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Review ARTICLE

Front. Pharmacol., 24 October 2011 | https://doi.org/10.3389/fphar.2011.00061

Emerging therapies for acute coronary syndromes

  • 1 Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
  • 2 Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA

In the majority of cases acute coronary syndromes (ACS) are caused by activation and aggregation of platelets and subsequent thrombus formation leading to a decrease in coronary artery blood flow. Recent focus on the treatment of ACS has centered on reducing the response of platelets to vascular injury as well as inhibiting fibrin deposition. Novel therapies include more effective P2Y12 receptor blockers thereby reducing inter-individual variability, targeting the platelet thrombin receptor (protease activated receptor 1) as well as directly inhibiting factor Xa or thrombin activity. In this review we discuss the clinical data evaluating the effectiveness of these various new ACS treatment options.

Introduction

Over the past two decades improvements in detection and management have reduced the incidence, the morbidity and the mortality of acute coronary syndromes (ACS).Yet there are more than 1 million events yearly in the United States alone and ACS remains a leading cause of death in patients over 65 years of age (Yeh et al., 2010). The term ACS denotes unstable angina, non-ST-elevation myocardial infarction and ST-elevation myocardial infarction and ischemic sudden death with the exact diagnosis dependent on the extent and severity of myocardial damage. Necropsy studies have shown that 65% of sudden deaths resulting from ACS occur from thin-cap fibroatheromas; lesions characterized as possessing a thin fibrous cap (<65 μm) overlying a necrotic core. The remaining events are precipitated by superficial erosion of the fibrous cap (Virmani et al., 2000). These processes lead to platelet activation and aggregation, the formation of fibrin rich thrombi, and the partial or total occlusion of the coronary artery resulting in an ACS. With plaque rupture or erosion there is release of tissue factor and exposure of subendothelial collagen and von Willebrand factor (vWF). Circulating platelets adhere to the exposed collagen and vWF and undergo cytoskeletal rearrangement, generation of cyclooxygenase I (COX-I) dependent thromboxane A2 (TXA2), and release the contents of stored granules including adenosine diphosphate (ADP). Interaction of TXA2 with the TXA2 receptor and ADP with its receptor (P2Y12) initiates positive feedback activating additional platelets in a regional manner and promoting the expression of the GpIIb–IIIa receptors. Coincident activation of factor X via tissue factor results in thrombin generation, which elicits additional platelet degranulation and TXA2 release (Chackalamannil and Xia, 2006) and catalyzing the formation of fibrin, which serves as the cross-link between GpIIb–IIIa receptors on neighboring platelets (Figure 1).

FIGURE 1
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Figure 1. Mechanism of acute coronary syndromes and targets of anti-platelet and anti-thrombotic agents.

Contemporary medical therapies are designed to promote plaque stability, reduce platelet activation and aggregation, prevent thrombus formation, and minimize myocardial oxygen demand. New pharmacotherapies for ACS reflect efforts to improve efficacy and minimize complications of anti-platelet and anti-thrombotic therapies by increasing target specificity and reducing inter-individual variation in therapeutic response. In this review we will describe recent advances in pharmacological therapy for ACS with particular attention to platelet aggregation and thrombus formation. Agents targeting glycoprotein IIb/IIIa (Gp IIb/IIIa) receptors will not be discussed.

Aspirin and P2Y12 Inhibitors

Aspirin irreversibly blocks COX-I, inhibiting generation of TXA2 and consequent platelet activation. In an early study assessing the effect of aspirin in ACS, 1266 patients with unstable angina were randomized to 324 mg aspirin or placebo. Use of aspirin resulted in a 51% reduction of either death or MI at 12 weeks (p = 0.0002); without an increase in bleeding with sustained benefit at 1 year follow up (−43%, p = 0.008; Lewis et al., 1983). Subsequent smaller studies corroborated this benefit, and a meta-analysis of 15 randomized trials including 135,000 patients identified a reduction in the combined incidence of MI, stroke, or vascular death in ACS patients treated with aspirin (−30 ± 4%, p < 0.0001). Subsequently, virtually every trial assessing ACS pharmacotherapy has been performed on the background of aspirin therapy (Lewis et al., 1983; ISIS Collaborative Group, 1988; Antiplatelet Trialists’ Collaboration, 1994; Antithrombotic Trialists’ Collaboration, 2002).

The term “aspirin resistance” initially denoted patients who suffered a vascular event while on aspirin therapy, yet specifically refers to the inability of aspirin to sufficiently suppress TXA2 production or platelet aggregation in vitro (Hennekens et al., 2004). The determination of aspirin resistance is complicated by the variable prevalence (6–26%) among studies depending on the laboratory assay employed (Gum et al., 2001; Gasparyan et al., 2008). Small prospective observational studies have identified increases in the risk of MI (OR 2.0, CI 1.2–3.4, p = 0.006), cardiovascular death (OR 3.5, CI 1.7–7.4, p < 0.001), and composite death, MI or CVA (OR 3.12, CI 1.1–8.9, p = 0.03) in patients with high platelet reactivity (HPR) on aspirin therapy (Eikelboom et al., 2002; Gum et al., 2003; Gasparyan et al., 2008). As a result, the concept of dual anti-platelet therapy (DAPT) emerged in order to reduce the rate of vascular events among those with HPR on aspirin therapy, and specifically to reduce the rate of reinfarction during and after percutaneous coronary intervention (PCI).

Clopidogrel is a thienopyridine pro-drug (Table 1; Figure 2) that requires cytochrome 2C19 (CYP2C19) biotransformation to the active metabolite, an irreversible P2Y12 receptor inhibitor. In a large prospective secondary prevention trial (n = 19,185), clopidogrel alone compared to aspirin did not significantly reduce recurrent vascular events (stroke, MI, or vascular death) among those with a history of myocardial infarction (−3.7%, p = 0.66), and was associated with similar rates of bleeding (9.27 vs. 9.28%; CAPRIE Steering Committee, 1996). However, when administered together, clopidogrel and aspirin provide more complete and uniform suppression of platelet activation via dual pathways for the lifespan of the platelet (average of 5–7 days; Moshfegh et al., 2000). The CURE trial randomized 12,562 patients with UA or NSTEMI to aspirin or DAPT with aspirin and clopidogrel. Patients randomized to DAPT had a reduced incidence of composite cardiovascular death, non-fatal MI, or stroke which was evident at 24 h (HR 0.66, CI 0.51–0.86, p < 0.05) and persisted for at least 12 months (HR 0.80, CI 0.72–0.90, p < 0.001). The event rate was driven primarily by a reduction in non-fatal MI. Not unexpectedly, the combination of clopidogrel and aspirin was associated with increased major bleeding rates (HR 1.38, CI 1.12–1.67, p = 0.001), although there was no difference in life threatening bleeding. Among the subgroup managed with a planned invasive strategy, the addition of clopidogrel was also associated with a significant reduction in composite cardiovascular death, non-fatal MI, or urgent target vessel revascularization at 30 days (HR 0.70, CI 0.50–0.97, p = 0.03), with no difference in major bleeding (HR 1.13, CI 0.61–2.1, p = 0.69; Mehta et al., 2001; Yusuf et al., 2001; Wright et al., 2011).

