Circulation November 14, 2017 Issue

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Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and back-stage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center and Duke National University of Singapore.

What is the evidence we have for LDL-lowering therapy in primary prevention? For individuals with an LDL cholesterol above 190 mg/dL, well, you may think you know the answer, but today's featured discussion may surprise you like it did for me, and this is a must-listen in my opinion for those of us taking care of these patients. More soon right after these summaries.

How can we enhance the survival and therapeutic potential of human pluripotent stem cell-derived endothelial cells? Well, the first paper in today's journal tells us how. The first author Dr. Lee, corresponding doctor Dr. Yoon, from Emory University School of Medicine in Atlanta, Georgia, developed a novel, fully-defined, cell culture system to generate endothelial cells from human pluripotent stem cells. They not only showed that these endothelial cells had pro-angiogenic activities and exerted favorable therapeutic effects in repairing limb ischemia, but also showed that encapsulation of these cells in a biocompatible peptide amphiphile nanomatrix gel improved long-term survival of these endothelial cells in an ischemic environment and improved vessel-forming properties. This novel cell culture system and gel-mediated transplantation may serve as a novel platform for cell-based therapy.

The next study brings us one step closer to application of immunomodulatory therapies in pulmonary arterial hypertension. In the study, first author Dr. Saito, corresponding author Dr. Rabinovitch, and colleagues from Stanford University School of Medicine isolated lung immune complexes and pulmonary arterial hypertension target antigens from lung tissues from 16 patients with pulmonary arterial hypertension and 12 controls. SAM domain and HD1 domain-containing protein, which is an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from patients with pulmonary arterial hypertension. These immune complexes resulted from elevation in products of human endogenous retrovirus K. The human endogenous retrovirus K deoxyuridine triphosphate nucleotidohydrolase, or dUTPase, activated B cells, elevated cytokines and monocytes and pulmonary endothelial cells, and increased pulmonary arterial vulnerability to apoptosis, thus contributing to sustained inflammation, immune dysregulation, and progressive obliterative vascular remodeling. Furthermore, rats treated with the human endogenous retrovirus K dUTPase developed pulmonary hypertension. In summary, this study suggests that harnessing mechanisms that repress human endogenous retrovirus K expression and its sequelae could prevent and reverse pulmonary arterial hypertension.

The next study looked at the association of timing of coronary angiography with ischemic outcomes of non-STEMI who are at high risk with a Gray score of more than 140 in the TAO Trial. In this report from first author Dr. Deharo, corresponding author Dr. Steg, and colleagues from L'Hopital Bichat from Paris, France showed that in these high risk, non-STEMI patients, a very early invasive strategy of coronary angiography within the first 12 hours was associated with a lower risk of death in MI at 180 days compared to an early strategy of between 12 to 24 hours or a delayed strategy of between 24 and 72 hours. The bleeding risk was not different between patients managed with the very early, early, or delayed strategy. These observations deserve prospective confirmation in a randomized trial.

The next study provides contemporary mortality trends for STEMI and non-STEMI. In this paper from first author Dr. Puymirat, corresponding author Dr. Danchin, and colleagues from Hopital europeen Georges-Pompidou in Paris, France, the authors assess trends in the characteristics, treatments, and outcomes for EMI from five month-long registries conducted five years apart and spanning 1995 to 2015, including more than 14,000 patients admitted to cardiac intensive care units in metropolitan France. They observed major changes in the characteristics and management of both patients with STEMI and those with non-STEMI over the last 20 years. The mean age decreased in patients with STEMI and remained stable in patients with non-STEMI, whereas diabetes, obesity, and hypertension increased. At the acute stage, intended primary PCI increased from 12 to 76 percent in patients with STEMI. In patients with non-STEMI, PCI within 72 hours from admission increased from 9 to 60 percent. In parallel with these changes, six-month mortality consistently declined in patients with STEMI, whereas in patients with non-STEMI, six-month mortality reached a plateau after 2010. The authors concluded that future challenges will be to reduce pre-hospital mortality and to improve long-term survival after the acute myocardial infarction event.

That wraps it up for your summaries. Now for our feature discussion!

What evidence do we have from randomized trials supporting the benefit of LDL cholesterol lowering as primary prevention among patients with an LDL cholesterol above 190 mg/dL? You may be surprised to know that until today's journal, we had very little trial evidence supporting this. But I'm so pleased to have with us the corresponding author of our featured paper today, Dr. Kausik Ray from Imperial College, London, who's going tell us a bit more and discuss this very intriguing paper with our Editor for Digital Strategies, Dr. Amit Khera from UT Southwestern. Welcome, both.

