Hmmm there seems to be a problem fetching this series right now. Last successful fetch was on August 14, 2017 20:12 ()
What now? This series will be checked again in the next day. If you believe it should be working, please verify the publisher's feed link below is valid and includes actual episode links. You can contact support to request the feed be immediately fetched.
Archive this series
Dr. 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. Sanjay Kaul and Darren McGuire will be joining me in just a moment to share their perspectives on the EMPA-REG OUTCOME trials. Are the results with empagliflozin in diabetic patients at high risk, are they too good to be true. First, here are the highlights from five original papers in this week's issue.
The first paper is from Dr. Gilboa, from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention in Atlanta, Georgia, and Dr. Marelli from the McGill Adult Unit for congenital heart diseases in Montreal, Quebec, and colleagues. These authors recognize that because of advancements in care there has been a decline in mortality from congenital heart defects over the last several decades. However, there are still no current empirical data documenting the number of people living with congenital heart defects in the United States.
These authors address this gap in knowledge by using prevalence data from Quebec, Canada, in the year 2010, as a foundation for a mathematical model, and estimated that in the United States in the year 2010, approximately 2.4 million people, including 1.4 million adults, and 1 million children were living with congenital heart defects. This estimate is significant, because it corresponds to a 63% increase in the estimated size of the adult population with congenital heart defects in the United States since the year 2000. This has significant implications for resource allocation for health services delivery that will need to account for this growing population of adults with congenital heart defects.
The second paper is from first author Dr. Tabot, and corresponding author Dr. Liao, from the University of Chicago, and colleagues who aim to understand better the common complication of angiodysplasia leading to nonsurgical bleeding in patients with left ventricular assist devices. The authors studied 101 patients with heart failure, left ventricular assist devices, or orthotopic heart transplants. They found that compared to patients with heart failure, or transplant patients, patients with left ventricular assist devices had elevated serum levels, and endothelial expression of angiopoietin-2, which is a potent angiogenic mediator.
Elevated levels of angiopoietin-2 in these patients increase angiogenesis in vitro, and were associated with bleeding events. Furthermore, they found that increased thrombin levels in left ventricular assist device patients were associated with elevated angiopoietin-2 levels. In aggregate, therefore, the results indicate that high levels of thrombin induced endothelial angiopoietin-2 expression, which may then contribute to angiodysplasia and non-surgical bleeding in patients with left ventricular assist devices. The clinical implications are that clinical studies angiopoietin-2, and factor 12 inhibitors may therefore be indicated to prevent nonsurgical bleeding in patients with left ventricular assist devices.
The third paper is Dr. Gordon from Hasbro Children's Hospital in Rhode Island, and Dr. Kieran from the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues who addressed the Hutchinson Gilford Progeria Syndrome. An extremely rare, fatal segmental premature aging syndrome, where without specific treatment, death usually occurs at an average age of 14 1/2 years from an accelerated atherosclerosis.
A PRIA single arm clinical trial has demonstrated that the protein farnesyltransferase inhibitor, Lonafarnib, ameliorates some aspects of cardiovascular and bone disease in this syndrome. The current trial sought to further disease outcomes by additionally inhibiting progerin prenylation using pravastatin and zoledronic acid on top of Lonafarnib in 37 participants with the Progeria syndrome. Results showed that the composite primary study outcome of increased rate weight gain and decreased carotid artery echodensity was achieved. Overall, participants experienced increased bone density, size, and structural properties. However, unlike the PRIA single arm Lonafarnib monotherapy trial, mean carotid-femoral pulse wave velocity and mean carotid artery adventitial echodensity were not improved. In addition, rates of carotid and femoral artery plaques and extraskeletal calcifications all increased.
In summary, compared PRIA Lonafarnib monotherapy treatment, additional bone mineral density benefit, but likely no additional additional cardiovascular benefit was obtained with the addition of pravastatin and zoledronic acid. The authors concluded that since increased bone fracture is not a disease feature, the addition of a combination of statin and biphosphonate to Lonafarnib therapy is not recommended for clinical treatment of Progeria syndrome. However, it is reasonable to consider statins if concurrent lipid abnormalities need to be treated.
