Circulation January 23, 2018 Issue

Dr. Carolyn Lam:               Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA.

Dr. Joseph Hill:                  I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.

                                                I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim.

Dr. Carolyn Lam:               Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial.

Dr. Dharam Kumbhani:  Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.

                                                At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.

                                                Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.

                                                One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field.

Dr. Carolyn Lam:               Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.

                                                Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think?

Dr. Dharam Kumbhani:  Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well.

Dr. Carolyn Lam:               Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it?

Dr. Dharam Kumbhani:  Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome’s investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.

                                                However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo.

Dr. Carolyn Lam:               That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic?

Dr. Joseph Hill:                  Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content.

Dr. Carolyn Lam:               Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are.

Dr. Joseph Hill:                  Absolutely.

Dr. Carolyn Lam:               That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but-

Dr. Joseph Hill:                  Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit.

Dr. Carolyn Lam:               Exactly. That was striking to me too.

Dr. Joseph Hill:                  From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital.

Dr. Carolyn Lam:               Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers?

Dr. Laura Mauri:                No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation.

Dr. Carolyn Lam:               Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction.

Dr. Joseph Hill:                  Your favorite topic.

Dr. Carolyn Lam:               Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that?

Dr. Laura Mauri:                Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.

                                                The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control.

Dr. Carolyn Lam:               Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial?

Dr. Laura Mauri:                Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients.

Dr. Carolyn Lam:               What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it?

Dr. Laura Mauri:                Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step.

Dr. Carolyn Lam:               That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six.

Dr. Joseph Hill:                  Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that.

Dr. Carolyn Lam:               Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting?

Dr. Laura Mauri:                I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print.

Dr. Carolyn Lam:               That’s great, and to discuss it as well.

Dr. Dharam Kumbhani:  Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year.

Dr. Carolyn Lam:               Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.