TABLE 1
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Table 1. Pharmacodynamics and pharmacokinetics of P2Y12 inhibitors in ACS.

FIGURE 2
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Figure 2. Structure of P2Y12 inhibitors.

Despite these population level benefits, there is considerable inter-individual variability in response to clopidogrel that at least partially result from heterogeneity in CYP2C19 (Angiolillo et al., 2007). The most common CYP2C19 variant is CYP2C19(2, which has an allelic frequency between 25 and 55% depending on the ethnic population. Individuals with at least one copy of CYP2C19(2 have reduced plasma concentrations of the active clopidogrel metabolite and have reduced in vitro platelet responsiveness to clopidogrel (Kim et al., 2008; Kubica et al., 2011). Moreover, the CYP2C19(2 variant has been associated with significant increases in the risk of vascular events in a number of prospective studies and sub-studies of large ACS trials (reviewed elsewhere; Angiolillo et al., 2007; Kubica et al., 2011).

The concept of “tailored” anti-platelet therapy has emerged to describe an approach of providing stronger platelet inhibition to those patients with a lower risk of bleeding, in the early phases of ACS when ischemic complications are the highest, or in patients with residual HRP on DAPT (Wiviott et al., 2007; Antman et al., 2008). The latter have been identified as a high risk subset, with as much as a 6.7-fold increase in the 30-day risk of composite death, myocardial infarction, or revascularization in those undergoing PCI (Hochholzer et al., 2006). In patients with HPR, clopidogrel dose escalation can incrementally reduce platelet activity and decrease the incidence of HPR from 37 to 14% (p = 0.002; Gladding et al., 2008). However, whether HPR should dictate subsequent therapy is unclear. The GRAVITAS trial randomized patients that had undergone PCI with subsequent identification of HPR to placebo or an additional loading dose of clopidogrel (600 mg) and increased maintenance therapy (150 mg daily). There was no difference in the composite MI, cardiovascular death, or stent thrombosis rate at 6 months (HR 1.01, CI 0.58–1.76), despite a dose-associated reduction in HPR in those randomized to higher-dose clopidogrel (38 vs. 60%, p < 0.001; Price et al., 2011).

In order to overcome the impact of CYP2C19 heterogeneity on platelet responsiveness novel ADP receptor antagonists have been developed. Prasugrel is a thienopyridine structurally similar to clopidogrel (Table 1; Figure 2) but less dependent on CYP2C19 biotransformation, and provides faster and more pronounced platelet inhibition (Table 1; Mega et al., 2009b). In TRITON-TIMI 38, patients (n = 13,608) with ACS and planned PCI were randomized to prasugrel (60 mg loading dose followed by 10 mg daily) or clopidogrel (300 mg loading dose followed by 75 mg daily) for a median of 14.5 months. Prasugrel significantly reduced the incidence of non-fatal MI, (HR 0.76, CI 0.67–0.85, p < 0.001) driving a significant reduction in the composite cardiovascular outcome that also included cardiovascular death and stroke (HR 0.81, CI 0.73–0.90, p < 0.001). This benefit was associated with a significant increase in the risk of bleeding, including that classified as life threatening (HR 1.5, CI 1.1–2.1, p = 0.01) and fatal (HR 4.2, CI 1.6–11.1, p = 0.002; Wiviott et al., 2007).

TRIGGER-PCI, designed to evaluate the efficacy of prasugrel in patients undergoing PCI with HPR on clopidogrel therapy, was stopped after a preliminary analysis revealed low event rates and an unlikely benefit of prasugrel. The ongoing TRILOGY-ACS trial is evaluating prasugrel in patients with ACS undergoing medical management with HPR on clopidogrel therapy (Chin et al., 2010).

Unlike the thienopyridines, ticagrelor does not require conversion to its active metabolite and provides reversible inhibition of P2Y12 – features that theoretically confer less inter-individual variation (Table 1; Figure 2). In preclinical studies ticagrelor was not associated with greater bleeding than clopidogrel and provided more rapid and effective platelet inhibition (Husted et al., 2006; Storey et al., 2007). The PLATO trial compared ticagrelor to clopidogrel in ACS. In PLATO 18,624 patients admitted with ACS were randomized to ticagrelor (180 mg load, 90 mg twice daily) or clopidogrel (300 or 600 mg load, 75 mg daily). Ticagrelor was associated with a significant reduction in the composite endpoint of vascular death, myocardial infarction, or stroke (RR 0.84, CI 0.77–0.92, p = 0.0003) as well as all cause mortality (HR 0.78, CI 0.69–0.89, p < 0.001) with no significant increase in the rate of composite major bleeding (HR 1.04, CI 0.95–1.13, p = 0.43). There was an increase in the intracranial bleeding rate (HR 1.87, CI 0.98–3.58, p = 0.06; Wallentin et al., 2009) although subgroup analyses demonstrated no increased bleeding rates in those identified as “high risk” from TRITON-TIMI 38 including those >75 years old (HR 1.04, CI 0.84–1.29, p = 1.0), <60 kg (HR 0.82, CI 0.60–1.12, p = 0.12) and with known cerebrovascular disease (HR 0.99, CI 0.71–1.37, p = 0.77; Wallentin et al., 2009).

Two novel anti-platelet agents have recently entered clinical trials for ACS: atopaxar and vorapaxar. Both are synthetic antagonists of the platelet thrombin receptor (protease activated receptor 1), and have the potential advantage of impeding platelet aggregation during rapid thrombin formation such as ACS (Morrow et al., 2009). In phase II trials with atopaxar, Japanese patients with ACS (n = 241) were randomized to 50–200 mg daily or placebo in addition to standard therapy (>96% aspirin, >89% clopidogrel) for 12 weeks. The bleeding rate was similar among all doses of atopaxar and placebo (5.0 vs. 6.6%, NS). However, there was an increased frequency of liver enzyme elevation among patients randomized to the 100 (6.2%) and 200 mg (14.8%) doses (Goto et al., 2010b). In phase II trial of vorapaxar, patients (n = 1030) with stable CAD undergoing non-urgent PCI receiving vorapaxar (10–40 mg load, with 0.5–2.5 mg daily) for 60 days had bleeding rates that were comparable to placebo (41% grouped vorapaxar vs. 35% placebo, NS). Moreover, those randomized to vorapaxar had non-significant reductions composite death or myocardial infarction (5% grouped vorapaxar vs. 7% placebo, NS; Becker et al., 2009). Phase III trials including more than 40,000 patients with ACS (TRACER) or a history of vascular disease (TrA2P-TIMI 50) are underway (Morrow et al., 2009; Van De Werf, 2010).

Anti-Thrombotic Agents

Heparins

The heparins complex with anti-thrombin-III (AT-III) and accelerate AT-III mediated inhibition of factor Xa and thrombin (Figure 1). Unfractionated heparin (UFH) represents the cornerstone of anti-thrombotic therapy in ACS, but has a number of limitations. UFH poorly inhibits clot-associated thrombin activity resulting in persistent proaggregant and procoagulant thombin activity at the site of arterial thrombosis. Additional concerns with UFH include heparin-induced thrombocytopenia and thrombosis (HITT), the necessity of frequent monitoring, and platelet-activating effects at therapeutic doses (Xiao and Theroux, 1998).

