Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 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 - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 190 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is, can't stop, won't drop that BP, that just won't quit diagnosis and treatment of resistant hypertension. Dr. Khyati Patel 00:45 Dr. Kane, I'm really excited because I get to see this in primary care all the time, where patients are on multiple medications and for whatever reason, their blood pressure is still not controlled. So this is right up my alley as well. Dr. Sean Kane 00:58 Love it. And even in the ICU, we see lots of patients with very resistant hypertension, but more commonly, it's for a variety of other reasons. So we're really just focused today on kind of that ambulatory care patient with chronic drug resistant hypertension, and what a great way to kind of transition to like a typical patient that we might see in clinic, right? Dr. Khyati Patel 01:16 And I believe there is a new drug in the category of endothelin receptor antagonists called aprocitentan (Tryvio). So we kind of go over that a little Dr. Sean Kane 01:26 bit too for sure. So imagine that you have a 60 year old woman coming to clinic with hypertension follow up. She has a history of diabetes, chronic kidney disease, with an EGFR of about 30 hypertension and preserved EF heart failure. Two weeks ago, she was seen in clinic, she had her Amlodipine dose increased, and she's been monitoring her blood pressure at home, and she says she hasn't missed any doses. So she's been adherent to her blood pressure medications. She sometimes feels a little bit fatigued or dizzy, but really, she's doing pretty well in terms of not having a lot of side effects to her current blood pressure medications. Dr. Khyati Patel 02:02 And those blood pressure medication, as you said, you know, amlodipine, 10 milligrams daily. That dose was recently increased. She was on five milligrams before that, so just two weeks ago, was increased to 10. And then she's also on hydrochlorothiazide, 25 milligrams, which is, if you think about it, you know, kind of on a max dose. You could argue you can go to 50 and then lysin upon 20 milligrams. So this is definitely not the max dose. Dr. Sean Kane 02:26 So today in clinic, her blood pressure reads at 146 over 92 and that's pretty similar to what her home readings have been in the mid 140s over around 90 ish, diastolic, and her heart rate, both at clinic and at home, is around 70 ish, Dr. Khyati Patel 02:41 and all the other labs are normal, including the serum potassium, except that we've noticed a little bit elevated bun and serum creatinine, obviously, because patient has CKD. So the question here is, you know, does this patient has what we call resistant hypertension? And if yes, then do we need to change her current anti hypertensive regimen? And we'll Dr. Sean Kane 03:03 definitely talk about that new medication at the end as well. So really, I think we should start Dr. Patel with defining what is resistant hypertension. And at face value, I think it's kind of obvious that it's hypertension that's hard to treat, right? But there's actually a really specific definition, and we have guidelines that are linked in our show notes about resistant hypertension. Dr. Khyati Patel 03:20 Yeah. So I mean starting off with one of the first criteria is when a patient needs more than three antihypertensives to get their blood pressure to goal. And usual blood pressure goal is that less than 130, over 80. And so if you typically imagine our starting antihypertensives are the calcium channel blockers or the ace or the ARB or thiazide, or thiazide like diuretic. But the caveat here is that all of those drugs should be maxed out to their highest doses, Dr. Sean Kane 03:49 and some patients can't tolerate the max dose, so it's whatever, either the max labeled dose or the max tolerated dose. The second criteria is going to be that you actually have to have accurate blood pressure readings for the patient. Again. This sounds obvious, but in clinical practice, this is actually pretty common that the blood pressure reading is not accurate. So that means proper blood pressure technique. It means that you have two readings on two separate occasions that validate or verify that that blood pressure is above goal. Dr. Khyati Patel 04:16 This is my biggest pet peeve, Dr. Kane, I'll tell you how many times I've gone to my own doctors, and they bring me in. I'm like, running, you know, trying to find parking, running to the office. I'm barely sitting. They bring me in, walk right in, and what they do first thing is put on a cuff and check the blood pressure. They don't give that resting time, all of that, that's really important. Check the position right. My feet are always dangling. I'm sitting on the exam chair. So I think this is kind of emphasizing that the measurement needs to be accurate. And then if the patient is doing it at home, we need to also make sure that their technique is appropriate, and they're doing, you know, not using a wrist monitor, for example, and doing that brachial cuff monitoring, yeah. Dr. Sean Kane 04:57 And a great transition to that is that the third criteria is. A you need to exclude white coat hypertension. White coat hypertension is where patients tend to have higher blood pressures in clinic because they're really worried that their blood pressure number is going to be really elevated, and they're going to kind of get in trouble with that high blood pressure have more stuff added, like more medications, or, you know, opening the door to problems, right? So they're worried about that. And when they go to the clinic and see the white coat the provider that they're going to have a high blood pressure. So the way that you diagnose this or mitigate that issue is that you need to have them check their blood pressure at home. So in addition to having a good blood pressure technique in clinic, they also need to be checking their blood pressure at home. And that home blood pressure monitor, or ambulatory blood pressure monitor, needs to confirm that their blood pressure is, in fact, what you think it Dr. Khyati Patel 05:45 is, yeah, when they're not in the office in front of the white coat, right? And the other thing is, you know, this comes across a lot too, like my first suspicion is, is a patient taking their medication? Yes, they're, you know, three or four anti hypertensives on the chart. But are they truly taking it right? As we know, as the number of medication increases, the adherence decreases. So here, 50 to 80% of the patient that are prescribed antihypertensive medications could have suboptimal adherence. That's one estimated data. And 25% of the patients may not even fill their antihypertensive their first antihypertensive medication because either whatever reason, lack of education or some sort of stigma or pre formed notions they have, they don't think they need that many I had one patient long time ago, said, I'm going to take one medication for my blood pressure, one for my cholesterol and one for my diabetes, and that's it. I'm not going to do more than that, right? So