Maternal mortality in the United States is significantly higher than other industrialized nations, and it is at its highest level since 1965. A particular area of crisis is within peripartum cardiomyopathy (PPCM), which is a major cause of pregnancy-related deaths. In this presentation, Dr. Deborah Crabbe, Cardiologist at Temple University Hospital and Professor of Medicine at Lewis Katz School of Medicine at Temple University, outlines the REBIRTH Trial , a randomized trial that reviews the use of bromocriptine therapy for the treatment of PPCM.
REBIRTH is a trial that will randomize 200 women at 60 centers across North America to determine if bromocriptine therapy improves myocardial recovery for women with PPCM. Temple University Hospital is participating in this study, and is looking for patient referrals. To refer a patient for this study, please call 215-707-3898.
Refer a patient for the REBIRTH Trial
So something I've always been interested in heart failure and women. And I'm gonna give you kind of my vision of the 20 year perspective of this particular area and some areas uh which there'll be future directions. All right, let's see. So far slide, it's not advancing. Ah There we go. So the objectives for today is to kind of give you an idea of the evolution of the knowledge regarding heart failure in women. And this is now a pretty big space. So this will, I'll give you some salient um areas, but I won't be able to cover everything. I'm gonna review some of the sex specific differences in the natural history of heart failure in women and review some of the disparities in heart failure for diverse groups of women. And then at the end, I'll give you some ideas of future innovations and heart failure carefully. So the world circa 1998 um Bernadine Healy had already gone to the NIH and realized that there weren't any women in any of the clinical trials. And she put out a mandate that women had to be included. And if they weren't included, there had to be an explanation as to why they weren't in clinic clinical trials. By 1998 the major focus in cardiovascular diseases and women had really was um around coronary heart disease progression, its outcomes, its prevention. And there were concerted efforts on improving the risk assessment of women for coronary disease and for cardiovascular awareness um increases, there was little attention at all paid to heart failure care or outcome. And somewhere between 19 seventies to early two thousands, a number of papers came out about heart failure and gender based differences. Actually, sex-based differences. One of them is this first paper that was from the Framingham group that looked at the prognosis of people in the natural history of heart failure and showed that the prognosis of women was significantly better than men after the onset of symptomatic heart failure, they followed up that paper with a second paper in the 19 nineties that suggested that the impact of age on survival was greater for women than men. However, when you adjusted for age, women still had a survival advantage. Well, the only thing at that point in time that was associated with pro uh survival from heart failure was the ability to impact remodeling. And that put a lot of people interested in looking at parameters of LV remodeling. One of the first studies to come out was in 1996 by the UN C group that looked at sex-based differences in survival based on the etiology or type of heart failure. And what they found is that women with the non ischemic cardiomyopathy had improved survival compared to men and worsen survival if they had an ischemic cardiomyopathy. And just around the time when I became junior faculty, I had the privilege of being able to work with human cells. And we did a, a study looking at human cells and looking at the differences by sex and postinfarction and non ischemic patients who are awaiting transplant. And what we found was sex-based differences occurred among the women who had post myocardial infarction. Remodeling exclusively on those patients who had an ischemic cardiomyopathy. In other words, the women had reduced cellular remodeling compared to men. I believe it was the first paper uh done in human subjects on that topic. So, out of the interest of continuing to understand these sex-based differences that were being observed in in the clinical arena, early observations really showed that the face of heart failure was different in men and women, risk factors were similar. But the proportion that these risk factors played in the development of heart failure were different. For instance, diabetes is a very potent risk factor for heart failure. But in women, it's a fivefold in if it increases your risk fivefold compared to three fold in men, they noticed that it was more common for women to have a non ischemic cardio uh etiology for their heart failure, that hypertension. Although a potent risk factor for heart failure in general, that it was much more potent as a risk factor in women with a threefold increase in risk for heart failure. If you have hypertension and advancing age also was an important risk factor for women compared to men. And then came the HS trial. If all of you remember hers, hers was the estrogen trial that looked at the impact of estrogen in terms of outcomes for women and prevention of heart disease. There was this particular study had post menopausal women in it and they had had coronary heart disease and they followed them. And this was one of the first papers to identify the nine predictors of heart failure progression in women. And as you can see, diabetes, atrial fibrillation, renal insufficiency, smoking BM I and LVH and prior M I were very potent predictors of whether a woman would progress to heart failure and