Acute coronary syndromes (ACSs), which include ST-segment elevation myocardial infarction, non–ST-segment elevation myocardial infarction, and unstable angina, present a considerable burden to the health care system. Furthermore, many patients with a first ACS event will develop another event within 1 year. To prevent this, higher-risk patients with ACS are revascularized when possible after presentation and then prescribed ongoing treatments to prevent recurrent vascular events. These include agents that prevent platelet aggregation and subsequent coronary thrombosis. However, some patients will develop a recurrent event despite treatment with these drugs, prompting a search for additional strategies to augment the effectiveness of current therapies. One such approach is add-on therapy with oral anticoagulant drugs. These agents may act synergistically with antiplatelet agents in preventing thrombosis. In conclusion, new oral anticoagulants might represent an attractive therapeutic strategy if they do not result in unacceptable bleeding.
Scope of Problem
In 2007, there were >1.1 million hospitalizations for acute coronary syndromes (ACSs) in the United States: 731,000 for myocardial infarction (MI), 431,000 for unstable angina pectoris, and 10,000 for MI and unstable angina pectoris. Every year an estimated 785,000 Americans will have an ACS event and approximately 470,000 will have a recurrent event. Improvements in treatment have resulted in an increasing number of patients surviving a first event; however, a substantial percentage of this growing population will have a recurrent event or die within 1 year after a first MI. Guidelines recommend the use of several therapies that are commenced in the hospital and continued after discharge. These include 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, β blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking drugs for higher-risk patients. In addition, dual antiplatelet therapy with acetylsalicylic acid plus a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) is recommended. This additional therapy reflects the proved benefit of a multitargeted antiplatelet strategy over aspirin alone in preventing recurrent events.
Pathophysiology of ACS
The event triggering an acute coronary event is plaque disruption, whether rupture or erosion, which promotes intracoronary thrombus formation in 2 ways. First, exposure of the circulating blood to collagen in the plaque’s extracellular matrix can precipitate platelet adhesion and activation. Second, tissue factor produced by macrophages and exposed smooth muscle cells in the ruptured plaque activates coagulation, resulting in the production of thrombin and the ultimate generation of fibrin.
The process of coagulation follows a “cascading” pathway, whereby circulating coagulation proteins sequentially activate those below them in the sequence. Activated factor X is the immediate proximate step required for thrombin production. There is a close and interdependent relation between specific cells and coagulation, and based on the nature and characteristics of the cell surface, the process is considered to occur in 3 overlapping stages ( Figure 1 ) : (1) initiation, which occurs on a tissue factor-bearing cell (such as is exposed after plaque disruption in an ACS) that activates factor VII and then factor Xa, with the generation of initially small amounts of thrombin; (2) amplification (or activation), in which the focus of the process shifts from the tissue factor-bearing cell to platelets, which accumulate activated cofactors on their surfaces to prepare the substrate for large-scale thrombin activation; and (3) propagation ( Figure 1 ), in which these cofactors combine with activated coagulation proteins to generate large amounts of thrombin on the platelet surface.
Initial platelet activation is enhanced by cleavage of the platelet receptor protease-activated receptor 1 (also called the thrombin receptor) by small amounts of thrombin, which is generated during the early phase of coagulation as a response to exposed tissue factor. Thrombin contributes to later phases of coagulation in multiple ways: it converts circulating fibrinogen to fibrin, which stabilizes the structure of the thrombus, and it continues to activate platelets.
The codependence of platelet activation and coagulation explains why combined antiplatelet and anticoagulant therapies have been proved effective in the acute phase of this condition.
Pathophysiology of ACS
The event triggering an acute coronary event is plaque disruption, whether rupture or erosion, which promotes intracoronary thrombus formation in 2 ways. First, exposure of the circulating blood to collagen in the plaque’s extracellular matrix can precipitate platelet adhesion and activation. Second, tissue factor produced by macrophages and exposed smooth muscle cells in the ruptured plaque activates coagulation, resulting in the production of thrombin and the ultimate generation of fibrin.
The process of coagulation follows a “cascading” pathway, whereby circulating coagulation proteins sequentially activate those below them in the sequence. Activated factor X is the immediate proximate step required for thrombin production. There is a close and interdependent relation between specific cells and coagulation, and based on the nature and characteristics of the cell surface, the process is considered to occur in 3 overlapping stages ( Figure 1 ) : (1) initiation, which occurs on a tissue factor-bearing cell (such as is exposed after plaque disruption in an ACS) that activates factor VII and then factor Xa, with the generation of initially small amounts of thrombin; (2) amplification (or activation), in which the focus of the process shifts from the tissue factor-bearing cell to platelets, which accumulate activated cofactors on their surfaces to prepare the substrate for large-scale thrombin activation; and (3) propagation ( Figure 1 ), in which these cofactors combine with activated coagulation proteins to generate large amounts of thrombin on the platelet surface.
