Chapters Transcript Video New Therapies in Hypertrophic Cardiomyopathy So everyone here probably heard of obstructive cardiomyopathy. Um It's a chronic progressive disease of the maya site. Um that leads to, you know, an unexplained LV. Hypertrophy. So these are patients without hypertension or some other reason to have hypertrophy. It often leads to a dynamic left ventricular outflow tract obstruction, which is a result of hypertrophy. We also see systolic anterior motion of the mitral valve and elevated LV filling pressures really on a cellular level. What we're seeing is um abnormal sarcoma here. Um mutations of the circle near that lead to basically too many active mice and cross bridges, which lead to dysfunction in the circle here, From a genetic standpoint, this is probably the most common congenital heart disease, estimated to be about one in 500 people. Uh so there's probably 500 people here. So there's probably at least someone here that either has hypertrophic cardiomyopathy or at least has a mutation that puts them at risk for it. In terms of what we know about its genetics, it's auditable dominant and there's an incomplete age dependent penetrates with variable expression. So not everyone who has the gene develops the phenotype. The traditional therapy for this really has been beta blockers, calcium channel blockers and sort of the last resort was disappear. Um I'd a lot of patients failed therapy continue to have symptoms. Shortness of breath fatigue is MIA, which over time lead to the development of invasive techniques. Either open heart surgery with a surgical procedure to literally shave down the septum shaved down the myocardial or uh an alcohol septal ablation, which is essentially a controlled infarction of the septal tissue. Uh you know, neither one of these was a great solution to the problem. Surgical requires open heart surgery and all the risks and recovery related to that. And alcohol septal ablation was a little bit less obviously less invasive but not as complete reduction in myocardial tissue and also could lead to complications. You're injecting alcohol into the heart, which can lead to a larger infarct than you intended. So there were not real great therapies for these patients thankfully. Over the past, I would say 10 years there's been a variety of molecules have been uh explored as possible therapies for obstructive cardiomyopathy. Magic Hampton is sort of the first in class to be FDA approved. Uh it is a selective cardiac myosin 80 P ace inhibitors. So it's selective to the heart itself. It doesn't affect any other muscle tissues and what it really does is it reduces those acting Miocene cross bridges and this improves sarcoma. Your function uh in the have a pointer here I guess. Um so basically just a sort of a schematic. There's too many mice and bridges. It leads to hyper contracted city impaired relaxation. Diastolic dysfunction increase in the myocardial oxygen demand of the tissue and impaired compliance. All leads to LV dysfunction and symptoms have a canton sort of trims these and reduces contra activity improves compliance of the heart improves diastolic function. The big trial that really came out recently is the Explorer HCM trial which was multi center trials randomized double blind placebo controlled. So all the stuff that gets the statisticians really worked up explored a five mg daily doses a. P. O. Medicine In patients with symptomatic hypertrophic obstructive cardiomyopathy. So a total of 251 patients. The characteristics that were looked for were people with either a provoked or a resting gradient across the L. V. 50 millimeters of mercury or greater. These were patients that had normal ejection fractions uh and uh symptoms new york heart association class two or three people that were excluded were people that had syncope, e people that had VT in the past six months. And the primary endpoints were at 30 weeks they wanted to look at compared to baseline cardiopulmonary exercise testing and looking at 02 consumption, an improvement in that as well as an improvement in class. Um Also the another endpoint was a more dramatic increase in 02 consumption at peak with no change in reported symptoms. Here's a diagram really showing the study how it was designed. There was an initial echo at weeks zero. Um does hit rations were at weeks eight and 14. And this is based on the L. V. O. T gradients and I can talk about that in a little bit at 30 weeks. There was a repeat echo and that was sort of the end of the trial. Um and there was a post file up treatment at eight weeks. There's been a subsequent longer term study and there's also ongoing um study looking at five year outcomes. Again this is a little bit more blown up picture of it but at the bottom you'll see exactly which types of testing we're done. Tt was done frequently. Stress echo was done at the beginning and end. There were EKGs there were self assessments that were done by the patient to assess their quality of life their symptoms. There was also cardiopulmonary exercise test and evaluations by a physician. So the symptoms were being about were being evaluated by a physician. Like I said protocol echoes were performed every two weeks and they were also performed at week 0 18 and 30. Those were reviewed by a core lab that was at Brigham and the things that were being looked at were LV mass LV volume index tissue Doppler as well as the M. R. And the presence of systolic motion of the anterior of the mitral valve. The core lab was at Brigham and the images were blinded to whether people were on therapy or off therapy. But because dozing adjustments were made based on the echoes. The time point of the when the