CHAPTER 42: PERCUTANEOUS CORONARY INTERVENTIONS IN ACUTE MYOCARDIAL INFARCTION AND ACUTE CORONARY SYNDROMES

At its inception,¹ coronary angioplasty was envisioned as a procedure for patients with stable, single-vessel coronary artery disease (CAD). Original angioplasty balloon catheters were too large, bulky, and difficult to navigate through vessels other than the proximal portions of major epicardial vessels. Coronary lesions were required to be concentric and noncalcified. Even in these simple lesions, the initial success rate was 64%.² Over the past 40 years, improvements in catheter design, development of atraumatic steerable guidewires, development of flexible, highly deliverable stents, and development of highly effective antithrombotic and antiplatelet therapy have made percutaneous coronary intervention (PCI) a dominant revascularization strategy. Furthermore, use of PCI has revolutionized the care of patients with acute myocardial infarction (AMI) and acute coronary syndrome (ACS).

Although PCI was originally used in stable patients, recent data from the National Cardiovascular Data Registry³ demonstrate that the use of PCI has now shifted to use in AMI and ACS (Fig. 42–1); from 2010 to 2014, use of PCI has remained constant in AMI/ACS, whereas there has been a 50% reduction in use for stable CAD patients. Currently, in US practice, PCI is used in 80% of AMI/ACS patients and only 20% of stable CAD patients.

This chapter will provide a historical perspective and review of the seminal trials that led to establishment of PCI as the backbone of therapy for AMI/ACS. ST-segment elevation myocardial infarction (STEMI) can be easily diagnosed with an inexpensive, widely available tool (12-lead electrocardiogram [ECG]); similarly, ACS can be easily diagnosed with biomarker (troponin) and ECG changes. These illnesses present dramatically, can be lethal, and have been a scourge of Western civilization for the past 50 years. Fortunately, the enormous mortality risk has prompted AMI/ACS to be prospectively studied in hundreds of thousands patients. As a result, an enormously robust data set of clinical trials has tested all aspects of care from ambulance arrival to hospital discharge. We will review the evidence base using a patient-centered approach. We will discuss evidence-based decisions from admission to discharge. We will conclude with review of the evidence that widespread adoption of PCI for AMI/ACS has contributed to decline in overall adjusted cardiovascular mortality in the West.

Reperfusion therapy for AMI had its inception with the initial treatise by Fletcher et al⁴ describing the use of intravenous (IV) thrombolytic therapy in patients with thromboembolic disorders, including myocardial infarction (MI).⁴ Shortly after this, Boucek and Murphy⁵ published their observations of using catheters to deliver fibrinolytic therapy to the aortic root of patients presenting with AMI, and Favaloro et al⁶ applied saphenous vein aortocoronary bypass surgery to patients presenting with acute infarction. Two groups, one in Spokane, Washington,⁷ and one in Göttingen, Germany,⁸ performed emergency catheterization before surgical revascularization for AMI and, for the first time, knowledge of the coronary anatomy during AMI became available. DeWood et al^9,10 described the high prevalence of total coronary occlusion in the early hours after acute transmural MI and defined the role of the ECG injury current in identifying a population of patients most likely to have acute total occlusion of the infarct artery and thus most likely to benefit from emergency revascularization.

In 1978, Rentrop et al^11,12,13 performed emergency guidewire recanalization of an acute thrombotic coronary occlusion and subsequently reported on the first 13 patients with AMI treated with mechanical reperfusion. These investigators reported their selective catheter infusion of intracoronary streptokinase results at the American Heart Association (AHA) meetings in 1979, and the modern era of reperfusion therapy was born.¹⁴ When the works of DeWood and Rentrop were disseminated, enormous research interest in reperfusion therapy was generated in both Europe and the United States, and a number of randomized trials quickly followed. Khaja et al¹⁵ first demonstrated the efficacy of intracoronary streptokinase administration in establishing coronary reperfusion, and the Western Washington investigators documented improved survival in patients with AMI treated with intracoronary streptokinase therapy.¹⁶ Because of the necessity of selective coronary angiography for this treatment, it quickly became apparent that a severe residual stenosis persisted in most patients after successful fibrinolysis. O’Neill et al¹⁷ demonstrated that balloon angioplasty could effectively treat the residual stenosis and that this resulted in less recurrent ischemia and better preservation of ventricular function. This report was the first to suggest an advantage of balloon angioplasty over fibrinolytic therapy. Logistic constraints and the limited number of trained operators and catheterization facilities hindered the development of both intracoronary streptokinase and primary angioplasty as reperfusion strategies in the mid-1980s.

The large GISSI (Gruppo Italiano per lo Studio del la Sopravvivenza nell’Infarto Miocardico)¹⁸ and ISIS (International Study of Infarct Survival)-2¹⁹ trials, published in 1986 and 1988, respectively, definitively established the efficacy of IV streptokinase in improving survival in patients with AMI. IV streptokinase with aspirin gained widespread use and became the standard of care as reperfusion therapy for patients with AMI. Research interest soon focused on the development of new fibrin-specific fibrinolytic drugs that could be administered IV. However, many investigators were still concerned about the severe underlying residual stenosis remaining after medical reperfusion therapy. Three major randomized trials, the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) trial, TIMI (Thrombolysis in Myocardial Infarction) II-A trial, and a European Cooperative trial,^20,21,22 were designed to determine the value of routine percutaneous transluminal coronary angioplasty (PTCA) after thrombolytic therapy. These studies gave surprising and disappointing results. Not only was routine PTCA unnecessary, but it actually appeared harmful, and balloon angioplasty was mostly abandoned as an immediate adjunct to reperfusion with fibrinolytic therapy in the 1990s.

Interest still persisted in the use of PTCA without antecedent fibrinolytic therapy (primary PTCA). Large credit should be given to the pioneering work of Hartzler et al²³ in Kansas City, Kansas, who demonstrated the feasibility of primary PTCA. At the same time, Brodie et al²⁴ in Greensboro, North Carolina, as well as O’Neill et al²⁵ and Grines et al²⁶ in Royal Oak, Michigan, concluded that primary PTCA had been inadequately tested as a reperfusion modality. These three groups joined forces and organized the original PAMI (Primary Angioplasty in Myocardial Infarction) study group. This group, as well as investigators from the Zwolle group²⁷ and the Mayo Clinic,²⁸ published the results of the first large randomized trials comparing primary PTCA with fibrinolytic therapy in 1993. These trials demonstrated superior outcomes with primary PTCA compared with fibrinolytic therapy and established primary PTCA as the preferred reperfusion strategy for patients with AMI.

Clinical Outcomes

Keeley et al²⁹ performed a meta-analysis of 23 randomized trials incorporating 7739 patients comparing primary PCI (PPCI) with fibrinolytic therapy for STEMI. PPCI is superior to fibrinolytic therapy in reducing short-term mortality (5.3% vs 7.4%; P = .0003); nonfatal reinfarction (2.5% vs 6.8%; P < .0001); stroke (1.0% vs 2.0%; P = .0004); and the composite end point of death, nonfatal reinfarction, and stroke (8.2% vs 14.3%; P = .0001) (Fig. 42–2). These results were maintained at long-term follow-up and were independent of the type of thrombolytic agent used (streptokinase vs fibrin-specific thrombolytics) and whether patients were directly admitted or transferred emergently for PPCI. The incidence of intracranial hemorrhage was significantly less with PPCI (0.05% vs 1.1%; P < .0001), but the overall risk of major bleeding (mostly related to access site bleeding) was higher with PPCI (6.8% vs 5.3%; P = .03).

The survival benefit of PPCI compared with fibrinolytic therapy reported in this meta-analysis was substantial (21 lives saved per 1000 patients treated) and is of similar magnitude to the survival benefit of fibrinolytic therapy compared with placebo reported by the Fibrinolytic Therapy Trialists Collaborative Group³⁰ (19 lives saved per 1000 patients treated). The relative reduction in death and nonfatal reinfarction is similar across all subgroups of patients treated, including elderly patients, women, diabetics, patients with anterior versus nonanterior infarct location, and patients with prior infarction, and all patient risk groups. Of note, the greatest absolute benefit occurs in patients who are at highest risk, especially if they are younger than 75 years of age. The SHOCK (Should We Revascularize Occluded Coronaries for Cardiogenic Shock?) trial,³¹ which randomized 302 patients with cardiogenic shock to emergency revascularization versus medical stabilization, found a lower 6-month mortality with emergency revascularization (50% vs 63%; P = .03). The survival benefit was especially pronounced in patients who were treated within 6 hours of symptom onset and in patients younger than age 75 years.

The initial early clinical benefit of PPCI over fibrinolytic therapy in reducing death and reinfarction appears to be maintained at late follow-up. The PAMI investigators found that death or reinfarction was lower at 2 years with PPCI than with fibrinolytic therapy³² (14.9% vs 23.0%; P = .03). Similarly, the Zwolle Netherlands investigators found lower mortality (13.4% vs 23.9%; P = .01) and less reinfarction (6.2% vs 21.9%; P <.0001) with PPCI than with streptokinase at 5 years.³³ Both studies found a lower frequency of hospital readmissions with PPCI. The meta-analysis by Keeley et al³⁴ also showed that the initial benefit with PPCI was maintained at late follow-up at 6 to 18 months.

