Coronary conundrums

Acute coronary syndrome (ACS) is an umbrella term for a group of symptoms associated with acute myocardial ischaemia. It encompasses a spectrum of disorders including unstable angina pectoris, non–ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). Patients presenting with chest pain represent a very large proportion of all acute medical hospitalisations and identifying those with ACS is a diagnostic challenge.

Once diagnosed with ACS there are two different treatment approaches according to the underlying pathogenesis. Both approaches utilise antiplatelet and anticoagulant drugs. Aspirin has long been the gold standard, but it is associated with undesirable gastrointestinal side effects. Additionally clopidogrel, the classic P2Y12 receptor antagonist, has been available for many years, but a recent black box warning has highlighted that some patients do not metabolise the drug effectively and therefore may not receive its full benefits. Furthermore, the incidence of bleeding associated with both antiplatelets and anticoagulants is a substantial concern. The limitations of available agents have encouraged the development of new therapeutic options that target different points along the coagulation cascade.

Eli Lilly's prasugrel (Effient, Efient and Prasita) is an antiplatelet that represents an advance over clopidogrel, with more potent and consistent inhibition of the same P2Y12 receptor. Prasugrel was launched in several countries in 2009, including the US, for use in patients with ACS who are managed with percutaneous coronary interventions (PCI). The approval of prasugrel was based on results from several trials, including the TRITON-TIMI 38 trial. The trial, of more than 13,000 patients, found that prasugrel was associated with a significant 18 per cent reduction in the relative risk of the combined endpoint of cardiovascular death, nonfatal heart attack or nonfatal stroke compared with clopidogrel.

However, the prasugrel prescribing information contains a black box warning, which highlights its bleeding risks. Furthermore, only patients who require immediate primary PCI for STEMI, experience stent thrombosis during clopidogrel treatment, or have diabetes mellitus, are appropriate candidates for prasugrel administration, according to National Institute for health and Clinical Excellence (NICE) guidelines in the UK. However, there is an ongoing clinical trial called TRILOGY-ACS, which is investigating prasugrel versus clopidogrel in patients who are medically managed following a diagnosis of unstable angina pectoris and NSTEMI. The results of this trial may expand the clinical use of prasugrel.

Awaiting approval
AstraZeneca's ticagrelor (Brilinta, Brilique) offers a potential further advance on clopidogrel and prasugrel as it is a reversible inhibitor of the P2Y12 receptor. Ticagrelor was approved in December 2010 in the EU for use, in combination with aspirin, in patients with ACS, including those managed medically, undergoing PCI or undergoing coronary artery bypass surgery. AstraZeneca (AZ) said: "We believe it will become an attractive option for physicians seeking a more effective antiplatelet treatment than clopidogrel."

Ticagrelor's approval was based on a review of its clinical programme, including results from the PLATO trial. PLATO established the superiority of ticagrelor on clopidogrel, for the primary endpoint of reduction of cardiovascular events (cardiovascular death, myocardial infarction or stroke) without an increase in overall major/fatal bleeding. Ticagrelor is waiting for approval in the US. In December 2010 the US Food and Drug Administration (FDA) issued a complete response letter stating that it wanted additional analyses of the PLATO trial. AZ responded in January 2011, submitting further information focusing on interactions between ticagrelor and high-dose aspirin. Analysts at inThought give ticagrelor a 97 per cent probability of gaining FDA approval.

Merck's vorapaxar, formerly SCH-530348, is a protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation. Vorapaxar has shown positive results in the phase II trials. There are two large phase III trials which are investigating the efficacy and safety of vorapaxar. The first trial (TRA-CER; NCT00527943) will involve 13,000 patients with non-ST-segment-elevation ACS. The second trial (TRA 2°P - TIMI 50; NCT00526474) will include 26,500 patients who have experienced a myocardial infarction, ischaemic stroke, or have documented peripheral vascular disease.

In January 2011, the combined Data and Safety Monitoring Board (DSMB) for the two studies recommended that patients with a history of stroke should not continue to receive vorapaxar due to an increase in intracranial haemorrhage. The DSMB also recommended that patients discontinue vorapaxar and investigators begin closing out the TRA-CER study. Efficacy and safety data from the TRA-CER study will be available later in 2011. Analysts at inThought have found that the likelihood of vorapaxar being approved has dropped from 60 per cent to 40 per cent following the DSMB decision.

Meanwhile two direct factor Xa inhibitors, a class of anticoagulant drugs, are in phase III development for ACS. These drugs act directly upon factor X in the coagulation cascade without using antithrombin as a mediator. The first of these drugs is rivaroxaban (Xarelto; Bayer). Rivaroxaban has been approved for the prevention of venous thromboembolism in adult patients undergoing hip/knee replacement surgery. It is undergoing evaluation in ACS patients in the phase III ATLAS ACS-TIMI 51 trial, which will evaluate the efficacy and safety of rivaroxaban for secondary prevention in patients receiving standard antiplatelet therapy of low-dose aspirin with or without a thienopyridine, such as clopidogrel. The aim is to recruit more than 14,000 patients and the estimated completion date for the primary endpoint is June 2011.

The second factor X inhibitor is otamixaban (sanofi-aventis). It is being evaluated in a phase III trial (NCT01076764) comparing the efficacy and safety of otamixaban with unfractionated heparin + eptifibatide. The primary endpoint is the composite of all-cause death and new myocardial infarction. It is expected that more than 13,000 patients will be enrolled, and the estimated study completion date is June 2012. Rivaroxaban and otamixaban each have a 51 per cent likelihood of approval, according to inThought analysts.

Antiplatelets and anticoagulants form a fundamental part of successful management of ACS, both in the acute setting and in the prevention of secondary events. The most successful future antiplatelet or anticoagulant drug will have a low risk of bleeding, a rapid onset of action and good bioavailability with a predictable response. Although significant advances have been made, there is still room for new drugs to be used in place of, or alongside, existing therapies.

The Author
This article was written by Celeste Burness of Adis International (Wolters Kluwer Health Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought.
For information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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