HF in ACS - which is the paradise?
I am Dr. Chenniappan, Senior Consulant Cardiologist at Tritrappoli. Today I am going to talk on Heart Failure in Acute Corners Syndrome, which is the paradise. From though we concentrate on the treatment of acute Corners Syndrome in Acute Face with the thrombolysis or PCI, many times we do not focus our attention on the post-ASIS management. Although the patient has undergone re-vascularization, he continues to be a vulnerable patient because of three factors. Only there is vulnerable block, there is vulnerable blood and vulnerable myocardial. We treat vulnerable block because of lipid core and fibres capistine, and lipid copies thick, these patients, although they have undergone re-vascularization, continue to have vulnerable block. So, we treat them with statins and AC inhibitors and so on. Whereas, the patient also has vulnerable blood, where the platelets are activated, and coagulation system is also activated. So, we treat it with dual anti-platelet therapy, as well as anti-thromytherapy such as happens. In addition to this, the patient also has vulnerable myocardial, which did not get but supply for some time. So, this vulnerable myocardial actually is going to produce the heart failure because of the adverse remodeling, and also it can produce sudden death because of some arithmias YouTube vulnerable myocardial. Today, we focus our attention to the vulnerable myocardial, and how the vulnerable myocardial in post-ASIS status is going to produce heart failure, and how to deal with the heart failure in acute phase of acute myocardial infarction, especially stem. So, heart failure under acute myocardial infarction. Heart failure, complicating acute myocardial infarction is very common. Among patients with acutemacal infarction, the heart failure is the most powerful predictor of death, as well as it has got very important implications for the treatment. And the incidence of heart failure among patients who are hospitalized for acutemacal infarction may vary from 14% to 36%. It is not the problem of acutemacal infarction also. As the years go by, there is a significant increase in the cumulative incidence of heart failure acutemacal infarction. As you can see from this slide, at around 72 months after acutemacal infarction, the incidence of heart failure is going to be 22.1%. And if you look at closely, the one near cumulative risk of developing acutemacal infarction after AMA is 11.4%, at two years it is going to be 14.5%, and of course, at the end of five years it is going to be 22%. That means, one in five with acutemacal infarction likely to develop heart failure in the next five years. There are various factors which can produce the long-term heart failure after acutemacal infarction. The most important predictor as shown here is the acutemacal infarction in post ermy status. So that means, if the patient develops acutemacal infarction during the acut phase of acutemacal infarction, he is prone for late heart failure or chronic heart failure after acutemacal infarction up to five years. And what are the predictors in acutemacal infarction itself which will tell us that this patient can develop heart failure during the acutemacal infarction phase. There are cardiac issues and non-cardic issues. The cardiac issues are late presenting AMA, which may not qualify for the re-vascularization. The second myocardial infarction, our third myocardial infarction, significant multiversal coronary artery disease, and already existing LV dysfunction. There are many non-cardics causes such as diabetes maritus, chronic kidney disease, cardio renal syndrome, atrial fibrillation, pulmonary hypertension, as well as significant biomarker elevations, such as very high proponing and anti-proBNP. So if you briefly look at how post-marker infarction develops, this slide beautifully tells us how adverse remodeling can go to ultimate heart failure. To start with, there is an infarct area in the topmost picture. This infarct area over the course of time undergoes significant damage and there is a significant damage to the extracellular membrane, there is a macrophage invasion and there is lot of loss of tissue resistance. So this area becoming weaker and weaker and the remaining areas, the remaining normal areas try to contract vigorously to compensate for this area which is not working. So ultimately this infarct area undergoes what is known as infarct expansion, where the myocardium becomes thinned out as well as it becomes dyskinetic. So this because of the cell slippage as well as the intracellular collagen development in this area of myocardium fraction. So this area of the myocardium fraction is going to produce enormous stress on the normal myocardium. So this normal myocardium now has to work hard and also compensate for the myocardium which is not working. So ultimately because it is working hard, it demands increases, the sub-endocardial perifusion decreases. So ultimately what happens is the normal myocardium also undergoes significant elbow dysfunction and the patient slants up with a spherical heart which is mimicking a dilated cardiomyopathy. So this is how the ultimately the chronic post-infarctian failure develops which starts as a regional left ventricular dysfunction and ultimately goes on to produce global left ventricular dysfunction. What is very important to understand is the second and third pitches. So the second