Low molecular weight heparin (LMWH) provides greater factor Xa inhibition, a reduced incidence of HITT, and more predictable bioavailability and elimination characteristics than UFH. A number of trials comparing enoxaparin to UFH demonstrated comparable or superior efficacy with regard to ischemic ACS endpoints yet small increases in bleeding with enoxaparin, particularly when invasive strategies were employed (Antman et al., 1999, 2006; Goodman et al., 2000; Wallentin et al., 2003; Ferguson et al., 2004). A meta-analysis encompassing 12 randomized trials (n = 49,088) comparing enoxaparin to UFH in ACS concluded that there were significant reductions in the incidence of MI (HR 0.75, CI 0.65–0.86, p < 0.001) at 30 days, with an increase in major bleeding (HR 1.25, CI 1.04–1.50, p = 0.02). The net clinical benefit endpoint (death, MI, or major bleeding), approached significance at 30 days (HR 0.90, CI 0.76–1.00, p = 0.051; Murphy et al., 2007). Other LMWHs have also been evaluated in ACS but are in less frequent clinical use due to inferior clinical results (tinzaparin, dalteparin) or increased bleeding (nadroparin; Klein et al., 1997; Michalis et al., 2003; Katsouras et al., 2005; Table 2). As LMWHs are cleared renally and given that monitoring tests are less reliably available, UFH is preferable in those with advanced chronic kidney disease.

TABLE 2
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Table 2. Low molecular weight heparins in ACS.

Direct Factor Xa Inhibitors

Direct factor Xa inhibitors block the coagulation cascade at an earlier step and are able to inhibit free and clot-associated factor Xa. Currently there is one direct factor Xa inhibitor FDA approved for use in ACS (fondaparinux) with three others in preclinical trials (apixaban, rivaroxaban, otamixaban). Fondaparinux is a synthetic pentasaccharide that mimics the AT-III binding portion of heparin and enhancing the anti-factor Xa activity >300-fold (Table 3; Figure 3). It is administered parenterally, eliminated renally, with little inter-individual variability and no need for routine monitoring.

FIGURE 3
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Figure 3. Structure of factor Xa and direct thrombin inhibitors.

TABLE 3
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Table 3. Pharmacodynamics and pharmacokinetics of anti-coagulants in ACS.

The utility of fondaparinux in ACS was first assessed in the dose finding PENTALYSE trial. STEMI patients (n = 333) undergoing thrombolysis were randomized to 48–72 h of UFH or one of five fondaparinux doses for 5–7 days. Patients receiving fondaparinux had lower 30 day revascularization rates (39 vs. 51%, p = 0.054) with a similar major bleeding risk (7.1 vs. 7.1%; Coussement et al., 2001). In the PENTUA trial patients with UA or NSTEMI were randomized to one of four doses of fondaparinux or enoxaparin for a period for 3–7 days after identification of ACS. Fondaparinux at the lowest dose (2.5 mg daily) provided a non-significant reduction in composite death, MI, or recurrent ischemia at 9 days (27.9 vs. 35.7% in the enoxaparin group, NS) with no major bleeding and comparable rates of minor bleeding (3.9 vs. 4.8%, NS; Simoons et al., 2004).

In the largest ACS trial to date (OASIS-5), over 20,000 patients with UA or NSTEMI were randomized to fondaparinux (2.5 mg daily) or enoxaparin (1 mg/kg twice daily) for a mean of 6 days. There was no difference in the incidence of composite death, non-fatal MI, or refractory ischemia (HR 1.01, CI 0.9–1.13) between fondaparinux and enoxaparin. However, major bleeding was significantly decreased with fondaparinux at 9 days (HR 0.52, CI 0.44–0.61, p < 0.001) and all cause mortality was lower at 30 (HR 0.83, CI 0.71–0.91, p = 0.02) and 180 days (HR 0.89, CI 0.80–1.0, p = 0.05; Yusuf et al., 2006a). OASIS-6 was designed to determine whether fondaparinux was superior to UFH in STEMI patients who underwent mechanical revascularization or pharmacological thrombolysis (Yusuf et al., 2006b). Patients were randomized to fondaparinux (2.5 mg daily for 8 days or until discharge) or UFH (for 24–48 h); those in which UFH was deemed unnecessary (primarily following streptokinase administration) were randomized to fondaparinux or placebo. Fondaparinux was associated with a significant reduction in the incidence of the death or reinfarction at 30 days (HR 0.86, CI 0.77–0.96, p = 0.008); an effect that persisted to 6 months. There was no difference in bleeding rates.

The reductions in the composite cardiovascular outcomes with fondaparinux in the OASIS trials were restricted to those who underwent conservative management or thrombolysis, while the benefit of fondaparinux was not apparent in patients who underwent primary PCI. Furthermore, fondaparinux was associated with increased catheter related thrombi, prompting the subsequent use of procedural intravenous fondaparinux. In the event patients managed under a conservative strategy proceed to PCI on fondaparinux, current guidelines recommend a transition to an agent with anti-thrombin activity.

Otamixaban is a synthetic parenteral factor Xa inhibitor with a rapid onset of action and biliary clearance (Table 3; Figure 3). Phase II trials in patients undergoing planned PCI and those with high risk ACS are promising. Compared to UFH with eptifibatide, otamixaban has been associated with reductions in the rate of death or myocardial infarction at 7 days (HR 0.52, CI 0.28–0.98 with 0.105 mg/kg/h) with comparable rates of bleeding (3.1 vs. 2.7%; Cohen et al., 2007; Sabatine et al., 2009). The ongoing TAO trial is powered for ischemic endpoints and is evaluating otamixaban vs. UFH and eptifibatide in patients with ACS undergoing a planned invasive strategy.

Two orally administered synthetic factor Xa inhibitors are presently in phase III trials: rivaroxaban and apixaban (Table 3; Figure 3; Rothberg et al., 2005). Rivaroxaban is an orally administered factor Xa inhibitor, with high bioavailability and a rapid onset of action. ATLAS TIMI 46 was a phase II trial in which patients admitted with ACS and subsequently stabilized were randomized to placebo or escalating doses of rivaroxaban. Compared to placebo, rivaroxaban was associated with a non-significant decrease in the primary efficacy endpoint (death, MI, stroke, recurrent ischemia requiring revascularization) at the lowest dose (5 mg twice daily; HR 0.60, CI 0.29–1.25) with dose-dependent increases in bleeding (HR 1.71, CI 0.76–3.85 with 5 mg twice daily; Mega et al., 2009a). A phase III trial of 2.5 and 5 mg twice daily rivaroxaban is presently underway (ATLAS 2 TIMI 51).

Phase II trials with apixaban have yielded similar results (Alexander et al., 2009). The phase III APRAISE-2 trial, patients with ACS (n = 7832) were randomized to placebo or 5 mg twice daily of apixaban in addition to standard DAPT. At a mean follow up of 241 days, apixaban therapy was not associated with a reduction in composite cardiovascular death, MI, or stroke (HR 0.97, CI 0.8–1.1, p = 0.51) while resulting in increased major bleeding (HR 2.59, CI 1.5–4.5, p = 0.001; Alexander et al., 2011).