heart failure. As you know, is a condition that has a wide range of severity. Some people will develop with some of these risk factors. Heart failure would preserve DF, others will develop heart failure, reduced DF. So the epidemiology of heart failure back then, I excuse me, the epidemiology of heart failure is changing. As you know, back in 2018, in the current era, we had about 6.5 million people with this condition. And now in 2023 we have 6.7 million people with this condition according to the N Haines data from back in 2018, we saw an uptick is represented on the slide in the number of cases of women who had heart failure and the number of women who were um uh the mortality for heart failure, which was higher in women than men at the time. This uptick, however, has kind of come down into the modern era where the prevalence and incidents is similar. However, for every decade, the number and percentage of women increase in terms of uh the prevalence of heart failure. And that's largely because more recognition of he puff and the differences in um um how women live and how much longer they live compared to men in general. So then we started to look at the heartfield registries because we really wanted to understand in various heart failure scenarios. Really did we see a difference in mortality. Remember, the Framingham Studies basically show overall the natural history, but there was some controversy as to whether or not this was true in the short term, for instance, the first year after the s symptoms started. So registry data started to look at the in hospital mortality for acute decompensated heart failure. And these are data from two larger registries that were done. And the in hospitals mortality was similar in men and women. But in the alarm study, which is the largest um one of the first and largest registries that looked at this type of data, women had higher rates of nuance at heart failure and they were more likely to have right heart failure as well. This registry was very important because it's the first one to include all four continents and patients um uh across the globe. So a lot has been learned about heart failure over the last 20 years back then, we basically were just worrying about F Puff a little bit and heart failure in terms, MC F non ischemic cardiomyopathy. But we started to recognize that there and appreciate, I think that there are various heart failure, um pathologies that uniquely affect women. Of course, P PC M is at the top of that list, but so is stress induced cardiomyopathy hef path and I guess variants of monoka depending upon how severe that minoa sy syndrome is. We started to realize and appreciate that autoimmune diseases were very important in terms of developing cardiovascular illness. And and they were uniquely conditions that had a high predominance of women in them. And so they were differentially affected. We appreciated stress induced cardiomyopathy and its variations and particularly SCAD, which has sometimes been associated with the stress cardiomyopathy. And then of course pregnancy and the cardiovascular conditions of pregnancy, which put women at risk for developing a cardiomyopathy usually in the peripartum period leon. So with the evolution of these recognitions early observations, another early observation was is that well, if we all these women with heart failure out there why are only 20% of the clinical trials um having heart failure, uh women with heart failure in, in them. And it brought to the question to whether or not do women benefit from the standard heart failure therapies that have been developed at the time since the early 2000 studies and beyond have looked at this. The earliest ones are beta blockers and there was an ace inhibitor controversy for a while But the data from some beta blocker um uh uh clinical trials such as Merit HF which initially was a post hoc analysis showed that women or suggested that women um benefited from beta blockers. However, um a post hoc analysis was not a good way to really give certainty that that was true. And so subsequent power trials like CBUS two and then ultimately, a meta analysis of the beta blocker trials show that women in fact did benefit from beta blocker therapy. And as I mentioned, early concerns for the benefit ace in inhibition in studies like save and solve um gave way to um um studies like hope in the air trials where women were in them at a reasonable amount of representation and ace inhibitors uh were found to be uh beneficial. Newer studies. Rnesglts and Alacron also suggest benefit. But we also noticed that there were many disparities in the heart failure care for women. There was under utilization of heart failure care therapies. Here's an example of that, this is a meta analysis of uh 31 studies, uh 31 patients with heart failure and they included both randomized clinical and registry studies and they looked at patients and reported heart failure outcome. However, they excluded a LVEF criterion. They had preset dem demographics and clinical variables. They looked at risk of death and survival. And if you look at the baseline characteristics in this study, you can see ace inhibitor inhibitor inhibitor use is under used in women as is beta blockers as was sperm inal lactone and uh as was the Jackson at the time, also confirming the under utilization of therapies that are now considered standard perhaps except for ditch. Additional um knowledge came out about the healthy lifestyle that can impact women in terms of preventing their risk from heart failure. Data from the women's health initiative, observational studies showed that women ages 50 for 59 at baseline who were in good health eventually were um ineligible for the male trial, main trial and were free