Acute ST-Elevation Myocardial InfarctionChapter 1

PCI-treated patients experience lower shortterm mortality rates, less non-fatal reinfarction and less haemorrhagic stroke than those treated by fibrinolysis but with an increased risk for major bleeding. PCI appears to have its greatest mortality benefit in high-risk patients. In patients with cardiogenic shock, an absolute 9% reduction in 30-days' mortality with coronary revascularization instead of immediate medical stabilization was reported in the SHOCK trial. In NRMI-II, patients with CHF and a 33% relative risk reduction with primary PCI compared with a 9% relative risk reduction with fibrinolytic therapy. Primary PCI in patients with anterior STEMI reduces mortality compared with fibrinolytic therapy, but there is no difference in patients with non-anterior STEMI. Findings from a recent meta-analysis suggest that for STEMI populations with a mortality risk < 4.5%, primary PCI is unlikely to improve 30 days mortality, relative to fibrinolytic therapy. Time from symptom onset to reperfusion is an important predictor of patient outcome. The mortality benefit with PCI exist when treatment is delayed by no more than 60 minutes. If the expected door-to-balloon time exceeds the expected door-to-needle time by more than 60 minutes, fibrinolytic treatment with a fibrin-specific agent should be considered unless it is contraindicated. This is particularly important when symptom duration is less than 3 hours but is less important with longer symptom duration, when less ischaemic myocardium can be salvaged. In both, the CAPTIM trial, which showed lower mortality with prehospital fibrinolysis than with primary PCI, and the PRAGUE-2 trial, which showed lower mortality with primary PCI after interhospital transfer than with on-site fibrinolysis. PCI was superior to fibrinolysis when symptom duration was greater than 2 to 3 hours but not when symptom duration was shorter. In the early hours of STEMI, prompt fibrinolytic therapy can decrease infarct size and the risk of developing cardiogenic shock.9

Potential complications of an invasive strategy for treating STEMI include problems with the arterial access site; adverse reactions to volume loading, contrast medium, and antithrombotic medications, technical complications, and reperfusion events. Reocclusion occurs in 10 to 15% of patients after PTCA but in fewer than 5% after stent implantation. Likewise, angiographic restenosis occurs in 30 to 40% of patients after PTCA but in 15 to 20% after stent implantation.

Primary PCI might be considered in hospitals without on-site cardiac surgery, provided that a proven plan for rapid transport to a cardiac surgery operating room exists in a nearby hospital with appropriate haemodynamic support capability for transfer.

Improvement in ejection fraction (EF) from baseline to 6 months was substantial when reperfusion was achieved < 2 hours from symptom onset, but was modest and relatively independent of time to reperfusion after 2 hours. There were no differences in 1 or 6 months mortality by time to reperfusion by PCI. There were also no differences in other clinical outcomes by time to reperfusion by PCI, except that re-infarction and infarct artery reocclusion at 6 months were more frequent with later reperfusion. This is different from lytic therapy, where time to reperfusion is inversely related to outcome.

Justifying the aphorism “TIME IS MUSCLE”, a multivariate analysis by O'Neill (2005) demonstrated that prolonged door-to-balloon (P < 0.0001) and pain onset to-door time (P = 0.025) remained independent predictors of final infarct size. However, adding to the controversy, in patients with late presentation, an RCT study (Schomig et al 2005) demonstrated that in patients with AMI without persisting symptoms presenting 12–48 hours after symptom onset, primary PCI reduces infarct size compared with usual care. This suggests that although reperfusion time does matter for primary PCI, the window may be extended beyond 12 hours.