these are their patient beliefs attached to adherence, and we need to rule that out that that's not because of the adherence issue. Dr. Sean Kane 06:47 So those are really the four criteria for what is the defining characteristics of resistant hypertension in terms of why it's bad. So obviously, like, if someone needs a bunch of medications to control their blood pressure, that's bad, but people who are diagnosed with treatment resistant hypertension have a variety of risk factors that you could probably predict based on having uncontrolled hypertension. So if a patient is diagnosed with resistant hypertension, they're more likely to progress on their CKD, have CKD, or progress all the way to end stage kidney disease. They're more likely to have heart attacks, strokes, heart failure, and even die of cardiovascular complications. So the typical complications associated with hypertension are still holding true here, and probably are even magnified, because these are patients that have resistant hypertension, as the definition would suggest, right? Dr. Khyati Patel 07:38 So those are all the consequences of what can happen if we don't control it, but then we have some maybe preventative stuff in the lifestyle category that maybe we can work on or address to resolve that hypertension that could be resistant then first and foremost is the weight. Right? So obesity is a common cause. BMI over 30 can double the risk of resistant hypertension. And if you look at the guidelines, especially like lifestyle related guidelines, losing weight definitely does lower the blood pressure, right? So kind of win, win situation here? Dr. Sean Kane 08:15 Then we have sleep apnea, especially if it's untreated, where they are either undiagnosed or are not compliant with their, let's say CPAP machine, things like that, and then kind of related to that poor sleep quality or not getting enough sleep. So we're talking like seven to eight hours per night. If they're not achieving that, where they have uncontrolled sleep apnea, they probably are at a higher risk for complications, in terms of more risk of resistant hypertension. Dr. Khyati Patel 08:41 And then dietary issues come in play too, right? So when we think about diet, we think about sodium, reading that label and looking out for the sodium amount. There's a lot of inter individual variations, but in general, sodium and water stay together. So if your body retains more sodium, it's going to retain more water, and there's going to be more volume pushed against the blood vessels, increasing the blood pressure, right? So that's a simple physiology here. Alcohol is another one too. Heavy consumption is associated with that too. And so one of the lifestyle recommendation includes, you know, lowering or limiting the amount of alcohol, and Dr. Sean Kane 09:18 then, of course, physical activity. So, you know, different guidelines have different recommendations, but in general, we want moderate intensity activity for most days of the week, for probably 30 minutes a day, and it depends on what guidelines you look at. But in general, the more active a person is, the lower their blood pressure will be. Dr. Khyati Patel 09:36 Yeah, and then there are other factors that we don't normally go after thinking about lifestyle. Normally, we think diet and exercise as main lifestyle factors. But if you think about the pillars of lifestyle medicine, as we are celebrating that month, this month thinking about, how do we address that stress and anxiety, right? Maybe patient has underlying depression, how are they dealing. With those symptoms and maybe improving that could also help lower the blood pressure. And I ask all my patients, how are you sleeping? You know, poor sleep quality has also been associated with increased blood pressure, not just because they have sleep apnea, but because there's some underlying reasons stress that, you know, they're not able to get enough sleep, a good quality sleep. Dr. Sean Kane 10:21 Then, of course, there are medications that increase your blood pressure, and we need to be aware that there are issues in terms of if you're on medication X that can actually increase your blood pressure, and either you need an alternative or maybe not take that medication at all, at a minimum. So patients can be on some of these medications that we're about to cover that increase your blood pressure, but it should always be a risk versus benefit discussion. So for example, incense, so we're talking ibuprofen, naproxen, Meloxicam, things like that. Those medications are very commonly used for osteoarthritis in elderly patients, and although it does increase your blood pressure, if a patient is completely non functional and they don't have an alternative analgesic for their osteoarthritis, they may accept a slightly higher blood pressure because they literally can't use their hands or walk very well. Alternatively, though some patients might be a okay on Tylenol instead, which doesn't increase their blood pressure. So it's a risk and benefit that needs to be considered for many of these medications. Absolutely. Dr. Khyati Patel 11:18 And Dr. Kane, I think you know, our students bring up this, like drug drug interaction all the time. You know, NSAIDs and anti hypertensive have a drug interaction. So when we talk about that in particular, it's because NSAIDs are going to block the production of healthful prostaglandins that could act as vasodilators, like the e2 and itu, and that's what kind of leads to that constriction of the blood vessel, also retention of some of that sodium that happens in the kidney too, due to these prostaglandin functions. And so NSAIDs block it, and that's why we see the opposing effect of the antihypertensives that the NSAIDs can bring about. Dr. Sean Kane 11:59 We should be really clear here when we talk about NSAIDs, although aspirin is an NSAID, this is always a dose dependent side effect. So for that kind of quote, unquote, baby aspirin or low dose aspirin of 81 milligrams, that is such a low dose, it does not cause hypertension, and most patients that take it are taking it for a really good reason, so we're not going to target that 81 milligram of aspirin as part of our drug induced hypertension approach, because it's not causing that problem. Aspirin doses of like 975 milligrams, you know, multiple times a day, that's where we would be more worried about aspirin, in this case, being a culprit for causing hypertension. Dr. Khyati Patel 12:34 Yeah, and that low dose aspirin has lot more benefits that would outweigh that little risk, right? So we're not seeing that oral contraceptives is another one, and this is something that we keep in mind when we are prescribing the estrogen, progestin combination contraceptives, rather than the either agents alone. Lot of the time we think, Oh, these combinations are also available in post menopausal hormonal replacement therapy, but those are pretty smaller concentrations. So those are okay, but if you think about just traditional oral contraceptives that are combined, they use a little bit of a higher dose of estrogens and progesterones and so those definitely can impact the blood pressure. Dr. Sean