Cardiac Amyloidosis, Cardiomyopathy, Amyloidosis discussed on Cardionerds



Louis University. She has since been at Johns Hopkins for Residency Cardiology Fellowship and advanced heart failure fellowship. Her early research search pursuits were in heart failure with preserved ejection fraction from this and former advanced heart failure training she developed a strong clinical interest and research interest in in the early diagnosis and treatment of cardiac amyloidosis which is why she makes such a perfect person to continue our discussion on amyloid. Absolutely absolutely totally Great Jovan has been a mentor to me. She's been a year ahead of me in residency and then fellowship and has been guided me along the way we used to share clinic together and when she left to pursue her heart streams in advanced heart failure. I it was a real loss so I used to send her snap chats every clinic day which she ignored and threw it into the trash so jovan thanks so much for joining. Think for having so. We're real excited to have you. We are going to get started with in some questions that we are dying to get your take on first. We'd like to talk a little bit more about heart failure therapy in cardiac amyloid so so we wanted to get your opinion from a practical standpoint on the management of these patients in terms of medical therapy that traditional medical Michael therapy that we use for cardiomyopathy patients. What are sort of the do's and don'ts that are specific to cardiac amyloid yeah? I think that's great to discuss. fess up front with cardiac amyloidosis actually like many aspects of heart failure understanding the human dynamic. Derangement is probably the best way to understand why we do do. And why we don't treat cardiac amyloid with certain quote Unquote Standard Heart. Failure Therapies Cardiac amyloidosis as we may now as an infiltrative restrictive of cardiomyopathy the amyloid fiber deposition leads to buy ventricular hypertrophy and the LV is generally thick non dilated needed and non defensible. So this really does limit the heart's ability to various stroke volume and there is actually kind of a fixed stroke volume advanced restrictive disease so even though the major symptom manifestation of Obama light is congestion there is also this propensity for hypo dialing. HEP Of Alenia. Nia with over dire recess and importantly the hypothermia from diary says may manifest dizziness lightheadedness precinct. syncope does often to need to be distinguished from dizziness. For example from neuropathy interesting over that that can be seen in. What as one of the manifestations of amyloid correct performer apathy is mean another major manifestation of teacher Emelin so the humidity Amex are also? You know why eighth Feb is very sensitive in credit cardiac amyloid. There is a loss of atrial kick or reduction in stroke volume and this could be really consequential and then lastly there's also a heart rate dependency to to maintain your cardiac output and a need to avoid certain drugs. which will talk about a little bit like Betablockers that may lower your heart rate depending on the patient most patients chance do develop congestion though an require? Initiation of loop diuretics on which is a mainstay of therapy and often times pretty high doses are needed to achieve symptom relief. As I mentioned the caveat with diabetic titrate has just to be on the lookout for over diary system. hypoglycemia symptoms that patients will report court. If they are experiencing this are lightheadedness dizziness precinct. Piece syncope they may have an AK I in their labs or have a lower them baseline blood pressure. There is in this case. What may be tricky distinguishing the symptoms of lightheadedness and dizziness from another common carmody amyloid patients? which is autonomic neuropathy? With the which can also manifest as lightheadedness and dizziness precinct opinion syncope Visayas diabetics in particular Matola zone is sometimes needed as a booster and manifestation has is good enough renal function and especially with hypoglycemia. I do try to add ons for locked him. I think one important lesson I've learned just owing to the restrictive nature of the Aziz and one of my clinical humid enact mentors docker Wittstein. taught me early on is you may never actually normalize the JV P or you know have normal filling pressures in patients with cardiac amyloidosis patients are dependent on filling pressures to maintain their stroke volume so with diabetic tight. Ration- what I'm really assuming for is symptom relief and decongestion more than anything. That's really interesting job. What I'm hearing from you is that Dia? Radic's are really the mainstay of therapy in treating treating cardiac amyloid really to get to decrease in congestion and symptom management which is counter to what were traditionally thought with cardiomyopathy where our mainstay mainstay is really trying to get them on goal. Directed therapy are really pushing Beta blockers. Ace inhibitors year. You're really reaching for diabetics. I and so coronal acting on for example is not necessarily from the guideline directed therapy perspective. But more for to