 Hi everyone, I'm Joe Rogers president and CEO of the Texas Heart Institute and I'd like to thank you for the kind Invitation to speak at the women's symposium this year. My topic is to discuss with you the diagnosis and management of heart failure in women. I Think this cartoon highlights one of the real Challenges that we have in medicine and that is an appreciation for the fact that men and women do respond differently to a variety of different conditions You know throughout the entire spectrum of health care and we need to be mindful of those We need to study them and I'll talk a little bit more about that as my comments move forward So I'll start this way and just ask you if these two heart failure patients are the same on the left side of the slide is a 60-year-old Gentleman who has a long-standing history of heart failure Comes to the office with three weeks of worsening symptoms and is hypotensive and a cartoon of what his ventricle might look like in Cross-section and echo image showing unmarkedly enlarged left ventricle Which is certainly dysfunctional and a chest x-ray that despite having symptoms of heart failure doesn't show a lot of pulmonary edema and Contrast it on the right side of the slide to a very typical female presentation of Heart failure an 80-year-old woman with a long-standing history of hypertension who gets breathless suddenly Presents to the emergency room with a blood pressure of 185 over 120 and her cardiac anatomy and her physiology is very different, right? It's a very thickened Ventricle oftentimes the left ventricular cavity is small and oftentimes on chest x-ray There's marked pulmonary edema and despite the fact that both of these patients carry a diagnosis of heart failure The pathobiology of this is very different. So we'd like to explore that a little bit more in the context of this talk To briefly remind you of the incidence of heart failure From individuals in their early 20s through their older age You'll see in this slide that up until the age of about 80 the incidence of heart failure is about one and a half times that of of Women in men but once People get to the age of about 80 it flips and the incidence of heart failure increases In women to that be greater than that of the incidence of heart failure in men With regards to hospitalizations, this is some data from the AHA statistical Summary that's put out each year you can see that there's been a narrowing of heart failure hospitalizations between men and women although in the late 1990s in the early 2000s the hospitalization rate for women was higher In in women than in men, but it's become more equal now and If you look at mortality you can appreciate the fact in the top couple of lines in the slide that the mortality rate for incident heart failure in women is lower than in men and in this really interesting cohort the southern community cohort study which was a Population of largely population of women Great preponderance of African-Americans tended to be low income But you can see in this in this analysis that the the white women and black women in this cohort study have about a similar Survival rate over eight years So so there are some important Differences between men and women who have heart failure and we'll explore this a little bit further as the talk goes on So I think that this slide helps summarize some of these important differences between men and women who have a diagnosis of heart failure If you look over on the left that compared to men women with heart failure are much more likely to be older They're much more likely to have heart failure with preserved ejection fraction and have antecedent hypertension diabetes Obesity and oftentimes have more kidney dysfunction and atrial fibrillation, which as you know is a commonant I mean as a common concomitant illness in heart failure and in the cartoons on the right I think that this frames up this difference in a really interesting way You can see that there are some important differences in drivers of heart failure. There are obviously some important gender-specific Issues including the treatment for breast cancer, which is predominantly a female disease and of course there are peripartum cardiomopathies The remodeling that women get in response to cardiac injuries different than it is in men But I really like this idea that that heart failure in women is predominantly sort of an endothelial inflammation microvascular disease as opposed to men which is predominantly a Macrovascular disease that's characterized by myocyte necrosis and scar formation and that leads to very different kinds of phenotypes Women as we've already mentioned tend to have more heft-peft. They're more predisposed it seems to talk a subocardium apathy and obviously to peripartum cardiomopathy and I'll show you a little bit of data coming up just to demonstrate that That the prognosis in women they tend to have a better survival But they have more symptoms and a worse quality of life than men And here's some of that data This was some data published a couple of years ago in the journal the American College of Cardiology just looking at outcomes, but also clinical symptoms and also and quality of life at the top of this graph on the left You can see the KCCU KCCQ clinical summary scores Women in blue men in red with lower numbers representing a lower quality of life You can see that women with heft-reft tended to have a lower quality of life score than men who had heart failure Below that the clinical features women tended to have more symptoms more breathlessness both with exertion and at rest more edema And more of the physical findings of heart failure than men But it's interesting and somewhat ironic that they have better longer term outcomes So if you look at a composite outcome of mortality and hospitalizations their mortality rate was lower Their rate of first hospitalizations for heart failure is lower cardiovascular death and all-cause mortality is lower and I think again driving to this this fundamental Concept that the pathobiology of heart failure and men and women is different and we shouldn't be treating them The same way we should be thinking about the particular drivers of heart failure in women and thinking a little bit about whether or not There are important differences in the therapies that we select and I hope I can convince you by the end of this talk That that maybe we should be thinking a little bit differently about some of the treatments I'd like to turn our attention though before we get to the treatment of heart failure To how we might think about preventing heart failure in women because ultimately we'd like to prevent Heart failure in both men and women and this is an example of some of the Comorbidities associated with heart failure in both men and women from a paper that was published in Jack heart failure a couple of years ago And I think what you can appreciate is that