Introduction
Myocardial infarction (MI) is caused by atherothrombosis (see Chapter 3 ), with platelets playing a pivotal role in the initial onset of MI and its recurrence. Antiplatelet therapy targets this key element in the pathobiology of cardiovascular ischemic events. Patients who have suffered an MI have a sustained heightened risk for recurrent ischemic events and therefore have the potential to benefit from long-term antiplatelet therapy as part of secondary preventive management ( Figures 35-1 and 35-2 ). Antiplatelet therapy, however, also increases the risk of bleeding. Accordingly, the type, intensity, and duration of antiplatelet therapy after MI should be tailored in accordance with the patient’s risk of subsequent ischemic events and of bleeding. This chapter considers the rationale for antiplatelet therapy for long-term secondary prevention in patients with MI, reviews trials of specific agents and strategies, and describes the application of clinical trial evidence in real-world practice.
Epidemiology of Recurrent Atherothrombosis
Myocardial Infarction as a Marker of Long-Term Atherothrombotic Risk
Atherothrombotic events, including MI and ischemic stroke, remain a primary contributor to morbidity and mortality worldwide (see Chapter 2 ). Among patients with established atherosclerosis, those who have suffered a previous acute thrombotic ischemic event have sustained activation of coagulation ( Figure 35-3 ) and are at higher risk than those with no history of such an event. Thus a history of previous spontaneous (type 1) MI marks the presence of an underlying disease state predisposing the patient to recurrent spontaneous atherothrombotic ischemic events.
Several modern observational data sets have characterized long-term ischemic risk in patients with previous atherothrombosis. An analysis of data for 64,977 stable outpatients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry evaluated the risk of cardiovascular death, MI, and stroke over a 4-year period based on a clinical history of either cardiovascular risk factors only, known atherosclerosis but no previous ischemic event, or a previous ischemic event ( Figure 35-4 ). Patients with a previous ischemic event had the highest risk of cardiovascular death, MI, or stroke at 4 years (18.3%) compared with patients with stable atherosclerosis (12.2%) or risk factors alone (9.1%). Although this risk was higher for those within 1 year of their event (21.1%), it remained heightened for those patients who had survived more than a year from their most recent event (17.2%).
The long-term risk of recurrent major cardiovascular events after MI was characterized in a Swedish Registry including 97,254 patients surviving after hospitalization for an MI. Within the first year, the rate of recurrent MI, stroke, or cardiovascular death was 18.3%, with a majority of these events being recurrent MI (56%), followed by cardiovascular death (31.0%) and ischemic stroke (13.4%). An additional 4.2% of patients died from noncardiovascular causes—approximately one-third the rate of death from cardiovascular causes. For those patients who survived 1 year after their MI without a recurrent event, the rate of subsequent cardiovascular death, MI, or stroke was 20% over 3 years. Although recurrent MI was the most frequent event (40.8% of the population), the relative proportions of cardiovascular death (40.6%) and stroke (18.6%) were higher than those within the first year. Independent predictors of recurrent events included age, previous MI, previous stroke, and diabetes. Other national registries have estimated similar adjusted rates of subsequent recurrent MI, stroke, or death, ranging from 16.7% to 21.3% at 3 years in patients who had survived 1 year from MI.
Types of Atherothrombotic Events in Stable Patients with Previous Myocardial Infarction
Because atherosclerosis is a systemic condition, patients with symptomatic disease in any vascular bed are at heightened risk for systemic atherothrombotic events. In the REACH registry, when stratified by symptomatic vascular bed compared with patients with risk factors alone, patients with established atherosclerosis were at higher risk for cardiovascular death, MI, stroke, or hospitalization for atherothrombosis regardless of the symptomatic vascular bed and were at the highest risk when multiple vascular beds were symptomatic.
In patients presenting with acute MI, the risk of early ischemic complications generally is related to the culprit coronary lesion or associated coronary interventions. More potent antiplatelet strategies reduce the risk of periprocedural MI (type 4a MI) occurring in the setting of percutaneous coronary intervention (PCI), as well as stent thrombosis (type 4b MI). After discharge, however, the risk of stent-related complications decreases, whereas the risk of recurrent spontaneous events remains relatively constant (see Figure 35-2 ). Moreover, in a study of cardiovascular events occurring after successful PCI in 697 patients with acute coronary syndrome (ACS), rates of recurrent events related to the culprit lesion and to non-culprit lesions were similar ( Figure 35-5 ). In addition, non-culprit lesions leading to recurrent atherothrombosis frequently were angiographically mild at initial angiography but were associated with markers of instability, including thin-cap fibroatheroma (see Chapter 10 ).
