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. This podcast is Narrator - ? 00:12 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 166 I'm your co host, Dr. Kane, Dr. Khyati Patel 00:36 and I'm Dr. Patel, and the title of today's episode is thiazide. Throw down hydrochlorothiazide versus chlorthalidone, the ultimate showdown for hypertension management and Dr. Sean Kane 00:47 Dr. Patel. Obviously, today we're talking about a newer trial that was published in the New England Journal of Medicine, which is linked in the show notes that compared chlorthalidone versus hydrochlorothiazide. And specifically, we're going to be focusing on the cardiovascular outcomes that are seen in this trial. And this has been a hotly debated topic for a long time, so it's kind of nice that we have some more clarity for this topic. Dr. Khyati Patel 01:10 Yeah, there's certainly been some abs and flow when it comes to the comparison of these two agents. But let's get started with setting a stage with a case. Let's say KW is your patient. He is a 75 year old male past medical history significant for hypertension, hyperlipidemia and osteoarthritis. Here for medical roles, visit the blood pressure here today is 139 over 84 at home, he's been measuring and it's been averaging 135 over 85 the current anti hypertensives are hydrochlorothiazide, 25 milligrams daily, lisinopril, 20 milligrams daily, atorvastatin, 20 milligrams daily, for hyperlipidemia, and then he takes the extended release Tylenol for osteoarthritis pain. The labs are okay. However, the provider wonders if we need to change anything along the lines of the hypertension management and ask if changing hydrochlorothiazide to chlorthalidone would be a better option to lower blood pressure to a goal level, because he has heard that it's more potent and has better benefits than hydrochlorothiazide when we consider cardiovascular health. So the question is, how should we proceed? How should we respond? Dr. Sean Kane 02:23 Yeah, so maybe we can go into a little bit of background about thiazides in general, and then more specifics about the different thiazides that are available. You know, all of the thiazide, or thiazide, like diuretics, work similarly, and the main mechanism here is that in the distal convoluted tubule in the kidney, it makes it harder for sodium to be reabsorbed into your blood, so your kidney is going to waste more sodium than it normally would, and water kind of follows that sodium, so if you're peeing out more sodium, you're going to pee out more water. So it does have a diuretic effect. That's why they're called thiazide diuretics with a smaller blood volume. We think that that's the main mechanism in terms of reducing blood pressure. Dr. Khyati Patel 03:01 And as you said, Dr. Kane, they're, you know, all working the same way. So when we refer to all, we have three agents, the hydrochlorothiazide, which is the main one, more common one brand name, Microzide, or HydroDIURIL. Who even knows the brand name of hydrochlorothiazide because we've used it for ages, it feels like and then we also have chlorthalidone. The brand name is Thalitone, and indapamide, the brand name is Natrilix or Indipam. Dr. Sean Kane 03:32 And you know of the three. It's probably no surprise to anyone who stepped foot in a pharmacy that hydrochlorothiazide is by far the most common agent. If you look at Medicare Part D data from 2020, chlorothaladone prescriptions in the US are about 1.5 million versus hydrochlorothiazide, 11 point 5 million. Or in other words, for every one prescription of chlorothaladone prescribed, there are 10 prescriptions of hydrochlorothiazide, so 10 times more commonly prescribed. Dr. Khyati Patel 04:01 Yeah, and you can even dive into older prescriber versus younger prescriber, like the thought is that the younger prescribers don't seem to really prescribe this because they're not even familiar with chlorthalidone as much as they are with the hydrochlorothiazide. Part of the reason could be because, you know, hydrochlorothiazide is so commercialized, it's available in combination with other anti hypertensive drugs, so like when we have to use dual therapy or make therapy easier for patients, or reduce pill burden and stuff, you know, these combinations do come in handy, and it's slightly cheaper than chlorthalidone, there are some attractive features to buy. We have more hydrochlorothiazide use, and, Dr. Sean Kane 04:45 you know, kinetically, there are some big differences here. So chlorthalidone and indapamide, one of the reasons why, historically, we thought that these might be better agents is that they have a longer half life. So chlorthalidone and indapamide have really long half life of 40 to 60 hours. Versus heterochorthiazide, we're looking at eight to 15 hours. So because of that, you see a longer duration of an antihypertensive effect, also more robust effect on blood pressure. So chlorothaladone, historically provided more potent blood pressure reduction, but the flip side of that is that you see more electrolyte problems, because it is more potent, generally speaking. And we'll see this in the New England trial that we'll talk about in a second. The perception is that chlorthalidone is about one and a half to two times more potent. So if you're on