Angiographic Outcomes and Myocardial Salvage

Since 2005, there has been consensus that timely reperfusion can improve survival through achievement of coronary patency and salvage of ischemic myocardium. PPCI can achieve TIMI grade 3 flow in the infarct artery in more than 90% of patients^{35,36,37,38,39,40} versus 54% with fibrinolytic therapy.^35,36 Achieving TIMI grade 3 flow has a major impact on short- and long-term mortality,³⁵ and the advantage of PPCI in achieving high rates of TIMI grade 3 flow is likely responsible for much of the observed mortality advantage. Indeed, there appears to be a tight inverse relationship between the ability to achieve TIMI grade 3 flow and short-term mortality with either reperfusion strategy (Fig. 42–3). Newer fibrinolytic strategies using combination therapy with low-dose fibrinolytics and platelet glycoprotein (GP) IIb/IIIa inhibitors have shown improved TIMI grade 3 flow rates in small pilot trials,^41,42,43 but these rates are well below the TIMI grade 3 flow rates achieved with primary PCI, and they have not shown any mortality advantage in the large GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) V⁴⁴ and ASSENT (Assessment of the Safety and Efficacy of a New Treatment Strategy)-3 trials.⁴⁵

Late angiographic outcomes with PPCI have been substantially improved with the use of stents.^46,47 With stenting, reocclusion occurs in 5% to 6% of patients,⁴⁸ restenosis in 20% to 22% of patients, and target vessel revascularization in 7% to 8% of patients. After fibrinolytic therapy, late reocclusion of the infarct artery occurs in 20% to 28% of patients when adjunctive PCI is not used.^49,50

There is a broad scientific consensus that when facilities and resources are available, PPCI is the superior reperfusion modality.⁵¹ With that debate settled, attention has turned to limitation of infarction size. The last decade has seen numerous pharmacologic and mechanical strategies to limit infarct size. They are summarized in Table 42–1. To conduct comparative trials, new laboratory methods of quantifying infarct size were required. Extensive work has been done with technetium-99m scintigraphy.^52,53,54 Stone et al⁵⁵ pooled scintigraphy data from four reperfusion trials to determine predictors of final infarct size. First, it is apparent that large heterogeneity of final infarct size exists after PCI. Infarct (< 10% of left ventricular mass) occurred when the infarct artery had baseline TIMI grade 3 flow or when the right coronary artery was the culprit. Symptom onset to balloon time was critically important for up to 3 hours of symptom duration. After 3 hours, MI size did not appear to vary with prolonged times to reperfusion. More recently, cardiac magnetic resonance imaging (CMRI) has emerged as a powerful tool to accurately measure region at risk and final infarct size.⁵⁶ The CRISP (Counterpulsation Reduces Infarct Size Pre-PCI) AMI investigators have analyzed 333 patients with anterior MI undergoing PPCI with or without balloon counterpulsation. While no reduction with balloon pump was found, extensive data on predictors of MI size were found.⁵⁷ MI size was moderate at 1 to 4 hours and large after 4 hours. Baseline TIMI grade 3 flow predicts a small MI. Importantly, large heterogeneity of infarct sizes occurred. Factors such as extent of collateral flow, extent of repetitive occlusion-reperfusion, left ventricular wall stress, and other determinants of local oxygen demand cannot be measured. For this reason, although statements about broad populations can be made, risk of large infarction can only be crudely predicted on an individual basis. Opportunities to decrease infarct size based on decreasing time to reperfusion exist, but are narrowly confined to anterior MI location when reperfusion can occur within 3 to 4 hours of symptom onset. These two basic observations help explain the results of most recent trials attempting to limit infarct size after PPCI.

Systems of Care and Time to Reperfusion

An international consensus has developed over that past 10 years regarding mechanical reperfusion therapy. The Keeley et al²⁹ meta-analysis of 23 trials comparing angioplasty to fibrinolytic therapy first coalesced the scientific opinion regarding use of PCI when catheterization laboratories and operators were immediately available. Subsequently, Danish investigators demonstrated that PCI provided better outcomes not only when patients presented to a PCI-capable facility, but also when transport to a PCI facility was required.⁵⁸

For these reasons, scientific debate has turned from acceptance of the superiority of PCI to attempts to more widely apply this therapy to entire populations. Wharton et al⁵⁹ have promulgated initiation of PCI programs in nonsurgical centers. Aversano et al⁶⁰ have proven that excellent PCI results can be obtained in the C-PORT (Atlantic Cardiovascular Patients Outcomes Research Team) investigation. The C-PORT trial evaluated PPCI at hospitals with catheterization laboratories but without cardiac surgery or elective PCI. Using skilled operators who perform PCI at nearby tertiary centers, the C-PORT investigators documented lower 6-month composite event rates of death, reinfarction, or stroke with PPCI versus lytic therapy (12.4% vs 19.9%; P = .03).⁵⁸

The American College of Cardiology (ACC)/AHA guidelines recommend PPCI as the preferred reperfusion strategy for patients with STEMI if it can be performed promptly (within 90 minutes of recognition) by experienced operators.⁵¹ Based on these guidelines, there has been a nationwide effort through the ACC, the AHA, and others to reduce door-to-balloon times to less than 90 minutes.^61,62 Hospitals with coronary interventional services, dedicated physicians, nursing and administrative leadership, and established detailed protocols are best able to meet these guidelines.

An alternate approach to expanding PCI sites is to centralize care and to create regional PCI centers. Henry et al⁶³ and Ting et al⁶⁴ have demonstrated excellent clinical results with organized referral networks throughout Minnesota. Similarly, the RACE (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments) investigators demonstrated improved care processes and improved reperfusion times throughout North Carolina.⁶⁵ A nationwide initiative, based on the success of the RACE program in North Carolina, was recently implemented to create networks in nearly 20 areas around the United States,⁶⁶ with the goal of increasing the number of patients treated within guideline goals for first medical contact to device times. Preliminary results showed a modest, but significant, increase in the proportion of patients who achieved reperfusion in a timely manner across the United States.⁶⁷

The management of patients with STEMI presenting to hospitals without interventional services is more challenging. The results from randomized trials (predominantly from Europe) indicate that outcomes are better when patients with STEMI who present to non-PPCI hospitals are transferred promptly to an interventional facility for PPCI compared with being given fibrinolytic therapy at the local hospital.^{68,69,70,71,72} The additional treatment delays of PPCI compared with fibrinolytic therapy (door-to-balloon time minus door-to-needle time) in these trials have ranged from 55 to 103 minutes. Unfortunately, in the United States, transfer delays are much longer than this. Data from the National Registry of Myocardial Infarction found median delays of 180 minutes from arrival at the noninterventional hospital to balloon inflation at the PPCI hospital, with only 4.2% of transferred patients achieving door-to-balloon times of less than 90 minutes.⁷³ Consequently, many patients presenting to non-PPCI hospitals in the United States may not be eligible for PPCI because of the long potential treatment delays. There are currently nationwide and statewide efforts to reduce time to PPCI. It has been shown that with well-defined goals, commitment from administrative and clinical leaders, standardized protocols, integrated systems of transfer, and data feedback to monitor progress, door-to-balloon times for patients presenting to noninterventional hospitals can be dramatically reduced and can approach and meet guidelines for timely treatment with PPCI.^74,75 In addition, regionalization of STEMI care to interventional centers using coordinated emergency medical technician transport and in-the-field teletransmitted ECGs can markedly reduce transfer delays.

Currently, the ACC/AHA guidelines recommend that patients with cardiogenic shock and patients who are ineligible for fibrinolytic therapy should be transferred for PPCI. Decisions regarding triage of remaining STEMI patients should depend on an assessment of time and risk—time to presentation, time delay to PCI, risk of bleeding from fibrinolytic therapy, and risk of the STEMI. High-risk patients presenting early with long delays to PPCI should preferentially be treated with fibrinolytic therapy, but patients presenting later should preferentially be transferred for PPCI, even with longer delays to PCI.

In metropolitan areas, a new approach has been tried. Major hospitals are designated as STEMI centers. Ambulances are equipped to perform 12-lead ECGs, and when a STEMI is identified, these patients are selectively taken to STEMI centers even if other non-STEMI hospitals are closer.^76,77 In Ottawa, Canada, Le May et al⁷⁸ demonstrated that this system saves at least 1 hour of ischemic time. Even when patients delay in calling an ambulance for up to 80 minutes, reperfusion was achieved within a mean of 158 minutes of symptom onset.⁷⁷ It has long been demonstrated that field ECGs can save at least 1 hour of ischemic time. Now linking this program to triage to STEMI centers appears to dramatically lower total ischemic time.

Unfortunately, the United States lags in implementation of this approach. A 2013 survey by Bagai et al⁷⁹ found that bypass in emergency department (ED) markedly shortened reperfusion times but was only implemented in 119 of US hospitals. Since the greatest delay occurs with patient arrival to the ED, it is not surprising that national efforts to shorten door-to-balloon time have not resulted in substantial reductions in hospital mortality. Menees et al⁸⁰ reported that 515 hospitals in the Cath PCI Registry improved door-to-balloon time from 83 to 67 minutes between July 2008 and July 2009 (P < .001). Mortality was nearly identical (4.8% vs 4.7% P = .43). Similarly, Nallamathu et al⁸¹ reported that 423 hospitals in the Cath PCI Registry found door-to-balloon time decreased from 83 to 63 minutes (P < .001) between 2006 and 2011. A disturbing increase in risk-adjusted hospital mortality (4.7% vs 5.3%, P = .06) and an increase in 6-month mortality (12.9% vs 14.4%, P = .001) occurred. These sobering observations suggest that unless American systems of care change to the more uniform European models with more ambulance admission and triage to PCI facilities, it is unlikely that further improvement of in-hospital processes of care will result in any further reduction of mortality.

Gersh et al,⁷⁵ Stone et al,⁵⁵ and Brodie et al²⁴ have shown the critical time dependence of myocardial salvage. In the setting of anterior MI, salvage is likely to occur only if total ischemic duration (pain-to-balloon time) is less than 3 hours. Figure 42–4 depicts the time intervals for current MI care delivery models and the impact that delays have on final MI size.

Patients arrive in EDs by ambulance or car, can present to catheterization or noncatheterization facilities, and can present in metropolitan or remote locations. For the sake of argument, let us assume some standard time delay intervals. Let us assume that, whatever care setting exists, the patient has 30 minutes of pain before initiating action. The patient calls an ambulance or is driven to an ED. An ambulance arrives and hopefully is equipped to perform field ECGs. The most rapid reperfusion occurs when ambulances drive to a PPCI center where a STEMI alert has been called. Even more time can be saved when the emergency medical technician bypasses the hospital ED and transports the patient directly to the catheterization lab.⁸² Total ischemic durations of 60 to 90 minutes are realistic and would allow a substantial number of patients to have an MI aborted. Incremental delays occur if a patient is driven to an ED. Arrival, the initial encounter, undressing, and performing the ECG add at least 30 minutes. In total, even when a door-to-balloon time of 90 minutes is achieved, patients will not be reperfused within 3 hours of total symptom duration. If the emergency medical technician bypasses a PPCI center, add 30 minutes of ambulance time, and reperfusion still occurs under 3 hours. Patients driven by car to non-STEMI centers in metropolitan areas have further increments of time: time to ECG, time to decision to transfer, time to transfer, and time to catheterization laboratory. In the best of settings, reperfusion is unlikely to occur within 3 hours. Finally, for remote centers, if field ECGs are done, the time to transfer of 2 hours still permits reperfusion in 3 hours. It is unlikely that patients driven by car to remote EDs will be reperfused within 3 hours. This exercise demonstrates the central role of the 12-lead ECG and suggests that national attention be placed on educating patients to request ambulance transport and mandate that all ambulances picking up chest pain patients have the capability to perform and transmit 12-lead ECGs. It is realistic to believe that a national program, such as the DANAMI (Danish Trial in Acute Myocardial Infarction) effort, may result in timely reperfusion for the majority of patients.

