← Endocrine Feedback Loop
Endocrine Feedback Loop
EFL072 - Pre-Operative Use of Mineralocorticoid-Receptor Antagonists in Primary Aldosteronism
00:43:48
Loading summary
Transcript30 lines
- [00:01]
A
This is endocrine feedback loop. I am your host Chase Hendrickson and welcome you to this Journal Club Podcast series brought to you by the Endocrine Society. Thanks for joining us as we explore an important article recently published in one of the Society's clinical journals. Hello and welcome back to the Endocrine Feedback Loop podcast for our 72nd episode and the end of our sixth season. Before we get into today's episode, I would like to take just a few seconds to thank you all as our listeners. It means a great deal to have you all join us to hear these conversations. For today's discussion we will look at an article focused on the perioperative medical management of Primary aldosteronism. Over the last several years the medical literature has helped us to understand our need to better diagnose and treat primary aldo, so there is an increasing interest among endocrinologists in this topic and we were excited to review this recent paper. As with most of the studies we look at, the study design here contributes importantly to the findings, so we will consider that carefully. As always, we will end with our thoughts on how these findings should change the care we provide to our patients. I host this podcast and work at Vanderbilt Health in Nashville, Tennessee as a general Endocrinologist and Medical Director. As you might have guessed, the podcast Adrenal Expert is back in our virtual recording studio today. Cilly Liqueura comes to us from Columbia University in New York City where she co directs their Adrenal center, serves as their Clinical Chief of Endocrinology, and advises as an Associate Dean in their medical school. June Yang from Monash Health in Melbourne, Australia joins us today as our guest expert. She is an internationally recognized expert in primary aldosteronism and you all, as our listeners, will be quite familiar with her work from her many papers and talks on that subject. So as you can tell, the perfect pair of adrenal experts joins me today to discuss this paper. As usual, everything we discuss will be our opinions only and not those of our respective institutions or the Endocrine Society. For this episode of Endocrine Feedback Loop, we look at Mineralocorticoid Receptor antagonist pre Adrenalectomy in Primary Aldosteronism, which was published in April 2026 in the journal of Clinical Endocrinology and Metabolism. Jessica Goy from the Hospital Universitario Instituto di Investigacion Biomedica Ramon y Cajal served as the first author for this manuscript and was joined by colleagues from numerous institutions throughout Spain. I will now turn the discussion over to Salila. She will walk us through the main points that the authors make in their introduction and get June's insight on several key concepts along the way.
- [02:41]
B
Salila Great. Thank you for having me here, Chase, and it's nice to work with you in June. So, just to get started, as we know, primary aldosteronism is the most prevalent endocrine cause of secondary hypertension, with a reported prevalence of up to 12% among hypertensive patients seen in primary care and 20% of individuals with resistant hypertension. It's characterized by Renin independent aldosterone hypersecretion and diagnosis is important because patients with untreated primary aldosteronism have a significantly higher incidence of afib, mi, lvh, stroke and renal damage compared with those with essential hypertension. June, we wanted to get your thoughts on the biggest current challenges in the diagnosis and management of primary aldosteronism.
- [03:27]
C
Hi Salila and Chase. So at the moment the biggest challenges in diagnosis is perhaps still doctors not screening enough. Many still think of primary aldosteronism as a very rare cause of hypertension, with screening rates of only 1 to 2%, even in those with very high likelihood of having primary aldosteronism, such as those with resistant hypertension or hypertension and hypokalemia. And I guess the main challenge in management is that there are many bottlenecks in the full diagnostic pathway, such as adrenal vein sampling, to try and differentiate people with unilateral from bilateral disease. Unilateral disease is potentially curable by surgery, so adrenal vein sampling is quite important, but only offered by limited centres even in high resource settings. And I guess for the patients who require medical treatment, options are rather limited at the moment, with spironolactone being the most widely available and most affordable, but it also has the most potential to cause adverse effects. So there's definitely greater need to improve detection and management of primary aldosteroneism. Great.
