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Circulation on the Run

May 6, 2019


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.

Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor as well, at Circulation, and Director of the Pauley Heart Center in Richmond, Virginia at BCU Health.

Dr Carolyn Lam:                Now, we've heard of the PIONEER heart failure trial and that is a sacubitril/valsartan in acute decompensated heart failure. A very important trial, but was powered on the surrogate outcomes. Now, in today's issue though, we're going to hear a little bit more about the clinical outcomes from the PIONEER heart failure trial, a very important paper, a very important discussion coming right up. Greg, what paper do you have to start us off?

Dr Greg Hundley:             Carolyn, I've got another favorite of our little discourse, your next Carolyn's Quiz. Except this time it's essay format, so it's open ended questions. And so here's my question to you. What paper addresses an important issue related to hookah inhalation. So Carolyn, do you know a little bit of the origins of hookah and then how does its use compare to e-cigarettes or conventional cigarettes?

Dr Carolyn Lam:                Oh, okay. Well at least the quiz wasn't asking if I smoke hookah. Okay, so hookah, that water pipe smoking pipe, fun stuff. I think, is it a Middle Eastern origin? And frankly I don't know of any data to say whether it is better or worse than cigarette smoking.

Dr Greg Hundley:             Yeah, you're exactly right. Hookah, it's a longstanding practice, primarily confined to men from the Middle East. But in the 1990s it was introduced with fruit flavored pre-packaged tobacco products and that ignited a sharp uptake of hookah smoking by young women and also men in the Middle East, and then a migration to our western culture. Now, believe it or not, in the United States and in the United Kingdom, hookah has a prevalence of 15% to 25% among university students. And today, twice as many secondary school children smoke hookah as they do cigarettes, and more adults have tried or currently use hookah than electronic cigarettes.

                                                So, what does this article discuss? Well, it focuses on hookah inhalation byproducts, because the charcoal traditionally is used to heat the hookah tobacco in the water pipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products, not only carbon rich nanoparticles and oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide, a putative vasodilator molecule that will dilate the arteries independent of endothelial dysfunction.

                                                So, this study enrolled three groups of patients. First, there were 30 26-year-old hookah smokers. Second, there were 20 in which the flavored hookah tobacco product was heated electrically, not by the charcoal. And then finally, 15 age matched cigarette smokers who smoked one cigarette.

Dr Carolyn Lam:                Wow, what was the result?

Dr Greg Hundley:             Unfortunately, nicotine levels increased similarly with all types of smoking. Now, flow-mediated arterial dilation, a marker of endothelial function, did not become impaired after smoking charcoal heated hookah, but instead increased by about 43%. In contrast, flow-mediated arterial dilation decreased by 27% after smoking electrically heated hookah, compared to the decrease after cigarettes smoking. For hookah smokers, vasodilation increased 138% times more than in the other two groups. Therefore, the acute endothelial dysfunction was masked by those high levels of carbon monoxide that are generated from the charcoal. Remember, carbon monoxide is a very potent vasodilator.

                                                What do we take away from this, Carolyn? With respect to large artery endothelial function, smoking hookah is not as harmless as discussed by an excellent editorial by Naomi Hamburg from the Whitaker Cardiovascular Institute at Boston University School of Medicine.

Dr Carolyn Lam:                Oh wow.

Dr Greg Hundley:             You know, importantly, the carbon monoxide is blocking our ability to appreciate endothelial dysfunction with traditional measures. So Carolyn, what about your article?

Dr Carolyn Lam:                Going from smoking to exercise, this one looking at intensity of exercise that should be performed after heart transplantation. This is a study from Dr Nytrøen and colleagues from Oslo University Hospital in Norway, and they performed a multicenter prospective randomized controlled trial of 81 patients at a mean of 11 weeks only after a heart transplantation. And these patients were randomized to either nine months of high intensity training, which is a four by four minute intervals at 85% to 95% of peak effort, or to moderate intensity continuous training defined as 60% to 80% of peak effort. And the primary outcome was the effect of high versus moderate intensity exercise on the change in aerobic exercise capacity assessed as VO2 peak.

Dr Greg Hundley:             So, what did they find here?

Dr Carolyn Lam:                First, it's important to note that it is the first study to test this and to show that the effect of nine months of high intensity training in de novo recipients of heart transplants produced a clinically meaningful, significantly larger increase in peak VO2 and muscular exercise capacity compared to moderate intensity continuous training. Importantly, the study also showed that the approach was safe with high adherence and high completion rates. 96% of patients completed the study, during which time the exercise adherence for both groups was 81% and there were no serious exercise related adverse events.