Initial platelet activation is enhanced by cleavage of the platelet receptor protease-activated receptor 1 (also called the thrombin receptor) by small amounts of thrombin, which is generated during the early phase of coagulation as a response to exposed tissue factor. Thrombin contributes to later phases of coagulation in multiple ways: it converts circulating fibrinogen to fibrin, which stabilizes the structure of the thrombus, and it continues to activate platelets.
The codependence of platelet activation and coagulation explains why combined antiplatelet and anticoagulant therapies have been proved effective in the acute phase of this condition.
Progress in Oral Antiplatelet Strategies
The oral availability and ease of administration of antiplatelet agents have allowed these drugs to be investigated after the acute phase of the hospital admission, where dual therapy with acetylsalicylic acid and clopidogrel has been shown to confer continued protection against vascular events compared to aspirin alone. The more potent adenosine diphosphate receptor antagonists prasugrel and ticagrelor have greater efficacy than clopidogrel when used with acetylsalicylic acid. However, this comes at a cost of an increase in noncoronary bypass-related major bleeding (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.03 to 1.68 for prasugrel plus aspirin; HR 1.25, 95% CI 1.03 to 1.53 for ticagrelor plus aspirin) compared to clopidogrel plus acetylsalicylic acid. Increasing the dose of clopidogrel during hospitalization does not decrease ischemic end points in an ACS population, but it does result in increased major bleeding events, whereas increasing the dose of aspirin has no net effect.
Importantly, even using the newer agents, the residual event rate in ACS remains at about 10%, suggesting that a therapeutic plateau has been reached with current antiplatelet strategies.
Oral Anticoagulants for ACS
Recurrent ischemic events tend to cluster after cessation of unfractionated or low-molecular-weight heparin in patients with ACS. In addition, high levels of prothrombin fragment persist for up to 6 months after an acute coronary event, suggesting that anticoagulant drugs after discharge may confer additional benefit beyond that provided during the acute phase. Warfarin with aspirin was compared to aspirin alone after acute coronary events in several randomized trials. In a comprehensive meta-analysis of 14 randomized controlled trials including >25,300 patients, dose-adjusted warfarin plus acetylsalicylic acid significantly lowered the incidence of recurrent MI and stroke compared to acetylsalicylic acid alone. This benefit was restricted to studies where the international normalized ratio target was 2.0 to 3.0 (odds ratio 0.73, 95% CI 0.63 to 0.84) and was not associated with a decrease in mortality.
Although these trials were conducted before the widespread use of dual antiplatelet therapy, risk of major bleeding increased >2 times in patients receiving combination therapy (odds ratio 2.32, 95% CI 1.63 to 3.29). Despite this, there was evidence of a net clinical benefit because the number needed to treat to avoid an adverse event (33) was far fewer than the number needed to harm by causing 1 major bleeding event (100).
However, challenges with warfarin have been a major obstacle to the use of the drug in this setting. Warfarin requires routine coagulation monitoring and frequent dose adjustments to compensate for the many food–drug and drug–drug interactions that interfere with its effects. This has a major impact on compliance and therapeutic efficacy. In a large international randomized trial of oral anticoagulant therapy in patients with unstable angina, countries were ranked according to percentage of patients receiving study medication at follow-up. In >1/2 of enrolling countries (8 of 14), <70% of patients were receiving study medication at 35 days. In these countries, there was no decrease in outcomes in patients receiving warfarin (risk ratio 1.17, 95% CI 0.86 to 1.60) and no difference in major bleeding events (risk ratio 1.58, 95% CI 0.84 to 3.00). In contrast, in good-complier countries, there was a decrease in ischemic events (risk ratio 0.68, 95% CI 0.48 to 0.95) accompanied by an excess in major bleeding events (risk ratio 2.71, 95% CI 1.26 to 5.83).
New Oral Anticoagulants
Some novel oral anticoagulants with properties that overcome the practical limitations of warfarin have recently become available. These agents all have a more stable pharmacokinetic profile, have fewer food–drug and drug–drug interactions, and can be administered in a standard dose without the need for routine monitoring. In patients with ACS, these agents provide an opportunity to further decrease ischemic events after discharge; the challenge remaining is to do so in the current environment—where dual antiplatelet therapy is the standard of care—without an unacceptable increase in bleeding complications.
