Dec 14, 2020
This week's episode features author Adnan Kastrati and Associate Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature Ticagrelor Prasmul in patients with ST segment elevation myocardial infarction undergoing primary PCI. More on that story later, though. How about we grab a cup of coffee and look at some of the other papers in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would. And actually, I'm going to talk about two papers and they're all about BET, BET or promo domain, an extra terminal epigenetic reta proteins. And in particular, this one called BRD4. Now these proteins have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecular BET protein inhibitors, such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet genetic studies elucidating the biology of BET proteins in the heart have not been conducted. Well, at least until this week's issue where we have not one, but two papers, both elegantly using mouse genetic studies.
Dr. Carolyn Lam:
In the first from Dr. Srivastava from Gladstone Institute of Cardiovascular Disease in San Francisco and Dr. Jain from Perlman School of Medicine in Philadelphia and their colleagues, they found that BRD4, that particular BET epigenetic reader protein, forms a transcriptional regulatory module with GATA4, a lineage determining transcription factor in cardiomyocytes. This BRD4 GATA4 module was a critical orchestrator of mitochondrial bioenergetics in the adult heart.
Dr. Greg Hundley:
Well Carolyn, that is a wonderful summary. What are the clinical implications?
Dr. Carolyn Lam:
Identification of this new BRD4 interaction partner, such as GATA4 could provide new insights into developing epigenetic based therapies for heart failure. And the second paper is from Dr. Joseph Hill and Thomas Gillette from University of Texas Southwestern Medical Center and their colleagues. And what they found was that BRD4 was essential to the maintenance of mitochondrial electron transport chain function via transcriptional regulation of a nuclear mitochondrial gene network. BRD4 heterozygous deletion resulted in delayed heart failure, whereas pharmacological BRD4 inhibition using JQ1 induced modest changes in mitochondrial genes suggesting potential cardiac toxicity in targeting BRD4 at baseline.
Dr. Greg Hundley:
So what does this mean for us clinically, Carolyn?
Dr. Carolyn Lam:
As more potent and specific inhibitors are developed targeting BRD4 for clinical settings in oncology and other diseases, we must carefully monitor bezel cardiac performance for functional and mitochondrial deterioration. Important clinical message there.
Dr. Greg Hundley:
Great job, Carolyn. Well, my first paper is entitled "An Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaques" And it comes to us from Dr. Tomas Neilan and his colleagues at the Mass General Hospital. The study was situated in a single academic medical center. And Carolyn in this paper, there are actually three studies described. First, there's a primary analysis that evaluated whether exposure to an immune checkpoint inhibitor during treatment for cancer was associated with atherosclerotic cardiovascular events among 2,842 patients versus 2,842 controls that were matched by age, a history of cardiovascular events and cancer type.
Dr. Greg Hundley:
In the second study, a case crossover analysis was performed with an at risk period defined as the two year period after, and the control period as the two year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events including myocardial infarction, coronary revascularization, and ischemic stroke. And secondary outcomes included the individual components of that primary outcome.
Dr. Greg Hundley:
Finally, in the third study in this paper, there's an imaging stub study of 40 individuals, and it looked at the rate of atherosclerotic plaque progression compared from before and after starting the immune checkpoint inhibitor. All study measures and outcomes were blindly adjudicated in this third study.
Dr. Carolyn Lam:
Wow, a three in one. That really sounds novel. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. In the matched cohort study, there was a three-fold higher risk for cardiovascular events after starting an immune checkpoint inhibitor. There was a similar increase in each of the individual components of the primary outcome. In the case crossover study, there was also an increase in cardiovascular events from 1.37 to 6.55 per hundred person years at the two year time point.
Dr. Greg Hundley:
And then lastly, Carolyn, in the imaging study, the rate of progression of total aortic plaque volume was three fold higher after immune checkpoint inhibitors from 2.1% per year to 6.7% per year after receiving these agents. The association between immune checkpoint inhibitor use and increased atherosclerotic plaque progression was attenuated with the concomitant use of statins or corticosteroids.
Dr. Carolyn Lam:
Wow, Greg. So I suppose what all this shows is that we need to be aware of the cardiovascular risk prior to, during and after treatment with immune checkpoint inhibitors and perhaps, you know, optimize these cardiovascular risk factors. Thank you, Greg.
Dr. Greg Hundley:
You bet. Well, Carolyn, my next paper is from Dr. George Vlachojannis from University Medical Center at Utrecht. These authors conducted a randomized control multi-center trial in the Netherlands enrolling STEMI patients planned to undergo primary PCI. Now patients were randomly allocated to receive in the ambulance before transfer a 60 milligram loading dose of Prasugrel, either being crushed or as integral tablets. The independent primary end points were thrombolysis in myocardial infarction, TIMI three flow in the infarct related artery at initial coronary angiography, and complete greater than they go to 70% ST segment resolution one hour post primary PCI. The safety end points were TIMI major and bleeding academic research consortium, or BARC, greater than three bleedings and secondary end points included platelet reactivity and ischemic outcomes.
Dr. Carolyn Lam:
Nice trial design. So what did they find?