Rescue (also known as salvage) PCI is defined as PCI within 12 hours after failed fibrinolysis for patients with continuing or recurrent myocardial ischaemia. Rescue PCI has resulted in higher rates of early infarct artery patency, improved regional infarct-zone wall motion, and greater freedom from adverse in-hospital events than with a deferred PCI strategy or medical therapy. A major problem in adopting a strategy of rescue PCI lies in the limitation of accurate identification of patients for whom fibrinolytic therapy has not restored antegrade coronary flow. Unless unsuccessful fibrinolysis is recognized and corrected quickly (within 3 to 6 hours of onset of symptoms) salvage of ischaemic myocardium is unlikely. Unfortunately, clinical markers of reperfusion, such as relief of ischaemic type chest discomfort, partial resolution of ST-segment elevation, and reperfusion arrhythmias, have limited predictive value in identifying failure of fibrinolysis. In a prior era, in which the practice of PCI was less mature, immediate catheterization of all patients after fibrinolytic therapy to identify those with an occluded infarct artery was found to be impractical, costly, often associated with bleeding complications. This strategy is being re-evaluated in clinical trials testing facilitated PCI in the contemporary PCI setting.

Among patients who fail fibrinolytic therapy, rescue PCI was associated with consistent improvements in clinical outcomes despite time delays from symptom onset to treatment that ranged from 4.3 to 6.9 hours as was shown by two recent major trials of rescue PCI (MERLIN and REACT). Primary composite end point in these trials included death, reinfarction, stroke or severe heart failure at any time within six months. Benefits of rescue PCI were obtained in MERLIN and REACT despite inclusion of patients in these trials that required transfer to institutions with interventional capacities. Medium transfer time was only 85 min in REACT. This supports the fact that improved systems are urgently needed if full benefits of rescue PCI are to be realized in transferred patients. Most appropriate adjunctive pharmacotherapy in patients undergoing rescue PCI also needs to be outlined for improving outcomes. Unsuccessful rescue PCI is associated with a high mortality rate.

In contrast, repeat fibrinolytic therapy was not associated with significant improvements in all-cause mortality or reinfarction but was associated with an increased risk for minor bleeding.

A 3% increase in absolute risk of stroke was observed with rescue PCI and contrary to expectations, majority of strokes in MERLIN trial were thromboembolic rather than haemorrhagic. There was a 13% increase in risk of minor bleeding with rescue PCI but there was no excess of major bleeding.

ABORTED MI: A new target for reperfusion therapy: Treatment within an hour after symptom onset may result in 25% of aborted infarction and is in combination with complete (70%) ST-segment resolution (without 13enzyme rise). Aborted MI is associated with better survival and may become a new end-point in clinical trials of STEMI.

The ASSENT-4 PCI trial randomized 1667 patients to PCI with or without full-dose TNK with a primary endpoint of 90 days death, cardiogenic shock or congestive heart failure. The TNK plus PCI patient had significantly higher rates of repeated myocardial infarction (p = 0.0279), repeat target vessel revascularization (p = 0.0041), stroke (p< 0.0001) and, in the primary trial, end point of death, congestive heart failure or shock (p = 0.0045). There are several hypotheses to explain this failure such as:

A recent meta-analysis of RCTs by Keeley and Grines to compare facilitated and primary PCI also showed higher event rates (death, non-fatal MI, TVR rates) in facilitated PCI arm.15

