Acute ST-Elevation Myocardial Infarctionchapter 1

The over-reaching goal is to keep total ischemic time with 120 minute (ideally within 60 minutes) from symptom onset to initiation of reperfusion treatment. The following modus operandi should be followed by medical system based on the mode of patient transportation and capabilities of the hospital which receives the patient.

Transportation by emergency medical services (EMS) is recommended and self-transportation should be discouraged. If the EMS has fibrinolytic capability and patient qualifies for therapy, prehospital fibrinolysis should be treated within 30 minutes of arrival of EMS on the scene. If EMS is not capable of administering prehospital fibrinolysis and patient is transported to a non-PCI-capable hospital, door to needle time should be within 30 minutes, if fibrinolysis is indicated. However, if EMS is not capable of administering prehospital fibrinolysis and patient is transported to a PCI-capable hospital, EMS arrival-to-balloon time should be within 90 minutes. Following presentation to a non-PCI-capable hospital, it may be considered appropriate to consider emergency interhospital transfer of the patient to a PCI-capable hospital for mechanical revascularization in following three situations:

Duration of thienopyridine therapy for patients receiving a stent (BMS or drug-eluting stent [DES]) during PCI for ACS, clopidogrel 75 mg daily [IB] or prasugrel 10 mg daily [IB] should be given for at least 12 months. If the risks of morbidity because of bleeding outweigh the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered [IC]. If coronary artery bypass graft (CABG) is planned and can be delayed, as mentioned earlier, clopidogrel should be withdrawn for at least 5 days and prasugrel for at least 7 days prior to coronary artery bypass (CABG), unless the need for CABG and/or the net benefit of the thienopyridine outweighs the potential risks of excess bleeding [IC]. Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing drugeluting stent (DES) placement (IIbc). In STEMI with a prior history of stroke and transient ischemic at least for whom primary PCI is planned, prasugrel is not recommended as part of a dual antiplatelet therapy regimen.

An angiotensin receptor blocker (ARB) should be administered to STEMI patients who are intolerant of ACEIs and who have either clinical or radiological signs of heart failure or LVEF less than 0.40 [IC]. Valsartan and candesartan have established efficacy for this recommendation.

An intravenous ACEI should not be given to patients within the first 24 hours of STEMI because of risk of hypotension. Refractory hypertension may be one possible exception. Aldosterone blockade is recommended [IA] for post-STEMI patients without significant renal dysfunction (creatinine should be ≤ 2.5 mg/ dL in men and ≤ 2.0 mg/dL in women) or hyperkalemia (potassium should be ≤ 5.0 mEq/L) who are already receiving therapeutic doses of an ACE inhibitor, have an LVEF ≤ 40% and have either symptomatic congestive heart failure (CHF) or diabetes. In the recently presented (ACC 2013) REMINDER trial, 1012 subjects with acute STEMI without diagnosis of heart failure, and with LVEF > 40% were randomized to receive either eplerenone 25 mg or placebo within 24 hours of onset of symptoms on top of standard therapy. The primary composite endpoint (which comprised of CV mortality, rehospitalization or hospitalization extended due to HF, sustained VT or VF, EF < 40% after 1 month, natriuretic peptide elevation > 1 month was significantly altered in favor of eplerenone (p < 0.0001). However, despite numerical trends (nonsignificant) in favor of VT/VF and HF re-hospitalization, biomarker component of the end-point accounted for most of the overall benefit. Hyperkalemia was not significantly increased.

Advantages of primary PCI include achieving complete reperfusion in 90 to 95 percent of patients, having lower risk for reinfarction and stroke, and allowing definitive characterization of coronary anatomy and LV function.

On the basis of these data, patients with STEMI who present to hospitals with PCI capability should have primary PCI as the preferred and routine reperfusion strategy.

Summary of current recommendations based on ACCF/AHA 2013 Guidelines is as following; most of the recommendations match with ESC 2012 Guidelines except where indicated.