As previously discussed, without dramatic changes in systems of care, it is unlikely that most US patients will be reperfused before 2 to 3 hours of total symptom duration. For this reason, other measures to decrease infarct size have been actively explored (see Table 42–1). One method may be to decrease reperfusion injury.⁸³ Reperfusion injury refers to damage to the myocardial tissue caused when blood supply returns to the tissues after a period of ischemia. In this situation, restoration of flow results in inflammation and oxidative stress damage. Furthermore, reperfusion injury may be related to a complement-dependent inflammatory response, the formation of oxygen-free radicals, or another mechanism and manifested as no-reflow phenomenon. Studies evaluating agents to reduce reperfusion injury have generally been disappointing. Adenosine can potentially reduce reperfusion injury by suppressing free radical formation and by preventing neutrophil activation. AMISTAD (Acute Myocardial Infarction Study of Adenosine) I⁸⁴ evaluated adenosine in STEMI patients who were treated with PPCI or lytic therapy. They found a 33% reduction in infarct size in patients with anterior wall infarction who were treated with adenosine but no benefit in inferior infarction. AMISTAD II,⁸⁵ which evaluated only patients with anterior wall infarction, found no benefit with adenosine in the primary end point of death or congestive heart failure at 6 months but did find a trend toward smaller infarct size with adenosine (17% vs 27%; P = .07) and a significantly smaller infarct size in the high-dose adenosine group (11% vs 27%; P = .02). In a post hoc analysis of AMISTAD II, Kloner et al⁸⁶ reported that when patients were treated within 3 hours of symptom duration mortality was lower at 1 month (5% vs 9%; P = .014) and 6 months (7% vs 11%; P = .033). In addition, combined death and congestive heart failure were lower at 6 months in the adenosine group (12% vs 17%; P = .022). Thus, there appears to be a signal for clinical benefit for anterior MI patients who are treated within 3 hours with high-dose IV adenosine.

Intracoronary administration of supersaturated oxygen with an arterial oxygen partial pressure of 760 to 1000 mm Hg has been tested in two clinical trials—AMIHOT (Acute Myocardial Infarction with Hyperoxemic Therapy) I⁸⁷ and AMIHOT II.⁸⁸ The outcome in the anterior MI groups treated within 6 hours were pooled and reported by Stone et al.⁸⁸ The authors reported on 301 patients with anterior MI who were treated with less than 6 hours of symptom duration with control (n = 79) or a 90-minute selective intracoronary infusion of supersaturated oxygen after PCI. They found a reduction in infarct size by technetium-99m sestamibi of 25% versus 18% (P = .02). No difference in 30-day major adverse cardiovascular and cerebrovascular events occurred. The investigators plan a confirmatory 60-minute infusion trial in the same population.

Numerous studies in experimental animal models of AMI have documented the effectiveness of systemic hypothermia, initiated before reperfusion, in reducing infarct size. New technology has now made systemic hypothermia feasible in patients with STEMI. Current endovascular systems used for achieving systemic hypothermia deploy catheters with coils that are placed in the inferior vena cava via the femoral vein through which cold saline is circulated. These systems can provide rapid cooling and have been evaluated in patients with STEMI in the COOL MI (Hypothermia as an Adjunctive Therapy to PCI in Patients With Acute Myocardial Infarction)⁸⁹ and ICE-IT (Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention) trials.⁹⁰ Because of logistical problems resulting in delays in initiating cooling in both of these trials, many patients were not cooled to target temperatures before reperfusion, and neither of these trials met its primary end point, which was reduction in infarct size. More recently, two small trials—RAPPID ICE⁹¹ and CHILL-MI^92—have pooled results and demonstrated a reduction of infarct size and decrease in heart failure for anterior MI. The pooled results of these trials suggested that hypothermia reduced infarct size in patients with anterior infarction when cooling to target temperature was achieved before reperfusion.

Nichol et al⁹³ have studied use of ice-saline peritoneal lavage as a method to rapidly cool patients. They found no reduction in infarct size and a evidence of increased stent thrombosis for patients who were cooled. Overall, these small trials suggest a benefit for reduction in infarct size primarily in anterior MI patients, but there are no definitive conclusions and the suggestion of increased acute stent thrombosis must be addressed.

A simple, noninvasive method of limiting postreperfusion infarct size has been tested in three trials. Experimental models suggest that transient, intermittent limb ischemia⁹⁴ decreases myocardial infarct size in an ischemia-reperfusion model. This phenomenon is likely caused by production of platelet-derived microvesicles, which are produced in the ischemic limb and decrease reperfusion injury.⁹⁵ Botker et al⁹⁶ randomized 251 consecutive patients to four cycles of 5 minutes of upper limb ischemia caused by a blood pressure cuff inflated 20 mm Hg above systolic pressure. Cycles involved 5 minutes of ischemia and 5 minutes of release for four cycles. Overall, a trend toward lower MI size occurred for the treatment group, and salvage index was higher in the remote ischemic conditioning group (0.69 vs 0.57; P = .03). Importantly, Sloth et al⁹⁷ subsequently reported that long-term outcome was improved with remote ischemic conditioning. The major adverse cardiovascular and cerebrovascular events rate was lower (13.5% vs 25.6%; P = .018) at 3.8 years, and mortality was also lower (4% vs 12%; P = .027). Subsequently Crimi et al⁹⁸ reported on 100 patients with anterior MI treated < 6 hours after symptom onset who were randomized to repetitive lower limb ischemia or sham. Creatine kinase myocardial band (CK-MB) area under the curve was reduced by 20% (P = .043) and 50% ECG ST-segment resolution was improved (66% vs 37%; P = .015). White et al⁹⁹ randomized 197 patients with TIMI grade 0 flow to remote ischemic conditioning or control and measured infarct size by CMRI. They found that remote ischemic conditioning reduced MI size by 27% (18% ± 10% vs 24% ± 12%; P = .009). Peak troponin T was also lower in the remote ischemic conditioning group (2296 ± 263 ng/L vs 2736 ± 325 ng/L; P = .037). These three trials provide strong but not definitive evidence that infarct size is decreased and long-term outcomes are improved for patients with large MI treated before reperfusion. In addition, Yellon et al¹⁰⁰ even suggest this technique may be of benefit in less developed countries that only have IV thrombolysis capability.¹⁰⁰

Another simple, inexpensive drug to limit MI size (IV metoprolol) has been tested in a moderate-size randomized trial. Ibanez et al¹⁰¹ and Pizarro et al¹⁰² have reported the outcomes on 270 patients with Killip class I to II anterior MI presenting < 6 hours after symptom onset. Patients were randomized to treatment with up to three IV bolus infusions of metoprolol 5 mg or placebo. CMRI infarct size was smaller with metoprolol treatment (25 ± 15 g vs 32 ± 22 g; P = .012). In addition, 6-month CMRI ejection fraction was higher (48.7% ± 9.9% vs 45% ± 11.7%; P = .025). The prespecified combined end point of death, congestive heart failure admission, reinfarction, and malignant arrhythmia was lower with metoprolol (10.8% vs 18.3%; P = .065). Unfortunately, these promising initial results did not translate into clinical benefit in the Early BAMI (Beta Blocker Acute Myocardial Infarction) trial recently reported at the 2016 ACC Scientific Sessions. In summary, these clinical trials suggest some room for optimism concerning infarct size reduction.

Pardee¹⁰³ first linked the acute injury current on the ECG to the diagnosis of AMI in 1918. It was not until 1979, however, that DeWood linked ST-segment elevation to acute coronary occlusion. The demonstration of a high prevalence of thrombotic occlusion in the early hours of STEMI was the catalyst for reperfusion therapy either with thrombolytic or mechanical reperfusion. Shortly thereafter the Western Washington Group¹⁰⁴ demonstrated the marked prognostic difference between anterior and nonanterior MI. The pooled analysis of technetium-99 single-photon emission computed tomography infarct size by Stone et al⁵⁵ has furthered linked the prognostic difference in MI location to the demonstration that left anterior descending artery infarcts are larger than left circumflex or right coronary artery infarcts. In addition, they demonstrated that a steep gradient of time dependence for myocardial salvage exists for anterior MI up to 3 hours of symptom duration. Thereafter, myocardial infarct size has little time dependence. Conversely, nonanterior MIs are generally smaller and have little time dependence for myocardial salvage. Thus, infarct reduction strategies must be focused on anterior MI patients in whom reperfusion is likely within 3 hours.

Figure 42–5 outlines the ECG triage for infarct size reduction. In particular, patients presenting early with large anterior MI must be rapidly reperfused, and the entire team should treat these patients as though a knife has entered the heart. The therapeutic agents aimed at decreasing infarct size previously discussed are most likely to benefit these patients.

Mechanical reperfusion therapy has improved greatly since its introduction in the early 1980s as a result of increased operator experience, better equipment, and the introduction of new adjunctive therapies. The most important and widely studied of these adjunctive therapies have been platelet inhibitors, antithrombotics, stents, distal protection, thrombectomy, and multivessel PCI.

Antithrombotic Therapy and Arterial Access

The initial inciting event during STEMI is a plaque rupture with thrombotic occlusion mediated by platelet activation, thrombin-mediated cleavage of fibrinogen to fibrin and platelet-fibrin crosslinks to form the initial hemostatic plug. Some component of mechanical obstruction from the disrupted plaque also occurs. Enormous scientific effort has been undertaken to treat each arm of this acute occlusion (Fig. 42–6). It is not possible to predict how important each factor is in individual patients. The reason mechanical reperfusion will always be superior to thrombolytic therapy is because a mechanical obstruction to flow exists in up to 50% of cases,¹⁰⁵ and this can never be overcome by pharmacologic means alone.