heterochlorothiazide 25 that would be as if you're on chlorthalidone 12.5 milligrams as an example. Yeah. Dr. Khyati Patel 05:38 And you could do, you know, more comparison of all the pkpd, the onset of action, the half like the duration, as well as looking at potency per dose. And like you said, Dr. Kane, it kind of roughly amounts to one to two from hydrochlorothiazide to chlorothaladone. Partly, there is a another theory here, that the chlorothalon and dapamide, particularly in this drug category, can induce a secondary vasodilation, but hydrochlorothiazide doesn't. So probably another reason is to why we're seeing a little bit better blood pressure reduction here, and then looking at metabolism and excretion, you know there, these are differently metabolized and excreted. So for example, hydrochlorothiazide is not metabolized and is excreted via our kidneys unchanged versus indapamide and chlorthalidone, which are both extensively metabolized via liver, and then chlorthalidone is excreted unchanged by your kidneys. So you gotta have to take in consideration kidney function, but more so in terms of the drug's efficacy, rather than safety. Dr. Sean Kane 06:49 You know, Dr. Patel, even though they have different half lives, we actually dose them the same way. So they're dosed once a day, typically in the morning, because they do have a diuretic effect, and we don't want to keep patients up at night peeing. Generally, we're going to start at a low dose, like 12 and a half or 25 milligrams, and then titrating it based on blood pressure goals and response, but also tolerability. So specifically, we're looking at electrolytes being low or high because of the thiazide diuretic. Generally speaking, if someone has a credit and clearance less than 30, we typically don't use thiazide diuretics for edema. Remember these. These are diuretics, so they help with edema in addition to blood pressure. So if you want to remove fluid in someone who has a low creatinine clearance, typically, we're going to look at for a loop diuretic in those cases. And in part because of that, but in part because of older data, we also thought that perhaps these days would not be as effective as a blood pressure reduction agent if you have a low creatinine clearance. And there are some small studies and short term studies that say maybe that isn't the case, that maybe these are still effective even if you have a low creatinine clearance, but that's been the classic teaching Dr. Khyati Patel 07:57 100% and just one thing I would like to add, since our study is looking at older patient population, is that when it comes to dosing, you know, generally, we start with the low dose, then our normal young adult patient population, again, that has to do with making sure patients are not getting too sudden of a blood pressure reduction or electrolyte changes. Dr. Sean Kane 08:20 In terms of why we're using these agents, the main one is going to be for hypertension. So this is a first line therapy for hypertension, and actually, historically, way back in JNC seven days, thiazides were the only preferred therapy for hypertension. And now we have dihydropyridine calcium channel blockers like Amlodipine. We have aces ARBs and thiazide. So there's really four potential options for most patients. So that is the most common reason that you're going to see, but you'll also see this for volume overload as an agent to help with edema. Again, loop diuretics are going to be typically more effective, and sometimes we'll even combine loop diuretic plus a thiazide for kind of augmented diuresis, but usually it's one or the other. And then finally, sometimes we'll also use this for kidney stone prevention, and the reason for that is kind of interesting. So thiazide diuretics will actually promote calcium reabsorption into the blood, so you pee out less calcium, and that can actually help with calcium based kidney stones. So some patients may be on a thiazide to help reduce the amount of calcium in their urine to help with kidney stones. Yeah. Dr. Khyati Patel 09:28 And some of the side effects, looking at thiazides in general, are dose dependent. Some are not dose dependent. The dose dependent side effects are our biggest culprits. One of the dose limiting side effect of Diaz I diuretic is the electrolyte disturbances, namely hypokalemia. So as we talked about earlier, we're getting rid of sodium in the distant carbonated tubules, and that means there is more sodium available in the collecting tubule, that's where the sodium potassium pump. Gets activated, leading to transferring sodium to interstitium and transferring potassium into the collecting tuple, that leads to more excretion of the potassium, and that leads to hypokalemia, then Dr. Sean Kane 10:14 we can also see things like hyponatremia, and obviously we're wasting more sodium than we normally would. But there's also a condition called SIADH (syndrome of inappropriate antidiuretic hormone). And thiazides are one of the many drug classes that are implicated with that. Dr. Khyati Patel 10:29 And as you said earlier, Dr. Kane hypercalcemia, although sometimes we can use that mechanism of hypercalcemia favorably for kidney stone prevention, some somewhat in my neck of the wood, hyperglycemia has been seen as one of the side effects, too, and