Introduction
Despite improvements in secondary preventive care and risk factor modification, there is a persistently elevated risk of recurrent cardiovascular (CV) events after experiencing a myocardial infarction (MI), with more than 10% of patients developing recurrent MI, refractory angina, hospitalization, or death within the subsequent 6 months. Therapies to minimize atherothrombotic complications in patients with MI have evolved over the past several decades. The current standard of care for antithrombotic therapy during the initial presentation of acute coronary syndrome (ACS) focuses on dual antiplatelet therapy (DAPT) in addition to parenteral anticoagulation (see Chapter 18 and Chapter 19 ). However, once ACS is stabilized, long-term secondary prevention of recurrent thromboembolic events focuses on antiplatelet therapy only. Despite the development of more potent and effective antiplatelet medications, patients with stabilized ACS continue to experience recurrent adverse CV events after their index event.
During the acute management of ACS, parenteral anticoagulants are administered to inhibit the generation of thrombin, the levels of which remain elevated long after ACS. Because of the persistently elevated risk of recurrent adverse CV events after ACS, oral anticoagulants have been studied for the long-term care of patients following ACS. Initial studies that investigated warfarin in this setting showed promising results with regard to reducing ischemic events; however, because of an associated increased bleeding risk, in addition to the inherent difficulties with the prescription and administration of warfarin, routine adoption of vitamin K antagonists (VKAs) for secondary prevention into standard clinical practice did not occur.
With the advent of nonvitamin K oral anticoagulants (NOACs), in addition to the emerging pathobiological evidence that emphasizes the role of thrombin in thrombus formation and thromboembolic events after ACS, there has been renewed interest in the use of long-term anticoagulation in patients who are stable after ACS. The results have been mixed, with the most promising data coming from the addition of low-dose oral direct factor Xa inhibitors to standard therapy for stabilized ACS. Importantly, using optimal dosing strategies and applying therapies to the appropriate populations provides the ability to maximize benefit and minimize risk.
Role of Thrombin in Acute Coronary Syndrome
In ACS, disruption of an atherosclerotic plaque exposes the underlying thrombogenic contents to circulating blood (see Chapter 3 ). Platelets adhere to exposed collagen and von Willebrand factor, resulting in platelet activation and release of thromboxane A 2 and adenosine diphosphate, which triggers further platelet activation. Plaque rupture also prompts the subendothelial release of tissue factor, which activates coagulation factors. Coagulation factors assemble on activated platelets, which results in the formation of factor Xa and leads to the conversion of prothromin into thrombin (factor IIa). Thrombin triggers further coagulation and platelet activation, and prevents the degradation of fibrin (see Chapter 18 ).
Thrombin induces further platelet activation by binding to transmembrane proteins with extracellular thrombin-binding sites known as protease-activated receptors (PARs). There are two human PARs: PAR-1, which is the most important source of platelet activation, and PAR-4. Thrombin binds to the extracellular PAR domain, cleaves the receptor, and triggers a cellular process that ultimately induces platelet activation. Thrombin is also responsible for triggering its own generation and expansion, with approximately 95% of thrombin generation occurring after initial thrombus formation.
The formation of a thrombus after ACS occurs via two pathways: one driven by platelets and one driven by thrombin ( Figure 21-1 ). High-shear conditions, such as those in the coronary arteries, tend to form platelet-rich thrombi. However, because thrombin generation leads to further thrombin production and platelet aggregation, a reduction in blood flow creates a setting for a more thrombin- and fibrin-rich thrombus.
Importantly, although thrombin generation is enhanced immediately after the onset of ACS, it does not return to normal after clinical stabilization. Biomarkers of thrombin generation, such as D-dimer, prothrombin fragments, and thrombin–antithrombin complexes, remain elevated for at least 6 months to 1 year after ACS. Nonetheless, the contribution of thrombin to thrombus formation is not routinely targeted by medical therapy once ACS is stabilized. During this period, patients continue to experience an appreciable risk of adverse CV events, which may be partially caused by the elevated thrombin levels that continue to enhance thrombus formation.
Current Therapy and Outcomes Following Acute Coronary Syndrome
The current standard of care for antithrombotic therapy during the acute management of MI includes DAPT, which consists of aspirin in addition to a P2Y 12 inhibitor and parenteral anticoagulation, usually with either intravenous unfractionated heparin or low-molecular-weight heparin (see Chapter 13 ). These therapies target multiple components of the coagulation cascade to maximally inhibit thrombus growth and minimize atherothrombotic complications ( Figure 21-2 ). After the acute period, therapy for stabilized ACS shifts away from the early emphasis on reducing elevated thrombin levels to focus solely on targeting the contribution of platelets to thrombus formation.