Dr Greg Hundley:             Wow. So it looks like we've been hearing about that in training and athletes. Are there any caveats?

Dr Carolyn Lam:                Yeah, and that's an important question. High intensity training in this study required one to one interaction with physical therapists, and of course that's not feasible in most cardiac rehabilitation programs. It also requires motivated, medically stable patients who can maintain high exercise intensity ranges. So further research is really required to determine if these initial improvements at peak VO2 and muscular endurance persist in the long-term period post heart transplantation and, of course, whether they're associated with favorable clinical outcomes. All this is discussed in a beautiful editorial entitled "Can a Hit Result in a Home Run?" by Mark Haykowsky, Wesley Tucker, and Peter Brubaker.

Dr Greg Hundley:             Carolyn, that's fantastic. In my next study, I'm going to switch over and discuss diabetes and the age of diagnosis of type two diabetes and its association with cardiovascular mortality and risk findings from the Swedish National Diabetes Registry. The study was conducted between 1998 and 2012 and the analysis cohort comprised 318,083 patients with type two diabetes mellitus matched with just under 1.6 million controls. Participants were followed for total mortality, cardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation.

Dr Carolyn Lam:                Huge study. Important question. What did it show?

Dr Greg Hundley:             Over a median follow up of about five and a half years, patients with type two diabetes diagnosed under the age of 40 years had the highest excess risk for the most common cardiovascular related outcomes. All risk attenuated progressively with each increasing decade. By the time type two diabetes was diagnosed at an age greater than 80 years, adjusted hazard ratios for cardiovascular disease and non-cardiovascular mortality were all less than one. In addition, survival for those diagnosed beyond 80 years was the same as controls, whereas it was more than a decade less when type two diabetes was diagnosed in adolescence.

Dr Carolyn Lam:                Okay, so Greg, what does this mean for us clinically?

Dr Greg Hundley:             The observations of this study amplify support for preventing and delaying type two diabetes onset in younger individuals and raises questions as to diagnostic strategies, as to whether we should even screen or implement management strategies for those individuals that are diagnosed with diabetes beyond the age of 80 years.

Dr Carolyn Lam:                Interesting. Well, for my last paper, I have a basic science paper and this one really provides insights into endothelial dysfunction. It looks at
S-Adenosylhomocysteine, which is a precursor of homocysteine, and elevated levels of these are positively associated with the risk of cardiovascular disease and with development of atherosclerosis, but its role in endothelial dysfunction has been unclear. So authors Dr Ling from Sun Yat-sen University in Guangzhou, China and Dr Ke from Shenzhen Center of Disease Control and Prevention in Guangzhou, China, these co-corresponding authors and their colleagues performed a series of elegant mouse experiments and showed that the inhibition of S-Adenosylhomocysteine hydrolase resulted in elevated plasma levels of S-Adenosylhomocysteine, which then induced endothelial dysfunction via epigenetic upregulation of the p66Shc-mediated oxidative stress pathway.

                                                Furthermore, plasma S-Adenosylhomocysteine levels were positively associated with oxidative stress levels and inversely associated with flow-mediated dilation and methylation of p66Shc promoters in patients with coronary artery disease and healthy controls. So, this study really provides a novel molecular insight into mechanisms by which this molecule, S-Adenosylhomocysteine, may be associated with endothelial injury and contribute to the development of atherosclerosis. So that brings us to the end of our summaries, Greg. Let's move on to our feature discussion.

Dr Greg Hundley:             Welcome everyone to the second half of our presentation where we have an outstanding interview with David Morrow from Brigham and Women's Hospital and Dr Justin Ezekowitz from Edmonton to discuss a letter that we've received, "The clinical outcomes in patients with acute decompensated heart failure randomized to sacubitril/valsartan or enalapril in the PIONEER HF trial. David, can you remind us just a little bit about, first, your New England Journal study, and then how this letter adds to the prior findings?

Dr David Morrow:            I think it's first worthwhile to place a little bit of context in that paradigm heart failure trial, which was a preceding trial in patients with chronic heart failure, who were ambulatory patients, who had to be tolerating a stable dose of an ACE inhibitor or an ARB, and could not have had a current acute decompensation of their heart failure, were randomized to sacubitril/valsartan versus enalapril with a significant reduction in major clinical cardiac events with sacubitril/valsartan. And that finding from that trial has led to changes in guidelines and clinical practice for patients with chronic heart failure with reduced ejection fraction.