- [04:32]
B
And that's super helpful to put into the context that you know. Depending on whether aldosterone overproduction is driven by only one or both adrenal glands, primary aldosteronism is subclassified as either the unilateral or bilateral in its form. So bilateral disease is treated with the minivalocorticoid receptor antagonist or an mra, while the treatment of choice for unilateral forms of hyperaldosteronism is adrenalectomy. Unilateral adrenalectomy offers a definitive cure for unilateral primary aldosteronism. In the majority of cases and has also been shown to be effective in reducing target organ damage and the incidence of cardiovascular events, so proof of lateralization is generally recommended before proceeding with operative management. Adrenal vein sampling AVS represents the most reliable diagnostic procedure to detect lateralizing aldosterone hypersecretion and is a valuable tool for guiding surgical intervention. In this study, the authors note that it's technically demanding and not widely available in their area. Therefore, in some cases the decision to refer a patient for surgery relies on the identification of a unilateral adrenal tumor on cross sectional imaging, so CT or mri. And since cross sectional imaging does not provide functional information, this may lead to incorrect classification of disease subtype, potentially resulting in a missed opportunity for definitive surgical cure or adrenalectomy performed on the wrong side. On the other hand, the authors note that with the advent of partial unilateral or partial bilateral adrenalectomy for primary aldosteronism and postoperative subtype evaluation using CYP11B2 staining, the role of AVS has become less critical in guiding surgical treatment decisions. And I'm curious to hear June's thoughts on this statement by the authors about the role of avs in the CYP11B2 staining in the post surgical setting.
- [06:26]
C
So I agree with the authors that adrenal van sampling is not widely available and is often a limiting factor, but I respectfully cannot fully support the comment that adrenal van sampling will be less critical in guiding surgical decisions. And with respect to bilateral adrenalectomy, that's almost never performed for people with primary aldosteronism because the consequences of losing both adrenal glands and the subsequent adrenal insufficiency is really harder to deal with than just offering medical treatment for primary aldosteronism other than in the most severe situations. Partial unilateral adrenalectomy is also not commonly performed because aldosterone production may come from multiple small nodules within the adrenal gland rather than just a dominant adenoma that's visible on Adrenal CT. Now, CYP11B2 or Aldosterone Synthase staining certainly helps us determine if the adenoma removed at surgery is indeed the source of aldosterone production. But if the tissue removed does not express CYP11B2, well, we can't really reverse the surgery. Adrenal vein sampling is still the current gold standard for subtyping and ensuring that aldosterone production is indeed lateralised. However, in the near future functional imaging using a variety of radio traces taken up by aldosterone producing tissue may diminish the role of adrenal Van sapling Thank
- [07:53]
B
you June and the 2016 Endocrine Society guideline on primary aldosteronism clinical practice proposes the use of MRAs to achieve optimal blood pressure control and hypokalemia correction before undergoing adrenalectomy. However, there is no specific indications are provided about the optimal dosing period of preoperative MRA therapy, and only a few studies with small sample sizes have investigated the relationship between preoperative treatment with MRA and post surgical outcomes among patients with primary aldosteronism thus far. So to address this evidence gap in the preoperative management of primary aldosteronism, the main aim of this study was to compare the incidence of complications and post surgical outcomes among primary aldosterone patients who received pre op treatment with MRA and those who did not, both in the immediate postoperative period and at short term follow up after adrenalectomy.
- [08:49]
A
After that very nice setup, we'll move into the methods to understand how the authors try to answer that question. As we'll see shortly, the authors use a retrospective cohort design as a reminder. We've looked at many many of these over the years, so I'll be brief. A cohort study, either in its retrospective or prospective forms, is designed by putting people subjects into at least two different groups and that is based on an exposure. In its simplest form, as we'll see here, you have a group that is exposed to something and a group that's not exposed unexposed to something and then you follow those individuals over time. That's what makes it a cohort study. In a prospective cohort study you're following these individuals in real time. So you've started the investigation at enrollment and then you're following with them waiting for the outcome outcome or outcomes of interest to develop. In a retrospective study, which is what the authors do here you are starting your study after all this data has happened. So this is not happening in real time. None of the data collection is an ongoing, it's a one time event. You do have to be able to reconstruct the time sequence or else you can't do a cohort study. It would have to be a cross sectional study. But you're looking back to a database or chart review different ways that you could do this. So that's what the authors do here specifically for this study. It comes out of the spinal registry and the way this registry works and where the data comes from is that it is looking at primary aldosteronism that was diagnosed and or followed at the dates between January of 2018 up through December of 2024. And this is a huge registry, and the patients who contribute to it comes from 37 different tertiary centers in Spain. In this study, they first of all, while looking at this database, they looked at all patients who had been diagnosed with primary aldosteronism. So that got them nearly 1,000 patients. They narrowed it then because they wanted to specifically look at those individuals who had undergone an adrenalectomy and had data on MRA treatment, whether they were on it or not. So that narrowed it down quite a bit, but still had 355 patients. As they looked through these individuals, they were reporting the diagnostic criteria that were used. And in a second, I'm going to get June's input on this, but really briefly at a high level. The authors point out that the cutoff for the aldosterone to renin ratio varied by center, so they didn't report specific numbers for that. They stated that suppression testing was performed if a patient did not meet criteria for overt primary aldosteronism. And then finally, that the subtyping that Salila told us about already that was performed with imaging and or adrenal vein sampling. Okay, June, thoughts on that? We've got several different things here. Help us understand is fairly consistent with what's done in other parts of the world, or there's some variety here. Help us put that in context of different forms of practice.