Direct Thrombin Inhibitors

Unlike the heparins, direct thrombin inhibitors are independent of AT-III, reduce the formation of fibrin monomers and abrogate the direct platelet-activating effects of thrombin on platelets. Direct thrombin inhibitors are also active on clot-bound thrombin, providing a regional specificity that heparins lack. Bivalirudin is approved for ACS, while dabigatran is currently in clinical trials.

Bivalirudin is a synthetic and reversible direct thrombin inhibitor (Table 3; Figure 3; Sibbing et al., 2008). Initially evaluated in patients with unstable or post-infarction angina undergoing planned angioplasty (n = 4098), bivalirudin therapy (1 mg/kg bolus then 2.5 mg/kg/h) reduced composite death, myocardial infarction, and repeat revascularization at 7 days (HR 0.78, CI 0.62–0.99, p = 0.039) with a reduced risk of bleeding (HR 0.34, CI 0.26–0.45, p < 0.001; Bittl et al., 2001). Subsequently REPLACE-2 was designed to compare the combination of UFH and GpIIb–IIIa inhibition to bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h for procedure duration) with provisional GpIIb–IIIa inhibition (if procedural complications dictated) in the setting of urgent or elective PCI (n = 6010). Bivalirudin was associated with a similar incidence in composite rate of death, myocardial infarction, and urgent revascularization (7.6 vs. 7.1%, p = 0.40), with a highly significant decrease in bleeding (2.4 vs. 4.1%, p < 0.001; Lincoff et al., 2003).

These trials, together with CACHET (Bittl et al., 2001; Lincoff et al., 2002) supported the use of bivalirudin during PCI, although patients with high risk ACS had been excluded. The ACUITY trial randomized nearly 14,000 patients with high risk UA or NSTEMI to (1) UFH or LMWH plus GpIIb–IIIa inhibitor, (2) bivalirudin plus GpIIb–IIIa inhibitor, or (3) bivalirudin alone. Bivalirudin alone conferred similar efficacy with respect to the primary cardiovascular endpoint (death, MI, urgent revascularization; HR 1.08, CI 0.93–1.24, p < 0.001 for non-inferiority) with significantly reduced major bleeding (HR 0.53, CI 0.43–0.65, p < 0.001) compared to the heparin group (Stone et al., 2006).

Finally, the HORIZONS-AMI trial was designed to specifically address whether or not bivalirudin offered a superior risk–benefit profile in patients with STEMI undergoing planned PCI. Patients with STEMI (n = 3602) within the preceding 12 h were randomized to heparin and GpIIb–IIIa or bivalirudin monotherapy (0.75 mg/kg bolus, then 1.75 mg/kg/h), with anti-thrombin therapies generally discontinued at PCI completion. Bivalirudin was associated with a reduced incidence of the composite outcome (death, reinfarction, revascularization, stroke, or major bleeding) at 30 days, driven primarily by decreased rates of major bleeding (HR 0.60, CI 0.46–0.77, p < 0.001), and death. All cause mortality at 30 days was significantly lower in the bivalirudin group (HR 0.66, CI 0.44–1.0, p = 0.047), an effect maintained at 3 year follow up. The bleeding and survival benefits of bivalirudin were evident in those that had received heparin therapy prior to randomization, and at all stages of renal disease – subgroups in where LMWH have proven less safe (Ferguson et al., 2004; Cohen et al., 2006), or are unadvised due to primary renal elimination and concern for bleeding risk (Robson, 2000; Sun et al., 2007). Whether or not early initiation of bivalirudin provides incremental benefit is the focus of the ongoing EUROMAX trial, in which patients with STEMI and planned PCI will be provided bivalirudin or UFH by emergency medical personnel.

Dabigatran is a synthetic, competitive, and reversible direct thrombin inhibitor with good oral bioavailability (Table 3; Figure 3). Recently approved for the prevention of stroke in patients with atrial fibrillation (Connolly et al., 2009), dabigatran is undergoing evaluation in ACS. In a phase II dose finding study, patients with ACS and at high risk for additional events were randomized to dabigatran twice daily or placebo a median of 7 days after the event and treated for 6 months. Preliminary findings demonstrated no difference in rate of composite cardiovascular death, non-fatal myocardial infarction, or stroke (3.8% on placebo, 4.6% 50 mg, 3.5% 150 mg) or the risk of bleeding (0.54% on placebo, 0.81% 50 mg, 1.73% 150 mg), although there was a trend toward increased minor bleeding at every dose (Oldgren et al., 2009).

Conclusion

Platelet aggregation and thrombus formation comprise the intermediary events between plaque instability and MI, and pharmacological inhibition of these events has led to substantial reductions in ischemic complications and mortality. Newer agents are characterized by more predictable pharmacokinetics, reduced inter-individual response variability, and activity at the site of coronary occlusion. Recently approved agents (bivalirudin, fondaparinux, prasugrel, ticagrelor) have improved outcomes in clinical trials by more effectively balancing the anti-ischemic benefits and bleeding risks during ACS. Identifying the timing and setting of anti-platelet and anti-coagulant initiation, and the subgroups in which one agent provides a comparably favorable risk-benefit profile remains an area of active investigation (Table 4).

TABLE 4
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Table 4. Recent trials of ACS therapies.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Alexander, J. H., Becker, R. C., Bhatt, D. L., Cools, F., Crea, F., Dellborg, M., Fox, K. A., Goodman, S. G., Harrington, R. A., Huber, K., Husted, S., Lewis, B. S., Lopez-Sendon, J., Mohan, P., Montalescot, G., Ruda, M., Ruzyllo, W., Verheugt, F., and Wallentin, L. (2009). Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 119, 2877–2885.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Alexander, J. H., Lopes, R. D., James, S., Kilaru, R., He, Y., Mohan, P., Bhatt, D. L., Goodman, S., Verheugt, F. W., Flather, M., Huber, K., Liaw, D., Husted, S. E., Lopez-Sendon, J., De Caterina, R., Jansky, P., Darius, H., Vinereanu, D., Cornel, J. H., Cools, F., Atar, D., Leiva-Pons, J. L., Keltai, M., Ogawa, H., Pais, P., Parkhomenko, A., Ruzyllo, W., Diaz, R., White, H., Ruda, M., Geraldes, M., Lawrence, J., Harrington, R. A., and Wallentin, L. (2011). Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365, 699–708.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Angiolillo, D. J., Saucedo, J. F., Deraad, R., Frelinger, A. L., Gurbel, P. A., Costigan, T. M., Jakubowski, J. A., Ojeh, C. K., and Effron, M. B. (2010). Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (Switching Anti Platelet) study. J. Am. Coll. Cardiol. 56, 1017–1023.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Angiolillo, D. J., Shoemaker, S. B., Desai, B., Yuan, H., Charlton, R. K., Bernardo, E., Zenni, M. M., Guzman, L. A., Bass, T. A., and Costa, M. A. (2007). Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy In Diabetes Mellitus (OPTIMUS) study. Circulation 115, 708–716.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Antiplatelet Trialists’ Collaboration. (1994). Collaborative overview of randomised trials of antiplatelet therapy –I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 308, 81–106.