Despite medical therapy for stabilized ACS with DAPT, mortality risk persists for at least 6 months after admission for MI ( Figure 21-3 ). Furthermore, the risks of hospital readmissions, recurrent adverse CV events, and mortality persist for up to 5 years after MI, with greater morbidity and mortality in high-risk patients. The persistently elevated risk of recurrent ischemic events after MI has prompted research into alternative and more potent antithrombotic strategies. One approach has been the investigation of prolonged administration of more potent antiplatelet therapies (see Chapter 35 ). Clopidogrel, prasugrel, and ticagrelor are each platelet P2Y 12 inhibitors; the latter two achieve higher degrees of platelet inhibition than clopidogrel and have an associated reduction in recurrent major CV events. Moreover, the addition of the PAR-1 antagonist vorapaxar has also been shown to improve efficacy for secondary prevention. Each of these alternatives for enhanced antiplatelet therapy comes with a cost of an increased rate of moderate or severe bleeding.
These studies all support the concept that platelets contribute to the pathogenesis of thromboembolic events in patients stabilized after an MI and that more potent platelet inhibition reduces the recurrence of adverse CV events. However, their results also show a persistent appreciable risk of major CV events even in patients treated with potent antiplatelet strategies. For these reasons, investigators have studied the use of long-term anticoagulation for the secondary prevention of adverse CV events in patients stabilized after an MI.
Vitamin K Antagonist Therapy after Myocardial Infarction
The use of oral anticoagulants to treat MI dates back to the 1940s, when oral VKAs were found to reduce mortality in this setting. Subsequently, numerous studies in the 1990s and early 2000s investigated the usefulness of warfarin after MI. In the WARIS II trial, patients with recent MI were randomized to either aspirin 160 mg, warfarin with an international normalized ratio (INR) target of 2.8 to 4.2, or aspirin 75 mg in combination with warfarin with an INR target of 2.0 to 2.5. Warfarin (relative risk [RR], 0.81; 95% confidence interval [CI], 0.69 to 0.95; P = .03) and warfarin plus aspirin (RR, 0.71; 95% CI, 0.60 to 0.83; P = 0.001) significantly reduced death, nonfatal MI, or thromboembolic stroke compared with aspirin 160 mg, at the cost of significant increases in major nonfatal bleeding ( P <.001). There were no significant differences in efficacy between the two anticoagulation arms. In the ASPECT-2 trial, patients were randomized to three similar arms and had similar results to that in the WARIS II study. High-intensity anticoagulation (hazard ratio [HR], 0.55; 95% CI, 0.30 to 1.00; P = .0479) and moderate-intensity anticoagulation, in addition to aspirin (HR, 0.50; 95% CI, 0.27 to 0.92; P = .03), significantly reduced death, MI, or stroke compared with aspirin alone. There were no significant differences in efficacy between the two anticoagulation arms.
A meta-analysis of 10 trials of warfarin after ACS was conducted, including the WARIS II and ASPECT-2 trials ( Figure 21-4 ). The results, which were driven strongly by the results in the WARIS II and ASPECT-2 trials, demonstrated that warfarin plus aspirin reduced the annual rate of MI (2.2% vs. 4.1%; RR, 0.56; 95% CI, 0.46 to 0.69), ischemic stroke (0.4% vs. 0.8%; RR, 0.46; 95% CI, 0.27 to 0.77), and revascularization (11.5% vs. 13.5%; RR, 0.80; 95% CI, 0.67 to 0.95) compared with aspirin alone, at the cost of an increase in major bleeding (1.5% vs. 0.6%; RR, 2.5; 95% CI, 1.7 to 3.7). There was no observed differences in mortality between aspirin plus warfarin versus aspirin alone.
Despite warfarin’s promising ability to reduce recurrent adverse CV events in patients with stabilized ACS, its use in this setting has ultimately not been favored. The reasons behind the lack of adoption of warfarin for routine secondary prevention after MI are multifactorial; they are driven mostly by concerns with regard to bleeding, the practical challenges of administering warfarin, and the advent of more potent antiplatelet strategies.