and third pitches as you know, no, they start as the yearly phase of adversely modeling by macrophage invasion and also the loss of excess membrane, ultimately they go on to produce the infarct expansion. So at this time the patient develops a good heart failure in post-emi-status. So the interventions in these two stages are correct and very important interventions at these stages definitely can prevent subsequent global dysfunction of the heart on chronic post-infarctian failure. So this is the area we are going to concentrate on how correctly we can treat the yearly heart failure in acute myocardial infarction. So our important aim in post-reversal constation patient is not only stabilize the block, not only stabilize the vulnerable blood but also stabilize vulnerable myocardial. We can stabilize vulnerable myocardial in four ways, only to prevent adverse remodeling just as I described in the last slide and we can prevent archmias and sudden death. As well as we can produce some chemo-dynamic alterations by reducing after load and pre road so that we can make sure that the viable myocardium is not going in for a heart failure. So conventionally we do all these four important steps in the management of the world of myocardium by using AC inhibitors and sometimes if angiotensil receptor blockers, the known beta blockers such as the metaprolol carbideinol and of course aldostone inhibitors or aldostone antagonist. So these are the conventional drugs enduring the acute myocardial infarction phase which is going to stabilize the vulnerable myocardial and of course the acute treatment. The early and optimal myocardial reperfusion is the one of the important factors which can prevent acute heart failure after an acute myocardial infarction. That's why the early re-vascularization either with a PCI or a trombolysis is a very important key to prevent acute as well as chronic heart failure post myocardial infarction. The next factor which is going to produce all these three key elements of the vulnerable patient is angiotensil 2. As you see from this slide, the angiotensil 2 is actually going to produce the vulnerable R3 because it can produce a significant vascular remodeling. It can produce vulnerable block and also increase inflammation. So it actually increases the vulnerability of the plot to rupture and produce a 3 trombosis after a month. And it is also can have a significant impact on the vulnerable blood by activating the playclips and activating the coagulation system by producing the plasma no-gen activated inhibitors. And it has got also a role in the vulnerable myocardial. Because angiotensil 2 is going to increase the contractility, it is going to increase programmed cell death of apoptosis and it can produce hypertrophy and it can significantly increase the fibrosis and also have a hand on the heart rate. So this is the angiotensil 2 which is the one of the worst molecules which has got the role in all the three elements of the vulnerable patient. So blocking angiotensil 2 is the very important step in the management as well as in the prevention of acute heart failure post amide and it can be done in variety of ways. We can block the angiotensil 2 by blocking the conversion of angiotensil 1 to 2 by blocking converting enzyme inhibitor through converting enzyme inhibitors. So the converting enzyme inhibitors are not only going to prevent the formation of angiotensil 2 but they can also upregulate a very important molecule called bradykin. The second step to block angiotensil 2 is to block the 81 receptor on which the angiotensil 2 is going to act. In addition to that, we can use aldosterone antagonist which can also produce some benefit by reducing the aldosterone which is going to produce further increase in fibrosis and elbow dysfunction. So these are the three steps of what is known as running angiotensil in aldosterone system inhibition. So these three drugs work and to block the raw system and produce benefits in post amine heart failure. Among these three molecules, AC inhibitors are the best because it has been shown in patients with impaired ejection fraction of less than 40% and those who are experiencing heart failure in the yearly phase of amine, AC inhibitors should be administered within 24 hours. So that's why the AC inhibitors are considered first-line therapy for all patients with the microinfractions, especially with elbow dysfunction, being symptomatic or asymptomatic. So then the question comes, if you want to use an AC inhibitor, which is going to be the AC inhibitor. So long back, we have a very important trial called Aertral which is acute infarction Ram April efficacy study. To this study was done to determine whether AC inhibitor of Ram April reduces the mortality in patients with evidence of heart failure after microinfarction. So this trial Aertral is a multi-central multinational randomized double-blind placebo control trial where more than 2,000 patients has it more than 18 years with evidence of heart failure, 3 to 10 days after microinfarction with heart failure were included. severe heart failure as well as the ongoing ischemic patients were excluded from the trial. And the follow-up of this trial is going to be, it was going to be more than 15 months and the primary endpoint was all-cast mortality. So here the Ram April was used to start with 2.5 milligram per day and ultimately the target dose of 5 milligram