Initial trials of streptokinase (SK) performed in 1980s showed a pronounced mortality benefit, with an 18 percent mortality reduction in the GISSI-1 trial and a 25 percent reduction in the ISIS-2 trial. The benefit extended to 42 percent reduction when aspirin and SK were combined. The GUSTO-1 trial showed a slight mortality benefit (14%) in patients receiving tPA and IV heparin and compared with SK (with either IV or subcutaneous heparin). Risk of hemorrhagic stroke was statistically lower in patients receiving SK compared to those receiving tPA group (6.9% vs 7.8%, P = 0.006). Trials of rPA (GUSTO-3) and TNK (ASSENT-2) showed similar rates of mortality and ICH as tPA, with an overall rate of death or nonfatal stroke of approximately 7 percent. TNK was, however, associated with fewer noncerebral bleeding complications and lower rates of transfusion in ASSENT-2 trial.

Thus, newer bolus agents have not surpassed the mortality benefits seen with tPA. However, combined benefits of the ease of administration, diminished potential for dosing errors and lower rates of noncerebral bleeding have led to increasing use of these agents in most centers.

A comparison of different thrombolytic agents along with their dosage has been shown in the Table 1.4:

Management of patients with hemorrhagic complications following fibrinolytic therapy is outlined in Flow chart 1.3.

Occurrence of a change in neurological status after reperfusion therapy, particularly within the first 24 hours after initiating of treatment, is considered to be due to ICH until proven otherwise.

ST-segment resolution is calculated by taking the sum of ST-elevation (typically measured 20 m/second after the J point) in leads V1–V6, I, and aVL 20for anterior MI, and adding to the sum of ST-depressions in leads II, III, and aVF; or, for interior MI, taking the sum of ST-elevations in leads II, III, aVF (and I, aVL, V5, V6, if present) and adding the sum of ST-depressions in leads V1–V4. Timing of ECG following reperfusion does not appear to influence the close correlation between ST-resolution and outcomes significantly. However, since failed reperfusion therapy identifies patients at highest risk, early assessment of ST-resolution within 60 to 90 minutes after fibrinolysis is recommended. Percentage of ST-resolution can then be calculated from baseline to some time period after reperfusion which can extend to 180 minutes in some cases after fibrinolysis or immediately after PCI.

Since troponin remains elevated longer (even weeks after a large MI) than CK-MB and CK-MB returns to normal range within 48–72 hours; it is, therefore, the preferred marker for assessing a recurrent infarction.

This has been successfully practiced in European countries. A posthoc analysis of the primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: A randomized study (CAPTIM trial) showed that in patients presenting early (< 2 hours after symptom onset), there was a strong trend for lower mortality with prehospital fibrinolytic therapy versus primary PCI (2.2% vs 5.7%, P = 0.053), whereas in patients randomized later (> 2 hours) there was no benefit to early fibrinolytic therapy, suggesting that time delays are very important early after onset of symptoms but are less important later.

Analysis of studies in which > 6000 patients were randomized to prehospital or in-hospital fibrinolysis has shown a significant reduction (17%) in early mortality with prehospital treatment. A much longer mortality reduction was found in patients treated within first 2 hours than in those treated later in a meta-analysis of 22 trials. More recent posthoc analyzes of several randomized trials and data from registries have further confirmed the clinical usefulness of prehospital fibrinolysis. Thus, all these studies have reported outcome data similar to that of primary PCI, provided early angiography and PCI were performed in these patients who needed intervention. A prospective trial, properly sized and randomized, is needed to truly put to the test hypothesis that prehospital fibrinolysis is associated with a similar or better clinical outcome than primary PCI.

When opting for fibrinolytic therapy as the reperfusion strategy in a given patient, prehospital fibrinolysis should be the treatment of choice. This is especially relevant in developing countries like India with few tertiary care centers, predominantly rural population and where people either have to travel long distances to avail of medical facility or have to overcome urban traffic congestion. However, administration of prehospital thrombolysis needs tremendous infrastructure and a co-ordinated program by government or private sector or both.

In MERLIN trial, despite a significant decrease in rates of subsequent revascularization, rescue PCI did not improve 30-day survival (9.8% for rescue PCI and 11% for conservative therapy, P = 0.7). However, in REACT trial, event-free survival was significantly higher in patients treated with rescue PCI compared to conservative therapy or repeat fibrinolysis (84.6% vs 70.1% vs 68.7%, respectively, overall P value = 0.004).

A recent meta-analysis of eight trials enrolling 1,177 patients demonstrated a significant reduction in risk for heart failure and reinfarction and a trend toward reduction in all-cause mortality when compared with conservative therapy. However, rescue PCI was shown to result in increased risk of stroke and minor bleeding.

