Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. And now Narrator - Dr. Abel 00:29 on to the show. Dr. Sean Kane 00:31 Welcome to Episode 32 of HelixTalk. I'm your co host, Dr. King, I'm Dr. Sherman, and I'm Dr. Patel. Today we're talking about a newly approved drug for heart failure, and this new drug class is called an Arni or an angiotensin receptor neprilysin inhibitor. And before we get there, I think we should cover a little bit of kind of the background of heart failure to better understand where this new drug class kind of fits in with heart failure management. Speaker 2 00:57 So we all know that ACE inhibitors and angiotensin receptor blockers, the ARBs, they reduce mortality in systolic heart failure, where the left ventricular ejection fraction is less than 40% and so the idea here is to inhibit the RAAS system, which is the renin angiotensin aldosterone system, and block the compensatory mechanisms that actually are aiding into the whole process of heart failure. So basically, if we do not block the RAAS system, eventually it increases the sodium and water retention, causes the vasoconstriction, and this all leads to increased preload. That's why a patient usually present with symptoms of pulmonary congestion or peripheral edema, and this eventually increases the myocardial oxygen demand. Speaker 3 01:52 And then furthermore, the system can also cause cardiac remodeling, mostly hypertrophy or excess growth of the cardiac myocytes, and that ends up making the heart's contraction less efficient. So because of that, there's an additional risk of fatal arrhythmias. Dr. Sean Kane 02:05 So basically, what we're saying is that if we inhibit the RAAS system, which involves angiotensin, aldosterone and renin, if we inhibit this system, we can block some of these bad things that cause remodeling and mortality and heart failure. Absolutely and specifically we're looking at systolic heart failure, which is where the ejection fraction is less than 40% and that's exactly the patient population that was studied with this new drug class. So the new drug class, as we said, is called an Arni, which is an angiotensin receptor neprilysin inhibitor. It's basically a combination of an ARB, Angiotensin Receptor Blocker, plus this new drug called the neprilysin inhibitor. And basically, neprilysin is an enzyme in everyone's body, just like Ace and other enzymes in your body, that basically degrades down beneficial proteins that are already in your blood. So as an example, neprilysin is involved in getting rid of BNP or B type natriuretic peptide or bradykinin. Both of these are beneficial in terms of preventing some of the remodeling and preventing some of the sodium overload, or fluid overload that we can see in heart failure. Speaker 2 03:16 So are you trying to say that if we block this enzyme that degrades this beneficial enzymes, basically, then we can have beneficial effects of less vasoconstriction and less retention of sodium and water. Dr. Sean Kane 03:30 Yeah. So basically, neprilysin is a bad guy, and we're inhibiting the bad guy to let these good, beneficial hormones increase their half life in the body. Speaker 3 03:39 And what's interesting is, they went right off the bat to a combination product. So the combination of this neprilysin and an ARB, instead of just going to just marketing as a signal agent, I believe they did that, because in some of these experimental studies, that combo is better than either agent alone. And the other thing too, that's interesting is, I want to be clear that you never combine one of the neprilysin inhibitors with an ACE inhibitor, it's going to be with an ARB, because if you combine it with an ACE inhibitor, due to their natural effects on increasing bradykinin. So we're increasing bradykinin, and then we're also working on its blocking its degradation as well. So we can end up with with some additional concerns about angioedema. Dr. Sean Kane 04:20 Yeah, and right now we have one single agent on the market that is under this new drug class called an Arni. And that new drug is called ENTRESTO. And that's the brand name. The generic is made up, again, of two different drugs, valsartan, which has a brand name of diavan and also sacubitril. And this is our new neprilysin inhibitor. So when you have ENTRESTO you're getting both valsartan plus sacubitril in one single component. You can't get them separately. They're not sold separately. You get one in one dosage form. Speaker 2 04:52 And this medication was approved after a trial that was performed and published in September 2014, Mean the trial's acronym is paradigm, HF trial, and this trial basically led FDA to approve the drug in July 2015, and like you mentioned, Dr. Kane, the patient in this trial were systolic heart failure patient, mainly of New York heart failure Association, class of two, three and four, who had the left ventricular ejection fraction less than 3035, to 40% and who had the B and P levels higher than 100 to 150 Yeah. Dr. Sean Kane 05:32 So if we just kind of break down some of those