Invasive evaluation is considered both after fibrinolytic therapy and in patients who did not undergo primary percutaneous coronary intervention (PCI) to minimize short-term ischemic complications. Furthermore, complete revascularization should also be considered in STEMI patients who undergo primary PCI of the culprit artery but with other severe stenosis. Cardiac catheterization and revascularization should always be considered in patients with recurrent ischemic chest discomfort or with poor left ventricular function.^1–3

Ischemia-driven PCI after fibrinolysis

The DANAMI-1 trial⁴ was the first and only prospective randomized study comparing an invasive strategy (PCI or coronary bypass surgery) with a conservative strategy in 1008 patients with a first STEMI and predischarge inducible myocardial ischemia after fibrinolysis. The primary combined endpoint (mortality, reinfarction, and admission with unstable angina) was significantly reduced even after long-term follow-up. Thus, patients who have received treatment with fibrinolysis and have inducible ischemia before discharge should undergo coronary angiography and be revascularized as appropriate.

Routine invasive evaluation and PCI early after fibrinolysis

Theoretically, in STEMI patients successfully reperfused with thrombolytics, routine mechanical repair of the infarct-related artery could eliminate residual stenosis, thus reducing reocclusion and related events. In the late 1980s studies of systematic cardiac catheterization and percutaneous procedures in STEMI patients with prior fibrinolytic therapy yielded disappointing results.^5–7 However, current interventional practice, including the use of stents, thienopyridines, and IIb/IIIa inhibitors, has led to studies that support the role of early routine angioplasty in the management of STEMI patients treated with fibrinolysis.

Six randomized studies (a total of 1835 patients) support routine coronary angiography and, if applicable, PCI shortly after fibrinolysis (SIAM III,⁸ GRACIA-1,⁹ CAPITAL-AMI,¹⁰ the Leipzig Prehospital Fibrinolysis Study,¹¹ WEST¹² and CARESS-in-AMI.^12a In the present era of stents and glycoprotein IIb/IIIa inhibitors, early elective stenting following fibrinolysis is feasible and safe. Moreover, it permits rapid patient risk stratification, substantially reduces hospitalization, improves left ventricular outcome, prevents reocclusion and, consequently, reduces the incidence of adverse coronary events at one year. Early routine PCI is defined as a planned early percutaneous repair of the culprit artery in patients with STEMI who have been successfully reperfused with fibrinolytics. It should be distinguished from facilitated and rescue PCI,³ both examined elsewhere in this book as reperfusion strategies in STEMI.

Completeness of revascularization for multivessel coronary artery disease after primary PCI

Multivessel coronary disease is present in approximately 50% of patients with STEMI. Both the American College of Cardiology/American Heart Association (ACC/AHA) guidelines^1,13 and the European Society of Cardiology (ESC) guidelines^2,3 recommend that, in patients with multivessel disease, primary PCI should be directed only at the infarctrelated artery, with no clear statement about PCI of non-culprit lesions. One exception may be a patient with severe multivessel disease and persistent shock after PCI of the infarct-related vessel, for whom same-procedure revascularization (or bypass surgery) may be considered to reduce the ischemic burden. However, PCI of non-culprit vessels simultaneously or soon after primary PCI in stabilized patients has seldom been studied in randomized controlled trials, and observational studies provide contradictory findings.

Two observational studies reported that multivessel PCI, although feasible, was associated with a higher incidence of major adverse cardiovascular events (MACE) than infarct-related artery revascularization.^14,15 Other observational studies have shown the opposite, with significantly improved clinical outcomes when complementary multivessel disease revascularization is performed,^16–18 even simultaneously.¹⁷

Two randomized trials (PRIMA,¹⁹ HELP AMI²⁰) evaluating the impact of complete revascularization in patients with STEMI also failed to give an answer. Although the hypothesis that complete and simultaneous revascularization could improve ejection fraction was supported by the PRIMA study, in HELP AMI (69 patients), the one-year incidence of repeat revascularization was similar between patients randomized to culprit lesion treatment only or to complete multivessel revascularization. Therefore, there is no evidence to recommend complete revascularization for multivessel coronary disease after primary PCI.

Invasive evaluation and PCI for patients initially not undergoing primary reperfusion

Patients often seek medical attention too late and either do not receive reperfusion therapy or reperfusion therapy fails to successfully recanalize the artery. Thus, it was suggested that achieving coronary patency in either of these situations might have a beneficial effect by preventing adverse left ventricular remodeling, improving left ventricular function,^21–23 increasing electrical stability, and providing collateral vessels to other coronary beds for protection against future events (the open artery hypothesis).

