Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 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. Narrator - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to Episode Nine of HelixTalk. I'm your co host, Dr. King. I'm Dr. Schuman, and I'm Dr. Patel, and today we're talking about the evidence for the combination of an ACE inhibitor, an Angiotensin Receptor Blocker, an ARB and aliskiren, or Tekturna, which is a direct renin inhibitor. Speaker 2 01:08 So before we get into all this mumble jumble of drugs, let's talk about what the renin system is all about. Speaker 3 01:15 Well, the first step in there is look at the compound angiotensinogen, and this is something that's produced in the liver and then it's converted via renin to angiotensin one. It's actually some of the extra pieces the peptides are cleaved right off. Dr. Sean Kane 01:31 And as you might suspect, aliskiren or Tekturna is a direct renin inhibitor. So this is where Tekturna or aliskiren acts. It inhibits this enzyme that converts angiotensinogen to angiotensin one, Speaker 2 01:44 and then eventually we need an enzyme called ACE that would convert angiotensin one to angiotensin two. So you can imagine our ACE inhibitors are going to block this step right here. Dr. Sean Kane 01:58 And then the final step, once angiotensin two is produced is that it goes to the kidney and acts on the angiotensin receptor. And this is where our ARBs, or angiotensin receptor blockers, work. We call these ARBs. Speaker 2 02:10 And the final result of the angiotensin two when it goes to the kidney and binds to the angiotensin receptor is it increases the antidiuretic hormone. It increases the aldosterone production. The end result is increased vasoconstriction and increased sodium retention. So you can imagine there is increased retention of the water as well. All this resulting into high blood pressure. Dr. Sean Kane 02:35 So then you could probably also imagine that when you give aliskiren, an ACE inhibitor or an ARB, we're going to block that effect, we'll diurese better, and we'll have a lower blood pressure because we're getting rid of water and sodium. Speaker 2 02:48 So all this mechanism, you think that would go hand in hand really well together, because the end result will be lower blood pressure and lower water retention. However, is it really wise to combine all these three agents together. So that is what we're going to discuss today. Dr. Sean Kane 03:04 So to start off, we're going to talk about just a brief overview of the three drug classes. The first drug class that we'll talk about are angiotensin converting enzyme or ACE inhibitors. Speaker 3 03:14 Some examples of these may be ones you're familiar with, as well as some you may not. Lisinopril, also known as Prinivil or Zestril, is one of the more commonly used ones. But then we have other ones, such as enalapril or Vasotec. And like many of the ACE inhibitors that are available orally, they're prodrugs. But enalapril has an active agent called enalaprilat, and that one is available in an IV formulation that can theoretically be used for acute hypertension when it's given on a short time period. And then we have a few other ones, ramipril and captopril. And of course, they all end in -pril, which will be able to distinguish them from some of these other agents and other classes. Dr. Sean Kane 03:50 So Dr. Patel, what are some adverse effects that are unique to ACE inhibitors we'll get? We'll assume that the audience already knows about things like hypotension and, you know, orthostasis and dizziness from what you would get with any anti hypertensive. But what's unique to ACE inhibitors that we may not see with, let's say hydrochlorothiazide or a beta blocker. Speaker 2 04:10 So there are a couple that comes to mind, and it's very important to let our patient know ahead of time. First one is dry cough. It's exactly just like that, where you have the urge to clean your throat. So it's not a productive cough, it's just a dry, tickling cough. 10% of the patient who are prescribed this medication known to have the side effect. Dr. Sean Kane 04:34 So is this side effect that you would just have something like dextromethorphan to take care of, Speaker 2 04:40 unfortunately, not because the mechanism for the side effect is that the ACE enzyme would then be used to break down the bradykinin, in addition to affecting or converting the angiotensin one to angiotensin two. So this is the pathway that's affected. We have. The breakdown of the bradykinin is affected, and that is why the tickling cough reflex occurs. Dr. Sean Kane 05:07 And you probably suspect that in general practice, it's not a good idea to use a medication to treat the adverse effect of another medication too, right, right? Speaker 2 05:15 So that's the reason we won't be using gastromotherapy to treat the ACE induced cough. Dr. Sean Kane 05:21 So Dr. Schuman, in addition to the ACE induced cough, are there any other adverse effects that are very unique to ACE inhibitors? Speaker 3 05:27 Yes, one fairly unique one is called angioedema. And this is, this is a sort of, almost an anaphylactic type of reaction that occurs within some of the mucous membranes. So think the tongue and the lips and some of the mucosa of the mouth, for example, you can see some swelling there, since some individuals, they can be a little bit annoying too, but they can also be dangerous to the point when it starts to cut off some of the breathing pathways. And it seems to be more common in African Americans, with about point 1% in a general Caucasian population versus point 2% in African