Preview Mode Links will not work in preview mode

Circulation on the Run

Jan 21, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts of Circulation on the Run and if you don't know what this show is about, well, you have to listen to the previous episodes in January please.

                                I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:   I'm Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, before we pick up our coffees and begin discussing a couple of the paper, let's just tell everyone that this feature paper, they have to listen to because it is the results of the cardiac amyloidosis section, or sub-set of the APOLLO study. Have to listen to this one. But how about the other papers in today's issue Greg?

Greg Hundley:   Right Carolyn, the first one I'm going to start with is from Alexander Fanaroff at Duke University and the DCRI. And basically, this particular paper was looking at the procedural volume and how that might affect outcomes with those that are performing PCI. So they divided the cohort into those individuals that had less than 50 PCIs per year, 50 to 100 and then greater than 100 PCIs per year. So, this is looking at our national cardiovascular data registry within the United States, and of course, as you know, that's linked to Medicare claims data for those that are over 65 years in age. So they had 723,644 PCIs performed by 8,936 operators. And the surprise in this study was that those low volume operators, less than 50 PCIs per year had a one year rate of 15.9% of MACE as opposed to those that were high volume operators that had 16.9% MACE rates. That was significant at a P value of .004.

Dr Carolyn Lam: Wait a minute, this seems different from prior reports. Are you saying that those with low volume operators actually had lower mortality?

Greg Hundley:   Yeah, exactly. And you've pointed out something, cause previously what's been shown is that high volume operators have lower 30 day and in-hospital mortality rates. And that was actually confirmed in this study. But out of a year it was really the low volume operators in unadjusted results had lower rates of all MACE.

                                A very nice editorial by Dharam Kumbhani from UT Southwestern points out that high volume operators do tend to take on more serious cases, those with higher numbers of cardiovascular risk factors. And so, when they did adjustments and accounted for all those risk factors, actually the event rates were the same. Still though, they're the same. And so what could be going on? And the editorialist and also the authors of the paper point out, "Hey, maybe we shouldn't just be focusing on PCI volume per operator, but other quality metrics to look at outcomes. And so this really builds in to the whole quality discussion. Adherence to therapy with the patients in your health care system. What about operator longevity? An operator that may have been doing this for 10 years but has a lower volume, maybe that could come into play. So future studies I think, certainly all over the world in this field, this paper's going to direct us to focus more on other quality issues and not just procedural volume.

Dr Carolyn Lam: So, quality versus quantity. Interesting.

                                Well switching gears to a paper that I thought was nice, it is from Dr Lubitz from Massachusetts General Hospital in Boston and colleagues, and they sought to answer the question of whether refining a phenotypic classification of heart failure would facilitate genetic discovery. So, to do that, they defined all cause heart failure among almost 500,000 participants in the UK bio-bank and performed a GWAS study and then later refined the heart failure phenotype by classifying individuals with left ventricular dysfunction but without coronary artery disease as having nonischemic cardiomyopathy and then repeated the GWAS. And basically they found that the GWAS in the all cause heart failure yielded multiple genetic signals for known heart failure risk factors, such as coronary artery disease and atrial fibrillation.

                                However, after refining the heart failure phenotype to a nonischemic cardiomyopathy sub-set, this enhanced the detection of genetic loci associated with dilated cardiomyopathy, which appeared to operate independent of the traditional heart failure risk factors. So that was pretty interesting.

Greg Hundley:   So where do we go from here with that Carolyn? I mean, what is this telling us and how are we going to move forward with this information?

Dr Carolyn Lam: I think the clinical implications are first that common genetic variants associated with both clinical and sub-clinical heart failure, because they looked at left ventricular dysfunction, these genetic variants may be leveraged to improve heart failure risk prediction and prevention. But obviously future studies are warranted to investigate the prognostic and therapeutic implications of these findings.

Greg Hundley:   Very good. Well I'm going to take us back into the cath lab again and we're going to address fractional flow reserve. And remember, typically, we get fractional flow reserve measures using guide wires, and that's kind of a tough thing to do sometimes in terms of adding links to the procedure, etc. So what these investigators did, they had 10 centers in the United States, Europe and Israel. And this was William Fearon from Stanford University who did this study. And they looked at 301 subjects and they had 319 evaluable vessels. Now what did they compare? They looked at guide wire derived fractional flow reserve versus angiographic derived. Simply, just when you're doing the injections, looking at how quickly that contrast flows down the coronary arteries.

