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Dec 12, 2016

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage 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. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal.

The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms.

Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo.

In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases.

The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking.

First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders.

The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers.

Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers.

The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation.

These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways.

The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States.

Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model.

In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman.

The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction.

The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial.

Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level.

Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level?

We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims.

Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events?

Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.

Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find?

Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25.

Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions?

Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example.

Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses?

Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here.

I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50?

One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you.

We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies.

Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred.

Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall.

As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs?

That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial.

Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help.

Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

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