Despite impressive results with successfully conducted rescue PCI, prognosis remains poor for those in whom rescue PCI is unsuccessful.

Despite demonstration of higher TIMI grade 3 flow rates with facilitated PCI compared to primary PCI at the time of initial coronary angiography, a meta-analysis of trials failed to show an improvement in final TIMI 3 flow rates with facilitated PCI. Moreover, facilitated PCI was shown to be associated with significantly increased rates of nonfatal reinfarction, urgent target vessel revascularization, stroke and death compared to PCI. Regimens employing fibrinolytic therapy were in particular associated with higher rates of adverse events. ASSENT-4 PCI trial randomized 1667 patients to PCI with or without full dose tenecteplase (TNK) with a primary end point of 90 days death, cardiogenic shock or congestive heart failure. The TNK plus PCI arm had significantly higher rates of repeat myocardial infarction, repeat target vessel revascularization, stroke and composite of primary end points.

The most recent of facilitated PCI trials has been FINESSE trial. It randomized patients presenting within 6 hours of symptom onset with STEMI into three arms:

No difference in the primary outcome (all cause mortality, rehospitalization for congestive heart failure, resuscitated VF occurring > 48 hours after randomization and cardiogenic shock) was found between the three strategies at 90 days. Rather, bleeding was significantly increased in patients who were randomized to facilitated PCI, especially in those receiving half-dose reteplase and abciximab. FINESSE trial thus seems to have finally drawn the curtains down for the concept of facilitated PCI.

The important trials in this regard are CARESS-in-AMI, CAPITAL-AMI, GRACIA, SIAM-III, WEST, and the more recent TRANSFER-AMI and STREAM. Both CAPITAL-AMI and CARESS-in-AMI included patients < 75 years of age with high-risk features and they underwent PCI within 3 hours of fibrinolytic therapy. Whereas CAPITAL-AMI compared full dose tenecteplase and 24immediate PCI versus tenecteplase alone and standard care, CARESS-in-AMI compared a strategy of half dose reteplase and abciximab with or without immediate PCI. CAPITAL-AMI reported a significant decrease in the composite end point of death, reinfarction recurrent ischemia and stroke at 6 months and CARESS-in-AMI reported a significant decrease in primary endpoints of death, reinfarction and recurrent ischemia at 30 days. Notably, there was no increase in bleeding rates in either of the trials. Twelve-month follow-up CARESS-in-AMI showed persistent significant benefit in the PCI arm for refractory ischemia and recurrent MI but no difference in terms of death and admission for heart failure.

In comparison to early routine invasive approach in aforesaid two trials, GRACIA-1 and WEST trials performed PCI following successful fibrinolysis relatively late (12–24 hours): GRACIA-1 reported a significant decrease in primary endpoint of death, reinfarction or revascularization at 1 year compared to standard care (9% vs 21%, P = 0.0008). In contrast, the smaller WEST trial showed just nonsignificant trends towards differences in primary endpoints of death, reinfarction, refractory ischemia, cardiogenic shock and major ventricular arrhythmias at 30 days between the PCI and the conservative arms.

Other studies (SIAM III, GRACIA-2) have assessed outcomes of PCI performed in the intermediate period (3–12 hours) after successful fibrinolysis. In these trials, routine PCI was performed after full dose reteplase or tenecteplase and benefit was demonstrated both in terms of epicardial and myocardial reperfusion and composite clinical endpoints at 6 months.

More recent in these series of trials has been TRANSFER-AMI. More than 1000 high-risk patients with STEMI in this study were randomly assigned to interhospital transfer for intended routine early PCI (within 6 hours after fibrinolysis) or an ischemia-guided strategy, in which patients were transferred for angiography only in the case of failed fibrinolysis or recurrent ischemia. The actual median interval from lysis to balloon inflation was 3.9 hours. As in the early trials, rate of recurrent ischemia was significantly reduced with early routine PCI as compared to a selective invasive approach, without any significant increase in rates of bleeding. The latest of the reports has been AMICO Registry. In this Registry, FAST-PCI strategy (reduced-dose fibrinolytic therapy followed by urgent PCI) was shown to reduce the mortality and combined endpoint of death, reinfarction and stroke among STEMI patients, without increasing the risk of stroke or bleeding, compared to PCI. Fibrinolysis before hospital admission also increased the initial infarct-related artery (IRA) patency and decreased the likelihood of shock at presentation.