                                And so, in this study the mean fractional flow reserve value was 0.81 and 43% of the vessels they studied had an FFR less than or equal to that magic number of 0.8. Interestingly, the angiographic obtained FFR measures were 94% sensitive and 91% specific for identifying the guide wire derived FFR. That's really incredible. And importantly, the accuracy of this contrast measure was 87% for FFR values between 0.75 and 0.85, that magical threshold.

Dr Carolyn Lam: Well that is impressive, suggesting that we don't need guide wires. I mean, is that true for all patients? All vessels?

Greg Hundley:   Right, so that's sort of the kick here, this is really interesting new data but let's look at the patients that they studied. First of all, they were relatively stable I would say. They had either angina or maybe even unstable angina and non-ST elevation MIs. But no ST elevation MIs. The average stenosis by angiography that they looked at was about 63% and then, very importantly, you have to look at the exclusion criteria. So things that, other conditions within the heart that are going to impact FFR were excluded. So, all their patients had an EF greater than 45%. Nobody had a CABG. Nobody had a chronic total occlusion. Nobody had a heart transplant, aortic stenosis, no heart valve surgery, no left main. It couldn't have had a recent stent within 12 months. It couldn't have had severe diffused disease, no collaterals, no in-stent thrombosis or stenosis. So this technique I think could be useful when you've got that patient perhaps with stable angina, single vessel disease, stenosis severity of 50 to 60% and none of these other conditions, preserved EF etc. But for many of the patients that we send to the cath lab, this technique, we still need a little bit more development. We don't know its utility. You've got another paper?

Dr Carolyn Lam: I've got another few papers because I'm going to drag you out of the cath lab right now and into the ICU. And we're talking about cardiogenic shock and it's really nice that we have these three papers in today's issue. One's an original paper and two are On my Mind articles. Now the original paper talks about the randomized shock cool trial. This is from Dr Thiele from the heart center Leipzig in University Hospital in Germany. And it is an un-blinded, randomized trial of 40 patients with cardiogenic shock undergoing primary percutaneous coronary intervention. And without a classical indication from mild therapeutic hypothermia, but randomized one-to-one to mild therapeutic hypothermia for 24 hours versus control. And basically the mild therapeutic hypothermia did not show a substantial beneficial effect on the primary outcome of cardiac power index at 24 hours or on any other of the hemodynamic parameters. And there was also no difference in the short and long term outcomes. So a neutral trial.

                                But taking a step back and just talking about these patients with cardiogenic shock and all the different ways that we have now to keep them alive, I really want to highlight these two On My Mind papers. One is by Drs Gill, Grunau and MacRedmond from University of British Columbia. And they really talk about the need to define limits for extracorporeal cardiopulmonary resuscitation. In a very similar vein, Drs Mulaikal, Nakagawa and Prager from Columbia University also wrote a beautiful piece on ECMO, ECMO as a bridge to no recovery. And when is enough enough? So really, really interesting conversations and discussions regarding what is death, when do we have to put a time limit perhaps to these therapies? And yet not limit the potential life-saving effects of these. I really strongly encourage our listeners to read these papers and also to stay tuned because coming right up, a very important paper on the APOLLO study in our feature discussion.

                                For today's feature paper we're discussing the results of a sub-study of the APOLLO study. Now this deals with cardiac amyloidosis, a super, super hot subject. And we have super, super hot guests today on the show. The first our corresponding author, doctor Scott Solomon from Brigham and Women's Hospital as well as our associate editor doctor Justin Ezekowitz. Welcome both, and let's just plunge straight into it. So Scott, tell us, tell us about this APOLLO sub-study.

Scott Solomon: APOLLO is a study of patients with hereditary transthyretin amyloidosis and, as you know, that hereditary transthyretin amyloidosis is an inherited disease caused by mutations of the transthyretin gene and these mutations cause the transthyretin protein to misfold and then accumulate as amyloid fibrils which go to the nerves and go to the heart. And we know that this can cause severe polyneuropathy and cardiomyopathy, partly depending on which mutation the patients have. And we, as cardiologists, are aware that when amyloid infiltrates the heart it can increase cardiac wall thickness, it can cause increase in chamber stiffness, it can result in severe diastolic dysfunction and these patients, often with cardiac involvement of amyloid, have a really markedly reduced life-span and really poor quality of life.