Pubmed Abstract | Pubmed Full Text

Antithrombotic Trialists’ Collaboration. (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324, 71–86.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Antman, E. M., Mccabe, C. H., Gurfinkel, E. P., Turpie, A. G., Bernink, P. J., Salein, D., Bayes De Luna, A., Fox, K., Lablanche, J. M., Radley, D., Premmereur, J., and Braunwald, E. (1999). Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 100, 1593–1601.

Pubmed Abstract | Pubmed Full Text

Antman, E. M., Morrow, D. A., Mccabe, C. H., Murphy, S. A., Ruda, M., Sadowski, Z., Budaj, A., Lopez-Sendon, J. L., Guneri, S., Jiang, F., White, H. D., Fox, K. A., and Braunwald, E. (2006). Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N. Engl. J. Med. 354, 1477–1488.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Antman, E. M., Wiviott, S. D., Murphy, S. A., Voitk, J., Hasin, Y., Widimsky, P., Chandna, H., Macias, W., Mccabe, C. H., and Braunwald, E. (2008). Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction) analysis. J. Am. Coll. Cardiol. 51, 2028–2033.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Aoki, J., Lansky, A. J., Mehran, R., Moses, J., Bertrand, M. E., Mclaurin, B. T., Cox, D. A., Lincoff, A. M., Ohman, E. M., White, H. D., Parise, H., Leon, M. B., and Stone, G. W. (2009). Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 119, 687–698.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Becker, R. C., Moliterno, D. J., Jennings, L. K., Pieper, K. S., Pei, J., Niederman, A., Ziada, K. M., Berman, G., Strony, J., Joseph, D., Mahaffey, K. W., Van De Werf, F., Veltri, E., and Harrington, R. A. (2009). Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 373, 919–928.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bittl, J. A., Chaitman, B. R., Feit, F., Kimball, W., and Topol, E. J. (2001). Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty study. Am. Heart J. 142, 952–959.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Caixeta, A., Dangas, G. D., Mehran, R., Feit, F., Nikolsky, E., Lansky, A. J., Aoki, J., Moses, J. W., Steinhubl, S. R., White, H. D., Ohman, E. M., Manoukian, S. V., Fahy, M., and Stone, G. W. (2011). Incidence and clinical consequences of acquired thrombocytopenia after antithrombotic therapies in patients with acute coronary syndromes: results from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Am. Heart J. 161, 298–306.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cannon, C. P., Harrington, R. A., James, S., Ardissino, D., Becker, R. C., Emanuelsson, H., Husted, S., Katus, H., Keltai, M., Khurmi, N. S., Kontny, F., Lewis, B. S., Steg, P. G., Storey, R. F., Wojdyla, D., and Wallentin, L. (2010). Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 375, 283–293.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

CAPRIE Steering Committee. (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348, 1329–1339.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chackalamannil, S., and Xia, Y. (2006). Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert Opin. Ther. Pat. 16, 493–505.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chin, C. T., Roe, M. T., Fox, K. A., Prabhakaran, D., Marshall, D. A., Petitjean, H., Lokhnygina, Y., Brown, E., Armstrong, P. W., White, H. D., and Ohman, E. M. (2010). Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes (TRILOGY ACS) trial. Am. Heart J. 160, 16–22.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cohen, M., Bhatt, D. L., Alexander, J. H., Montalescot, G., Bode, C., Henry, T., Tamby, J. F., Saaiman, J., Simek, S., and De Swart, J. (2007). Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 115, 2642–2651.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cohen, M., Mahaffey, K. W., Pieper, K., Pollack, C. V. Jr., Antman, E. M., Hoekstra, J., Goodman, S. G., Langer, A., Col, J. J., White, H. D., Califf, R. M., and Ferguson, J. J. (2006). A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes. J. Am. Coll. Cardiol. 48, 1346–1354.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Connolly, S. J., Ezekowitz, M. D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., Pogue, J., Reilly, P. A., Themeles, E., Varrone, J., Wang, S., Alings, M., Xavier, D., Zhu, J., Diaz, R., Lewis, B. S., Darius, H., Diener, H. C., Joyner, C. D., and Wallentin, L. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Coussement, P. K., Bassand, J. P., Convens, C., Vrolix, M., Boland, J., Grollier, G., Michels, R., Vahanian, A., Vanderheyden, M., Rupprecht, H. J., and Van De Werf, F. (2001). A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur. Heart J. 22, 1716–1724.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dangas, G., Mehran, R., Guagliumi, G., Caixeta, A., Witzenbichler, B., Aoki, J., Peruga, J. Z., Brodie, B. R., Dudek, D., Kornowski, R., Rabbani, L. E., Parise, H., and Stone, G. W. (2009). Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J. Am. Coll. Cardiol. 54, 1438–1446.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dangas, G. D., Mehran, R., Nikolsky, E., Claessen, B. E., Lansky, A. J., Brodie, B. R., Witzenbichler, B., Guagliumi, G., Peruga, J. Z., Dudek, D., Mockel, M., Caixeta, A., Parise, H., White, H., and Stone, G. W. (2011). Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction the HORIZONS-SWITCH analysis. J. Am. Coll. Cardiol. 57, 2309–2316.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Diercks, D. B., Pollack, C. V. Jr., Hollander, J. E., Blomkalns, A. L., Emerman, C. L., Rokos, I. C., Larson, D. M., Hoekstra, J. W., Mehran, R., and Stone, G. W. (2011). The time dependence of antithrombin initiation in patients with non-ST-segment elevation acute coronary syndromes: subgroup analysis from the ACUITY trial. Ann. Emerg. Med. 57, 204–212.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Eikelboom, J. W., Hirsh, J., Weitz, J. I., Johnston, M., Yi, Q., and Yusuf, S. (2002). Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 105, 1650–1655.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ferguson, J. J., Califf, R. M., Antman, E. M., Cohen, M., Grines, C. L., Goodman, S., Kereiakes, D. J., Langer, A., Mahaffey, K. W., Nessel, C. C., Armstrong, P. W., Avezum, A., Aylward, P., Becker, R. C., Biasucci, L., Borzak, S., Col, J., Frey, M. J., Fry, E., Gulba, D. C., Guneri, S., Gurfinkel, E., Harrington, R., Hochman, J. S., Kleiman, N. S., Leon, M. B., Lopez-Sendon, J. L., Pepine, C. J., Ruzyllo, W., Steinhubl, S. R., Teirstein, P. S., Toro-Figueroa, L., and White, H. (2004). Enoxaparin vs. unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 292, 45–54.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

FRAX. I. S. Study Group. (1999). Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX. I. S. (FRAxiparine in Ischaemic Syndrome). Eur. Heart J. 20, 1553–1562.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

FRISC Study Group. (1996). Low-molecular-weight heparin during instability in coronary artery disease, fragmin during instability in coronary artery disease (FRISC) study group. Lancet 347, 561–568.

