The PLATO Trial (Ticagrelor vs Clopidogrel) and the Influence of Genetic Non-Responders

[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.

I think so. Of course, ticagrelor in comparison to generic clopidogrel is more expensive, and therefore, some physicians and healthcare providers are considering whether we can get away with an equally effective but cheaper treatment by doing genetic testing. But this is not the case. The superior efficacy of ticagrelor means it has been recommended as the first-line treatment over clopidogrel, regardless of genetic testing.^3-4 Genetic testing is not really recommended at all in this patient population, because they should be receiving ticagrelor, which has been shown to positively influence long-term event rates.

Is the recommended dosage still the same as in the PLATO trial?

Yes. Use a 180 mg loading dose in patients with acute coronary syndrome as soon as possible after arrival to the hospital, and use 90 mg twice daily thereafter. These patients should be continued on ticagrelor for one year; that is the current recommendation. No one really knows exactly how long the treatment should be maintained. Shorter time periods, of course, have also been discussed. Of note, the event rates in the PLATO trial showed a continuous separation of the event curves between clopidogrel and ticagrelor, showing a continuous gain from having patients on ticagrelor out to one year.

Was the number of poor metabolizers in the 2010 genetic substudy consistent with the general population?

Yes, it was very consistent. The C2C19 polymorphism has now been investigated in many studies and there are meta-analyses as well. I believe approximately 27% of the population has the loss-of-function C2C19 allele in West European/North American Caucasian populations and it is even more common in Asian populations. Quite a substantial proportion of the population, really, and a fact that should lead to an increased use of ticagrelor, because we know physicians do not like to discharge patients after stenting without adequate protection against stent thrombosis. If you have been using clopidogrel and considering it effective, it is, in fact, not effective in a substantial proportion of patients. Ultimately, I expect there will be a switch from clopidogrel to one of the newer agents: ticagrelor or the alternative, prasugrel. Neither of these agents is influenced by this polymorphism.

What do we know about prasugrel in relation to ticagrelor?

Prasugrel has not been as thoroughly investigated as ticagrelor. There was a genetic substudy in the (prasugrel) TRITON trial⁵ with around 2-3,000 patients, far less than the PLATO trial. TRITON clearly showed that prasugrel is more effective in patients with a poor response to clopidogrel. It is less clear that prasugrel is superior in patients with a normal response to clopidogrel. There is an ongoing trial comparing prasugrel to clopidogrel in a medically managed population — TRILOGY⁶ — that will be presented in August 2012. This trial will hopefully will also give us additional information on the genetic aspects with prasugrel.

You presented a poster at the 2012 American College of Cardiology Scientific Session that was a subanalysis of the genetic substudy.⁷ What did you find?

Among patients with acute coronary syndromes, a small group exists, made up of only 2% of all patients who are homozygous for this polymorphism. They have two loss-of-function alleles and therefore have an extremely poor clopidogrel response. In this small group, ticagrelor was also superior to clopidogrel. The majority of patients with the loss-of-function allele are heterozygous for this polymorphism and have an intermediate response to clopidogrel. Our subanalysis showed that ticagrelor was superior in homozygous low responders as well as heterozygous intermediate responders and in normal responders to clopidogrel.

Tell us about your own practice in Sweden. Do you ever use clopidogrel?

Immediately after the 2011 summer, when the treatment became reimbursed in Sweden, our practice switched to using ticagrelor as the first treatment in all comers with acute coronary syndromes. In Sweden, this switching is now becoming more widespread and it is similar in Europe, as ticagrelor is recommended as the first-line treatment in all comers with acute coronary syndromes. Many hospitals rapidly switched, not least because the health economy is so good with ticagrelor. Ticagrelor is proven to be a cheap treatment considering number of life years gained. PLATO was an unusual trial in acute coronary syndromes because of the mortality reduction. Thus, in the health economy analysis, it was not necessary to model that ticagrelor might eventually save lives based on reduction of non-fatal events. Instead ticagrelor reduced mortality beginning with the first months of treatment and these gains come at a low cost in relation to most other treatments.

Dr. Wallentin can be contacted at lars.wallentin@ucr.uu.se.

Disclosure: Dr. Wallentin reports that he has received grants for clinical research from AstraZeneca Pharmaceuticals LP and Bristol-Myers Squibb Company.

References

1. Wallentin L, Becker RC, Budaj A, Cannon CP, et al; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009 Sep 10;361(11):1045-1057.
2. Wallentin L, James S, Storey RF, Armstrong M, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010 Oct 16;376(9749):1320-1328.
3. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-e122.
4. AstraZeneca press release. BRILINTA® (ticagrelor) added to American College of Chest Physicians recommendations on antithrombotic therapy and prevention of thrombosis. Posted February 21, 2012. Available online at https://www.astrazeneca-us.com/about-astrazeneca-us/newsroom/all/12799413?itemId=12799413. Accessed May 9, 2012.
5. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007 Nov 15;357(20):2001-2015.
6. ClinicalTrials.gov: A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects (TRILOGY ACS). Available online at https://clinicaltrials.gov/ct2/show/NCT00699998?term=TRILOGY&rank=3. Accessed May 15, 2012.
7. Wallentin L, James S, Storey R, Barratt B, et al. Greater efficacy of ticagrelor compared to clopidogrel in acute coronary syndrome is not driven by outcomes in poor metabolizers of clopidogrel. J Am Coll Cardiol 2012;59;E500. Available online for download at https://content.onlinejacc.org/cgi/content/full/59/13_Suppl_S/E500. Accessed May 9, 2012.