This paper is accompanied by an excellent editorial by Dr. Francis Collins, who describes our journey in seeking a cure for this rare disease of Progeria. The fourth paper is by first author, Dr. Grisenti and corresponding author Dr. Tilley from Lewis Katz School of Medicine, Temple University in Philadelphia, and colleagues who aimed to better understand the role of leukocyte expressed beta-2 adrenergic receptors in regulating immune cell responses to acute cardiac injury. The authors achieved this aim by studying wild type mice who were irradiated, and then transplanted either with isoform specific beta adrenergic receptor knock out bone marrow, or wild type bone marrow. These chimeric mice, after full reconstitution then underwent myocardial infarction surgery.
Results showed that immune cell specific beta-2 adrenergic receptor expression was essential to the repair process following myocardial infarction. In the absence of beta-2 adrenergic receptors, vascular cell adhesion molecule-1 expression was increased in leukocytes, inducing their splenic retention following injury, and leading to impaired scar formation, followed by rupture and death. Splenectomy partially restored the beta-2 adrenergic receptor deficient leukocyte infiltration into the heart, but gene therapy to rescue the leukocyte beta-2 adrenergic receptor expression completely restored all injury responses back to normality.
This study is clinically important because it highlights a bit of a tension that we're facing. On the one had, beta adrenergic receptors are known to regulate cardiac function and remodeling following myocardial injury, by their effects through cardiomyocytes. That's why we use beta blockers to prevent, at first, cardiac remodeling. However, the current studies now indicate that inhibition or deletion of the immune cell expressed beta-2 adrenergic receptor causes leukocyte dysfunction, and impaired immunomodulatory responses to myocardial injury. These results may, therefore, have implications on the use of beta blockers around the time of acute myocardial injury, such as myocardial infarction, or perioperatively. This is really an area that needs further research and understanding.
The fifth paper is by Dr. Herman, from the hospital of the University of Pennsylvania, and colleagues who report on the one year clinical outcomes of SAPIEN 3 transcatheter aortic valve replacement in high risk and inoperable patients with severe aortic stenosis. Now, as a refresher, in the initial partner trial of transcatheter aortic valve replacement for high risk and inoperable patients with severe symptomatic aortic stenosis, there was a demonstration of marked survival advantage compared to medical management ... But a high one year mortality of 24% in the high risk, and 31% in inoperable patients.
More recently, the lower profile SAPIEN 3 prosthesis system has become available. Which has a balloon expandable cobalt chromium frame, with bovine pericardial leaflets, and an external fabric seal. The early 30 day outcomes of this system have been reported, and show a very low rate of adverse events.
The current study now reports the one year survival, and showed that all cause survival was more than 85% for all patients, above 87% in the high risk, and above 82% in the inoperable subgroups. Furthermore, there was a high rate of transfemoral access at 84%, and a high all cause and cardiovascular one year survival in the high risk transfemoral subgroup of 89% and 93%, respectively. Between 30 and 365 days, the incidence of moderate perivalvular aortic regurgitation did not increase. There was no association between mild perivalvular leak and one year mortality. Although, a small increase in disabling stroke occurred.
These results, which likely reflect device iteration and procedural evolution, support the use of Taver as a therapy to consider in high risk and inoperable patients with aortic stenosis.
Those were the highlights from this week's issues, and now for our feature paper. We will be discussing the perspective paper entitled "Is the Mortality Benefit With Empagliflozin in Type 2 Diabetes Too Good to be True?". To discuss this, we have two very special guests. First, Dr. Sanjay Kaul, writer of this paper, and from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire, deputy editor of circulation from UT Southwestern. Welcome, Sanjay and Darren.
Dr. McGuire: Thanks, Carolyn.
Dr. Kaul: Thank you, Carolyn.