                                The APOLLO study was a study of a new agent that is designed to reduce transthyretin, it's a transthyretin knock-down agent. It's basically an RNAi therapeutic, it basically is a small, interfering RNA that basically blocks the production of transthyretin and this is one of several approaches that are currently being considered for amyloid disease. And APOLLO is primarily designed as a study to look at neuropathy. The primary end-point was a neurologic scale to look at neuropathy, but it was also designed to secondarily look at some cardiac end-points, especially in the patients who were felt to have cardiac involvement.

Dr Carolyn Lam: Cool. And so your current paper deals with that cardiac amyloidosis sub-set, but it was pre-specified, it was planned, right?

Scott Solomon: Yeah, it was a pre-specified sub-group. In fact, what we did is we actually did echocardiograms on everybody in the study and then defined a pre-specified cardiac sub-population that was comprised of patients who had a very high likelihood of having cardiac amyloid involvement, and so this was patients who had a baseline left ventricular wall thickness of 13mm or greater and no history of either aortic valve disease or hypertension. And so this was a group that we thought most likely had evidence of cardiac involvement. And just so it's clear, we did echocardiography on everybody in the study and in this paper we reported in both everybody and in the pre-specified cardiac sub-population. So we looked a number of things in these patients including various measures of cardiac structure function including wall thickness, left ventricular mass, ejection fraction, cardiac output, atrial size, volumes and myocardial strain which, as you know, has been particularly useful in assessment of patients with amyloidosis. And we also looked at reduction or improvement in Anti-proBNP which, as you know, is a very good measure of the severity of heart failure in patients.

                                And so, of the 225 patients who enrolled overall in the APOLLO study, 126 were part of this pre-specified cardiac sub-population. And in this group of patients, we've observed a reduction in left ventricular wall thickness of about a millimeter. And this was statistically significant in the patients who were treated with patisiran compared with placebo. We also saw an improvement in global longitudinal strain and improvement of cardiac output and an increase of left ventricular end-diastolic volume. In this case an increase in end-diastolic volume is actually a good thing because these patients often start out with smaller end-diastolic volumes because of the increased wall thickness. Those improvements in echocardiography were really paralleled by dramatic improvements in Anti-proBNP and we started out with patients with abnormal Anti-proBNPs in the range of about 800. These were significantly reduced, highly significantly reduced with a P value of about seven times 10 to minus eighth at both nine and 18 months, so pretty dramatic relative reduction in Anti-proBNP in the patisiran group compared to placebo.

Dr Carolyn Lam: Super exciting, and it really adds to mounting evidence isn't it? That we're sort of reaching a really effective treatment for these patients and who knows how common they are. But Justin, you've been thinking a lot about this, what are your thoughts?

Justin Ezekowitz: This is a terrific paper, and this is a groundbreaking therapy. Scott, this really has something for everybody, for example functional Anti-proBNP and echocardiographic measures of improvement and also less deterioration which I think is also holding it in its tracks. The question is, if you have 126 patients in the cardiac sub-group, whether or not this is really prime for clinical integration, as to start using this therapy broadly or do we need to really broaden the scope and do larger outcome studies with this therapy for these patients, recognizing some of the gaps in any clinical trial design and implementation. So what are your thoughts on that?

Scott Solomon: First of all, it's important to remember that the APOLLO study was designed primarily to look at the neurologic outcomes, not the cardiac outcomes. The cardiac outcomes were technically considered exploratory and, in fact, although really pretty impressive in this group, this wasn't really how the study was designed. And so the current indication for this particular therapy. Patisiran is for the improvement in the neurologic outcomes, not for the cardiac. So I think that there will need to be additional studies that will look more specifically at the cardiac effects, although I think these are among the most impressive findings we've seen with any agent that is interfering with transthyretin. And just to put this in context, there are a variety of ways in which amyloid can be affected and one of the other approaches to this disease has been not to reduce the production of transthyretin but to stabilize transthyretin.

