Percutaneous Coronary Intervention in Acute ST-Segment Elevation Myocardial Infarction

Introduction

ST-segment elevation myocardial infarction (STEMI) represents the most malignant presentation of coronary artery disease (CAD) resulting from acute thrombus-mediated closure of a coronary artery with the exception of inaugural sudden cardiac death. Recent epidemiological evidence shows a steady decline in the acute myocardial infarction (MI) rates, proportion of patients with STEMI, and a reduction in STEMI-related in-hospital and 1-year mortality, probably due to increased effectiveness of preventive strategies and better therapy ( Fig. 20.1 ). The clinical characteristics of patients with STEMI seem also to have changed over time. A recent retrospective analysis of a nationwide inpatient database of 738,433 patients with STEMI admitted within 24 hours after pain onset who underwent primary percutaneous coronary intervention (PPCI) between 2004 and 2012 showed an increase in unadjusted in-hospital mortality from 3.9% to 4.7% over the study period. After adjustment, however, mortality decreased over time (a 5% reduction in the adjusted risk). Moreover, there was an increase in the proportion of patients with ≥3 comorbidities (from 14.8% to 29.0%) and those with intubation or cardiac arrest on presentation (from 3.2% to 7.8%) and both conditions had a strong independent association with mortality. Notwithstanding these trends, STEMI still remains one of the most important causes of morbidity and mortality in developed countries, with an in-hospital and 1-year mortality in the range of 5% to 6% and 7% to 18%, respectively.

In most cases, STEMI results from acute thrombotic occlusion of a large epicardial coronary artery, typically occurring as a consequence of atherosclerotic plaque disruption, erosion, or fissuring, which leads to exposure of thrombogenic material (plaque lipid content, collagen, and subendothelial extracellular matrix) to circulating blood with subsequent intraluminal thrombosis and acute vessel occlusion. Other causative factors of lesser importance include acute plaque expansion (such as occurring due to intraplaque hemorrhage leading to acute closure without or with minimal intraluminal thrombus formation), embolism, spontaneous dissection, coronary inflammation, and extracoronary factors. Interruption of coronary blood flow results in myocardial ischemia in the blood-deprived myocardial area which, if severe enough and of sufficient duration, results in ischemic myocardial necrosis. As acute coronary thrombosis is often abrupt in onset and the ensuing ischemic damage progresses rapidly to necrosis following blood interruption, the rationale for prompt reperfusion therapy (pharmacological or mechanical removal of occlusive thrombi), aiming at early restoration of coronary blood flow to the infarct-related artery (IRA), is strong. Timely reperfusion results in myocardial salvage, increased electrical stability, and reduced incidence of fatal ventricular arrhythmias in the acute phase, as well as preservation of left ventricular function and improvement in short- and long-term patient survival. The evidence is definitive that reperfusion therapy with PPCI or fibrinolysis improves both survival and quality of life of patients with STEMI. PPCI refers to a strategy of emergent coronary angiography followed by coronary angioplasty with or without stenting of the IRA and without prior administration of fibrinolytic therapy. PPCI was introduced in the early 1980s as a reperfusion strategy in patients with STEMI. In the last decade, PPCI has become the dominant reperfusion strategy (and the standard of care) for STEMI and it continues to evolve. Current guidelines recommend PPCI as the default reperfusion strategy for patients with STEMI presenting within the first hours from the symptom onset.

Over the last two decades, considerable efforts have been made at the societal and medical community levels to improve the reperfusion therapy of patients with STEMI by working in three fields: (1) increased availability of centers capable of performing PPCI and building of triage and transfer systems of care to provide timely access to reperfusion in STEMI patients; (2) improvement of the PPCI equipment including new generations of coronary stents and their delivery systems and adjunct pharmacologic therapy (antithrombotic/anticoagulant drugs); and (3) development and evaluation of pharmacological or mechanical strategies to enhance myocardial salvage during PPCI procedures via optimizing acute procedural success, attenuation of distal embolization, microvascular obstruction (MVO) and reperfusion injury, and providing hemodynamic support. The main focus of this chapter is to summarize recent developments in the field of PPCI in patients with STEMI.

General Aspects

Primary Percutaneous Coronary Intervention Versus Fibrinolysis as Reperfusion Strategy for ST-Elevation Myocardial Infarction

Restoration of coronary blood flow in the occluded coronary artery and the subtended myocardial tissue, as rapidly as possible, is the fundamental aim of early STEMI therapy. The introduction of fibrinolytic therapy represented an important development in the treatment of STEMI. The application of fibrinolytic agents early after symptom onset was associated with reduced mortality compared to no reperfusion. A meta-analysis of initial fibrinolytic trials demonstrated that the absolute mortality benefit at 5 weeks following fibrinolysis was 3% for patients presenting within 6 hours, 2% for patients presenting between 7 and 12 hours and 1% (statistically insignificant) for those presenting between 13 and 18 hours. Despite the clear benefits of fibrinolysis compared with no reperfusion, it has serious limitations related to the high proportion of patients with relative or absolute contraindications to this therapy, life-threatening bleeding complications (disproportionately affecting elderly patients), a narrow window of therapeutic action after symptom onset due to rapid time-dependent loss of efficacy, limited ability to restore normal blood flow in the IRA even if applied in a timely fashion, and frequent reocclusions of the IRA resulting in recurrent ischemia or reinfarction within subsequent months. Apart from markedly attenuating these limitations, PPCI has other advantages over fibrinolytic therapy such as restoration of significantly higher rates of Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 in the IRA (a finding that is both durable due to enhanced stability of the reopened vessel and relatively independent of time from symptom onset), salvage of greater amounts of myocardium, delineation of coronary anatomy and hemodynamic status resulting in improved risk stratification, and facilitation of patient care and earlier hospital discharge. In earlier trials, balloon angioplasty (without stenting) was compared with fibrinolysis in terms of efficacy and safety. An earlier meta-analysis of 10 randomized trials of balloon angioplasty versus fibrinolysis showed a significant reduction of 30-day mortality (4.4% vs. 6.5%), lower rates of death or nonfatal reinfarction (7.2% vs. 11.9%) and stroke (0.7% vs. 1.1%) by balloon angioplasty. Another meta-analysis of randomized trials that compared PPCI (with balloon angioplasty only or coronary stenting) with fibrinolysis in patients with STEMI showed that PPCI is superior to fibrinolysis in terms of improving early and late survival as well as in reducing the incidence of reinfarction, intracranial bleeding, reocclusion of IRA, and recurrent myocardial ischemia. Randomized trials have shown that coronary stenting has greater efficacy than fibrinolysis or balloon angioplasty only as reperfusion strategy in patients with STEMI.

PPCI improves survival even in patients with STEMI who have contraindications to fibrinolysis or in patients presenting outside the therapeutic window of fibrinolysis. Superiority of PPCI over fibrinolysis has been witnessed particularly in high-risk patients and in centers without on-site cardiac surgery. The DANish trial in Acute Myocardial Infarction-2 (DANAMI-2) trial demonstrated that the benefit of PPCI is largest in high-risk patients; in patients with TIMI risk score ≥5, there was a significant reduction in the mortality with PPCI versus fibrinolysis (25.3% vs. 36.2%; P = .02) which was not observed in the low-risk group (TIMI risk score 0 to 4). The benefit of PPCI over fibrinolysis was maintained at long-term follow-up. A further report from the DANAMI-2 trial showed that 8-year composite of death or reinfarction was 34.8% in patients treated by PPCI versus 41.3% in patients treated with fibrinolysis ( P = .003). Of note, PPCI reduced the risk of reinfarction (13% vs. 18.5%) and mortality (26.7% vs. 33.3%) among patients randomized at referral hospitals. A large meta-analysis that included 23 randomized controlled trials (8140 patients) and 32 observational studies (185,900 patients) analyzed a series of outcomes of patients treated with PPCI or fibrinolysis ( Fig. 20.2 ). In randomized trials, PPCI was associated with reductions of short-term (6-week) mortality by 34%, long-term (≥1 year) mortality by 24%, short-term reinfarction by 65%, long-term reinfarction by 51%, and stroke by 63% compared with fibrinolysis. In observational studies, PPCI was associated with reductions of short-term mortality by 23%, long-term mortality by 12% (statistically insignificant), short-term reinfarction by 53%, long-term reinfarction by 42% (statistically insignificant), and stroke by 61% compared with fibrinolysis. The differences in major bleeding between both reperfusion strategies did not reach the level of statistical significance in randomized trials or observational studies. The study reinforced the recommendation that PPCI should be offered to STEMI patients if transport to invasive hospitals can be completed within 120 minutes. Evidence available also suggests that PPCI is cost-effective compared to fibrinolysis.

The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines define PPCI as a class 1 indication in patients with STEMI for 3 conditions: patients with STEMI with ischemic symptoms <12 hours (level of evidence A), patients with STEMI with ischemic symptoms <12 hours who have contraindications to fibrinolysis irrespective of time delay from the first medical contact (FMC; level of evidence B), and patients with STEMI and cardiogenic shock or severe heart failure irrespective of the time delay from the STEMI onset (level of evidence B). The recent guidelines of the European Society of Cardiology (ESC) for STEMI treatment recommend PPCI over fibrinolysis within the following timeframes: maximum expected delay from STEMI diagnosis to PPCI (wire crossing) of ≤120 minutes; maximal time from STEMI diagnosis to wire crossing in patients presenting at hospitals with PPCI of ≤60 minutes; and maximum time from STEMI diagnosis to wire crossing in transferred patients of ≤90 minutes (class 1, level of evidence A; Table 20.1 ). Moreover, a strategy of PPCI is indicated in the absence of ST-segment elevation but with evidence on suspected ongoing ischemic symptoms suggestive of MI in the following situations: hemodynamic instability or cardiogenic shock, recurrent, or ongoing chest pain refractory to medical treatment, life-threatening arrhythmias or cardiac arrest, mechanical complications of MI, acute heart failure or recurrent dynamic ST-segment or T wave changes, particularly with intermittent ST-segment elevation (class I, level of evidence C). If timely PPCI cannot be performed after STEMI diagnosis, fibrinolytic therapy is recommended within 12 hours of symptom onset in patients without contraindications (class 1, level of evidence A). Of note, when FMS-to-device time is anticipated to be in excess of 120 minutes, guidelines recommend administration of fibrinolytic agents within 30 minutes of arrival or within 10 minutes from STEMI diagnosis followed by emergency transfer to PPCI centers for coronary angiography and percutaneous coronary intervention (PCI).

