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Circulation on the Run

Dec 16, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart center and Duke National University of Singapore.

Dr Greg Hundley: And I'm associate editor, Dr Greg Hundley, from VCU Health, the Pauley Heart Center, in Richmond, Virginia.

Well Carolyn, our feature discussion, are results from the Odyssey study and they're presented by Professor Wouter Jukema from Leiden University Medical Center, regarding the relationship between ultra-low LDL levels in both ischemic and hemorrhagic stroke. The study really seeks to answer the question related to concerns that ultra-low LDL levels, less than 15 milligrams per deciliter, in patients treated for ischemic heart disease could increase the risk of hemorrhagic stroke, but more to come on that intriguing question. Carolyn, how about your first paper?

Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis from Humanitas Clinical and Research Center and Institute of Genetic and Biomedical Research respectively in Rozzano Milan in Italy. Now, these authors used single cell RNA sequencing to map the cardiac immune composition in the standard Murine non ischemic pressure overload heart failure model. They then integrated their findings using multi parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence in both the mouse and the human. And they found that despite the absence of infectious agents or an autoimmune trigger, induction of disease led to immune activation that involved far more cell types than previously thought. And that included neutrophils, B cells, natural killer cells, and mast cells. And this really opens up the field of cardio immunology to further investigation using toolkits that have already been developed to study these immune subsets.

Dr Greg Hundley: Ah, so Carolyn, do they have any specific examples?

Dr Carolyn Lam: Hmm, indeed they did. They found that activation lead to up regulation of key subset specific molecules such as pro inflammatory cytokine onco statin M in pro-inflammatory macrophages, and PD1 in T regulatory cells. Now these are significant because they may help to explain clinical findings such as the refractivity of heart failure patients to anti TNF therapy and cardio toxicity during anti PD1 cancer immunotherapy respectively, for the more these subset specific molecules may become useful targets for the diagnosis or therapy of heart failure.

Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is from Ambarish Pandey from University of Texas Southwestern Medical Center and it's entitled Incorporation of Biomarkers into Risk Assessment for Allocation of any Hypertensive Medication, According to the 2017 ACC, AHA High Blood Pressure Guidelines, a Pooled Cohort Analysis.

Dr Carolyn Lam: So I suppose asking does consideration of troponin or BNP inform cardiovascular risk in those with hypertension?

Dr Greg Hundley: Great question Carolyn. So in this study, the authors included participant level data from 12,987 participants across three cohort studies, ERIC, the Dallas Heart Study and MESA. And they were pooled excluding individuals with prevalent cardiovascular disease and those taking antihypertension medications at baseline. Participants were analyzed according to blood pressure treatment group from the 2017 ACC AHA Blood Pressure Guideline and those with high blood pressure, 120 to 159 millimeters of mercury, were further stratified by biomarker status.

Dr Carolyn Lam: Okay. So what did they find Greg?

Dr Greg Hundley: Participants with elevated blood pressure or hypertension, not recommended for any hypertensive medication with versus without either elevated high sensitivity, cardiac troponin T or N terminal pro BNP, had a 10-year cardiovascular incidence rate of 11% and 4.6%, with a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85 individuals respectively.

In addition, among participants with stage one or stage two hypertension recommended for antihypertensive medication with a blood pressure less than 160 over a hundred millimeters of mercury, those with versus without an elevated biomarker had a 10-year cardiovascular incidence rate of 15.1% and 7.9% with a 10-year number needed to treat, to prevent one event of 26 individuals and 49 individuals respectively.

Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does this mean we should be checking biomarkers in everyone?

Dr Greg Hundley: Great question again Carolyn. These results suggest that a biomarker based approach to cardiovascular risk assessment may help identify high risk individuals with elevated blood pressure or stage one hypertension who are currently not recommended for any hypertensive medication, according to the 2017 ACC AHA Blood Pressure Guideline, but who may benefit from blood pressure lowering therapy. And it seems the more we research blood pressure measures, the more we learn regarding individualizing targets for blood pressure lowering.

Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper sought to understand to what extent do drug costs, which are potentially actionable factors, contribute to medication non-adherence? A very interesting and relevant question, and this is from Dr Nasir from Yale New Haven Health System and colleagues who identified more than 14,000 US adults with a reported history of atherosclerotic cardiovascular disease in the national health interview survey from 2013 to 2017. Now participants were considered to have experienced cost related non-adherence if in the preceding 12 months they reported either skipping doses to save money or taking less medication to save money or delaying filling a prescription to save money. And they used survey analysis to obtain national estimates.

Dr Greg Hundley: Okay, Carolyn. So what did they find?