of heart failure eligible for this study. Um This observational study and they evaluated four lifestyle variables, diet, smoking, physical activity BM I and created a health lifestyle score and this um lifestyle risk factor was dichotomy is either healthy or those who are unhealthy. The end points were incident, hospitalist, incident, hospitalized heart failure and heart failure risk. And what they found is that there's an inverse greater relationship between healthy lifestyle score and incident heartfire So that overall a healthy lifestyle was protective for post menopausal women. And the importance was is that you didn't have to have risk factors in order to get the protection. So even if you're a woman without hypertension, coronary heart disease or diabetes, living a healthy lifestyle, uh in that post menopausal period will help prevent you from getting heart failure. And finally, heart failure action trial came out also in the mid two thousands tens. This study was done by a former Temple faculty member, Doctor Iliana Pina. She was the lead on this multi center trial and she reported the effects of exercise training outcomes on heart failure and looked at heart failure in women specifically. And the multi center trial exercise produced exercise training or had patients with New York Heart Association class two and four heart failure in the low ef and had exercise training. Uh as um the intervention, they did a predefined analysis of women and the study had about 28% of women patients were randomized to either usual care or exercise training and they were maintained in the optimal medical therapy. And what they found is is that women benefited for exercise trades at training with a 26% reduction in primary endpoint compared to men. All new data that was not known back in the two thousands. However, there still remains a huge underutilization of advanced therapies in women. Women are underrepresented in all C RT trial studies. They're less than 30%. Most data show women have a great clinical benefit from C RT compared to men. But women receive fewer referrals for C RT and ventricular assist device is underutilized in women despite smaller and more durable beds. So, are we narrowing the gap in care for these women over the last 20 years? I don't know. But this is data that came out of the guidelines um get with the guidelines program for programs, the hospitals that participate in that for um, making sure that they have evidence based therapies and that they need these um cutoffs. And if you look at this information, you can see that there's in this part. Peop I should say that hospitals that are enrolled in this particular program seem to be doing reasonably well in terms of getting um a guideline based therapies to both men, women and African Americans. With the exception of the hydraulic nitrates, um combination of discharge where about 2520 I guess it's 30% of the patients are on this drug at discharge. Despite uh clinical trial evidence that fixed dose um, nitrates and hydrALAZINE are beneficial at reducing mortality in patients by about 43%. So we have a challenge. Now we're in the middle of a huge challenge for women. And this challenge is is that the maternal mortality in the United States is outstripping other industrial nations. This is a slide from 2020 showing the comparison between the United States and the number of deaths per 100 live births compared to the rest of the country. So for an industrial night industrialized nation, we're doing an awful, awful job at protecting women during childbirth. Us, maternal mortality is highest level. And since 1995 this was an article that came across the the news feeds and unfortunately, most of these women are women of color that are being affected. So, where are the future directions to make an impact in heart failure for women? Well, there will be lots of research that needs to be done about etiology, risk factors and therapies going down the road. But one area that we really can make an impact and is a call to action right now because of the maternal health crisis is in the area of peripartum cardiomyopathy. We still have a under record underrepresentation of women in clinical trials. And as I stated to you, there's still disparities in the delivery of care, but in this particular condition, peripartum cardiom can be a very lethal condition for some women. So let's review that a little bit. Peron cardiomyopathy is defined as a non ischemic cardiomyopathy with the ef of less than 45%. It commonly presents in the first month um after um delivery and can um uh be presenting up to five months after delivery. However, there have been early presentations. We actually have a patient in house who presented in her last month of pregnancy. And the studies that have looked at women that present early and the women that present in the classical way show that they're phenotypic no different. So you can see postpartum in the last month of pregnancy. The risk factors include African American race, preeclampsia, hypertension, multi gestational pregnancies, and advancing maternal age. And it's a major cause of pregnancy related deaths. Peripartum cardiomyopathy occurs in about 1 to 2000 live births in the United States. Um If you look at the countries, it depends on which countries you look at. In terms of the incidents in Africa, it can be as high as one in every 100 birds. And it's a very, very uh fatal condition. I think in those places, most women um are diagnosed, as I said during that period. In the postpartum period, women tend to recover about 50% but there are a subset of women who are left with a cardiomyopathy and chronic heart failure. And I think many of us have seen them over the years come through the system. Um In the