Kane 13:15 Then another drug class that should make sense are some pathomimetic drugs. So most of the ADHD type medications like Ritalin, methylphenidate, Adderall, things like that, definitely can increase your blood pressure. We also have other ones, like decongestants, like Sudafed or pseudophedrine, many illicit drugs that are stimulants like cocaine or methamphetamine and then something even like phentermine for weight loss, all of these are increasing sympathetic tone, and that's going to cause vasoconstriction and have a higher cardiac output, which gives you a higher blood pressure. So again, it's a risk versus benefit for these patients. But definitely this would be on my list of things, of how necessary is it for a patient? Dr. Khyati Patel 13:54 Yeah, and talking about risk versus benefit, you know, obviously those patients who are post transplant the calcineurin inhibitors, like the cyclosporine or tacrolimus, it's necessary. They will need to be on that medication, but these do cause sodium retention and some renal vasoconstrictions that can add into that hypertensive Dr. Sean Kane 14:14 physiology, and then primarily for chronic kidney disease patients, we think about recombinant EPO product. So epoetin alfa, which is Epogen or Procrit, or darbepoetin (Aranesp), these increase your blood volume by giving you more red blood cells. So it's used for anemia, but in the process of increasing your blood cell counts, it can cause hypertension. So all of these products have warnings related to they can worsen hypertension, and even if a patient has uncontrolled hypertension, that's a contraindication for use, because they're more likely to have a cardiovascular event if you give them an APO product and their blood pressure is already really high, yeah, Dr. Khyati Patel 14:53 ...And the last but the not the least, we want to mention some antidepressants, such as the SNRI, especially, even the venlafaxine again, because they block the reuptake of the norepi and that's where you increase that sympathetic tone, and that leads to increased blood pressure. Duloxetine is in this category, but it's not implicated to increase blood pressure as much as the venlafaxine or the Effexor. Dr. Sean Kane 15:19 is then another antidepressant is Bupropion. The main brand names are Wellbutrin or Zyban, and these are norepinephrine dopamine reuptake inhibitors, which means, you know, on that norepinephrine side, just like our SNRIs, they're going to give you more norepinephrine, so that sympathomimetic style neurotransmitter can increase heart rate and blood pressure, right? Dr. Khyati Patel 15:41 Dr. Kane, we kind of covered like lifestyle issues as well as medications that could be doing it. But then we have some secondary causes of hypertension that are probably we cannot change. I think very first one to consider is primary aldosteronism, right? So it's just that patient is producing too much aldosterone, Dr. Sean Kane 16:00 exactly, and aldosterone has a lot of effects in the body. So it causes volume expansion, so you have more vascular volume. It increases Sympathetic Nervous tone, so all of the things associated with hypertension, aldosterone augments or triggers some of those pathways. And we bring this up specifically, because obviously there's a number of reasons for secondary causes of hypertension. But if you took patients with resistant hypertension, about one in five of them are going to have too much aldosterone. This primary hyperaldosteronism, versus just normal population, is about 8% so prevalence is more common to have too much aldosterone among patients that have resistant hypertension, Dr. Khyati Patel 16:40 and I believe Dr. Kane, we could do a test to figure out if they do have that or not. Dr. Sean Kane 16:44 Yeah. And it's a little bit complicated, because there's a lot of nuance to it. The test basically involves checking an aldosterone level, a renin level, and then looking at that ratio. But it has to be done in the morning. The patient has to sit for 30 minutes. They can't have a low potassium level, and they can't be on a variety of drugs that are going to impact this test. So we're talking like ACE inhibitors, ARBs, beta blockers, things like that. So we're not going to get too much into the testing, but if they screen positive using this ratio thing, then you actually have to do more testing as well. So we're not going to get into it, but there are tests that you can do for this. Dr. Khyati Patel 17:18 Yeah. And as we mentioned, there some other health conditions, secondary health conditions that could be increasing blood pressure too, such as the sleep apnea or the CKD even mentioned, but also, if somebody has renal artery stenosis, pheochromocytoma, as well as Cushing syndrome, again, these all will need additional workup to confirm. But if you ruled out the adherence, the lifestyle, some of the common things that we can rule out, then these are the diagnostic that we should go after. Dr. Sean Kane 17:49 And a great example would be pheochromocytoma. So this is where you have a tumor on your adrenal gland that's making adrenaline. So you can, all day long, give them an ACE inhibitor or whatever, but at the end of the day, if, if you know that they have this tumor, you just need to remove the tumor, right? And like all the drug therapy in the world is not going to fix that tumor. So it really highlights the importance of thinking about, is there an underlying reason why they have resistant hypertension? And if there is, you might need to fix that underlying reason, as opposed to just give four or five, six drugs to the patient. Dr. Khyati Patel 18:20 Yeah, and that makes sense, because I feel like that treatment approach should be multi prong while the options are existing, yeah. Dr. Sean Kane 18:29 So, Dr. Patel, you mentioned lifestyle modifications to prevent hypertension. Not surprisingly, we should also be recommending these non pharmacologic treatments as part of our treatment approach for resistant hypertension, right? Dr. Khyati Patel 18:42 And those non farm approaches are going to be considered along with our farm approaches, right? So again, they kind of go hand in hand. We talked about obesity being one of the main reasons, and so weight loss, usually we aim somewhere between five to 10% of the body weight that does make a difference in the blood patient's blood pressure. And I mean, imagine patients going through metabolic surgeries, for example, and they lose a ton of weight. Some of them have to actually come off of their blood pressure medication, because the blood pressure just gets regulated by itself. The other one we talked about, you know, dietary inclusion of more sodium can cause hyper high blood pressure. And so let's talk about sodium restriction. And now if you look at different guidelines, they know you will find different numbers, but ideally, we want to target less than 2300, milligrams per day for most patients. Now go out, look up some other nutrition labels. You know, our American diet is not conducive whatsoever to do this restriction. But at the end of the day, I tell my patients, the best way to do it is, you know, try to eat