Table 20.1

Time Targets in the Management of Acute STEMI

Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177.

Time Intervals	Target
Maximum time from FMC to ECG and diagnosis a	≤10 min
Maximum expected delay from STEMI diagnosis to primary PCI (wire crossing) to choose primary PCI strategy over fibrinolysis (if this target time cannot be met, consider fibrinolysis)	≤120 min
Maximum time from STEMI diagnosis to wire crossing in patients presenting at primary PCI hospitals	≤60 min
Maximum time from STEMI diagnosis to wire crossing in transferred patients	≤90 min
Maximum time from STEMI diagnosis to bolus or infusion start of fibrinolysis in patients unable to meet primary PCI target times	≤10 min
Time delay from start of fibrinolysis to evaluation of its efficacy (success or failure)	60–90 min
Time delay from start of fibrinolysis to evaluation angiography (if fibrinolysis is successful)	2–24 h

ECG , Electrocardiogram; FMC , first medical contact; PCI , percutaneous coronary intervention; STEMI , ST-segment elevation myocardial infarction.

a ECG should be interpreted immediately.

Time-To-Reperfusion and Outcome of Primary Percutaneous Coronary Intervention

Knowledge of the speed with which ischemic myocardium succumbs to necrosis following an abrupt occlusion of a coronary artery is important to understanding the time dependency of efficacy of reperfusion regimens and the degree of benefit from reperfusion in patients with STEMI. Reimer et al. assessed the spatial and temporal progression of myocardial damage following coronary artery occlusion in anesthetized dogs. In this study, acute coronary artery occlusion resulted in myocardial ischemia that gradually progressed to necrosis, which was typically complete at ∼6 hours after vessel occlusion. Following coronary occlusion, a rapid phase of cell death occurred mostly in the subendocardial layers, and about half of the ischemic myocardium that was necrotic at 24 hours was already dead 40 minutes after the occlusion. A second phase of cell death occurred more slowly in the midepicardial and subepicardial myocardium. This phase of myocardial necrosis was pretty much complete within 6 hours of coronary occlusion and about one-third of ischemic myocardium was still salvageable at 3 hours after the coronary occlusion.

Time-to-reperfusion interval is an estimate of overall duration of myocardial ischemia that encompasses the time interval from the onset of symptoms of coronary occlusion to the initiation of reperfusion therapy—fibrinolysis or PPCI. It is a multi-component metric that includes: the interval from the symptom onset to the FMC by emergency medical service (EMS; patient delay); the interval from FMC to a PPCI hospital (prehospital system delay); and the time interval from hospital arrival to PPCI (door-to-balloon [DTB] time delay). In case of an initial referral to a hospital without PPCI in patients intended to be treated with PPCI, the prehospital system delay consists of the time interval from the FMC to the hospital without PCI, the in-hospital time (door-in-door-out [DIDO] time interval), and time interval from hospital without PCI to the hospital with primary PCI. The term system delay signifies the sum of the prehospital system and DTB time delays. Apart from its association with the duration of myocardial ischemia, time-to-reperfusion interval is an index of quality and readiness of the health care system to provide reperfusion therapy in a timely fashion.

Evidence available shows that time-to-reperfusion (or total ischemic time) is crucial for fibrinolysis and important for PPCI. Cardiac magnetic resonance (CMR) imaging studies demonstrated a close relationship between time-to-reperfusion and infarct size, amount of myocardium salvaged, or MVO. A prior study used contrast-enhanced CMR (performed 5 ± 3 days after PPCI) to assess extent of myocardial necrosis or severe MVO in 64 patients with first STEMI in relation to time-to-reperfusion interval. The mean time-to-reperfusion was 190 ± 110 minutes and transmural necrosis and severe MVO was present in 65% and 23% of the patients, respectively. For patients without transmural necrosis or MVO, transmural necrosis only, or both conditions, the mean time-to-reperfusion was 90 ± 40 minutes, 110 ± 107 minutes, and 137 ± 97 minutes, respectively ( P < .001). Importantly, for every 30-minute longer delay, the adjusted risk of transmural necrosis or MVO increased by 37% ( P = .032) and 21% ( P = .021), respectively. The finding of lower rates of transmural necrosis or MVO in patients with residual blood flow in the IRA suggested that establishing some blood flow in the IRA before PPCI (i.e., with prehospital fibrinolysis) could be beneficial. A study of 70 patients with STEMI successfully treated with PPCI within 12 hours from the symptom onset showed significantly larger infarct size and MVO and reduced myocardial salvage (assessed by CMR 3 ± 2 days after hospital admission) with longer time-to-reperfusion delay. Thus, for patients with symptom-to-balloon intervals of ≤90 minutes, >90 to 150 minutes, >150 to 360 minutes, and >360 minutes, the infarct size was 8%, 11.7%, 12.7%, and 17.9% of the left ventricle, respectively. Accordingly, salvaged myocardium markedly decreased when reperfusion occurred >90 minutes after coronary occlusion. In another study that included 208 patients with STEMI undergoing PPCI within 12 hours from symptom onset and T2-weighted and contrast-enhanced CMR, there was a close relationship between myocardial salvage index, the proportion of area at risk salvaged, and the time-to reperfusion interval. Thus, myocardial salvage index was 85% (71% to 100%) in patients with symptom-to-balloon time <60 minutes and 26% (12% to 55%) in those with symptom-to-balloon time between 600 and 720 minutes ( Fig. 20.3 ). However, only 5 of 208 patients (2.4%) were reperfused within the first hour from symptom onset.

Large clinical studies mostly support an association between time-to-reperfusion and outcome after PPCI. The Zwolle cohort of 1791 patients with STEMI treated by primary angioplasty showed that the adjusted risk of 1-year mortality increased by 7.5% for each 30-minute increase in symptom-to-balloon time. Data from the National Registry for Myocardial Infarction (NRMI) showed no association between symptom onset-to-balloon time and survival in a cohort of 27,080 consecutive patients with acute MI treated with primary angioplasty. In this study, however, the DTB time (median 1 hour and 56 minutes) correlated with in-hospital mortality; the adjusted odds of mortality was significantly increased by 41% in patients with a DTB time between 121 and 150 minutes and by 62% in patients with a DTB time between 151 and 180 minutes. The authors suggested that DTB appears to be a valid quality-of-care indicator that should be considered when choosing a reperfusion strategy. However the NRMI data should be interpreted in the context of very long DTB time (and consequently long symptom onset-to-balloon time) and impact of survival bias introduced by not considering patients who died before hospital arrival. An analysis of 2635 patients enrolled in 10 randomized trials of primary angioplasty versus fibrinolysis demonstrated that with increasing time-to-presentation interval, major adverse cardiac event (MACE) rates increased after fibrinolysis but remained relatively stable after angioplasty. A publication from the DANAMI-2 trial involving only the PPCI substudy showed that 3-year mortality did not differ among patients with symptom onset-to-balloon times <3 and 3 to 5 hours. However, mortality was significantly increased in patients presenting ≥5 hours from symptom onset (hazard ratio [HR] = 2.36; 95% confidence interval [CI] 1.51 to 3.67; P < .001) and the difference in mortality remained significant after adjustment for potential confounders. A shorter symptom onset-to-balloon interval was associated with higher rates of TIMI flow grade of 3 after PPCI and with a smaller proportion of patients with a left ventricular ejection fraction ≤40. An analysis that included 2056 patients from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial showed that delay to reperfusion therapy was associated with greater injury to the microcirculation, assessed by myocardial perfusion grade or ST-segment resolution. In patients with symptom-to-balloon onset times ≤2, >2 to 4, and >4 hours, 3-year unadjusted mortality rates were 2.6%, 4.4%, and 7.2%, respectively (log-rank test P = .007). A study of 3391 Japanese patients with STEMI undergoing PPCI showed a close association between symptom onset-to-balloon time and a composite of 3-year death or congestive heart failure (13.5% vs. 19.2%; risk reduction of 29.7% for symptom onset-to-balloon time <3 hours vs. >3 hours). The association remained significant after adjustment for potential confounders. No difference in the composite of 3-year death or congestive heart failure was found in subgroups of patients according to short (≤90 minutes) versus long (>90 minutes) DTB times (16.7% vs. 18.4%, risk reduction of 9.2%; P = .54). However, a DTB time of ≤90 minutes was associated with lower incidence of death or congestive heart failure only in patients presenting within the first 2 hours from symptom onset (11.9% vs. 18.1%; P = .01) but not in those presenting more than 2 hours from symptom onset (19.7% vs. 18.7%; P = .44). The study demonstrated a significant interaction ( P for interaction = .01) between DTB time and time to presentation.

Reasons for the reported inconsistencies with regard to the relationship between the ischemia time estimated by time-to-reperfusion interval and outcome remain unclear. One possibility may be that the reperfusion is offered in the relatively flat part of the ischemia time myocardial salvage curve, particularly in those presenting late after symptom onset. Thus, a short DTB time may be associated with a better clinical outcome (lower mortality) when it is a part of an overall short symptom-to-reperfusion time but may show a weaker (or no) association with mortality when placed at the end of a long ischemic time interval. Another important reason for the controversial findings may involve the inaccuracy of measurement of the time-to-reperfusion interval, particularly the patient-related delay component. It has been reported that patients with STEMI do not seek medical care for 1.5 to 2 hours after symptom onset and that this interval has remained fairly stable over time. Other studies suggested that patient-related delay accounts for up to two-thirds of the overall ischemic time and it is greatest among women, older adults, patients with diabetes, patients of low socioeconomic status, and those presenting during night time. Apart from being a large component, the patient delay is the most poorly estimated part of the total ischemic interval. In general, it is accepted that patients provide low credibility data regarding symptom onset due to recall bias (common in patients with STEMI, particularly under the effect of opiates) and stuttering course with intermittent pre-infarction angina symptoms, obscuring the exact time of STEMI onset.