Dr. Kausik Ray: Hi.

Dr. Amit Khera: Thanks for having us.

Dr. Carolyn Lam: Kaus, you are a familiar voice and so pleased to have you here. Please tell us, is this the first evidence we have from a randomized trial for primary prevention in those with LDL above 190? Tell us about it.

Dr. Kausik Ray: Yeah, it is. It really came about because we were interested in familial hypercholesterolemia and we used the level of 190 to talk about either primary hypercholesterolemia, which may have a genetic basis, or not. I kept hearing that there is no trial evidence, so you're not going to be able to ethically do a trial today despite the fact there's not much evidence, because most of us think that it's a bad thing to leave people on placebo in patients above 190, so I thought the only way to do this was to go historically to the WOSCOPS Study, which is, as you remember, 6,500 people, elevated LDL cholesterol. Interestingly, you go to WOSCOPS, the median LDL in that population is very close to 190. So, that gives a good starting point, thinking that we'll have at least half the population.

Now interestingly in WOSCOPS, although none of the patients had a history of myocardial infarction, a very small number of the 6,500, about 1,000 actually had evidence of some other vascular disease, so maybe a TIA, maybe angina, maybe some sort of ECG non-specific change of coronary disease. Today, you would say, well, actually, you've got to give these people a statin because there's evidence of vascular disease, PVD, et cetera. So we had to take those people out and that left us with 5,529. Once you break people down by LDLs above and below 190, you have 2,560. You could actually look at the randomized treatment effect of pravastatin, which was the statin chosen, over a five year period both above and below 190.

But interestingly, this was the first study and what we showed was that in this population, even with as little as 23% reduction in LDL cholesterol, over a five year period, you saw a statistically significant 27% reduction in CHD and if you take the usual 3 point MACE of current clinical trials, there was a 25% reduction, already statistically significant. We also had the ability to link data over 20 years. Remember, after the five year randomized treatment period, it becomes observational in nature, but what it showed was that when you gave nearly 40% in each arm statins and you followed people up this legacy effect, over a 20 year period, the people with the LDL above 190, that translated into this 28% reduction in CHD death. It translated into a 25% reduction in CV death, and actually an 18% reduction in all-cause mortality, which you didn't see in the population with slightly lower LDL cholesterol.

This is the best evidence we're ever going to get, really, and answer the question about what should we do in this patient population. Should we treat with lipid-lowering therapy? The answer, unequivocally, is yes, and the longer you treat, the more likely you are to see survival benefits.

Dr. Carolyn Lam: Oh, my goodness! I just love his paper. I have to humbly admit. I mean, it's in the guidelines already that we should treat these individuals with LDL above 190, and it really made me think how I'd taken for granted that there would be a whole body of evidence behind it from randomized trials, and you are right! This is the first, and likely going to be the last we're going to get, because we can't randomize them. So, congratulations. What you said just now, I can already hear myself playing this podcast to my patients. May I just ask, are there other remaining questions to answer, and then what do you also say to those that say, well what are the harms? How do you balance that with any potential harms?

Dr. Kausik Ray: In this particular study, given there was overall safety data observed in the WOSCOPS Trial population and in their extended follow-up in the overall 6,500 person cohort, we didn't go on and look at that. There was no evidence of harm in the extended follow-up of 6.500 people, so we didn't see the potential added gain in specifically looking for that. The main question we wanted to answer, because people had always pulled primary and secondary prevention patients together, and in fact, your best evidence is actually from CTT, pooling of primary and secondary prevention patients where they break the data down by an upper limit of about 175. With patients above 175, they don't specifically answer that question. So, to answer your question, we didn't look at that in the overall WOSCOPS Trial population. There was no signal for harm that was noticed. Even things like glucose elevation, if you remember in WOSCOPS, tended to be a little bit lower.

Dr. Amit Khera: Let me comment on a few things about this paper. First, I want to congratulate Dr. Ray and his colleagues. I was a history major and I think this is a great use of a historical tool. At this point, I think we can talk about WOSCOPS. It's 22 years old. It is part of the medical history and a very seminal article. I think they got creative because, as he mentioned. We have guidelines that support this treatment, but this is almost an unanswerable question, whether you say it's from ethics, or from equipoise, it was essentially unanswerable. So, they had to go back and take this historical study where practice patterns were different, to be able to look at this question. It was pointed out, there's pretty clear evidence in here and I think if you look at that during the five-year study period of the randomized period, pretty clear evidence that treating participants with LDLs above 190 without vascular disease certainly lowers cardiovascular disease events.

