Acute coronary syndromes (ACS) result from unstable coronary artery plaques that rupture and can lead to coronary ischaemia, unstable angina and myocardial infarction. The treatment goals in ACS focus on reducing ischaemia, preventing further progression of thrombotic plaque by disturbing the milieu of thrombosis and platelet aggregation taking place within the coronary artery and, in the case of ongoing ischaemia, physically opening the occluded coronary lumen by fibrinolysis, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). However, while the incidence of death from coronary artery disease (CAD) and myocardial infarction (MI) has been declining, the overall three-year mortality after surviving an acute MI is still roughly 30%, and CAD remains the number one cause of death in the US.1,2 Despite adequate antiplatelet and antithrombotic therapy, recurrent ischaemia, ST-elevation MI (STEMI) and urgent revascularisation frequently occur after initial treatment, indicating that, despite best efforts, our current therapies are lacking.3 Recent data have demonstrated that as a result of environmental and genetic influences, a significant proportion of patients exhibit decreased levels of platelet inhibition despite standard doses of aspirin and clopidogrel.4 Additionally, major bleeding in the setting of an acute ischaemic episode brings with it a serious increased risk of death and re-infarction, and is a more powerful predictor of death in the setting of PCI than peri-procedural MI.5 Determining the pharmaceutical agent that can best complement the current armamentarium of aspirin, adenosine diphosphate (ADP) antagonists and heparins to decrease platelet activity and active thromboses, while at the same time preventing a major bleeding event, is the current challenge in today’s clinical research in treating ACS. This article will focus on the current research on antiplatelet and antithrombotic medications for the treatment of patients presenting with ACS, with a particular focus on new agents that may hold promise in decreasing adverse bleeding events in the setting of PCI. See Table 1 for a summary of current pharmaceutical agents and their mechanisms of action and Table 2 for a summary of emerging antiplatelet and antithrombotic agents.
Direct Thrombin Inhibitors
Studies have demonstrated a significant association between bleeding severe enough to require blood transfusions in the setting of myocardial ischaemia and an increase in long-term cardiovascular mortality; this is particularly noted in the elderly population.6–9 In contrast to either unfractioned heparin (UFH) or low-molecular-weight heparin (LMWH), the newer direct thrombin inhibitors, such as bivalirudin, inactivate thrombin by binding directly to active sites on the thrombin molecule, thus focusing on the direct mediator of thromboses without affecting other factors in the clotting cascade. This presumably leads to a decrease in adverse bleeding compared with current agents while maintaining adequate anticoagulation to prevent coronary thrombus formation during an ACS episode.10
The HORIZONS-AMI trial evaluated 3,600 patients with STEMI who underwent urgent revascularisation and were treated with the standard therapy of UFH and abciximab, or with bivalirudin alone. The bivalirudin group of patients experienced a significant decrease in the primary end-point of major adverse clinical events, which included death, re-infarction, target vessel revascularisation and major bleeding. While there was an increase in major adverse cardiac events in the 24 hours after PCI in the bivalirudin group, with a 1% increase in incidence of acute in-stent thrombosis, the overall 30-day re-infarction rates were similar between the bivalirudin and UFH groups and the overall net adverse clinical events were significantly reduced in the bivalirudin arm. This reduction was driven mainly by a decrease in major bleeding events with major bleeding occurring in close to half as many patients in the bivalirudin arm compared with the UFH arm.11 Additionally, one-year follow-up of the HORIZONS trial did not demonstrate a significant increase of in-stent thrombosis in patients who had received bivalirudin compared with standard therapy.12
The ACUITY trial addressed the use of bivalirudin in patients presenting with non-STEMI (NSTEMI) and high-risk unstable angina, who proceeded to urgent revascularisation. In this trial 14,000 patients were treated with clopidogrel prior to PCI plus either bivalirudin alone, bivalirudin plus a GpIIb/IIIa inhibitor or a GpIIb/IIIa plus UFH or enoxaprin. The study demonstrated that bivalirudin alone was not inferior to either UFH or enoxaprin plus a IIb/IIIa inhibitor at decreasing ischaemic complications, such as death, MI or repeat revascularisation at 30 days post-PCI. At the same time the bivalirudin alone arm had a 50% decreased risk of major bleeding episodes.13
Subsequent one-year analysis demonstrated that patients in the ACUITY trial who received bivalirudin alone had a similar overall cardiac mortality at 12 months after PCI compared with patients who received IIb/IIIa inhibitors plus heparin prior to PCI.14 An analysis of the ACUITY results, stratified by patient age, demonstrated that bivalirudin compared with GpIIb/IIIa plus heparin therapy did not lead to an increase in ischaemic events at any age, while major adverse bleeding events were reduced significantly across all age groups, with the greatest decrease in bleeding noted in patients over 75 years of age.15 Thus, while bivalirudin appears to at least have equal overall efficacy at reducing direct adverse cardiac events in the post-PCI period compared with standard heparin and GpIIb/IIIa administration, the significant decreased risk of bleeding realised in patients treated with bivalirudin alone is likely to lead to an overall superiority of bivalirudin at reducing long-term cardiac events in patients who present with acute ischaemic episodes.