that has to do with, you know, decrease hyper polarization of beta cells in the pancreas, and that leads to decrease insulin secretion. And so that hypokalemia and this decrease insulin secretion are kind of like interconnected they're not contraindicated for patients with diabetes, and so there are still in patients who have diabetes and have hypertension, these are still the primary for anti hypertensives, recommended to be used, but you got to watch out for those who have uncontrolled diabetes and monitor blood sugar if necessary, and Dr. Sean Kane 11:19 then, kind of In a similar vein, in patients who have gout, we have a concern about using thiazides in those patients, because thiazides can cause an increase in uric acid levels in the blood, so hyperuricemia, and it occurs because the thiazide actually promotes reabsorption of uric or uric acid in the kidney back into the blood. So again, it doesn't mean you can't use thiazides in patients with gout, but if they have high uric acid levels or they have many gout attacks, maybe this is not the best antihypertensive option for those patients Dr. Khyati Patel 11:51 and those who have additional risk factors like kidney disease, because of the hypokalemia, there is The increased potassium and hydrogen ion excretion in the collecting tubules. So some cases of metabolic alkalosis are also reported. These agents do have sulfa moiety in the chemical structure themselves. So we gotta watch out for patient sulfa allergy. And what does that mean is, if patient has sulfa allergy, and you see the reaction was rash, you could still go ahead and use these agents, but provide patient education to look out for things such as rash, you know, swelling and your edema, any trouble breathing and stuff. If the sulfa allergy, however, is anaphylaxis, we would probably avoid using the thiazide diuretics, because we could use other agents instead. Dr. Sean Kane 12:42 And interestingly, Dr. Patel, a lot of the data about sulfa allergies does discriminate between an allergy to a sulfa antibiotic versus a sulfa non antibiotic. And essentially, the main sulfa antibiotic used right now in today's practice is sulfa methoxazole, trimethoprim or Bactrim is the brand name. So usually in patients who are allergic to Bactrim, as long as it isn't a life threatening reaction, all of those other non sulfa antibiotic based drug molecules are fairly safe to use. But as you said, if someone had a very severe reaction, even if that cross reactivity rate is really low, it's something that we would be more concerned Dr. Khyati Patel 13:20 about absolutely, and then kind of wrapping up the background information, you know, monitoring. So usually, after starting a dose or changing the dose, we're going to monitor patient within two to four weeks for efficacy, things such as, you know, patient's blood pressure, or if you're using it for fluid overload, you know, status for edema. And then safety monitoring would include lab parameters such as the electrolytes, as we mentioned earlier, as well as kidney kidney function. Dr. Sean Kane 13:49 And you know, Dr. Patel, prior to this New England journal article coming out, we did have some previous literature about using thiazide diuretics in patients who had hypertension. You know, most of the data historically was actually with chlorthalidone, not with hydrochlorothiazide. So the all hat trial is one of the main trials that comes to mind, where it compared four different anti hypertenses, and chlorthalidone was the thiazide that was used in that trial. And again, many other trials did use chlorthalidone. So the thought was, well, maybe we should use the most evidence based thiazide, which at the time was corethaladone, as opposed to hydrochlorothiazide. Dr. Khyati Patel 14:27 But as we look at on the flip side, some of the observational studies. So for example, a study published in JAMA in average adult, 51 year of age, it was a comparative cohort study that showed that using chlorothaladone or hydrochlorothiazide, and then, kind of comparing the cardiovascular outcome, there was no difference between Dr. Sean Kane 14:51 the two. And then finally, there was a retrospective cohort study in Canada that showed that chlorothaladone was at least associated again, cause and effect. You can't prove. But associated with a higher risk for EGFR decline. In that case, they defined it as a 30% reduction, or worse, also a higher risk of cardiovascular events, higher risk of hypokalemia compared to hydrochlorothiazide. So again, that was a retrospective study that perked the interest of, you know, deciding whether a prospective trial would be appropriate to really evaluate clinical outcomes between these two thiazide diuretics Dr. Khyati Patel 15:26 and fast forward. That's where this diuretic comparison project study comes in play. Now, Dr. Kane, this is not a randomized, you know, prospective, controlled study, it's more they call it the pragmatic study design, which is that it's really using the real world clinical practice to study the intervention. And when we say interventions here, we're comparing chlorothaladone versus hydrochlorothiazide, and this was largely done in VA population. So we're looking at patients 65 years or older, and what they did is they, in order to do this