One of the best things about working on the editorial board is being able to work closely with authors, and I have to also thank Dr. Ray and his colleagues for being so gracious in working with us closely in some modifications as this went along. We hope, and I hope he feels this way, too, that at the end of the day, the product ends up being even better than where we started. That's our goal is to really help and work with authors in that way and they were incredibly responsive. The two things I thought they did really well that were insightful to the US guidelines and beyond. One is they also restricted to the group without diabetes, without ASCVD less than 7.5%, and some other parameters to really hone down on what we have in the current US guidelines and still the finding was consistent that the statin therapy benefited that group.

The other part was just acknowledging that the legacy part, the long-term effect, is really valuable. They published heavily in this area, but at that point, it becomes an observational component. It's not part of the randomized period. The reason that adds value, if you look at our guidelines above the age of 21, an LDL above 190 can be treated with a statin, there would be less controversy if your LDL was 200 and you're 55, but if you're 22 or 23, I think there may be more angst. That's where the long-term data is important, because we're not looking necessarily always at 10 years, but we're looking at 20 or 30 or 40 or 50 years. I think this does at least shed some light. I appreciate the study population was older, but a least it helps us look at maybe some of the long-term benefits.

If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus, when you guys did this, the group with the LDL less than 190 had essentially similar benefit. The p-interaction was no. I think we have to acknowledge that the LDLs were higher in that group than what would seem because the lowest level was 155. Is it above 190, or should it be above 160 where we treat patients with statins?

Dr. Kausik Ray: Yes, and I really want to thank the editors, because there were certain things that you pushed us with analyses and I think that you could make the case that if you have a LDL cholesterol above 155, over a five-year randomized treatment period, there was a significant reduction in CHD and MACE as well. So, you could make that point that actually the cutoff should perhaps be pulled down even further to about 155. What's interesting is, these groups, when you broke them down, age was identical, BMI was identical, blood pressure, and everything else. The only thing that was different, really, was the LDL cholesterol, which impacted on total cholesterol. TGs, HDLs were absolutely identical. I think you could probably make the case.

I think the one thing that we didn't see, although it's observational in those with slightly lower LDL cholesterols, is that over the 25 year period, they seem to get slightly less mortality benefits. Now, that could be a chance finding, because it's observational. We don't really know the implications of that, but I think over a five-year period, this is the best evidence you're going to get for primary prevention, right?

Dr. Amit Khera: Agreed. The US guidelines do say above 160, it's a point of consideration. It can be a factor to consider as we think about treatment, so perhaps this helps bolster that point as well.

Dr. Kausik Ray: It's not just the American guidelines. In the European guidelines, when they use score, if you look at LDL cholesterol levels, the European case fatality 10 year risk is 2.5%, which is equivalent roughly to 7.5% fatal and non-fatal MI in the pooled cohort equation. There they still have diet and lifestyle, but it says, "Consider pharmacological," and one of the things I thought was really interesting is if you did a 10 year risk calculation in this group, 67% of the population with an LDL above 190, you would have said the predicted 10-year risk was below 7.5%, but the 10-year observed risk was double that. It was 15%. If you did the same thing for the group between 155 and 190, your ten-year risk predicted would be in most of these people, you would have said about 90% actually are less than 7.5%, so you wouldn't have given them a statin. But, their observed event rates in the placebo group was about 11%.

So, I think that it tells you if you have an isolated elevated cholesterol above 155, you're probably going to be underestimating risk if you're using global risk score, and perhaps a discussion with the patient about risks and benefits in the way that most of us try to do and citing data like this might encourage patients to actually start that therapy earlier, which most of us probably believe from genetic and legacy effect is probably beneficial. That's one of the other implications of this.

Dr. Amit Khera: This is why one has to read not just the abstract, but all the details, because there are so many kernels of interesting findings in this paper beyond just the highlights that we hit upon.

Dr. Carolyn Lam: Thank you both for just a marvelous discussion of an incredible paper that is really, really going to be extremely clinically relevant. We're so proud to be publishing this in Circulation this week.

Audience, you heard it right here. Don't forget to tune in again next week as well to Circulation on the Run for even more hot news.

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