Clinical trials enrolling stable patients with previous MI have prospectively adjudicated recurrent MI and applied the Universal Definition of MI classification system to categorize events according to their etiology (see Chapter 1 ). In such cohorts of stable patients, recurrent MIs are predominantly new spontaneous events (type 1 MI, 78%), with lower relative frequencies of demand ischemia (type 2 MI, 10%), PCI-related MI, or stent thrombosis (type 4 MI, 12%). These data indicate that as patients stabilize from an acute MI, the type of recurrent coronary event for which they are at risk switches from events primarily related to the culprit lesion and coronary intervention to those primarily occurring in the setting of de novo plaque rupture elsewhere in the coronary tree (see Figure 35-2 ). This pattern is likely to persist in coming years, particularly as procedural risk and stent-related complications continue to decrease with improvements in technology.
In addition to their risk of spontaneous MI, patients with previous MI are at higher long-term risk for ischemic stroke. As patients survive beyond their first year after MI, the proportion of recurrent cardiovascular events that are ischemic strokes remains similar or increases; for example, in the REACH registry, the proportion of events that were ischemic strokes was 13.4% within 1 year after MI, increasing to 18.6% beyond 1 year after MI. Although the risk of an incident ischemic stroke is greatest in patients who have suffered a previous stroke, at a population level a majority of incident strokes occur as first strokes in patients with atherosclerosis.
Rationale for Antiplatelet Therapy for Long-Term Secondary Prevention
Because atherosclerosis is a systemic disease and patients with a history of MI are at heightened long-term risk for spontaneous atherothrombotic events across vascular territories, strategies using systemic preventive therapies are necessary to reduce this risk. Components of medical secondary prevention target specific processes involved in the pathobiology of atherothrombosis, including dyslipidemia and inflammation, and activation of both the coagulation cascade and platelets (see Chapter 13 ).
Secondary prevention strategies to reduce atherothrombotic risk include lifestyle interventions, lipid lowering, blood pressure lowering, and antithrombotic therapy (see Chapter 34 ). Although both oral antiplatelet and anticoagulant strategies have been studied for secondary prevention, anticoagulants at traditional therapeutic doses have generally resulted in excessive bleeding and are currently not used routinely for this purpose. Trials evaluating very-low-dose anticoagulants, however, have shown efficacy when such agents are added to antiplatelet therapy in patients with ACS, and future trials in stable populations may expand the use of this strategy to long-term secondary prevention (see Chapter 21 ). Several antiplatelet agents targeting differing mechanisms used alone or in combination are currently used for the first year after an MI and are now supported by evidence showing benefits for long-term secondary prevention.
Clinical Trials of Antiplatelet Therapy for Secondary Prevention after Myocardial Infarction
Aspirin
Aspirin has been studied for ischemic risk reduction in multiple randomized trials and analyzed in a meta-analysis conducted by the Antithrombotic Trialists’ Collaborative. In early iterations of the meta-analysis, a total of 287 randomized, controlled studies involving 135,000 patients in trials of a variety of antiplatelet agents were combined and showed a reduction in 36 serious vascular events prevented per 1000 patients with prevous MI treated for 2 years ( Figure 35-6A ). A more recent analysis that focused specifically on the efficacy and safety of aspirin for primary and secondary prevention included 6 trials in patients with previous MI and 10 trials in patients with previous stroke or transient ischemic attack (TIA). In the secondary prevention population, aspirin reduced the risk of any serious vascular event by 19% (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.75 to 0.87), with an absolute risk reduction of 1.49% per year versus placebo. There were consistent reductions in coronary mortality, myocardial infarction, and ischemic stroke.
