Genetic Influences on Antiplatelet Therapy Outcomes Stir Debate

Discussant Dr. Kurt Huber of Wilhelminen Hospital, Vienna, emphatically stated that routine genotyping for loss-of-function alleles is not warranted today in clinical practice, in PLATO-type patients or anyone else. As yet there are no prospective, randomized intervention studies to show that altering treatment on the basis of genetic testing leads to better clinical outcomes. Moreover, the tests are generally not reimbursable and the 2-3 hours required for results are an impediment to fast-track management of high-risk ACS patients.

What makes more sense today is simply to make routine use of more efficient antiplatelet drugs such as prasugrel or ticagrelor, instead of clopidogrel, in patients who are at medium to high risk of thrombotic complications related to stenting, Dr. Huber said. Examples would be individuals with ST-elevation MI, high-risk non–ST-elevation MI, or prior stent thrombosis.

Discussant Robert M. Califf expressed doubt that what he termed the “nirvana” promised by pharmacogenetics proponents will ever come to pass. The notion of using genetic testing to assign patients to the drug they are likely to best respond to, with resultant better outcomes overall at less cost to the health care system, is immensely appealing, but it flies in the face of recent evidence regarding the powerful influence that environment exerts on DNA.

“I predict that for most complex diseases, the proportion explained by genes is going to be quite small and there will be many other factors involved, leaving you always with this question: After you know the genes, is it enough that it would cross a threshold to change clinical practice?” observed Dr. Califf, vice chancellor for clinical research at Duke University, Durham, N.C.

It will probably prove more fruitful to fine-tune various functional assays that measure the integrated output of genes and other factors, he added. Examples include platelet function tests for guidance in antiplatelet therapy and INR measurement in prescribing warfarin.

Simultaneously with Dr. Wallentin’s presentation, the PLATO genetic analysis study was published online in the Lancet (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61274-3]). Dr. Pare’s study was also simultaneously published online (N. Engl. J. Med. 2010 Aug. 29 [doi:10.1056/nejmoa1008410]).

PLATO was funded by AstraZeneca; Dr. Wallentin disclosed that he has received research grants from that company as well as numerous others with an interest in antithrombotic agents. Dr. Pare reported receiving consulting fees from Bristol-Myers Squibb and Sanofi-Aventis, the funders of ACTIVE A and CURE, respectively. Dr. Huber and Dr. Califf disclosed receiving research grants and consulting fees from numerous pharmaceutical companies with an interest in antiplatelet therapies.