When primary angioplasty was started in the 1980s, an IV heparin bolus of 5000 to 10,000 U was the only anticoagulant available. Oral aspirin was also administered in the ED based on data from the thrombolytic trials. Great strides have been made in optimizing dosage of heparin based on rapidly available activated clotting time (ACT) measurements.¹⁰⁶ Most scientific effort in the late 1980s revolved around understanding whether immediate PTCA could be performed after thrombolytic therapy. While thrombolytics dissolved coronary clots, they also activated platelets though a thrombin-mediated pathway and caused intramural plaque hematoma.¹⁰⁷ Both of these outcomes led to recurrent occlusion after PTCA; thus, overall outcomes were harmful.

In the early 1990s, it became apparent that platelet activation was crucial to arterial thrombosis. At this time, the first the IV antiplatelet agent, abciximab, became available.¹⁰⁸ Five large, randomized trials have evaluated abciximab as adjunctive therapy with PPCI and have shown a reduction in the composite end point of death, reinfarction, or urgent target vessel revascularization (TVR) at 30 days. These trials have been summarized in a meta-analysis.¹⁰⁹ The greatest benefit was seen in the ADMIRAL (Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-Up) trial,¹¹⁰ in which abciximab was often given early at the time of randomization before PPCI. In addition to better clinical outcomes, the ADMIRAL trial found improved infarct artery patency before PCI and improved left ventricular ejection fraction at 6 months with abciximab. In contrast, the CADILLAC⁴⁷ (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial showed improvement in 30-day outcomes with abciximab, but most of the benefit of abciximab was seen in patients treated with PTCA alone (4.8 % vs 8.4 %; P = .02) and no benefit was seen in stented patients (4.5% vs 5.7%; P = not significant). There was no improvement in left ventricular ejection fraction at 7 months. Abciximab did reduce acute thrombosis in stented patients (0% vs 1.0%; P = .03) and decreased arterial reocclusion in all patients (0.4% vs 1.4%; P = .01).

The route of abciximab administration has been tested. Stone et al¹¹¹ found that intracoronary administration of abciximab decreased infarct size in anterior MI patients. Subsequently, eight other randomized trials have been performed, and pooled data¹¹² found that compared with IV administration, intracoronary abciximab decreased major adverse cardiovascular events (MACE) and reinfarction but did not reduce overall mortality. Abciximab is still an important adjunct during PPCI. IV administration allows reliable, profound, immediate platelet blockade. Dosing is not affected by renal function and can provide an excellent bridge until oral antiplatelet agents become effective. Finally, the agent is immediately reversible with platelet transfusions. All of these factors makes it an attractive agent for IV antiplatelet therapy during PPCI.

Currently, abciximab has a Class IIa indication in the ACC/AHA guidelines for use with PPCI for STEMI, and eptifibatide has a Class IIb recommendation.¹¹³ Recently, the novel IV direct-acting P2Y₁₂ inhibitor cangrelor has been tested in PCI patients. Steg et al¹¹⁴ summarize the patient-level data on 24,910 patients, 12% of whom had PPCI. Overall, acute stent thrombosis was decreased by 41% (P = .008), whereas mild bleeding was increased (P > .0001) when cangrelor was tested against placebo or clopidogrel. Subgroup analysis of the STEMI patients were not reported. Administration of cangrelor with switch to an oral P2Y₁₂ inhibitor may provide optimal initial and long-term antiplatelet therapy. The immediate onset of action and IV route of administration make this agent an attractive option during PPCI.

Around the same time that abciximab was developed, new direct thrombin inhibitors were being tested during elective PTCA.¹¹⁵ It became apparent that bleeding complications were significantly decreased with weight-adjusted, double bolus administration of bivalirudin. The HORIZONS¹¹⁶ (Harmonizing Outcomes With Revascularization and Stents)-AMI trial compared bivalirudin with unfractionated heparin (UFH) plus GP IIb/IIIa inhibition in STEMI patients undergoing PPCI in an effort to determine the optimum anticoagulant therapy. This trial randomized 3602 patients with STEMI and symptom onset of 12 hours or less. At 30 days, patients who were assigned to receive bivalirudin alone had a significantly reduced rate of net adverse clinical events compared with the control group (9.2% vs 12.1%; relative risk [RR], 0.76; 95% confidence interval [CI], 0.63-0.92; P = .005) because of a lower rate of major bleeding (4.9% vs 8.3%; RR, 0.60; 95% CI, 0.46-0.77; P < .001), with similar rates of major cardiovascular events. The clinical benefit of bivalirudin over heparin plus GP IIb/IIIa that was driven by reduced bleeding was preserved at 3 years of follow-up. This study was done in nonshock patients with 94% use of femoral access.

Subsequent to the HORIZONS-AMI trial, three other major trials (Euromax,¹¹⁷ HEAT PPCI [How Effective Are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention],¹¹⁸ and BRIGHT [Bivalirudin in Acute Myocardial Infarction Versus Glycoprotein IIb/IIIa and Heparin Undergoing Angioplasty]¹¹⁹) performed direct comparisons of safety with UFH versus bivalirudin. Table 42–2 summarizes these results. It is apparent that a gradient of benefit exists for bivalirudin when femoral access is used more frequently. UFH appears to be equally as safe as bivalirudin when radial access is used.

Now that consensus exists about use of PPCI as the optimal reperfusion therapy and now that processes of care (ie, door-to-balloon time) have been optimized, attention has turned to optimizing the safety and durability of PPCI. Major technical advances have changed the performance of PCI in general and PPCI in particular. Stent technology has vastly improved, and bare metal stents (BMS) and drug-eluting stents (DES) can both be delivered routinely through 6-Fr catheters. This in turn has allowed radial artery access to be routinely used in men and women. European, Canadian, and Asian operators have more rapidly adopted this technique compared to US operators. Once operators became proficient in radial access, this technique became increasingly used for STEMI intervention. Karrowni et al¹²⁰ performed a meta-analysis of 12 studies (n = 5055) comparing outcomes of radial versus femoral intervention. The mortality was decreased for radial intervention (2.7% vs 4.7%; P < .001), and site bleeding was also decreased (2.1% vs 5.6%; P < .001). Stroke risk was not increased, and door-to-balloon time was not prolonged. For these reasons, Hinohara and Rao¹²¹ have urged adoption of radial access as the optimal approach during STEMI intervention. Hess et al¹²² describe a learning curve that stabilizes after operators perform 30 to 50 radial interventions. Unfortunately, in the HORIZONS-AMI trial, which was predominantly based in the United States, only 6% of interventions were performed via radial access. Recently, Kadakia et al¹²³ have demonstrated that radial intervention is particularly effective for rescue PCI, showing less bleeding complications in this high-risk population.

Stent and Antiplatelet Therapy

When stents were first tested in the 1990s during elective PCI, a substantial risk of stent thrombosis was noticed.¹²⁴ Colombo et al¹²⁵ at made a major contribution to the field by proving that high-pressure balloon inflation decreased thrombotic risk. Leon et al¹²⁶ further demonstrated that ticlopidine therapy also decreased risk of stent thrombosis. Since AMI angioplasty was being performed in a thrombotic milieu, stents were not tested in these setting until Grines et al⁴⁶ conducted the Stent PAMI trial. The Stent PAMI trial first documented a clear benefit of stenting by comparing the heparin-coated Palmaz-Schatz stent with balloon angioplasty. Placement of stents reduced restenosis, reocclusion, and the need for TVR after PPCI for STEMI. However, stented patients had lower TIMI grade 3 flow rates after PCI and a disturbing trend toward higher mortality at 1 year. The CADILLAC trial⁴⁷ evaluated the role of stenting and platelet GP IIb/IIIa inhibition with abciximab in 2082 patients with STEMI who were treated with PPCI. Stented patients had a clear benefit over balloon angioplasty alone in reducing 6-month restenosis (22% vs 41%; P < .01), reocclusion (5.7% vs 11.3%; P = .01), ischemic TVR (6.8% vs 14.7%; P < .001), and MACE (10.9% vs 18.3%; P < .001). In contrast to Stent PAMI, the CADILLAC trial, using the newer generation MultiLink stent (Guidant Corporation, Indianapolis, IN), showed no degradation of TIMI flow after stenting and no difference in 6-month mortality. Based on these data, stenting is recommended for routine use in eligible patients with STEMI who are treated with mechanical intervention.

DES have proven very effective in reducing restenosis and TVR compared with BMS after elective and urgent PCI. There is concern that the incidence of stent thrombosis with DES may be higher in the setting of STEMI and that the benefits of DES may not be as great as with elective and urgent PCI. Two randomized trials found conflicting results with DES versus BMS in STEMI. The TYPHOON¹²⁷ (A Multicenter Randomized Trial Comparing Sirolimus-Eluting Stents to Bare Metal Stents in Primary Angioplasty for Acute Myocardial Infarction) trial (n = 705) found less TVR with sirolimus-eluting stents versus BMS (5.6% vs 13.4%; P < .001), whereas the PASSION¹²⁸ (Randomized Comparison of Paclitaxel-Eluting Stent Versus Conventional Stent in ST-Elevation Myocardial Infarction) trial (n = 617) found no difference in target lesion revascularization between paclitaxel-eluting stents and BMS (6.2% vs 7.4%; P = .23).

In the pooled data from several clinical trials with follow-up ranging from 8 months to 1 year, DES resulted in a marked reduction in target lesion revascularization with similar rates of death, reinfarction, and stent thrombosis. Recently, Sabaté et al¹²⁹ have provided definitive proof of long-term superiority of DES over BMS in the EXAMINATION (Clinical Evaluation of the Xience-V Stent in Acute Myocardial Infarction) trial. Patients undergoing PPCI (n = 1498) were randomized 1:1 to everolimus-eluting stents or BMS and followed for 5 years. All-cause mortality was reduced with everolimus-eluting stents (9% vs 12%; P = .047). Thus, when resources are available and compliance with long-term P2Y₁₂ inhibitor therapy is expected, DES is preferred over BMS for PPCI.

Biodegradable stents may further enhance arterial patency. They have now been tested in PPCI. The Prague group¹³⁰ found excellent 1-year patency in 67 patients with STEMI intervention. A large interventional trial is being planned that will test the efficacy of these new platforms in PPCI.