help normalize the potassium so patients don't have to take you know just like bucket. Tuck it loads of potassium. Yeah that's correct so the other standard therapies that you mention Rasa Habituation Beta blockade. That you know we are really trying to push on our dilated cardiomyopathy map. The patients have not shown similar efficacy in cardiac amyloidosis patients and again this really goes back to the underlying he amex and the concept of having a relatively fixed stroke volume so online dilated cardiomyopathy. Were you Vasil dilate in reducing increase your cardiac output. There's really but not this ability in amyloid and instead you just kinda potentiate hypertension a lot of time. Betablockers can do the same You know again related related to the negative Aina Trophy and current trophy nonetheless. There are definitely patients. Who've Kinda me on clinic there hypertensive with cardiac amyloid there on ace inhibitor? Or they're on Beta blocker because of a history of a fifth and tolerating these medications. Fine so in these cases I usually don't stop the drug but definitely regularly monitor symptoms inches. Have a low threshold to discontinue and related to this. I think one useful clinical pro to throw out there in the diagnosis of cardiac amyloidosis. Is You you know you have a heart failure patient diagnosis in the hospital. Of course everyone wants to start guideline directed medical therapy and you may not have diagnosed amyloidosis at this point will a clue that this may be. AMYLOID is patient tanks when you start. Logos Beta blocker or ace. Inhibitor on initiatives prompted. Think about if that is what's going on in the ideology aetiology so that was a great summary of traditional cardiac medications and how they defer in the in the treatment of cardiac amyloid. But what's really exciting about this particular disease entity it has been. I think the advent of novel therapies particularly for tr which is why there is now such a greater push to diagnose this disease at an earlier time now that we have a therapy. We'd love to hear more from you about the drugs that have been developed that are sort of in the pipeline Particularly the attract trial that came out at New England Journal in two thousand eighteen eighteen looking at two feminists. Yeah I think this is What's incredibly exciting about diagnosing and treating amyloid in this era? I'm there's just been a large surge of disease modifying therapy before we kind of dive into two families and attract in. I think it's important to review so what we're targeting here. which is the translate written? Protein translate written at transport. Protein is synthesized in the liver and it comes together to form a Just kind of like a four leaf clover in its natural state. So with T. T. R.. Cardiac transplant written the issue. Is it destabilizes in dissociates associates in the monomers missiles and then deposited as amyloid fibers In various organs but as we talked about particularly the heart and the peripheral nervous the system so this can happen either due to a pathogenic mutation such as in variant teacher amyloid or not do genetic mutation in its natural state which is called wild type T to our amyloid so all the different therapies that have emerged in the past few years target. Different parts of this pathogen pathway by either suppressing teacher reformation in the case of Thomas and others stabilizing the TR trimmer or by degrading the amyloid fibers that have already deposited moving onto damnedest. So it's a stabiliser and as of two thousand nineteen you know after I tracked. It was kind of fast tracked. It's the only FDA approved therapy for the treatment of cardiac amyloidosis. The attract trial was a phase three clinical trial it looked at famine EST versus placebo in both variant and and wild type teacher. Cardiac patients It's a once a day Peo- medication and mechanistically it works by binding. Tr Tetra with very high affinity and so basically inhibits a step. Where the Touch Moore dissociates into monomers which is the rate limiting step of that cascade so attract international placebo controlled like I mentioned and patients enrolled either had near accreditation class. One two three heart heart failure so the trial did exclude classes for her failure. Patients the primary endpoint was mortality credit vascular hospitalizations but he's a secondary endpoints were improvement in the KC Q.. And six minute walk test. Q- It's the Kansas City Cardi Mafi questionnaire basically focused on quality of life really commonly used in all heart failure trials. Thank you guys. Okay I was asking for the audience. It was so stupid people So commonly talked about what the ATTRAC- Trial Zero really unique statistical method for analysis. So I thought we should mention here. It's the Finkelstein show. I love this. It calculates a win ratio But really I think this method capitalizes on rare disease and a small cohort it really increase the sensitivity in power of the trial points. Eh prioritize the importance of mortality and morbidity so and you know usually composite end points you look at all of them together Finkelstein gene show and fell this