fresh foods as much as possible. Less packaged foods, less processed foods, is the way to eliminate all that extra sodium, because sodium is added as a preservative and. So it's not really tasting salty to you, but it's added as a preservative. And you don't even know that, because it's not part of that nutrition label. Dr. Sean Kane 20:08 And of course, don't eat out. Most restaurants are going to have a lot of sodium in most of the foods. Obviously, it depends on where you go and what you eat, but on average, you're going to get pretty salty food if you're going to a restaurant. So Dr. Patel, 2300 milligrams per day is what is recommended for most patients. But depending on what guideline you look at, there are a variety of other recommendations. So for example, there's a more stringent goal in some guidelines of less than 1.5 grams per day, or less than 1500 milligrams per day. I think everyone agrees that if you achieve that goal, your blood pressure will be lower, but there's a concern that the evidence hasn't borne out that that actually improves clinical outcomes. So the blood pressure does go down, but because of that low sodium intake, the body actually increases or activates the sympathetic nervous system and the renin angiotensin aldosterone system. So we haven't potentially seen some of the clinical benefit, probably because of that offset that happens. So it's a little bit controversial in terms of how low should you recommend for patients? I can tell you that 1500 milligrams a day is a crazy low amount of sodium, so most patients won't be compliant with that anyway. But it should be noted that there's some controversy around the goal for patients, right? Dr. Khyati Patel 21:20 And even if patient is, you know, trying to change their dietary habits and getting in the habit of reading nutrition labels, there's lot of nutrition informations available for restaurants and stuff. So like, if you're going to Panera, or if you're going to McDonald's, you could always look up the nutrition facts of the products that they're selling, and you could make an informed decision. Dr. Sean Kane 21:43 Another recommendation is going to be reducing alcohol intake, so less than two drinks per day for men, or less than one drink per day for women, probably even lower than that, if they're okay with that, but that would be the maximum that they should be consuming per day. Yeah. Dr. Khyati Patel 21:56 And the other important component of the lifestyle modification is physical activity. And so here it's that moderate to vigorous intensity, or higher intensity aerobic exercise to be done about 150 minutes per week. There's been lot of conflicting data coming out. Should you all concentrate that two days a week? Where is it? Spread it out. Spreading it out is a little bit better schedule wise as well. But in a nutshell, it's that 150 minutes of goal to hit per week. And this is not for weight loss. If you are considering weight loss, you need a little bit more than just 150 so this is more just for that aerobic benefit that the heart will get release of those endothelins that come from the physical activity that can work as a vasodilators to help lower that blood pressure. Dr. Sean Kane 22:45 So then moving on to pharmacologic therapy. So assuming that we've talked to the patient about the non pharma therapy, which is really important, the first step for our pharmacologic therapy is to make sure that we're optimizing the three drugs that they're on that gave them the definition or met the criteria for resistant hypertension in the first place. So that means that making sure that we're on the maximum tolerated dose of all three of those medications, and also making sure that they're actually taking it and just being honest with the patient that we as healthcare providers recognize that many patients are not adherent to their antihypertensives, and they need to be honest with us. They're not in trouble if they're not doing it right, but we need to know that so that so that we're not adding a fourth, fifth med that is wasting their time and our time and things like that. Dr. Khyati Patel 23:27 Dr. Kane, I still remember this case that was referred to me for resistant hypertension. Long, long, long time ago. Patient was paraplegic. Also with nephrology, trying to control the blood pressure. The primary was trying to do that. She was also with cardiology. Everybody was trying to lower her blood pressure. She comes to me on the first day. I tell her to bring all her medications. I go through it one by one, and she tells me, out of the five that's been prescribed, she takes two and a half of them. And that tells you that every provider, rather than assessing the concern, understanding patient beliefs or addressing the herons issues, they're just saying, Oh, it's not working. Let's add another medication. But never go and ask the patient, are you taking them? Are you having concerns about them? Let's talk through them, right? And that's really important to do. The other thing to make sure, you know, as we discussed, there are some primary antihypertensives to consider optimizing those therapies important. One of them is making sure that patients on appropriate diuretic regimen that we can do with either the thiazide or thiazide like diuretic, but we know that they have lesser efficacy if the patient's EGFR declines. And so those examples are hydrochlorothiazide, we we are okay to use it and most patient populations. However, when the EGFR drops below 45 it's not as effective. We may have to switch patient to either the stronger chlorothalardone version or indepamide, which can work at a lower EGFR. There. A little bit more potent, have a lot longer half life. Yes, they do come with a little extra electrolyte and renal monitoring, but they are a little bit more potent than just the hydrochlorothiazide. So if your patients on hydrochlorothiazide and not responding, maybe there is a consideration to do to switch to either of these two. Dr. Sean Kane 25:18 And then similarly, as that EGFR continues to decline, so we're talking less than about 25 to 30. It might be appropriate to switch the thiazide to a loop diuretic, and Dr. Patel, usually we don't use loop diuretics as antihypertensives for a variety of reasons, but in this case, we know that for treatment resistant hypertension, they do tend to have higher blood volumes, and we also know that the thiazides don't work as well. So the guidelines actually recommend torsemide, and it's preferred by the guidelines just based on a longer half life and the ability to have once daily dosing versus twice daily dosing, bumetanide, Furosemide, you would at least need bid dosing. There is no clinical trial that says like torsemide is definitely better. So it's really just based on that dosing frequency with a slightly higher or longer half life. Yeah. Dr. Khyati Patel 26:04 And then some of the European guidelines recommend, if the EGFR is below 30, that you combine the two, right? So you combine the loop diuretic and chlorothalidone. But again, as we know, these are two different diuretics working into different parts of the kidneys and impacting the electrolytes to even