Dr. Greg Hundley:
Well, Carolyn, a total of 727 patients were assigned to either crushed or integral tablets of Prasugrel. The median time from study treatment to wire crossing during primary PCI was 57 minutes, and the primary end point of TIMI three flow in the infarct related pre primary PCI artery occurred in 31% in the crushed group versus 32.7% in the integral group. No difference, P .064. Complete ST segment resolution one hour post primary PCI was present in 59.9% in the crush group and 57.3% in the integral group. Again, no difference, P equals .055. Platelet reactivity at the beginning of primary PCI measured as the P2Y12 reactivity unit, differed significantly between the groups. Crushed was 192 versus integral was 227 and the P value was less than 0.01. TIMI major and BARC greater than three bleeding occurred in 0% in the crushed group and 0.8% in the integral group and in 0.3% in the crushed group versus 1.1% in the integral group respectively. So there were no differences observed between groups regarding ischemic events at 30 days.
Dr. Greg Hundley:
So Carolyn, in conclusion, prehospital administration of crushed Prasugrel tablets does not improve TIMI three flow in the infarct related artery, pre primary PCI or complete SD segment resolution one hour post primary PCI in patients presenting with STEMI planned for primary PCI.
Dr. Carolyn Lam:
Interesting and interesting stuff with platelet reactivity and bleeding. Thank you, Greg. Well, there are other papers in today's issue. There's an in-depth paper by Dr. Katsanos on stroke prevention in atrial fibrillation, looking forward. There's a research letter by Dr. Berger on myocardial injury in adults hospitalized with COVID-19 and another by Dr. Hacker on again, immune checkpoint inhibitor therapy and how that induces inflammatory activity in large arteries.
Dr. Greg Hundley:
Well, Carolyn, I've got a couple other papers to talk about in this issue. There's a On My Mind piece from Dr. deFilippi entitled "Navigating Testing for COVID-19." There's a Perspective from Dr. Ridker entitled "Equipoise Trust and the Need for Cardiologists to Randomize Patients into Anticoagulation Trials in the Time of COVID." There's an ECG challenge from Dr. Arias entitled, "A Paced Tachycardia." And then finally, there's an exchange of letters from Drs. Liu regarding a prior publication entitled "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets." Well, Carolyn, how about we get to the world of anti-platelet therapy, ticagrelor prasugrel in patients with ST segment elevation myocardial infarction, shall we?
Dr. Carolyn Lam:
Yes, let's go Greg.
Dr. Greg Hundley:
Well welcome, listeners, to our featured discussion today on this December 15, and we are going to learn and discuss a little more, a paper pertaining to ticagrelor versus prasugrel in patients with ST segment elevation myocardial infarction. And our lead author today is Adnan Kastrati from Deutsches Heart center in Munich. And we also have our own Associate Editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen. Adnan, maybe I'll start with you. Could you tell us a little bit about the background related to this article and what was the hypothesis that you wanted to address?
Dr. Adnan Kastrati:
First of all, thank you very much for having me here to share with you some thoughts. Thank you, Dharam, for handling our paper in Circulation. We are very honored to have it published there. About these are the ISAR REACT-5 series of studies dedicated to optimizing the antiplatelet therapy in patients and anticoagulant therapy in patients with acute and chronic coronary syndromes, mostly who are undergoing a PCI procedure. We started to think about that study immediately after the publication of the platelet trial. We showed the superiority of prasugrel in patients with acute coronary syndromes. These were the two new ADP receptor antagonists at the time. And so as a physician, we are interested to know which of them was better because there was no direct comparison. And so that's why we decided to have an open-label trial randomized. Most of the centers were situated in Germany. Two centers were situated in Italy. The private end point was adopted to the private end point of the trials in this skill. Only one difference was there, instead of cardiovascular death, we put all cause death in the primary end point. Why? Because all cause death may also reflect the gradient end bleeding between the two drugs. We wanted to have a more integrative endpoint in this sense. So it was a combination of all cause death, myocardial infarction, and stroke.
Dr. Adnan Kastrati:
It was a one year followup study. The study had two groups of steady patients, which was about 40% of the patients, included in the multicentral trial. And what we found in this trial, it was the same results as it was found in the whole trial. The advantages seen for prasugrel was present here also. Although we lost the significance in the evaluation of the primary endpoint. It was a 31% increase or 24% decrease with prasugrel in that sense. But otherwise everything was in the same direction as in the whole trial. And if you look also in the components of the primary end point…, you have the chance to see that numerically, it was the same trend for all components. Although the trial was not powered for going to evaluate the component of the prime end point. This was the main result.
Dr. Greg Hundley:
It sounds like you had 1,653 patients with STEMI randomized to receive ticagrelor or prasugrel and 10% experienced the primary end point in the ticagrelor group, but only 7.9% in the prasugrel group. But the P value was only .10. We saw trends toward favoring prasugrel rather than sort of a definitive difference. Is that a correct summary?