Addressing Variations in Platelet Inhibition and the Overall Effect of Clopidogrel
Clopidogrel is a prodrug that must be metabolised by a number of enzymes, including CYP1A2 and CYP2C19, in order to be converted into its active form. Thus, any concurrent medicines taken, environmental factors and even genetic polymorphisms that alter the function of enzymes such as CYPC19 can lead to a significant alteration in the biologic activity of clopidogrel in the bloodstream. Studies have shown that cigarette smoking and proton pump inhibitors (PPIs) in particular can alter CYP1A2 and 2C19 function,16–18 leading to increased mortality in patients presenting with MI who were treated with clopidogrel and either actively smoking cigarettes or taking commonly used PPI medications.19,20 Additionally, genetic mutations in genes, such as CYP2C19 have been recently demonstrated to lead to decreased platelet disinhibition by clopidogrel and increased ischaemic events in post-PCI in patients with acute MI treated with clopidogrel.21 Some studies have estimated that as many as 25% of patients are clopidogrel-insensitive and do not demonstrate sufficient antiplatelet activity to prevent ongoing thrombosis.22 To overcome this newly identified deficiency in the pharmacology of clopidogrel, new antiplatelet medications that avoid metabolism in the liver are being created, but since these medications are likely to have a more rapid onset of action and more complete level of platelet inhibition, the risk of major bleeding events may also be elevated as a result.
Prasugrel is not a prodrug and thus avoids the P450 metabolic steps and is metabolised relatively quickly, which leads to a more rapid onset of action and higher degree of platelet inhibition compared with clopidogrel.23 Studies have shown that the administration of prasugrel at just 30 minutes prior to PCI achieves equivalent platelet inhibition and reduction of adverse events compared with a loading dose of clopidogrel given two hours prior to PCI.24 The benefit of prasugrel compared with clopidogrel has been demonstrated in the TRITON TIMI 38 trial, which randomised 13,608 patients to either a 60mg loading dose and a 10mg per day maintenance dose of prasugrel or a 300mg clopidogrel loading dose followed by a 75mg per day maintenance dose prior to urgent PCI for NSTEMI. At 15 months, there was a significant decrease in the primary end-point of cardiovascular death, non-fatal MI and non-fatal stroke in the prasugrel group. This end-point reduction was driven mainly by a substantial decrease in non-fatal MI in the prasugrel group. Conversely, there was a significant increase in major bleeding events and life-threatening bleeding in the prasugrel group, with most of the patients suffering major bleeding in the prasugrel arm having a history of stroke, being over 75 years of age and having a bodyweight of less than 60kg.25 Thus, it appears that prasugrel, if utilised in a pre-selected, low-risk-of-bleeding population, can lead to a significant decrease in adverse cardiac events in patients undergoing PCI for NSTEMI compared with clopidogrel.
