Oct 10, 2022
This week, please join author Michelle O'Donoghue and Associate Editor Parag Joshi as they discuss the article "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease."
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 co-hosts, 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 Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, very interesting feature this week. Evolocumab, another application for that in patients with established atherosclerotic cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other very interesting articles in this issue?
Dr. Carolyn Lam:
Oh, I'd love that. And I'd like to go first, because Craig, have you heard of hybrid debranching repair? I know, I know. I had that same look, and can I tell you about it? Because I found it so interesting.
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
Now, the management of complex aortic aneurysmal disease involving the visceral vessels is challenging due to its very high morbidity and mortality. After four decades of experience in open repair, only a few centers worldwide report laudable results. And numerous factors limit total endovascular repair, including the access to devices, experience in deploying them, and several anatomical restrictions. So, hybrid debranching procedures were introduced for those patients who are unfit for the open or endovascular excluded patients. And while these have been developed, small series have only been done and revealed a wide range of short term results. So, today's paper is very important, and it's from Dr. Oderich from UT Memorial Herman Texas Medical Center and colleagues.
It's a large multi-institutional study, which contains the five year outcomes in 200 patients offering greater clarity in the usefulness and limitations of these hybrid debranching repair procedures. What they found was that hybrid aortic debranching had a low early mortality when done in lower risk patients, but mortality remained very elevated in high risk patients. And so, this suggests that deep branching could be a good alternative in patients adequate for traditional open repair, although pulmonary complications are quite common. The bypass grafts to the visceral vessels had very good patency with a five year primary patency of 90%. Permanent spinal cord injury occurred in 6%, suggesting that deep branching in experienced centers may offer outcomes comparable to centers of excellence for open thoracoabdominal aortic aneurysm repair.
Dr. Greg Hundley:
Wow, Carolyn, very nice and so beautifully explained.
Dr. Carolyn Lam:
You know what, Greg? I'm on a roll and I'd like to tell you about one more, this time a preclinical study. First, a little bit about the background. You see, transplantation with pleuripotent stem cell derived cardiomyocytes, as we know, represents a very promising therapeutic strategy for cardiac regeneration. We even have first clinical studies in humans, but yet little is known about the mechanism of action underlying graft induced benefits. So in this paper from Dr. Weinberger from University Medical Center Hamburg in Germany and colleagues, they explored whether transplanted cardiomyocytes actually actively contribute to heart function by injecting these cardiomyocytes with an optogenetic off on switch in a Guinea pig cardiac injury model.
Dr. Greg Hundley:
Wow, Carolyn, this is so interesting. So what did they find?
Dr. Carolyn Lam:
So, light induced inhibition of endo-grafted cardiomyocyte contractility resulted in a rapid decrease in left ventricular function in about 50% of the animals that was fully reversible with the offset of photo stimulation. So in conclusion, this optogenetic approach demonstrated that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force generating myocardium can serve as a regenerative therapeutic strategy.
Dr. Greg Hundley:
Oh wow, Carolyn. That was just fascinating. Such incredible preclinical science in our journal. Well, Carolyn, this next paper comes to us from the world of myocarditis. And Carolyn, it involves a population based cohort of 336 consecutively recruited patients with acute myocarditis enrolled in both London and Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal Brompton Hospital, investigated the frequency and clinical consequences of dilated cardiomyopathy and arrhythmogenic cardiomyopathy genetic variants in this population based cohorts of patients with acute myocarditis. Now, Carolyn, all participants underwent targeted DNA sequencing for well characterized cardiomyopathy associated genes and their comparison to healthy controls, of which they had 1,053 that were sequenced on the same platform. Case ascertainment of their outcomes in England was assessed against their national hospital admission data, and the primary outcome was all cause mortality.
Dr. Carolyn Lam:
So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So these authors identified for dilated cardiomyopathy or arrhythmogenic cardiomyopathy associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of desmoplakin truncating variants in those with normal LVF, and then titin truncating variants in those with a reduced LVF. So Carolyn, importantly, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing would be considered in patients with acute myocarditis to help reassure the majority of individuals that don't have one of these genes, while improving the management of those that do have one of the underlying genetic variants. Very interesting findings from the world of myocarditis.
