Dr. Amin Yehya, heart failure specialist at Sentara, discusses prevalence of heart failure and future projection of current trends as reported from the Annual Scientific HFSA Meeting.
Well, good morning everyone. Um Thanks for joining us today for grand rounds. I'm sorry, I'm not in Norfolk. I'm in Williamsburg today. I have an outreach clinic. Um I'm gonna be talking to you about the latest from the latest uh HFS A Heart Care Society of America Annual Scientific Meeting which happened around 10 days ago. I was in attendance. So I would like to share with you um the latest updates and um important trials that were presented there. Uh in the meeting, these are my disclosures um outline as I mentioned, I'm gonna talk about heart failure stats, which is uh published also the first week of October of this year with at the HFS A by the journal of cardiac failure. I'm gonna talk also about three late breaking trials that are pertinent to our clinical practice and heart failure for all uh that, you know, uh the lifetime risk of heart failure has increased from 1 to 5 to 1 in four people aged 40 older. So the um lifetime risk has increased as we're seeing here with heart failure from 1965 to 89 to the current one from 19 9 to 2014. What about the prevalence? And this graph as I presented um last month actually at uh the clinical um cardiovascular updates at sa. Um we had 6 million adults now 6.7 million adults with heart failure the year 2020. But with 2023 we're close to 7 million and this number continues to increase. So this is the most recent updated slide uh about the prevalence of heart failure and its future projection as things continue to be as they operate now. And then when you look at the the prevalence by age as we get older, we are definitely more prone to have heart failure. It's because of multiple reasons, increasing risk factors, um and also other comorbidities as well. So uh as we see when we're 80 above the, our preval, the prevalence of heart fail significantly increases what worldwide uh updates showing that some countries like Taiwan, the prevalence of Hartford is significantly high. And in Spain and South Asia, the prevalence also uh is significantly increased. And we can see here in the United States where 2.4 up to three percent, we have patients with heart failure. What about uh the incidence of heart failure by race and ethnicity in the states? Uh As you can see here that black population have significantly increased risk uh of uh having heart failure compared to Hispanic white and Chinese. So, uh and that will be also talking, we will be talking more about it in the other slides. But as you can see, again, um minorities have higher risk of um incidence of heart failure. And when we divided heart failure into three, now subgroups, one with heart failure with reduced ejection fraction, heart failure, with midrange ejection fraction and heart failure with preserved ejection fraction, which is less than 40% between 4050 greater than 50. Uh the distribution on 45% of patients have reduced ef which is ejection fraction, less than 40%. And as you can see the distribution by percentages uh of fractions. Um most of the patients we see are in between 16 to 25% and um most of the patients and they preserve between 50 to 60%. What about the GDMT? And what is the benefit of guideline directed medical therapy? As also if you attended my talks at the cardiology conference and I emphasize the importance of putting patients with heart failure and reduced ejection fractions on the four pillars of guideline directed medical therapy including ARNI uh Secu Valsartan, basically beta blocker like carvedilol, metol, Sain and Bisoprolol. Uh Mr A beat spironolactone or um AONE and SGLT two inhibitors. Uh They saw in clinical trials basically in data that if patients are on none of these four pillars of GDMT, their two year mortality is around 35%. But when we add RNI beta blocker and Mr A and SGLT two, the two year mortality rate is 10%. So it's significantly lower than 35%. But the residual risk is still there at 10% of patients. Despite being on guideline directed medical therapy, 10% of patients die. And this is an important slide also published uh from HFS A um where we can see the number needed to treat. But that is with how many patients we need to treat, to reduce one outcome uh for the number needed to treat. The best medication of the GDMT is Mr A which is spinal lactone or Aleon or the beta blockers. We talked about we need between 6 to 9 patients respectively to reduce um one mortality. While the hospitalization rate, risk reduction, we can see it on the last um basic column. Um you know, with our need, we have to treat 21 patients to reduce hospitalization of one patient. So um putting it all together, we need to have our patients on the four pillars of GDMT to improve their survival and uh reduce the risk of hospitalization. So, looking at the current uh GDMT therapy and how well are we doing uh in optimizing these patients on the medications or even having them on the medicines? Uh This is uh basically me analysis and or different trials that showed um even patients who are on target. I don't know if you can