Pubmed Abstract | Pubmed Full Text

Gasparyan, A. Y., Watson, T., and Lip, G. Y. (2008). The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J. Am. Coll. Cardiol. 51, 1829–1843.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gladding, P., Webster, M., Zeng, I., Farrell, H., Stewart, J., Ruygrok, P., Ormiston, J., El-Jack, S., Armstrong, G., Kay, P., Scott, D., Gunes, A., and Dahl, M. L. (2008). The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc. Interv. 1, 620–627.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goodman, S. G., Cohen, M., Bigonzi, F., Gurfinkel, E. P., Radley, D. R., Le Iouer, V., Fromell, G. J., Demers, C., Turpie, A. G., Califf, R. M., Fox, K. A., and Langer, A. (2000). Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J. Am. Coll. Cardiol. 36, 693–698.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goto, K., Lansky, A. J., Fahy, M., Cristea, E., Feit, F., Ohman, E. M., White, H. D., Alexander, K. P., Bertrand, M. E., Desmet, W., Hamon, M., Mehran, R., and Stone, G. W. (2010a). Predictors of outcomes in medically treated patients with acute coronary syndromes after angiographic triage: an Acute Catheterization And Urgent Intervention Triage Strategy (ACUITY) substudy. Circulation 121, 853–862.

CrossRef Full Text

Goto, S., Ogawa, H., Takeuchi, M., Flather, M. D., and Bhatt, D. L. (2010b). Double-blind, placebo-controlled phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J. 31, 2601–2613.

CrossRef Full Text

Gum, P. A., Kottke-Marchant, K., Poggio, E. D., Gurm, H., Welsh, P. A., Brooks, L., Sapp, S. K., and Topol, E. J. (2001). Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am. J. Cardiol. 88, 230–235.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gum, P. A., Kottke-Marchant, K., Welsh, P. A., White, J., and Topol, E. J. (2003). A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J. Am. Coll. Cardiol. 41, 961–965.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hamon, M., Rasmussen, L. H., Manoukian, S. V., Cequier, A., Lincoff, M. A., Rupprecht, H. J., Gersh, B. J., Mann, T., Bertrand, M. E., Mehran, R., and Stone, G. W. (2009). Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial. EuroIntervention 5, 115–120.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hennekens, C. H., Schror, K., Weisman, S., and Fitzgerald, G. A. (2004). Terms and conditions: semantic complexity and aspirin resistance. Circulation 110, 1706–1708.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hochholzer, W., Trenk, D., Bestehorn, H. P., Fischer, B., Valina, C. M., Ferenc, M., Gick, M., Caputo, A., Buttner, H. J., and Neumann, F. J. (2006). Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J. Am. Coll. Cardiol. 48, 1742–1750.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Husted, S., Emanuelsson, H., Heptinstall, S., Sandset, P. M., Wickens, M., and Peters, G. (2006). Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur. Heart J. 27, 1038–1047.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

ISIS Collaborative Group. (1988). Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.ISIS-2 (Second International Study of Infarct Survival) collaborative group. J. Am. Coll. Cardiol. 12, 3A–13A.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

James, S., Budaj, A., Aylward, P., Buck, K. K., Cannon, C. P., Cornel, J. H., Harrington, R. A., Horrow, J., Katus, H., Keltai, M., Lewis, B. S., Parikh, K., Storey, R. F., Szummer, K., Wojdyla, D., and Wallentin, L. (2010). Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the platelet inhibition and patient outcomes (PLATO) trial. Circulation 122, 1056–1067.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jolly, S. S., Faxon, D. P., Fox, K. A., Afzal, R., Boden, W. E., Widimsky, P., Steg, P. G., Valentin, V., Budaj, A., Granger, C. B., Joyner, C. D., Chrolavicius, S., Yusuf, S., and Mehta, S. R. (2009). Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J. Am. Coll. Cardiol. 54, 468–476.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Joyner, C. D., Peters, R. J., Afzal, R., Chrolavicius, S., Mehta, S. R., Fox, K. A., Granger, C. B., Franzosi, M. G., Flather, M., Budaj, A., Bassand, J. P., and Yusuf, S. (2009). Fondaparinux compared to enoxaparin in patients with acute coronary syndromes without ST-segment elevation: outcomes and treatment effect across different levels of risk. Am. Heart J. 157, 502–508.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Katsouras, C., Michalis, L. K., Papamichael, N., Adamides, K., Naka, K. K., Nikas, D., Goudevenos, J. A., and Sideris, D. A. (2005). Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months. Am. Heart J. 150, 385–391.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kim, K. A., Park, P. W., Hong, S. J., and Park, J. Y. (2008). The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin. Pharmacol. Ther. 84, 236–242.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Klein, W., Buchwald, A., Hillis, S. E., Monrad, S., Sanz, G., Turpie, A. G., Van Der Meer, J., Olaisson, E., Undeland, S., and Ludwig, K. (1997). Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 96, 61–68.

Pubmed Abstract | Pubmed Full Text

Kubica, A., Kozinski, M., Grzesk, G., Fabiszak, T., Navarese, E. P., and Goch, A. (2011). Genetic determinants of platelet response to clopidogrel. J. Thromb. Thrombolysis 32, 459–466.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kumar, D., Dangas, G., Mehran, R., Kirtane, A., Bertrand, M., Ebrahimi, R., Guagliumi, G., Brar, S., Fahy, M., Heller, E., Moses, J., and Stone, G. (2010). Comparison of bivalirudin versus bivalirudin plus glycoprotein IIb/IIIa inhibitor versus heparin plus glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes having percutaneous intervention for narrowed saphenous vein aorto-coronary grafts (the ACUITY trial investigators). Am. J. Cardiol. 106, 941–945.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lewis, H. D. Jr., Davis, J. W., Archibald, D. G., Steinke, W. E., Smitherman, T. C., Doherty, J. E. III, Schnaper, H. W., Lewinter, M. M., Linares, E., Pouget, J. M., Sabharwal, S. C., Chesler, E., and Demots, H. (1983). Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 309, 396–403.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lincoff, A. M., Bittl, J. A., Harrington, R. A., Feit, F., Kleiman, N. S., Jackman, J. D., Sarembock, I. J., Cohen, D. J., Spriggs, D., Ebrahimi, R., Keren, G., Carr, J., Cohen, E. A., Betriu, A., Desmet, W., Kereiakes, D. J., Rutsch, W., Wilcox, R. G., De Feyter, P. J., Vahanian, A., and Topol, E. J. (2003). Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 289, 853–863.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lincoff, A. M., Kleiman, N. S., Kottke-Marchant, K., Maierson, E. S., Maresh, K., Wolski, K. E., and Topol, E. J. (2002). Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the comparison of abciximab complications with hirulog for ischemic events trial (CACHET). Am. Heart J. 143, 847–853.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lopes, R. D., Alexander, K. P., Manoukian, S. V., Bertrand, M. E., Feit, F., White, H. D., Pollack, C. V. Jr., Hoekstra, J., Gersh, B. J., Stone, G. W., and Ohman, E. M. (2009). Advanced age, antithrombotic strategy, and bleeding in non-ST-segment elevation acute coronary syndromes: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J. Am. Coll. Cardiol. 53, 1021–1030.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lopes, R. D., Peterson, E. D., Chen, A. Y., Roe, M. T., Wang, T. Y., Ohman, E. M., Magid, D. J., Ho, P. M., Wiviott, S. D., Scirica, B. M., and Alexander, K. P. (2010). Antithrombotic strategy in non-ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the ACTION (acute coronary treatment and intervention outcomes network) registry. JACC Cardiovasc. Interv. 3, 669–677.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mega, J. L., Braunwald, E., Mohanavelu, S., Burton, P., Poulter, R., Misselwitz, F., Hricak, V., Barnathan, E. S., Bordes, P., Witkowski, A., Markov, V., Oppenheimer, L., and Gibson, C. M. (2009a). Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29–38.