per day was achieved in two days. And the important result is there is a significant reduction in all-cast mortality in Rammett group with absolute reduction of around 5 percent and a relative reduction of 23 percent. And what is very important to realize is this important benefit came within the 30 minutes of starting Ram April. There is no significant reduction in rein-farction or stroke. So the primary advantage was reduction of heart failure. The drug was well tolerated in this dose with acute microinfarction. So this is a Catalan Markov which clearly tells you that the mortality is not a cardiac mortality, the all-cast mortality was significantly reduced with the Ram April group. And of course the death was reduced, the severe persistent heart failure was reduced, rein-farction and stroke having a neutral outcome. And irrespective of the subgroup, the benefit was seen in the Ram April group. So the trial concluded that it demonstrated the efficacy of Ram April on mortality and morbidity of heart failure post a minor who are newer heart association 1 to 3 patients. And there was 27 percent reduction in death and 23 percent reduction in the progression to severe or resistant heart failure. So after this trial, it became a standard procedure to start the Ram April in patients with a clip class 3 or 2 patients with a heart rate of more than 100 with anti-remi who got the ejection fraction of less than 40 percent. And the 40 percent survey would benefit was seen on the first day itself and it underline the value of initiating AC inhibitors such as Ram April as soon as the patient has evidence of heart failure. And what is very important to realize is the significant reduction in all cost mortality. So to reduce death, to reduce one death, you have to just eat 9 patients. So a very small N&T demonstrate a great efficacy of Ram April in my call infarction. Then the question came whether the ARBs are equal in AC inhibitor in acute post a minor heart failure. So here in violin study, the captopril was compared with Valsata with a dose of 320 milligram per day and the risk reduction was 20 percent. And it was demonstrated that this ARB of Valsata is non-inferior to Ram April. It is not equal but non-inferior to Ram April. So that's why the recommendations continued to suggest that the AC inhibitors like Ram is the first drug of choice because of significant reduction in the mortality and the dose you are going to use is 10 milligram whereas in Valsata it should be 320 milligram and the number needed to cheat to get one benefit in Ram April is just 9. So that's why the ACCH guidelines came up with statement that an angiotensin converting enzyme inhibitor should be administered within first 24 hours to all patients with a stemming with anterior location and heart failure are rejection fraction of less than 40 percent unless it is contraindicated. So that AC inhibitor through our tribino it is going to be Ram April. Then came the sensation, the sensation of ARB and your dense interceptor blocker plus neprosiline inhibitor. So long in the treatment of heart failure we were concentrating on blocking the bad guys like the angiotensins, the sympathetic system and the aldocerone and the vasopressens etc. This idea came to hold off we also upregulate the good guys like natural peptides. So the combination of receptor blocker like Valsata and succubutrile which is the inhibitor of neprosiline which is going to degrade the good substances such as the natutic peptides adenomodulin and other important radicine and other important molecules which are going to help in heart failure. So this combination is called ARNI and it has produced significant beneficial effects and it has significantly reduced for mortality in heart failure by variety of mechanisms by increasing vasodiritation, decreasing sympathetic activity and increasing parasympathetic activity, increasing naturalysis and also by reducing the fibrosis and also reducing the arithmias. So the paradigm heart failure trial clearly demonstrated that the ARNI was much superior to anaeropl in reducing the morbidity and mortality in heart failure and this heart failure is going to be chronic heart failure. Here to get one benefit the number needed to cheat is 21. Once again demonstrate a superior efficacy of ARNI over AC inhibitor like anaeropl in the benefit of the treatment of chronic heart failure. But the only important factor we have to remember regarding the paradigm heart failure trial is here if you look at the key exclusion criteria the acute coroner syndrome were excluded. So the ARNI was better than AC inhibitor like anaeropl only in the sitting of the chronic heart failure and this may not apply to a acute post infarction failure. To test this hypothesis that whether the ARNI can work in acute heart failure, please remember acute heart failure a trial was done called pinar heart failure where ARNI was superior to the AC inhibitors in reducing the surrogate end points by reducing the anti-probe NP. So in this trial it was shown that ARNI was safe in the treatment of acute heart failure. But still the question remained that whether this acute heart failure with acute microinfarction whether the ARNI will work or not. So that's why the main question at this point was when ARNI will beat AC inhibitor like Ramapuri in early post infarction failure to reduce post infarction events such as alchismatality, death, and