a larger degree. So you may see more disruptions there, more monitoring might be needed. Dr. Sean Kane 26:28 So then, once we've done all of that, so really, we've just talked about making sure we're adherent, optimizing our three drug regimen, which is the baseline regimen for these patients, the next option, and this is a great NAPLEX question, or board question, is, for those patients, the next drug that you add, all guidelines agree, is you add an MRA, a mineralocorticoid receptor antagonist. So we're primarily talking about spironolactone, or maybe eplerenone for these patients. And the reason for that is that there is a trial done called the pathway to trial, where they took patients with resistant hypertension and they randomized them to a couple different drugs, including Spironolactone. doxazosin or bisoprolol, a beta blocker, and the Spironolactone was the best in terms of reducing blood pressure among those resistant hypertension patients. Dr. Khyati Patel 27:12 So yeah, that's something that we do in our clinic too. Consider the possibility of adding that spironolactone, eplerenone is also an available option, but that's not as commonly used as spironolactone comes with a little bit of disadvantages, such as, you know, if somebody is already on an ACE or ARB, and you're adding Spironolactone on top of that, you do have the increased risk of hyperkalemia, or that reduced, you know, renal function, especially in patients who have CKD. So again, these parameters will need to be closely monitored in the initial times of adding these agents. Dr. Sean Kane 27:46 Now, spironolactone tends to be the agent that is picked because it's once daily, versus eplerenone which is twice daily. And the downside to it is that it has some unique side effects, because in addition to blocking the mineralocorticoid receptor, it also blocks androgens in the androgen receptors in the body. So in men, they can get kind of gynecomastia or erectile dysfunction. Women, they can get menstrual irregularities. So it's one of those things that you start at see how they do if they don't tolerate the side effects, then you might switch over to eplerenone, Dr. Khyati Patel 28:15 yeah, because the eplerenone does not have that androgen blocking effect. And so the ADR profile and this terms definitely is better. We still have to monitor the renal function and electrolytes. Dr. Sean Kane 28:27 And a good clinical Pearl here is that for heart failure with reduced ejection fraction when you're adding that MRA, this is a case where eplerenone is dosed once daily. This is how it was done in the clinical trial. But when you're using it for hypertension, you need it b ID, so it's nuanced, but it's actually kind of important that if you're trying to get it for that hypertension component, you do need bid dosing because of the half life. Dr. Khyati Patel 28:48 Yeah, and that's where, again, adherence will need to be emphasized with the patient. What about then adding another agent thereafter? Dr. Kane, what is the consensus or guideline recommendations on that. Dr. Sean Kane 29:00 So basically, once you get to antihypertensive number five, which, let's just pause for a second and think about how ridiculous that is. Think about any disease state ever that has five drugs that you take, right? Maybe heart failure, maybe diabetes, but it's pretty uncommon that you're going to need five drugs. But given that, it's actually really hard to study, like, what is the best fifth drug therapy to study. So all of what we're about to talk about is expert opinion in terms of, we don't have a clinical trial saying what is the best fifth agent, but we do have reasonable thoughts in terms of why you might favor one over the other based on patient specific factors, right? Dr. Khyati Patel 29:35 And so then we look at certain things, such as, is the patient's heart rate higher, right? So above 70, maybe because their heart is beating so fast that cardiac output needs to be reduced, and that we can do by calming down that sympathetic drive by using beta blockers, right? So we could even consider using beta blockers that have that vasodilatory effect, such as the Carvedilol or labetalol. So now. Only the central action, we get a little bit of a peripheral action as well. Dr. Sean Kane 30:03 And then another one to think about is nebivolol, and that one doesn't block Alpha One receptors to cause vasodilation. It has a nitric oxide induced vasodilation. But again, all three of these beta blockers are potentially advantageous because of that vasodilation component, which is also kind of what we're looking for. Dr. Khyati Patel 30:23 I say this all the time, Dr. Kane Alpha agonists are added. The clonidine is more of the common one that I've seen, but guanfacine is another one that is also in this category. Again, patients are on, you know, be, you know, started with once daily to up to tid use of clonidine, but patches probably become a little bit easier in terms of administration or adherence when they have to take that fifth medication. Yet, on top of it, again, rebound. Risk of rebound during the period of non adherence is pretty big, so patient needs to be educated to continue taking these drugs, and if they have any side effects and concerns, it needs to be tapered down in collaboration with the provider, Dr. Sean Kane 31:03 a couple clinical pearls related to this. So the clonidine patches literally take three days to start working. So more on the inpatient side, where we're kind of waiting for their blood pressure to get better, like in the next couple hours, if you put that clonidine patch on, it won't work for a couple days. So that is not going to acutely manage anything, but on the outpatient side, that's not a big deal, right? We also have extended release or XR versions of both clonidine and guanfacine. With clonidine, it's expensive, so that's a common reason to not pick it and use the patch instead. And for guanfacine, technically the ER formulations for ADHD, but there's no reason that you couldn't use it for hypertension. It's just not that formulation hasn't specifically been studied for hypertension. Yeah. Dr. Khyati Patel 31:47 And again, emphasizing the fact that for either the beta blockers or these alpha agonists, alpha two agonists, if you abruptly stop, stop the treatment, the rebound hypertension can occur. And so again, emphasizing to take it regularly, and if they're experiencing any side effects, to talk with the providers, so we can have a tapering plan. Dr. Sean Kane 32:07 And then that moves us to our next potential drug class of alpha one blockers. So again, alpha two agonists are different than alpha one blockers. Alpha One blockers are mentioned in the European guidelines that are in our show notes, but not in the US guidelines and in the European guidelines, they specifically like doxazosin, er, although terrazasin is also something you could consider, but they like doxazoson Just because you have the ER formulation. And the big caveat here is that historically, we're talking like now, probably 20 plus years ago, the all hat trial used doxason, and they actually stopped that arm of the trial earlier than the