Oral Antiplatelet Therapy

In CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy-TIMI-28)¹³¹ 3491 patients receiving fibrinolytic therapy for STEMI were randomized to a 300-mg oral loading dose of clopidogrel and 75 mg daily thereafter versus placebo. The primary composite efficacy end point of an occluded infarct-related artery at angiography, death, and recurrent MI before angiography (between 48 and 192 hours after the start of study medication) occurred in 21% of the placebo group and 15% of the clopidogrel group (odds ratio [OR], 0.64; 95% CI, 0.53-0.76) without significant increase in the rate of bleeding. Dangas et al¹³² further demonstrated that pretreatment with 600 mg is superior to 300 mg without an increase in bleeding during PPCI.

The TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel)-TIMI 38¹³³ investigators tested the new P2Y₁₂ receptor antagonist prasugrel in 3534 patients undergoing PPCI. Seventy-one percent of patients received UFH, and femoral access was used in 91% of patients. The primary end point of cardiovascular death, nonfatal MI, or nonfatal stroke was lower in the prasugrel group (6.5% vs 9.5%; P = .0017). Zeymer et al¹³⁴ studied the pharmacokinetics of clopidogrel 300 mg versus prasugrel 60 mg. They demonstrated a higher level of platelet inhibition at 2 and 4 hours after therapy for prasugrel patients. Even then, 53% of prasugrel patients had inadequate platelet inhibition after 2 hours. The delayed length of onset for platelet inhibition with these oral agents explains a 2% to 4% incidence in acute thrombosis that occurs in some of the bivalirudin trials. It is possible that rapid termination of bivalirudin leaves patients unprotected because oral P2Y₁₂ agents have not yet achieved therapeutic levels. Thus, in patients who would have catastrophic consequence to stent occlusion, IV abciximab or cangrelor should be considered.

Oral ticagrelor has also been compared to clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial.¹³⁵ Ticagrelor is a rapid oral P2Y₁₂ inhibitor. A total of 18,624 patients with AMI and ACS PCI where randomized to clopidogrel 300 mg or ticagrelor 90 mg loading dose and subsequent therapy of 90 mg twice a day. A total of 7008 patients (37%) were undergoing STEMI intervention. The ticagrelor group had a lower event rate (9.8% vs 11.7%; P < .0001). Stent thrombosis was decreased from 3.8% to 2.9% (P = .01). An even more rapid onset of platelet inhibition can be achieved by crushing the ticagrelor tablet for oral administration. Time to maximal plasma concentration decreased from 4 to 2 hours, and substantial platelet inhibition occurred within 1 hour of oral administration.¹³⁶ Thus, when drug availability permits, prasugrel or oral crushed ticagrelor are the preferred P2Y₁₂ inhibitors. If any doubt about efficacy exists, abciximab or cangrelor should be administered.¹³⁷

In the initial trials of primary PTCA, plaque dissection and intraluminal thrombosis were difficult to treat with balloon angioplasty and heparin alone. Reocclusion of the infarct-related artery occurred in 5% to 15% of cases and worsened survival. In this context, treating other vessels that were stenosed but had normal blood flow was considered harmful. Thus, the practice of primary angioplasty evolved with treatment of the infarct artery only. As antithrombotic, antiplatelet, and stent therapy became established, the issue of complete revascularization was again raised. Three recently performed well-done randomized trials provide enormous information on this issue. Wald et al¹³⁸ first reported the PRAMI (Preventive Angioplasty in Acute Myocardial Infarction) trial. In this trial, 2420 patients with STEMI undergoing PPCI were screened, and 465 patients with multivessel disease were randomized to immediate multivessel PCI or PCI of the infarct artery only. Two-vessel disease occurred in 61% and three-vessel disease in 39% of patients. The primary end point of death, recurrent MI, or refractory angina was lower in the multivessel PCI group (21 of 234 vs 53 of 231 patients; P < .001). Cardiac mortality was also lower (11 of 234 vs 22 of 231 patients; P = .004).

In a similar trial, Gershlick et al¹³⁹ randomized 297 patients to multivessel (n = 146) versus culprit-only (n = 150) PPCI. MACE was lower in patients assigned to multivessel PCI (10% vs 21.2%; P = .009), whereas mortality trended but was not significantly lower (1.3% vs 4.1%; P = .14). Engstrøm et al¹⁴⁰ took a different approach in the PRIMULTI trial. These investigators used physiologic lesion assessment with fractional flow reserve to treat infarct-only vessels versus treatment of all hemodynamically significant lesions. They screened 3854 patients who required STEMI intervention and randomized 313 patients to infarct vessel–only PCI or multivessel PCI guided by fractional flow reserve. The primary end point of death, reinfarction, or ischemia-driven revascularization occurred in 22% of culprit-only versus 13% of multivessel PCI patients (P = .004). In aggregate, these trials suggest that in a background of high usage of P2Y₁₂ inhibitors, multivessel PCI is safe and associated with improved clinical outcomes compared with culprit-only revascularization. Whether PCI of nonculprit vessels can be deferred for 1 or more days remains to be established.

PPCI is effective in restoring normal epicardial coronary flow (TIMI grade 3 flow) in more than 90% of patients with STEMI, but more than half of these patients will have suboptimal flow at the tissue level, as evidenced by poor angiographic blush scores or lack of complete ECG ST-segment resolution.¹⁴¹ Although achieving TIMI grade 3 flow in the epicardial coronary artery is important, optimal outcomes with reperfusion therapy also require optimal myocardial reperfusion. Patients with suboptimal myocardial reperfusion, as evidenced by abnormal myocardial blush or lack of ST-segment resolution, have worse outcomes.¹⁴²

The causes of abnormal myocardial reperfusion after PPCI are not clear. One potential cause is distal embolization of thrombus and fragments of atherosclerotic plaque at the time of PCI, resulting in obstruction of the distal microcirculation. Several distal protection devices, including the PercuSurge System (Medtronic, Sunnyvale, CA) and the Filter Wire (Boston Scientific, Natick, MA), have been tested in clinical trials with the hope that distal protection will prevent distal embolization and will result in improved myocardial reperfusion and better outcomes. The EMERALD (Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberalized Debris) trial¹⁴³ showed no benefit with the GuardWire (PercuSurge System) in reducing infarct size or improving ST-segment resolution or myocardial blush despite retrieving visible thrombus or atheroma in more than 70% of patients.

Rheolytic Thrombectomy

The largest randomized trial using the AngioJet (Boston Scientific), the AIMI (AngioJet Rheolytic Thrombectomy in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction) trial,¹⁴⁴ showed no benefit compared with PPCI alone. There was no difference in ST-segment resolution and myocardial blush, and surprisingly, infarct size was slightly larger with the AngioJet. There was also an increased mortality in the AngioJet group, raising safety concerns. However, recent experience from several registries has documented the safety of the device. The AIMI study investigators concluded that there is no indication for the routine use of rheolytic thrombectomy with PPCI for STEMI.

Based on the results of the EMERALD¹⁴³ and AIMI¹⁴⁴ studies, there is general agreement that distal protection and rheolytic thrombectomy are not indicated for routine use with PPCI for STEMI. However, patients with large thrombus burden (Fig. 42–7) frequently have distal macroembolization, and studies have shown that macroembolization is harmful and leads to impaired myocardial reperfusion and worse clinical outcomes. Therefore, it seems reasonable to perform adjunctive thrombectomy in patients with angiographically large thrombus burden before PPCI.

Aspiration Thrombectomy

Vlaar et al¹⁴⁵ reported the 1-year results of the single-center TAPAS (Thrombus Aspiration Compared to Balloon Angioplasty) trial, which randomized 1071 patients (before angiography) with STEMI and symptom onset within 12 hours to a simple aspiration catheter before PCI or to PPCI alone. Adjunctive aspiration resulted in enhanced rates of normal angiographic myocardial perfusion (blush) and ST-segment resolution. At 1 year, mortality was significantly lower in patients treated with thrombectomy (5.6% vs 9.9%; hazard ratio [HR], 1.81; CI, 1.16-2.84; P = .009). The EXPIRA (Thrombectomy With Export Catheter in Infarct-Related Artery During Primary Percutaneous Intervention) trial¹⁴⁶ demonstrated a reduction in infarct size by cardiac magnetic resonance and a reduction in microvascular obstruction at 3 months in patients treated with thrombectomy during PPCI.

The initial enthusiasm for routine use of aspiration thrombectomy has been dramatically tempered by two large nationwide randomized trials. The first large nationwide study was performed through a nationwide Swedish coronary angiography and angioplasty registry.¹⁴⁷ A total of 7244 patients undergoing PPCI were randomized to manual aspiration or control while undergoing PPCI. All-cause mortality at 30 days was 2.8% in thrombectomy patients versus 3.0% in control patients. The TOTAL trial¹⁴⁸ was an unblinded randomized trial of 10,372 patients undergoing PPCI from August 2010 to July 2014. The primary end point of cardiovascular death, recurrent MI, cardiogenic shock, or New York Heart Association class IV heart failure occurred in 6.9% of thrombectomy patients versus 7.0% of PPCI patients (P = .86). At 6 months, stroke risk was higher in the thrombectomy group. These findings were maintained at 1 year.¹⁴⁹ Ghatak et al¹⁵⁰ performed a meta-analysis of 20 published trials of aspiration thrombectomy. A total of 21,281 patients were treated in these trials. Rates of mortality, TVR, recurrent MI, and stent thrombosis were the same. Only stroke was different and higher in the thrombectomy patients. Thus, routine thrombectomy does not enhance outcomes and should be reserved for large thrombus burden before or after stent implantation.

Treat in the Emergency Department

Strong evidence suggests that mechanical reperfusion is most effective in promoting myocardial salvage when it can be accomplished less than 3 hours after symptom onset. This is especially true for patients presenting with anterior MI. For this reason, systems should be in place to facilitate admission to the catheterization laboratory. Bradley et al¹⁵¹ have shown that local “service champions” are required to establish an institutional philosophy for rapid reperfusion. In the ED, a brief, focused history and physical examination and a 12-lead ECG should be all that is required to initiate a “STEMI ALERT.”

Most established programs have well-designed paging systems and can quickly activate catheterization laboratory staff and interventional attending staff. Patients should be given an IV heparin bolus and a loading dose of an adenosine diphosphate (ADP) blocker at first medical contact; they can be switched to bivalirudin in the catheterization laboratory if bleeding risk is increased or femoral access is required. Nitrates should be avoided, especially in patients with inferior MI with right ventricular involvement. Use of nitroglycerin in this setting may lead to hypotension. Rapid transfer to the catheterization laboratory is critical, and any other test, consult, or imaging that delays transport should be avoided unless absolutely necessary (eg, suspected intracranial hemorrhage or acute stroke).