see my pointer here. Um 28% of patients from the evolution A HF which is a kind of a um registry between uh Asia and Japan, like Japan mainly and Europe. And they found that 20% only of patients are on the optimal doses of RN A ace or R and 70% only on optimal dose of beta blocker and 5% on MRAS which is pretty significantly low. Um And when patients are on the 50% of the doses, as you can see here, it is still pretty low. So we have still much of room uh to have our patients optimize on the medications and to make sure that uh they are on the appropriate medications. What about heart failure and midrange and heart failure and preserved ejection fraction? Um We can see here now that the heart failure with midrange ejection fraction, which is ef between 41 and uh 49 the only medication other than diuretic, which diuretics can only improve uh how patients are feeling and quality. Um is the SGLT two inhibitors, SGLT two inhibitors currently in the state class two A medications for um midrange ejection fraction. And also, as you can see here with hot through the preserved ef which is ef more than 50%. It is the class two A in Europe in the European Society um of cardiology. Uh they announced that in Europe, the SGR two inhibitors is class one medications for patients to preserve midrange under GDF. So in the States, we still uh lying behind that in Europe, SGLT two is class one medications for midrange. Uh We have the Ace Arbor R two B and Mrasr two B uh which is a level of evidence and for patients who have preserved RNR two B, uh Ace and Arbs are not, uh Mras are two B. Um R. Uh the R is, you know, if patients are not tolerating uh army. So we looked at uh hospitalizations and overall mortality with being on the medicines. What about the trends in heart failure, rated mortality among adults in the States? And again, this is the latest data uh that's published less than two weeks ago. We saw that the hospitalization, the mortality rate has come down. Um But then there was a trend to increase mortality from 2012 to 2019, which again, it is pretty interesting despite having more medications. Now, the mortality rate of patients continue to rise and increase. And that's because maybe we're seeing sicker patients and those patients who are not responding to these medications are technically sicker and more resistant. And when we use certified, these patients um into not, you know, when we certify these patients by the all cause of death. Men usually um die more from heart failure. As we can see. It's in red here compared to women which is in blue. What about uh the different subgroups uh based on age uh be preserved, borderline and reduced TF what about the five years outcomes? As you can see here, patients with life expectancy in the United States between six and red, this is the normal population as we grow older. Definitely the uh lifetime expectancy goes down. But um as we noted that patients with um reduced DF which is in blue, they have lower uh expectancy than patients were preserved in the younger patient population. And as we get older, again, this number goes down. So when you have heart failure, be it preserved or reduced? Uh your overall um means of median survival drops as we go down and even at the regular age. Um So this is a very nice slide just like to look at uh because it uh entails all the primary heartware hospitalizations. Uh We can see how with time patient, the number of primary HF hospitalizations have been increasing. Also, we're looking at the unique patients admitted for heart failure, the number continues to increase and also with single HF admissions. So we're seeing a rise in um heart failure hospitalization. Be it primary or readmission? What about cost 30 day readmissions? And and this is what we try to do in every institution is we wanna reduce the readmission rate. And despite all efforts, the all cost 30 day readmission rate is less sta stable, but it's still under a little bit rise too uh for patients who have at least two heart hospitalization. This number as you can see here from 2016, 2017 is increasing and postdischarge, hyper readmission continues to rise. So we have a lot of work to do trying to break that cycle of readmission rate and trying to pre prevent hospital readmission. Not just because our numbers look good for the hospital, but the more patients get rehospitalized for heart failure, the more the cha the higher the chances they have increased morbidity and mortality. So heart hospitalization is never good um for neither the patients nor the health care system. And then when we look at the trends in hospitalization among young adults and the young adults, as you can see in the other slide, look at the age of 60 above. But what about patients between 18 to 45? And as you can see here, we're seeing especially these days, I came off service on Monday and we have a lot of patients now in the IC us with ages in the twenties, thirties and forties waiting either for heart transplant or struggling with their heart failure. And we're seeing more and more of these patients. So heart failure is not anymore being the disease of the elderly. And when we look at the patient population