Risk distribution alongside the time-to-reperfusion is rather complex and of importance in understanding the time-dependent efficacy of PPCI in patients with STEMI. Prior studies have shown that patients presenting early after symptom onset have the highest risk score which is consistent with observation that early presenters have the largest cumulated ST-segment elevation reflecting the largest initial areas at risk and prompting urgent seeking of medical aid. This group of patients with STEMI benefit from PPCI mostly in terms of myocardial salvage, preservation of ventricular function, and survival due to early intervention of the ischemic lesion. Patients who present later after symptom onset may have smaller initial area at risk producing milder symptoms and their outcome may be influenced by the survivor-cohort effect, meaning that they have already survived the highest risk of death in the early hours after coronary occlusion. However, late presenters may have a more adverse cardiovascular risk profile. Prior reports showed that patients who presented later were older, more often women, diabetic, and had a past history of coronary bypass surgery. Adjusting for these factors considerably attenuates the association between time-to-reperfusion and mortality (from highly significant in univariable analysis to a borderline significance after adjustment in a multivariable model). Patients with a greater delay on admission are also expected to present more frequently with additional adverse characteristics such as impaired renal function, peripheral arterial disease, and greater inflammatory burden, factors not accounted for in the multivariate model. Associated comorbidities and the less favorable cardiovascular risk profile may mask the benefits of mechanical reperfusion due to myocardial salvage and the unfavorable outcome after coronary intervention may erroneously be attributed solely to the longer time-to-reperfusion interval. Therefore, it is highly probable that a more adverse baseline risk profile of patients with longer delay to presentation may explain, at least in part, the apparent association between time-to-reperfusion interval and mortality. These considerations are important because the apparent reduction of benefit from PPCI with increased time to presentation may be interpreted as a poor incentive for a prompt intervention in patients with delayed presentation who benefit from this treatment.

Door-To-Balloon Time and Outcome of Primary Percutaneous Coronary Intervention

Time-to-reperfusion or total ischemic time is an important metric of reperfusion, yet concerns have been raised that this metric is hardly measurable and consequently inaccurate. Although DTB is only a part of total ischemic time, it has been the most commonly used quality-of-care metric in patients with STEMI. DTB is actionable and easy to measure, compare, and reproduce. DTB time is an important indicator of patient characteristics and of the experience of the institution providing PPCI. Comorbid conditions, absence of chest pain, delayed presentation after symptom onset, less-specific ECG findings, and hospital presentation during off-hours were associated with longer total DTB times. Longer DTB times were encountered in patients of older age, female sex, nonwhite race, and those with complex medical histories. DTB delay also depends heavily on hospital-related characteristics. Thus, presentation at night and treatment at lower-volume facilities were strong independent predictors of longer DTB interval. A greater experience with PPCI is associated with shorter DTB times and lower in-hospital mortality in patients with STEMI treated with PPCI. A pooled (patient-level) analysis of 22 trials with 6763 patients in the setting of the Primary Coronary Angioplasty Trialist versus Thrombolysis (PCAT)-2 Collaboration found that PPCI was superior to fibrinolysis irrespective of the DTB time the treating institution was able to achieve or patient baseline risk. The strength of association between DTB and mortality may depend on the patients’ risk profile and the presentation delay. Thus, in a study of 2322 patients with STEMI followed up for a median of 83 months, delays in DTB time impacted late survival in high-risk but not low-risk patients and in patients presenting early but not late after the symptom onset. A further study demonstrated that a combination of shorter DTB time (<90 minutes) with a shorter symptom onset-to-door time (<4 hours) was associated with lowest longer-term mortality. Other studies have also demonstrated that short DTB times (≤90 minutes) were associated with a lower mortality in early presenters but not in late presenters.

DTB has been the focus of considerable efforts and initiatives at regional and national levels aiming at its improvement. A 2006 survey that included 365 hospitals in the United States that have applied at least one strategy to decrease the DTB time in American hospitals showed that the mean of median DTB time of each hospital was 100.4 ± 23.5 minutes and 40% of hospitals had DTB times greater than 110 minutes. The authors identified 28 strategies used by hospitals to reduce DTB times. After adjustment for eventual confounders, six strategies were associated with a positive impact on DTB times ( Table 20.2 ). Although the association between these strategies and DTB times was significant, causality remains unproven and the evidence in support of the individual component strategies remains limited. Later, the DTB Alliance—a nationwide campaign initiated by the ACC and composed of clinicians, organizations, and hospitals working jointly to improve reperfusion in patients with acute MI—proposed two additional strategies to improve systems of care for patients with STEMI: senior management commitment and a team-based approach. A report from the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) - Get With the Guidelines registry showed that performance of prehospital electrocardiograms was associated with a 10-minute reduction in the FMC-to-balloon time. Moreover, data from the same registry showed that direct referral of patients to the catheterization laboratory, i.e., bypassing the emergency department, was associated with on average 20-minute reduction in the FMC-to-device time interval. A recent report from a registry that included 33,901 transferred STEMI patients showed that the direct transfer of STEMI patients to the catheterization laboratory for PPCI was associated with significantly faster reperfusion (median DTB 116 vs. 191 minutes) and lower in-hospital mortality (4.6% vs. 11.2%; P < .0001) compared with transfer first to the emergency department/ward. As a result of national efforts to decrease DTB time, the median DTB time was reduced from 96 minutes in 2005 to 64 minutes in 2010 and the proportion of patients with a DTB ≤90 minutes has increased from 44.2% to 91.4% over the 6-year period beginning in 2005. However, it is widely accepted that there is a great variability and heterogeneity in using these strategies across various hospitals, regions, or countries.

Notwithstanding these characteristics, studies that have assessed the association of DTB or measures to reduce it with markers of reperfusion or outcome after PPCI have given conflicting results. An earlier study that included 1791 patients with STEMI from the Zwolle cohort found no association between DTB and 1-year mortality. However, the study found an association (even after adjustment) between symptom-to-balloon time and 1-year mortality which was stronger in low-risk patients. A recent study of 786 patients with STEMI treated with PPCI between 2008 and 2013 also found no association between DTB categorized at <30, 30 to 59, 60 to 89, and ≥90 minutes time intervals and 30-day mortality. Furthermore, in a subgroup of 262 patients, the DTB did not correlate with infarct size assessed by CMR 3 to 5 days after index event. Notably, the symptom onset-to-balloon time correlated closely with both outcomes. Conversely, a 2009 report from the National Cardiovascular Data Registry that included 43,801 patients with STEMI reported a median DTB time of 93 minutes with 57.9% of patients treated within 90 minutes. Longer DTB times were associated with a higher adjusted risk of in-hospital mortality, which increased in a continuous nonlinear fashion (DTB interval 30 minutes, mortality 3.0%; 60 minutes, 3.5%; 90 minutes, 4.3%; 120 minutes, 5.6%; 150 minutes 7.0%; 180 minutes 8.4%; P < .001). A recent meta-analysis of 32 studies involving 299,320 patients showed that patients with STEMI and longer (>90 minutes) DTB had higher risk of short-term (pooled odds ratio [OR] = 1.52 [1.40 to 1.65]) and mid-term (pooled OR = 1.53 [1.13 to 2.06]) mortality compared with patients with shorter DTB times. A nonlinear time-risk relationship was observed and the association between longer DBT and outcome was stronger for patients with shorter prehospital delays.

Data on the impact of the improvements in the DTB times on mortality are also inconsistent. An earlier analysis from the NRMI registry reported a significant reduction in mortality, from 8.6% to 3.1%, associated with a decline in DTB times from 111 minutes in 1994 to 79 minutes in 2006. Conversely, a study involving patients included in a quality improvement database in Michigan found no change in short-term mortality between 2003 and 2008 despite a decrease in DTB time from 113 minutes to 76 minutes. A recent study of 96,738 admissions for PPCI between July 2005 and June 2009 (a period coinciding with national efforts to reduce DTB times) at 515 hospitals participating in the CathPCI Registry showed that median DTB times declined significantly, from 83 minutes in the first 12 months (2005–06) to 67 minutes in the last 12 months (2008–09) of the survey ( P < .001). Despite improvements in DTB times, unadjusted in-hospital mortality (4.8% vs. 4.7%, P = .43), adjusted in-hospital mortality (5.0% vs. 4.7%, P = .34), and unadjusted 30-day mortality (9.7% vs. 9.8%, P = .64) remained unaffected. Finally, a recent report from the National Cardiovascular Data Registry CathPCI Registry that included data from 423 hospitals and 150,116 PPCI procedures performed between January 2005 and December 2011 showed a significant reduction in DTB time from a median of 86 minutes in 2005 to 63 minutes in 2011 ( P < .0001). Although risk-adjusted mortality increased (from 4.7% to 5.3%; P = .06 for in-hospital mortality and from 12.9% to 14.4%; P = .001 for 6-month mortality) due to changing characteristics of patients undergoing PPCI over time, shorter DTB times were associated with lower in-hospital (adjusted OR = 0.92 [0.91 to 0.93] for each 10-minute decrease) and 6-month (adjusted OR = 0.94 [0.93 to 0.95]) mortality, with both risk estimates calculated per each 10-minute decrease in DTB. Thus, although DTB remains an excellent process-of-care metric for expediting a patient’s arrival in the cardiac catheterization laboratory, its association with the outcome after PPCI remains controversial. Concerns were raised that DTB is only one component of total ischemic time and once it is reduced to a certain level, the time before arrival at a hospital may become a more important factor. Consequently efforts with the intention to improve outcomes after PPCI should be directed throughout the ischemic time interval including increased patients’ awareness of the STEMI symptoms, shortening of transfer times between medical facilities, or even improving in-hospital and post-discharge care to improve long-term outcome after PCI. A short DTB may be closely correlated with improved outcomes after PPCI in the setting of short symptom-to-balloon times but not in the setting of long delays after symptom onset and measures that reduce DTB by a few minutes may not translate into large benefits if this reduction occurs at the end of prolonged total ischemic times. Furthermore, there is a possibility that low-risk STEMI patients are treated more quickly and that patients with complications may take longer to treat, which may dilute the impact of reduced DTB time on mortality. Following the 2013 ACC/AHA guidelines for STEMI therapy, the FMC-to-device (in essence any type of device [wires, balloons, stents, aspiration catheters, or other]) time is increasingly being used instead of DTB. The FMC-to-device time interval is accurately measurable, encompasses a longer portion of ischemia time (by including prehospital delay), allows a better assessment of the impact of prehospital strategies aiming at reducing the interval itself and DTB (like prehospital ECG transmission, bypassing of hospitals without PCI facility or emergency departments) on time-to-reperfusion, and may be a suitable metric in the setting of regional network systems of STEMI care. A Danish study (a country that has implemented regional STEMI systems of care) of 6209 patients with STEMI undergoing PPCI within 12 hours from symptom onset showed an association and dependence of long-term (median 3.4 years) mortality on the system delay. Thus, for delays 0 to 60 minutes, 61 to 120 minutes, 121 to 180 minutes, and 181 to 360 minutes long-term mortality was 15.4%, 23.3%, 28.1%, and 30.8%, respectively ( Fig. 20.4 ). Of note, in multivariable analysis adjusting for other potential correlates of mortality, the system delay was associated independently with mortality (a 10% increase in the adjusted risk for mortality per 1 h delay). Although the FMC-to-device metric has advantages and is increasingly being used as a quality benchmark in the setting of STEMI systems of care, many hospitals still remain focused on DTB and use it as a public performance measure.

