Circulation November 1, 2016 Issue


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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. Our interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

Well, those were your summaries! Now, let's on to Rome.

Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

Dr. Eric M. : Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

Dr. Carolyn Lam: That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

Dr. Mark P: Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

Dr. Carolyn Lam: OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

Dr. Mark P: Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

Dr. Carolyn Lam: With bypass compared to medical, yes.

Dr. Mark P: Exactly.

Dr. Eric M. : I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

Dr. Carolyn Lam: That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

Dr. Eric M. : I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

Dr. Mark P: Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

Dr. Carolyn Lam: You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

Dr. Mark P: I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

Dr. Carolyn Lam: Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

Dr. Nancy S.: So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

Dr. Carolyn Lam: Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

Dr. Mark P: So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

Dr. Carolyn Lam: Kudos to you, Nancy! And from your point of view, was it fun?

Dr. Nancy S.: It actually was fun.

Dr. Carolyn Lam: (laughs)

Dr. Nancy S.: You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

Dr. Carolyn Lam: [inaudible 00:21:34] how long?

Dr. Nancy S.: We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

Dr. Eric M. : First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in next week for more.

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