Following this, a silver lining for facilitated PCI has been the results of Canadian WEST trial (2006). This was a pilot randomized trial of approximately 300 patients with STEMI, comparing three strategies: pre-hospital lysis and usual care, prehospital lysis and provisional rescue PCI in case of failure to achieve ST segment resolution and mandatory invasive management within 24 hours in other cases and primary PCI. There are two interesting features to this trial, which makes it complementary to ASSENT-4 PCI: the average time from symptom to randomization was short (approximately within 2 hours) and patients received state of the art antithrombotic therapy (with patients undergoing PCI after lytics receiving clopidogrel and in many instances GPIIb/IIIa blockers). Finally, PCI was performed early but not immediately after lysis, which makes it logistically convenient and gives ample time for potent antithrombotic therapy. Interestingly, mortality was lowest and very similar in the two groups which underwent intervention: lytic facilitated PCI and primary PCI (1%). Thus, WEST trial suggests that there may be room for facilitated PCI, provided lysis can be implemented very early and PCI can be preceded by state-of-the-art anti-thrombotic and antiplatelet therapy. Further information about future of facilitated PCI have become available from results of FINESSE and CARESS IN AMI trials which were recently presented at the ESC Congress, held in Vienna in September 2007. FINESSE had enrolled 2452 patients in various centres in Europe and USA. Mean age was 60 years and 65% of patients had high risk MI and 46% had anterior wall MI. Symptom duration was 20 minutes to 6 hours. Exclusion criteria included situations when angiography was expected to be done before 60 minutes or after 4 hours of presentation. Patients were randomized to three arms (i) Primary PCI (with in-lab abciximab) (ii) Facilitated PCI following abciximab started upfront (iii) Facilitated PCI following half dose reteplase and abciximab. No significant improvement of primary end points were noted in any group (death, cardiogenic shock, readmission for heart failure). Pre-PCI TIMI3 flow was best in the reteplase group but post-PCI TIMI3 flow was same in all the groups. Major bleeding and intra-cerebral bleeding was higher in the reteplase group but did not reach statistical significance. The study investigators concluded that primary PCI (with in-lab abciximab) within 4 hours of medical contact is more beneficial than facilitated abciximab or facilitated reteplase (half dose + abciximab groups). Reasons cited for failure of facilitated arms were that probably wrong study population (up to 6 hours of symptom onset) was chosen, no upfront clopidogrel was used routinely (FINESSE was a pre-CLARITY trial) and enoxaparin was used only in a subset of patients. The investigators concluded that the case for “facilitated PCI” (or preferably it should be called “Pharmaco-invasive PCI”) is still probably valid if (i) presentation is within 2–3 hours of symptom onset (ii) anticipated long delay to primary PCI is present (iii) large viable 16myocardium is present (iv) pre-PCI TIMI3 flow is already present. Such speculations have been kept alive by reports of Thiele et al (2006) and PATCAR Pilot trial (2007). In the latter trial, the group which received pre-hospital reteplase followed by urgent PCI had initial IRA TIMI flow grades of 2 to 3 in 82% and full reperfusion (TIMI angiographic perfusion score ≥ 20) in 67% compared to 37 and 22% respectively in the group which received primary PCI. Further evaluation of the strategy of pre-hospital fibrinolytic acceleration of STEMI treatment coupled with urgent PCI (FAST-PCI) in a large multicentre randomized trial multicentre randomized trial compared with primary PCI seems warranted.

CARESS IN AMI enrolled 1650 patients from seven countries in Europe between 2005–07. STEMI patients presenting before 12 hours from symptom onset and less than 75 years old with ST-elevation/new onset LBBB along with chest pain were admitted to centres without PCI facilities. Patients were in “high-risk” category (Killip class > 2). Mean age was 60 years. All patients were given aspirin, reteplase, unfractionated heparin and were randomized to either facilitated PCI or medical therapy (±Rescue PCI if needed). Abciximab and Clopidogrel were given in-lab. Median time from pain onset to reteplase therapy was 170 minutes and from reteplase to coronary angiography was 136 minutes in the facilitated group and 212 minutes in the rescue group. Incidence of death, re-infarction and refractory ischaemia was 11.1% in medical rescue PCI group and 4% in facilitated PCI group. Bleeding however, was higher in the facilitated group. Thus, this trial is the fourth one (after SIAM III, GRACIA-1 and CAPITAL-AMI) which confirms ESG guidelines for early angioplasty after lysis, i.e. “high-risk” STEMI patients should be immediately transferred for PCI after lytic therapy. TRANSFER- AMI trial presented at ACC'08 confirmed the superiority of routine PCI within 6 hours following conventional TNK-tPA and upfront clopidogrel compared to standard lytic therapy. 12-month follow-up of CARESS-AMI presented at ESC'08 showed persistent significant benefit in the PCI arm for refractory ischaemia and recurrent Ml but no difference in terms of death and admission for heart failure. More support in this regard has come from very recent GRACIA-2 and FAST-MI trials. STEMI guidelines presented at the same conference has accorded Class IIa status to PCI after successful lysis within 3–24 hours of lytic therapy initiation. There is no similar recommendation from ACC/AHA.