Dr Carolyn Lam: Listen to this. So they found that one in eight patients with atherosclerotic cardiovascular disease reported non-adherence with medications due to cost, representing nearly 1.5 million estimated patients missing doses, 1.6 million taking lower than prescribed doses and 1.9 million intentionally delaying a medication fill to save costs, all in the United States. Patients less than 65 years of age, had a three fold higher rate of medication noncompliance due to cost, with significantly higher rates in women and among patients from low income families and those without health insurance. Now the take home message I think is that the removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapies to reduce atherosclerotic cardiovascular disease, morbidity and mortality.

Dr Greg Hundley: Great paper, Carolyn. We've got a couple other articles in this issue. Let's just run through so our listeners get a synopsis. So Dr Javed Butler from University of Mississippi Medical Center has a nice white paper regarding heart failure endpoints in cardiovascular outcome trials of SGLT2 inhibitors in patients with type two diabetes. Dr Brahmajee Nallamothu in a perspective piece, discusses issues related to the legal prosecution of stent cases and the 70/30 rule. Remember Carolyn, the 70/30 rule, the operator may say a stenosis is 70% of an intracoronary luminal narrowing, but in review, others seem to think it's less than 30% and often these cases are prosecuted for performing coronary artery interventions on these lesions, but what Dr Nallamothu argues is perhaps, these definitions are really related to how that stenosis was measured. Are you taking approximately dilated segment or a distantly dilating segment as your reference point? Really interesting perspective piece.

The next article is from Dr Prateeti Khazanie at the University of Colorado in Denver and provides an on my mind piece with Dr Mark Drazner regarding ethical issues that arise during cardiac transplant allocation process. They review some of the pitfalls associated with current physician subjective assessments used for heart transplants in the United States. Dr Neil Kay presents another EKG challenge related to T, a new wave alternans and consumption of alcohol in association with combinations of antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist provides new data in a letter, a research letter, regarding the association of extracellular volume fraction and MRI measure of interstitial fibrosis in the setting of chronic mitral regurgitation.

And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter referring to an earlier publication related to LVAD adverse outcomes and cardiac transplantation. Well, shall we move on to that feature discussion?

Dr Carolyn Lam: Yeah, let's do that, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and we're very excited today to have Dr Wouter Jukema from Leiden University Medical Center who's going to tell us about the utility of PCSK9 inhibitors on the impact of both ischemic and hemorrhagic stroke. A large study that comes from the Odyssey study. Welter, we are so glad that you're with us this morning, afternoon, evening, wherever you may be in the world. Could you tell us, what were the thoughts behind putting this study together?

Dr Wouter Jukema: As we all know that patients with acute coronary syndromes, ACS, are at an increased risk for a subsequent stroke. And we also do know that lowering of atherogenic lipoproteins, including LDL cholesterol of course, reduces the risk of ischemic stroke in chronic atherosclerotic cardiovascular disease or recent ACS.

However, concerns have been raised about very low LDL cholesterol levels and the potential risk and increased risk of hemorrhagic stroke.

So the effect of lipid lowering by PCSK9 inhibition, both ischemic and hemorrhagic stroke is actually not fully determined. So what we therefore did to better investigate this is that in the obviously outcomes trial, the main publication was of course in New England Journal of Medicine already, we did a pre-specified analysis. We was designed to assess the effect of LRO come up on the ischemic as well as on the hemorrhagic stroke in patients with a recent ACS in obviously outcomes, all patients had a recent ACS and we have hypothesized that for patients treated with LRO come up that would be one, A, a reduction in risk of ischemic stroke, B, without an increase in hemorrhagic stroke. And we also hypothesize that the results would be irrespective of baseline LDL cholesterol and the history of cerebral vascular disease.

So that was our background and objectives and we investigated this in urology outcomes trial a huge, huge trial. If you may all recall post ACS patients one to 12 months post ACS, they all had a run in period two to 16 weeks of high intensity or maximum tolerated dose of atorvastatin or rosuvastatin, and then you had to meet certain lipids criteria and then you were randomized to LRO come up circuitously every two weeks or placebo. And of course all the patients and investigators were blinded to lipid levels and treatment location. So this was a design.

Dr Greg Hundley: Wouter that was a fantastic description of why we're studying this particular series of issues as both ischemic and hemorrhagic strokes.

Tell us a little bit about your study results?

Dr Wouter Jukema: We looked at the entire population of the Odyssey outcomes trial. This is almost 19000 patients and then we looked if they had a history of prior cerebral vascular disease or we have no history of cerebral vascular disease. The majority, almost 18000 did not have a history of cerebral vascular disease and over 900 did have a history of cerebral vascular disease. And we've also looked at our baseline LDL cholesterol levels. Well, if you can of course, be sure we appreciate people with history of cerebral vascular disease or way out, there are a different study population. So that's of course what you may expect anyway. And that's what we saw.

