammatory properties of abciximab such as the anti-inflammatory effects from cross-reactivity with the leukocyte αMβ2 integrin and inhibition of the vitronectin receptors in the endothelial cells in the culprit vessel. These effects on the platelets and on the coronary endothelial cells result in reduced reperfusion injury and a greater degree of myocardial salvage.

The beneficial effect of intracoronary abciximab was studied by Wohrle and colleagues. In a study of 403 patients, 294 received intracoronary abciximab and 109 patients received intravenous abciximab (20mg bolus followed by 10mg infusion for 12 hours). The 30 day major adverse cardiac events (death, myocardial infarction and urgent revascularization) were significantly reduced in the IC group compared to the IV group (10.2% vs. 20.2%, p<0.008). The benefit was more evident among those who had TIMI flow grade 0/1 prior to the PCI procedure (11.8% vs. 27.5%, p<0.02).

A retrospective analysis of 59 patients undergoing PPCI demonstrated the feasibility and efficacy of intracoronary and intravenous eptifibatide. There was an increase in the final TIMI myocardial perfusion grade 3 (54%) with the administration of eptifibatide. This study was small and retrospective without a control group and hence further ongoing randomized studies will provide a definitive answer on the role of intracoronary eptifibatide administration in improving microvascular function.

Intracoronary thrombolytic administration
In addition to the drugs mentioned previously and the beneficial effects of intracoronary glycoprotein IIb/IIIa inhibitors, the beneficial effects of intracoronary administration of fibrinolytic were determined among patients undergoing primary PCI by Sezer and colleagues. A total of 41 patients were randomized to undergo PCI with or without IC streptokinase. Two days following the procedure, patients who had IC SK had significantly better coronary flow reserve (2.01±0.57 vs. 1.39±0.31), index of microvascular resistance (16.29±5.06 U vs. 32.49±11.04 U), collateral flow index, mean coronary wedge pressure, systolic wedge pressure and diastolic deceleration time compared to the control group. However, there was no difference in the left ventricular size and function at 6 months.

Adjunctive anti-embolic devices
In addition to pharmacotherapy, several thrombus extraction   , proximal and distal protection devices   have been used during PPCI among patients with heavy thrombus burden in the infarct related arteries in order to minimize distal embolization. The largest study using a distal protection device during PPCI is the EMERALD trial (Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris) by Stone and colleagues. This study consisted of 501 patients with STEMI from around 7 countries. In total 252 patients underwent PPCI using the distal protection device (PercuSurge, GuardWireTM Plus, Medtronic Inc. Calif.). Aspiration was performed in 97% of the cases and in 73% visible debris was aspirated. There was no difference in the primary endpoint of ST segment resolution at 30 minutes following the PCI (63.3% vs. 61.9%, p=0.78) and the infarct size between days 5 and 14 using Tc 99m Sestamibi scan (12% vs. 9.5%, p=0.15) between the groups that had PCI with and without the device respectively. This was associated with no difference in the major adverse cardiac events at 6 months between the two groups (10% vs. 11%, p=0.66).

A study using the thrombus extraction device during primary PCI was performed by Svilaas and colleagues called the TAPAS study (Thrombus Aspiration in Percutaneous coronary intervention following Acute myocardial infarction Study) consisting of 1071 patients with acute myocardial infarction from a single center. Of these, 535 patients were randomized following coronary angiography to thrombus extraction and 536 patients were randomized to conventional PPCI. Thrombus was aspirated in 72.9% of the cases which was confirmed on histopathological examinations. The major component of the aspirated debris consisted of platelets in 67.7% of cases and erythrocytes in 15.1% of patients. Patients randomized to thrombus extraction had significant improvement in the myocardial blush grades (Grade 0/1 17.1% versus 26.3%, p<0.001) and ST segment resolution (complete ST segment resolution in 56.6% versus 44.2%, p<0.001) compared to those who had conventional PPCI only. Of the patients who had better MBG and ST segment resolution had better clinical outcomes at 30 days. Impaired myocardial blush (Grade 0 or 1) was related to worse outcomes (14.1%) as compared to Grade 2 blush (8.8%)  or Grade 3 blush (4.2%, p<0.001).