Americans. Dr. Sean Kane 05:59 I think it's important to note that, you know, even though it's double the incidence in African Americans, it's still 0.2% so I would never, ever say that African Americans should not receive an ACE inhibitor because of a double risk of angioedema, but it's something that we should at least be aware of as healthcare providers. Speaker 2 06:17 That is true. There are other reasons that we know that ACE and ARBs don't work as well in African American patients to lower blood pressure, as we have discussed in our jnca guidelines. So just to keep that in mind as well, perfect. Dr. Sean Kane 06:31 So then moving on from our ACE inhibitors, the next drug class that we talked about are our angiotensin receptor blockers or ARBs, Speaker 3 06:39 and this class, again, just like with -pril being the clue on your ACE inhibitor system, we have -sartan as kind of the little suffix at the end that will clue us in as to this class of medications. So we have losartan (Cozaar), olmesartan (Benicar) and valsartan (Diovan) as three of the more common ones. But there are many, many other ones, such as irbesartan, candesartan, and others that may be less commonly seen. Speaker 2 07:04 And when it comes to side effect, again, related to the angioedema that we see with ace inhibitor, there is some cross reactivity of that side effect with angiotensin receptor blockers as well. So if the patient had angioedema to ace inhibitor, you have to be really careful if you are going to switch them to R because there could be that cross reactivity that might play a role in there. Dr. Sean Kane 07:27 On the upside, though, because we're not inhibiting the ACE enzyme, which is responsible for bradykinin breakdown, we do not see the dry cough or the bradykinin induced cough with ARBs like we saw with ACE inhibitors. So although angioedema, we will see some cross reactivity, we won't see that with dry cough. So in patients who have an ace induced cough, that is very bothersome to them, and ARB is an excellent alternative agent that doesn't have that side effect. Speaker 3 07:55 And now moving to the new kid on the block, which we'll call a brand name, is tecterna, and then the generic aliskiren, Speaker 2 08:02 and that is the only agent that's out in this particular drug class so far. Dr. Sean Kane 08:07 And because all of these drugs work on the renin angiotensin aldosterone system, they all have adverse effects that they share together. One of those adverse effects is hyperkalemia. So because of the way that they work on the kidney to get rid of sodium, they actually retain potassium. So patients will have higher potassium levels in their serum than a patient who doesn't take the drug. Speaker 3 08:29 And then, with that, you can also have some acute kidney injury that could potentially cause issues with perfusion, and then, thus potentially some acute kidney injury. And therefore, it's important to monitor things like potassium and serum currently on a semi regular basis, especially a few weeks after initiating therapy, or if you were to do a dose change, and you want to make sure to use clinical judgment. If you're assessing the renal function, if some you start to see a little bit of a spike, it may be warranting further evaluation, but you don't necessarily want to just stop it right off the bat. A general rule in some of the recommendations in literature is to wait for about a 30% change would be something significant enough that you want to take action. Speaker 2 09:07 And something also to keep in mind is that these drugs are not recommended in your pregnant patients. So if they have high blood pressure or diabetes, and you are using the ACE or the ARBs to help their high blood pressure, or, you know, help with microalbuminuria prevention, it's not going to be an ideal choice, because we've known that it's a known teratogen during trimester one, it's category C during trimester two and three, it's Category D. Dr. Sean Kane 09:38 So in summary, I think based on the fact that these are category C or D. It's probably a good idea to avoid these in pregnant women because of the risk to the fetus. So now that we have a good idea of what the drugs are, what are some adverse effects, the pharmacology of the drugs and how they work, why would we want to combine two or even three of the agents at the same time for a patient? Well, I Speaker 3 09:59 think one. Way to look at it is that we want to hit something from a few different angles. We know that if you just block one aspect of the system, the body can actually find ways to work around it, and so it can up it can up regulate, you know, if you're working middle of the stream, it can find pathways upstream to then go around that enzyme that you're blocking and still get to that interaction with with the angiotensin receptors, and so by hitting all three, we're limiting the amount of workarounds that there are. Speaker 2 10:27 A second possible benefit, one would think why we combine all these three agents together would be better clinical effects, such as patients who have systolic heart failure, who have protein area, whether that's related to diabetes or just plain old nephropathy, or patients who we are using this medications for possible CBD prevention. Dr. Sean Kane 10:50 So again, thinking about this newer drug, aliskiren, and at one point, the drug company, the manufacturer of Tekturna, actually combined this with an ARB at one point, and they called it Valturna, which was valsartan (Diovan) combined with Tekturna (aliskiren). But this was actually removed from the market in 2012; why was that? Speaker 3 