- [11:36]
C
Yes, there is certainly a bit of variability in how primary aldosteroneism is detected and diagnosed around the world. And the cutoff for the aldosterone renin ratio can vary by center. The centers that have the lower aldosterone renin threshold, I guess, will allow more people to. To then undergo the testing pathway, undergo further aldosterone suppression testing. And the ones who have a very high threshold may, I guess, inadvertently leave out some people who may have primary aldosteronism. In this study, their criteria for diagnosing overt pa, where patients did not have to undergo any suppression testing, that's fairly standard. So that consists of very high aldosterone suppressed renin or plasma renin activity and low potassium. The nature of suppression testing, however, was not reported, so it is a little bit difficult to tell what types of patients were then allowed to undergo adrenal band sampling because there are quite a few different suppression tests to choose from. With regards to subtyping, only half the patients had adrenal band sampling, while the other half had surgery based on adrenal imaging alone. The likelihood of an aldosterone producing adenoma can be very high if the patient has biochemically overt PA together with a unilateral adrenal adenoma on ct. But in the absence of overt biochemical features, we really can't rely on imaging alone to diagnose unilateral pa. So it's clear whether some of the patients who underwent surgery actually had an aldosterone producing adenoma. And furthermore, the cutoff for lateralization on adrenaline sampling was also variable between centers reported to be between 2 to 4. So typically we would require the lateralization index, which is calculated as the aldosterone to cortisol ratio in one adrenal vein compared to the other adrenal vein, to be at least four for aldosterone production to be considered lateralized and for us to consider proceeding to surgery. But here the lateralization index threshold was 2 to 4, so it's again possible that some people with the lower lateralization index may not have had genuinely sort of unilateral disease. Also, the use of ACTH can impact on the lateralization index, and here couldn't find information on whether adrenal vein sampling was done with or or without ACTH stimulation. And that will be quite important to clarify.
- [14:14]
A
The authors then go on to list different comorbidities that were tracked and accounted for in the statistical methods, and they use fairly standard definitions, so we won't go into depth in that here. As far as the management goes, June alluded to it already, but the decision on whether to proceed with a unilateral adrenalectomy was based on the AVS or imaging results, and 77% of the individuals were treated preoperatively with either spironolactone or a pleurinone. This gets us back to an important consideration in cohort studies is that whether you ended up in one group or another, whether you were exposed or unexposed, that is not a random allocation. An RCT does that, but a cohort study, an observational study, does not do that. So you have to ask the question. The majority of individuals were treated preoperatively, so why did a clinician choose to treat those individuals as opposed to the minority of individuals who were not treated? That already begins to hint that there might be something different. We don't know that for sure. It's always a question in these studies, but we do have to at least ask that, and we're going to Come back to that question several times as we proceed back to the details of the management here. Among other parameters, the authors tracked and reported post operative hypoaldosteronism and the related need for fludrocortisone. So, June, help us with this. Just make sure we all understand how is that assessment made? Why does that make sense? What's important to know about that?
- [15:42]
C
So it's an important endpoint to look at because a patient with a unilateral aldosterone producing adenoma would typically have suppressed aldosterone production from the contralateral gland. And that's in fact what's observed on drain or vein sampling. In a patient with unilateral pain, it may be reported as lateralization to one side with contralateral suppression. And so if this hyper functioning adenoma is surgically resected, then the contralateral gland will not be able to regain function straight away and therefore the patient may develop hypoaldosteronism and require flu cortisone supplementation until the remaining adrenal gland wakes up, presumably following increased renin angiotensin II production in the setting of low aldosterone concentration. And so the authors here are looking for that particular endpoint and seeing if using preoperative Mr. Antagonist can reduce that endpoint.