                                                But there were several important aspects that still left gaps for our clinical care, in that because of a run in period in that trial, so a period where patients had to tolerate sacubitril/valsartan, the stability of the patients that I just described, it often left practitioners in the position of caring for patients who might not meet those inclusion criteria, particularly those patients who are hospitalized where there is an opportunity, often, to update their care to be consistent with current standards and current guidelines. And so we designed the PIONEER heart failure trial with that in mind, to study specifically patients with acute decompensated heart failure, all patients with heart failure with reduced ejection fraction. And they were randomized within hospital initiation after an initial period of stabilization to either sacubitril/valsartan or enalapril in a double blind, double dummy design.

                                                The primary endpoint for the PIONEER heart failure trial was a biomarker, so NT-proBNP, and we saw that there was a significantly greater reduction in
NT-proBNP by four to eight weeks as an average endpoint, by 29% more with the sacubitril/valsartan versus enalapril. And we also saw that the adverse events, the tolerability of the two regimens was similar and the event rates did not differ in the sacubitril/valsartan group.

                                                And so that was the primary result of the trial that was published in the New England Journal of Medicine. We had, in addition, some exploratory clinical end points, one of which was a broad composite which included all-cause mortality, the need for an LVAD implantation, referral for transplantation, heart transplantation, as well as rehospitalization for heart failure. And so, what was new in the letter that we have published in Circulation, is that we specifically looked at the clinical end points and additional exploratory end points, looking at the harder composite of cardiovascular death and rehospitalization for heart failure. And we had particular interest in that because it's being used as a primary end point that was consistent with the paradigm heart failure trial that I described in chronic heart failure. That was really the reason for undertaking this additional analysis.

Dr Greg Hundley:             So how did you define rehospitalization for heart failure and what did you find?

Dr David Morrow:            Rehospitalization for heart failure, we actually used the same clinical endpoint committee as for the paradigm heart failure trial and used the same definition, which requires that patients had clinical evidence of heart failure, which could include both symptoms as well as biomarker values and evidence of congestion on physical exam. We needed graphic evidence of pulmonary edema. Together, they had to have a clinical presentation that was consistent with heart failure, and then also who have been hospitalized for the management of that decompensation.

                                                And so what we found overall was that there was a significant reduction in cardiovascular death or heart failure with the sacubitril/valsartan over the eight week double blind study period, such that it was a 42% reduction in that end point and an absolute 6% reduction in cardiovascular death or rehospitalization for heart failure with sacubitril/valsartan compared with enalapril.

Dr Greg Hundley:             And David, looking at these fantastic figures, for listeners, please take a look at this letter, it looks like the two groups separated early. Can you suggest a mechanism for why that might've occurred?

Dr David Morrow:            We agree that it does appear that the separation begins early on. We did not have sufficient statistical power to test individual hypotheses much earlier time points, but the relative risk reduction appears homogeneous over that period. And when we look specifically at 30 days, for example, the relative risk reductions are comparable. So we do think that observation you just made is correct and consistent.

                                                And I think that there's evidence of support for rather early effects on hemodynamic stress. So we have the primary end point with NT-proBNP where we saw that there was separation between the groups that was actually statistically significant on that continuous end point of a natriuretic peptide value already by one week of therapy, which was quite remarkable to us. We had planned as our primary end point the four to eight weeks period where we had expected, based on previous work, that there would likely be a reduction in this slightly different population. But in fact we saw those curves in NT-proBNP separate already by one week. We've also had subsequent work that we presented in abstract form looking at other biomarkers such as troponin and soluble SD2, so biomarkers of wall stress and myocardial injury, and also seeing reductions in those markers that appear also to occur early on.

Dr Carolyn Lam:                Justin, can we bring you into this conversation here right now? What do you think are the clinical implications of this particular research letter and then perhaps of PIONEER in general?

Dr Justin Ezekowitz:        Thanks Carolyn, and my compliments to Dr Morrow and the team for putting this together as a research letter because that's often a challenge to get to the core information from the study. And I would, again, draw the listeners to get a look at the figures that they put together and especially the way in which they separate early out. And we did ask to be cautious with statistical power about rehospitalization, but it's quite a driving factor for the overall end point and one that shouldn't be lost, because that has the biggest probably clinical implications, that the curves separate early between the groups on an ACE inhibitor versus to sacubitril/valsartan. And given they separate early, one of the clinical implications is, why wait? So why wait for when people have been outside the hospital to change the medication but instead use that as an opportunity when they're in front of you as a clinician to consider switching them over to a newer therapy and consider what they’ve been on from the majority of patients being on an ACE inhibitor or an ARB, but it is the right time when you have them in observation.