CrossRef Full Text

Mega, J. L., Close, S. L., Wiviott, S. D., Shen, L., Hockett, R. D., Brandt, J. T., Walker, J. R., Antman, E. M., Macias, W. L., Braunwald, E., and Sabatine, M. S. (2009b). Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 119, 2553–2560.

CrossRef Full Text

Mehran, R., Lansky, A. J., Witzenbichler, B., Guagliumi, G., Peruga, J. Z., Brodie, B. R., Dudek, D., Kornowski, R., Hartmann, F., Gersh, B. J., Pocock, S. J., Wong, S. C., Nikolsky, E., Gambone, L., Vandertie, L., Parise, H., Dangas, G. D., and Stone, G. W. (2009a). Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 374, 1149–1159.

CrossRef Full Text

Mehran, R., Nikolsky, E., Lansky, A. J., Kirtane, A. J., Kim, Y. H., Feit, F., Manoukian, S., Moses, J. W., Ebrahimi, R., Ohman, E. M., White, H. D., Pocock, S. J., Dangas, G. D., and Stone, G. W. (2009b). Impact of chronic kidney disease on early (30-day) and late (1-year) outcomes of patients with acute coronary syndromes treated with alternative antithrombotic treatment strategies: an ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) substudy. JACC Cardiovasc. Interv. 2, 748–757.

CrossRef Full Text

Mehta, S. R., Yusuf, S., Peters, R. J., Bertrand, M. E., Lewis, B. S., Natarajan, M. K., Malmberg, K., Rupprecht, H., Zhao, F., Chrolavicius, S., Copland, I., and Fox, K. A. (2001). Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358, 527–533.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Michalis, L. K., Katsouras, C. S., Papamichael, N., Adamides, K., Naka, K. K., Goudevenos, J., and Sideris, D. A. (2003). Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am. Heart J. 146, 304–310.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Michelson, A. D., Frelinger, A. L. III, Braunwald, E., Downey, W. E., Angiolillo, D. J., Xenopoulos, N. P., Jakubowski, J. A., Li, Y., Murphy, S. A., Qin, J., Mccabe, C. H., Antman, E. M., and Wiviott, S. D. (2009). Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur. Heart J. 30, 1753–1763.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Montalescot, G., Wiviott, S. D., Braunwald, E., Murphy, S. A., Gibson, C. M., Mccabe, C. H., and Antman, E. M. (2009). Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373, 723–731.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Morrow, D. A., Scirica, B. M., Fox, K. A., Berman, G., Strony, J., Veltri, E., Bonaca, M. P., Fish, P., Mccabe, C. H., and Braunwald, E. (2009). Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the thrombin-receptor antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am. Heart J. 158, 335–341.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Moshfegh, K., Redondo, M., Julmy, F., Wuillemin, W. A., Gebauer, M. U., Haeberli, A., and Meyer, B. J. (2000). Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy. J. Am. Coll. Cardiol. 36, 699–705.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Murphy, S. A., Gibson, C. M., Morrow, D. A., Van De Werf, F., Menown, I. B., Goodman, S. G., Mahaffey, K. W., Cohen, M., Mccabe, C. H., Antman, E. M., and Braunwald, E. (2007). Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur. Heart J. 28, 2077–2086.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

O’donoghue, M., Antman, E. M., Braunwald, E., Murphy, S. A., Steg, P. G., Finkelstein, A., Penny, W. F., Fridrich, V., Mccabe, C. H., Sabatine, M. S., and Wiviott, S. D. (2009). The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38) analysis. J. Am. Coll. Cardiol. 54, 678–685.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Oldgren, J., Budaj, A., Granger, C. B., Harper, R., Khder, Y., van de Werf, F., and Wallentin, L. (2009). LB04: randomised dabigatran etexilate dose finding study in patients with acute coronary syndromes post index event with additional risk factors for cardiovascular complications also receiving aspirin and clopidogrel (RE-DEEM), AHA 52.

Parodi, G., Antoniucci, D., Nikolsky, E., Witzenbichler, B., Guagliumi, G., Peruga, J. Z., Stuckey, T., Dudek, D., Kornowski, R., Hartmann, F., Lansky, A. J., Mehran, R., and Stone, G. W. (2010). Impact of bivalirudin therapy in high-risk patients with acute myocardial infarction: 1-year results from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc. Interv. 3, 796–802.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Price, M. J., Berger, P. B., Teirstein, P. S., Tanguay, J. F., Angiolillo, D. J., Spriggs, D., Puri, S., Robbins, M., Garratt, K. N., Bertrand, O. F., Stillabower, M. E., Aragon, J. R., Kandzari, D. E., Stinis, C. T., Lee, M. S., Manoukian, S. V., Cannon, C. P., Schork, N. J., and Topol, E. J. (2011). Standard- vs. high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305, 1097–1105.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pride, Y. B., Wiviott, S. D., Buros, J. L., Zorkun, C., Tariq, M. U., Antman, E. M., Braunwald, E., and Gibson, C. M. (2009). Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel (triton)-thrombolysis in myocardial infarction (TIMI) 38 substudy. Am. Heart J. 158, e21–e26.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Robson, R. (2000). The use of bivalirudin in patients with renal impairment. J. Invasive Cardiol. 12(Suppl. F), 33F–36F.

Pubmed Abstract | Pubmed Full Text

Rothberg, M. B., Celestin, C., Fiore, L. D., Lawler, E., and Cook, J. R. (2005). Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann. Intern. Med. 143, 241–250.

Pubmed Abstract | Pubmed Full Text

Sabatine, M. S., Antman, E. M., Widimsky, P., Ebrahim, I. O., Kiss, R. G., Saaiman, A., Polasek, R., Contant, C. F., Mccabe, C. H., and Braunwald, E. (2009). Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet 374, 787–795.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schiele, F., Meneveau, N., Seronde, M. F., Descotes-Genon, V., Dutheil, J., Chopard, R., Ecarnot, F., and Bassand, J. P. (2010). Routine use of fondaparinux in acute coronary syndromes: a 2-year multicenter experience. Am. Heart J. 159, 190–198.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sculpher, M. J., Lozano-Ortega, G., Sambrook, J., Palmer, S., Ormanidhi, O., Bakhai, A., Flather, M., Steg, P. G., Mehta, S. R., and Weintraub, W. (2009). Fondaparinux versus enoxaparin in non-ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am. Heart J. 157, 845–852.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sibbing, D., Busch, G., Braun, S., Jawansky, S., Schomig, A., Kastrati, A., Ott, I., and Von Beckerath, N. (2008). Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur. Heart J. 29, 1504–1509.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Simoons, M. L., Bobbink, I. W., Boland, J., Gardien, M., Klootwijk, P., Lensing, A. W., Ruzyllo, W., Umans, V. A., Vahanian, A., Van De Werf, F., and Zeymer, U. (2004). A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: the pentasaccharide in unstable angina (PENTUA) study. J. Am. Coll. Cardiol. 43, 2183–2190.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Steg, P. G., James, S., Harrington, R. A., Ardissino, D., Becker, R. C., Cannon, C. P., Emanuelsson, H., Finkelstein, A., Husted, S., Katus, H., Kilhamn, J., Olofsson, S., Storey, R. F., Weaver, W. D., and Wallentin, L. (2010a). Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis. Circulation 122, 2131–2141.