heart failure program here, we've had patients over the years who have come and needed that support transplant, emergency care. The rate of death for cardiac transplant in the first postpartum year remains high. It's five the rate of death or cardiac transplant during the first year. Uh postpartum remains high as about 5 to 10%. Well, there is a pervasive I should say leading hypothesis and why this condition occurs. And that hypothesis, the prolactin hypothesis, this is the pathway uh involving prolactin production. And the hypothesis is is that there is an overproduction of prolactin, a particular form of prolactin which is a 16 kill adult in prolactin. It gets uh elevated because um there is a loss of stat three inhibition of um of the um manganese uh dim dim mua enzyme which comes um which decreases, excuse me, which decreases because this enzyme is not present. There's an increase in reactive oxygen species activity and there is activation through the ma ma matrix metalloprotein aes and cathepsin to cleave that 23 kal and prolactin that to the pituitary to the 16 Kalin prolactin. And unfortunately, this form of prolactin is very lethal. It's a vaso inhibit and it can cause uh problems with angiogenesis apoptosis and it's pro AOP and it causes problems with the capillary structures. And the belief is that this is the problem. This belief has been borne out through animal models that have attempted to recreate this. There's been a stat three knockout mouse that shows this pathway is important and prolactin uh and bromocriptine which is a prolactin inhibitor rescues the cardiom myopathic phenotype. So, the very first study was a proof of concept done in South Africa by a lady by the name of Karen S Sliwa. There was a pilot study with 20 people African Americans had a recent onset of P PC M. They were randomized to eight weeks of bromocriptine plus standard therapy versus standard therapy for heart failure alone. And what they found was improved outcomes in women with bromocriptine. However, there and a high mortality rate as you could see from the control group. Likewise, another um study that was done in Burkina faso showed 96 women who presented with P PC M who received four weeks of romaine um 2.5, twice daily versus standard therapy. And while they had low efs in the beginning uh or similar, I should say eef at the end of the treatment, you see improved survival with uh with bromocriptine um compared to the control these studies and others prompted um investigators from the peripartum cardiomyopathy network to propose a randomized trial looking at bromocriptine therapy to date. Most of the studies on bromocriptine therapy and P PC M have very small cohorts and are not um powered in some ways um to be conclusive and the data is, is not conclusive. So, bromocriptine, as you may remember is an Erard derivative, which is a dopamine D two receptor agonist and a serotonin receptor agonist. Generally, it was used, I think for Parkinson's hyper prolactinemia prolactinomas. It also was used in the United States in the 19 nineties for lactation suppression. However, it was taken off the market for various uh um for, for reasons which we will talk about here, but it's still available for other indications if you look at the um IP a study out of the University of Pittsburgh that did a natural history study on Romari on um I'm sorry, Peripartum cardiomyopathy. Um and compare that subset with some of the trials and registries that looked at bromocriptine treatment. You will see that in the patients that received bromocriptine, um they received a 62% of the patients had a um complete recovery. Um and only 3% of those people in that trial had severe heart failure. None of them went to transplant as opposed to what the natural history was. Um Looking at both based on ef um uh in the IP P study, ef is an important predictor for those women who have ef less than 30%. Um the chance of recovery becomes reduced and the more likelihood that they will have and more rocky course increases. And you can see that in the IP A subset you had about 18.5% that went on to severe heart failure or um and or death transplant or that compared to the IP A registry where the EF was a little higher was significantly higher. I should say about less than 45% where you see less heart failure, uh complications and less depth. So, summary of the bromocriptine trials, there have been South African and West African studies that showed an improvement in bromocriptine. Uh I'm sorry, improvement in outcomes with bromocriptine poor outcomes in the control group been evident in the European North American controls. So the patients were a little bit sicker. But the German Multi Center study, which looked at the differential between the first and one week of therapy versus eight week of theory sound no difference in recovery. But there were no major events in any woman given bromo kine and there was no standard, but there was no standard alone control group which limits the study. These previous bromocriptine trials suggest that perhaps bromocriptine um if uh confirmed, could have a significant impact on mortality for women, particularly those with the worst DFS. And so rebirth was discovered and developed or designed. I should say rebirth is a study that's going to randomize 200 women from 60 centers across North America, um which include the United States and Canada to receive either eight weeks of bromocriptine versus placebo along with background therapy for heart failure. The study will determine if the therapy improves myocardial recovery and overall event free survival for women. Now, if you're, if a woman is in the trial and the main trial, she cannot breastfeed because of the lactate suppression of the bromocriptine. And