- [16:43]
A
Speaking of endpoints, we'll get to the outcomes. And the authors, borrowing from standard descriptions from other reports, split outcomes into two different types of outcomes. They have clinical outcomes and biochemical outcomes. And each of these has three different varieties. So we'll start with clinical outcomes. And you've got three different categories that you could put somebody in. You could be somebody who's considered to have had a complete success. You could have been considered to have a partial responder or an absent responder. So we'll go into the details. It's a bit in the weeds, so I'll go through them quickly and then we'll consider them again as we go along. But for a clinical complete success, that would be normal tension without any blood pressure medications. To be a partial responder, you had an unchanged blood pressure with fewer blood pressure medications or a lower blood pressure with same or fewer blood pressure medications. If you were an absent responder, that meant that you did not have a change in your blood pressure and you also did not have a decrease in your blood pressure medication. So those are the clinical categories. Complete success, partial responder, absent responder. The other option for the outcomes are the biochemical responses. Again, that has three varieties. So you could be considered to have been cured, have a partial cure or an absent cure. So if you were cured, that meant that you had a normal potassium off of supplementation with a normal aldosterone to renin ratio. The partial cure also included a normal potassium off of supplementation, but that included a raised aldosterone to renin ratio with a greater than 50% reduction in the aldosterone. The last one is an absent cure and so that is persistent hypokalemia and or a raised aldosterone to renin ratio. So again, three for biochemical cure, partial cure and absent cure. One last note in Outcomes, the authors mention that 45 patients had to be excluded due to needing a mineralocorticoid receptor antagonist due to suboptimal post surgical responses. So June, thoughts on this as to what the authors might have been referring to here.
- [18:50]
C
So I presume this means that the patients had persistent hypertension and persistent hyperaldosteronism. Biochemical response is quite important in the assessment of surgical response after removing an aldosterone producing adenoma because the biochemical cure is what you're looking for. That removal of aldosterone excess clinical response, however, may depend on factors other than just aldosterone excess. So in this case, the fact that patients needed Mr. Antagonist straight away makes me think that it's the biochemical response that is missing. I note that another 38 patients later reported in the results also had absent biochemical success based on the criteria that Chase described earlier. So altogether about 83 patients did not have a good response to surgery, did not have a good biochemical response to surgery. This is not too surprising given that only half of the patients had adrenal vein sampling before surgery. And so and the lateralization criteria used in AVS was quite lenient. So some people with bilateral PA may have undergone adrenalectomy and therefore leading to that absent biochemical success post surgery.
- [20:08]
A
Before I turn it over to Salilah, just as a quick reminder, so we've got two groups are exposed and are unexposed, and that's based on exposure to a mineralocorticoid receptor antagonist. And then we have our outcomes, two different categories, the clinical outcomes and the biochemical. So Leela is now going to go through the results and a lot of data, but we'll keep that in mind as we hear about those.
- [20:28]
B
Great. Thank you, Chase. So I'll try to summarize the discussion for the results. So there are A total of 355 surgically treated patients that were included, of which 162, or about 45% were female AVs was performed in about half so 175 patients, with 119 patients having unilateral disease, which is about a third of the cohort. All the remaining individuals underwent surgery based on CT and our MRI findings, so cross sectional imaging. This revealed one or more adrenal nodules in about 93% of cases and the median size of this nodule was about 17 millimeters or 1.7 centimeters at the time of hyperaldosterone diagnosis. The mean age of this group was 52 years and most of the population, about 70%, had either grade 2 or grade 3 hypertension. The median number of antihypertensive medications was three and about a third of patients had resistant hypertension. Hypokalemia, as we previously discussed, occurred in a large portion of the cohort, so 77% of them and concomitant Max was detected in 42 of the 101 patients who had available 1mg deck suppression testing data. Of the 82 patients who did not receive any MRA treatment prior to surgery, the sex distribution was comparable and the median number of antihypertensive medications in use at the time of diagnosis of hyperaldosteronism was 3 in both the pretreated and the non pretreated groups, despite similar mean age, the pretreated patients displayed longer duration of hypertension with a median of 9 years versus 6 years with a P value of 0.041 and a higher lifetime incidence of hypokalemia. Pretreated group it was 80.2% versus 65.9% in the non pretreated group, again with a statistically significant P value and also they had a greater plasma aldosterone concentration. I'd like to have June's thoughts on what this means and how to think about this.