between 18 to 45 there is around 767,000 hospitalizations and most of these patients are men. Um as we can see here and the increase in morbidity has gone over with time. We're seeing more diabetes, more obesity, hypertension, smoking, and chronic kidney disease. And, and here black adults, as we saw in other slide, they have higher comorbidity burden compared to whites and Hispanics. And when we look at this specific population and the trends, we saw that there's an overall increase in hospitalization and inflation adjusted cost of care. So the cost of care going up hospitalization and throwing up and um all the morbidity and mortality that comes with it. And when we look deeper into these patient population, we found that around 50% of all adults, young adults, um between 18 and 45 are black adults, which is pretty significant. Um I mean, we listened to doctor Mark East um in his talk about um equity and um race and patients with heart disease uh overall, but also in heart failure, we see that again, most of the young adults, 50% of them are black patients. And also we talked about disparities in care and 50% of the adults hospitalized for heart failure are in the zip codes in the lowest quartile of median household income. And when we looked at that, um basically the map of the United States and we can see that in the South. South holds 49% of the total heart failure hospitalization throughout the nation. And that's I believe because of multiple factors, one of them increase the comorbidities and called the stroke belt. We have a lot of um stroke hypertension diabetes, obesity among others. Um So um that's pretty impressive slide. I wanted to share with you all um the slide because again, we have a lot of work to do trying to. Now talking about primordial uh risk factors uh modification, even like patients before getting hypertension, we're trying to be proactive to reduce those risks of um hypertension to prevent patients to go into hypertension that can lead to heart failure. So a lot of work to do and a lot of um uh job that a lot of education and uh support that needs to be given. And when we looked at the trends of hospitalization, also according to sex, we saw mortality, males are higher but also hospitalizations, men have higher hospitalization rate compared to women. And when we look at the trend of hospitalizations based upon race, and again, this is another slide which is very important and powerful to watch in the sense that seeing that black patients have significantly higher hospitalization rate to heart failure compared to other races. Be it Hispanics and whites? What about the five years outcome in patients hospitalized with heart failure? Be it preserved, reduced or midrange? Ef um So we can see here that within years of admission, everybody have increased hospitalization rate and preserve is 46 for mortality reduces 46 and uh borderline is 8%. And I look again, all patients you know, still have high mortality rates, readmission rates. Be it reduced borderline or preserved. And this is again, this is an important slide to watch and to look at and to, you know, make us also respect patients with preserved ef because these patients not just, they don't have ischemic, they can have some coronary artery disease or uh whatnot, but they have other comorbidities being COPD, hypertension diabetes. This lipidemia is coronary artery disease and usually more resistant to therapy. And in the past, that common thought process that uh reduced, have significantly different mortality, higher mortality rate than preserved. But as we can see here, be it preserved, reduced. And when you get hospitalized, your mortality readmission rate is significantly comp compare is comparable to uh other uh forms of heart failure. So again, when we looked at the different uh racial groups, we can see that freedom from without hospitalization, the black is definitely lower than others. I mean, they hospitalize more. And again, we can see here the all cause hospitalization, time to all cause hospitalizations in days and time to death. Um as we talk about it. So this is basically kind of um the latest um heart failure statistics that were published at HFS A and I wanted to share with you. Um And there were three late breaking clinical trials that were presented that are pertinent to our practice. There were other uh trials that were there. Uh But um we don't utilize these services uh like we don't utilize these. Um you know um studies and especially like, for example, called rebalance HHF, which is using splenic nerve um Nerv, which is in development. Uh but I want to talk about step HF uh trial. The Step HF trial uh was presented at the also European Society of Cardiology meeting uh last uh month or so ago. But at HFS A, they looked at the specific subgroup and they presented the date of that. So what is STEP HF trial? It looked at the effects of semaglutide across the range of left ventricle ejection fraction and obesity, phenotype of heart failure with preserved ejection fraction. The step HF trial basically, and doctor Butler was the presenter at HFS A. So the ST chef, it randomized patients um aged 18 or older with a BM I here