Maternal mortality in the United States 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 REBIRTH Trial
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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 the overproduction of prolactin a particular form of prolactin which is a 16 kill adult and 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. I it's pro apoptotic 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 Romine, 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 for 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.
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