A meta-analysis of thrombectomy devices and distal protection devices consisting of 14 clinical trials of 2630 patients demonstrated that there was no benefit in terms of reduction in death and reinfarction with the anti-embolic devices compared with standard PCI (4% vs. 4.5%, p=0.35). There was also no reduction in death and reinfarction when the thrombectomy and distal protection devices compared with standard PCI were analyzed separately (4.4% vs. 4.2%, p=0.95 and 3.5% vs. 5%, p=0.20 respectively).

There are several potential reasons for the failure of the anti-embolic devices to improve clinical outcomes. First, in addition to distal embolization there are a number of other potential factors that result in microvascular dysfunction. Thus the removal of thrombus alone might not be sufficient to restore microvascular function. Hence treatment strategies consisting of anti-embolic devices alone without addressing the other factors responsible for microvascular dysfunction does not lead to improved outcomes following an acute myocardial infarction. In addition, the use of devices can result in dislodgement of thrombus proximally into the non-culprit vessels, into the unprotected side branches and distally during the initial stages of trying to cross the lesion using the wire and the device which could lead to further myocardial damage in the previously uninvolved territories.

Delayed Primary PCI
Although significant benefit has been demonstrated with primary PCI compared to fibrinolytic therapy among those who present early after symptom onset, it is important to determine the efficacy of primary PCI for patients who present late (>24 hours). This was examined by Hori et al in a small study of 83 patients presenting >24 hours after symptom onset comparing those who did (n=44) and did not (n=39) undergo PTCA. At six months there was no difference in the left ventricular ejection fraction and regional wall motion score between the two groups. However, a five year Kaplan-Meier event free survival analysis (free from death, non-fatal reinfarction and congestive cardiac failure) demonstrated that PTCA was associated with better outcome (p<0.0001).

OAT study
The positive benefit with delayed PCI in the study by Hori et al was not demonstrated in the much larger OAT (Occluded Artery Trial) trial. This study consisted of 2166 patients who had occluded arteries on coronary angiography 3-28 days after myocardial infarction (1082 underwent PCI and 1084 had medical therapy). The primary endpoint of death, reinfarction and New York Heart Association heart failure class IV at 4-year follow-up was not different between the PCI group and the medical therapy group [17.2% vs. 15.6% (HR 1.16, 95% confidence interval 0.92-1.45, p=0.2)]. When analysed separately for individual endpoints there was no difference in the occurrence of reinfarction (7% vs. 5.3%, p=0.13), heart failure (4.4% vs. 4.5%) and death (9.1% vs. 9.4%) between the two groups. The differences in the outcomes between the OAT study and the previous studies could be attributed to the aggressive medical therapy (86% of patients received beta-blocker therapy) in the OAT study compared to previous studies.

Specific considerations in primary PCI
Although PPCI is the optimal strategy for patients with acute STEMI it is also overcome by a number of limitations including the logistical difficulties of implementing the service particularly for patients who present to non-PCI centers. Some of these issues have been addressed in randomized clinical trials and are discussed in this section.