Dr. Carolyn Lam:
Great. And a great clinical take home message. Thank you, Greg. Well, this next paper sought to investigate the influence of age on the diagnostic performance of cardiac troponins in patients presenting with suspected myocardial infarction. Dr. Atul Anand from the BHF Center for Cardiovascular Science and University of Edinburgh and colleagues did this by performing a secondary analysis of the high stakes stepped wedge cluster randomized control trial that evaluated the implementation of a high sensitivity cardiac troponin ISA in consecutive patients presenting with suspected acute coronary syndrome.
Dr. Greg Hundley:
Oh wow. Carolyn. Super interesting, and very applicable clinically. So what did they find here?
Dr. Carolyn Lam:
In older patients presenting with suspected MI, the majority of cardiac troponin elevations are explained by acute or chronic myocardial injury or type two MI. The specificity and positive predictive value of high sensitivity cardiac troponin to identify myocardial infarction decreases with age and is observed, whether applying sex specific or age adjusted 99th percentile diagnostic thresholds or a rolling threshold for the triage of patients at high probability of myocardial infarction. Serial troponin testing incorporating an absolute change in troponin concentration increased the discrimination for myocardial infarction in older adults.
Dr. Greg Hundley:
Oh wow, Carolyn. Such clinically applicable findings in this particular study, particularly when managing our aging population. Well, Carolyn, how about we discuss some of the other articles in this issue. And there's a very nice In-depth piece by our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac Memory.” And then, there's an exchange of letters by Drs. Giannitsis and Mueller regarding the article, “Unexpected Sensitivity Issue of Three High Sensitivity Cardiac Troponin I-Assays in Patients with Severe Cardiac Disease and Chronic Skeletal Muscle Diseases.”
Dr. Carolyn Lam:
Nice. There's also a Research Letter by Dr. Szendroedi on “Impaired Mitochondrial Respiration in Humans with Prediabetes: A Footprint of Prediabetic Cardiomyopathy.” And there's a CV case series by Dr. Kalra on very high cholesterol mimicking homozygous familial hypercholesterolemia. Interesting case. Well, I suppose that wraps it up. Let's go on to the feature discussion, shall we, Greg?
Dr. Greg Hundley:
You bet.
Evolocumab. Welcome listers to this feature discussion on October 11th, and we're very fortunate today. We have with us Dr. Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag Joshi from UT Southwestern, the Associate Editor for this paper. Well, Michelle, can you describe for us some of the background information that went into the preparation of your study, and then what was the hypothesis that you wanted to address?
Dr. Michelle O'Donoghue:
Sure. Happy to do so, and thank you for having me. So by way of background, the Fourier study, which was previously published in the New England Journal, compared Evolocumab to placebo in 27,000 plus patients with established atherosclerotic cardiovascular disease, and Evolocumab significantly reduced the risk of major adverse cardiovascular events. But, the follow up duration was relatively short. Median follow up was 2.2 years. So this was now an open label extension study to Fourier known as the Fourier OLE study that allowed an additional median follow up time of five years, during which time all patients were now treated with open label Evolocumab. T.
He primary hypothesis that we were testing in this extension study was primarily to look at long term safety. We had limited data to really assure us of the safety of PCSK9 inhibitors over the course of several years. And so, safety was the primary hypothesis that we were testing, but also of course of key interest, during the parent Fourier study, we know that the benefit for cardiovascular risk reduction appeared to grow over time. So this was also an opportunity to see that pattern and to see whether or not there was in fact legacy effect for patients who were treated earlier with Evolocumab versus placebo.
Dr. Greg Hundley:
Very nice, Michelle. And so, sounds like we have a substudy of the Fourier trial. Can you describe for us a little bit more, for this substudy, your study population and your study design?
Dr. Michelle O'Donoghue:
Sure. So the patients enrolled in the open label extension were a subset of those who participated in the parent study. So as I previously mentioned, more than 27,000 participated in Fourier. It was a global study. For the open label extension, it was more than 6,500 patients who participated, and those were patients who were at sites in Europe and United States. And so, those patients were then followed on average for a meeting of five years. So that means that all together, patients who had been randomized to Evolocumab in the parent study had potentially more than eight years of drug exposure for us to examine safety.
Dr. Greg Hundley:
Very nice. And so, what did you find?