than 30 into either receiving semi glut, which is um we uh we call it now OIC and uh to either receiving again that or just subcutaneous placebo and they increase the dose from 0.25 up to 5.5 to 1 to 1.7 to 2.4. Um And then they followed these patients after 52 weeks until which is the end of treatment to 57 weeks. The key inclusion criteria was mainly patients with ejection fraction, more than 45%. And they're having NY A classification 2 to 4 Kansas City uh cardiomyopathy questionnaire less than 90. Uh What does that mean? Um Usually this KCCQ uh questionnaire, the lower the number, the worse. Uh So if it's above 90 patients have better quality of life. So patients less than 90 that these patients are uh more symptomatic and limited because of their heart disease. Uh and also they look at a six minute walk. So they wanna make sure these patients are able to walk more than 100 m, the more they walk, the better. And they have at least one of the following, having elevated left ventricle filling pressures that could be measured invasively through your right heart cath or have elevated neritic peptides and elevate a structure acu abnormalities, BB MP and anti pro B MP or structural abnormalities being having at least left ventricular hypertrophy or increased left atrial size and others that were um specified in the trial. And these patients should uh have higher hospitalization in the past 12 months and are on ongoing treatments for diuretics or have a structure of acu aal is as stated above. The key exclusion criteria from ST HF trial was having patients having prior bariatric surgery because this medicine as we know now um has shown to reduce total body weight. Um Also these patients have recent self reported weight change more than 5 kg exclusion criteria to entering a trial. If these patients had recent adverse cardiovascular event or heartware hospitalization or they had high blood pressure, more than 160 or they have HP one C more than 6.5 or known medical history of diabetes. So these patients are not diabetic. So this medicine was not used for patients with diabetes. This medicine was used for patients. Uh you know, with HHB one C less than 6.5 they can be prediabetics but they're not diabetics for. Um So when they looked at the trial with the step a check, which was published in Jack heart failure. Again, this is a recent publication in the past month uh which showed that the patients with um who are on semi glut, they have significantly improved outcomes in patients with preserved ef and the preserved here is 40 uh 5% as you can see and above. So the plasma volume and stress volume was lower. The low visceral fat was in pericardial and intramuscular fat was lower. There's lower demand for cardiac perfusion and there was lower intracardiac pulmonary pressures, reduced inflammation through CRP improve insulin sensitivity and metabolic efficiency uh and improve the microvascular function and the vascular protection. And the primary out they looked at the weight which there was significant reduction in weight, there was improvement in symptoms and the symptoms uh was measured through KCCQ, as I mentioned and reduced physical activity limitations. So they're able to walk more and more than 100 m on a six minute walk and increase exercise capacity. So that was published at um and presented at the European Society of Cardiology in the past 1 to 2 months ago, what we talked about HFS A which um 10 days you talk the risk stratified to these patients and they classify these patients based upon their ejection fraction. So the study looked at ef more than 45%. But we are looking now at the patients who are between 4045 and above 50. Although uh we know SGLT two inhibitors improved heartware outcomes across the ranges of EFP preserve reduced or midrange. Uh benefits of other therapies such as Remras or Arbs are restricted to patients with. As we saw as I showed, you also in the prior slide to reduce and midrange ejection fraction, but they are not much true to preserve. Efre is class two B um as in Mras as well and Arabs. So that created a debate. So, you know, if it's um if there was a difference between midrange and preserved for Rmras and Arbs, is it the same for um as uh semi glut basically? So in the step HF trial, the semi glut, which is 2.4 mg which is given sub Q um showed statistically significant and clinically mile improvement in symptoms as we saw and physical limitations and exercise function and inflammation and it reduced the body weight. So this study that was presented, we performed the pre pre specified analysis of semi glut effect on these clinic key trial, end points and you have between 45 to 49 to 50 to 59 and more than 60%. So we're looking at the different subgroups of uh preserved and midrange. So at 52 weeks, um since randomization, we saw that the drop in the weight of around 10.7% on patients who received the medicine compared to patients who received placebo. That's the weight part. And when we looked at uh stratification based upon the ejection fraction, there was no difference uh among the different subgroups, there was a drop in ejection fraction overall. Uh for all the patients between 45 