New Oral Anticoagulant Therapy in Stabilized Acute Coronary Syndrome
Warfarin has multiple limitations, including drug and food interactions, variability in dosing based on genetics, delayed onset and offset, and the need for frequent monitoring and dose adjustments. NOACs that avoid many of these issues have been studied in several disease states, such as atrial fibrillation (AF) and venous thromboembolism (VTE). Because of the previously promising results of warfarin in MI, several studies were conducted to determine whether NOACs might have a role after ACS ( Table 21-1 ).
| Trial | Study Drug and Doses | Duration | Mechanism of Action | Primary Endpoint | Secondary Endpoint |
|---|---|---|---|---|---|
| RE-DEEM (2011): 1861 patients (phase II) | Dabigatran 50 mg bid; 75 mg bid; 110 mg bid; 150 mg bid vs. placebo | 6 mos | Oral direct thrombin inhibitor | Major and nonmajor clinically relevant bleeding; vs. placebo: dabigatran 50 mg: HR, 1.77; 95% CI, 0.70–4.50 dabigatran 75 mg: HR, 2.17; 95% CI, 0.88–5.31 dabigatran 110 mg: HR, 3.92; 95% CI, 1.72–8.95 Dabigatran 150 mg: HR, 4.27; 95% CI, 1.86–9.81 | Reduction in D-dimer concentration; dabigatran analysis: 45% reduction compared with placebo ( P <.001) |
| RUBY-1 (2011): 1279 patients (phase II) | Darexaban 5 mg bid; 10 mg qd; 15 mg bid; 30 mg qd; 30 mg bid; 60 mg qd vs. placebo | 26 wks | Oral direct factor Xa inhibitor | Major and nonmajor clinically relevant bleeding; vs. placebo: darexaban: HR, 2.28; 95% CI, 1.13–4.60; P = .022 | All-cause mortality, nonfatal MI, nonfatal stroke, and severe recurrent ischemia: no significant difference for darexaban vs. placebo |
| AXIOM-ACS (2011): 2753 patients (phase II) | TAK-442 Stage 1: 10 mg bid; 20 mg bid; 40 mg qd Stage 2: 40 mg bid; 80 mg qd; 80 mg bid Stage 3: 160 mg qd; 120 mg bid vs placebo | 24 wks | Oral direct factor Xa inhibitor | Incidence of TIMI major bleeding; no significant difference for TAK-442 vs. placebo | No efficacy outcomes |
| APPRAISE (2009): 1715 patients (phase II) | Apixaban 2.5 mg bid; 10 mg od; 10 mg bid; 20 mg qd | 6 mos | Oral direct factor Xa inhibitor | Major and nonmajor clinically relevant bleeding; vs. placebo: apixaban 2.5 mg bid: HR, 1.78; 95% CI, 0.91–3.48; P = .09 apixaban 10 mg qd: HR, 2.45; 95% CI, 1.31–4.61; P = .005 apixaban 10 mg bid and 20 mg qd discontinued because of excess total bleeding | CV death, MI, or ischemic stroke; vs. placebo: apixaban: HR, 0.95; 95% CI, 0.80–1.11; P = .51 |
| APPRAISE-2 (2011): 7392 patients (phase III) | Apixaban 5 mg bid vs. placebo | Maximum follow-up of 241 days (early termination) | Oral direct factor Xa inhibitor | CV death, MI or ischemic stroke; vs. placebo: HR, 0.95; 95% CI, 0.80–1.11; P = .51 | Major bleeding: HR, 2.59; 95% CI, 1.50–4.46; P = .001 |
| ATLAS ACS-TIMI 46 (2009): 3491 patients (phase II) | Rivaroxaban Range of od and bid doses (5–20 mg) vs. placebo | 6 mos | Oral direct factor Xa inhibitor | Major bleeding; significantly increased with rivaroxaban in a dose-dependent manner | Death, MI, stroke, or severe recurrent ischemia; vs. placebo: HR, 0.79; 95% CI, 0.60–1.05; P = .10 |
| ATLAS ACS 2-TIMI 51 (2012): 15,526 patients (phase III) | Rivaroxaban 2.5 mg bid; 5 mg bid vs. placebo | Maximum follow-up of 31 mos (mean, 13) | Oral direct factor Xa inhibitor | CV death, MI, or stroke; vs. placebo: HR, 0.84; 95% CI, 0.74–0.96; P = .008 | Non-CABG major bleeding; incidence compared with placebo: rivaroxaban (2.1% vs 0.6%; P <.001) |
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