Antiplatelet drugs should prevent secondary ischemic events and should be safe for long-term use – without incurring an unacceptable increase in bleeding risk. This goal remains elusive, as mortality and morbidity remain high in coronary artery disease (CAD).

On Wednesday morning, three experts came together during a State of the Art session at the ISTH 2015 Congress to discuss controversies, progress and future directions in the treatment of CAD.

From left, Freek Verheugt, Christian Gachet, and moderator Andrew Frelinger

From left, Freek Verheugt, Christian Gachet, and moderator Andrew Frelinger

Christian Gachet of Université de Strasbourg, France, discussed existing and potential treatment targets, Desmond Fitzgerald of University College Dublin, Ireland, focused on proteomic signatures of antiplatelet drugs and new approaches to exploring drug effects, and Freek Verheugt of Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands, discussed triple therapy for percutaneous coronary intervention in atrial fibrillation.

Gachet said that improved treatment efficacy in CAD patients is offset by increased bleeding risk. Stroke patients, in particular, need better treatment due to high bleeding risk, as do patients with peripheral artery disease, who often are overlooked in drug development.

Current treatment targets are COX1 (targeted by aspirin), the P2Y receptor (targeted by thienopyridine compounds and by direct antagonists), and the αIIbβ3 integrin (targeted by GPIIb/IIIa inhibitors).  Promising new treatment targets include the thrombin receptor PAR1, the platelet-specific collagen receptor GPVI, and possibly the GPIb-von Willebrand factor axis. Several other targets are under preclinical investigation.

Gachet reviewed findings from recent trials and noted that bleeding risk remains problematic. “So far the price to pay for higher efficacy has been an increased bleeding risk, and whether new receptors or signaling molecules might efficiently replace the currently targeted αIIbβ3 integrin, the P2Y12 receptor, or COX1 is still an open question,” he said.

Fitzgerald noted that pharmacological response to antiplatelet drugs is highly variable in patients with acute coronary syndrome, but that proteomic analysis is shedding light on how various factors affect treatment response. These findings could be used to provide individualized antiplatelet drug therapy.

His group has evaluated the proteomic signatures of various drugs alone and when used in combination, and demonstrated clear drug signatures with marked differences between the drugs and drug combinations. The findings suggest that individuals have distinct platelet “proteome barcodes” that remain evident in the presence of the drug and that, despite this, the effects of the drugs are distinguishable. This may improve understanding of drug effects, monitoring of drug response, and tailoring of drug therapy.

“Proteomics may distinguish patient groups in a way that’s not possible with classical or clinical observations,” he said.

Verheugt discussed the use of combined anticoagulant and antiplatelet therapies (triple therapy) in patients with atrial fibrillation and CAD. He reviewed the risk of stroke and coronary thrombosis, the existing recommendations and guidelines, and the limited randomized data that are available, including those from the WOEST trial, the ISAR-TRIPLE trial, and the MUSICA-2 trial.

The use of safer oral anticoagulants and the omission of aspirin from therapeutic regimens are potential new approaches to achieving the goal of minimizing hemorrhagic risk in this group of patients. Results of ongoing clinical trials – including the PIONEER AF-PCI trial – may point to the optimal antithrombotic strategy, he said.

The PIONEER AF-PCI trial is one of three evaluating non-vitamin K oral anticoagulants in atrial fibrillation patients undergoing coronary intervention for stable coronary disease or acute coronary syndrome. All three include a no-aspirin arm, and all include evaluation of the modern P2Y12 blockers prasugrel and ticagrelor.

Gachet reported receiving personal fees from The Medicine Company and AstraZeneca. Fitzgerald reported having no disclosures. Verheugt reported receiving educational and research grants from Bayer Healthcare and Boehringer-Ingelheim, and honoraria for consultancies/presentations from Daiichi-Sankyo, Bristol-Meyers Squibb/Pfizer, Boehringer-Ingelheim, and Bayer Healthcare.

 

By Sharon Worcester |June 24, 2015