Network Systems Optimizing Reperfusion in Patients with St-Elevation Myocardial Infarction

PPCI is a preferred reperfusion strategy in patients with STEMI and its maximal benefit in terms of reduction of mortality and morbidity is achieved if this therapeutic strategy is offered in a timely manner, that is, as soon as possible following the symptom onset. The need for expedited reperfusion by PPCI has led to the development of STEMI systems of care with a focus on prehospital diagnosis of STEMI, direct transfer to a center capable of performing PPCI, and 24/7 on-call services with activation times no longer than 30 minutes. In order to reduce time to PPCI and increase the number of patients with STEMI reperfused in a timely manner by this preferred reperfusion strategy, several hospitals in the United States embarked on beyond-the-hospital initiatives to coordinate care for patients with STEMI. Although the initial efforts were not fully developed systems and mostly included measures to coordinate the first and subsequent contacts of patients with STEMI with EMS and inter-hospital transport, they markedly reduced delays in achieving reperfusion and inspired efforts for more complete systems to optimize reperfusion in patients with STEMI. In 2007, the AHA launched the initiative Mission: Lifeline encouraging communities to develop their own systems to optimize reperfusion therapy in patients with STEMI. The goal of the initiative was implementation of urban, suburban, and rural ideal systems of care for patients with STEMI that allow the timely delivery of the appropriate lifesaving therapies to all patients in all places. A system is defined as an integrated group of entities within a region coordinating the provision of diagnostic and therapeutic services; a STEMI care system includes EMS providers, referral centers/non-PCI hospitals, and receiving centers/PPCI hospitals. In general, the systems of care consist of a series of multidisciplinary, orchestrated, hospital-wide measures aiming at reduction of the time-to-reperfusion in patients with acute coronary syndromes, particularly STEMI. Recently, experts have proposed the essential components that a contemporary system of care for patients with STEMI should have ( Table 20.3 ). Analysis of various regional systems of care for patients with STEMI across Europe, the United States, and Canada has shown that for most countries in Europe and many regions in North America, geographic conditions and availability of PPCI centers enable provision of PPCI given the systems of care are in place.

Although regional STEMI treatment systems using standardized transfer protocols have been shown to improve the treatment times, performance of these systems remains poorly investigated and, even in the most sophisticated systems, the treatment delays are relatively common. A recent prospective, observational study of 2034 patients transferred for PPCI in the setting of a regional STEMI system showed that treatment delays occur even in efficient STEMI systems of care. Delays of the greatest magnitude were due to diagnostic dilemmas (median delay, 95.5 minutes) and nondiagnostic initial electrocardiograms (median delay, 81 minutes). Thus, up to 50% of patients with STEMI fail to meet the guideline recommended goals of FMC-to-device time of less than 120 minutes. Furthermore, there are several barriers to system implementation including a highly fragmented health system comprising approximately 4750 acute care hospitals and >15,000 EMS agencies (in the United States) as well as remarkable heterogeneity in organization, protocols, and practices across systems, hospital or cardiology group competition, EMS transport and financial issues. In 2012, the Duke Clinical Research Institute in collaboration with the AHA initiated the Mission: Lifeline STEMI Accelerator Project with the following goals: (1) comprehensively accelerate the implementation of STEMI care systems in 17 selected large metropolitan regions across the United States; (2) facilitate effective delivery of STEMI care in a timely, coordinated, and consistent manner; and (3) improve clinical outcomes of STEMI patients by broadly improving use and timeliness of reperfusion therapy. The results of the project are encouraging. A report from the Accelerator Project involving 484 hospitals and 1253 EMS agencies in 16 regions in the United States with 23,809 patients presenting with STEMI between July 2012 and December 2013 showed a modest but significant increase in the proportion of patients meeting guideline goals of FMC-to-device time including patients presenting directly to a PCI hospital (50% to 55%) or transferred patients (44% to 48%). Of note, trends toward lower in-hospital mortality compared to national data toward the end of the measurement period were observed. Another report from the project assessed whether implementing key care processes was associated with system performance improvement. In 167 hospitals with 23,498 patients surveyed between March 2012 and July 2014, uptake of four key care processes increased after intervention: prehospital catheterization laboratory activation (62% to 91%), single call transfer protocol from an outside facility (45% to 70%), emergency department bypass for EMS direct presenters (48% to 59%), and transfers (56% to 79%). The improvement of these indexes was associated with significant reductions in the FMC-to-device times. The most recent report from the Mission: Lifeline Accelerator 2 project that included 10,730 STEMI patients in 12 metropolitan regions (in the United States) including 132 PCI hospitals and 946 EMS agencies, surveyed between April 2015 and March 2017, showed a better cooperation between EMS and hospitals, improved reperfusion times, and reduced in-hospital mortality. More specifically the proportions of patients with a FMC-to-device time of ≤90 minutes (67% to 74%), a FMC-to-catheterization laboratory activation of <20 minutes (38% to 56%; P < .0001), and emergency department dwell time of <20 minutes (33% to 43%; P < .0001) were significantly increased. Notably these improvements corresponded to a significant reduction in in-hospital mortality from 4.4% to 2.3% ( Fig. 20.5 ) which was not observed in hospitals not participating in the project during the same time period. These studies clearly demonstrated that coordinated care of STEMI patients through regional-based systems coordinating hospitals and EMS systems can reduce the time-to-reperfusion and mortality of patients with STEMI. They offer support to the ACC/AHA STEMI guidelines recommendation that “all communities should create and maintain a regional system of STEMI care that includes assessment and continuous quality improvement of EMS and hospital-based activities.”

Primary Percutaneous Coronary Intervention in Late Presenters

Registry data have shown that between 9% and 31% of patients with STEMI present more than 12 hours from the symptom onset. For patients with STEMI presenting beyond 12 hours from the symptom onset, fibrinolysis is associated with little or no benefit and may even be harmful and thus it is not recommended. On the other hand, PPCI remains a therapeutic option even though evidence available on the benefit of this therapeutic modality is limited or controversial. Registry-based studies have suggested a potential benefit of PPCI in patients with STEMI presenting >12 hours from the symptom onset. In the NRMI-2 registry, which included 7258 patients with STEMI presenting >12 hours from the symptom onset, 1631 patients (22%) received invasive treatment within 6 hours of admission, and 5727 patients received conservative therapy. Compared with those who received conservative therapy, patients who received invasive treatment had lower in-hospital mortality (3.4% vs. 6.6%), less recurrent ischemia or angina (10.7% vs. 13.8%), and a reduced incidence of recurrent MI (1.2% vs. 2.2%). After adjustment, invasive therapy was associated with a 33% reduction in the adjusted risk for mortality. In another registry of 2036 patients with STEMI presenting 12 to 24 hours from symptom onset, without cardiogenic shock or pulmonary edema and not reperfused by fibrinolysis, 910 (44.7%) underwent invasive treatment. Patients with an invasive approach had lower mortality at 12 months than patients with a conservative approach (9.3% vs. 17.9%). The mortality benefit persisted after adjustment (a 27% reduction in the adjusted risk) or propensity matching (adjusted relative risk [RR] = 0.73, 95% CI 0.58 to 0.99). Scintigraphic studies showed that substantial myocardial salvage by PPCI (more than 50% of initial area at risk salvaged) occurs in 41% of late comers (>12 hours from the symptom onset).

Studies that have investigated the efficacy of PCI in late presenters on a randomized basis have given conflicting results, mostly because some studies addressed the late presenters, whereas other studies addressed the occluded vessel. The Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) randomized 365 patients with STEMI presenting 12 to 48 hours from the symptom onset to invasive or conservative treatment. The study demonstrated a significant reduction of the scintigraphic infarct size (median infarct size 8% vs. 13% of the left ventricle, P < .001) and a trend toward a reduction of secondary end point of death, recurrent MI, or stroke at 30 days (4.4% vs. 6.6%) with invasive treatment. A later update from the BRAVE-2 trial demonstrated a mortality benefit out to 4 years in patients assigned to invasive treatment (11.1% in patients assigned to invasive treatment vs. 18.9% in patients assigned to conservative therapy; P = .047; Fig. 20.6 ). The DEsobstruction COronaire en Post-Infarctus (DECOPI) trial randomized 212 patients with first Q-wave MI and an occluded vessel to percutaneous revascularization or medical therapy 2 to 15 days after symptom onset. The primary end point was a composite of cardiac death, nonfatal MI, or ventricular tachyarrhythmia. At 6 months, left ventricular ejection fraction was 5% higher in the invasive group compared with the conservative therapy group ( P = .013) and more patients had a patent artery (82.8% vs. 34.2%, P < .0001). At a mean of 34 months of follow-up, there were no significant differences in the primary end point between patients assigned to invasive or conservative therapy (7.3% vs. 8.7%, P = .68) but the overall costs were higher for invasive treatment. The Occluded Artery Trial (OAT) randomized 2166 stable patients who had an occluded IRA (by cardiac catheterization) to PCI with stenting or optimal medical therapy 3 to 28 days after acute STEMI. The primary end point was a composite of death, MI, or New York Heart Association class IV heart failure. At 4 years, the rate of the composite end point was not statistically different between the PCI and the medical therapy groups (17.2% and 15.6%, respectively; HR = 1.16; 95% CI 0.92 to 1.45; P = .20), with no interaction between treatment effect and any subgroup variable (age, sex, race or ethnic group, IRA, ejection fraction, diabetes, Killip class, and the time from MI to randomization). During a 6-year median survivor follow-up (longest 9 years), there was no significant difference between the two treatment strategies in the rates of either the primary end point or its individual components. Due to the study size, the OAT trial had an important negative impact on the use of invasive treatment in the stable late presenters with STEMI. A meta-analysis of 10 randomized trials (OAT trial included) with 3560 patients with acute MI presenting between 12 hours and 60 days after symptom onset demonstrated significant reduction in long-term mortality (6.3% vs. 8.4%) with invasive treatment. Eight of 10 included studies showed improvements in long-term survival. There was a greater improvement in left ventricular ejection fraction over time in patients who received invasive treatment (+4.4% change in the left ventricular ejection fraction) compared to patients who received medical therapy. However, the results of this meta-analysis need to be interpreted with caution, in light of the considerable heterogeneity across the studies.

