TRACER – an extended lesson in ‘bleeding in Acute Coronary Syndrome’
One of the key things that we were encouraged to convey to our patients during the recruitment process for this study was that the trial drug was not likely going to cause excess risk of bleeding. This arguably was the conclusion that was drawn from analysis of previous studies on vorapaxar on over 20,000 patients.
In one perspective, it was one of the studies which was very flexible in term of its inclusion criteria. You may recruit any patients with ACS whether or not they are undergoing intervention. For those undergoing PCI it is encouraged to recruit them prior to the procedure, and that the study drug is continued during procedure. No adjustment whatsover needed to the dose of antiplatelets or heparin. Even for patients going for CABG, there was no strict protocol as when to stop the drug (or even the decision whether to stop them or not).
Due to this flexibility, there were groups of patients that ended up receiving dual antiplatelets, heparin/low molecular weight heparin and Glycoprotein IIbIIIa inhibitors – and undergoing PCI without requiring dose adjustment or interruption in therapy. Looking at the protocol, it reflected a highly confident trial premises, which somehow crossed the boundaries of cautions practised by other antiplatelets trials like ATLAS2 (using oral factor Xa inhibitor in ACS).
The trial result which was published in early November 2011 in NEJM showed a failure to reach primary endpoint of significant reduction in composite of death from CV causes, MI, stroke and ischaemic endpoints (including revascularisation). There was a significant reduction in key secondary endpoint of composite of death from CV, MI and stroke though this cannot be declared as superiority endpoint due to failure to achieve primary endpoint.
On the other hand, there were significant excess of bleeding including fatal bleeding and intracranial haemorrhage, and bleeding according to GUSTO or TIMI criteria.
There was no reduction in stent thrombosis, though there was a significantly reduced events (with no increased bleed) in a group of patients who did not receive thienopyridine.
In the discussion, the authors concurred that “the magnitude of the increase (in bleeding) was not expected on the basis of preclinical and phase 2 data, which suggested that PAR-1 blockade does not increase the risk of bleeding over an above the risk with aspirin and clopidogrel”, and went on to admit the over-confidence nature of their study protocol: “Rather, the results of our study are consistent with previous study indicating that more potent antithrombotic therapy incrementally increases the risk of bleeding.”
[VORAPAXAR is a thrombin receptor antagonist that blocks Protease-activated Receptors on platelet leading to inhibition in thrombin-induced platelet activation, without interruption in haemostatic function]