lysinopril arm or the Amlodipine arm, because what they saw was a slightly higher risk of heart failure in patients that got doxazosin. And we don't know. Is it that doxazine increases the risk of heart failure, or it just doesn't protect from the risk of heart failure like lysinopril does as an example. So the main time that you might consider this would be a men who have BPH, because that alpha one blockade is going to help with benign prostatic hypertrophy, where they have difficulty urinating because of an enlarged prostate. But there's some big side effects to these alpha one blockers, in addition to the potential risk of heart failure. Dr. Khyati Patel 33:17 That's a good summary on the Alpha One blockers, and I don't get to see them added as much, but the next one, the hydralazine, I do get to see added along with the clonidine and stuff, especially when they have reduced ejection fraction heart failure, adding a little bit of nitrate along with that hydralazine may serve a little bit better, because we do have Some mortality data in this patient population. However, if you are deciding to use hydralazine because it has potential to increase that sympathetic tone and retain sodium, it's advised that patients on a diuretic regimen and beta blocker to kind of counter that sympathetic tone and sodium retention that comes from hydralazine and Dr. Sean Kane 34:01 Dr. Patel. One thing that I forgot, but then remembered, as I was preparing for this episode, was that hydralazine is one of the very few drugs that's associated with drug induced lupus, and this is great for NAPLEX or board exams, things like that. So lupus is going to be an autoimmune condition where you're going to get rash and a variety of other health complications. And what I didn't understand is that the risk of lupus with hydralazine is dose dependent. And I think that's interesting, because many times when we have immune mediated reaction to a drug therapy, it's almost never dose dependent. It's you either have it or you don't have it. But in the case of hydralazine, one of the reasons for the maximum dose of hydralazine is that the higher dose you take, the higher the risk is of lupus. So the guidelines recommend that you don't exceed 150 milligrams per day of hydralazine, primarily for that reason, Dr. Khyati Patel 34:52 yeah, and again, the risk is pretty high, as you're saying. Dr. Kane, like five to 10% of incidences per year. Sure, and so I would, I would be all about keeping them on a lower dose as possible. Dr. Sean Kane 35:05 And then, just for completeness sake, the other drug commonly associated with drug induced lupus is procainamide, which is a class 1A antiarrhythmic that basically we never use. But it is one of those trivia factoids of pharmacy that procainamide and hydralazine are associated with drug induced lupus. Dr. Khyati Patel 35:22 Yeah. And when you when you bring this up and emphasize it in this manner, I do remember this being a little asterisk, type of side effect of hydralazine. I remember studying for NAPLEX long time ago. You know, on the outpatient side, if it's not a hypertensive urgency or emergency, I've seen people getting started on once daily, and then moving up to T ID. You know, I think lupus is one of the reasons, too, but also that potential of causing that vasodilation and sudden drop in blood pressure is another reason, maybe on that hospital side, or inpatient side, when we are dealing with that urgency and emergency, T ID regimens are initiated. But if they're initiated on the outpatient side, I've usually seen it starting at once daily and then kind of going up if their blood pressure is Dr. Sean Kane 36:07 not controlled. So then Another consideration is that if hydralazine doesn't work, most guidelines recognize that Minoxidil is going to be one of our very last line therapies before we get to the new one in just a second. So Minoxidil is not recommended in almost all cases, and I think in my entire clinical practice, I've only used minoxidil one time in one patient. And the reason why Minoxidil is not recommended is that, just like hydralazine, you need to have a beta blocker and a loop diuretic, because minoxidil increases sympathetic tone and it increases sodium retention. So it does that even more than hydralazine does. So it's really important to have that. And then the side effect profile, you can get hirsutism, which is hair growth on the face, and then that sodium retention, these patients are going to get edematous, and they can have a higher heart rate and things like that. So there's a lot of side effects that come along with minoxidil, but it is a very effective vasodilator, so it really becomes a risk and benefit. I would only consider this if you've truly maximized all of the other stuff that we just talked about, right? Dr. Khyati Patel 37:11 And I just want to say this out loud, I know our audience understands when we say, use minoxidil for hypertension. That's an oral formulation. Minoxidil is also available for hair growth treatment over the counter, like Rogaine is one of the brand names a lot of generics out there too. The topical version, obviously is not going to work for hypertension, so even though it's over the counter, that's mainly for, you know, growing the hair on your head, but the oral version is what we are talking about here for resistant hypertension, Dr. Sean Kane 37:41 and Dr. Patel, we are laughing or smiling jokingly that, of course, no one would do this, but I think you and I both know that at some point in the history of medicine, someone has given topical minoxidil for hypertension. I'm sure it's happened. So then that kind of brings us to our last drug therapy, which is actually a newer drug that was approved by the FDA in 2024 the brand name is Tryvio. The generic name is aprocitentan. And this is again newly approved 2024 and this is a totally new drug class, specifically approved for resistant hypertension. Dr. Khyati Patel 38:14 And as a as we mentioned earlier, this falls under a category of drug called endothelial receptor antagonist era. So the underlying mechanism here is that et one, that's one of the endothelial expression is increased in via the cytokines or inflammation, angiotensin two and vascular mechanical stress. And so when we have these antagonists, they're going to block the effect of ET one, all the bad effects we just talked about, by binding it to the endothelium receptors. And so by binding it to the receptors, it's going to cause vasodilation, reduction in that inflammation and so forth and so on. Dr. Sean Kane 38:57 There's even evidence that blocking endothelial one or et one can have other beneficial effects. So for example, endothelial one causes not just vasoconstriction, but also fibrosis and inflammation, and it works in the kidney in terms of sodium and water retention. So there may be other blood pressure effects that are also helped with eras, in addition to some like fibrotic type things, especially with the heart, with eras as well. Dr. Khyati Patel 39:21 And I would say that the drug class is not new. Dr. Kane, we've had other eras in the market, but we don't get to here in the mainstream. It's