In aggregate, the benefit of PPCI in late presenters with STEMI lacks strong evidence. For patients with STEMI presenting between 12 and 24 hours, the current ESC guidelines give a class I (level of evidence: C) for the use of PPCI in patients with time from symptom onset >12 hours, in the presence of ongoing symptoms suggestive of ischemia, hemodynamic instability, or life-threatening arrhythmias; a class IIa (level of evidence: B) for a routine PPCI strategy in patients presenting 12 to 48 hours after symptom onset; and a class III (level of evidence: A) for the routine use of PPCI in asymptomatic patients and an occluded IRA >48 hours after onset of STEMI. The ACC/AHA guidelines give a class IIa recommendation (level of evidence: B) for the use of PPCI in patients with STEMI presenting between 12 and 24 hours who have evidence of ongoing ischemia. The consensus is, however, that patients with STEMI presenting late (>12 hours from the symptom onset) should undergo coronary angiography. Moreover, it is reasonable to perform PPCI in late presenters with STEMI who manifest severe heart failure or have electrical or hemodynamic instability or persistent ischemia. Some experts also recommend performing PPCI in these patients if subtotal occlusions in the IRA with collateral circulation in the territory distal to the occlusion were found in coronary angiography.

Interhospital Transfer for Primary Percutaneous Coronary Intervention

The lack of PCI facilities in hospitals that receive patients with STEMI, the wider therapeutic window, and the proven superiority of PPCI over fibrinolysis have led to the concept of emergency interhospital transfer for PPCI instead of initial fibrinolysis in the presenting hospital in patients with STEMI. Although the number of PCI-capable hospitals increased by almost 50% and 90% of Americans live within 60 minutes of a PCI-capable facility, there are multiple scenarios in which patients with STEMI can end up in a hospital without a PCI facility. In case the diagnosis of STEMI is not immediately clear to the EMS or when patients with STEMI self-present to the nearest emergency department, these patients also may find themselves in hospitals without a PPCI facility. Earlier randomized trials of on-site fibrinolysis versus interhospital transfer plus PCI have confirmed that transfer of patients for PPCI is a better treatment than fibrinolysis at the initial hospital. The results of these trials have been summarized in two meta-analyses. The first meta-analysis of six randomized trials performed before 2003 including 3750 patients showed that a strategy of patient transfer plus PPCI was associated with a 42% reduction in the 30-day incidence of combined end point of death, reinfarction, and stroke compared with a strategy of on-site fibrinolysis. The other quantitative review of studies that have involved patient’s transfer for PCI have suggested that for every 100 patients treated, PPCI after interhospital transfer instead of on-site fibrinolysis prevented seven MACEs defined as death, nonfatal reinfarction, or nonfatal stroke.

More recent studies provided further evidence on the benefits of transfer of patients for PPCI compared with on-site fibrinolysis. A prior study randomized 401 patients presenting to community hospitals to a strategy of on-site fibrinolysis or intravenous tirofiban and transport for PPCI. The delay to reperfusion defined as interval from admission to start of fibrinolysis or PPCI was 35 and 145 minutes, respectively. The composite end point of death, reinfarction, or stroke was lower in patients assigned to the transport plus PPCI strategy at 30 days (8.0% vs. 15.5%, P = .019) and 1 year (11.4% vs. 21.5%, P = .006). A study of 850 patients with STEMI enrolled in the PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency fibrinolysis (PRAGUE)-2 trial showed that the 5-year composite end point of death, reinfarction, stroke, or revascularization was 40% in patients assigned to a strategy of transfer plus PPCI versus 53% in patients assigned to on-site fibrinolysis in the presenting hospital ( P < .001). A large registry including 16,043 STEMI patients treated with in-hospital fibrinolysis, 3078 treated with prehospital fibrinolysis, and 7084 treated with PPCI indicated that transfer for PCI is better than prehospital fibrinolysis even in early presenters in whom the treatment is initiated within 2 hours. A strategy of patient transfer for PPCI instead of on-site fibrinolysis inevitably incurs additional time delays imposed by transport, logistics, and organizational and technical aspects of PCI procedures. PCI-related time delay is an integral part of treatment algorithms for patients with STEMI. The recently published results from a prospective multicenter STEMI registry in Spain showed that in early STEMI patients assisted in noncapable PCI centers, in situ fibrinolysis was associated with worse prognosis (a 1.91-fold increase in the adjusted risk for 30-day mortality) than the transferred patients and the study recommended transfer to a PCI-capable center for all patients with a FMC-to-device time <140 minutes.

PCI-related delay has been the subject of intense investigation and, historically, many time intervals at which mortality rates of PCI after patients’ transfer and on-site fibrinolysis are at equipoise have been proposed. In many studies, the PCI-related delay was calculated based on published summarized data and not on individual patient data. Consequently, several prior estimations were subsequently found to be flawed and corrected, in general, by expanding the metric. A report from the PCAT-2 Trialists’ Collaborative Group demonstrated that for PCI-related delays up to 120 minutes, PPCI was associated with a 26% reduction in mortality compared to fibrinolysis or in 19 lives saved per 1000 patients treated. The absolute reduction in mortality with PPCI widened over time from 1.3% within the first hour to 4.2% after >6 hours after symptom onset. The most thorough time-based analysis that used individual patient data showed that PPCI is superior to fibrinolysis up to a PCI-related delay of 120 minutes. In this study, even in the group of patients presenting within 1 hour, mortality was lower with PPCI (4.7% vs. 6.0%) indicating that even in early presenters with PCI-related delays of 60 minutes or less there is no reason to prefer fibrinolysis instead of PPCI as reperfusion strategy. In 192,509 patients entered into the NRMI 2 to 4 registries, the mean PCI-related delay at which mortality benefits of PPCI and fibrinolysis were at equipoise was 114 minutes (95% CI 96 to 132 minutes). Of note, the study showed that PCI-related delay was not static and varied considerably depending on the risk characteristics of patients, such as age, symptom duration, and infarct location. Thus, PCI-related delay varied from <1 hour for patients <65 years of age with anterior infarction who presented within <2 hours to almost 3 hours for patients >65 years of age, with nonanterior infarction who presented >2 hours from symptom onset. A regression analysis including 27 trials with 4399 patients randomized to PPCI and 4474 patients randomized to fibrinolysis found that the higher the risk of patients the larger the reduction in mortality achieved by PPCI. It was calculated that for each 10-minute increase of PCI-related delay, there was a 0.75%, 0.45%, and 0.0% mortality benefit in high-, medium-, and low-risk patients, respectively. A report from the NRMI 2 to 5 registries assessed the impact of PCI-related delay in 107,028 patients with STEMI within 12 hours of pain onset: 11,662 patients undergoing PCI after transfer and 95,366 patients undergoing onsite fibrinolysis. In the whole sample, in-hospital mortality was 4.9% among patients treated with PCI and 8.1% among patients treated with onsite fibrinolysis. Among matched patients (9,506 patients in each treatment strategy), in-hospital survival was similar (4.8% vs. 6.2%) but the composite end points of death/MI or death/MI/stroke were lower with PCI. The PCI-related benefit was time dependent. The mortality was lower with PCI compared to on-site fibrinolysis for PCI-related delays <60 minutes and reduced for PCI-related delays 60 to 90 minutes and the difference was almost absent at PCI-related delays exceeding 90 minutes ( Fig. 20.7 ). The number needed to treat to show superiority of PPCI over onsite fibrinolysis went from 23, to 44, and to 250 for PCI-related delays <60 minutes, 60 to 90 minutes, and >90 minutes, respectively. The regression analysis showed that mortality benefit of PCI over onsite fibrinolysis for PCI-related delays beyond 120 minutes (which occurred in 48% of the patients) was negated ( Fig. 20.8 ). The equipoise for mortality for patients presenting within 2 hours from the symptom onset was longer (about 132 minutes). For the composite end point of death/MI/stroke, equipoise occurred at about 158 minutes.

Although these studies showed that longer delays reduce the survival benefits of PPCI, a longer PCI-related delay could be acceptable and beneficial in high-risk STEMI patients, such as cardiogenic shock. In essence, a flexible PCI-related delay according to the risk profile of STEMI patients is suggested. The assessment of the relationship between PCI-related time delay and outcome provides helpful information for optimization of the PPCI network. In an attempt to shorten PCI-related time delay, direct transportation of patients to hospitals capable of performing PPCI rather than transporting them to the nearest hospital without PCI facility has also been suggested. Concerns have also been raised that transfer of patients for PCI may be associated with issues related to antithrombotic/anticoagulant adjunct therapy. Administration of low-molecular-weight heparin and glycoprotein IIb/IIIa inhibitors (GPI) at the STEMI-referring hospital was associated with longer delays to reperfusion compared with administration at the STEMI-receiving hospital, whereas early use of unfractionated heparin was not. The transferred patients who underwent treatment were more likely to receive excess doses of unfractionated or low-molecular-weight heparin (28% and 54% increase in the adjusted risk, respectively) and were at increased risk for major bleeding (a 10% increase in the adjusted risk for bleeding).