Reversible Agents
Currently, virtually all antiplatelet agents are irreversible. Thus, if a patient has a major bleeding episode in the setting of clopidogrel or abciximab administration, the clinician cannot quickly reverse the antiplatelet effects of these medicines in order to help control the haemorrhage. To combat the problem of adverse bleeding episodes in the setting of PCI, reversible antiplatelet and antithrombotic agents have been developed. PRT060128 is both an intravenous and an orally administered reversible ADP antagonist. Currently, a phase II trial of PRT060128 is under way in which 800 patients set to undergo PCI for non-urgent CAD will either receive a loading dose of clopidogrel followed by 75mg of clopidogrel for 60 days or a loading dose of PRT060128 followed by varying doses of oral PRT060128 for 60 days.26 REG1 is the first specific, direct-acting, antidote-controlled anticoagulant. It consists of an anticoagulant component (RB006), a single-stranded nucleic acid that selectively and potently binds to and inhibits factor IXa. The antidote component, RB007, is a complementary nucleic acid that binds to and neutralises RB006 and allows a patient’s coagulation to return to normal. Recent phase I trials demonstrated the safety of REG1 with no significant major bleeding noted in the trial.27
Factor Xa Inhibitors
The new antithrombin inhibitor otamixaban is an injectable factor Xa inhibitor that appears to be a more powerful antithrombotic agent than heparin. In a trial of 947 patients undergoing non-urgent PCI who were treated with varying doses of otamixaban versus UFH, patients treated with otamixaban had greater levels of anti-Xa inhibition with similar rates of major bleeding compared with the UFH patients.28 Additionally, in a recent study the factor Xa inhibitor fondaparinux reduced major bleeding at 30 days by 40% compared with the LMWH enoxaprin in patients presenting with NSTEMI.29 However, the recent APPRAISE trial demonstrated that the use of the oral factor Xa inhibitor apixaban, along with ASA and clopidogrel, led to significantly increased major bleeding events compared with placebo in patients presenting with ACS.30 Thus, while it appears that factor Xa inhibitors may have the potential to reduce adverse bleeding events in patients with ACS compared with other antithrombotics, the recent APPRAISE trial casts a shadow of doubt over the efficacy of this class of medications in reducing major bleeding events in the setting of ACS. The upcoming APPRAISE 2 trial, which will examine the use of lower doses of apixaban in patients undergoing PCI, will help to determine the efficacy of factor Xa inhibitors at reducing the rate of major bleeding episodes. The current studies on the use of factor Xa inhibitors have not provided a clear explanation of how this class of medicines may affect bleeding rates in patients undergoing PCI.
Conclusion
In order to achieve adequate platelet and coagulation inhibition to prevent recurrent ischaemia and coronary thrombosis in the setting of ACS, and in particular in patients undergoing PCI, multiple antiplatelet and antithrombotic agents including aspirin, clopidogrel and IIb/IIIa receptor antagonists are standardly utilised. These medicines, while allowing for excellent antithrombotic activity, also lead to significant major adverse bleeding events. An adverse bleeding event can be catastrophic in the setting of a patient undergoing PCI or in the midst of coronary ischaemia and can lead to severe adverse outcomes, including recurrent MI and even death. Thus, newer antithrombotic agents are necessary to prevent major adverse bleeding episodes.
Medications such as bivalirudin have been shown to prevent recurrent ischaemia and mortality while at the same time significantly reducing adverse bleeding events in patients undergoing urgent PCI. Additionally, novel reversible antiplatelet and antithrombotic agents have been developed to allow the interventionalist to immediately disable the antithrombotic effect of anticoagulants and antiplatelets in the setting of a major bleed during or post-PCI. These agents are currently undergoing phase II clinical trials and may soon revolutionise the manner in which patients undergoing PCI are anticoagulated in the future.
While clopidogrel has been the mainstay of antiplatelet therapy along with aspirin in patients experiencing ACS, recent data have demonstrated that since clopidogrel is a prodrug, multiple environmental factors, medications and even genetic polymorphisms can interact with clopidogrel’s metabolism and lead to decreased platelet inhibition and an increased thrombotic risk among patients taking clopidogrel and undergoing PCI in the setting of ACS. New rapidly acting antipurigenic agents such as prasugrel and ticagrelor have exhibited promise in bypassing hepatic metabolism and providing a consistent antiplatelet effect in all patients. Nevertheless, these rapidly acting antiplatelet agents should be used with caution, especially in patients with a high risk of bleeding, as their rapid platelet inhibition may lead to significant adverse bleeding events. While there is significant ground to be gained in the reduction of morbidity and mortality from ACS, one must exert extreme caution to ensure that by creating more potent antithrombotic and antiplatelet agents, the risk of major bleeding is not increased. By approaching the use of new pharmaceutical agents in the setting of PCI with an eye towards reducing adverse bleeding events, we can work to ensure that morbidity and mortality can be reduced in patients undergoing PCI for years to come.