This transcript has been edited for clarity.
Chet Rihal, MD: Hi. I'm Dr Chet Rihal, former chair of the department of cardiovascular medicine and a practicing interventional cardiologist at Mayo Clinic in Rochester, Minnesota. Today I'm joined by my colleagues, Dr Naveen Pereira and Dr Michael Farkouh, the principal investigators of the TAILOR-PCI trial that was presented at the late-breaking clinical trial sessions of the virtual American College of Cardiology 2020 Scientific Sessions (ACC 2020). Naveen and Mike, congratulations on the trial coming to fruition and a very exciting presentation at the virtual conference.
Naveen Pereira, MD: Thanks, Chet. It was a privilege and pleasure to present the trial at the ACC; they have done an amazing job. Congratulations to you, Chet, as study chair of TAILOR-PCI, and to my good friend and colleague at the Peter Munk Cardiac Centre at the University of Toronto, Mike Farkouh.
Rihal: So, we've seen the presentation. How should clinicians take these results, digest them, and apply them to our patients?
Pereira: As you know, a lot of studies have shown that patients who carry the CYP 2C19 loss-of-function genotype have an increase in ischemic events when they take clopidogrel. So this is a high-risk population identified by their genetic makeup. With TAILOR-PCI, we focused on that group and attempted to demonstrate whether genotype-guided therapy in that group would be better than just giving everyone clopidogrel. The results showed a 34% reduction in events. We found about a 5.9% event rate in the group that received clopidogrel versus a 4.4% event rate in those who received a genotype-guided treatment. That was a pretty significant difference, but it was statistically not significant. We were expecting a 50% reduction but saw a 34% reduction. So it was a modest effect but not statistically significant.
Rihal: The P value was.055, so we just missed significance. But the fact remains that there was a reduction in events in the genotype-directed arm. Mike, you've been interested in precision medicine for some time, and it's been difficult to demonstrate clear benefits for individualization of pharmacotherapy. How should clinicians take the results of TAILOR-PCI and incorporate them into the day-to-day management of their patients?
Michael Farkouh, MD, MSc: We've tried to explore the opportunities and advantages of a personalized approach from a research perspective. It is quite attractive to healthcare providers, insurance and government agencies, and state-run healthcare systems to find ways we can target emerging therapies to the populations most likely to benefit. Here we have a simple, cost-effective bedside test, and we're using it in patients who are largely being managed with clopidogrel. That was a big surprise to us from the beginning: Up to 70% of patients in our centers in the TAILOR-PCI trial, which includes Canada, the United States, Mexico, and Korea, are being treated with clopidogrel. Therefore, there was a real advantage to evaluate the practice of using clopidogrel in patients who may be at highest risk for not being able to metabolize the drug. They were the patients who could be designated to receive the newer therapies.
Rihal: Naveen, how does this trial compare and contrast with the POPular Genetics trial?
Pereira: One of the questions that's been raised is why bother with genetic testing at all? Why not give everyone ticagrelor or prasugrel? The POPular Genetics trial did just that. In one arm, everyone received ticagrelor; the other arm was similar to ours, a genotype-guided arm. So most of the patients got clopidogrel, but those with the CYP2C19 loss-of-function genetic makeup got ticagrelor.
They reported a composite endpoint of ischemic events and bleeding. But if you just look at the ischemic rates, for the genotype-guided arm where most people got clopidogrel, it was about in the mid-4% range. If you look at the event rate in the ticagrelor group, it was around 4.7%. It shows how far we have moved from the PLATO study, when the event rates were in the 10%-12% range. Now we have the drug-eluting stents and improved guideline-directed therapy.
So if you look at the event rate in our genotype-guided arm, it's similar to the ticagrelor arm, at about 4.4%, where only the CYP2C19 loss-of-function patients get ticagrelor and everybody else gets clopidogrel. This is remarkable. If you take it across the populations—patients with STEMI, or our patients with acute coronary syndrome and some stable patients—the event rates are in the mid-4% range all across, which creates a case for adopting a precision medicine approach to treating patients with antiplatelet drug therapy.
Rihal: Mike, I assume you're going to be doing a pharmacoeconomic analysis of these data. You personally have had experience in the US and Canadian healthcare systems and you've collaborated with people from around the globe. Can you tell us what you're expecting or how important you believe a pharmacoeconomic analysis of the TAILOR-PCI data will be?
Farkouh: Whenever we have an effective management strategy, which I believe we have demonstrated with the TAILOR-PCI trial, it is a proof-of-concept trial. And cost-effectiveness or pharmacoeconomic analysis is always warranted and welcome. But in this particular case, I think it's even more important, because the guidelines across many jurisdictions (Canada being an exception because we have voted for ticagrelor to be frontline therapy), including Mexico and Korea and the other international sites in our network, recommend that patients be treated with one of these therapies.
Therefore, a therapy such as clopidogrel, a generic, well-tolerated treatment given to millions of patients, and the idea that we can evaluate whether it's cost-effective to actually institute a pharmacogenomics strategy, is very important, because it will have tremendous implications for healthcare systems. The lower cost of drugs would allow us to spend resources in other arenas in the cardiovascular space and otherwise.
Rihal: Naveen, a lot of this is predicated on doing a point-of-care test. You mentioned this in the presentation. Could you describe how this was done in TAILOR-PCI so the audience can understand what a point-of-care genotype test looks like?