For patients requiring interhospital transfer for PPCI, delays in the referral hospital are relatively frequent. To quantify the delays in the referral hospital a new performance measure, i.e., the DIDO time, has been introduced and a DIDO ≤30 minutes has been recommended. The performance of this metric was assessed in a retrospective cohort of 14,821 patients recruited in the ACTION—Get With the Guidelines registry. The study showed that the DIDO time was 68 minutes (interquartile range 43 to 120 minutes) and only 11% of the patients had a DIDO time ≤30 minutes. The study identified older age, female sex, off-hours presentation, and non-EMS transport to the first hospital as independently associated with a DIDO >30 minutes. Patients with a DIDO time of ≤30 minutes were significantly more likely to have a DTB time ≤90 minutes compared with patients with a DIDO >30 minutes (60% vs. 13%) and a significantly lower in-hospital mortality (2.7% vs. 5.9%; adjusted OR for in-hospital mortality =1.56 [1.15 to 2.12]). Thus, based on the results of this study, a DIDO time ≤30 minutes is rarely achieved and this parameter contributes to reperfusion delays and in-hospital mortality. A recent study reported a DIDO median (25th to 75th percentile) time of 51 (35 to 82) minutes and that only 14.1% of the patients had a DIDO interval ≤30 minutes. The study also identified female sex, more comorbidities, longer symptom duration, arrival by means other than ambulance, arrival at a hospital not exclusively transferring patients for PPCI, arrival at a center with a low STEMI volume, and an ambiguous ECG as independent correlates of longer DIDO time. Moreover, when turnaround was timely, 70% of patients received timely PPCI (door-to-device time ≤90 minutes).

Interfacility transfer for PPCI from referring facilities to PCI centers causes delay in treatment of patients with STEMI which may impact the efficacy of PPCI. In the CREDO-Kyoto acute MI registry that included 3820 patients with STEMI undergoing PPCI within 24 hours from symptom onset, the symptom onset-to-balloon time (median with 25th-75th percentiles) was 5.0 hours (3.5 to 9.1 hours) in patients undergoing PPCI after interfacility transfer ( n = 1725 patients) and 3.6 hours [2.5 to 5.9 hours] in patients who underwent PPCI after direct transfer to a PPCI facility ( P < .001). The cumulative 5-year incidence of death or hospitalization for heart failure was significantly higher in the interfacility transfer patients than in those with direct admission (26.9% vs. 21.2%; log-rank P < .001). After adjustment for potential confounders, there was a 22% increase in the adjusted risk for death or hospitalization for heart failure associated with interfacility transfer. Along the same lines more than one-third of transferred U.S. STEMI patients fail to achieve first door-to-device time ≤120 minutes despite estimated transfer times <60 minutes. Delays were mostly related to process variables, comorbidities, and lower annual PCI hospital STEMI volumes. A prospective nationwide Polish registry of 70,093 STEMI patients showed that 39,144 (56%) were admitted directly to a PCI center. As compared with patients directly admitted in PCI centers, transferred patients had longer symptom-to-admission time intervals (by 44 minutes; P < .001), longer total ischemic time (270 [180 to 420] minutes vs. 228 [156 to 378] minutes), and higher propensity-matched 12-month mortality (9.6% vs. 10.4%; P < .001). Based on these data, transport of a patient with STEMI to a non-PCI hospital should be a “never event” except for rare instances when the patient is critically unstable and unlikely to survive longer transport.

In summary, prompt referral of patients with acute MI to centers with PCI facilities should be the primary objective of first contact EMSs. This is currently feasible for the large majority of patients with STEMI in the United States and should be attempted in the future for all patients with STEMI seeking medical aid. Nearly 90% of the adult population in the United States lives within 60 minutes of a hospital with a PCI facility and even among those living closer to hospitals without a PCI facility, almost three-fourths would experience less than 30 minutes of additional delay related to direct referral to a hospital with a PCI facility. The development of regional systems of STEMI care is a matter of utmost importance for improving the treatment of patients with STEMI. Current guidelines do not focus on relative PCI-related delay or specific DTB or DIDO times as quality-of-care metrics of reperfusion therapy. Instead they recommend the FMC-to-device metric and set a limit of ≤120 minutes. This corresponds to a PCI-related delay of 110 minutes (given that the recommended FMC-to-needle [fibrinolysis] is 10 minutes) which is in the range of the times identified in old studies and registries to choose PPCI as reperfusion strategy ( Fig. 20.9 ). A flexible consideration of what degree of PCI-related delay is acceptable for high-risk STEMI patients also seems justified.

Facilitated Percutaneous Coronary Intervention

Facilitated PCI refers to a deliberate strategy of administration of pharmacological drugs aimed at restoring anterograde flow in the IRA prior to proceeding to definitive revascularization by PCI in patients with STEMI. It was conceived as an option for filling the time gap between patient presentation and performance of PCI. The pharmacological regimen consists of drugs known for their ability to restore flow such as full-dose or half-dose fibrinolysis, or a combination of half-dose fibrinolysis with GPI. As data about the ability of GPI to reopen the IRA is controversial, the isolated use of these drugs may or may not be part of the strategy of facilitated PCI. Two factors underpin the rationale behind the concept of facilitated PCI: first, ventricular function and prognosis have been found to be better in patients with STEMI who present at the time of PPCI with spontaneous TIMI flow grade 2 or 3 compared with those who have a TIMI flow grade of 0 and 1 in the IRA; second, a large proportion of patients with STEMI are unable to receive mechanical reperfusion without a certain time delay due to a variety of reasons. Facilitated PCI was hypothesized to offer a reduction in ischemia time, earlier reperfusion, higher TIMI flow rates in the IRA and facilitated guidewire/balloon passage, decreased clot burden, and lower incidence of distal embolization.

The Bavarian Reperfusion Alternatives Evaluation (BRAVE) trial was the first randomized trial to evaluate the impact of facilitated PCI with reteplase plus abciximab on left ventricular infarct size estimated by single photon emission computed tomography (SPECT). Although the study reported a higher rate of pre-PCI TIMI flow grade 3 in the IRA in the facilitated PCI group, no reduction in infarct size was observed in this group. These results were confirmed by several subsequent clinical trials on this issue. The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT)-4 PCI study was a randomized trial of patients with STEMI presenting within 6 hours from the symptom onset, scheduled to undergo PCI after an anticipated delay of 1 to 3 hours who were assigned to standard PCI ( n = 838) or PCI preceded by administration of full-dose tenecteplase ( n = 829). All patients received aspirin and a bolus without an infusion of unfractionated heparin. The investigators of ASSENT-4 PCI planned to enroll 4000 patients, but the Data and Safety Monitoring Board recommended early cessation due to higher in-hospital mortality in the facilitated PCI group than in the group with standard PCI. The primary end point of ASSENT-4 PCI was death, congestive heart failure, or shock within 90 days from randomization. This occurred in 19% of patients in the facilitated PCI group and 13% in the group with standard PCI (RR = 1.39, [1.11 to 1.74]; P = .005). There were more in-hospital strokes (1.8% vs. 0%, P < .001) and a higher incidence of ischemic complications such as reinfarction (6% vs. 4%, P = .03) and repeat target-vessel revascularization (7% vs. 3%, P = .004) among patients treated with facilitated PCI than among those treated with standard PCI. The ASSENT-4 PCI trial concluded that a strategy of facilitated PCI consisting of full-dose fibrinolysis (tenecteplase) plus antithrombotic co-therapy and preceding PCI by 1 to 3 hours was associated with worse clinical outcome than a strategy of PPCI alone and cannot be recommended. A meta-analysis by Keeley et al. which included 17 trials of STEMI patients assigned to facilitated PCI ( n = 2237) or PPCI ( n = 2267) showed that facilitated PCI was associated with significantly worse short-term outcomes (up to 42 days) than PPCI alone: death (5% vs. 3%), nonfatal reinfarction (3% vs. 2%), urgent target-vessel revascularization (4% vs. 1%), major bleeding (7% vs. 5%), hemorrhagic stroke (0.7% vs. 0.1%), and total stroke (1.1% vs. 0.3%). The increased rates of adverse events were observed mainly when fibrinolytic therapy was used to facilitate PCI. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial served to further confirm the inefficacy and even detrimental effects of facilitated PCI in patients with STEMI. The study enrolled 2452 patients with STEMI presenting within the first 6 hours from the symptom onset who were randomly assigned to a strategy of facilitated PCI with half-dose reteplase plus abciximab versus abciximab alone versus conventional PCI with abciximab given in the catheterization laboratory. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary end point was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. In the combination therapy-facilitated group, abciximab-facilitated group, and PPCI group, the primary end point occurred in 9.8%, 10.5%, and 10.7% of the patients, respectively ( P = .55); 90-day mortality rates were 5.2%, 5.5%, and 4.5%, respectively ( P = .49); early ST-segment resolution occurred in 43.9%, 33.1%, and 31.0% ( P = .01 and P = .03, respectively). Overall, there was a graded increase in the rates of bleeding, intracranial hemorrhage, and transfusions in the PCI-facilitated groups.

The evidence offered by the ASSENT-4 PCI trial, the meta-analysis by Keeley et al. and the FINESSE trial discourages the use of fibrinolysis either at full- or half-dose combined with GPI as pharmacological facilitation of PCI. The reasons for the failure of facilitated PCI are not entirely clear. However, pre-PCI fibrinolysis may be associated with increased risks of bleeding and enhanced platelet activation.

Routine Use of Percutaneous Coronary Intervention After Fibrinolysis – Pharmacoinvasive Strategy

While the strategy of facilitated PCI was associated with worse outcomes, the pharmacoinvasive strategy—routine use of a fibrinolytic agent or GPI prior to subsequent, planned PCI—was associated with clinical benefit in patients with STEMI. As a rule, in the setting of this strategy, angiogram and planned PCI are performed after 2 to 24 hours of presentation ( Fig. 20.10 ). This strategy is mostly applied in patients undergoing transfer from one hospital without PCI to a hospital with a PCI facility. The main reason for PCI following fibrinolysis is the suboptimal outcome of fibrinolysis, in terms of suboptimal and instability of blood flow restoration and clinical outcome.