inclusion criteria again, these were patients who had systolic heart failure, so they had a low ejection fraction. These were patients that were not New York heart association class one, so they had some symptoms, either at rest or with exertion, and they had to have a BNP level that was greater than, basically a low normal level, which helps solidify the diagnosis of a heart failure patient. And as Speaker 3 05:58 always, when I look at a study to first glance, I want to know. Okay, we know their inclusion, but what kind of patients were they excluding from? And it doesn't make sense. So in this case, it does mean anyone with a systolic blood pressure less than 95 or 100, anyone with a GFR less than 30 mL per minute per 1.73 square meters, and potassium greater than 5.2 is also excluded, as well as anyone with history of angioedema, which we already talked about a little bit, or unacceptable ADRs to an ACE or an ARB. Dr. Sean Kane 06:29 And you know, a lot of these exclusion criteria are pretty consistent with what we typically see with aces and ARB. So if you're hypotensive, we probably won't give you something that will reduce your blood pressure. If you're hyperkalemic, we probably shouldn't give you something that will increase your potassium in terms of the renal dysfunction. You know, a patient, even a hemodialysis patient, can have an ace or an ARB, it's just that they're at higher risk for things like hyperkalemia. So it's not that down the road we won't see ENTRESTO used in a dialysis patient population as an example, but certainly in the phase three trial, they're not going to pick patients that are at a higher risk for some of the adverse effects associated with their drug. So remains to be seen if it will be used in that patient population. But it's important to know that in the paradigm HF trial, they were excluded. Speaker 3 07:15 I'm sure somebody will eventually get to it, not by the industry, but the sponsors, but somebody's gonna go ahead and publish that data later on. Yeah. Dr. Sean Kane 07:23 So in terms of the trial design, one of the most important things to note about it is what they call the run in phase. And run in phases aren't that uncommon, but in this particular situation, it's actually pretty relevant, right? Speaker 2 07:35 And so from what I believe, the trial had two different run in phases. They first had all their patients enroll in an enalapril run in phase, after which some patients didn't qualify. So the rest of the patients then were placed under Entresto Running Phase, and basically they had to quote, unquote, pass from that running phase before they were randomized to either treatments. Dr. Sean Kane 07:58 The real sticking point here is that with each run in phase. This is pre randomization, and about 10% of patients who went into the run in phase had to drop out because of adverse effects. So in a sense, what happened is the study got rid of patients that would normally have an adverse effect associated with these medications. And then when the actual study happens, and we don't see these patients have these adverse effects, and it makes both drugs look way better, because we've basically gotten rid of problematic patients, if you will, during the run in phase that would normally manifest hyperkalemia, hypotension or other adverse effects during the study period. It makes your adverse effect incidents look way better if you've gotten rid of these problematic patients. I've got to Speaker 3 08:40 say, Dr. Kane, I'm not exactly a fan historically, of these kinds of studies. They do this all the time. In some of our psychiatric studies, call them an enrichment study, where you place the patient on the drug and either can't handle the drug or do terrible on it, then they're out of the study. And then anyone who essentially tolerates and does well on the drug, it's randomized to either continue the drug that worked, or they switched to placebo, and of course, they're going to continue to do well in the drug or get worse if they go to placebo. So once again, makes things look really good, but is it really something that can be validated in an average real world population? That's always been my concern and frustration, absolutely. Dr. Sean Kane 09:17 So you know, as we said, the drug was recently approved by the FDA. As far as I know, it's not available on the market at this time where you could buy it in a pharmacy, but it will be soon, and one of the biggest issues is going to be, as a healthcare provider, or even a patient, if you have heart failure, the decision point of how long do you wait to see what is kind of the real world adverse effect of these medications versus what was observed in the trials, Given that we had this pretty extensive run in phase to get rid of people who were problematic Speaker 3 09:45 patients, right? How many of those patients are going to end up being some of the population that you may actually see in practice, right? Speaker 2 09:51 And if you see the actual trial and the schematic, you will see that X number of patients were, you