used mostly for the pulmonary hypertension, not really the resistant hypertension, treatment resistant hypertension. So we've had drugs like bosentan, macitentan, ambrisentan, these are currently available in the market for the treatment of pulmonary hypertension. Dr. Sean Kane 39:45 Yeah, so really, same drug class is just now specifically looking at resistant hypertension. The dose for this medication is 12 and a half milligrams once a day. You actually don't titrate it. You're either on it or not on it. In the clinical trial, they actually did study a higher dose of 20. Five milligrams, but it was not more effective, and it had more side effects, primarily edema. So that's where the 12 and a half milligrams comes from, Dr. Khyati Patel 40:07 and when we talk about side effects. So these eras, first and foremost, there are potential teratogenic drugs, and so obviously box warning for pregnancy related contraindication is there. But also we get to see hepatotoxicity. Especially, I remember this looking at bosentan, so it's more specifically seen with boat sent in, but it's also an overall class warning as well. Dr. Sean Kane 40:33 And as I mentioned, the higher dose that was studied did cause more edema. So not surprisingly, we see fluid retention even at the lower doses. Is a dose dependent side effect. So for that fluid retention reason, all of the eras are not recommended in patients with heart failure, if they have pulmonary edema or bad peripheral edema. And many of these patients, I mean, they should be on a diuretic already, but you might need to give them a higher dose of that diuretic if you're going to start this medication. Dr. Khyati Patel 40:58 Anemia has also been noted. It's there's an interesting trend with it. On average, we've seen decrease of hemoglobin by point eight, gram per deciliter. What we get to see is, with the initiation of this therapy, we see a little dip in the hemoglobin that which kind of stabilizes during the therapy, and then once we stop the therapy, it kind of reverses itself. And so this is more of that reversible side effect, Dr. Sean Kane 41:23 and the last one for men, this whole drug class, all eras, are associated with decreased sperm count. It can also cause testicular atrophy and infertility. So obviously, if a patient is starting on this and they want to have children, they need to be aware that that's a potentially long term side effect, definitely a short term side effect of the whole drug class, including aprocitentan. Dr. Khyati Patel 41:45 So talking about the side effects and stuff, it's important, because then we can figure out what's the best patient to use it. But how has the efficacy of this particular new agent, aprocitentan, have been like Dr. Kane? Dr. Sean Kane 41:58 So the phase three trial that got it approved was called the precision trial, and they looked at patients that had systolic blood pressures more than 140 despite being on three antihypertensives. So kind of thinking about the criteria that we typically use for resistant hypertension, and their primary endpoint was blood pressure reduction at four weeks. So couple thoughts about this one. From an efficacy standpoint, they did show a mean reduction of about four millimeters of mercury, so they did meet that criteria. Dr. Khyati Patel 42:29 No joke, four millimeter. Wow, that's a lot of blood pressure reduction. Dr. Sean Kane 42:34 But then just thinking about the four week time period. And in all fairness to the trial, they had other phases of the trial where they extended it out, they kind of re randomized patients, stuff like that, but the four week time point was the main clinical outcome that the FDA looked at. And if you think about it, most people are going to be on this life long, basically. So to just study it for four weeks, I think, is a little bit silly. And again, they did have a 40 week extension that was probably more for the side effects as opposed to the efficacy. But efficacy. But I'm a little bit surprised that the FDA is okay with a chronic med being studied for four weeks and then calling it a day. Dr. Khyati Patel 43:09 And there were some other issues with the trial too, right, where we just talked about how MRA should be the fourth therapy if a patient does not respond to, you know, the primary three antihypertensives, what was the issue here? Dr. Sean Kane 43:24 So they did not allow for Spironolactone during the trial. So if you're on it, you had to stop it, and they did not allow you to start it during that, at least that four week time period, which is odd, because both the European and the US guidelines say that that is the recommended fourth line therapy. We actually have a clinical trial showing that that's better than some other therapies that were studied in a clinical trial. So I don't know what why they do that. I can tell why would they not look at it either as an alternative to Spironolactone or as an add on to Spironolactone? That's not how the trial was designed. So I don't think it actually answers the main question that I'd have of, is it better than spironolactone, or is it good to add to Spironolactone? We don't know that answer. Dr. Khyati Patel 44:01 And so in addition to that, Dr. Kane, obviously, this is a brand new drug. So there is, you know, obviously, cost associated with that. Other thing we look at when it comes to blood pressure reduction is, you know, how cost effective this is therapy and like that, four millimeter for Mercury reduction compared to tier three, tier four drug copay. That seems a little bit too much to justify going back to our patient. Remember, she was a 60 year old patient with diabetes, CKD, EGFR is at 30 hypertension and preserved ejection fraction, heart failure. The blood pressure readings at home as well as in the office, were kind of in that 140, to 90 zone. So obviously, still, you know, elevated, not at goal, and this is where patient is saying they're checking the blood pressure at home appropriately. They're taking the medications, right, so the adherence is confirmed. But we see some caveats here, right in the medication. So patient was on hydrochlorothiazide, 25 mm. Grams. Amlodipine had recently been increased to 10 milligrams, but their Lisinopril was still at 20 milligrams. Dr. Sean Kane 45:06 It's unlikely, Dr. Patel that we're going to drop 10 millimeters of mercury or more with going up on our Lisinopril, but we should still do that, because it's part of our approach. Right is that we maximize our first three antihypertensives. So we should definitely do that today, but we should also look at what other med she's on. And we didn't go through every single med that the patient is on, but we're thinking about any meds that cause hypertension, specifically NSAIDs for like, osteoarthritis, but really, any other med that we talked about, yeah, Dr. Khyati Patel 45:33 ruling those out are important, and so are ruling out, like, lifestyle related factors, right? So if the patient is overweight or obese. You know, considering some weight loss can be helpful based on the medical conditions they have, seems like they may not, but they shouldn't have as much physical activity restrictions. And