Dr. Lam: To start us off, I'd really love if Darren could please introduce this new content category of circulation. Frame of reference section, of which this is one of the papers, a perspective article.
Dr. McGuire: Sure, so we envisioned, as we're evolving circulation to our new editorship, an opportunity for authors, luminaries in the field, to give us in a very encapsulated form, a laser focus perspective on a specific topic. These come in two flavors, the perspectives piece, which this is, is a little more evidence and scientific quantitatively based. Then we'll also have a section called on my mind, which is more of a free-flowing opinion editorial targeting possibly a contentious or controversial issue. These are going to be very short, and hopefully very entertaining, and kind of teasers for the readership of the Journal.
Dr. Lam: Sanjay, you made it very personal, and I like that, too. Share with us how this idea came about.
Dr. Kaul: Well, I was very impressed at the reception that the results of the EMPA-REG outcome trial received at the EAST meeting at Starcom last year. While I was witnessing the applause, I had polar reactions. On one hand, I thought that after nearly five decades of trials with checkered history, with regards to cardiovascular outcomes, here we have for the first time a trial demonstrating not only cardiovascular benefit, but a mortality benefit. I thought maybe it's time to take the trumpets out and sort of herald this holy grail, which we had failed to achieve. On the other hand, realizing that we had been fooled before many times by trials, yielding implausibly large treatments actually, that were never replicated at subsequent trials.
I had a skeptical response to it, and sort of asked this question rather tongue-in-cheek, or maybe used as a rhetorical tool to address whether this mortality benefit was too good to be true.
Dr. Lam: You know, you didn't just question it. You examined the data, and provided even more evidence. That's what I was impressed with in your paper. That table where you provided base factor, as well as a Bayesian analysis. Could you break that down for us, and explain what you found?
Dr. Kaul: Yes, I was trying to sort of examine the strength of the evidence, in terms of the quantitative aspect. Yes, the effect size for the cardiovascular benefit was quite impressive. For the primary endpoint, which was a compositive cardiovascular, death, non-fatal MI, and non-fatal stroke, the p-value was not very robust. It was .04. The p-value tends to overestimate the strength of evidence. I utilized base factor, which basically is a metric that allows the two competing hypotheses to predict the data. Using the base factor, I was able to demonstrate that the alternative hypothesis was stronger than the null hypothesis by eight-fold. The p-value of .04 translated into a base factor of .13. Which is not strong evidence against the null hypothesis. It requires independent confirmation and subsequent trials.
A p-value of .04, while meeting the superiority criteria, would not be sufficient enough to meet the FDA's requirement of substantial effectiveness. Substantial effectiveness just basically means that the FDA requires two trials, each with a p-value less than .05. In 1998, they modified their regulatory requirement, and accepted that one single trial would be sufficient, provided that there would be a persuasive p-value. Persuasive basically is defined as a p-value less than .001. The base factor allows us to sort of interpret the strength of the evidence, with respect to the primary composite endpoint was not strong enough to meet this requirement. With respect to cardiovascular mortality, as well as all cause mortality, which trumps all other endpoints, it was persuasive enough.
Dr. Lam: What's your conclusion on that?
Dr. Kaul: What is controversial about that was that in the three specified statistical plan, the so-called hierarchical testing strategy, the non-inferiority for three point MACE, followed by non-inferiority for four point MACE, and followed by superiority of three point MACE, and lastly, superiority of four point MACE. Because the p-value of four point MACE superiority was .08, one can argue purely from a statistical perspective that you stop your testing strategy, and any analysis beyond that would be deemed exploratory. Even though cardiovascular mortality and all cause mortality was prespecified, the purist would argue that since you failed superiority for four point MACE, you really can't proceed further. You can analyze, but it will be considered an exploratory analysis.
I sort of wept and said that because Christopher Columbus had prespecified that he will be discovering the route to India, the fact that he stumbled upon America does not mean it doesn't exist because he had not prespecified it. I think all cause mortality is the most meaningful endpoint, and the least subjective measurement error. It meets the key attributes of regulatory decision making. Which it's prespecified, it's highly persuasive, therefore, it meets the replication criteria, and the p-value is so robust that even if you adjust for nearly 100 multiple comparisons, the p-value would still hold. It meets all the regulatory criteria for approval.