and to 60. So effectively, the medicine stays the same among the all ejection fractions between 45 to 49 50 59 and more than 60. What about the anti pro B MP? As most of you know, anti pro B MP in patients who are obese because of adipose and different enzymes. So you expect if you lower the body weight and lower the adipose tissue, your anti Pro B MP will go higher because again, adipose has this um negative effect on the B MP. So the patients lost weight, but again, that's the beautiful part of it is that despite losing weight, the patients also had a further reduction in anti PRO B MP. So which is important because again, you expect it to be higher. And when they looked at different subgroups, each subgroup did not um basically it crossed um the confidence interval but the overall total, there was no he did not cross cross the line of unity. Um So we can say that the overall population did not um have any difference, be it. Yeah, 45 to 49 50 59 or 60. So it's good. And all what about KCCQ? Again? The higher the number in KCCQ, the better? Um there was increase in KCCQ between placebo which is in gray to the blue one in patients who received the CMO glut, there was an increase in 7.8 points which is significant as you can see here, it's on the other side which is increased, which is great. Most of the patients who benefited from it are in the um preserved ef but when we look at data analyzed, it is the overall patients be it any of these ranges they benefited from it. The study was not significantly power to look at each one of those, but the overall was beneficial. What about the CR PC RP is inflammation for? Um you know, we we're doing currently clinical trial at SA um and the P I on it, which is one of the medication IL six inhibitors uh for patients with preserve ef because we're thinking that higher CRP can cause more. Um you know, inflammation, inflammation can worsen heart failure. So the semi glut um show that there is a reduction which also was significant among all the different subgroups. Um Again, it works for all the different uh subgroups of um midrange to preserve ef what about the six minute walk? Most of the patients who benefited were in the 50 to 6 50% ef and above and again, so there was an increase in six minute walk by 20.3 m which for some might not be significant. But I always uh like to share that patients with uh pulmonary hypertension. Most of the medications have like shown benefit in patients, um, if they are able to walk 15 to 20 or even uh maybe a little bit um um meters or a little bit more. Um So most of the drugs were approved for it. So this drug actually uh showed that it is beneficial among the whole different subgroups of uh patients with preserved and Midrin injection fraction. So again, uh semaglutide improved symptoms, physical mutation, exercise function, um and reduce inflammation and body weight to a similar extent across the LVEEF subgroups. There was no safety concerns in any of the subgroups and the data support treatment with semi glut for improving, improving heart fated symptoms and physical limitations. Um As above um in heart failure with preserved, you have regardless of ejection fraction at baseline. The second study I wanna talk to you about is guide HF, guide HF we all know uh and have heard of it, uh which is the primary results of the prospective single arm trial of hemodynamic, guided management of heart failure by carding them, which is called the guide HF and SIA um is and was uh the participant of this clinical trial. So, a cardio system which is a, a pulmonary pressure sensor monitor, which is implanted in the pulmonary artery showed benefit in patients with New York Heart Association class three and prior heart ization in the Champion trial prior to the GHF. And that's what led to the commercial approval of the, of the sensor in 2010 and it was approved in the United States in 2014. And patients were, you know, implanted with CardioMEMS and has shown to continue improvement in reduction in the heart care hospitalization if they had HF heart hospitalization in the past year with the F um independent ejection fraction. But NY A class three, the heart failure of the GHF trial was designed to evaluate the efficacy of cardiom in an expanded patient population. So they looked at patients with NY A class 2 to 4 with either heart care hospitalization or elevated anti prob MP. Um So the randomized arm was reported um in the Society of cardiology two years ago and was published in Lancet as we're gonna see in next slide. But in the HFS A, they're publishing the data um and they presented it again uh 10 days ago in a single arm which we're gonna talk about. So the end, my arm is the arm that was published two years ago at Lancet and they found that in patients with NIH last 2 to 4, either with prior heart hospitalization or anti PRO B MP when they randomize the patient, 1 to 1 by the treatment by cardiom versus control, which is just a regular care. And with the primary outcome be heart fair hospitalization, urgent heart farre visit or death. Um They found that there was no statistical difference in outcomes when they randomized these patients. Uh Again, I know I