therefore, we are having a complimentary trial to look at those w for those women who want to breastfeed and therefore, they will not receive bromocriptine, but they'll be in a cohort study of up to 50 women. Um And we'll know whether or not breastfeeding has an impact. That's a pretty big question as well in this space given that prolactin levels are prolonged during breastfeeding. The inclusion criteria is a new diagnosis for P PC M. It has to be post delivery and within the first five months of postpartum as is the standard definition. The EF cut off originally for the study is less than 35% within two weeks of the consent, each woman will receive an echo um generally, but other modes of um assessment of um LVEF are acceptable as long as within the two weeks. Cut off, this LVEF cut off now has been expanded to help with enrollment. And so, um if we uh have a patient who's 40% or less, they're still eligible with a IRB exception. They have to be over 18 years and again, the subjects have to agree not to breastfeed. There's a number of exclusion criteria. I'm not gonna go through each one of them, but clearly breastfeed. Breastfeeding or wanting to breastfeed is an exclusion. They cannot be currently pregnant. Obviously. And if they have uh the need for advanced therapies like um durable LVAD support or ECMO support, we're excluding them. The other exclusions are pretty standard um, exclusions for trials. Patients who can are not compliant and patients who obviously too sick for the study, the dosing will be 2.5 mg of bromocriptine twice daily for two weeks. It'll be followed for six weeks. Uh uh 2.5 mg um for a week, a total of eight weeks. Um the doses uh been determined by the previous two trials. Um, the European trial or the German trial that I mentioned and then the pilot study, um that was done in Africa proof of concept. Again, the risk and limitations for bromocriptine is bromocriptine is that it prevents breastfeeding. Um, it can cause nausea. We're finding that some patients in the trial when they first get on it early on have mild hypertension that usually um um resolves um without um much intervention, there is a fear radical risk of thromboembolic events in bromocriptine. And that's why the lactation, that's why it was taken off the the market for that indication. However, um because of this, um this was not present in any of the previous trials of P PC M, but women who are generally were treated with at least prophylactic um anticoagulation as will be the case in our study. So protocols call for low dose um Xarelto 10 mg daily. And if women have an indication uh for um a higher dose or a dis different um an anticoagulation regimen, they can continue that anticoagulation that'll be accounted for in their trial. Women randomized to placebo will get a second placebo to maintain the blinding primary end points for the study will be an LV. Remodeling endpoint. LVEF is six months and um post randomization and secondary endpoints will be echo for LVEF at 12 months and survival up to three years um will also be uh uh an end point as well as um survival for three years free from heart failure, hospitalization. Um African American women really have been uh particularly affected by that by this particular condition in a subset analysis of uh patients who self identified their own race. It was extremely important to realize that um African American women tended to come into the cohort. This is from IP A I believe um at a lower ef at entry. And also throughout the following of 6, 12 months of the natural history, they tend to have a much greater risk for development P PC M. And they also have more likely to have hypertension and hypertensive forms of uh of the uh associated with dilated cardiomyopathy. There's also gonna be a biomarker study which will give us biomarkers of the prolactin pathway and the impact of those biomarkers um as therapy has been instituted and there's an echo core that will give us parameters of LV strain. Um Sorry LV, remodeling global strain and LV. Um mo um volume assessments, breastfeeding, the potential therapeutic impact of pro prolactin suppression and bromocriptine has led to some worrying that women who have P PC M should not be breastfeeding. And you know, breastfeeding is a very important part of maternal bonding, especially in places where um resources are very limited such as third world countries. So this question is potentially going to be answered in this particular study. There's gonna be a 50 cohort uh study of women who will be excluded for the trial, as I mentioned. And they will have the same entry criteria as a randomized trial. But we will be evaluating the impact of breastfeeding on myocardial recovery uh in women with PPP CN. So E PC M remains a very important component of uh maternal morbidity and mortality. Um Bromocriptine has promising data, but there is no large randomized trial. This will be the largest randomized trial with multi center involvement in the United States and Canada, it'll answer some really important questions about um P PC M therapies and the benefit of bromocriptine for those who have mild LV, dysfunction and those who have severe LV dysfunction. And it will also answer the question about breastfeeding and its impact on the natural history of P PC M. The trial has a network web page and so if any of you should see any women who fit the criteria, I hope you'll refer them to us. Um And this is the web page. And again, as I said, the study continues till 2027. And uh we're very privileged to be a site in such an important landmark um study that will help guide therapy for heart failure in women in this particular space. So, thank you very much for your attention. And I'll take any questions that might be