echo is obtained is not wasn't blinded to the reviewers and again does filtration was at eight or 14 weeks based on L. V. O. T gradient. These are the baseline characteristics for the patient, 60 years old, 40% female and pretty average slice of patients that we run into that have HCM 8% were on had had prior reduction therapy. And most of these patients, 75% were on a beta blocker, 17% calcium channel blocker. Um The results at the end of the trial, the echo results showed a significant reduction in LV mass and the left atrial volume index as well as improvement in the tissue dollars. Uh The baseline L. VOT gradients that were the highest showed the greatest reduction at the end of the trial. So the people with the worst degree of obstruction seemed to benefit the most from this medicine. And in terms of the micro valve study wasn't powered for this outcome. But there was significantly more patients had resolution of their salmon mitral regurgitation on therapy than off therapy. That's great. But I think the real important thing is the quality of life improvement that the patients experienced. So at the beginning of the trial, only 6% of these patients had class one symptoms. By the end it was 55%. So more than half of the people in the trial by the end had class one new york heart association class symptoms, which Is fantastic. And I think on the other side of the spectrum, you had 29% of these patients reported or were valued by by a physician and found to have class three symptoms by the end of 30 weeks. That was down less than 5%. So these are people that you're dramatically improving what they can do during the day. Uh Here is the end points in terms of the primary endpoint, which was cardiopulmonary exercise testing. This was there was a statistically significant improvement in New York Heart Association class as well as peak 02 in cardiopulmonary exercise testing. And I don't think this slide mentions it, but I'm going to get to the effects on the L. V. In a second. A sub study of this group was evaluated with cardiac M. R. It was less than 40 patients but it gives really good images. And these patients had a cardiac MRI's at day one and at the completion of the trial. And this really was specifically looking to quantify the changes in the LV mass because obviously echoes, you know, it's a subjective Again, this is a small subset of the patients in that trial was only about 35 people. Um and at the completion of the trial, there was a statistically significant reduction in the LV mass as calculated by CMR cardiac function in this portion of the trial, there was about a 6.6% reduction in left ventricular ejection fraction as calculated by CMR at the completion of the trial. So a small reduction in LV function. This is a really cool picture showing uh the effect with CMR. Um the white arrow is pointing to a papillary muscle. But there you I think it's pretty clear that there's been a significant reduction in the LV mass here by CMR compared to placebo. Um And this is another picture I think that's even more extreme in showing reduction in LV mass. Um conclusions from this maverick Hampton is associated with favorable remodeling of the LV. So you get a reduction in LV mass, improved improved left atrial volumes. Your diastolic function improves, you get a significant reduction in your resting and L. Vot gradients more importantly for the patient is a significant improvement in their functional capacity. And this comes sort of at the cost of a small reduction in left ventricular ejection fraction. Um Just to quickly talk about how we use this in the real world. This is sort of from the manufacturer guidelines and had a treat patients with it. So initiate with five mg a day. You wanna check echo and make adjustments based on the echo. If the gradient remains greater than 20 you can Make dose titrate. If there's a dramatic reduction in gradient, you can reduce your dose and you want to check echoes every 12 weeks after they reach a stable dose. And what you're looking for is a preserved ejection fraction with a gradient less than 30. Um And for patients that do get a reduction in LV EF. The recommendation is hold therapy recheck in four weeks, continue to check until the EF goes back above 50 and then you can restart at a lower dose. Um This is a case that here at Sentara of a patient that we've had on therapy for um several months now. Middle aged gentlemen refractory symptoms. High dose beta blockers continues to have dystonia. This is his baseline echo which shows a pretty significant gradient across the L. V. O. T. Um And if you could play this video, I guess the video is not gonna play after 12 weeks of five mg a day. This obviously looks worse, but the scale is completely different here. So it's it's pretty close to a 50% reduction in this gentleman's gradient and significant improvement in symptoms. If you could play this, this is a follow up echo, I want to say, at 30 weeks. So there's been a significant improvement in just sort of gradient and play that this is our most recent echo after. Um Now it's been almost, I think five months of therapy and this is his resting gradient. Now, after five months it's a significant it's 12 m. So it's it's, you know, a dramatic improvement and he's had a dramatic improvement in symptoms. So we have um we're starting to enroll, get more patients on therapy. The patients that we have had on therapy, we're seeing tremendous improvements in both their symptoms and also their their values on Echo Published December 7, 2022 Created by Related Presenters Luke Kohan, M.D. CardiologyInternal Medicine View full profile
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