Direct thrombin inhibitors
These agents inactivate soluble and fibrin-bound thrombin and limit thrombogenesis and thrombus growth.
Ximelagatran: This drug was the first in a new class of oral direct thrombin inhibitors developed for the prevention and treatment of thromboembolic events. In the Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial, 1,883 patients within 14 days of an MI and with ≥1 risk factor for a recurrent event (age >65 years, diabetes mellitus, previous MI, known multivessel coronary disease, previous ischemic stroke, peripheral arterial disease, symptomatic heart failure, or a history of hypertension) were randomized to escalating doses of drug or placebo. All patients received aspirin 160 mg/day. None had undergone recent percutaneous intervention and none received dual antiplatelet therapy. Ximelagatran significantly decreased the primary end point of all-cause death, nonfatal MI, and severe recurrent ischemia (HR 0.76, 95% CI 0.59 to 0.98) with nonsignificant excess bleeding (HR 1.97, 95% CI 0.80 to 4.84). There was no evidence of a dose response in this phase 2 study; however, this did provide proof that an orally active anticoagulant other than warfarin may favorably affect outcomes when given to patients in the long term after MI. The drug has not undergone further development because of an unacceptable incidence of liver toxicity.
Dabigatran: Dabigatran, the second direct thrombin inhibitor to come to the market, shows more therapeutic promise because it is not associated with the hepatic toxicity discovered with ximelagatran during clinical trials. In RE-DEEM (a phase 2 trial), 1,861 patients with recent MI and ≥1 additional risk factor for a recurrent event were randomized to 1 of 4 escalating doses of dabigatran or placebo. Patients were enrolled within 14 days of their event and, in contrast to the ESTEEM trial, most patients (99.2%) were receiving dual antiplatelet therapy at enrollment. The primary end point was a composite of major or clinically relevant minor bleeding according to the International Society of Thrombosis and Haemostasis (ISTH) definition during the 6-month treatment period.
There was a dose-dependent increase in bleeding in patients receiving dabigatran. There was no decrease in death, stroke, or MI in the treatment group, although the study was not powered for this end point. There was, however, a greater early decrease in the D-dimer concentration in patients receiving dabigatran. This was associated with a decrease in the composite ischemic end point. There was no relation between the dose of dabigatran and the decrease in D-dimer. Interestingly, this lack of relation between dose and prevention of ischemic events was also noted with ximelagatran in ESTEEM, suggesting that, for the 2 drugs, a therapeutic plateau may have been reached with the lowest evaluated dose.
In the initial report of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran at a higher dose (150 mg 2 times/day) was associated with a small increase in MI compared to warfarin in a population with atrial fibrillation. Although this difference was no longer apparent with more rigorous analysis of the database, a subsequent meta-analysis of all studies with dabigatran has lent some support to the initial RE-LY analysis. However, absolute risk differences for MI in these non-ACS populations are very small (0.14% to 0.17%) and the clinical implications of these findings can be resolved only with an adequately powered trial in an ACS cohort.
Factor Xa inhibitors
These agents directly inhibit the enzyme directly responsible for thrombin formation. Factor Xa inhibitors that have recently been evaluated in patients with ACS include darexaban, apixaban, and rivaroxaban.
Darexaban: This agent was evaluated in the RUBY trial in 1,279 patients with high-risk ACS. In this dose-escalation phase 2 study, all patients received dual antiplatelet therapy, and a dose-dependent increase in bleeding events was seen in the 6 active treatment arms (pooled HR 2.275, 95% CI 1.13 to 4.60). There was no effect overall on ischemic events, although a numeric decrease was noted in patients receiving the lowest dose. However, these data were not considered promising enough to justify further development of darexaban in patients with ACS.
Apixaban: In the phase 2 trial Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE), 1,715 patients within 7 days of an ACS and ≥1 additional risk factor for recurrent events were randomized to 1 of 4 doses of apixaban or placebo. The 2 higher-dose arms were discontinued because of excess bleeding. The 2 lower doses (2.5 mg 2 times/day and 10 mg 1 time/day), although resulting in a dose-dependent increase in bleeding, were associated with a numeric decrease in ischemic events, and the 10-mg dose was selected as the platform for the phase 3 trial.
APPRAISE-2 was conducted in 858 sites in 39 countries. High-risk patients with an ACS within 7 days were randomized to 5 mg 2 times/day of apixaban or placebo. Most patients (81%) were on dual antiplatelet therapy. The dose of apixaban was decreased to 2.5 mg 2 times/day for patients with renal impairment. In contrast to the studies discussed eariler, where high risk was defined by 1 additional clinical risk factor, patients in APPRAISE-2 were required to have ≥2 of the following additional risk factors: ≥65 years of age, diabetes mellitus, MI within previous 5 years, cerebrovascular disease, peripheral vascular disease, clinical heart failure, or left ventricular ejection fraction <40% in association with the index event, impaired renal function, and no revascularization after the index event.