Door-to-balloon and door-to-needle times
One of the main challenges faced with primary PCI is the timely implementation of treatment to patients with ST elevation myocardial infarction. In an analysis of over 27,000 patients from the NRMI database (National Registry of Myocardial Infarction) of patients with STEMI who presented from June 1994 to March 1998 to 661 community and tertiary hospitals in the United States, Cannon et al demonstrated that the adjusted odds of mortality increased by 41-62% for door-to-balloon in excess of 2 hours. In this analysis the median door-to-balloon time was 1 hour 56 minutes. Around 8% of patients achieved a door-to-balloon time less than 60 minutes. The unadjusted mortality rose from 4.2%-8.5% with increasing door-to-balloon time (p<0.001). In another analysis of the NRMI study, Pinto and coworkers studied the hospital PCI related delays [Door to balloon time (DB)-door to needle time (DN)] among 192,509 patients with STEMI treated with primary PCI (65,600) and fibrinolysis (n=126,909). This analysis demonstrated that 65% of patients presented within 2 hours of symptom onset. They demonstrated that as DB-DN increased, mortality increased also (p<0.001). For every 30 minute increase in the DB-DN there was approximately 10% increase in the relative risk of in-hospital death (p<0.001). Another study from the NRMI study demonstrated that only a small proportion of patients (15%) received PPCI with door-to-balloon times <120 minutes, of which only 4% had door-to-balloon time <90 minutes.

Institutional volume
The data from the NRMI also determined the impact of institutional volume on mortality outcomes following PCI for acute myocardial infarction. A total of 450 hospitals in the United States were divided into quartiles according to the volume of primary angioplasty. The in-hospital mortality was reduced by 28% when PCI was performed in high volume centres compared to the low volume centres (p<0.001). The crude mortality rate was 7.7% among patients who underwent PPCI in high volume centers compared to 5.7% among those who underwent PCI in high volume centers (p<0.001).

Magid et al compared primary PTCA and fibrinolytic therapy in relation to the volume of primary angioplasties carried out in different hospitals among 62, 299 STEMI patients who underwent either therapy from 1994 to 1999. This study classified hospitals into 3 groups based on the number of primary angioplasties performed annually: low-volume group ≤16 procedures per year; intermediate-volume group 17-48 procedures per year and high-volume center ≥49 procedures per year. This study demonstrated that primary PTCA was associated with a significant reduction in mortality over fibrinolysis when primary PCI was performed in a high (3.5% vs. 5.4%, p<0.001) and intermediate (4.5% vs. 5.9%, p<0.001) volume center compared to a low volume center (6.2% vs. 5.9%, p=0.58). Thus in this analysis, primary PTCA in the low volume center did not offer mortality benefit over fibrinolytic therapy.

PPCI without surgical back up
The Atlantic C-PORT trial (Cardiovascular Patients Outcomes Research Team) investigated the feasibility of performing primary PCI in centers without surgical back up. A total 225 patients were randomized to undergo primary PCI and the remaining 226 patients were randomized to fibrinolytic therapy in 11 hospitals without cardiac surgery availability. The primary endpoint of death, recurrent myocardial infarction, stroke and median hospital length of stay was significantly reduced among those who underwent PPCI compared to those who received fibrinolysis (10.7% vs. 17.7%, p=0.03) at 6 weeks. This benefit extended to 6 months in favor of PPCI (12.4% vs. 19.9%, p=0.03). When analyzed for individual outcomes at 6 months, there was no benefit in terms of reduction in mortality (6.2% vs. 7.1%, p=0.72) and stroke (2.2% vs. 4%, p=0.28) with the PPCI strategy compared to fibrinolysis. However there was significant reduction in recurrent MI (5.3% vs. 10.6%, p=0.04) and median length of hospital stay (4.5 days vs. 6 days, p=0.02). Although this study is criticized for its early termination due to funding issues, it demonstrates that PPCI is feasible in centers without cardiac surgical back up.

DANAMI study
The feasibility and safety of transport of patients from peripheral hospitals to centers where PPCI is performed was evaluated in the DANAMI-2 study (Danish Multicenter Randomized study on fibrinolytic therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction) which enrolled 1572 patients between December 1997 to October 2001. A total of 1129 patients presented to 24 referral hospitals and 443 were admitted to 5 invasive treatment centers. All patients were randomized to undergo either primary PCI or fibrinolysis using IV alteplase. The primary endpoint of this trial consisted of death, clinical evidence of reinfarction or disabling stroke at 30 days. Of those who were transferred from the referral centers, the primary endpoint occurred in 8.5% of cases in the PPCI group and 14.2% in the fibrinolysis group (p=0.002). Similarly, among patients who were admitted directly to the invasive centers, the primary endpoint occurred in 6.7% of patients who underwent PPCI and 12.3% of patients who had fibrinolysis (p=0.05). Among all patients, the incidence of reinfarction was 1.6% in those who had PPCI and 6.3% among those who had fibrinolysis (p<0.001) with no difference in the incidence of death and stroke. In this study, 96% of patients were transferred to a median distance of 50 km (range 3-150 km). The median transfer time was 67 minutes (interquartile range 50-85 minutes). Of these 43% of patients were transferred within <60 minutes.