know, taken out of this trial, but they never. Say really, how many percentage of these patients experience, what percentage of whatever adverse effect that they had? So we're missing that data. We don't know if it's published elsewhere or the manufacturer is keeping under the tab, but we're missing out on that Dr. Sean Kane 10:14 data exactly. So then if we do look at the trial, you know, they randomized more than 8000 patients. So this was a very large systolic heart failure trial. Basically they randomized you to either get Enalapril 10 milligrams twice a day, or you get ENTRESTO, which was 200 milligrams twice a day. And just to give you some statistics, about 5% of the patients have this 8000 patient study. About 5% were African Americans. This is relevant because African Americans have about doubling the risk versus Caucasians of getting angioedema. And as we'll talk about, angioedema is one of the problems associated with both Enalapril, which is an ACE inhibitor, and also ENTRESTO, which is this new class, the Arni class. In addition to that, only about 7% of the patients were from North America. Most of the patients were from Europe, which again, limits some of the external validity to an American population, not only because of race, but because of different practices that we have in the US that may be different than what we observed in the trial. Speaker 3 11:13 And would also argue, potentially, again, things like diet, there's some some lifestyle differences as well that across the globe is going to be concerning about extrapolating it exactly. Speaker 2 11:22 And like you already mentioned, you already mentioned Dr. Kane that these patients had NYHA class two to four heart failure, but most patient resided in that class two. So about 70% of these patients came from the rest. 25% were class three. And like you see in most of these kind of trials, you almost always never see a class four failure patients. So there were almost none class four failure and Dr. Sean Kane 11:47 that's actually very common in these heart failure trials, partially because these class four heart failure patients usually don't meet inclusion and exclusion criteria because they're sicker, so they're more likely to have renal dysfunction, hyperkalemia, hypotension, but also from the manufacturer's point of view, it's kind of in their interest to not include them, because their mortality rates are very, very high, and also they're more likely to have adverse effects during the study. So it's very common to see these class two and class three heart failure trials, but given the scope of how common systolic heart failure is, you know, it's the number one cause of hospitalization among adults greater than 65 years of age. This is a huge market. I wouldn't be surprised if a few years down the road, we do see a stage four trial of ENTRESTO versus an ACE inhibitor. We just don't have that data Speaker 3 12:37 right now. Another interesting point of demographics to consider is the breakdown of males and females. So in this study, 80% of those enrolled were men. So apparently, Dr. Patel women don't get heart failure enough. So I get, I guess there wasn't. Was a lot in there, really. Speaker 2 12:51 I thought I was taught something else, that women are at high risk of getting heart disease than men. Dr. Sean Kane 12:56 So it turns out that, just like our aces and our ARBs, the Arni drug class shouldn't be used in women who are pregnant. It's considered a teratogen. So that could explain part of it could also be related to the demographics that were just included in the trial, that it was a European trial, or because of the kinds of patients that ended up getting enrolled, it was a vast majority of men, which, again, we see very few women. We see very few African Americans, and we see very few Americans. Period. That's a problem for applying the data to our patient Speaker 2 13:28 population, but that doesn't prevent from us using this medication if it is useful for your female patient. Exactly. So the primary endpoints of this trial, actually, we're looking at the cardiovascular death or CHF related hospitalization, what we found is that obviously these outcomes were better with ENTRESTO. So when you look at overall the study duration, the hazard ratio was point eight. So they found about 20% related reduction of this cardiovascular death and CHF hospitalization altogether. Dr. Sean Kane 14:01 And if you put numbers on that, if you received ENTRESTO, 21.8% of the patients had this primary endpoint, versus if you received enalapril, 26.5 so that gives you a number needed to treat of 21 which is actually a fairly good number. If you really think about for every 21 patients that get ENTRESTO instead of enalapril, one patient doesn't die of cardiovascular disease or get hospitalized for a heart failure exacerbation, Speaker 3 14:28 and a really stellar number need to treat, generally, is going to be within the single digits, but, and then really right around to 20, still pretty good. So we're right, right on at the edge