Two contemporary trials have recently re-evaluated this hypothesis: OAT (Occluded Artery Trial)²⁴ and TOSCA (Total Occlusion Study of Canada-2).²⁵ In the OAT,^24,26 2166 stable high-risk (ejection fraction of < 50% or proximal occlusion) patients with an occluded infarct artery 3–28 days after myocardial infarction (20% of whom received fibrinolytic therapy for the index event) were randomized to medical therapy or PCI. Exclusion criteria included NYHA class III or IV heart failure, rest angina, serum creatinine greater than 2.5 mg/dL, left main or three-vessel disease, clinical instability, or severe inducible ischemia on stress testing if the infarct zone was not akinetic or dyskinetic. PCI did not reduce the occurrence of death, reinfarc-tion, or heart failure. Furthermore, there was a trend toward excess reinfarction during four years of follow-up in the invasive group compared with the medical therapy group.

In the TOSCA-2 trial,²⁵ 381 patients with an occluded native infarct-related artery (IRA) 3–28 days after myocardial infarction were randomized to PCI with stenting or optimal medical therapy alone. At one year, although patency of the infarct-related artery was significantly higher in the PCI group (83% vs 25%), left ventricular ejection fraction did not differ between the groups. These studies demonstrate that elective PCI of an occluded infarct-related artery 3–28 days after myocardial infarction in stable patients has no incremental benefit beyond optimal medical therapy in preserving ventricular function and preventing cardiovascular events.

Although the mortality of patients with STEMI has decreased in recent years because of faster and more frequent administration of reperfusion treatment, some patients still experience poor clinical outcomes, which are closely linked to infarct size and onset of heart failure, among other factors. One of the main risks faced by patients with extensive infarctions who survive the hospitalization phase is the development of progressive ventricular dilation and dysfunction in the following months. Determinants of ventricular remodeling include large infarct size, anterior location, lack of patency of the infarct artery, use of thrombolytic agents, and lack of negative T-wave resolution. Although this left ventricular remodeling process could have a compensatory purpose, it often occurs in association with the development or worsening of heart failure and leads to greater mortality. In fact, heart failure is the main cause of cardiac mortality after the acute phase of STEMI;^27,28 therefore, treatments aimed at avoiding or reversing remodeling have been recognized as a goal of therapy and include pharmacologic interventions, stem cell transplantation, and mechanical interventions.

Pharmacologic therapy

Several trials have established that angiotensin-converting enzyme (ACE) inhibition, started in the early phase of STEMI with captopril, enalapril, ramipril, trandolapril, fosinopril or zofenopril, reduces adverse cardiac remodeling and mortality after STEMI.^29–36 The benefit is greater in high-risk patients such as those with depressed ejection fraction (SAVE,²⁹ TRACE³¹), those who develop heart failure after myocardial infarction (AIRE³⁰), and those with anterior myocardial infarction (SMILE,³³ FAMIS³⁴), although it can be extended to all STEMI patients (ISIS-4³⁵ and GISSI-3³⁶).

Several meta-analyses of ACE inhibitors have confirmed their beneficial effects in patients with STEMI regardless of whether administration is early (within 48 hours of infarction) or late (> 48 hours to 16 days).^32,37–39The administration of an ACE inhibitor is associated with a significant reduction in mortality (50 lives saved per 1000 patients treated in high-risk patients and five lives saved in low-risk patients), a significant reduction in heart failure (absolute reduction of 3.5%), and significant reduction in the incidence of reinfarction (absolute reduction of 2.4%).

Angiotensin II receptor blockers have also been tested in patients with STEMI. Initial studies (OPTIMAAL⁴⁰ and VALIANT⁴¹) found that the angiotensin II receptor blockers losartan and valsartan, respectively, were not superior to captopril in high-risk patients after STEMI. Furthermore, the VALIANT study did not show any additional benefit with the combination of valsartan and captopril. Thus, angiotensin II receptor blockers should not be administered in addition to an ACE inhibitor immediately after myocardial infarction, although they are recommended as a substitute in patients who cannot tolerate ACE inhibitors.

Atrial natriuretic peptide has also been examined as a pharmacologic approach to preventing adverse remodeling early after STEMI. Atrial natriuretic peptide suppresses the renin-angiotensin-aldosterone system and endothe-lin-1, which stimulate left ventricular remodeling. Compared to nitroglycerin, atrial natriuretic peptide improved left ventricular ejection fraction and prevented left ventricular hypertrophy.⁴² However, recent concerns about the possible adverse effects of infusing B-type natriuretic peptides have discouraged further studies.⁴³

In addition to their antiarrhythmic properties, beta-blockers have beneficial effects on left ventricular remodeling after acute myocardial infarction and are associated with an improvement in left ventricular ejection fraction (LVEF), reduction in volume indexes, and incremental fractional shortening. They should be given early after STEMI, and are more effective when combined with ACE inhibitors and as continued therapy.^44–46

Stem cell therapy

The evidence that stem cells may reconstitute necrotic myocardium and improve cardiac function in animals⁴⁷ has led to clinical studies that initially examined the feasibility and safety of this therapy and later evaluated its efficacy in reversing adverse cardiac remodeling.⁴⁸ Pharmacologic mobilization of bone marrow stem cells with growth factors and catheter-based percutaneous intracoronary infusion of bone marrow-derived cells are the only methods that have been used to date for stem cell administration in patients with recent myocardial infarction.