pragmatic study design, they utilize their procedures in the electronic health records as well as their point of care monitoring system. And what this did is it took away the need for having special patient recruitment for the study, no special research site staff, any special like research study or clinic visits and procedures and data capture, because all of this was done in the existing care that the VA providers provided to The veterans, and then all the data was collected from the EHR at the VA, if you Dr. Sean Kane 16:45 think about it. Dr. Patel, this is a huge cost savings thing, because you're kind of using an existing infrastructure to identify patients, to randomize them, to keep track of them, and we're looking at two fairly inexpensive drugs. So it's not like a drug company is going to come along and spend millions of dollars to fund this trial. So the only way this trial would be done is by a government grant, and in this case, using VA patient population, and they were able to enroll, as we'll talk about, more than 10,000 patients, using this very unique study format to be able to quickly and efficiently get the number of patients that they needed. Yeah. Dr. Khyati Patel 17:21 So this, this was a multi center, VA, different VA sites, open label, yet, randomized study, and they included patients 65 years and older, as I said, with blood pressure of above 120 but no blood pressure reading that was less than 120 in the past 90 days. Again, we're looking at older patient population. They're being sensitive to the fact that they could be at higher risk of hypotension, and, you know, dizziness and falls and things like that. Dr. Sean Kane 17:51 And you know, the main study aim was looking at major cardiovascular outcomes and death in these older patients. And they look specifically at people who were currently on hydrochlorothiazide at baseline, and we'll talk later, this is actually kind of a benefit and a limitation in that all of the patients that were randomized had blood pressures more than 120 and were on at least heterochlorothiazide. And we'll talk about their on average, on multiple blood pressure medications, but at least one of them had to be heterochlorothiazide. Yeah. Dr. Khyati Patel 18:21 And just to be specific, you know, as we mentioned earlier, this was a pragmatic study design. Most of the research team was VA personnel and academic investors that were employed by the VA. However, there was an independent data monitoring group that reviewed data twice a year for efficacy and safety. So speaking of intervention, Dr. Kane, you know, basically what they did is they randomly picked patients who were on hydrochlorothiazide. They randomly pick patients to either continue the hydrochlorothiazide or switch them to chlorothaladone. And so if, let's say they were on hydrochlorothiazide, 25 milligram or 50 milligram, they were converted to chlorothaladone 12.5 or 25 milligram, respectively. Dr. Sean Kane 19:07 And then basically, after that, everything else was up to the provider, as they normally would do. So it is open label, so the provider knows what dose the patient's getting, what drug the patient's getting, and the provider is charged with doing everything after that. So, managing the hypertension, making any medication changes, monitoring for side effects, collecting labs, all of that stuff was basically up to the prescriber, the provider, as it would be in a pragmatic trial in real life as well. Dr. Khyati Patel 19:36 And as far as the end points go, the primary endpoint, as we discussed, was the first occurrence of composite outcome, and this was a composite of non fatal CV event or non cancer related death. And the non fatal CV events were defined as my cardio infarction, stroke, any hospitalizations for heart failure or any urgent need for revascular. Station for unstable angina. Dr. Sean Kane 20:03 And they did have some secondary endpoints, like a non fatal cardiovascular event, also non cancer related death. So kind of some of those individual endpoints from the composite and then they had some safety endpoints, like electrolyte problems, primarily hypokalemia, the need for hospitalizations and acute kidney injury, which, again, all of these are known side effects of thiazides that we've known for a long time. And the perception has always been that chlorthalidone, because of its longer half life and higher potency, might be worse from a safety standpoint. Dr. Khyati Patel 20:33 And so Dr. Kane, like any large trial design would do, this was an intent to treat analysis they were hoping to have about 1055 primary outcome events to have 90% power to detect that chlorothalon would reduce these primary outcome by 17.5% with the two sided alpha of point oh, four nine. And there was an assumption that, you know, the annual incident rate for such a primary outcome with hydrochlorothiazide, was 3% and so primary endpoint as well as secondary endpoints, were tested using appropriate statistical analysis. However, the authors were very explicit. Secondary endpoints were not adjusted for multiplicity. Dr. Sean Kane 21:20 So the study itself, in terms of the results, ran from June of 2016 all the way to October 2021 and a typical patient was in the trial for 2.4 years on average. And this is pretty