Cardiac Catheterization and Angiography

Arterial access should be performed by the route that the cardiologist is most experienced with. Ideally, radial intervention is preferred (Fig. 42–8). In patients who are unstable and in whom right heart catheterization, temporary pacing, or circulatory support may be required, ultrasound-guided femoral access should be performed. Access route will impact further management, as depicted in Fig. 42–7. If radial access is chosen, continued UFH therapy should occur. For patients who require femoral approach, switching to bivalirudin may decrease bleeding risk. An ACT is measured, and additional UFH or bivalirudin is given to prolong the ACT to greater than 300 seconds or 200 to 250 seconds if platelet GP IIb/IIIa inhibitors are used. Left ventriculography is valuable before intervention, even in patients who are hemodynamically unstable, to assess the severity of ventricular and valvular dysfunction, to help identify the infarct artery (if this is uncertain), and to aid in making decisions regarding the necessity for adjunctive therapy, such as mechanical circulatory support and pulmonary artery catheter insertion. Occasionally, papillary muscle rupture, ventricular septal defect, or, rarely, even frank free wall rupture will be demonstrated when not previously suspected, prompting urgent surgery. Alternatively, demonstration of normal left ventricular function may raise early concerns of nonischemic diagnoses such as aortic dissection or pericarditis. A femoral venous sheath may be helpful in patients with occlusion of the right coronary artery to allow access for temporary transvenous pacing if necessary, although most operators do not routinely obtain venous access. In patients with hypotension or in patients who are hemodynamically unstable, placement of a pulmonary artery catheter is useful to define and monitor hemodynamics. The use of a pulse oximeter to monitor oxygen saturation may be helpful. After diagnostic coronary and left ventricular angiography, patients are triaged to the most appropriate therapy. Approximately 10% of patients who are undergoing emergency coronary angiography do not undergo primary angioplasty and are triaged to bypass surgery or medical therapy.

Primary Percutaneous Coronary Intervention Procedure

If stenting is planned and an ADP blocker had not been previously given, one is given before initiation of PCI. Crushed ticagrelor or prasugrel may provide faster-onset antiplatelet blockade. If any concern remains regarding platelet inhibition, abciximab or cangrelor should be administered. PPCI is generally performed with 6- or 7-Fr standard guiding catheters and soft- or floppy-tipped 0.014-inch steerable guidewires. The soft tip can almost always cross the soft, fresh thrombus (in contrast to a chronic total occlusion) and is less traumatic than stiffer wires. The guidewire is advanced well down the infarct artery to ensure that it is in the true lumen and not in a small side branch or under an intimal dissection because navigation distal to the occlusion is usually done blindly. If the infarct-related artery is totally occluded, reperfusion will often be established after the occlusion is crossed with the guidewire. If not, it may be preferable to cross the occlusion with a balloon and then withdraw the balloon without inflating it (dottering the lesion) to establish reperfusion. The more gradual reperfusion provided with the wire or dottering technique may result in fewer reperfusion arrhythmias than immediate balloon inflation and allows assessment of the thrombus burden and the size of the distal vessel. Balloon angioplasty or stenting of the infarct lesion is performed with techniques similar to conventional PCI. No flow (TIMI grade 0-1 flow) or slow flow (TIMI grade 2 flow) may occur after successful opening of the epicardial infarct artery obstruction. This is generally caused by microvascular dysfunction from spasm, distal emboli, or endothelial injury and may be treated with intracoronary adenosine, nicardipine, or nitroprusside, which often helps to improve flow. Intracoronary abciximab may also help with no reflow, although this approach is mainly supported by small clinical studies. Performance of culprit-only versus multivessel PCI depends on the patient’s clinical stability, total contrast usage, and complexity of nonculprit lesions. Simple, short lesions may be approached, whereas complex, calcified, or bifurcation lesions might be better treated later after the patient has stabilized and therapeutic antiplatelet effect is present. Exceptions to this rule are made in patients with severe multivessel disease and refractory cardiogenic shock. Proper stent sizing is crucial, especially if a DES is used. DES undersizing can lead to stent malapposition, which is associated with stent thrombosis. To properly size the vessel, angiography assessment after intracoronary nitroglycerin injection should be performed. Operators should have a low threshold for use of intravascular ultrasonography when the vessel diameter is in doubt.

After Care for Percutaneous Intervention

Postprocedure care has been standardized in a number of recent randomized trials. After the procedure, anticoagulation is discontinued unless there are other reasons to resume it, such as the need for mechanical circulatory support, severe left ventricular dysfunction with concern about left ventricular thrombus, or atrial fibrillation. If a femoral artery closure device is not used, the sheath is generally removed at 2 to 3 hours, when the ACT is below 170 seconds. If bivalirudin is used, the sheath is generally removed at 2 hours. Patients who are not at high risk can be transferred from the catheterization laboratory directly to the subacute unit (rather than the coronary care unit) and can be targeted for discharge on day 2 (day 0 = day of admission). All patients without contraindications should be treated with aspirin indefinitely, an ADP blocker for 1 year, β-blockers, and a statin. Angiotensin-converting enzyme (ACE) inhibitors should be used in patients with congestive heart failure, hypertension, or low ejection fraction (< 40%). Patients who develop symptoms or ECG changes of recurrent ischemia or reinfarction should undergo emergency repeat catheterization and intervention if indicated.

Decision Making in ST-Segment Elevation Myocardial Infarction Intervention

From the time of presentation, the clinical team treating a patient with STEMI is faced with complex decisions that interact and may counteract other decisions. For this reason, bottom line conclusions drawn from randomized trials or guidelines can never dictate a treatment path for each individual patient. Decisions faced in STEMI intervention are depicted in Fig. 42–8. Regardless of mode of presentation, rapid performance and competent analysis of the 12-lead ECG are the first steps. Skilled reading either on site or by transmission is essential so that “false activations” can be limited. Once a firm diagnosis of STEMI is made, activation of the STEMI team and transport to the catheterization lab are essential. A heparin bolus and a P2Y₁₂ inhibitor should be rapidly administered. If logistically feasible, strong consideration should be given to remote ischemic conditioning while en route to the catheterization lab. If a patient was treated with thrombolytics, heparin and abciximab have been most studied and are likely to provide the safest antithrombotic and antiplatelet therapy.

Upon arrival to the catheterization lab, a rapid assessment of hemodynamic stability is made. If stable and if the operator is experienced with the radial approach, heparin should be continued with ACT titrated to 250 to 300 seconds. Choice of antiplatelet therapy should take into account age, history of stroke, and likelihood of oral tolerance. Chewable ticagrelor may have the earliest onset of platelet blockade and bridges the gap until oral agents become therapeutic.

If patients are unstable, early initiation of hemodynamic support makes the procedure safer. In addition, encouraging data suggest that unloading the left ventricle with true mechanical support may decrease infarct size.¹⁵² Use of intra-aortic balloon counterpulsation has proven ineffective in this setting. Recently, the Impella 2.5 (Abiomed, Danvers, MA) axial flow left ventricular support device was approved by the US Food and Drug Administration (FDA) and currently is the only FDA-approved device for hemodynamic support in AMI cardiogenic shock. Radial access for coronary angiography and angioplasty with angiographically guided femoral puncture (from a catheter inserted to the distal aorta) for the mechanical support device placement may be an ideal approach when circulatory support is required.

Once the infarct artery is identified, intracoronary abciximab may be considered if not already administered. Routine thrombectomy is not useful, but if extensive clot burden exists (Fig. 42–9), it will prevent extensive macroembolization. Routine use of DES should occur. Proper sizing and proper stent opposition are essential to prevent stent thrombosis, and intravascular ultrasound–guided implantation should be strongly considered. Finally, whether to treat other severely stenotic vessels immediately or not depends on clinical stability, underlying renal function, and total contrast dose administered. Fractional flow reserve–guided revascularization of the nonculprit lesions is extremely helpful. If other severe lesions cannot be treated at the initial procedure, patients should return to the catheterization lab in 2 to 5 days, but definitely prior to discharge, so that complete revascularization can be accomplished. Patients who are hemodynamically unstable or in frank shock should have complete revascularization at the initial procedure, with circulatory support in place.

Invasive versus Conservative Approaches

Most patients with non–ST-segment elevation (NSTE)-ACS in the United States undergo cardiac catheterization. The evidence for invasive management is based on several randomized trials that showed improvement in MACE, improved symptoms, improved quality of life, and reduction in readmission. Moreover, early definition of coronary anatomy has been shown to be associated with earlier discharge.

A 2006 meta-analysis of seven trials that randomized 8375 patients¹⁵³ found that the invasive approach improved mortality (4.9% vs 6.5%; RR, 0.75; 95% CI, 0.63-0.90), nonfatal MI (7.6% vs 9.1%; RR, 0.83; 95% CI, 0.72-0.96), and readmission for unstable angina (RR, 0.69; 95% CI, 0.72-0.96) (Fig. 42–10). Similarly, in a propensity score–matched retrospective study of 19,704 patients, an invasive approach in patients with ACS was associated with reduction in cardiac mortality, all-cause mortality, and readmission.¹⁵⁴ The benefits were greater in patients with higher risk (ie, elevated biomarker, ST-segment changes, higher TIMI or GRACE [Global Registry of Acute Coronary Events] risk scores). An updated meta-analysis of 10,150 patients¹⁵⁵ found that both men and women with positive biomarkers or ST-segment deviation benefit from an invasive strategy. Interestingly, men with negative biomarkers or ST-segment deviation also had benefit, with reduction in the risk of death, MI, or rehospitalization. On the basis of these randomized trial findings, US guidelines recommend early catheterization, particularly in intermediate- and high-risk NSTE-ACS patients¹⁵⁶ (Table 42–3).