The Grupo de Análisis de la Cardiopatía Isquémica Aguda (GRACIA) 2 and the Which Early ST-elevation myocardial infarction Therapy (WEST) randomized trials reported comparable efficacy and safety of pharmacoinvasive and PPCI strategies. Both studies, however, included limited numbers of patients and consequently were underpowered for clinical end points. The GRACIA-1 trial randomized 500 patients with STEMI after receiving full-dose fibrinolysis with recombinant tissue plasminogen activator to either angiography plus PCI (within 24 hours of fibrinolysis) if indicated or ischemia-guided conservative approach. The primary end point was a composite of death, reinfarction, or revascularization at 12 months. The invasive therapy was associated with a significant reduction in the incidence of the primary end point (23% vs. 51%; risk ratio = 0.44 [0.28–0.70]; P < .001). The Southwest German Interventional Study in Acute Myocardial Infarction (SIAM) III trial randomized 163 patients to immediate (transferred within 6 hours after fibrinolysis for angiography and stenting of the IRA) or to delayed stenting (elective angiography and stenting of the IRA 2 weeks after fibrinolysis). Immediate stenting was associated with a significant reduction in the 6-month composite end point of ischemic events, death, reinfarction, or target-lesion revascularization (25.6% vs. 50.6%, P = .001). The Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI) trial included 600 patients ≤75 years of age with at least 1 high-risk feature (extensive ST-segment elevation, left bundle branch block of new onset, previous MI, Killip class >2, or left ventricular ejection fraction ≤35%) who presented within 12 hours from symptom onset and were treated initially in non-PCI hospitals with half-dose reteplase, abciximab, heparin, and aspirin. Patients were randomized to immediate transfer for PCI (299 patients) or standard care with transfer for rescue PCI (301 patients). The primary outcome was a composite of 30-day death, reinfarction, or refractory ischemia. In the group assigned to immediate PCI, 97% (289 patients) of patients underwent angiography and 85.6% (255 patients) underwent PCI. In the group assigned to standard care, 30.3% (91 patients) underwent rescue PCI. The primary end point occurred in 4.4% of patients assigned to immediate PCI and 10.7% of the patients assigned to standard care with rescue PCI as required ( P = .004) with no differences in major bleeding (3.4% vs. 2.3%, P = .47) or stroke (0.7% vs. 1.3%, P = .50). In the immediate PCI group the time interval from reteplase to angiography/PCI was 2.25 hours. The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) included 1059 high-risk patients with STEMI who presented to non-PCI hospitals within 12 hours from symptom onset. Patients were randomized to standard treatment, including rescue PCI (522 patients) or a strategy of immediate transfer for PCI within 6 hours after fibrinolysis (537 patients). All patients received aspirin, tenecteplase, and heparin or enoxaparin; concomitant clopidogrel was strongly encouraged. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days. In the group assigned to transfer for PCI, 98.5% underwent coronary angiography and 84.9% received PCI (2.8 hours after randomization); in the group assigned to standard care, 88.7% underwent coronary angiography and 67.4% received PCI (32.5 hours after randomization). At 30 days, the primary end point occurred in 11.0% of the patients assigned to the immediate PCI and in 17.2% of the patients assigned to standard treatment ( P = .004). Most of the benefit was due to a reduction in reinfarction or recurrent ischemia. The bleeding rates were similar in both groups. A series of meta-analyses supported the pharmacoinvasive strategy for patients with STEMI. A meta-analysis that included seven trials with 2961 patients comparing early routine PCI after fibrinolysis with standard therapy in patients with STEMI found that early routine use of PCI after fibrinolysis reduced the 30-day rate of reinfarction (2.6% vs. 4.7%, P = .003), the combined end point of death or reinfarction (5.6% vs. 8.3%, P = .004), and recurrent ischemia (1.9% vs. 7.1%, P < .001) without affecting the rates of major bleeding (4.9% vs. 5.0%, P = .70) or stroke (0.7% vs. 1.3%, P = .21). The benefits of routine use of PCI after fibrinolysis were maintained at 6 to 12 months of follow-up. Another meta-analysis of nine trials with a total of 3325 patients showed a 24% reduction in total mortality ( P = .06), a 45% reduction in recurrent MI ( P < .001), and a 65% reduction in recurrent ischemia ( P < .001) with no significant difference in the incidence of major bleeding or stroke in patients managed with early or immediate PCI after fibrinolysis as opposed to standard care. A more recent meta-analysis including 3195 patients (eight trials) showed that the composite end point of 30-day mortality reinfarction and ischemia was lower in the routine early PCI group compared with the ischemia-guided PCI group after fibrinolysis (7.3% vs. 13.5%; OR = 0.47 [0.32 to 0.68]; P < .001) driven by significant reduction in both reinfarction (OR = 0.62 [0.42–0.90]; P < .011) and ischemia (OR = 0.21 [0.10–0.47]; P < .001). The 30-day mortality or major bleeding rates were not significantly different between the strategies. This meta-analysis supported the use of routine early PCI within 24 hours of fibrinolysis when PPCI was not feasible.

The Strategic Reperfusion Early after Myocardial Infarction (STREAM) study evaluated whether a fibrinolytic therapy approach (prehospital or early fibrinolysis with contemporary antiplatelet and anticoagulant therapy) coupled with timely angiography (urgent in case of reperfusion failure or routine at 6 to 24 hours) provides a clinical outcome similar to that with PPCI in patients with STEMI who present early after symptom onset. In the STREAM trial, 1892 patients with STEMI (≥2 mm ST elevation in two contiguous leads) who presented within 3 hours of symptom onset and who could not undergo PPCI within 1 hour of FMC were assigned to a strategy of early fibrinolysis followed by coronary angiography in 6 to 24 hours or rescue PCI, if needed ( n = 944), or standard PPCI ( n = 948). The primary end point was a composite of death from any cause, shock, congestive heart failure, or reinfarction at 30 days. The early fibrinolysis group received tenecteplase, aspirin, clopidogrel, and enoxaparin in the ambulance or emergency room. Patients in the early fibrinolysis group were more likely to have TIMI-3 blood flow compared with the PPCI group (58.5% vs. 20.7%). The median time from symptom onset to the start of reperfusion therapy (tenecteplase or arterial sheath insertion) was 100 minutes in the early fibrinolysis group versus 178 minutes in the PPCI group. In the fibrinolysis group, emergency angiography was required in 36.3% of the patients; the remaining patients underwent angiography at a median of 17 hours after randomization. There were no significant differences in the primary end point between both treatment strategies (12.4% in the early fibrinolysis vs. 14.3% in the PPCI group; RR = 0.86 [0.68 to 1.09]; P = .21). The rates of intracranial hemorrhage were 1.0% in the fibrinolysis group and 0.2% in the PPCI group ( P = .04); after protocol amendment (the tenecteplase dose was halved in patients ≥75 years of age at the 20% planned recruitment), the difference was no longer significant (0.5% vs. 0.3%, P = .45). The main conclusion of the STREAM trial was that prehospital fibrinolysis followed by routine angiography within 6 to 24 hours in stable patients (or immediate or rescue PCI in case of failed reperfusion or unstable patients) is a reasonable alternative to PPCI when expected treatment delay was more than 1 hour. A recent report from the STREAM trial showed that the frequency of aborted MI (defined as ST-segment resolution ≥50%) was significantly higher among patients undergoing a pharmacoinvasive therapy than PPCI (11.1% vs. 6.9%, P < .01). Some limitations of the STREAM trial are worth mentioning: exclusion of patients who could receive PCI within 60 minutes (potentially biases the study in favor of fibrinolysis) and the amendment of the trial protocol; also, more than one-third of patients were recruited in an expensive system of care designed to promote prehospital fibrinolysis, which may not be directly applicable to other systems of care. Moreover, the high rate of no (or poor) responders to fibrinolysis (36.3% rate of urgent angiography in the fibrinolysis group) may support a strategy of expedited transfer to a PCI-capable facility of every patient undergoing fibrinolysis after STEMI. Finally, 1-year rates of all-cause (6.7% vs. 5.9%, P = .49) or cardiac (4.0% vs. 4.1%, P = .93) mortality were similar in patients randomized to pharmacoinvasive or PPCI treatment strategies.

Recent studies offer additional support for a pharmacoinvasive strategy, particularly in patients with STEMI with a prolonged PCI-related delay. In a prespecified analysis from the STREAM trial that included data from hospitals that randomized >10 patients, the 30-day clinical outcomes (a composite of death, congestive heart failure, cardiogenic shock, or MI) was analyzed according to PCI-related delays of ≤55, >55 to 97, and >97 minutes. The composite end point occurred in 10.6% versus 10.3% (≤55 minutes, P = .910); 13.9% versus 17.9% (>55 to 97 minutes, P = .148), and 13.5% versus 16.2% (>97 minutes, P = .470) of the patients assigned to a pharmacoinvasive or PPCI strategy. While there was no worsening of outcomes for the pharmacoinvasive strategy arm across the PCI-related delay spectrum, this occurred in the PPCI arm ( P for trend = 0.038). When PCI-related delay was analyzed for every 10-minute increment, there was an increasing trend toward benefit among pharmacoinvasive strategy assigned patients ( P for trend = .073). The recently published Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment–Elevation Myocardial Infarction (EARLY-MYO) trial showed that for patients with STEMI presenting ≤6 hours after symptom onset and with an expected PCI-related delay, a pharmacoinvasive strategy with half-dose alteplase and timely PCI was associated with better epicardial and tissue reperfusion compared to PPCI. However, the 30-day clinical outcome including rates of all-cause mortality, reinfarction, heart failure, major bleeding, or intracranial bleeding differed little between both strategies; minor bleeding was more frequent among patients undergoing a pharmacoinvasive strategy.

Some studies strongly suggest that transradial approach is particularly advantageous in patients undergoing a pharmacoinvasive strategy. In the British Cardiovascular Intervention Society Dataset that included 10,209 patients who received fibrinolysis and PCI between 2007 and 2014, transradial artery approach was used in 48% of the patients ( n = 4959). Transradial artery approach was associated with a significant reduction of in-hospital mortality (41%), major bleeding (55%), MACEs (28%), and 30-day mortality (28%). The study strongly suggested the use of transradial artery approach for PCI in the setting of pharmacoinvasive strategy. A recent report from the STREAM trial found that transradial approach was associated with improved clinical outcomes regardless of the use in the setting of PPCI or pharmacoinvasive therapy ( P for interaction = .730).