Dr. McGuire: Sanjay, let me just chime in here. I think it's also important, not only were these prespecified, but it's important, I think, for readers of these diabetes programs to realize that hospitalization for heart failure ... Although it's not part of the primary outcome ... In virtually every one of these trials, it is prospectively collected, chartered to find, and essentially adjudicated by blind endpoint adjudicators. You know, death is death. Cardiovascular death in these programs are all adjudicated, as well. I think the prospective collection and central adjudication also adds legitimacy to the hospitalization for heart failure are above and beyond the analytic issues.
Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it does look like, even looking at it from different angles, the data do look strong. At the end of the day, Sanjay, you concluded that it does need another trial. Results do need to be replicated. That was your conclusion. I'd love to hear Darren's take on this.
Dr. McGuire: I think what Sanjay is saying there, and I think what we all believe, was we would really love to see this observation with another member or members of the class. We're learning a lot in hindsight based on these observations, and people are exploring potential mechanistic underpinnings. We're learning a lot about the mechanisms of these medications, above and beyond their glucose uric effects. There's a lot of implication about renal physiology and hemodynamics, and altered myocardial metabolism. I think as Sanjay points out in the paper, some of this looks like a possible arrhythmic effect. We have a lot to learn about this mechanism of action, and whether or not this will be unique to impact gliflozin. It has been publicly announced, Boehringer Ingelheim is planning, they're in the planning phases for heart failure trials with empagliflozin to further explore this signal. I think they will address Sanjay's desire to have some replication in a different patient population. Still, we would love to see these extended into other patient populations. To both extend the use of the medications if they're found, but also provide further confirmation of the observations from EMPA-REG outcome.
Dr. Kaul: Carolyn, let me also add, I used the title as a rhetorical tool, as I stated earlier. I do conclude that the mortality data is not likely to be spurious. In the back of my mind, I still have that 1% skepticism that I would like to eliminate, because the findings were totally unexpected, and unprecedented, as we discussed earlier. If all the pathways, including the mechanistic pathways are aligned, I would have substantial reassurance, beyond any reasonable doubt that the findings are true. That's why I'm asking for replication. Not necessarily by empagliflozin in other trials, but by another molecule within the same class. I think that would be sufficient.
Dr. McGuire: Yeah, and I think it's really interesting to note there, is that I was involved in the early days of some of these drugs as they're being developed. When the other two members of this class went to the FDA, dapagliflozin and canagliflozin, they provided FDA's requirement and meta analysis from all of the phase 2B and 3 trials that had been completed to date. The meta analysis of the cardiovascular outcomes. Both dapagliflozin and canagliflozin had point estimates of cardiovascular death reduction of 30%, and 35%, respectively. When we saw those data, they were based on 25 to 40 total events. We chuckled, thinking this is spurious, from small events being analyzed. That there's no way they would prevent cardiovascular death. Sure enough, you know, you could almost superimpose those point estimate plots from the phase 2B-3 meta analysis, with the ultimate outcomes from EMPA-REG. There's some promising, although again, very statistically imprecise estimates that this may well be a class effect. As many of the listeners will know, there are ongoing cardiovascular outcomes trials for all of these medications. That will come some time in the next year or two.
Dr. Lam: That's fantastic. Thank you both for sharing those perspectives. I mean, I learned so much. I really think, Sanjay, your paper achieved exactly what you had meant for it to achieve, and exactly what circulation was hoping to create the discussion, as well.
Dr. McGuire: Thank you, Carolyn.
Dr. Kaul: Thank you very much.
Dr. Lam: You've been listening to Circulation on the Run. Thank you for listening. Don't forget to join us next week for more highlights and discussions.
59 episodes available. A new episode about every 7 days averaging 19 mins duration .