Dr. Michelle O'Donoghue:
Well, first, looking at the first hypothesis of safety, we saw no evidence that there was any increased risk of any adverse events of interest when it comes to PCSK9 inhibitors as a drug class, or achieving very low levels of LDL cholesterol. So there was no uptick in terms of neurocognitive events, the risk of diabetes. We do know that there was an increased risk of injection site reactions with the PCSK9 inhibitors, but not one that appeared to persist over time. So first was the safety, but importantly, I think that the more interesting results perhaps were those for MACE, for cardiovascular risk reduction. So we saw, even though all patients were being treated with open label Evolocumab during the extension phase, the benefit that was seen during the parent study persisted.
So there was a 15% reduction in the primary outcome, a broad composite of cardiovascular events. There was also a 20% reduction in the triple composite of cardiovascular death, MI, or stroke. And then perhaps of the most interest to your listeners is that there was a 23% reduction in cardiovascular mortality, and that was not something that was seen in the parent study. It really took time for that mortality benefit to emerge.
Dr. Greg Hundley:
Very nice. Michelle. Just a couple quick clarification points. Did you see these effects in both men and women? And then was there any impact of age on those results?
Dr. Michelle O'Donoghue:
Great questions. Some of those subgroup analyses are still ongoing, but no, we did not see any evidence of effect modification at first pass. But again, we'll be continuing to dig into all potential subgroups.
Dr. Greg Hundley:
Very nice. Parag, I know you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Parag Joshi:
Yeah, thanks. And congratulations again, Michelle. It's a really phenomenal study, and the findings, as you highlighted, are just really impactful for the field. I think for our journal at circulation, this is a really high impact finding in terms of extending out, giving us a rigorous way to look at long term follow up for people on PCSK9 inhibitors and really reassure that there is safety there. And as you highlighted, a sustained reduction in LDL cholesterol, other compounds in the space, Bococizumab in particular, that there were induced antibodies against the monoclonal antibody, and that sustained response was not there. So I thought that was also really reassuring, that over the course of eight years, we see sustained LDL reduction. And with that, really reaffirming the idea that the longer you can reduce LDL, there's an associated reduction in events.
And as you highlighted, the initial Fourier, there was some question about why there wasn't a CV death mortality signal while there was in the Odyssey outcome study and slightly different patient populations of course, but just really needed more time to start to tease that out. So all of this, I think this is the first that we're seeing this kind of long-term data on this impactful class of medications that really made this a fantastic manuscript for us at Circulation.
Dr. Greg Hundley:
Wow. Boy, Parag, I don't know that you could have stated that any better. So Michelle, looking forward, what is your group thinking? And then maybe just as your comment on the field in general, what do you think is the next study or series of studies that needs to be performed in this sphere of research?
Dr. Michelle O'Donoghue:
Well, I think he started to touch upon the areas of interest to us, is that I think that there are still many opportunities to answer more questions even within this existing data set. In particular, there was a dedicated neurocognitive substudy that was built into the parent study. And we also have that now through the extension period. So, that was a sort of more rigorous assessment of neurocognitive outcomes. And so, that's another analysis that we're going to be pursuing in the near future and I think is of potential key interest. And then beyond that, I think that the PCSK9 inhibitor class in general is just so interesting. There are additional compounds that are under study, such as small interfering RNA, so different mechanisms of getting to the PCSK9 protein. And I think it'll be reassuring to see whether or not they are consistent results, regardless of how you lower PCSK9, whether it translates into similar types of clinical benefit. So I think it's an exciting field. And then stay tuned. I think there'll be more to come.
Dr. Greg Hundley:
Parag, do you have anything to add? What do you see really as the next series of studies that might be performed here in this area of research?
Dr. Parag Joshi:
Yeah, I think Michelle hit the nail on the head that seeing confirmatory evidence here would be great. And then really, what's so exciting about this space is there's so much interest in ways to address this protein, including gene editing, vaccination against it. And now you're getting the necessary evidence that, hey, you can really suppress these levels in patients for years without concerning safety signals, at least from what we've seen so far. So that's more excitement as to long term ways to address cardiovascular risk.
Dr. Greg Hundley:
Wow. Well, listeners, we've been very fortunate today to have with us Dr. Michelle O'Donaghue from Brigham and Women's Hospital, and Dr. Parag Joshi from UT Southwestern as the Associate Editor of Circulation to really bring us these exciting results, highlighting that long term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events over eight years that did not exceed those observed in the original placebo arm during the parent Fourier study, and led to further reductions in cardiovascular events compared with delayed treatment initiation.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.