CrossRef Full Text

Steg, P. G., Jolly, S. S., Mehta, S. R., Afzal, R., Xavier, D., Rupprecht, H. J., Lopez-Sendon, J. L., Budaj, A., Diaz, R., Avezum, A., Widimsky, P., Rao, S. V., Chrolavicius, S., Meeks, B., Joyner, C., Pogue, J., and Yusuf, S. (2010b). Low-dose vs. standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 304, 1339–1349.

CrossRef Full Text

Stone, G. W., Mclaurin, B. T., Cox, D. A., Bertrand, M. E., Lincoff, A. M., Moses, J. W., White, H. D., Pocock, S. J., Ware, J. H., Feit, F., Colombo, A., Aylward, P. E., Cequier, A. R., Darius, H., Desmet, W., Ebrahimi, R., Hamon, M., Rasmussen, L. H., Rupprecht, H. J., Hoekstra, J., Mehran, R., and Ohman, E. M. (2006). Bivalirudin for patients with acute coronary syndromes. N. Engl. J. Med. 355, 2203–2216.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Storey, R. F., Husted, S., Harrington, R. A., Heptinstall, S., Wilcox, R. G., Peters, G., Wickens, M., Emanuelsson, H., Gurbel, P., Grande, P., and Cannon, C. P. (2007). Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J. Am. Coll. Cardiol. 50, 1852–1856.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sun, Y. P., Oh, S. F., Uddin, J., Yang, R., Gotlinger, K., Campbell, E., Colgan, S. P., Petasis, N. A., and Serhan, C. N. (2007). Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. J. Biol. Chem. 282, 9323–9334.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Trimarchi, S., Smith, D. E., Share, D., Jani, S. M., O’donnell, M., Mcnamara, R., Riba, A., Kline-Rogers, E., Gurm, H. S., and Moscucci, M. (2010). Retroperitoneal hematoma after percutaneous coronary intervention: prevalence, risk factors, management, outcomes, and predictors of mortality: a report from the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. JACC Cardiovasc. Interv. 3, 845–850.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Van De Werf, F. (2010). Thrombin receptor antagonists may become an important antiplatelet therapy for coronary artery disease. Eur. Heart J. 31, 2575–2576.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Van Rees Vellinga, T. E., Peters, R. J., Yusuf, S., Afzal, R., Chrolavicius, S., O’donnell, M., Mehta, S. R., Pluta, W., Sacha, J., and Eikelboom, J. W. (2010). Efficacy and safety of fondaparinux in patients with ST-segment elevation myocardial infarction across the age spectrum. Results from the Organization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) trial. Am. Heart J. 160, 1049–1055.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Virmani, R., Kolodgie, F. D., Burke, A. P., Farb, A., and Schwartz, S. M. (2000). Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., Horrow, J., Husted, S., James, S., Katus, H., Mahaffey, K. W., Scirica, B. M., Skene, A., Steg, P. G., Storey, R. F., Harrington, R. A., Freij, A., and Thorsen, M. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wallentin, L., Goldstein, P., Armstrong, P. W., Granger, C. B., Adgey, A. A., Arntz, H. R., Bogaerts, K., Danays, T., Lindahl, B., Makijarvi, M., Verheugt, F., and Van De Werf, F. (2003). Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 108, 135–142.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wiviott, S. D., Trenk, D., Frelinger, A. L., O’donoghue, M., Neumann, F. J., Michelson, A. D., Angiolillo, D. J., Hod, H., Montalescot, G., Miller, D. L., Jakubowski, J. A., Cairns, R., Murphy, S. A., Mccabe, C. H., Antman, E. M., and Braunwald, E. (2007). Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 trial. Circulation 116, 2923–2932.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wohrle, J., Desaga, M., Metzger, C., Huber, K., Suryapranata, H., Guetta, V., Guagliumi, G., Witzenbichler, B., Parise, H., Mehran, R., and Stone, G. W. (2010). Impact of transfer for primary percutaneous coronary intervention on survival and clinical outcomes (from the HORIZONS-AMI Trial). Am. J. Cardiol. 106, 1218–1224.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wright, R. S., Anderson, J. L., Adams, C. D., Bridges, C. R., Casey, D. E. Jr., Ettinger, S. M., Fesmire, F. M., Ganiats, T. G., Jneid, H., Lincoff, A. M., Peterson, E. D., Philippides, G. J., Theroux, P., Wenger, N. K., Zidar, J. P., and Jacobs, A. K. (2011). 2011 ACCF/AHA Focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 123, 2022–2060.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Xiao, Z., and Theroux, P. (1998). Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 97, 251–256.

Pubmed Abstract | Pubmed Full Text

Yeh, R. W., Sidney, S., Chandra, M., Sorel, M., Selby, J. V., and Go, A. S. (2010). Population trends in the incidence and outcomes of acute myocardial infarction. N. Engl. J. Med. 362, 2155–2165.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Yusuf, S., Mehta, S. R., Chrolavicius, S., Afzal, R., Pogue, J., Granger, C. B., Budaj, A., Peters, R. J., Bassand, J. P., Wallentin, L., Joyner, C., and Fox, K. A. (2006a). Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N. Engl. J. Med. 354, 1464–1476.

CrossRef Full Text

Yusuf, S., Mehta, S. R., Chrolavicius, S., Afzal, R., Pogue, J., Granger, C. B., Budaj, A., Peters, R. J., Bassand, J. P., Wallentin, L., Joyner, C., and Fox, K. A. (2006b). Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295, 1519–1530.

CrossRef Full Text

Yusuf, S., Zhao, F., Mehta, S. R., Chrolavicius, S., Tognoni, G., and Fox, K. K. (2001). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502.

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: prasugrel, ticagrelor, bivalirudin, fondaparinux, dabigatran, vorapaxar

Citation: Lilly SM and Wilensky RL (2011) Emerging therapies for acute coronary syndromes. Front. Pharmacol. 2:61. doi: 10.3389/fphar.2011.00061

Received: 01 September 2011; Accepted: 25 September 2011;
Published online: 24 October 2011.

Edited by:

Issy Laher, University of British Columbia, Canada

Reviewed by:

Sanjoy Ghosh, University of British Columbia, Canada
Subodh Verma, University of Toronto, Canada

Copyright: © 2011 Lilly and Wilensky. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

*Correspondence: Robert L. Wilensky, Cardiovascular Division, Hospital of the University of Pennsylvania, 3400 Spruce Street, Gates 9, Philadelphia, PA 19104, USA. e-mail: robert.wilensky@uphs.upenn.edu