Timing of catheterization has been evaluated in randomized and observational trials. Initially, it was thought that it may be beneficial to “cool off” an ulcerated thrombotic lesion with antiplatelet and anticoagulant agents for a few days. However studies found that earlier intervention is better, particularly in higher risk patients. The TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial randomized 3031 patients with NSTE-ACS to early (< 24 hours) versus delayed (> 36 hours) coronary angiography.¹⁵⁷ Early catheterization was performed at a median of 14 hours after randomization and was associated with reduced refractory ischemia (1.3% vs 3.3%; P < .0001), but early catheterization did not improve the primary end point of death or MI (9.6% vs 11.3%). However, 25% of the delayed group crossed over to early catheterization. Also, in high-risk ACS patients, there was a significant reduction in the risk of death, MI, or stroke (14.1% vs 21.6%; P = .008). The ISAR-COOL Intracoronary Stenting With Antithrombotic Regimen Cooling Off) trial randomized 410 intermediate-to-high-risk ACS patients to very early (median time, 2.4 hours) versus delayed (median, 86 hours) catheterization.¹⁵⁸ Early catheterization was associated with a reduction in death or large MI at 30 days (5.9% vs 11.6%; P = .04). The ABOARD (Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes) trial randomized 352 high-risk ACS patients to immediate (median, 70 minutes) versus next working day (median, 21 hours) catheterization.¹⁵⁹ There were no differences in peak troponin levels or clinical events. Conversely, the RIDDLE-NSTEMI (Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients) trial¹⁶⁰ randomized 323 non–ST-segment elevation MI (NSTEMI) patients to immediate (median, 1.4 hours) versus delayed (61 hours) intervention. The immediate strategy was associated with a lower composite of death or new MI at 30 days (4.3% vs 13%; P = .008) and at 1 year (6.8% vs 18.8%; P = .002). Although the LIPSiA-NSTEMI (Leipzig Immediate Versus Early and Late Percutaneous Coronary Intervention) trial¹⁶¹ reported no differences in outcomes in immediate versus early versus selective invasive strategies, 85% of patients in the “selective” arm underwent catheterization. Thus, one would not expect any difference in clinical outcome. In a post hoc analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, which randomized NSTE-ACS patients to different pharmacologic strategies, PCI was performed in 7749 patients.¹⁶² Approximately one-third of patients were treated within 8 hours of presentation, one-third between 8 and 24 hours, and the remainder after 24 hours. The two groups in which PCI was done early (< 24 hours) did equally well; however, patients who had PCI after > 24 hours had a significant increase in the individual components of death, MI, and ischemia. These differences were observed in both intermediate- and high-risk patients (Fig. 42–11).

Thus, in intermediate-to-high risk or unstable NSTE-ACS patients, it appears that earlier catheterization is better, whereas in low-risk, stable patients, catheterization may be delayed. Immediate angiography is recommended for hemodynamic instability, congestive heart failure, ongoing or recurrent ischemia, dynamic ECG changes, ventricular arrhythmias, or mechanical complications such as mitral regurgitation or ventricular septal defect (Table 42–4). In other ACS patients, catheterization is often performed the next working day.

Findings of Catheterization in the Patient With Non–ST-Segment Elevation Acute Coronary Syndrome and How It Influences Treatment

Unlike STEMI, the cause of NSTE-ACS is often a “nonocclusive” ruptured plaque. When the plaque is further analyzed, it may contain platelet thrombi, not fibrin-laden clots. Thus, thrombolytic therapy is not beneficial and, in fact, may be harmful and is not recommended. In our clinical and trial experience, single-vessel disease is found in the majority of STEMI patients, and PPCI is performed in approximately 90%. Conversely, in the NSTE-ACS patient,¹⁶³ single-vessel disease is present in only 30% of cases; multivessel disease is present in 40% to 50%, left main disease in 4% to 10%, and nonsignificant disease in 10% to 20%. Thus, catheterization (or coronary computed tomography angiography in low-risk patients) is essential to determine the most appropriate treatment strategy. Even in the 10% to 20% of patients with nonsignificant disease, defining the coronary anatomy has been shown to reduce readmissions.

To date, only one trial randomized patients with unstable angina to PCI versus coronary artery bypass grafting (CABG).¹⁶⁴ In this trial of 454 high-risk patients, there was no difference in mortality at 36 months, but more angina and revascularization in the PCI group. Other trials of both stable and unstable angina comparing PCI and CABG in patients with multivessel disease had similar findings. Thus, the choice of PCI or CABG often depends on the presence of factors that influence survival (diabetes, SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] score) but not on the presence of NSTE-ACS. The use of CABG varies widely based on patient risk and hospital center; publications from early randomized trials reported CABG rates of 16% to 50% in NSTE-ACS patients. A more recent publication reported that CABG was performed in 10% of NSTE-ACS patients.¹⁶⁵

Thrombectomy for Non–ST-Segment Elevation Acute Coronary Syndrome

Although angiographic evidence of thrombus may be present in up to 40% of ACS cases, it is usually not flow occlusive. A single study randomized 440 patients with ACS to adjunctive thrombectomy versus PCI alone.¹⁶⁶ There was no difference in microvascular obstruction as assessed by cardiac magnetic resonance imaging. Thus, routine thrombectomy is not recommended for patients with NSTE-ACS undergoing PCI.

Radial Access for Non–ST-Segment Elevation Acute Coronary Syndrome

One of the most common complications of the invasive strategy for NSTE-ACS is a vascular access complication, including bleeding. Although bleeding avoidance strategies include cautious dosing of antithrombotics, radial access has emerged as a valuable approach. Several trials and registries have reported reduction in bleeding using radial compared to femoral access. Valgimigli et al¹⁶⁷ randomized 8404 patients with ACS to radial versus femoral approach and found reductions in MACE and major bleeding as well as improved survival (1.6% vs 2.2%; RR, 0.72; 95% CI, 0.53-0.99; P = .045) in the radial group. The improvement in survival occurred predominantly in the NSTE-ACS group. A meta-analysis of nine studies with 220,126 NSTE-ACS patients¹⁶⁸ found reduction in major bleeding (OR, 0.52; 95% CI, 0.36-0.73; P = .0002), transfusions (OR, 0.61; 95% CI, 0.41-0.91; P = .02), and 1-year mortality (OR, 0.72; 95% CI, 0.55-0.95; P = .02). These data suggest that radial access should be the preferred approach for NSTE-ACS patients undergoing an invasive strategy.

Pharmacotherapy for Patients Presenting for Percutaneous Coronary Intervention During Non–ST-Segment Elevation Acute Coronary Syndrome

The primary goal of pharmacotherapy for NSTE-ACS is to alleviate ischemia using antiplatelets, antithrombotics, and adjunctive therapies to reduce myocardial oxygen demand. Pharmacotherapy in NSTE-ACS is crucial for management, because a substantial portion of patients will not immediately undergo coronary angiography and/or revascularization. Here, we summarize these therapies and translate their use into clinical practice.

Oral Antiplatelet Agents

Aspirin

Evidence-based guidelines universally advocate that patients with NSTE-ACS should routinely and indefinitely receive low-dose (75-100 mg) non–enteric-coated aspirin, after an initial loading dose of 300 to 325 mg. Aspirin is routinely given to all patients with CAD, and is assumed to equally benefit those undergoing and not undergoing an invasive management strategy.^169,170 Early evidence regarding the benefits of aspirin in the specific context of coronary revascularization arose from ISIS-2, a double-blind, randomized, two-by-two factorial, placebo-controlled trial that evaluated the effect of aspirin as an adjunct to thrombolysis (streptokinase) in the management of AMI. This large study demonstrated that 1 month of aspirin given alone or in combination with revascularization therapy significantly improved outcomes.¹⁷¹ It has subsequently been shown that high-dose and low-dose aspirin have equivalent cardiovascular outcomes; thus, low-dose (<150 mg daily) aspirin would seem most prudent in the absence of a direct comparison.¹⁷²

Clopidogrel

The addition of ticlopidine to aspirin substantially benefited patients with NSTE-ACS and established dual antiplatelet therapy (DAPT) as the standard of care. Clopidogrel was subsequently developed to circumvent the adverse side effect profile of ticlopidine. The efficacy of clopidogrel was initially studied in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which randomized patients in double-blind fashion to receive clopidogrel or placebo.^173,174 Clopidogrel reduced the composite end point of cardiovascular death, MI, and TVR within 30 days of PCI, and the reduction in MACE was maintained to 9 months of follow-up without differences in major bleeding. Studies also demonstrated that pretreatment with clopidogrel improves outcomes for invasively managed NSTE-ACS, with only a modest increase in minor bleeding. Several subsequent trials and meta-analyses have clarified the current preferred loading and maintenance doses of clopidogrel (600 mg followed by 75 mg daily).^175,176 If PCI is not planned for the same day, a 300-mg loading dose may be used.

Prasugrel

Prasugrel has a more rapid onset of action and reduced response variability compared with clopidogrel. TRITON-TIMI 38 randomized clopidogrel-naïve patients with moderate-to-high risk ACS undergoing PCI to receive either prasugrel or clopidogrel (both in combination with aspirin). Randomization occurred following ascertainment of coronary anatomy, with the exception of patients with STEMI. At 15 months of follow-up, the primary end point (composite of cardiovascular death, nonfatal MI, or stroke) was lower with prasugrel, driven by nonfatal MI and stent thrombosis. These benefits were somewhat offset by a significant risk of major and fatal bleeding in the prasugrel-treated versuss clopidogrel-treated group. Prasugrel increased mortality in patients with a prior stroke, and as such should not be given to patients with a history of transient ischemic attack or stroke.¹⁷⁷ Additionally, caution should be used in patients with low body weight (< 60 kg) or those > 75 years of age. It should also be noted that the TRILOGY (Prasugrel Versus Clopidogrel for Acute Coronary Syndromes without Revascularization) trial showed that there was no benefit of prasugrel compared with clopidogrel in ACS patients without ST-segment elevation not undergoing PCI and, as such, it is not recommended in guidelines for NSTE-ACS without PCI.

Ticagrelor

Ticagrelor was developed as the first reversible nonthienopyridine in an effort to avoid the variable pharmacokinetics of clopidogrel and the adverse safety profile of prasugrel. The PLATO trial randomized ACS patients to receive ticagrelor or clopidogrel. Patients with moderate-to-high risk ACS received an additional, blinded loading dose of clopidogrel or its placebo. At 12 months, ticagrelor significantly reduced the primary end point (cardiovascular death, nonfatal MI, or stroke), driven by reductions in cardiovascular mortality, nonfatal MI, and stent thrombosis without any difference in overall bleeding. An adenosine-mediated mechanism has been suggested for the survival benefit, and improved endothelial function has been found in separate studies with this agent. Major bleeding was higher in ticagrelor-treated patients, including fatal intracranial hemorrhage, but not all-cause fatal bleeding. Several adverse effects with ticagrelor were observed and were associated with discontinuation of therapy, including acute episodic dyspnea, bradycardia (rarely), and elevated serum creatinine and uric acid.¹⁷⁸ Because adverse events may be mediated by adenosine, taking the medication with coffee has been suggested. Lastly, patients taking > 100 mg of aspirin daily had increased bleeding rates with ticagrelor, and as such, aspirin doses < 100 mg are recommended.