                                And you may be aware of the ATTRACT trial which was presented at ESC and published in the New England Journal, which was actually an outcomes trial in patients with cardiomyopathy secondary amyloid and they used a drug which is a TTR stabilizer and showed a significant reduction in cardiac events and mortality. And I think that in the context of that study, this is extremely exciting as well because it says that there are multiple potential approaches to affecting transthyretin and potentially improving outcomes in patients with cardiac amyloidosis. There are other approaches that also are being tested. In fact, another therapy that works in a similar way to patisiran is atersin which is an agulo nucleotide anti-sense molecule. And so, I think that it's such an exciting time now in this field because there almost certainly will be several different approaches to transthyretin amyloidosis.

                                So, I think, Justin, to succinctly answer your question I don't think we're quite ready yet with patisiran but stay tuned because there will be more trials for sure. The other thing that we have to realize is that this study was done in mutant or hereditary amyloidosis but there's a very broad group of patients out there with wild type amyloidosis and there's no reason to think that a therapy like this won't work there as well. So that has to be tested too.

Justin Ezekowitz: I think, Scott, that's a true way to put it. I think one of the other questions is the substantial difference between the trials and sub-groups of the trial between the three major therapies you just described about wild type versus hereditary. It does make you wonder if either one individual therapy or a combination of the therapies might give the right way to precisely manage these individuals according to their phenotype, neurologic status or cardiac status.

So, I maybe just want to draw you on one other point which is that you used global longitudinal strain as one of your outcomes and it sounds like, and from all the data we've seen, it looks like GLS will be the way to go for earlier phase two and other types of studies. What are your thoughts based on experience?

Scott Solomon: Well in general I'm a big fan of global longitudinal strain because I think it is, in many respects, more robust than our standard measures of cardiac function like ejection fraction, it's not volume dependent the way ejection fraction is. In particular in amyloid heart disease, as you know, global longitudinal strain can be quite abnormal and, interestingly, it can be quite abnormal in a very specific pattern. And patients with amyloid is typically sparing at the apex, so the apical strain is relatively normal compared to the strain at the base of the heart. And this is kind of interesting and we've certainly been looking at this as well in amyloid heart disease but I agree that this global longitudinal strain as a measure of potential benefit for a therapy has a lot of potential.

Dr Carolyn Lam: You know, that's just so amazing. I just have one last question for both of you. Where do you think the field is going? Do you think it's going to be a race to treatment or a race to diagnosis? I shudder to think of the number of cases we're missing, what do you think Justin?

Justin Ezekowitz: Carolyn you just brought up a great point which is, one is our diagnostics need to improve and be broadly applicable and implementable in any health care system, so I think that race has to speed up and become more cost-effective and efficient to know who indeed we need to screen closer. That's point number one but number two is the therapies ... the race has to be focused around what will be the best way to treat patients rather than the cost-effectiveness initially, but then once we identify the three or four different agents that work with different groups and how you can combine them, then the consideration has to be how we can apply these more broadly to the groups that really haven't had a therapy that has had a meaningful impact trajectory.

Dr Carolyn Lam: Scott, what do you think?

Scott Solomon: Well I would add that one of the most exciting things I think in this area, Carolyn, and this is going to interest you I think because of your own interests, is that there's probably a lot of amyloid out there that we don't know about. Especially in these patients that we're currently calling heart failure with preserved ejection fraction. There's some data from Mayo clinic and from groups in Europe suggesting that 15 to 20% of patients with HFpEF, might actually have wild type transthyretin amyloid. And that means that we've got to get better at making this diagnosis, especially where our suspicions are high. Because we might all of sudden have a targeted therapy for some of these patients, so I think that's one area where things are really exciting. And then with respect to which of these therapies is going to be beneficial, I mean I think that we're still in the early stages, it's very possible as Justin said that even a combination of TTR stabilizers and knock-down agents are going to provide the best benefit. But I think we're going to see a lot of very interesting studies in the next several years in this field. It's really great to have a potential molecular target, and targeted therapy for a type of cardiomyopathy and I think this is one of the really few areas where we have that as this point. So I'm extremely excited.

Dr Carolyn Lam: Thank you so much for publishing your paper with us in Circulation.

                                Well audience you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                This program is copyright American Heart Association 2019.