11:10 The reason it was pulled from the market is there was an interim analysis that showed that individuals with diabetes actually had more adverse drug reactions from that combination, and that resulted in the labeling change to the lsdarin or tech turn itself, Speaker 2 11:24 and this increased adverse reaction was increased risk of renal impairment, such as the acute kidney injury, hyperkalemia, and increased anti hypertensive effect, aka hypotension. Speaker 3 11:37 And then a few of these studies also showed more non fatal strokes that occurred in that population as well. Dr. Sean Kane 11:43 So I think, based on that, that alone, at least, that really gives us concern about our proposed benefit of hitting the RAS system from multiple angles, that maybe that's not a good idea, given that we have an interim analysis showing harm and maybe not even benefit. So kind of piggybacking on that, the reason why the combination might be a bad idea. Would be combined adverse effects, so hyperkalemia, symptomatic hypotension, acute kidney injury, and then really what we would want to see is that we have some clinical benefits. So even if we're willing to accept, let's say, hyperkalemia, we probably want to see in patients with systolic heart failure that they have better mortality data than if they have monotherapy with an ACE or an ARB, as opposed to a combination with aliskiren. Speaker 2 12:26 But unfortunately, that is not the case when we look at the clinical data that is available. Dr. Sean Kane 12:31 So not only do we have worse adverse effects, but we don't get the clinical benefit that we would have hoped to see with a combination therapy. So let's think about some of the indications that we may have combination therapy for, or at least where it's been studied. I think the earlier studies looked at hypertension, and actually, if I'm not mistaken, when you combine allosky Urine with an ace or an R, we actually get a better effect with high blood pressure, so we get a greater reduction in blood pressure. Speaker 2 12:57 But then again, we are looking at the surrogate marker, right? You're just looking at, okay, yeah, you go ahead and you reduce the blood pressure. Does that translate into clinical benefits, therapy, or, more important, such as, you know, hospitalizations and mortality? Dr. Sean Kane 13:13 And as it turns out, it didn't. So are there any situations where we might combine an ACE, an ARB, or aliskiren with some other renin-angiotensin-aldosterone system agent. Speaker 2 13:25 So when it comes to hypertension, the recommendation is, do not combine. Do not combine ACE with ARB. Do not combine ACE + ARB + aliskiren. Or do not combine ACE or ARB plus aliskiren. In a possible situation when your patient has resistant hypertension, we've seen some benefit if you add an aldosterone antagonist such as spironolactone in addition to either ACE inhibitor or ARB. So moving Dr. Sean Kane 13:51 on to other indications of aces, ARBs and olyspiran proteinuria, or protein spilling into the urine because of renal damage is another potential indication for a renin angiotensin aldosterone agent, and really the nail in the coffin, if you will, for the combination of Ace Plus ARB, was a trial called the on target trial, which had over 25,000 patients in it, and it looked at ACE ARB, or the combination, in patients who were at higher risk for cardiovascular disease. Speaker 3 14:24 And what that study found was that dual therapy was associated with the same, or actually even worse, clinical endpoints compared to monotherapy. And they looked at things such as endpoints such as the need for dialysis, amount of renal impairment, etc. And so therefore there was no proof that the dual therapy slows the progression of protein area compared to the monotherapy, Speaker 2 14:43 and especially when it comes to again, going back to what we learned about Alex Karen, is this Alice Karen combination is absolutely a no no in patients who have diabetes or patients who have moderate to severe renal impairment. Dr. Sean Kane 14:56 So another potential indication for an ace or an. ARB, or olyskerin, is prevention of cardiovascular disease in people who are at very high risk for cardiovascular disease. And this was really born out of a trial called the hope trial, which gave an ACE inhibitor to patients who were at high risk and showed pretty good clinical benefit in that patient population. Speaker 2 15:17 But when we looked at the data from the target trial, we found that there was no difference in composite cardiovascular death or mis stroke or heart failure related hospitalization when they use dual therapy versus monotherapy, either with ace or Speaker 3 15:33 ARB and so then finally, one area that we know that has benefit for drugs that attack the renin-angiotensin system is going to be in heart failure. We know, for example, the role of ACE inhibitors in affecting cardiac remodeling. So there was one trial that showed benefit with the combination of multiple agents within this class, and that was the CHARM-Added trial. However, other trials are post-hoc analyses that show the complete opposite effect, so no benefit, and then almost all of the data, across all the studies for heart failure actually showed an increased ADR profile with minimal benefit, no benefit, or again, even harm. So increased side effects, increased potential for harm. You know that that's two strikes right there against the combination. So what they did say, though, was the combination of an of an ace, again, Lisinopril or another one of the prills plus Spironolactone is going to be a better option