in particular the prevalence of Anticidin hypertension is an important driver of Heart failure in women and this should be a target for our therapies to is a preventative measure in this in half of the population and it's in Contradistinction to some of the other drivers of heart failure that we know of in men including coronary disease and particularly smoking And I thought this was a very interesting paper that really looked at and described the additive impact of Risk factors for the development in heart development of heart failure women this is from the women's health initiative and on the right side of the slide you can see The incredible impact on incident heart failure by adding more than one of the risk factors on the left to the development of Symptomatic heart failure in all comers and then broken out by race African-American white and Hispanic But I think an important observation that these risk factors provide additive risk For women to develop ventricular dysfunction and symptomatic heart failure So again in a stylized kind of way if we're going to think about how to prevent heart failure in women There should be some different kinds of targets on the left side of the slide a Targets and strategies to prevent heart failure in women with reduced ejection fraction So heart failure with reduced ejection fraction and on the left side of the slide Many of the risk factors for ischemic disease as we know hypertension A hyperlipidemia smoking etc But on the right side of the slide some really nuanced and interesting ways to think about this I you know obviously in women we should be thinking about some of the the breast cancer therapies as drivers of non-eschemic cardiomyopathy The interesting and complex pregnancy related issues that can impact women's heart health Stress cardiomyopathy or takasubo as I've already mentioned and then diabetes and micro vascular disease Being important Considerations and targets for us And and medical issues in which we should pay attention to the development of non-eschemic cardiomyopathies in half ref and on the right side of this slide as a as a sort of a A stylized approach to thinking about heart failure with preserved ejection fraction And as I was looking at this figure It really was um striking to me that much of this can be tied together in the context of metabolic syndrome It's it's truncal obesity associated with hypertension and with um and with diabetes or insulin resistance That results in an inflammatory condition and causes endothelial cell dysfunction So I I tend to think that there's there's a connection here that we've not entirely made But we should be thinking about controlling these risk factors as best we can To prevent heart failure with preserved ejection fraction in women And I think maybe an underappreciated issue that we should all be aware of Is that and this has been shown in multiple studies Is that there is a difference in how men and women tolerate drugs or at least report Adverse events. So first of all, we're all very aware that women are underrepresented in clinical trials Uh universally but particularly in cardiovascular disease and particularly in heart failure And as a result of that we know less about the adverse events and adverse drug reactions in women But women seem to be a bit more susceptible to Adverse drug reactions and it leads to a difference in adherence to some of the drug therapy that we prescribe And we should be mindful and cognizant of those differences So I I suspect that some of you that uh are listening to this today have a very clear recollection of the dig trial The dig trial is a prospective trial to assess the impact of digoxin In patients who have HEF-REF And you you'll remember that there was no difference in a primary outcome of mortality and heart failure hospitalization but an early Analysis of that study suggested that women who were treated with placebo in that study Had a better survival rate than the women who were treated with digoxin And so it gave us an early signal that in fact there are different gender related differences in how people Respond to drug therapy and in a subsequent analysis that was published a couple of years later The explanation for this may have come out and that is women tended to have higher digoxin levels Then men did and that may have been part of the driver For the effect that we saw on mortality in the dig trial So what I've shown you in this slide is the most recent recommendations for the treatment of heart failure with reduced ejection fraction What I've included on here Are that what we know about the outcomes related to survival on Between men and women And I want to be clear that what I'm showing you here when the arrow says it goes up. It shows that there's an improvement in survival When it goes down, it's worse, but there are none of those and then if it's a horizontal arrow It has no known impact. So for example In the first Step in the management of heart failure with reduced ejection fraction It's recommended that we use an arnie an ace inhibitor or an r but really an arnie would be preferred based upon the clinical trials demonstrating that succubotryl valsartan is superior to ace inhibitors Tagged to an evidence-based beta blocker and a flexible diuretic regimen And the data that we have suggests that ace inhibitors do improve survival in men Arbs improve survival in men. There weren't enough women in those trials to really make a definitive statement A retrospective analysis of the trials of succubotryl valsartan suggests that both men and women derive Advantage from that is same with beta blockers. It seems that both men and women derive Similar kinds of benefits from beta blockade So that's the foundational element of our heart failure with reduced ejection fraction pharmacotherapy And then we tailored even a bit further down at the bottom of this slide In individuals who have preserved renal function in a normal serum potassium The addition of an mra would be a reasonable thought that's been shown to improve survival in both men and women There's some really compelling evidence, which we'll review shortly to suggest that individuals who have reasonable kidney function Will derive a survival advantage with an sglt2 inhibitor and that seems to have a fairly profound effect in both men and women A flexible diuretic regimen as you know diuretics have not been shown to have either a positive or negative impact on survival But important for symptom control Hydrolyzing and nitrates in in patients already on guideline directed medical therapy who are african-american Seems to be a survival advantage to both men and women by adding A fixed combination of hydrolyzing and nitrates And finally a drug that we don't use a lot in the united states or frankly in europe is evabridine But it has been demonstrated in people who have a persistent heart rate of over 70 on guideline directed medical