chronic post infarction failure. So this was the question. To answer this question the parades M-I-Trial was conducted. The parades M-I-Trial angiotensin receptor napalpsin inhibition that is ARNI following acute microinfarction and it is called parades M-I-Trial. It was presented in 2021 American College of Cardiology Conference and subsequently got published recently in New England Journal of Medicine in November 11, 2021. So the design of parades M-I was the people who are included are acute microinfarctions as early as half a day and two seven days acute microinfarctions from half a day to seven days with ejection fraction of equal or less than 40% and are the presence of pulmonary congestion. So these are the main patients that is acute microinfarction within six server, within actually 12 hours after admission. If they have a pulmonary congestion or ejection fraction less than 40% or both they were included in this trial. And who are excluded in this trial? Major exclusions in this trial were the patients with prior heart failure and chronic instability under very low EGFR of less than 30. In addition to this inclusion criteria patient must have one more risk enhancer such as age more than 70 years, EGFR of less than 60, diabetes, prior microinfarction, atrial fibrillation, ejection fraction of less than 30% killed it plus more than two or three and stemming without reperfusion. So the patient should have acute microinfarction as a reduced ejection fraction under pulmonary congestion plus one risk enhancer or the included criteria or the inclusion criteria. So in this trial, the two arms were succubitral valsator that is Arni in 1 arm and the Ram April in the other arm. The Arni to the target dose is 200 milligram twice a day and for Ram April, target dose is 5 milligram twice a day and more than 2000 patients in each arm. And what are we looking for the primary endpoint? The primary endpoint is cardiovascular death, heart failure and heart failure hospitalization and of course the how patient development of heart failure. The secondary endpoints where cardiovascular death are the first heart failure hospitalization. So these are the endpoints we are looking at by these two arms. If you look at the patients who are included, the patients with pulmonary congestion, patients with ejection fraction of equal or less than 40 percent are both. All the three groups are included in this trial. And this is the flow chart of this trial and 2000 and dot patients in each arm. And we already told you the target dose and of course this trial ran around 23 months and average dose used in the Arni arm was 75 milligram twice a day and in Ram April, surprisingly 1.8 milligram twice a day. So this is the average dose used throughout the trial of 23 months. Of course the beautifully, the two arms were matched in age, sex, prior heart failure, MMI, prior stroke, hypertension, diabetes, smoking, age, defibrillation and EGF are beautifully matched with each other. And of course the common micro-infraction was stemming and reperfusion was done in almost 90 percent of patients. Please remember this that these patients are developing in spite of so much of the incidence of so much incidence of reperfusion. Majority of Infants were anterior and time to randomization, mean randomization is 4 days. In fact, the mean addition fraction was 36 percent and clip class more than 2 or more than 50 percent of patients were in clip class 2 and all these patients were well protected. Please remember in our trial Ram April was compare with patients who received no drugs. Whereas today we have to compare Ram April or the Arni against those patients who are well protected and who are receiving all life-saving drugs such as dual anti-platelet, beta blockers, ultrasound antagonist, statins and of course prior AC inhibitor or ARP. So in well protected patients with all these good drugs is their additional benefit and is their additional benefit and if at all there is an additional benefit whether it is going to be Arni or it is going to be Ram April. But of course this is the primary outcome of cardiovascular death, first heart failure hospitalization or outpatient heart failure hospitalization. You can see the Arni arm was normally little better than the AC inhibitor or Ram April but you will look at the P value this is not statistically significant. So there is no statistically significant difference of the reduction of primary endpoint between the Ram April and the Arni. This is the primary outcome. When you look at the individual components of the primary outcome as you can see the primary outcome of the composite data is not statistically significant. Cardiovascular death is not statistically significant. Heart failure hospitalization is not statistically significant. Of course the outpatient heart failure which is defined as the patient requiring increase in the urethics for more than a few weeks are little better with the succubedital ulcerative group and definitely the cardiovascular death and hospitalizations are not produced by Arni statistically statistically significant manner. And of course if you can see the squares they are all the squares are around the midline only. Which means irrespective of various subgroups the Arni did not beat Ram April in a statistically significant way in reduction of the primary endpoint of cardiovascular death and hospitalization of