there. So yeah, these are, these are still good numbers. Speaker 2 14:39 And what they did also then, with the combined endpoint, they kind of separated those two out. So looking at CV death again, ENTRESTO did better than the comparator enalapril, the outcomes were 13.3% in ENTRESTO group versus 16.5 here, the number needed to treat was about 31 Dr. Sean Kane 14:59 and the. All cause mortality, not just cardiovascular mortality, was also lower with ENTRESTO. And they also looked at heart failure hospitalization, which was the second component of their primary composite endpoint, and that was also reduced with ENTRESTO. So in terms of hospitalization rates, it was 12.8% for ENTRESTO versus 15.6% with enalapril, with the number needed to treat at 35 Speaker 3 15:22 and again, as these numbers being fairly consistent within one another gives a little bit more of the validity that all these endpoints are somewhat similar. The other important consideration is going to be the safety of these medications. The tolerability. Interesting is that it was slightly better tolerated here, about 17 and eight point or 70.8% discontinued in this study, versus 90.8% in the enalapril study, and I was actually found to be significant P value, Dr. Sean Kane 15:48 point 02, and again, you have to remember that with that run in phase, we got rid of 20% of people who probably would have had an adverse event on the medication during randomization. So if you added those people in instead of roughly 20% of patients discontinuing for an adverse drug related event, it would probably be closer to 30 to 40% which kind of makes you a little bit more cautious about the adverse effect profile of the drug. And again, yeah, this the hypotheticals make that, you know, kind of solid extrapolation a little bit more difficult. Speaker 2 16:18 And what was also more interesting is that we're looking at reduction of blood pressure as well because we're combining two different medications together. So the symptomatic hypotension was a little bit more common in ENTRESTO group versus the enalapril group. So we're looking at 14% incidences of symptomatic hypotension in ENTRESTO group versus 9.2% in the enalapril group. The number needed to harm over here was 21 patients treated. Dr. Sean Kane 16:43 And to put a number on it, if you looked at a snapshot, at eight months into treatment, the blood pressure in the interest to group, the systolic pressure was about three millimeters of mercury lower than the patients who received enalapril. So numerically, that's not a really big difference. But in terms of symptomatic hypotension, as you said, Dr. Patel, we did see more with that. So certainly, that's kind of the point estimate, but some patients had more hypertension than the ones that received enalapril. So acute kidney injury is another thing that we think about with aces and ARBs, and in this study, they actually didn't do a very good job of having a good endpoint related to acute kidney injury, the endpoint that they used in the actual manuscript was a serum creatinine that was greater than 2.5 or three, and for the endpoint of greater than 2.5 enalapril was worse, where 3.3% of patients with ENTRESTO had this high serum creatinine versus 4.5% with enalapril. But this was not significant if they used to cut off serum creatinine of three. The reason that this is kind of a silly end point is that when we think about acute kidney injury, it really depends on where you start from. The actual number isn't that relevant. So if you have a baseline creatinine of one and you go to 2.5 that's really, really bad. But if you start at 2.2 and you go to 2.5 that's really not a big deal. Speaker 2 18:02 We're looking at the percent change from the baseline, and not really what the actual number is. Speaker 3 18:08 That's a pet peeve of mine, because I know whenever I talk to providers or students about use of ACEs and ARBs in patients that do have poor function talk, but it's not that they're contraindicated in a given creatinine clearance, or synchronicity, again, looking at that change from baseline, that is always been the driving point with these medications, and so to kind of dance around that here is a little bit strange, yeah. Dr. Sean Kane 18:31 And if you think about it, we do have different criteria that do a good job of describing acute kidney injury. We have things like the rifle criteria or the a, k, I, N criteria. There's a number of different criteria out there, but they all relate to kind of either a small absolute change or a relative percentage change. So if you dig deep into the data, they did have an endpoint of a greater than 50% change in serum creatinine, which is a very good endpoint that's used by things like the rifle criteria. And using that criteria, the incidence rates were about 16% in both groups, and they were not different. So at least in my opinion, I don't really like the fact that Novartis, the manufacturer of ENTRESTO, kind of picked this really strange acute kidney injury endpoint that made their drug look better when they