therapy To improve survival But it's beginning to become very confusing about how to Start and titrate these drugs in this traditional way We've taught people to do this over the years as shown on the left side of the slide Where you start with either an ace inhibitor Or an arb and then you add a beta blocker and then you add an mra And then maybe you switch to an arney and then you might add an sgl t2 inhibitor And you kind of go on and on through multiple steps, which oftentimes takes years to get patients on a guideline Directed approach to medical therapy, but on the right side of this slide Milton packer and john McMurray proposed a different kind of approach this rapid sequencing approach Where you start a beta blocker and an sgl t2 inhibitor And then very promptly add an arney and then shortly after that add a mineral or corticord receptor antagonist And then begin to titrate the doses Over the subsequent several months and I think that this kind of approach provides a little different and more contemporary framework That we should use to consider how to begin therapy for heff ref Here's some of the data looking at the sgl t2 inhibitors, you know This is a very interesting class of drugs. It was originally Tested in diabetics and a subgroup analysis demonstrated an improvement in heart failure in every subsequent trial in diabetics And now trials in heart failure patients without diabetes have demonstrated improvements in heart failure hospitalization and mortality A meta analysis of the of the diabetes trials shown in the top right demonstrating That the drug the outcomes favor treatment with the drug and then from the empereg trial shown here at the bottom in the middle demonstrating important 25 percent relative risk reductions in the population of patients Randomized to apagliflozin relative to placebo who had heff ref But a lot of women as we talked about have heff peff. So what do we know about the management of heff peff? Uh in this patient population and these are the guidelines that were released in 2013 and the high level recommendations The level one recommendations were for blood pressure control and the use of diabetics to control volume overload Everything else below that was a lower level recommendation We just didn't have a good database for any kind of pharmacologic approach But I want to try to convince you that there are a couple of drugs that you should be thinking about using In heff peff and and of course then it applies to the use of these drugs In women who are more likely to have this condition. The first is the top cat trial You'll remember the top cat trial was a heff Ref study. I'm sorry a heff peff study comparing spironolactone to placebo And the primary endpoint of top cat was cardiovascular death Aborted cardiac arrest or heart failure hospitalization and you'll remember That when you looked at that composite endpoint, there was no difference in outcomes between the two treatment arms of the trial But you'll also probably remember that we made a real effort to enroll patients from eastern europe And when we broke the data out And compared how the patients did in russia and the country of georgia compared to the americas You can see on the right side of this slide that the mortality rate in eastern europe was much lower And the drug didn't appear to have any impact Whereas if the patients were enrolled in the americas the mortality rate was much more what we would expect in this patient population And the drugs seemed to have an effect I think this has raised a lot of questions about whether the patients that were enrolled in eastern europe actually had heff peff And if they didn't have it it was unlikely that the drug was going to work So I think if you're seeing patients that that look like the patients who were enrolled in top cat in the americas It's likely that spironolactone has some advantage in that population And then as you know, this data was presented at esc. Just um last month The emperor preserved trial which was a heff peff trial In patients with symptomatic heart failure efs of greater than 40 and an elevated nt pro bmp And they were randomized to either a impagla flows in the sgl t2 inhibitor or placebo And the primary endpoint was cardiovascular death or heart failure hospitalization and once again We can see that the patients who were treated with an sgl t2 inhibitor Have an important reduction in that primary endpoint compared to patients who were randomized to placebo And that effect seemed to be persistent at least through three years and at the bottom of this slide You can see that the women tended to have even a little better Outcome than men with a 25 percent reduction in that primary endpoint So I want to begin to close up my comments by thinking about some of the important knowledge gaps We have for women who have heart failure We've been able to to look at some data in my earlier slides that show that women Tended to have a lower quality of life. They tended to have more Symptoms than men and they have a higher rate of medication adverse events And we should be thinking about all of those issues as we begin to tailor our approach to Women who have heart failure We need to be thinking more about managing their risk factors and how that may have a positive effect long term on their risks And be thinking about how differently women respond with regards to remodeling But I think that we all need to to make a commitment to enrolling more women in clinical trials and and begin focusing our attention And waiting our clinical studies so that we can make Important more important observations on the impact of some of the drug therapies that we're testing We need to be Compelled to begin studying how to prevent some of the negative impacts Of chemotherapy Particularly for breast cancer on women's heart health and we need to be thinking about some of the other Risk factors for conditions that oftentimes affect women like takasubo So i'll close this way and just remind you that heart failure in women is characterized by different ideologies Different comorbidities and a different response to cardiac injury women are much more likely to have heft-peft than men And the disease tends to go up in in incidents Is particularly common in the in their 80s and 90s There's really no compelling evidence that women should be treated with different drugs or doses than the consensus guideline directed medical therapy With the caveats that we talked about a little bit earlier and a real attention to the fact That women tend to be a bit more sensitive to some of these drugs than men And i think that there are important opportunities that remain to develop a deeper understanding of sex related heart failure biology Phenotypes and responses to therapy and the latter should actually be required a required element in clinical trials I thank you for your attention and i look forward to our panel discussion