PRAGUE study
The PRAGUE trial (PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency fibrinolysis) is another trial that tested the safety and feasibility of transport of patients with STEMI to a PCI center. This study consisted of 300 STEMI patients who presented to General Community hospitals within 6 hours of symptom onset and were randomized to receive fibrinolysis alone (n=99), receive fibrinolysis and transport for primary angioplasty (n=100) or undergo primary angioplasty without fibrinolysis (n=101). In the PRAGUE study, primary angioplasty was superior in terms of reductions in death, reinfarction and stroke compared to the fibrinolysis group and fibrinolysis and transport group (8% vs. 23% vs. 15%, p<0.02 respectively). The incidence of reinfarction was reduced using the transport strategy compared to fibrinolysis alone (1% PPCI vs. 7% fibrinolysis and transport vs. 10% in fibrinolysis group, p<0.03). Hence this study demonstrated the feasibility of transport of STEMI patients and that primary PCI was a superior strategy.

Electrocardiographic changes
A number of techniques have been adopted to assess reperfusion following percutaneous coronary intervention for acute myocardial infarction. The extent of ST segment resolution on the electrocardiogram is a commonly used method to assess reperfusion. Several studies have determined the relationship between the extent of ST segment resolution and their impact on left ventricular function improvement and clinical outcomes. Santoro et al demonstrated that patients with >50% ST segment resolution post PCI had significantly better wall motion score index (p<0.001), LVEF (p<0.001), and functional recovery (>0.22 decrease in infarct zone wall motion score index) [34% vs. 78%, p<0.001] at one month compared to those who had <50% ST segment resolution [74]. In addition to better LV function recovery, Matetzky et al demonstrated that patients with ST segment resolution >50% had significant improvement in congestive cardiac failure (19% vs. 28%, p=0.04) and long term (>2 years) mortality (OR 7.3, 95% confidence interval 1.9-28, p=0.004) compared to those who did not have significant ST segment resolution post PTCA. Likewise, Claeys et al demonstrated decreased cardiac death rate among those who had ≥50% ST segment resolution after successful PTCA compared to those who had <50% resolution.

Coronary flow velocity assessment
Coronary flow velocity assessments using coronary Doppler FloWire (Cardiometrics, Inc) can be used to determine myocardial functional recovery at a later stage. Kawamoto et al studied 23 patients with acute anterior myocardial infarction undergoing primary PTCA. Wall motion score index were measured by echocardiography before PTCA and one month following the procedure. During PTCA coronary flow velocities [average systolic peak velocity (ASPV) and deceleration time of diastolic flow velocity (DDT)] were measured. The one month wall motion score index was correlated with ASPV (r=-0.54, p=0.007) and DDT (r=-0.62, p0.002). The cut-off values to predict viable myocardium was 6.5 cm/s for ASPV (sensitivity 79%, specificity 89%) and 600ms for DDT (sensitivity 86%, specificity 89%). Thus, the Doppler FloWire during PTCA can be used to predict myocardial viability at a later stage. In addition to predicting myocardial viability, coronary flow reserve ≤1.3 measured using the Doppler FloWire during primary PTCA was associated with long term adverse events (cardiac death, reinfarction and congestive cardiac failure).