In a study considering the safety of antiplatelet therapy, aspirin increased the risk of major extracranial bleeding, primarily gastrointestinal (absolute risk increase of 0.4% per year ) and hemorrhagic stroke (absolute risk increase of 0.01% per year). Overall, the study investigators concluded that a net benefit was achieved with aspirin for secondary prevention due to the ischemic risk in that population. Although the optimal dose of aspirin for long-term secondary prevention has not been definitively established, the aggregate evidence favors aspirin doses of 75 to 162 mg daily. The CURRENT-OASIS 7 trial evaluated whether high-dose (300 to 325 mg daily) aspirin is superior to low-dose aspirin (75 to 100 mg daily) for 30 days in patients presenting with ACS (see Figure 35-6B ). In this acute setting, in which potent platelet inhibition might be expected to be most beneficial, there was no difference in the composite of cardiovascular death, MI, or stroke with high- versus low-dose aspirin (HR, 0.97; 95% CI, 0.86 to 1.09; P = .61); however, the rates of major gastrointestinal bleeding ( P = .04) and minor bleeding ( P = .04) were higher. These data indicate that the ischemic benefit from aspirin is achieved at a low dose (100 mg or less daily) and that higher doses result in more bleeding.
P2Y 12 Inhibitors
Oral therapies to inhibit the platelet P2Y 12 adenosine diphosphate (ADP) receptor are available. Each of the available oral agents (clopidogrel, prasugrel, and ticagrelor) are described in Chapter 19 (see Figure 19-2 and Table 19-1 ). The second-generation thienopyridine clopidogrel was studied head-to-head against aspirin as monotherapy for secondary prevention in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. A total of 19,185 patients with stable atherosclerotic vascular disease (6302 in the MI subgroup and 8446 with previous MI) were randomly assigned to receive either clopidogrel 75 mg daily or aspirin 325 mg daily, with follow-up periods ranging from 1 to 3 years. At a mean of 1.91 years of follow-up, clopidogrel was superior to aspirin for reducing the composite of cardiovascular death, MI, or stroke (relative risk reduction, 8.7%; P = .043), with a modest absolute risk reduction (ARR) of 0.51%. When subgroups were evaluated on the basis of their symptomatic vascular bed (peripheral arterial disease, previous MI, cerebrovascular disease), the benefit appeared to be most robust in patients with peripheral arterial disease, although statistical heterogeneity between groups was lacking. When studied in patients with ACS, the addition of clopidogrel to aspirin reduced the rate of recurrence of major cardiovascular events in the first 30 days and through 12 months by 20%, depending on the endpoint and whether the population had non–ST-elevation (NSTE) or ST-elevation ACS (see Chapter 19 ). Although the treatment duration was for 3 to 12 months after NSTE-ACS, the survival curves demonstrated continued separation over the course of follow-up, suggesting continued benefit over time. Subsequent trials evaluating more potent, less variable P2Y 12 inhibitors against clopidogrel in patients presenting with ACS have published consistent landmark analyses showing benefits of the more potent regimens even when landmarked at later timepoints.
CHARISMA Trial
The benefits of adding a P2Y 12 inhibitor to aspirin in ACS raised the hypothesis that such a strategy also may be beneficial in stable patients with risk factors for either long-term secondary prevention or primary prevention. This hypothesis was tested in the Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial. A total of 15,603 patients were randomly assigned to receive clopidogrel 75 mg daily or matching placebo, with all receiving aspirin (75 to 162 mg daily), over a median period of 28 months. Overall, there was no significant benefit of adding clopidogrel to aspirin for reducing cardiovascular death, MI, or stroke (risk ratio [RR], 0.93; P = .22) ( Figure 35-7 ), but there was more bleeding (for severe bleeding: absolute risk increase [ARI], 0.5%; P = .09; for moderate bleeding: ARI, 0.8%; P < .001). A marginally significant interaction ( P -interaction = .045) for efficacy was observed when the population subjects were subclassified by whether or not symptomatic disease was present initially. Subjects with symptomatic disease (secondary prevention) appeared to benefit (HR, 0.88; 95% CI, 0.77 to 0.998; P = .046), whereas among those who were asymptomatic (primary prevention), a trend toward harm was evident (20% increase in rate of primary endpoint; P = .20). A subsequent post-hoc analysis of the data explored the efficacy and safety of aspirin and clopidogrel for secondary prevention in more detail. In the group of 9478 patients with previous MI, peripheral arterial disease, or ischemic stroke, a significant reduction in cardiovascular death, MI, or stroke (HR, 0.83; 95% CI, 0.72 to 0.96; P = .01) was observed, with the greatest magnitude of benefit seen in those with previous MI (HR, 0.77; 95% CI, 0.61 to 0.98; P = .031) ( Figure 35-e1 ). Although exploratory in nature, these data support the hypothesis that a combination of aspirin and P2Y 12 inhibition would be effective for long-term secondary prevention in patients with previous MI.