amazing. Dr. Mattel, so they had more than 4000 providers from about 72 different vas, and they, between those providers at these VAs consented a little bit more than 16,000 patients. And then finally, about 13 and a half 1000 patients underwent randomization in a 5050, split between chlorothaladone and heterochlorothiazide. So in terms of the typical patient in the trial. So again, this is a VA patient population. So the mean age was 72 so a little bit on the older side. These were mostly men, mostly white, although 15% were black. The average BMI was pretty typical, so about 3132 and more than 40% of patients in both groups had diabetes. So pretty high incidence of diabetes in both arms. Dr. Khyati Patel 22:18 Interestingly enough, 11% of patients had previous history of stroke or MI. And this was kind of specified, because they did run some subgroup analysis in this patient population, the average systolic blood pressure at baseline was 139 millimeter per mercury. And as we said, 90. You know, most of these patients were on hydrochlorothiazide. We were talking 94.5% of patient who were randomized were on hydrochlorothiazide, 25 milligrams daily. But on average number of, you know, anti hypertensive medication, it was about 2.6 Dr. Sean Kane 22:55 so the primary outcome, again, that composite of cardiovascular endpoints, it was an event driven power calculation, they needed 1055 events, and they had more than that. They had 1377 events. So globally, the percentage incidence rate between the two groups was really similar. So with chlorthalidone, it was 10.4% with heterochorthiazide, it was 10% even. So that hazard ratio was 1.04 with a P value that was not significant, so there was no difference between the two groups, and they did meet statistical power. So we're less worried about a type two statistical error in this trial Dr. Khyati Patel 23:30 and secondary outcomes were kind of looking at these individual non fatal cardiovascular events like MI, stroke, heart failure, hospitalization, revascularization, or non cancer death, and all of these were not significantly different between the two groups. And again, there was the death from any cause was also looked at, and there was no difference between the two groups. Dr. Sean Kane 23:57 So they did do some subgroup analyzes, and one of the ones that did show statistical significance was a benefit towards chlorthalidone in patients that had a history of MI or stroke. And again, that was about 10% of the whole study. And what they found was a difference of 14.3% with chlorthalidone versus 19.4% with heterochoride in that primary endpoint. So it's roughly a 27% reduction number needed to treat of 20. But again, this is a subgroup analysis of an endpoint that was not, it was not a successful primary endpoint. So we do have to take this with a grain of salt that this may be a true signal, or it could just be statistical noise. Dr. Khyati Patel 24:37 Yeah, and dr, Dr. Kane, so far, you know the the primary endpoint, the secondary endpoint, we found no statistical significant difference. However, table kind of turns when we look at the safety outcomes, and so we noticed more new allergic or adverse reactions in chlorthalidone group than hydrochlorothiazide group. You're talking one point six percent in chlorthalidone group versus 0.3% in hydrochlorothiazide group. Mainly these were driven by cases of hypokalemia. Dr. Sean Kane 25:10 They looked at hypokalemia specifically, and it was 6% versus 4.4% so about 40% higher with chlorthalidone. They also looked at severe hypokalemia, which was defined as a potassium less than 3.1 that was 5% versus 3.6% again, about a 40% higher rate with chlorthalidone. And they also looked at the need for potassium supplementation, and not surprisingly, that was more common in those that received chlorthalidone, and also the need for lab monitoring – so again, it was pragmatic, so they left it up to the prescriber of how often they get labs. But those that were started on chlorthalidone did have more lab draws in that first year compared to hydrochlorothiazide. Dr. Khyati Patel 25:52 And overall, they looked at hospitalizations related to either hypokalemia, more severe hypokalemia or Aki, and they found no difference between the two groups overall. Just looking at two different groups and the use of these medication, the average daily dose was 12.3 milligrams. So close 12.5 milligram in chlorthalidone group versus 23 milligram. So let's just say 25 milligram in the hydrochlorothiazide group, which we kind of established earlier. It's kind of like that one to two relationship, the mean medication possession ratio. So this is based on prescription dispensed from the VA system was roughly the same in both groups, 79.5% in chlorthalidone versus 79.1% in hydrochlorothiazide. This again, dispensing of the refills was looked at more from the adherence perspective. However, they found that more patients were switched from chlorothaladone to hydrochlorothiazide 15.4% versus those who were switched from hydrochlorothiazide to chlorothaladone 3.8% and there is some debate that this has to do with the open label study design leading to these confounding decisions. Dr. Sean Kane 27:09 So in terms of some strengths of the trial, one big strength is the pragmatic trial design. We