hierarchical so it'll prioritize death and then then you it's like a ladder that you go up for endpoint so it allows you to sort of say say this endpoint is more important than this employment cetera crushing your stats class. No we didn't learn this incessant is that I love this method over. I'm not putting that up a real nerd so in terms of trial implants to feminist was shown to reduce mortality by thirty percents compared to placebo that generative number needed to treat of about seven point. Five just to prevent one death hospitalizations cardiovascular hospitalizations positions were reduced by thirty two percent number needed to treat correlating faddis. Four one hospitalization. I think one important lesson we can take home. I'm from attract. Is that earlier. Diagnosis in earlier. Treatment is way better. A subgroup analysis showed much more benefit in the class. One to two you near Kurt. Association patients compared to clashes three in mortality an cardiovascular hospitalizations and again class for patients weren't even enrolled and also kind of related to this notion of earlier treatment and earlier diagnosis is that It did take a little while for the benefit to be seen so the survival survival curve split at about eighteen months And in terms of hurtful layer hospitalizations occur of divergent about nine months. So you can't have a super sick a patient that you're starting on because they need to live a while to see the benefit from this drug Jovan that was a really great overview of the attract trial and it will be really exciting to see how the use of FAMAS hands out in day to day clinical practice. What has been your experience thus far with this drug? I think it's great to be able to offer therapy to my patients with chronic amyloidosis. So I'm in general very excited about it. I think besides being able to offer Therapy another major advantage is that it's really safe. And well tolerated. The trial itself had very few adverse events in clinical practice. I haven't had a patient. Don't need to come off drug. Because intolerance or side effect the big disadvantage which has been extensively discussed you know in nationwide international. Aw on an international level is the cost because amyloid was classified as a rare disease. The drug was costed as such. It can cost on average of two hundred thousand dollars per year. And it's by far the most expensive cardiovascular drug on the market. I think they're really needs to be headway. Made in this front especially if we diagnose amyloid in more and more patients as we expect to do so it will no longer be the rare disease that we have classified it as absolutely and so I know to famas sort of at this. Point is the coolest kid on the block. The one that we probably hear about the most. But tell us about the other. T. T. R. stabilisers. Yeah there are other stabilisers. That are Hopefully coming down the pipeline. Aj Ten was was recently published about in phase two clinical trial and there's an ongoing phase three clinical trial and the mechanism is interesting it mimics so mutation that has been found to be super stabiliser. Tr in the phase two clinical trial it was deemed safe and did reduce the rate of that Tetra. America Association Association. That we talked about was kind of this integral step in the cascade in both mutant. Wild type Emily so it'll be exciting to see what comes of further another trial data. It's an oral drug as well which is another advantage and I flew his. Al Is kind of the old kid on the block. I guess it's an end set in a a nonselective Stabiliser it's shown modest benefit in crop than has been shown to slow progression of neurologic impairment in those affected by neuropathy. I think they use in cardiac amyloid is a bit controversial. Because of the long term side effects events that use we tell all of our patients avoid end said all our patients with heart failure to avoid and says and has been shown with. I flew Reduction Gfr in volume retention so it has to be a select cohort that That gets this drug. That's pretty important to know so to fabulous. Aj Ten and a flu nestle as you mentioned. Our T. T. R. stabilisers Sir. But what about agents that are particularly working to suppress t t our production. Yeah this has been an exciting time for amyloid as well. There have been two drugs. Approved relatively recently for. At our peripheral neuropathy and that are actively being studied for cardiomyopathy in both aim to suppress. I teach our production. First of those participants are on Pattro and it was studied furniture up at the end. The Apollo trial the mechanism impetus rand so it is a small Paul interfering molecule in targets a sequence of the Amarna within tr and that sequences preserved in in those with the mutant and of course. It's impacting those with wild type. So in Apollo there was a significant improvement pollen or a decrease teach your levels overall improve quality of life. They did a pre specified subgroup analysis with cardiac involvement which led to the little talk about but that showed improvement in credit structure and function so decrease..

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