heart failure. Then we come to the secondary endpoints all the secondary endpoints the combination of CV death or hospitalization is not statistically significant and heart failure hospitalization or outpatient heart failure once again was little much better with the Arni group as we already mentioned outpatient heart failure was slightly reduced by Arni whereas CV death non-fetal amine and non-fetal stroke not statistically not significant and of course the all cost death as shown in the last column is not at all reduced by Arni when compared to the Ram April. Then this is the first and recurrent the Center for Ethical Committee that the Council for Ethical Committee, educated events once again we have they have shown that the CV death total heart failure hospitalizations and of course the total heart failure events are not significantly reduced once again this is the educated events by the ethical committee. So the Ethical Committee felt that the Arni and Ram April are almost equal in all this the individual components of the primary endpoint. So once again all the secondary endpoints as you can see it from here except for the outpatient heart failure reduction the Arni was same as the Ram April. Then we come to the safety having the efficacy so the efficacy of Arni is going to be the same almost same as Ram April in reduction of primary endpoints in acute heart failure post amine. What about the safety? So when you look at the serious adverse events they are almost same the hypotension was greater with Arni and cough was greater with Ram April whereas all the other adverse effects were exactly the same when compared to Arni and Ram April. When you look at the laboratory abnormalities on the kidney side potassium or on the liver side once again they are all same when compared to Arni and the Ram April and of course the permanent steady drug discontinuation which includes death is also going to be the same or the just like the adverse events. The patient discontinued Ram April because of cough and patient discontinued Arni because of hypotension. This is a very important point to be noted what caused the discontinuation cough and hypertension hypertension for Arni and cough was for the Ram April of course the renal impairment and hyperkalemia were same between Arni and Ram April. When you look at all death that is all cause mortality between Ram April and Arni once again room numerical superiority of Arni over AC inhibitor but not the statistically significant reduction in all deaths. So the summary which was written in the article just published in New England Journal of Medicine is this. In a vigorously managed enhanced risk AMA population compared to active therapy with Ram April the Arni did not result in significantly lower rate of CV death, heart failure hospitalization or outpatient heart failure requiring treatment. So this is the summary or the end point of that particular trial. The safety and tolerability of the circular valve satan in this AMA population was comparable to that of AC inhibitor. So the efficacy is same, the safety is same. The Ram April versus the Arni in post acute heart failure post amine starting from 12 hours to 7 days of admission. So now the question comes that how to compare the results of paradigm heart failure trial versus the paradise amitral. As I have mentioned in previous slides the paradigm heart failure trial was done in chronic heart failure and the drug used was unlawful versus Arni whereas in paradise amitral it is acute amy patient with a post infarction failure or the acute infarction failure the drugs compared where the Ram April and the Arni. So when you look at the paradigm heart failure a huge result an absolute reduction of 3.2% and 3 more than 130 patients benefited from the Arni. So huge result when compared to the anaerobic clear cut superiority of Arni over anaerobic in paradigm heart failure trial. Look at the paradise amitral the absolute reduction was only 0.5% and the only 23% were benefited more than Ram April with Arni and this is the result between the paradigm heart failure and Paragasame. So this brought a very important question whether the subset of patients over the chronic heart failure who are benefiting from Arni are going to be completely different from an AMA patient suffering from early acute myocardial infarction failure. So this is the important idea we get from the comparison of these two trials and of course here we have shown all the trials in post AMA heart failure starting with ACE inhibitor versus Val-Saturn, Captopril versus Val-Saturn in Val-In-Trial and of course this paradise amitral which was Ram April versus Suckabitri Val-Saturn. I want to remember I want to remind you again that the average dose used with Ram April was 1.8mg twice a day and the Suckabitri Val-Saturn was 140mg or 73mg twice a day or 140mg per day. So if you translate in a number needed to treat to get one benefit out of Arni when we call it that the number needed to treat to get additional benefit from Arni over Ram April is a huge number of 77mg that means to get one benefit of a cardiovascular hospitalization you have to treat 77 patients with Arni to get one benefit over Ram April. So this results in the efficacy of Ram April is ACE as equal to Arni in post AMA heart failure. So this may be the reason. So the development of acute myocardial infarction failure the pathology as I mentioned