do these trials because they're very, very real world, and typically the number of resources and the amount of time and cost is lower. So generally speaking, pragmatic trials have a little bit lower internal validity, meaning that we don't control as many things in the trial, but they have better external validity, which means that it's more representative of what would typically happen for a typical patient in the real world setting, which is a good thing. Dr. Khyati Patel 27:40 And I think the other strength Dr. Kane is, you know, not looking at just the surrogate outcome of blood pressure reduction, but focusing on the meatier morbidity and mortality outcome, the cardiovascular outcome, which this trial did focus on. Dr. Sean Kane 27:57 In terms of limitations. One of the biggest limitations to the trial is that they enrolled patients that were already on hydrochlorothiazide, so there's a selection bias concern here. So for example, one of the endpoints in the trial was allergic reaction. And the problem with that is that you've picked people who were already stable on hydrochlorothiazide, that you wouldn't expect them to have a new allergic reaction to hydrochlorothiazide, versus the people who were on hydrochlorothiazide switched to chlorthalidone. You do expect things to get different for those patients. So they're more apt to need more lab monitoring because you gave them a different therapy than what they're normally going to take. They're at a higher risk for allergic reactions, side effects, things like that, because it's a new regimen for them versus keeping everything stable. So it isn't like they randomized patients directly from nothing to hydrochlorothiazide or chlorothaladone. They took everyone that was on hydrochlorothiazide and then randomized them to keep doing the same thing, the stable regimen, or to do something different in terms of switching to chlorthalidone. Dr. Khyati Patel 29:00 And you know, similarly to this study design, the nature of open label could have also impacted the frequency of lab draws or the decision to switch back to hydrochlorothiazide. And to elaborate, that is, most clinicians know that chlorthalidone is a little bit more potent in terms of electrolyte disturbances, so they were more likely to mandate lab draws, closer monitoring of these electrolytes, compared to those who were on hydrochlorothiazide and perhaps those who were caught having hypokalemia. The providers went ahead and decided, okay, you know this is not acceptable. Let's change you back to hydrochlorothiazide, because you were doing fine. Your potassium was fine. So there were some open label study design related confounders here as well. Dr. Sean Kane 29:52 And although we are interested in blood pressure, as we mentioned, a strength is that we looked at hard cardiovascular outcomes. It. Is interesting, especially because we didn't see a difference in those hard cardiovascular outcomes, whether there is a difference in blood pressure, and in this trial, there was actually no difference in the mean systolic blood pressure. Patients were enrolled at a blood pressure of about 140 and throughout the entirety of the trial, they stayed at a blood pressure that was roughly 140 so given that we did not observe a difference in blood pressure, it's actually not that surprising that we didn't see any difference in cardiovascular outcomes. And one might argue, well, you know, these patients are above what would typically be a goal blood pressure of 130, over 80. Perhaps if we would have gone up on our doses of hydrochlorothiazide or chlorthalidone, that maybe we would have seen a difference, because we really were basically at a starting dose of both therapies, 12 and a half of chlorthalidone or 25 of hydrochlorothiazide. So perhaps if you increase the dose, we would have seen some difference in efficacy or safety in the trial. Dr. Khyati Patel 30:57 Yeah, lots of you know things to consider from the study perspective here, but kind of overall conclusion of the trial was that there was no difference in cardiovascular outcomes between hydrochlorothiazide and chlorthalidone and more patients in the chlorthalidone group had hypokalemia related laboratory draws and maybe the need for using potassium supplementation. Again, some of this could have been related to the study design, as we discussed earlier, but those were the overall significant study findings. Dr. Sean Kane 31:32 And for what it's worth, there are some other observational studies that have been published more recently that basically have concluded the same thing that hydrochlorothiazide versus chlorothaladone, there's not really a difference in cardiovascular outcomes, but chlorothaladone is associated with more of the hypokalemia and other electrolyte problems that have to be managed. Dr. Khyati Patel 31:53 So I think the takeaway point for me Dr. Kane is if, if the patient's blood pressure is controlled, leave him on hydrochlorothiazide. You don't need to change it to chlorothaladone in a hope that you would get better cardiovascular risk reduction, but because we know that chlorthalidone does have a little bit better potency, so if your patient needs additional blood pressure control, or you kind of in the area of that resistant hypertension, then perhaps changing