Myocardial Imaging
Myocardial imaging techniques such as dobutamine stress echocardiography, myocardial contrast echocardiography and Tc 99m sestamibi scans have been used as a tool to predict late functional recovery following primary PTCA for acute myocardial infarction. Dobutamine stress echocardiography (DSE) performed 3 days following an index myocardial infarction might be a better tool in the assessment of myocardial recovery compared with myocardial contrast echocardiography (MCE). In a study by Bolognese et al, the overall accuracy of predicting late functional recovery was 47% with MCE and 90% with DSE (p<0.001). Myocardial perfusion imaging using Tc 99m sestamibi scans can be used to identify patients at increased risk for large infarcts. This was indeed demonstrated by Kaltoft et al in a study where assessment of tissue perfusion by Tc 99m sestamibi scans was an independent predictor of infarct size after successful PTCA following an acute myocardial infarction.

Angiographic assessment of myocardial perfusion
Angiographic assessment by TIMI myocardial perfusion grade and myocardial blush grade has been developed as a simple tool to assess myocardial perfusion in the cardiac catheterization laboratory. In a previous study van’t Hof et al demonstrated that myocardial blush grade (MBG) measured during primary angioplasty was a predictor of long-term mortality. The mortality at a mean±SD follow-up of 1.9±1.7 years for patients with MBG 3 (normal blush) was significantly lower compared to those who had MBG 2 (moderate blush) and MBG 0/1 (no blush/minimal blush) [3%, vs. 6%, vs. 23%, <0.0001 respectively]. Another study from the same group demonstrated that combined major adverse cardiac events (death, reinfarction and target vessel revascularization) were significantly increased at 16±11 months among those with MBG 0/1 compared to those with MBG 2/3 following primary angioplasty for acute myocardial infarction (relative risk 1.8, 95% confidence interval 1.1-2.8, p=0.009).

Conclusions
Primary angioplasty is the optimal management strategy for patients with acute myocardial infarction and is associated with reduction in mortality and bleeding events.

==ACC/AHA Guidelines (DO NOT EDIT) ==

{{cquote|

Class I
1. STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact as a systems goal. (Level of Evidence: A)

2. STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital presentation as a systems goal unless fibrinolytic therapy is contraindicated (Level of Evidence: B)}}

Abbreviations and acronyms
ADMIRAL: Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term follow-up

ASPV: Average systolic peak velocity

C-PORT: Cardiovascular Patients Outcomes Research Team

DANAMI: Danish Multicenter Randomized study on fibrinolytic therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction

DSE: Dobutamine stress echocardiography

EMERALD: Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris

FTT: Fibrinolysis Therapy Trialists

GUSTO: Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes

IC: Intracoronary

ICH: Intracranial hemorrhage

LVEF: Left ventricular ejection fraction

MBG: Myocardial blush grade

MCE: Myocardial contrast echocardiography

NRMI: National Registry of Myocardial Infarction

OAT: Occluded artery trial

PAMI: Primary angioplasty in Acute Myocardial Infarction

PASSION: Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation

PRAGUE: PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency fibrinolysis

PTCA: Percutaneous transluminal coronary angioplasty

PCI: Percutaneous coronary intervention

PPCI: Primary percutaneous coronary intervention

RAPPORT: Reopro And Primary PTCA Organization and Randomized Trial

RIKS-HIA: Register of Information and Knowledge about Swedish Heart Intensive care Admissions

SESAMI: Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction

SK: Streptokinase

STRATEGY: Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs. Abciximab and Bare Metal Stent in Myocardial Infarction study

STEMI: ST elevation myocardial infarction

STOP-AMI: Stent versus Fibrinolysis for Occluded coronary arteries in patients with Acute Myocardial Infarction

TAPAS: Thrombus Aspiration in Percutaneous coronary intervention following Acute myocardial infarction Study.

TFG: TIMI flow grade

TIMI: Thrombolysis in Myocardial Infarction

TMPG: TIMI myocardial perfusion grade

TPA: Tissue plasminogen activator

TVR: Target vessel revascularization