a class 2 to 4 with Hartford hospitalization with anti BM peak with the medical therapy versus the control group. And the reason for that we're not gonna go into it today is that because COVID hit at that time, there was stall in um enrollment in the trial and not just that there was uh patients did not follow up and they did subgroup after it and they found that patients pre-covid did better, but that's a total different study. What I'm gonna talk about today is that uh the single arm which NYH A class three and when they looked at the patients with NY A class three, one of these patients like part of the patients who had elevated anti uh BNP or anti pro B MP. The other one were patients with NY A class three with prior HF hospitalization, which is their current recommendations for CardioMEMS. And the primary end point was heart fair hospitalization, urgent heart fair visit and death for elevated BNP. Again only versus prior heart fair hospitalization alone. The secondary outcomes via HF hospitalization, urgent visit or death independently or HF hospitalization of prior year versus year, post implantation and the script if we looked at the gate pressures and no ny A class. So this is the method is a single, the two groups and they looked at the elevated anti PRO B MP group alone and the prior HF hospitalization level and both um were with comparison only performed within, with the first two groups for equivalent, this is an important word equivalence. They wanted to see if these two groups separate the anti pro B MP or the prior HF hospitalization have equivalent in their outcomes. And um so there was 2600 patient sample size. But again, because of COVID, as I mentioned, they were dropped to 1358 at but even with that number, they were able to achieve power to determine the primary analysis. Um you know, to make sure it is uh they achieved significance or not. So, the primary end point and components were assessed using uh different statistical methods and this is the patient population that the prior HF patients are younger, more females than black at higher BM I, higher diabetes, higher ejection fraction, uh lower IC DS and lower GDMT for the elevated anti pro B MP patients were more male, lower BM I um and higher GDMT. But they had a lot of similarities. We see some differences, but there are a lot of similarities including all of them had M RT A class three. The geology of heart failure was similar among them. Uh the hemodynamics, the kidney function and the use of SGLT two U and the beta blockers and diuretics. So what did this study show? Remember they're looking for equivalence, which is there is no difference between uh the anti PRO B MP and the prior HF hospitalization. So the studies show that there is significant difference. So the outcomes of patients with anti Pro B MP, elevated anti PRO B MP are different than patients with prior HF hospitalization. So which is good. So um we can see here, you know, even with elevated anti PRO B MP, the number of patients requiring Harford hospitalization or urgent care or death is significantly lower, which is good in lower HF hospitalization and lower death and urgent visits. So again, it's it's good that they're not equivalent. So how does it like, you know, how can I look at it here? Um For patients who had prior HF hospitalization, this is this one arm like the uh part of the one arm, there was 54 reduction and hospitalization rate when patients were treated based upon cardiograms, which is a grade which is similar to what the champion trial initially showed for patients who had no prior hospitalization for heart failure but had anti prob MP. So that there's no hospitalization, the chance of them getting hospitalized year post implant was only 0.27. So it is again, significantly lower than patients who were hospitalized before and um use cardiom to reduce their hospitalization post one year. So this is important because again, it only shows subjects, event rate fall half to that of prior HF hospitalization as you can see it like half of those patients. So what about the P A pressures? Um No, the same thing, both patients had reduction in their P A pressures. Um Using the cardio being there having elated Antti Pro B MP or they had um basically uh harder hospitalization, KCCQ, which is Q uh basically quality of life cancer cardiomyopathy questionnaire, cancer city cardio questionnaire for uh basically patients with elevated anti pro B MP. Uh The overall summer they had better um which is the higher the number, the better um quality of life uh compared to patients who had heart fair hospitalization. So what does the study show basically that patients who are mildly symptomatic for heart failure, which is NH A class three with elevated anti prob MP level alone or those with HF hospitalization alone are not equivalent as we saw before that slide to each with respect to heart fated clinical events and represent distinctive outcome trajectories as we saw. And then despite this distinctive characteristics, we this demonstrates similar benefits of hemodynamic guided management. As you saw the P A pressure reduction and the improvement in NYC class and quality of life domain. As