Dr. Adnan Kastrati:
Yes, it is a correct summary. I would say this group of patients is the most interesting subgroup of patients in ISAR 5 trial. Why? Because the pretreatment strategy is the same. Because there have been a lot of discussions about non-S-segment segment elevation acute myocardial infarction due to the difference in pretreatment. Although it was intentional, some people felt it's different and they said you have two different strategies there. In the STEMI subgroup, the pretreatment strategy was the same, so it was a head to head comparison of two drugs, even according to the same strategy. This is one.
Dr. Adnan Kastrati:
Second, you have to look back at the trials in the same field…Both these trials, if you look closely to the results of for STEMI patients, both of these trials haven't shown a significant result for the STEMI subgroup. For plateau it was a P value of 007 and for tritan it was a P value of 0014 only. Why? Because in the tritan it was very specific. They included also patients after fever analyzes and the significance came only from the comparison of tritan in this group, not in the primary PCI group. In the plateau and ISAR-5 we excluded these patients.
Dr. Greg Hundley:
Dharam, we're going to turn to you now. Adnan's really framed this study nicely, but can you help us from your perspective, put this study in perspective with others that have been published in this space?
Dr. Dharam Kumbhani:
Yeah, thanks, Greg. And I want to congratulate Adnan and his group for providing the field with another really well conducted study in a very important field. The center has done some very, very landmark trials, and I think this is another one of those. It sort of helps us understand potentially the best treatment mechanism or protocol for patients undergoing primary PCI for STEMI in this case. As you nicely outlined sort of the background for this, the only other trial that I'm aware of in this space is directly comparing pasugrel and ticagrelor head to head was the Prague 18 trial, which was smaller. I think it was about under 1100 patients. So even the STEMI cohort here was larger than that trial. But that trial ended up being terribly underpowered and unfortunately, also discontinued prematurely. So there wasn't really any significant difference that was noted in that trial and there was also a high crossover to clopidogrel in that other trials.
Dr. Dharam Kumbhani:
So I think that trial, in fact, we had published a trial in circulation as well. And I think this study sort of helps to advance the field a little bit by providing a head to head comparison between the two drugs. If I may extend some of the discussion points that were brought up earlier, I think, again, there is a couple of things that jumped out to me. One is, as you mentioned, the semi cohort is very interesting and very important. The p-value for interaction between the STEMI and the non-STEMI population was not significant for the primary end point. So that is certainly important when considering these results.
Dr. Dharam Kumbhani:
And the second thing is the differences that were noted in the rates of reinfarction, both spontaneous as well as PCI related. And although that is very interesting, we certainly have to keep that first point in mind when considering that. I think it becomes more hypothesis generating that MI rates ended up being higher with ticagrelor compared with prasugrel, and then sort of trying to tease that out in terms of, was that just a play of chance? Do we end up seeing that, is there a real biological reason for that? All of the trials was extremely well done. There were about 29 patients that did not have one-year follow-up and there were about 67 or so MI events. I think it's very interesting, and I think for at least for me, when I review this trial, I think it brings up some very interesting hypotheses that I think we would need to test further. Those anyway, my sort of high-level thoughts on this excellent trial.
Dr. Greg Hundley:
Very good. Well, I'd like to ask you just in 20 seconds, each of you, what's the next study that needs to be performed in this field? Adnan, start with you.
Dr. Adnan Kastrati:
I don't expect trials doing the same thing that we have done in ISAR-X5. We are planning now that ISAR-X6 trial. They are finalizing the protocol, and it will be a large trial of 9,000 patients with acute coronary syndromes in which will test the need for aspirin after discharge. That means all the spaces will be with the potent P2I12 inhibitors. And one group, it will be a placebo controlled trial. One group will have aspirin after discharge, the other placebo. And this is now, for us, the most important thing in this area.
Dr. Adnan Kastrati:
If I have the chance to respond to Dharam about the mechanistic insights of this effect, I would say that we have shown aggressive cardiology, our data about platelet function. It is the biggest platelet function studies in this area, 600 patients. We have tested in patients after PCI. We tested ADP in used aggregation after ticagrelor and prasugrel. And prasugrel was associated with a 30% reduction in platelet aggregation in these patients. And I think that this offers the mechanistic basis also for our results. And the results will be published shortly.
Dr. Greg Hundley:
Very nice, and Dharam.
Dr. Dharam:
Thank you for that response, Adnan. And Greg, to your question, I agree. I think it would be hard, although the field would really benefit from having a head to head comparison between these two drugs again in a larger study. I do think a lot of the interest and excitement in the ACS field is on de-escalation strategies as the outline. And so I suppose that that's sort of where we'll see a lot more in terms of clinical trials.
Dr. Greg Hundley:
Very good. Well listeners, this has been a wonderful discussion and we appreciate the input from the primary author, Dr. Adnan Kastrati, from the Deutsches Heart Center in Munich and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern. Really reviewing prasugrel versus ticagrelor for primary PCI in patients with STEMI only, and showing really no difference in their primary endpoint of death, myocardial infarction, and stroke, with however an increased risk of reinfection in the patients receiving ticagrelor only.
Dr. Greg Hundley:
So on behalf of Carolyn and myself, we wish you a great week and look forward to catching you next week On the Run. This program is copyright the American Heart Association, 2020.