But regardless if you have the history of a vascular disease or you didn't have that, we saw a reduction of any stroke and actually it was 28% reduction of any stroke, which is quite impressive, in my opinion, as highly significant with a P value of point 0.05 and then afterwards of course, we tried to split it in ischemic stroke and hemorrhagic strokes.

So as I told you, any stroke was reduced with 28% and if you then look at ischemic stroke, it was 27%. Also significant at the P value of 0.01. And then of course, the big question, what would happen with hemorrhagic stroke. And actually this was numerically less also in the LRO come up group. So there was not only a reduction in any stroke, but also in ischemic stroke. But also in hemorrhagic stroke, but this was 17% and then of course you are in the low numbers. So the ischemic ratio for hemorrhagic stroke was 0.83 in favor of LRO come up. And of course that by itself is not significant to the low numbers, but numerically there were less hemorrhagic strokes on top of that, there were less ischemic strokes and that was, I think a very reassuring finding. And the interesting part is that these results were more or less independent.

If you have a history of cerebral vascular disease are not, so people without a price were benefiting and with a price were benefiting. And it was also statistically independent of your baseline LDL cholesterol level. So the results were basically the same. If you had a baseline LDL starting below 80 between 80 and 100 and over 100 the results were the same. LRO come up was always better than placebo. If you look at the data, you could see that it was perhaps doing slightly even better if you had a slightly higher cholesterol from the start, which is conceivable. But the formal test returned 80 did not say show any difference. So you could say the beneficial effect of other LRO come up on stroke in post ACA patients is independent of your history of cerebral vascular disease, is independent of your baseline LDL. LRO come up is just better for ischemic strokes as well as for hemorrhagic strokes at least there was no sign.

Never mind add to that, we did even go one step further and we looked at the risk of hemorrhagic stroke in relation to the HG LDL cholesterol level. So not your baseline LDL cholesterol level, but the achieved LDL cholesterol level in the LRO come up group because there you find the, of course very low numbers and we divided them and below 25 milligrams per deciliter, which we could continue really low between 25 to 15, 15 to 17 over 17 and the numbers of hemorrhagic strokes were exactly the same, always 0.1, 0.2, 0.3%. So very low. And it was certainly not the case that they do very low numbers. We saw more hemorrhagic strokes. So this is again very reassuring data. So even at very low levels of LDL during the trial. Of course we should realize that this trial is of course only a medium duration of two per date, but we didn't see more erratic strokes.

So in my opinion, this is very reassuring data.

Dr Greg Hundley: Very good. I loved all that analysis of subgroups. I want to ask you one quick subgroup question. Was there any difference in outcomes related to gender or age?

Dr Wouter Jukema: As far as we could see there was no differential effect in gender nor in age. Of course you should realize that in very advanced age, of course the numbers get small and if you then start dividing them again in the history of stroke or not, then of course the numbers will get low. But in general there is no age or gender difference.

Dr Greg Hundley: Fantastic. So where do you think, does this field progress from here and what do you think will be the next study that we need related to PCSK9 inhibitors and adverse effects?

Dr Wouter Jukema: I think we have shown now that patients with a recent ACS and dyslipidemia, despite incentive therapy, they do benefit from the PCSK9 LRO Come up, which is reflected by a decrease in the risk of stroke. You should of course realize that this is a post ACS population, so it was not targeted in a post stroke population. This is a atherosclerotic disease population, so the results are applying for an atherosclerotic population of course, many people that have a stroke in the past may have and also from embolic processes from a FIP or whatsoever, and those results may be the same but may of course they may also be different. So that situation was not tested here. This is a atherosclerotic post ACS population. Of course you may be interested in what would happen with strokes in an embolic population with a FIP and that would of course be a very nice trial to do as well. But then you have to do an entirely new trial. And some of these trials are of course underway, but I cannot, with my publication circulation, I cannot provide you with the answer.

Dr Greg Hundley: Well listeners, we've had a great discussion on our feature article today from Dr Wouter Jukema from Leiden university medical center and really some important insights related to PCSK9 inhibitors and the fact in this study, a large study, a sub study from Odyssey that indicates really no increase incidents of both hemorrhagic or ischemic stroke in patients that receive these agents and had previously sustained acute coronary syndromes.

I want to wish you all a great week and on the half of Carolyn and myself. Hope to see you next week. Take care now.

This program is copyright American heart association 2019.