Pretreatment With Oral Antiplatelet Agents

Administration of clopidogrel prior to PCI is known to improve outcomes. The PCI-CURE study revealed that patients who received pre-PCI treatment with clopidogrel had reduced cardiovascular death, MI, and stent thrombosis when compared with placebo.¹⁷⁴ This can be explained by clopidogrel’s slow onset, which is circumvented by early administration. In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction) trial, pretreatment with prasugrel did not decrease ischemic complications when compared with administration at the time of PCI and was associated with higher risk for major bleeding.¹⁷⁹ Prasugrel has a very fast onset, thereby rendering pretreatment unnecessary. Pretreatment with ticagrelor has only been studied in the STEMI PCI patient population, and given its rapid onset of action, pretreatment also did not result in any significant net clinical benefit compared to “on the table” administration.

Duration and Interruption of Oral Dual Antiplatelet Therapy

Based on guidelines and available data, we recommend at least 1 year of continuous DAPT in patients with NSTE-ACS and continuation as needed for patients with a low risk of bleeding. For patients with high bleeding risk, lower doses of prasugrel (5 mg daily) and ticagrelor (60 mg twice daily) are available if clinical judgement points to long-term use of a lower dose. Despite these recommendations, “real-world” practice often necessitates DAPT interruption within a year of PCI.¹⁸⁰ The context and process of making this decision are important to review; if DAPT is interrupted based on a specific physician-driven decision based on a new clinical development, outcomes were not unfavorable; however, if the DAPT course was disrupted without cardiologist input, then major complications occurred within a week. If DAPT interruption is warranted (eg, for an urgent noncardiac surgery), then clopidogrel is stopped for 5 days, prasugrel for 5 to 7 days, and ticagrelor for 5 days (despite its pharmacokinetic “reversibility”). Individual patient responses may vary, and platelet reactivity testing has been suggested to guide the timing of surgery but without a clinically proven algorithm.

Intravenous Antiplatelet Agents

Cangrelor

Cangrelor is an IV rapid-onset and rapidly reversible P2Y₁₂ inhibitor, making it a special agent for acutely ill patients who are unable to take or absorb oral medications. It achieves almost complete and immediate inhibition of ADP-induced platelet aggregation when administered as a bolus of 30 μg/kg, and continuous infusion sustains the high degree of inhibition. The plasma half-life is approximately 3 to 5 minutes, normal platelet function is restored within 1 hour after cessation of the infusion, and it has been studied in high-risk patients awaiting CABG.¹⁸¹ The rapid cessation is also beneficial if patients suffer a life-threatening complication. After initial trials showed favorable bleeding profiles, the CHAMPION-PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Patients Who Require PCI) study, a randomized, double-blind, double-dummy trial, was designed to evaluate the efficacy of cangrelor against clopidogrel loading during PCI in patients who had not previously received a P2Y₁₂ antagonist (including patients with stable angina and ACS). A composite end point of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours was lower in the cangrelor group compared with the clopidogrel group, driven by the reduction of acute periprocedural MI and particularly intraprocedure stent thrombosis; there were no differences in adverse events.¹⁸² Future studies are needed to determine the optimal way to transition ACS PCI patients from cangrelor to oral P2Y₁₂ inhibitors.

Glycoprotein IIb/IIIa Inhibitors

A large number of trials before the era of DAPT showed that patients undergoing angioplasty (greatest benefit) or stent experienced lower ischemic events, mainly driven by reduction in MI, when receiving adequately dosed GP IIb/IIIa inhibitors (GPIs) combined with UFH instead of UFH alone. In a head-to-head trial, abciximab was found to be superior to tirofiban during PCI.¹⁸³ Currently, GPIs (particularly eptifibatide and tirofiban) are indicated at the time of PCI in high-risk patients, whether or not they have been pretreated with a P2Y₁₂ inhibitor. GPI use has been limited as a result of high bleeding with GPIs because of the long post-PCI infusion and their delayed reversibility in case of an acute bleed (only by platelet transfusions with abciximab and with a 4- to 6-hour half-life for tirofiban and eptifibatide). GPIs are infrequently used as pretreatment in NSTE-ACS patients who receive DAPT and have intermediate- or high-risk features, as both the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) and ACUITY-Timing (Acute Catheterization and Urgent Intervention Triage Strategy Timing) studies showed no benefit to upstream GPI use in all ACS patients versus “on the table” administration only in those patients undergoing PCI.^184,185 If a patient has high-risk features, ongoing ischemia, and a long time to PCI (eg, patient awaiting transfer to a PCI-capable center), it is reasonable to initiate GPI therapy while awaiting PCI. Renal dose adjustment is important for eptifibatide and tirofiban safety because these and other agents are often incorrectly dosed in patients with renal dysfunction.¹⁸⁶

Antithrombotic Agents

Anticoagulation is recommended for all NSTE-ACS patients undergoing PCI at the time of diagnosis (class I practice guideline).¹⁷⁰ This is typically administered in the ED or in the cardiology unit as an IV infusion of UFH or a subcutaneous injection of low-molecular-weight heparin; the former requires dose adjustment to target an activated partial thromboplastin time of 50 to 70 seconds but may be more flexible (faster elimination) if an interruption is necessary. The latter does not require monitoring, but a dose reduction according to the renal function is pertinent, and the elimination half-life is many hours.

Parenteral anticoagulants used in patients with NSTE-ACS undergoing PCI include UFH (most commonly, 50 U/kg bolus followed by an infusion for partial thromboplastin time of 50-70 seconds), low-molecular-weight heparin (usually enoxaparin 0.3 mg/kg IV bolus or 1 mg/kg every 12 hours in the absence of renal failure), bivalirudin (with PCI, 0.75 mg/kg bolus followed by 1.75 mg/kg/h infusion; with dose reduction in renal failure), and fondaparinux (typically used without PCI). Heparin and bivalirudin are the agents of choice in the United States for patients undergoing an invasive approach because of their rather short half-lives in comparison to the longer elimination time of other agents, which may complicate arterial sheath removal timing after PCI.¹⁸⁷ In a recent meta-analysis of available trials comparing bivalirudin and heparin, the use of bivalirudin was associated with increased risk of stent thrombosis (mostly in STEMI patients, within a few hours of PPCI) but was associated with significantly less bleeding than heparin; however, the risk of bleeding was attenuated with transradial access rather than femoral access and when potent oral P2Y₁₂ inhibitors rather than GPIs were used.¹⁸⁸

A recent large trial in ACS patients treated with a mostly radial approach for PCI (which has been shown to lower access site–related bleeding) has shown similar composite cardiovascular outcomes between heparin and bivalirudin during PCI, lower bleeding, and lower total mortality. A post-PCI bivalirudin infusion appeared to limit acute stent thrombosis with this agent in STEMI.¹⁸⁹

Other Adjunctive Therapies

In addition to antiplatelets and antithrombotics, adjunctive therapy with oxygen is empirically administered in all patients, and especially for patients with oxygen saturation < 90%. If patients are experiencing ischemic chest discomfort, sublingual or IV nitroglycerin can be used. β-Blockade should be initiated within 24 hours to reduce heart rate, contractility, and blood pressure, as long as patients are not experiencing heart failure or low output, are at increased risk of cardiogenic shock, or have other contraindications to β-blockade.¹⁹⁰ Nondihydropyridine calcium channel blockers can be administered to reduce myocardial oxygen demand if β-blockers are contraindicated (eg, as a result of bradycardia or wheezing). Lastly, high-intensity statin therapy with either atorvastatin 80 mg or rosuvastatin 40 mg should be administered as soon as possible in patients presenting with NSTE-ACS. The PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) TIMI 22 trial revealed that patients who are treated with a high-intensity statin have reduced rates of recurrent MI, coronary heart disease mortality, need for revascularization, and stroke than patients treated with a moderate- or low-intensity statin.¹⁹¹

In the 20th century, an explosive increase in deaths as a result of heart disease occurred in the United States (Fig. 42–12). The deaths were overwhelmingly related to ischemic heart disease and AMI. This epidemic became rampant after World War II and spawned a massive effort to understand and develop new therapies. Once acute thrombotic occlusion was recognized as the inciting event, therapies including coronary bypass, PCI, and thrombolytic therapy were developed in the last quarter of the 20th century. These therapies, control of risk factors, and treatment of elevated lipids have resulted in substantial reduction in cardiac deaths. The trend started in 2000 and has continued.

Shah et al¹⁹² have found that PPCI use increased from 53% to 80% of STEMI interventions in a sample of all nonfederal hospitals in the United States from 2003 to 2011. This has been associated with a 25% reduction in hospital death rates. This decrease in risk of death occurred despite the fact that a significant increase in MI occurred for patients older than 85 years.¹⁹³ Krumholz et al¹⁹⁴ have demonstrated that from 1999 to 2013, as cardiac deaths have decreased, overall Medicare expenditure has dropped.

The most conclusive proof of national benefit to widespread use of PPCI comes from the comparison of the contemporary Swedish and British experience. National comprehensive databases allow detailed analysis of volumes and mortality. Chung et al¹⁹⁵ report that Sweden adopted PPCI more rapidly than Britain. Between 2004 and 2010, an excess of 10,000 deaths occurred in Britain. The largest difference in mortality occurred in 2004 when PPCI was more widely adopted in Sweden. By 2010, 50% of STEMI patients in both countries were treated with PPCI, and death rates were equivalent.

Overall, these observations strongly suggest that the decline in cardiac death that started in 2000 in the United States has been strongly related to widespread adoption of timely reperfusion therapy.

We would like to thank Dr. Pedro Martinez-Clark, who contributed to the previous version of this chapter in the 13th edition, and to Ms. JoAnna Moore for expert technical assistance in preparation of the manuscript.