Six Phase II randomized trials have evaluated the intra-coronary administration of mononuclear bone marrow stem cells in patients with STEMI early after revascularization of the culprit artery; three studies failed to demonstrate a beneficial effect on improvement of ejection fraction,^49–51 and three showed an initial mid-term benefit.^{52– 54} The REPAIR-AMI trial,⁵³ also designed as a double-blind study, including 204 patients from 17 European centers, is the largest study performed to date. It showed a significant increase in the LVEF (5.5 ± 0.7% versus 3.0 ± 0.7%; P = 0.014) between stem cell recipients and patients who received placebo. Technical differences in the characteristics or handling of the infused stem cells might explain the different outcomes observed between trials.⁵⁵ A meta-analysis of 10 studies (Phase I and II) of intracoronary stem cell therapy involving 698 patients with recent acute myocardial infarction (within 14 days of the event) showed that stem cell therapy was associated with a significant increase in LVEF (3.0%), reduction in infarct size (- 5.6%), reduction in end-systolic volume (- 7.4 mL), and a trend toward reduced end-diastolic volume (-4.6mL).⁵⁶ Intracoronary stem cell therapy was also associated with a significant reduction in recurrent AMI (P = 0.04) and with trends toward reduced death, rehospitalization for heart failure, and repeat revascularization. Thus, intracoronary stem cell therapy following PCI for STEMI appears to provide benefits for cardiac function and remodeling.

More conflicting results are observed in patients with acute myocardial infarction receiving granulocyte colony-stimulating factor (G-CSF). Although initial randomized studies showed a significant benefit in left ventricular remodeling,⁵⁷ four further studies did not find any differences in the left ventricular function among patients treated with the factor or placebo.^58–61 The divergent results may have been due to the absence of homing signals, timing of drug administration (in the study which showed a benefit, G-CSF was administered immediately after myocardial infarction, while in others administration was delayed for 3–5 days after revascularization), subpopulations of stem cells that were mobilized but not effective, and poorly defined study objectives. A meta-analysis including seven studies (Phase I and II) of G-CSF mobilized stem cells involving 318 patients with recent acute myocardial infarction (within 14 days of the event) showed that mobilization was associated with a significant increase in LVEF (2.9%) during follow-up, similar to that observed with intracoronary delivery of bone marrow-derived stem cells.

Mechanical interventions

Ventricular remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction, which results in a redistribution of cardiac workload, with increased regional stress in the susceptible infarct and peri-infarct zones. Therefore, a reduction in wall stress early after an MI may help attenuate remodeling. Such a reduction in wall stress can be achieved by appropriate cardiac resynchronization therapy with biventricular pacing. The first reports on the feasibility and safety of this approach early after STEMI have recently been published.⁶²

All STEMI patients are at increased risk of sudden cardiac death, most often due to ventricular arrhythmias and especially in the first months after the episode of infarction.⁶³ Thus, identification of patients at risk is essential. Determinants of arrhythmic complications include reduced LVEF,^63–69 ventricular premature beats and non-sustained ventricular tachycardia,^{64,65,70–72} late potentials,^73–75 QRS duration,⁷⁶ reduced heart variability,^77–81 and T-wave alter-nans.^75,82 Which risk factor to select and in which context is difficult to determine due to the limited amount of data directly comparing multiple risk factors. The most important initial parameter is probably LVEF, as most studies determining whether or not a patient who has had a myo-cardial infarction will require an implantable cardioverter defibrillator for primary prevention are based upon this parameter.^83–88

Apart from LVEF, major scientific societies do not strongly recommend a routine non-invasive assessment of the risk of ventricular arrhythmias (including signal-averaged ECG, 24-hour ambulatory monitoring, heart rate variability, evoked potentials, or T-wave alternans) in patients recovering from STEMI.^1,2 Thus, the therapeutic approach to prevention of arrhythmic death depends upon the identification of high-risk patients and the implementation of proven therapeutic and preventive measures. Several large-scale studies have demonstrated that treatment with beta-blockers, ACE inhibitors, aldosterone antagonists, and statins results in reduction of all-cause mortality but also of sudden cardiac death. In addition to optimal pharmacologic therapy, implantable cardioverter defibrillators (ICD) further decrease the risk of arrhythmic death.