we saw in KCQ. So these data from this study support the indication of cardiom implantation and hemodynamically guided management in the presence of anti PRO B MP level elevation even prior to heart failure hospitalization. So that was the message that if you're Nhnyh A class three and elevated anti PRO B MP, even if you're not hospitalized before cardiograms can improve your outcomes and reduce your chance of future heart fail hospitalization. The last trial I wanna talk to you about um is um the pioneer and paraglide uh HF. So it's mainly about using uh Rne or Circuit Valsartan in acute heart failure. And they looked at it across the ejection for spectrum and this was presented by Rob Metz from Duke. Um So the again, the titles, efficacy and safety of circuit Valsartan inpatient hospitalized with heart failure, looked at the pres specified pool, individual patient analysis pioneer HF and Paraglide HF. So, based on paradigm trial, which is uh used for patients with a reduced ejection fraction and paragon HF for patient with preserved ejection fraction with um these are outpatients who are not hospitalized, uh who received uh Secu Valsartan indicated that uh the United States for patients with chronic HF with most clearly evident in patients with EF below normal. The pioneer HF and Paraglide HF, they investigated in secure Valsartan versus ace or R following stabilization for acute heart failure. Basically, in patients with EF less than 40 with pioneer or more than 40 in paraglide injection, uh paraglide uh trial. So they did this food analysis of pioneer HF and PHF. And um to look at the estimate the safety and efficacy of circulator valsartan when initiated during hospitalization or soon after worsening of heart failure event within like 30 days among patients with heart failure across the spectrum of ejection fraction. So the pioneer HF they looked, they had 881 patients, they looked at CCU Valsartan versus uh Enalapril which is standard of care. Um The control group with EFS and 40% and it was initiated in the hospital and the paraglide HF, they looked at um Secretary Valsartan compared to Valsartan with ef more than 40% and uh 70% of these patients, the Secure Valsartan was initiated in the hospital and the 30% were initiated within 30 days from the event, the outcomes we're basically looking at the primary end point was the time average proportional change, ant pro B MP and baseline through week four and eight. The thought process, anti pro B MP is a marker for heart failure. The if we have drop in anti pro B MP, mean the heart rate is more controlled, an educated clinical end point were analyzed throughout the end of the follow up adjusting for the trial. So again, this is the pioneer HF descriptions and how there was no run period for any of this trial because this medicine was started, started in the hospital or straight within 30 days of hospitalization or worsening heart rate event. The median follow up for pioneer was eight week trial period. And uh that's why the anti prob MP was checked at four and eight weeks for paraglide. The median follow up of six months. And also anti prob MP was checked at four and eight weeks. So what did we see? Uh what did we see? Basically, we saw that uh the primary endpoint, the control group, as we saw before we had um the pioneer in Alper or Valsartan in Paraglide, the patients who were pooled independent of the injection fraction of both trials. There's a significant drop of anti PRO B MP control to that controlled group compared to the control groups. And even that was started week one from baseline. So these control groups, again, they are on medical therapy, they are on Valsartan or in Alper, which are the standard of care uh for patients. So, despite being on any of these two medications, uh patients are psych through Valsartan. There was significant drop or anti pro B MP or B MP. Basically, um at week one, week four and week eight and it continued, which is pretty significant. What about the cardiovascular death or heart fair hospitalization? Basically, the similar um benefit was shown here uh compared to the control group. And again, I I keep repeating it, the control group is not not medical therapy, the control group as these patients on medications, be it Enalapril for um, that trial or Valsartan as we saw before. So, um, with the con convert the control group, that's acu Valsartan, they have significantly lower mortality, cardiovascular death or heart hospitalization compared to the treatment uh control treatment group. And the P value is 0.0077 which is significant and the most important part of it is one event is prevented per four patients per year. So which is kind of the number you need to treat similar to it, but it's four patients treat them for a year. Uh with secu Vasin if these patients were hospitalized with heart failure or they had recent heart failure worsening within 30 days. If you treat them with secure vs, um these patients will one of four patients will have lower cardiovascular death or heart for hospitalization. Um So when they risk certify them by the ejection fraction in the in patients with DF less than 60% the benefit um of C