The latest in this list of trials is STREAM which included 1832 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour, patients were randomly 25assigned to undergo either primary PCI or fibrinolytic therapy with bolus tenecteplase (amended to half-dose in patients > 75 years of age), clopidogrel and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise angiography was performed 6 to 24 hours after randomization. Primary endpoint was a composite of death, shock, congestive heart failure or re-infarction up to 30 days. There was no statistically significant difference (p=0.21) between the fibrinolysis and primary PCI group. Thus, this study showed a strategic alignment of prehospital or early fibrinolysis and contemporary antithrombotic cotherapy coupled with timely coronary angiography resulting in effective reperfusion in a specific onset of patients with STEMI (as described above). However, early fibrinolysis was associated with a slightly increased risk of intracranial bleeding.

The average time of interval from fibrinolysis to PCI in the trials mentioned above has been 2 to 17 hours implying that transfer for PCI need not be undertaken on an emergency basis. Such a strategy (often referred to as Pharmaco-invasive strategy) emphasizes on very early fibrinolysis (< 2 hours) for achieving greater rates of successful reperfusion and at the same time allows a transition of care that causes less stress both to the patient and to ambulance crews.

The ESC 2012 has accorded class I (Level of evidence : A) status to PCI after successful lysis within 24 hours of fibrinolysis therapy independent from angina and/or ischemia. In the latest ACCF/AHA 2013 STEMI guidelines, coronary angiography +PCI in stable patients after successful fibrinolysis before discharge and ideally between 3 hr and 24 hr has been accorded class IIa of recommendation (Level of evidence B). Considerations should be given in both groups to initiating a preparatory antithrombotic (anticoagulant plus antiplatelet) regimen before and during patient transfer to the catheterization laboratory.

However, OAT trial has not closed the chapter of open artery hypothesis. Two years after publication of the OAT trial, a meta-analysis of 10 studies enrolling 3,560 patients that were randomized to either late PCI of the IRA (range 1–26 days after the MI) or optimal medical treatment was published. The primary endpoint of this meta-analysis was all cause mortality. In addition, left cardiac remodelling was also assesed in those studies with echocardiographic analyzes. Late PCI was shown to improve survival as compared with medical treatment [Or 0.49 (95% CI 0.26–0.94), P = 0.030] during a follow-up period of 2.8 years (42 days to 10 years). This beneficial effect in all-cause mortality reduction was associated with favorable effects on cardiac function and remodeling. Late PCI demonstrated significantly greater improvement in LV ejection fraction and LV end-diastolic and end-systolic volume indices. This meta-analysis by virtue of an adequate final sample size and long clinical follow-up fully addressed the open artery hypothesis. This hypothesis postulates that survival after MI depends on the effect of mechanical recanalization of the IRA which serves to improve LV remodeling and healing and enhances electrical stability.

Most of the patients included in the analysis (84%) showed total IRA occlusion. Degree of angiographic success was variable (range 72–100%) as were both the rates of stent implantation (range 0–100%) and the glycoprotein IIb/IIIa inhibitor usage. Thus, the setting in this meta-analysis was poorly representative of the current PCI technology and outcomes, and yet late PCI was still able to significantly reduce the all-cause mortality rate. Patients with subtotal occlusion derived greater benefit than patients with total occlusion. Patients symptomatic for angina or heart failure and those with residual ischemia or documented viability are more likely to benefit from late PCI at a long-term follow-up. Patients with uncomplicated AMI, especially with reduced life expectancy, however, may not benefit from routine PCI. Benefit in terms of remodeling was seen to be more obvious with a median follow-up of 4 years and this lends support to the hypothesis that restoration of antegrade blood flow to the peri-infarct area interrupts progressive apoptosis of the hibernating myocardium and prevents development of cardiomyopathy.

At the extreme end of the spectrum are patients with a chronic total occlusion (CTO), defined as a complete occlusion at least 3 months old. Benefit from recanalization in this setting is independent of time and is based on relieving symptomatic ischemia and angina, enhancing LV function, reducing predisposition to ventricular arrhythmias and improving tolerance of contralateral coronary occlusion. From a clinical standpoint, CTO 27recanalization is usually rewarding in symptomatic patients, or in patients with evidence of silent ischemia in a large territory at risk and/or with presence of viable myocardium.