Although the trial was planned to recruit 10,800 patients, the data safety monitoring board recommended the trial be stopped after enrolling 7,392 patients because of an excess in clinically important bleeding events without any decrease in ischemic events. The primary efficacy end point of cardiovascular death, MI, or ischemic stroke occurred in 7.5% of patients assigned apixaban and in 7.9% of patients randomized to placebo (HR 0.95, 95% CI 0.80 to 1.11). The primary safety end point of Thrombolysis In Myocardial Infarction (TIMI) major bleeding was observed in 1.3% of patients randomized to apixaban and in 0.5% of patients assigned placebo (HR 2.59, 95% CI 1.50 to 4.46). Incidence of ISTH-defined major or clinically important minor bleeding was similarly increased in apixaban-assigned patients (3.2% vs 1.2%, HR 2.64, 95% CI 1.87 to 3.72), and most of these bleeding events were major (2.7% vs 1.1%, HR 2.48, 95% CI 1.72 to 3.58).
As noted earlier, the APPRAISE-2 trial population was enriched with higher-risk patients to increase the likelihood of recurrent events. The difficulty with this approach is that many clinical factors that predict recurrent ischemic events also predict a higher likelihood of bleeding. One sobering message from this trial is that in the highest-risk patients with ACS identified in this way, excess bleeding overwhelms any observed decrease in ischemic events.
Rivaroxaban: Rivaroxaban is the most promising of the new oral anticoagulants for the ACS indication. In the phase 2 study Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 46 trial (ATLAS ACS-TIMI-46), 3,491 high-risk patients with ACS were randomized to escalating doses of rivaroxaban or placebo within 7 days of their ACS event. Randomization was stratified based on the investigators’ decision to use aspirin only or aspirin plus a thienopyridine (almost universally clopidogrel). Risk of clinically significant bleeding with rivaroxaban increased in a dose-dependent manner; however, there was an overall decrease in the secondary ischemic end point of death, MI, or stroke compared to placebo (3.9% vs 5.5%, HR 0.69, 95% CI 0.50 to 0.96).
On the strength of this, the ATLAS ACS-2 TIMI-51 (phase 3) study carried forward low-dose (5 mg 2 times/day) and very low-dose (2.5 mg 2 times/day) strategies from the phase 2 trial. Inclusion in this study required stabilization after an ACS event within the previous 7 days. Most patients (93%) were taking dual antiplatelet therapy (aspirin and clopidogrel) on enrollment. Patients <55 years of age required diabetes or previous MI; otherwise, additional high-risk features were not mandated for enrollment, so these patients were at lower risk than those in the other studies and notably at lower risk than those enrolled in APPRAISE-2. In addition, patients with previous stroke or transient ischemic attack were excluded if they were taking acetylsalicylic acid and a thienopyridine. This further lowered the risk of the cohort.
In total 15,526 patients were enrolled in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome -Thrombolysis in Myocardial Infarction 51 (ATLAS ACS-2 TIMI-51) study at 766 sites in 44 countries and followed for a median of 31 months. The 2 doses of rivaroxaban decreased the primary efficacy end point of death from cardiovascular causes, MI, or stroke compared to placebo (2.5-mg dose 9.1% vs 10.7%, HR 0.84, 95% CI 0.72 to 0.97; 5-mg dose 8.8% vs 10.7%, HR 0.85, 95% CI 0.73 to 0.98). In addition, the 2.5-mg dose (but not the 5-mg dose) decreased the risk of death from any cause (2.9% vs 4.5%, HR 0.68, 95% CI 0.53 to 0.87). The decrease in the ischemic end point was consistent across all subgroups with the exception of the small number of patients with previous stroke or transient ischemic attack receiving aspirin. Bleeding assessed using the ISTH definition was not an end point recorded in this study. However, the primary safety end point, TIMI-defined major bleeding, although not associated with coronary artery bypass grafting, was increased with the 2 doses of rivaroxaban (5 mg 2.4%, 2.5 mg 1.8%, placebo 0.6%, p <0.001 for the 2 doses vs placebo), but fatal bleeding was not increased.
The trials discussed earlier are presented in Table 1 . Mean baseline characteristics of patients with ACS in trials of the new oral anticoagulants are listed in Table 2 .