It has been hypothesized that infarct related artery (IRA) patency may favourably influence LV remodelling and electrical stability, even if accomplished at a time when salvage of ischaemic myocardium (i.e. more than 12 hours to days after coronary artery occlusion). Most studies, however, showed no significant benefit.

The Occluded Artery Trial (OAT) was undertaken randomizing patients to test whether routine PCI days to weeks after MI improves Longterm clinical outcomes in asymptomatic high-risk patients with an occluded IRA. The OAT investigators (Hochman et al 2006) published their report in over 2000 high risk stable patients with total infarct related coronary occlusion 3–28 days post MI (Median 8 days). In this open label randomized trial of PCI, usually employing bare metal stenting, a high rate of initial procedural success with good 1 year patency (among a subset) was achieved. Despite successful mechanical intervention, the expected decline in death, MI and heart failure did not occur. In fact, the reverse tended to be true. Hence, there was a statistically greater incidence of fatal and nonfatal MI in the intervention vs medical group as ascertained by investigators.

Explanations forwarded to explain the negative impact of PCI in occluded IRAs were:

A recently published (2008) meta-analysis of randomized controlled trials of 3,560 patients undergoing late PCI (> 12 hours from AMI onset) [Abbate et al.] showed that PCI of infarct related artery performed late (12 hours to 60 days) after AMI is associated with significant improvement in cardiac function and survival making the “Open Artery Hypothesis” a still valid one within 3 months from AMI.18

However in view of nearly four times higher incidence of acute stent thrombosis in bivalirudin arm (provisional GPIIb/IIIa inhibitor use) in contrast to UFH + GPIIb/IIIa inhibitor arm, STEMI Guidelines (ESC 2008) has granted only Class Ila recommendation for use of bivalirudin as an adjunct to primary PCI.21

These results were not reproduced by the larger CADILLAC trial. In this trial, composite of death, reinfarction, disabling stroke and ischaemia-driven TVR was similar in patients treated with stents with or without abciximab (9.5 vs 10.4%, P-NS). Some observers speculate that the strategy of GPI randomization after angiography, the late administration of abciximab in the CADILLAC trial may have blunted the effect of GPI on stented patients.

A recent meta-analysis of the studies involving GPIs in patients with STEMI (11 trials, involving 27,115 patients) demonstrated that when compared with the control group, abciximab was associated with a significant reduction in short-term (30 days) mortality (2.4 vs 3.4%, P = 0.047) and Longterm (6–12 months) mortality (4.4 vs 6.2%, P = 0.01). This was observed in patients undergoing primary PCI but not in those treated with fibrinolysis or in all trials combined.22

Inadequate data exist regarding use of small molecular weight GPIIb/IIIa inhibitor agents in AMI, hence use of epitfibatide or tirofiban for STEMI is not advocated at present.24

ONTIME-2 trial presented at ESC Congress 2008 (Munich) where higher dose of Tirofiban was used in the ambulance prior to primary PCI, demonstrated higher TIMI 3 flow and ST-segment resolution with decreased MACE and mortality. Earlier administration (< 75 minutes) produced better results. STEMI Guidelines (ESC 2008) has given Class IIa recommendation to Abciximab and Class IIb to Eptifibatide and Tirofiban for use in primary PCI. However, the guidelines did not have ONTIME-2 results at the time they were drafted.25

ACE-inhibitors: An ACE-inhibitor should be prescribed at discharge for all patients without contraindications after STEMI; start early in stable high risk patients (anterior MI, prevents MI, Killip Class > II (S3 gallop, rales, radiographic CHF, LVEF < 0.40).

Angiotensin receptor blocker indicated in patients who are intolerant of ACE inhibitors and with either clinical or radiologic signs of heart failure or LVEF < 0.40 (Candesartan and Valsartan have established efficacy)

Aldosterone blockade: in post-STEMI patients with serum cretinine 2.5 mg/dl in men or < 2.0 mg/dl in women or potassium < 5.0 mEq/l, already on ACEIs, LVEF < 0.40 and have either symptomatic heart failure or diabetes.

Beta-blocker: Start in all patients, continue indefinitely. Observe usual contraindications.