actually used kind of an agreed upon endpoint that was hidden deep in a supplement of the article, and in that particular endpoint, it didn't make the drug look safer than enalapril. So, you know, 16% of acute kidney injury sounds really bad, versus 3.3% of this really, really high serum creatinine level. I don't think that they did a good job in terms of New England Journal of Medicine. I don't think that they did a good job of making the authors kind of comply with what is normal standards for evaluation of acute kidney injury. Speaker 3 19:46 And another endpoint, again, that's a great point Dr. Kane would be to look at hyperkalemia. And so they considered, again, a cut off of six being severe hyperkalemia per the study. And they said that that was more more common here with enalapril 4.3% versus a 5.6% P value, again, significant number needed harm here of 77 so a little bit higher, but Speaker 2 20:08 still, is still a difference. They did the same thing with the elevated potassium level. What they did with serum creatinine. They kind of broke the levels in two different groups. So they looked at the severe greater than 6.0 millimole per liter, and then they also looked at 5.5 millimoles per liter, and that difference was not significant, versus the greater than six was significant. So again, it's interesting the way the data are portrayed over here, and I Dr. Sean Kane 20:33 think that really emphasizes, from a student point of view, how important it is that when you evaluate bias in an article, that you really come at it from what would I want to see in this endpoint point of view? Because the manufacturer was involved in designing the trial, right? And oftentimes manufacturers are involved in every single aspect of the trial, which is not really what we want. We want them to pay for the drug, pay for the study, but then have an independent group actually write it and publish it. And unfortunately, that doesn't happen very often. And because of that, it's really easy to kind of manipulate the data and change endpoints for the purposes of the manuscript that make the drug look better or worse. And you can really play around with that. Speaker 3 21:14 Yeah, a couple studies that I read, I really like the way they did. They either said, Yes, we did have individuals from the company that were involved. However, they either were not part of the write up, they were part of setting up and they backed out, as you mentioned, or even that they were not allowed to. They got to work on the manuscript, and not until the first draft was completed. Actually found a couple that thought that was very neat, so the first draft was completely written independently, and then the some of the individuals with the company or the industry, were then able to make some changes there. But again, everything else was already down on paper. Dr. Sean Kane 21:47 So to kind of wrap up some of the other adverse events, we did see cough, which is common with ACE inhibitors. We think anywhere from 10 to 20% of patients will have an ace induced cough due to excess bradykinin in this particular study, 14% roughly 14% of patients had a cough associated with enalapril, versus 11.3% with ENTRESTO, which wasn't really a big difference between the two, and kind of expected, given that they both can end up increasing bradykinin levels. And then finally, angioedema, which is somewhere between 0.1 and 0.2% incidence rates, depending on what study you look at, there was no difference. However, ENTRESTO had 19 patients versus enalapril 10 patients. You know, the incidence rates are so low you can't get a significant difference between the two, but it's certainly something that we would worry about, given that numerically, there were basically double the risk of angioedema with ENTRESTO versus with an ACE inhibitor. Speaker 3 22:43 So kind of looking back over the study as a whole, a couple things we can look at. One of them is, as we mentioned, it was interesting that they went straight at a combo product here and compared it to the ACE or the enalapril. And might have been interesting to have been able to compare the efficacy of this sacubitril specifically, and then not worry about whatever valsartan Dr. Sean Kane 23:03 valsartan is impact in there. And another consideration too, is if you're Novartis and you want to design the study, it's to your interest to make the Enalapril arm as weak as possible. What I mean by that is that they kept the dose at 10 milligrams. Vid in heart failure, we try to push the doses fairly high. So for enalapril kind of a goal level or gold dose can be as high as 40 milligrams a day or 20 bid because of that, some people say that, well, maybe the ARNI would have been just as good and not better than an ACE inhibitor, had you pushed up the enalapril dose. And certainly we'll never really know that, because I doubt that the manufacturer will redo this study to evaluate a difference in dose, but we do know that higher doses of ACE inhibitors and ARBs are associated with a reduced mortality. So if you can push