                                                The second observation I would make from this study is that although this was done in high quality sites and sites that know how to do clinical research, but also those who take care of patients that are on high quality medications, the baseline medication rate use wasn't perfect. So there's dual opportunity for looking at the baseline medications, which was MRAs and beta blockers, and use it as opportunity and an implication to use all the best medications. And in this case sacubitril/valsartan would be an opportunity.

                                                My final point would be, I think this study is critical from a clinician's perspective, as we've seen many biomarker-based studies where there's a reduction in the biomarker, but the clinical end point doesn't seem to change so NT-proBNP is great, but here is the judicated clinical endpoints. So for me, when I'm treating a patient, that means more to me than the lowering of a biomarker. We've seen other evidence where that doesn't always pan out, and so you are confident now that that is the case.

Dr Carolyn Lam:                Well put, Justin. And you had a question, didn't you, for David?

Dr Justin Ezekowitz:        Right. One of the questions I was trying to sort through, and we couldn't squeeze this fully into the research letter, was there were some patients who were randomized in the hospital but the overall PIONEER program allowed for up to 10 days, and when you look at the patients and when they were randomized and how they were cared for beginning of the hospital, end of the hostel, right after discharge, was there any difference that you saw across the spectrum of outcome?

Dr David Morrow:            Actually, the study drug was initiated in hospital for all patients. We did provide up to 10 days while in hospital for the outer limits of recruitment into this study because we recognized that some hospitalizations for acute decompensated heart failure are quite lengthy, and we wanted to give sites the opportunity to recruit patients who took longer to stabilize in this study than others. So it was starting from 24 hours after hospital presentation up to 10 days as a maximum, but all patients were initiated in hospital.

                                                The median turned out to be at 68 hours and at least three-quarters of patients were recruited and randomized within 98 hours. So the vast majority were early on. Overall, when we look at the consistency of the effects of the primary end points of the natriuretic peptide and a broader composite, we did not see any evidence of heterogeneity based on the timing of randomization relative to presentation. As you pointed out earlier, we have to recognize that the numbers do get smaller across that tier, particularly when we get out to the later window. Still. I would say that the primary results, almost in any trial you should always go by the primary result, and we did not see any heterogeneity to think that there was a different effect in those who were enrolled early or late.

Dr Carolyn Lam:                David, can I just chime in and say again, congratulations on this great work. Can I go back to one of the points that Justin made a bit earlier? This being a research letter, could you maybe share with the audience a bit, what's it like to write and be constrained to such few words and a single figure?

Dr David Morrow:            Well, as Dr Ezekowitz said, it does present a little bit of a challenge. You have to be very concise. We certainly were fortunate that we could leverage the primary publication for the majority of methods and other design elements that we didn't need to recapitulate. And so I think for, in particular, this type of research where there was something that we felt was quite important scientifically with potentially important clinical implications, but yet still was an additional exploratory end point that we could express concisely, the research letter was a very reasonable format to do that.

Dr Carolyn Lam:                I couldn't agree more. But Justin, how about from the editor's point of view? Could you share about the research letter?

Dr Justin Ezekowitz:        My compliments to Dr Morrow and his team, as I asked him a lot of questions that required both expanding on the things they had to say while constricting the number of words at the same time, and that's a huge challenge to get findings across. So they were able to meet that challenge. I think one of the key things was really honing down as to what the key messages are, as Dr Morrow just alluded to, you can refer to the main complication or a baseline trial publication for all the other details, but what were the core things that could be demonstrated in a publication that is of a limited number of words, tables, or figures. And I think that's the key is, what is the real hypothesis and question to be answered. And that's the way we focused on all the efforts. I did appreciate that it was not easy not to have a lengthy discussion. So we had a ... in the written discussion we have really just truncated this down to a few key sentences which summarize the overall study, so the reader could pick this up and know what the implications are without actually having to go into a lot of the detail that we've just been speaking about.

Dr Carolyn Lam:                Ah, I love it. And thank you so much for this conversation too. That helps us go under the hood a little bit. I'm sure everyone who's listening just wants to pick this up now because it's so concise, so beautiful to read, and just look at the figure.

                                                Thank you everyone for joining us today. Don't forget to tune in again next week to Circulation on the Run.

                                                This program is copyright American Heart Association 2019.