than a combination of an ACE inhibitor plus an R post MI, it's actually better to add Spironolactone or an aldosterone antagonist in patients post mi with low left ventricular ejection fraction or CHF or diabetes, and the reason is because we looked at some of the Spironolactone as an aldosterone antagonist, we know that angiotensin promotes the production of aldosterone, which does similar things in the body, again, that cardiac remodeling, hypertension, et cetera, that we alluded to with our ACE inhibitors. Dr. Sean Kane 16:53 So Dr. Patel, how do you kind of evaluate the data? Given that we have one trial that was prospectively done looking at the combination of an R plus an ace the charm added trial for heart failure, and then kind of the mountain of evidence against it, where it shows either no benefit or even harm. When combining the agents for heart failure, Speaker 2 17:13 I probably would go along with the evidence that weighs a little bit on to the dome combined side, because again, there are multiple data points Dr. Sean Kane 17:22 available, and I think this is one of those situations or scenarios where this happens all the time in clinical medicine, where we have some trial, sometimes it's even a very well conducted trial that shows profound benefit for some therapy, and then subsequent trials either show less enthusiasm for the benefit, or even no benefit for whatever the initial treatment or therapy was. So this is very common in evidence based medicine, and it's one of those situations where it's easy to pick out one trial that shows a benefit, but you really need to see a couple trials to definitively show a benefit of whatever therapy you're examining, right? Speaker 2 18:01 And it's also going along with that point, very important to look at, does your patient fit into that trial patient population? So if your patient has diabetes, and you're thinking of, you know, combining or using either monotherapy of one of these agents, you have to kind of look back and see, okay, were these patients included in that child that showed benefit or not. Dr. Sean Kane 18:23 So I do think it's interesting. And Dr. Schuman, you were touching on Spironolactone. I think it's interesting that we have pretty good evidence that shows that combining ACE, ARB, or aliskiren in some combination is probably not a good idea. But we have fairly good evidence that using Spironolactone in combination with an ACE or an ARB is actually a very good idea. It seems like we would see benefit or harm for both different sides, Spironolactone plus ACE/ARB or ACE/aliskiren. But we don't see that. We see a benefit with the Spironolactone combination, Speaker 2 18:54 and that Spironolactone combination, again, to summarize, will be more beneficial in patients who have heart failure or patients whose high blood pressure is hard to control, aka resistant hypertension. Dr. Sean Kane 19:06 I think it's important to recall, though, that the adverse effect profile of Spironolactone is going to be things like hyperkalemia, acute kidney injury, so we still need to be cognizant of that adverse effect profile. But at the same time, unlike with ACE/aliskiren combination, we actually have efficacy with combination, not just more adverse effects. Speaker 2 19:27 And so we talked about when it comes to cardiovascular conditions, we talked about heart failure, we talked about post mi use. There is some mention of these agents used in coronary artery disease as well. So the rule is, again, monotherapy. First line is your ace inhibitor. If ace not halimated, go for the ARB along with your beta blocker. But they should not absolutely use Alice Karen. Dr. Sean Kane 19:52 So the reason for selecting an ACE or an ARB, as opposed to Tekturna, is because of a lack of evidence for the combination. That is absolutely correct. Right? So to kind of summarize, anytime we're using an ACE inhibitor, an ARB, or aliskiren, or any combination thereof, which we shouldn't be doing, we need to be cognizant of the adverse effect profile. So that means we should be monitoring renal function for acute kidney injury via serum creatinine. We should also be thinking about the patient's potassium level. So any potassium level greater than five or five and a half mEq/L is probably a cut point where we should either be reducing the dose or even discontinuing therapy because of the risk for hyperkalemia that can cause cardiac problems. Speaker 3 20:33 Another one is to focus on specific populations, and that's what I want to emphasize. So aliscaran should not be used. It's actually contraindicated in patients with diabetes who are already receiving an ace or an ARB. And then furthermore, individuals who are pregnant should not receive the agents whatsoever. We have category C, for example, with the ACE inhibitors in the first trimester, with some evidence that they actually may be teratogenic. And then we have confirmed evidence in the second and third trimesters that they are, and thus it is Category D in those trimesters. Speaker 2 21:04 So bottom line of this podcast is it's never a wise idea to combine Alice Karen with ACE inhibitor or ARB. Dr. Sean Kane 21:12 So that concludes episode nine of HelixTalk. If you'd like to visit us online, we're at HelixTalk.com We've received a few five star reviews in iTunes, and we really appreciate more so that other viewers are more likely to find us in the iTunes Store. And with that, I'll conclude I'm your co host, Dr. Kane. I'm Dr. Schuman, Unknown Speaker 21:31 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 21:36 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.