your dose to the target dose, that's advantageous, Speaker 2 23:55 at least they pick the right kind of ACE inhibitor that has been studied and proven beneficial in heart failure compared to picking something that's not studied in heart failure. Dr. Sean Kane 24:04 Yeah, and you know, honestly, if I would have designed this study as an independent person, the real question here would have been to have valsartan versus valsartan plus sacubitril. But had they done that, an equal criticism of the study would have been that ACE inhibitors are the first line therapy for heart failure. Even though ARBs have been shown to be equally efficacious in heart failure, there would have been critics that would have said, well, you didn't use the first line agent. Therefore we don't believe the study. So you can't really win either if you're trying to break into this massive market that has been studied for decades and decades. Speaker 2 24:40 Yeah, so they are comparing it to the standards of care, but to me, still looks like Apple sources orange here at this point. Speaker 3 24:47 And then another point is that ENTRESTO did cause some more of symptomatic hypotension. I believe it was around three millimeters mercury was was the total change, but something like that could be magnified if you're dealing with six. Patient with CHF, so those in the classes three and four. So again, you want to be concerned about extrapolating to your patient and still looking for some of those adverse effects. Dr. Sean Kane 25:09 Then finally, the study was stopped early, and they have stopping criteria. Basically, they evaluate the difference in the primary endpoint as the study goes. And it would be unethical to continue the study if they see a statistically significant difference early on in the study. With that said, Though there's plenty of literature showing that if you have to stop a study early, generally speaking, the benefit that you see is often magnified, and as they study it again and again, the benefit seen actually diminishes over time. So although they should have stopped the study early for ethical reasons. Again, it's another criticism that the actual benefit may not have been this 20% benefit in the primary endpoint, but it could be less, or even just as as good as an ACE inhibitor. Speaker 2 25:54 So with every new medication that comes out in the market, we have to be very at the cost. In one of the articles, Novartis said that the cost will be $12.50 per day. But then when you compare that to some of the generic ACE inhibitors and ARBs that we have, this $12.50 per day, it's still a little bit more expensive for some of these patients. Dr. Sean Kane 26:15 Of course, Novartis will tell you that if they prevent mortality and get you out of the hospital, that that $12 a day is going to pay for itself by not causing hospitalization. Speaker 3 26:25 And another thing, as I again, I mentioned it again, but just the running periods, I can't say enough, how they really make it difficult, or muddies the water makes the drug seem more tolerable than it is. Or, again, in other studies, you know, makes the drug just, just really look a lot better by setting it up so individuals that end up in it, you know, are going to be the best of the best. Whereas, if you're looking at a complex patient population, you may not be able to find as many, right off the bat, a hot they're definitely going to do better there. And so it's just something to remember and to kind of temper your your emotions when you see, when you see a study that has these good results, but they use one of these run in phases. Dr. Sean Kane 27:03 And you know, I think as pharmacists, we're bound to have patients or other health care providers ask us about efficacy and safety of this quote, unquote, new heart failure drug. I think it's important to remember that it's not just about the efficacy of it, that it does appear to reduce mortality and hospitalizations, but we do see more hypotension with it. We probably see more angioedema with it, although that's fairly rare, and overall, it does appear to be better tolerated, but it's really difficult to interpret that given the run in period that we Speaker 2 27:33 had, obviously, as we mentioned, some of these side effects. We definitely do not want to combine it with the ACE inhibitor, so the manufacturer actually recommends a washout period of about 36 plus hours due to that risk of combined angioedema. Dr. Sean Kane 27:48 And this is a huge counseling point for any patient that is going to be starting ENTRESTO at least in the first year of it coming out, it's very likely that many patients will have received an ACE inhibitor at some point for their heart failure before being converted over to Entresto. So this 36 hour washout period is critically important to counsel a patient on, because if you don't do that, the risk of angioedema goes way higher. And that's really the reason why they didn't combine it with an ACE inhibitor, is that in clinical trials, an ACE inhibitor plus sacubitril had a massive amount of