valsartan or cardiovascular death or heartware hospitalization was consistent across the range of ejection fraction. What about the evidence of treatment? He heterogeneity? Um if they have more than 60% the inter there was interaction. So um basically the benefit, as you can see here um throughout the group, mainly with the f less than 60%. What about the safety and uh clinical efficacy? Um we can, we see for sure that cardiovascular death or heart for hospitalization. As I mentioned, the Se Valsartan group is significantly lower or compared to the control group. See, the hazard ratio is lower and significant does not cross the line of unity. And also the combined clinical composite be it CV, death hospitalization for heart failure and urgent heart failure visits is significantly lower in the secu Valsartan group compared to the control group and the control group is again medical therapy. And also we have questions about the safety is this medicine safe? And so we um there's the question raised when we looked at the safety of the medicine, the one of them is worsening renal function. And it's a defined my clinical trial with the increase in the creatinine more than 0.5 with simultaneous reduction in GFR by 25%. Um So patients on Civ Valsartan um that it's safe again, but it's not again, statistically significant because it cross the risk reduction. You're at a risk of one basically. So it's safe again, safer. But again, you can say it's for sure, safer is not significant. What about hyperkalemia which is an anticipated also adverse effect of the medicine. Patients on Secure Valsartan had more hyperkalemia which is potassium more than 5.5. Uh But again, it is not statistically significant. What about hypotension? Uh We saw more hypertension in the circular Valsartan group as anticipated, but that was not statistically significant compared to the control group. What about the angioedema uh similar, we didn't see any physical difference in angioedema or death among the different groups. So it's technically overall safe. So in summary, uh for this trial in the diverse population stabilized after worsening HF across the HF spectrum, including the new HF, compared it with a R. Secretary of Valsartan, led to a greater anti pro B MP as we saw that started at week one and continued to week eight because that's a specified val like time. Follow up four weeks and eight weeks, it reduced the cardiovascular death or heart for hospitalization and led to a higher rate of symptomatic hypertension as we saw but tended to be lower the worsening of renal function. But both of them were not significant, but we saw trends in hypertension and hyperkalemia but were low, led to worse l lower worsening of uh renal function in a pre specified subgroup with the f less than 60%. Um In secu Valsartan was associated with a more favorable reduction in clinical events as we saw in that uh graph. So was application. So this pool analysis data reinforces the overall benefits versus safety and tolerability of circulator. Valsartan in patients with worsening heart failure across the spectrum. Ef less than 60%. Um So this data support present professional society guideline recommendation to start Secretary of Valsartan as a de novo treatment in patients in the hospital with acute A HF. Now extending to the old spectrum of ejection fraction, mainly with less than 60%. And the recent AC Chahfs A guideline um state that R A should be initiated the NOVO in patients hospitalized with acute heart fail hospitalization with rejection infection before discharge. So we anticipate that we might have an update in the guidelines in the next year or so that can um recommend that RNE be initiated not just in acute heart fail with the UCF, but in patients with midrange and preserve ejection fracture. So this is technically the three most important uh clinical trials that were presented at HFS A that I thought they are relevant to our practice, especially we use a lot of secu valsartan in our clinics and the hospital and outpatient settings. So now we can feel better about potentially initiating it in patients with less than 60% in the hospital after the discharge. Also, I talked about as uh we saw that guy HF trial in a specified arm with NYC class three. So um this is gonna be a battle with um health care insurance companies to get it approved, but we have to make sure it's approved for before implanting it. The patients with NYC class three with heart failure symptoms. Uh they don't need to have a heart fair hospitalization. Technically, according to this arm of the study, uh to have benefits of future reduction of heart fair hospitalization. And the first one that um we looked at with the semaglutide. Um We saw that um the benefit of semaglutide um has is in with reduction in CRP reduction, anti PRO B and P reduction in weight. An improvement in KCCQ which is quality of life questionnaire has been um beneficial in all the subgroups of ef between 45 to 5050 to 59 and greater than 60. Um And also I discussed today the latest uh heart failure statistics that was presented also at the Hartford side of American annual meeting. Um And by that, I'm happy to take any questions.