Pharmacologic therapy

Beta-blockers

Several trials and meta-analyses from the pre-reperfusion era demonstrated that beta-blockers reduce mortality and reinfarction in patients recovering from acute myocardial infarction.^89,90 In the era of reperfusion therapy, convincing randomized data have shown that beta-blocker therapy improves survival during the acute phase of myocardial infarction. The CAPRICORN trial randomized 1959 patients with a LVEF of 40% or less to carvedilol or placebo 3–21 days after myocardial infarction.⁹¹ There was a significant reduction in all-cause mortality from 15% to 12%. Furthermore, sustained ventricular tachyarrhythmic events were reduced by more than 70%,⁹² confirming that treatment with beta-blockers (in addition to fibrinolysis or primary angioplasty, aspirin, and ACE inhibitors) reduces all-cause mortality and arrhythmic death.

ACE inhibitors

As pointed out previously, ACE inhibitors are one of the mainstay treatments for myocardial infarction and have been shown to improve survival. The best available data on the effect of ACE inhibitors on preventing sudden cardiac death come from a review of 15 randomized trials of ACE inhibitors which included 15 104 patients.⁹³ Overall mortality was reduced by 17%, with a significant reduction of 20% for sudden cardiac death. This beneficial effect on sudden cardiac death of reducing ventricular remodeling has been recently confirmed in patients with non-STEMI without clinical heart failure or overt left ventricular systolic dysfunction enrolled in the HOPE trial.⁹⁴

Aldosterone antagonists

Two trials (RALES⁹⁵ and EPHESUS⁹⁶) of aldosterone antagonists found significant reductions of all-cause mortality and sudden cardiac death. The RALES trial evaluated the effect of spironolactone in patients with congestive heart failure, half of whom had a history of ischemic disease. The risk for sudden cardiac death was reduced by 29%. In the EPHESUS trial, eplerenone administered 3–14 days after myocardial infarction reduced the risk of sudden cardiac death by 21%.

Statins

There is no information available from randomized trials to indicate a benefit of statins for prevention of arrhythmia in patients with STEMI. However, two observational studies in patients with ICD noted a potential benefit of statins in preventing ventricular arrhythmias.^97,98

Implantable cardioverter-defibrillator for primary prevention after the early phase of STEMI

The incidence of ventricular arrhythmias is higher during the first hours of an infarction, declines after the event, but remains elevated indefinitely in high-risk patients. The best approach to the selection of myocardial infarction patients to receive ICD therapy for primary prevention of sudden death has been explored in randomized trials in patients with left ventricular dysfunction and chronic myo-cardial infarction (MADIT 1,⁸³ MADIT 2,⁸⁵ CABG-Patch,⁸⁷ MUSTT,⁸⁴ and SCD-Heft⁸⁸) and in patients with left ventricular dysfunction early after the infarction event (DINAMIT⁸⁶).

Prophylactic use of an ICD has been shown to prolong life in patients with chronic myocardial infarction or ischemia and reduced left ventricular function^83–85,88 (see Chapter 40). However, as these studies have enrolled few patients with a recent myocardial infarction, the value of early ICD therapy is still uncertain. The DINAMIT trial is the only prospective randomized study comparing the role of prophylactic ICD compared with placebo in patients experiencing acute myocardial infarction within the preceding 6–40 days (average time from myocardial infarction to randomization was 18 days).⁸⁶ Inclusion criteria included LVEF ≤ 35% and reduced heart rate variability or elevated resting heart rate. The ICD group had a larger reduction (> 50%) than the control group in risk of death due to arrhythmia; however, this effect was offset by a similarly large increase in the risk of death from non-arrhythmic causes. The unexpected increase in mortality from causes other than arrhythmia may have been due to subsequent heart failure, of which ventricular arrhythmias were a harbinger. Consequently, prophylactic ICD therapy is not currently recommended less than 40 days after myocardial infarction. In addition, a recent substudy of MADIT 2 demonstrated no survival benefit for patients in whom the time interval from the index infarction to ICD implantation was less than 18 months, creating uncertainty about the benefit of prophylactic ICD therapy early after myocardial infarction in patients with left ventricular dysfunction.⁹⁹

After the initial phase, patients with STEMI carry a high risk of recurrence of ischemic events. Therefore, active secondary prevention is an essential element of long-term management.^100–102 A detailed review of all the measures available for secondary prevention is beyond the remit of this chapter; therefore, emphasis will be placed on the most important.

Discharge