here as I told you the patient undergoes adverse remodeling the infarct expansion and subsequently going heart failure may be completely different from a patient who has got a chronic heart failure and that may actually explain the difference between Arni and the Ram then what about the role of HGN2 inhibitors in post AMA heart failure. Once again it is tried in a very big trial with ampaglyphosin in impact AMA trial and we have to wait for the results of this trial to know what is the role of ampaglyphosin in the treatment or the prevention of heart failure in post AMA patients. So that's why you can see when you look at the recommendations of the early drugs you have to use in pale post AMA patients after re-vascularization will be a beta blocker, ACE inhibitor or Arni, ARB is only an alternative ACE inhibitor. The first choice is ACE inhibitor. If the ACE inhibitor is not tolerated, the only ARB have to use will be Palsata. All those are not terminus in the form of either spinal or epilionone and of course we have told you the best way to prevent an acute heart failure is the yearly and time-based re-vascularization and of course there are a lot of devices which can help us and the patient is quite sick. So sum up this presentation, heart failure at presentation and the course of treatment worsen the prognosis in acute connoisse syndrome. So heart failure is a very bad news in the presence of acute connoisse syndrome. Antispeed heart failure and preemptive strategies to prevent it. So we told you the risk factors which can produce heart failure in ACEs. Restartification of all ACE patients through different modalities to predict heart failure which may be clinical which can be biochemical or it can be also a co-based restartification. The GDMT that is the guideline directed medical treatment at the onset of heart failure is very important. As I showed you in the pathological slide, the yearly intervention of the adverse remodeling actually helps to prevent chronic progression of heart failure after AMI. ACE inhibitor like Ramapuri, even in low doses that is 1.8 milligram poised day, it benefits almost same as the new sensation of drug-like RME which is used around 140 milligram per day. Many times we think that only 10 milligram Ramapuri may be working but in this trial the average dose used was 1.8 milligram twice a day. So that's why when the patient is in lower set of repressor by example above 90, Ramapuri can be used whereas if it is going to be RME this historic pressure has to be above 100. So this is the first study to demonstrate the benefit in heart failure even low doses of Ramapuri which is one of the reasons primarily we switch over to ARB because we are increasing the dose of the ACE inhibitor will produce cough and we actually switch over to ARB. And serial follow after many years of acute chronic syndrome is important. As I told you there is a cumulative increase in the incidence of acute microanforction. After microanforction there is an increase in incidence of post-inforction failure. So let us compare these two drugs and determine which is the paradise in heart failure in acute chronic syndrome. The Ramapuri is there since 1993 an ARNI came in 2014. So Ramapuri was definitely Ramapuri that means an ACE inhibitor like anal april was definitely inferior to ARNI in chronic heart failure. For definitely ARNI was superior in chronic heart failure when compared to ACE inhibitor such as Ramapuri. But in patients with acute microanforction developing early acute heart failure the Ramapuri is almost equal to ARNI which had only minor numerical superiority. Even low dose of Ramapuri like 1.8 milligram per day can work and produce benefits such as ARNI. Can be used when the BP is above 90 whereas ARNI can be used only when the BP is above 100. As side effect yes you know the cough is a side effect which can be acceptable and it is not going to be a significant life threatening side effect whereas the side effect of ARNI is going to be significant hypertension which can produce significant syncopy or stroke. So the side effect profile itself is little more dangerous on ARNI. The Ramapuri is easily available unless costly as you know even you use the target dose of 10 milligram per day it is going to cost you only 20 rupees per day whereas there is ARNI is quite costly. So that's why the compliance on a long term basis may be better with Ramapuri when compared to ARNI. So what is the paradise in heart failure in acute condescendrom? The paradise is living longer with reduced hospitalization and with a very good quality of life. To reach this paradise you have a current and attractive and costly way and also you have conventional and cost effective way and both will take you to the paradise of heart failure in acute condescendrom. Of course to choose between the correct and attractive way versus the conventional and cost effective way it all depends upon the patient profile such as his blood pressure, his economic situations, his compliance, what is the ability to continue the track on a long term. Now all these things will decide whether you use a attractive option or you use a conventional option. Thank you for your patience.
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Disclaimer: The images depicted here are fictitious and meant for illustrative purpose only. Any resemblance to any person, living or dead is purely coincidental.
