Cath Lab Digest

[Editor's note: This article has been changed from the original published version. In PLATO, the maintenance dose of clopidogrel was a conventional 75 mg once daily, not 25 as originally written. Cath Lab Digest regrets the error.]

For acute coronary syndrome patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. Dr. Wallentin discusses ticagrelor and the discovery that genetic non-responders to clopidogrel did not affect the PLATO trial results.

Can you tell us about the PLATO trial?

The PLATO trial compared a new P2Y12 inhibitor, the first directly acting and reversible P2Y12 inhibitor, ticagrelor, to the standard treatment with clopidogrel on top of aspirin in patients with acute coronary syndromes. The trial essentially included all comers with acute coronary syndromes, meaning ST-elevation myocardial infarction (MI) patients and non-ST elevation MI patients who had one additional risk factor. Patients were randomized as early as possible after hospital admission and allowed into the trial regardless of whether they had been treated with clopidogrel or not beforehand, so there were both ‘clopidogrel-naïve’ and ‘clopidogrel-experienced’ patients in the trial.

The dose of ticagrelor was a 180 mg loading dose followed by a 90 mg twice daily maintenance dose. The comparator was clopidogrel at a loading dose of 300 mg, but another 300 mg was allowed in patients having a percutaneous coronary intervention. The maintenance dose of clopidogrel was a conventional 75 mg once daily. Patients were followed for an average of 9 months, from 6 months up to 12 months.

PLATO was an event-driven trial, so when enough events accumulated, the trial ended. Final results were reported in 2009¹ and were quite striking. As compared to the standard treatment of clopidogrel, ticagrelor reduced the composite primary endpoint of cardiovascular death, MI and stroke, with a relative reduction of 16% and an absolute reduction of 1.9%. Ticagrelor showed a reduction both in MI and cardiovascular mortality, along with a reduction in total mortality that was actually greater than the reduction in myocardial infarction.

In those patients receiving a stent (~65% of the trial population), ticagrelor demonstrated a reduction in stent thrombosis, along with a reduction in procedural and spontaneous MIs. Most of the reduction was seen during long-term treatment, meaning a stronger reduction in spontaneous MI at the one-year follow-up.

At that time, clopidogrel was the recommended and standard treatment, and the trial results sparked a great deal of discussion concerning whether the reason for the superiority of ticagrelor might be patients with a poor response to clopidogrel. It has been known for a number of years now that approximately 20 to 30% of patients are poor responders to clopidogrel. Clopidogrel is a pro drug that needs to be converted in the liver by two enzymatic steps to the active moiety, a process that is genetically regulated. Patients with a loss of function of the C2C19 conversion of clopidogrel pro drug to the active compound would not really convert clopidogrel rapidly enough to have a pronounced reduction of platelet activity. Therefore, we evaluated whether or not the ticagrelor superiority was different in patients with any loss-of-function alleles at C2C19 (the main genetic factor affecting clopidogrel conversion) and in patients without any loss-of-function alleles at C2C19, i.e., the normal responders. We had blood from 10,000 patients for extraction of DNA and genetic analyzers. The entire PLATO trial was performed in 18,000 patients, so the genetic material was from more than half of the trial participants. It is the largest genetic substudy ever performed. I would say it is the largest single genetic study performed in acute coronary syndromes and also in relation to C2C19 polymorphic influence on clopidogrel response.

The genetic substudy was published one year after the main trial, in October 2010.² Results showed that the loss-of-function polymorphism did influence the response to clopidogrel, especially at the initiation of treatment during the first 1 to 3 months, where there was a higher event rate in patients with a loss of function polymorphism in the clopidogrel group. Over the long term, presence of the polymorphism did not influence the event rate in the clopidogrel arms. There was no difference in the short or long term event rate in patients with the polymorphism receiving ticagrelor. Overall, the superiority of ticagrelor was seen regardless of the presence of the C2C19 polymorphism. Therefore, our conclusion was that ticagrelor is superior regardless of whether patients are genetically good or poor responders to clopidogrel.

At that time, there had been some discussion as to whether genetic testing should be used in order to identify responders to clopidogrel versus non-responders. It was suggested that clopidogrel might be used as the preferred treatment in the normal responders and perhaps another treatment used in low responders, but PLATO demonstrated that ticagrelor is superior and is associated with lower event rates, regardless of whether patients possess the loss-of-function alleles at C2C19. Ticagrelor, based on event rates, is the preferred treatment for acute coronary syndrome patients, regardless of any individual’s genetic influence on clopidogrel response.

The genetic substudy removed a barrier for widespread adoption of ticagrelor over clopidogrel.