In aggregate, these studies demonstrated that the approach of routine catheterization and PCI after an initial primary fibrinolysis strategy is beneficial in patients with STEMI. Current guidelines recommend a pharmacoinvasive strategy in all patients in whom the FMC-to-device time is expected to exceed the 120-minute limit (see Fig. 20.10 ). However, as recently reported, in the United States neither fibrinolysis nor PPCI is being optimally used to achieve guideline-recommended reperfusion targets.

Rescue Percutaneous Coronary Intervention

Despite confirmed superiority of PPCI over fibrinolysis, the latter remains an important therapeutic modality mostly due to limited availability of PPCI. Rescue PCI is defined as PCI performed within 12 hours after failure of fibrinolysis in patients with continuing or recurrent myocardial ischemia. In the absence of coronary angiography, partial (<50%) resolution of ST-segment resolution on the surface electrocardiogram, continuation of chest discomfort, and/or hemodynamic instability or heart failure, even though they are known to be imprecise, are used as markers of failed fibrinolysis. It has been reported that between 12% and 17% of patients with STEMI in the U.S. are treated with fibrinolytic therapy. Even with the use of the most advanced fibrin-specific fibrinolytic agents, fibrinolysis restores optimal epicardial blood flow TIMI 3 in just over half of STEMI patients. Earlier reports have shown that 20% to 30% of patients with STEMI develop early recurrent acute ischemia, thrombotic coronary artery reocclusion, or reinfarction 2 to 4 days after an apparently successful fibrinolysis. The less-than-optimal results with fibrinolysis are explained by time-dependent resistance to fibrinolysis, the plaque/thrombosis ratio at the site of coronary occlusion being 80% (plaque) to 20% (thrombotic material) on average, and that not infrequently plaque expansion contributing more than acute thrombosis to the acute coronary occlusion. In the presence of these and other factors, the establishment of TIMI flow grade 3 by fibrinolysis is less likely. Patients with an occluded IRA (TIMI flow grade 0 to 1) and those with suboptimal blood flow restoration (TIMI flow 2) have increased mortality compared to patients with restoration of TIMI flow grade 3 in the IRA. In the past patients with failed fibrinolysis have been treated with conservative therapy and watchful waiting, repeat fibrinolysis, or rescue PCI.

The efficacy of rescue PCI for failed fibrinolysis has been assessed in a number of randomized trials (six trials in a 2007 meta-analysis). Earlier trials included limited numbers of patients (from 28 to 151 patients) and underestimated the benefits of rescue PCI since it consisted of percutaneous transluminal coronary angioplasty (PTCA) without stenting. The superiority of coronary stenting over angioplasty in rescue PCI interventions has been shown in the Stent Or PTCA for Occluded Coronary Arteries after Failed Fibrinolysis in Patients with Acute Myocardial Infarction (STOPAMI)-4 trial, which showed a significantly higher salvage index (35% vs. 25% of the initial perfusion defect salvaged by rescue interventions) obtained by paired scintigraphic studies performed 7 to 10 days apart. The most important randomized trials in the setting of rescue interventions for failed fibrinolysis have been the Middlesbrough Early Revascularization to Limit Infarction (MERLIN) trial and the Rescue Angioplasty or Repeat Fibrinolysis (REACT) trial. The MERLIN trial randomized 307 patients with STEMI and failed fibrinolysis (failure of ST-segment elevation in the lead with maximal elevation to resolve by 50%) to emergency coronary angiography with or without rescue PCI or conservative therapy. The primary end point was all-cause mortality at 30 days. It should be emphasized that coronary stents were used in just half of the patients. Thirty-day all-cause mortality was similar in the rescue and conservative groups (9.8% vs. 11%, P = .7). The combined incidence of MACE was reduced in the rescue PCI group (37.3% vs. 50.0%, P = .02) driven by less subsequent revascularization (6.5% vs. 20.1%, P = .01). Reinfarction (7.2% vs. 10.4%, P = .03) and congestive heart failure (24.2% vs. 29.2%, P = .30) were less common among patients undergoing rescue PCI. There was an increased incidence of stroke (4.6% vs. 0.6%, P = .03) and blood transfusion (11.1% vs. 1.3%, P = .001) among patients treated by rescue PCI versus those treated by conservative therapy. The 3-year follow-up of patients of the MERLIN trial showed that rescue angioplasty compared with conservative treatment did not confer a survival benefit at 3 years (17.6% vs. 16.9%, P = .90) but was associated with fewer unplanned revascularization procedures (14.4% vs. 33.8%, P < .01).

The REACT trial included 427 patients with STEMI within 6 hours of symptom onset and 90-minute electrocardiographic criteria for failed fibrinolysis (less than 50% ST-segment resolution in the leads with previous maximal ST-segment elevation). Patients were randomly assigned to one of three options: rescue PCI ( n = 144), repeat fibrinolysis ( n = 142), or conservative therapy ( n = 141). Coronary stents were used in 68.5% of patients and 43.4% of patients received a GPI. The 6-month probability of event-free survival was significantly higher in patients assigned to rescue PCI (84.6%) compared with patients assigned to conservative therapy (70.1%) or repeat fibrinolysis (68.7%, P = .004). A subsequent report from the REACT trial showed that the 6-month advantage in the event-free-survival was maintained at 1 year of follow-up (81.5%, 67.5%, and 64.1% in rescue PCI, conservative therapy, and repeat fibrinolysis arms, respectively; P = .004) and that there was a significant reduction in mortality at a median of 4.4 years: mortality rates were 11.2% in the rescue PCI arm, 21.4% in the conservative therapy arm, 21.3% in the repeat fibrinolysis arm (HR = 0.43 [0.23 to 0.97] for rescue PCI vs. conservative therapy and HR = 0.41 [0.22 to 0.75] for rescue PCI vs. repeat fibrinolysis). Of importance was the finding that repeat fibrinolysis did not offer any benefit compared with conservative therapy.

A 2007 meta-analysis of randomized trials showed that rescue PCI was associated with insignificant 31% reduction in the relative risk for all-cause mortality and significant reductions in the risk for heart failure (27%) and reinfarction (42%) compared with conservative treatment. Moreover, repeat fibrinolysis was not associated with improvements of mortality or reinfarction, but it increased the risk of minor bleeding by 84%.

Patients with STEMI and failed fibrinolysis represent a high-risk group particularly for PCI-related bleeding complications. Recent studies have suggested that transradial approach is associated with better outcome and less bleeding complications compared with femoral artery approach in patients undergoing rescue PCI. An analysis from the STREAM trial in which the pharmacoinvasive arm included 379 patients (42.3%) undergoing rescue PCI showed that within the pharmacoinvasive therapy group, there was a trend for an advantage of transradial artery approach in terms of reduction of primary outcome (a composite of 30-day death, shock, congestive heart failure, or reinfarction) in the subgroup undergoing rescue PCI (13.4% vs. 26.3%; OR = 0.65 [0.39 to 1.07]). Moreover, within the group undergoing rescue PCI, radial approach was associated with less nonintracranial major bleeding compared with femoral artery approach (6.1% vs. 11.6%; P = .064). Among 9494 patients with STEMI undergoing rescue PCI between 2009 and 2013 in the National Cardiovascular Data Registry’s CathPCI Registry, transradial artery access was used in 14.2% of patients. In propensity-matched analyses, transradial artery approach rescue PCI was associated with significantly less bleeding (OR = 0.67 [0.52 to 0.87]; P = .003) and gastrointestinal bleeding (OR = 0.23 [0.05 to 0.98]; P = .05) but not mortality (OR = 0.81 [0.53 to 1.25]; P = .35) than transfemoral artery approach.

In summary, rescue PCI improves clinical outcome and should be recommended in patients with STEMI after failed fibrinolysis. Current guidelines recommend rescue PCI (class I recommendation, level of evidence: A) immediately after failed fibrinolysis (<50% ST-segment resolution at 60 to 90 minutes) or at any time in the presence of hemodynamic or electrical instability, or worsening ischemia.

Technical Aspects and Mechanical Strategies to Enhance Myocardial Salvage During Primary Percutaneous Coronary Intervention in St-Elevation Myocardial Infarction

From a technical point of view, PPCI is not substantially different to elective PCI. However, PPCI in the early phase of a STEMI can be more difficult and requires more expertise than routine PCI in a stable patient. PPCI is performed in conditions of increased risk due to hemodynamic and electrical instability, increased thrombogenicity associated with STEMI, and increased bleeding risk due to adjuvant treatments, particularly if PCI is performed following failed fibrinolysis and often complete occlusion of the stenotic coronary artery. The latter finding impedes visualization of the coronary artery, makes guidewire and/or balloon passage through the occluded lesion more difficult, and predisposes to distal embolization of thrombotic material with a potential for further worsening of microcirculation function. The presence of coronary artery thrombus increases the risk of distal embolization or side branch occlusion and suboptimal flow and tissue reperfusion after PPCI compared with elective PCI. Stent placement in acute thrombotic lesions has been reported to predispose for late stent malapposition after the bare-metal stent (BMS) or drug-eluting stent (DES) implantation, potentially due to thrombus sequestration behind the struts, which subsequently resolves and leads to eventual vasoconstriction in the acute phase, predisposing to stent underdeployment, malapposition, and increased risk of stent thrombosis. Operators performing PPCI in STEMI must act rapidly to restore coronary blood flow in the IRA as early as possible in order to stop evolving ischemia and progression to necrosis, and to increase chances of myocardial salvage and infarct size reduction. Vascular access is achieved via the radial or femoral artery, though radial artery access is increasingly being preferred. Adjunct antithrombotic therapy is used periprocedurally (see section on Periprocedural Antithrombotic/Anticoagulant Therapy in Patients With STEMI Undergoing PPCI). After the procedure, the patient is monitored continuously and in the absence of complications, is discharged from the hospital within a few days. Over the last two decades many mechanical ( Fig. 20.11 ) and pharmacological strategies have been developed to improve procedural success or boost myocardial salvage during PPCI procedures.