so encouraging physical activity should help out assessing their diet and seeing the pattern of, you know, those pre packaged processed foods kind of diverting the patient to more homemade foods or less processed foods to reduce that sodium restriction, and also assessing their alcohol use intake, right? And maybe kind of educating them on tailoring or curbing that a little bit can also help as well. Dr. Sean Kane 46:17 So in terms of drug therapy, we we mentioned that we'll definitely go up on the Lisinopril dose to the max dose of 40 milligrams a day. And when we do that, we're definitely going to check a sim, creatinine and a potassium level in about two weeks whenever we see the patient next Dr. Khyati Patel 46:30 Yeah, especially because she has that underlying CKD and that EGFR is hanging low, I would definitely like to do that in two weeks. Dr. Sean Kane 46:37 So then the next thing is thinking about optimizing the diuretic. Again, that diuretic is one of our three kind of core medications for hypertension, for this patient, so her EGFR is 30, and she's on that less potent hydrochlorothiazide that doesn't work as well as your EGFR is a little bit lower. So our options could be that we switch to the more potent, longer acting, better efficacy at lower EGFR, thiazides of chlorthalidone or indapamide. Or if we wanted to, we could consider, round this point, switching over to a loop diuretic like torsemide would be the expert opinion preferred loop diuretic, right? Dr. Khyati Patel 47:12 And then if you are confused as to which one you're going to choose one versus the other, keep in mind, patient has that underlying, preserved ejection fraction heart failure, they may have some underlying edema where they need a little bit more potent medication to get rid of the edema. And that's where loop director is going to come on the top. Dr. Sean Kane 47:30 And I would definitely not do it today, but at some point in the future, as that EGFR is around that you know, 30 or less or 25 or less mark, some guidelines do recommend the combination of a thiazide plus a loop diuretic in patients with more advanced CKD, but just remember that you're going to get a lot of electrolyte abnormalities when you combine both of those diuretics, so you're going to have closer monitoring and just be more cautious with those patients. Dr. Khyati Patel 47:56 And then once those changes have occurred, or the blood pressure in two weeks is still elevated. I think it's perfectly fine to add the MRA here. I probably would go with the Spironolactone first 25 milligrams daily, again, because this can also impact renal function and potassium. We're going to have to recheck it in two weeks. Dr. Sean Kane 48:16 And again, you highlighted it, but I want to highlight it again, because the patient has CKD and because now you have two drugs that cause acute kidney injury and hyperkalemia, this is the patient that you can't wait four weeks or a whole month to get new labs on that patient. We're extra worried about the combination of multiple drugs and the patient CKD in terms of they're at a higher risk of having a complication of our drug therapy, right? Dr. Khyati Patel 48:40 And so we're not going to make the, you know, A's inhibitor dose increase and addition of Spironolactone at the same time, but we're going to stagger it to see, like, hey, if, if there is abnormalities in the renal test or potassium, you know, where is it coming from? Dr. Sean Kane 48:57 So at some point, once we've maximized our lisinopril, added our spironolactone. We've reassessed all of our stuff. Again, give an opportunity for lifestyle changes. So maybe the patient is consuming like 10 grams a day of sodium. We should wait some period of time for her lifestyle changes to take effect, to see what the impact is. Assuming all of that has been done and we're still above our blood pressure goal, we have a lot of different options. Beta Blocker again, we were thinking labetalol, Carvedilol or nebivolol, those vasodilating beta blockers, or maybe an alpha two agonist, but probably not of clonidine or guanfacine. Those are all potential options to blunt some of that sympathetic tone. Dr. Khyati Patel 49:35 The other options in the pocket, although you know not our favorites, are the Alpha One blockers, like doxazozine, other therapies like the hydralazine and noxadil or procententan could be reasonable. Again, we kind of talked about the, you know, the perks or the caveats of these medications earlier. Dr. Sean Kane 49:54 So at this point, I think we have a pretty good plan for a patient. It's going to take a couple visits, really, to. See what impact we have with our drug therapy and what the next step would be for the patient. So Dr. Patel, to kind of wrap up today's episode with some key concepts from resistant hypertension, the number one thing for me is, what is the true definition of the diagnostic criteria for true resistant hypertension? That's that you have to be on three anti hypertensives. So we're talking ACE or ARB, plus a calcium channel blocker plus a diuretic. And despite that, you're not at blood pressure goal. We've ruled out that the blood pressure reading is inaccurate. We've ruled out white coat syndrome, and we've ruled out poor patient adherence to our drug therapy regimen. You have to meet all of those criteria to be classified as resistant hypertension. Dr. Khyati Patel 50:41 And then the first step we're going to do to address this is non farm therapy, especially that sodium restrictions in the diet. We're going to address that medication adherence and other lifestyle factors that could, again, on a longer run, not an immediate fashion, would provide benefits for treatment of resistant hypertension. Dr. Sean Kane 51:02 Then, from a drug therapy standpoint, probably the most important thing to know for board exams and NAPLEX is that after you've maximized those three core anti hypertensives, Spironolactone is our fourth line option for these patients, Dr. Khyati Patel 51:15 and if they do have side effects from spironolactone, eplerenone can serve helpful as well, but then after adding those MRAs, you know, really, what's next is based on expert opinion and patient specific factors. And those additional therapies may include beta blockers with a little bit of that peripheral vasodilatory activities, alpha two agonist, Alpha One blockers, hydralazine, minoxidil, and the most recent medication in the market, the aprocitentan. Dr. Sean Kane 51:46 So for the listener, if you want to see our show notes, it's available at HelixTalk.com this is episode 190 which includes references to the American and the European guidelines for resistant hypertension, with a lot more information than what we've covered today. We also have a mailing list that you can sign up for at HelixTalk.com and we love the five star reviews, so keep those coming with that I'm Dr. Kane Dr. Khyati Patel 52:08 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 52:15 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there Narrator - ? 52:26 to suggest an episode or contact us. We're online at HelixTalk.com. Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.