angioedema, and that's why they went with the ARB valsartan instead. Speaker 3 28:25 And then we again want to emphasize, do not give this medication in pregnant women, just like with our aces, just like with our ARBs, and Speaker 2 28:32 it's available in the tablet form. It's meant to be taken twice a day, and you can have a smaller dose combination. So they recommend that patient who's never been on an ACE inhibitor or ARB which will be unlikely, like what you said, Dr. Kane, you start them out the lowest combination, which is the 24 milligram of sacubitril and 26 milligram of valsartan. And then for those who were taking one or the other ACE or ARB inhibitor and now being switched to the ENTRESTO, we need to start them on the 4951 milligram combination, and then you can increase the dose as tolerated every two to four week. Titration is recommended. Dr. Sean Kane 29:12 So there are three dosages, and you are going to pick an initial dose based on whether you've had an ace and ARB or if you have a history of renal dysfunction. And then you can go all the way up to this maximal dose of about 100 milligrams per component. Speaker 3 29:25 Vid, I do find it kind of interesting that they did have specific guidelines on what dose to use in individuals with creatinine clearance less than 30 even though the same individuals were by definition, not allowed Dr. Sean Kane 29:36 in the study. So the in question that many providers are going to have is a do I either start a patient on ENTRESTO who has newly diagnosed heart failure, or am I converting patients who are on ACEs or ARBs who have systolic heart failure to ENTRESTO? And for me, the answer is maybe, but probably not. Speaker 2 29:53 Right now, I probably would say no. Maybe I would like to see another study to see if it's. The combination is better than valsartan alone in itself. I know it's not the standard of care comparison, like they did with enalapril, but I would still like to see if just let alone ARB is better than just combination. Speaker 3 30:12 And I'm always, I always prefer to see studies that are a little bit longer. I know it's really hard by you know, the credible cost involved in some of these industry sponsored studies, but Dr. Kane, as you mentioned about stopping the study early because of that benefit, what kind of numbers will be seen as you continue going on. So I would like to see those individuals who continue to use it, and if we start extrapolating out populations further to see if we still have benefit mortality in different time periods. And that's the kind of thing I want to see before I'm really invested in this drug. Dr. Sean Kane 30:43 What we're going to see is healthcare providers. Is this balance between a cool new drug that has really good efficacy data from one phase three trial versus a phase three trial that was stopped early, that had an expedited FDA approval period, that had a significant dropout rate because of a run in period. And there's really this balance of, how long do you wait if there really is a true mortality benefit by getting ENTRESTO versus Do you wait just long enough that if there is an issue with angioedema, or an issue in North American patients, or African American patients, something like that, that it manifests in Phase four trials, which is post marketing data that you'd be able to see whether or not it appears to be safe in a real world practice environment, as opposed to this phase three clinical trial. So we're Speaker 3 31:33 kind of in a different spot here than medications like spironolactone, which by the time they did the studies to find its mortality benefit, the drug had been out a while we had a lot of history of the medication, its use in populations. It was fairly cost effective at that time as well. So here it's we're showing this drug is great, but we don't have all that long history with it, and we certainly don't have the cheap cost. Dr. Sean Kane 31:55 And from Novartis point of view, given the time period that they have for patents expiring and things like that. And given how common style heart failure is, I guarantee you this is going to be a gigantic marketing push for them from both direct consumer advertising and also just prescribers that they want everyone to use ENTRESTO as soon as possible. And they're going to be pushing the heart failure trial as much as possible to get this out there, because they have a gigantic market share available to them, and they have to grab it up as soon as possible, before another Arnie makes it to market, or before their patent expires. So with that, we're going to go ahead and conclude so if you haven't done so already, we would really love a five star review in iTunes. We're also available at HelixTalk.com where you can find our contact information and a link to us in iTunes, or even play some of our previous episodes through the website. And with that, I'm Dr. King, I'm Dr. Schuman, Unknown Speaker 32:49 and I'm Dr. Patel, and study hard. Narrator - Dr. Abel 32:52 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com you.