it to chlorothaladone can provide a little bit better blood pressure reduction, although it does come with additional monitoring, closer monitoring, as as we discussed earlier, Dr. Sean Kane 32:32 yeah, and Dr. Patel because of the trial design, and we'll go back to our patient, kW in just a second. I do think it answers the question of if you have someone on 25 of hydrochlorothiazide, so they're already on that therapy, if you switch them to an equipotent dose of chlorothaladone, 12 and a half, there's basically no difference in cardiovascular endpoints or in blood pressure, but there's more side effects. So I think it answers that question. The question it may not answer is whether hydrochlorothiazide or chlorthalidone are better as initial therapy. And someone who is naive to a thiazide, or if you picked a higher dose, so a not equipotent dose, would you see any difference? So we don't know that as well, but it does answer the question of, if they're already on hydrochlorothiazide, you're not going to get a lot of bang for your buck in terms of any benefit if you just switch them to an equipotent, chlorothaladone dose. Dr. Khyati Patel 33:23 Yeah, and kind of applying the same principles to our patient, who is again of older age, is on hydrochlorothiazide, 25 milligram and Lisinopril. 20 milligram. Patient doesn't have any other cardiovascular disease, like the stroke and the Mi like that subgroup analysis that found significant findings in this study we discussed, the laboratory results are normal blood pressure is slightly above the goal and so kind of, you know, putting the evidence back on here, I don't think there's going to be any additional cardiovascular benefit for changing hydrochlorothiazide to chlorothalon If we are looking to control blood pressure a little bit more then, yeah, we could consider going up on the lysinopheral dose, but and then obviously additional you know, safety and efficacy monitoring would be applicable here, so making sure we are bringing patient on board with that shared decision making too. Dr. Sean Kane 34:16 And Dr. Patel, I firmly agree that going up on the Lisinopril is the right answer here for those that wanted to I think tthe other potential option would be to go to chlorthalidone, but maybe not pick 12.5 milligrams the equipotent dose, but maybe give 25 milligrams of chlorthalidone, knowing that it's going up on that thiazide dose, and, of course, monitoring for some of those side effects that we discussed. Dr. Khyati Patel 34:40 Yeah, that that is another alternative that we can consider for the patients too, but making sure patients are ready to do the laboratory work. Dr. Sean Kane 34:50 So, Dr. Patel, I think this was a good review of that New England journal article comparing the two thiazides. You know, for me, one take home point is that there are three main thiazides on the market: chlorthalidone, hydrochlorothiazide and indapamide. Mainly, these are used for hypertension, but of the three, hydrochlorothiazide is by far the most commonly prescribed medication, at least in the United States. Dr. Khyati Patel 35:12 And comparing hydrochlorothiazide to chlorthalidone, you know, chlorthalidone is slightly more potent in reducing blood pressure, but it is also potent in creating some of those electrolyte abnormalities compared to hydrochlorothiazide. Dr. Sean Kane 35:26 And then finally, as we talked about this new england journal article that was just recently published, which is referenced in the show notes, basically looked at cardiovascular outcomes comparing chlorothaladone versus hydrochlorothiazide, and there was no difference, but we did see more side effects, specifically hypokalemia, that needed to be managed, monitored, and more often potassium supplementation was required for these patients. For the listeners, if you want to read the trial for yourself, you can go to our show notes and look for that New England journal article citation. We can't update our website right now until early July, so you won't see it on the website, but you will see the show notes in the podcast app that you're listening to right now that will have the reference in there. You will be seeing website posts and things like that come July, with this episode and a couple of the other episodes that haven't made it to the website just yet, but they will be coming soon. Dr. Khyati Patel 36:19 And you know, Dr. Kane would like to thank our audience for supporting and presenting ideas of podcasts and topics that we can record, just to remind kindly to the audience too, that we have recently recorded podcast that is about different CGM and the outcomes of CGMS that's available that pharmacists need to know. And that's episode 162 continuous glucose monitors, also known as CGMS, are devices that are now becoming mainstream for diabetes management and care, and so they're kind of the new kid on the block. If you want to know everything about it, plus get a CE credit just for a small coffee price of $5 do give it a listen and support your favorite Dr. Sean Kane 37:06 podcast. So with that, I'm Dr. Kane Dr. Khyati Patel 37:09 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 37:13 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 - ? 37:24 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.