DAPT Trial
The Dual Antiplatelet Therapy after Drug Eluting (DAPT) trial was designed to evaluate whether prolonged DAPT would reduce thrombotic risk after coronary stenting. Patients undergoing coronary stenting were treated with DAPT (with either clopidogrel or prasugrel) for 12 months, and then those who were tolerating therapy and had not experienced an event were subsequently randomly selected to have their P2Y 12 inhibitor withdrawn or to continue for an additional 18 months. Because the primary criterion for enrollment was a coronary procedure, the population was heterogeneous, including patients undergoing procedures for ACS (42%) and those undergoing procedures for stable angina (38%) or other reasons (20%). Clopidogrel was the P2Y 12 inhibitor used in 65%, and prasugrel was used in 35%. Overall, the trial showed a significant reduction in both co-primary endpoints of stent thrombosis (0.4% versus 1.4%; HR, 0.29; 95% CI, 0.17 to 0.48; P < .001) and the composite of death, MI, or stroke (4.3% versus 5.9%; HR, 0.71; 95% CI, 0.59 to 0.85; P < .001) ( Figure 35-8 ). Bleeding was increased with DAPT (GUSTO-defined moderate or severe bleeding rate, 2.5% versus 1.6%; P = .001).
A subsequent subgroup analysis evaluated the efficacy and safety of continued DAPT versus withdrawal in the 3576 subjects with a history of a previous MI (secondary prevention) relative to those without a previous MI. Patients with previous MI were more likely to receive prasugrel (34% versus 31%). The study investigators observed a significantly greater magnitude of benefit of DAPT ( P -interaction, .03) in the patients with MI (3.9% versus 6.8%; P < .001) than in the no-MI patients (4.4% versus 5.3%; P = .08). An increase in GUSTO-defined moderate or severe bleeding rates with DAPT was similar in both populations, with an ARI of 1.1% in patients with MI ( P = .005) and 0.9% in those without MI ( P = .007). These subgroup findings are consistent in concept with those from CHARISMA, suggesting that patients with a previous MI have the most to gain with prolonged therapy with a P2Y 12 inhibitor and that there may be less benefit or even harm in patients with only risk factors or stable coronary disease and no history of MI.
PEGASUS-TIMI 54 Trial
The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial was designed to address the hypothesis that prolonged dual-antiplatelet therapy is beneficial in patients with previous MI regardless of previous coronary stenting. The study subjects were selected with the primary criterion of a history of a spontaneous MI 1 to 3 years before enrollment. In addition, patients needed to have at least one high-risk feature for ischemic complications (age 65 years or older, diabetes mellitus requiring medication, a second previous MI, multivessel coronary disease, or non–end-stage renal dysfunction) and be without specific risk factors for bleeding (history of ischemic stroke or intracranial bleeding, central nervous system tumor, or an intracranial vascular abnormality; gastrointestinal bleeding within the previous 6 months; or major surgery within the previous 30 days). Patients were randomly assigned to receive one of two doses of the non-thienopyridine P2Y 12 antagonist ticagrelor or a matching placebo, with all patients receiving low-dose aspirin. The two doses studied were a 90-mg dose, which was shown to be superior to clopidogrel in the ACS setting, and a 60-mg dose, which had not previously been studied in humans and was anticipated to provide a better tolerability profile compared with the 90-mg dose. At a median of 33 months, both doses of ticagrelor significantly reduced the composite of cardiovascular death, MI, or stroke (60-mg dose: HR, 0.84; 95% CI, 0.74 to 0.95; P = .004; 90-mg dose: HR, 0.85; 95% CI, 0.75 to 0.96; P = .008) ( Figure 35-9 ). The efficacy of ticagrelor was consistent for all components of the primary endpoint including stroke and cardiovascular death as well as MI. Both doses significantly increased TIMI major bleeding (60-mg dose: HR, 2.32; P < .001; 90-mg dose: HR, 2.69; P < .001), with no significant excess of fatal or intracranial bleeds. Based on the data from this trial, for every 10,000 patients who began treatment, 40 primary endpoint events would be prevented with the 90-mg dose and 42 with the 60-mg dose. This efficacy would come at a cost of 41 TIMI major bleeds with the 90-mg dose and 31 with the 60-mg dose.