Pereira: This was one of the keys to the success of TAILOR-PCI, to be able to use the point-of-care genotyping. For a lot of the pharmacogenetic clinical trials, which were more blood based—the warfarin trials, for example—it took time for the blood sample to go to the laboratory, the laboratory to process it for the genetic variants, and then to return the results.
And the key with pharmacogenetics is early institution of change in medical therapy based on the genotype information. The shorter the time, especially after PCI in patients with MI or acute coronary syndrome, the better it is.
So we used a point-of-care assay that was made by Spartan Biosciences, a Canadian company. All that was required was for the study coordinators to be trained. We did an initial validation phase. Study coordinators trained on 20 volunteers. They had to take a buccal swab, put it in the solution for PCR, and then they put it into this box and got a result within an hour at the bedside.
Potentially, you could have the testing kit in the cath lab, similar to how we check for activated plasma clotting time for heparin. In our trial, we showed a 99% concordance rate between the genotyping by this point-of-care assay and the laboratory-based genotyping. The assay was approved by the US Food and Drug Administration.
Rihal: This simple point-of-care assay can be done easily by a technician or nurse in the cath lab. This would really facilitate an individualized approach to antiplatelet therapy following PCI and for interventional cardiologists who think in terms of minutes rather than days.
Let me ask the critical translational question Mike: If you yourself had a stent, what would you do?
Farkouh: The use of antiplatelet therapy is very much based on hospital practice. But in many of the centers that largely use clopidogrel as the frontline therapy for PCI patients, genotyping is warranted and is supported by the evidence in this trial. In these hospitals, I believe we should be instituting testing routinely. I think it's very practical, it's cost-effective. Although our P value is around the.05 level and certainly not the most robust finding at 12 months, I do believe that this is warranted and will change practice. I think that is the reception we're getting among our investigators.
Rihal: You're extending the follow-up now.
Farkouh: We have been funded by the National Heart, Lung, and Blood Institute for follow-up to 24 months. It's probable that this will tighten up the confidence intervals and we will reach statistical significance. Of course, in the trials of personalized medicine particularly, we've always concentrated on clinical significance. The fact that we see a 35% reduction in the ischemic event rate is important. I'm hoping that at 24 months, tightening the confidence intervals will bring home statistical significance. And we'll still have a robust clinical finding.
Rihal: Naveen, trials looking at platelet phenotyping have been negative. Why? And why are these genotype trials more positive than negative?
Pereira: Platelet function testing is a difficult field, in terms of the assay variability, between the various assays that are used. Light aggregometry would be excellent to use, but it's difficult to implement by the bedside. And there's always a controversy about whether platelet function testing always correlates with real cardiovascular outcomes.
What led up to TAILOR-PCI was a solid body of evidence showing a remarkable association between having this loss-of-function CYP2C19 genotype and adverse outcomes. It makes sense from a pharmacologic perspective. If you're heterozygous for CYP2C19, you have one third less active clopidogrel in your bloodstream. If you're homozygous it could be up to 50% less active clopidogrel. If you have less clopidogrel, you could be at increased risk for events. And we saw that in TAILOR-PCI. There were about eight cases of stent thrombosis within the conventional clopidogrel group but just two cases of stent thrombosis in the genotype-guided group, so that's a pure phenotype of the antiplatelet effect of clopidogrel.
In addition, in the first 3 months, we saw an 80% risk reduction, which I think is a very important perspective. As we know, in the world of dual antiplatelet therapy, that 3-month window post-PCI is turning out to be a very critical point. Mike and I have talked about this: If we took a retroscope and timed a pharmacogenetic trial endpoint to be at 3 months, the true effect of your genetic makeup would show up. You don't expect a long-term effect. It's the same with warfarin and INR: The true effect of genetics is when you give your first and second dose of warfarin. It is critical that the first 3 months plays an important role in this drug-gene interaction.
Farkouh: The weight of this trial is not just to address antiplatelet therapy. It really is a proof of concept of the personalized medicine approach, and we learned a lot about it. We have two main challenges. One is the effect size we're trying to detect. It's not the 20%-25% relative risk reduction that we traditionally sample-size for our statistical assumptions in trials, but it may be in the order of 50%-60% reduction by targeting patients at risk.
The second element is the timing of the endpoint. We've learned a lot from the cancer folks, and having now conducted the TAILOR-PCI trial, that maybe it's the early effects that we're looking for, effects that show some promise that we can actually answer many, many questions by performing these kinds of analyses. I believe the methodologic and statistical assumptions we use for personalized medicine trials will be advanced by the TAILOR-PCI trial, in addition to answering the issue of clopidogrel pharmacogenomics.
Rihal: Mike and Naveen, I'd like to thank you for a very engaging conversation today, and my congratulations to you both and to the entire network of TAILOR-PCI—the investigators and coordinators, and the international sites that made this landmark study possible and feasible. I hope all of you in our audience have enjoyed this conversation. I certainly have learned a lot from it. And we look forward to having many more with you.
From the Mayo Clinic, this is Chet Rihal, signing off. I hope to see you again. Thank you.
Follow theheart.org | Medscape Cardiology on Twitter
© 2020 Mayo Clinic
Cite this: TAILOR-PCI and the Role of Genotype-Guided Antiplatelet Therapy - Medscape - Apr 07, 2020.