- [22:31]
C
I think the difference between the group that was pretreated versus those who were not possibly reflects the clinical severity of disease. And as Chase referred to earlier, this is not randomised, so clinicians would be more likely to prescribe if there was an indication to do so. And the patients who have hypokalemia or higher aldosterone concentration tend to have the more severe clinical phenotype and so more likely to receive an Mr. Antagonist. Given that this is a retrospective study, such selection bias is rather expected Whenever
- [23:06]
A
you're looking at these, one of the things I always think it's helpful is ideally you would prefer that the groups be different only based on this exposure. One group was exposed, one group's not exposed, but because it is an observational study, that's never going to be the case. And so what you have to do is first of all have to see, well, how else are they different? And then could it be those other differences that could be driving the outcomes that we're seeing here? And so I think, just like June said, this was very clearly indicating, at least this is how I would interpret it, that one group has a more severe form of primary aldosteronism than the other group does. And then we've got to try to connect that to could that be driving the outcomes that we see. So we'll come back to that in the discussion. But that was the takeaway that I saw when I first saw the data.
- [23:48]
B
Yeah, and that was my impression as well. And I think moving forward to discuss some of the other results. In the immediate pre surgical evaluation, people receiving MRA displayed higher mean potassium concentration than those who were not on mra, which coincides with what we've just been discussing about selection bias. And no other significant differences were detected and the prevalence of max overlapping with PA was comparable between the two groups. AVS and imaging results were comparable again between the pretreated and non pretreated patients and surgical eligibility was guided by lateralization at AVS in about a third of the pretreated group and a third of the non pretreated group. But there were 272 patients in the pretreated group and 81 patients in the non pretreated group. So moving on to discuss the postoperative data recorded within 30 days after surgery. There were 110 patients available to be evaluated in this group, 88 from the pretreated group and 22 from the non pretreated group. After a median period of 11 days for the pretreated group and 16 days for the non pretreated group following surgery, there were no significant differences observed in clinical or biochemical profiles. When the post surgical observation period was extended to a maximum of 90 days, 187 patients in the pretreated group and 53 in the non pretreated group were included in this analysis and that accounts for basically around 65% of both groups. So follow up six months or more after surgery of the overall cohort. So there were 37 pretreated and 8 non pretreated patients that required the addition of MRA therapy after adrenalectomy due to suboptimal surgical outcomes and 96 participants had a follow up shorter than six months that couldn't be evaluated. And following the exclusion of these cases, 214 patients were analyzed for follow up clinical and biochemical data and post surgical primary aldosterone surgical outcomes which Chase discussed how both the biochemical and clinical criteria that are used to assess the success of the surgical intervention. This subpopulation was composed of 162 people who received MRA therapy prior to surgery and 52 cases who were not pretreated with MRA and the baseline characteristics mirrored those observed in the initial cohorts with about a 55% male sex in both groups. The patients in the initial cohort with pretreated patients were significantly younger with a mean age of 52 versus 55 years and exhibited lower potassium levels after a mean follow up duration of 45 months for operated patients who did not receive any MRA in this pre surgical period and 36 months for those pretreated with MRA. Pretreated patients showed a lower prevalence of lvh at follow up 42.3% versus 71.4% with a significant P value and significantly better biochemical outcomes. Specifically, about 80% of pretreated patients achieved complete biochemical success compared to 57.1% of non pretreated patients, again with a significant P value. This observation led the researchers to further conduct univariable multivariable logistical regression analyses including baseline parameters that differed significantly after stratification for pre surgical treatment with MRA along with variables selected a priority to identify factors associated with complete biochemical outcome at follow up of greater than or equal to six months in operative patients not requiring post operative MRA therapy. In comparison between complete biochemical response and combined partial and absent outcomes. The use of MRA prior to adrenalectomy was the only variable independently associated with successful biochemical cure even after adjustment for age. The histopathological diagnoses of the surgically removed adrenal glands were comparable between patients pretreated with MRA and those non pretreated being predominantly classical. When stratified using the biochemical outcome criteria that Chase delineated previously, classical histopathology was more frequent in patients with complete or partial biochemical success than in those with absent response. Among patients preoperatively treated with mra, people with absent biochemical outcome were more frequently exhibited non classical histopathology compared to those achieving complete biochemical response. Interestingly, there was no significant difference in clinical parameters or outcomes that were observed between patients pretreated with MRA and those non pretreated and in comparison between patients with and without concomitant max at baseline. No significant differences were observed in clinical or biochemical outcomes at long term follow up.
- [28:37]
A
Now we're going to move into the discussion and Salita's gone through a lot of data. We are going to pick just some of the main ones that the authors highlight and that they spend a lot of time in their discussion on. That's where we're going to focus the discussion of the author's discussion. So I'll start with a couple of quotes. I'll first of all quote the authors as they summarize their work where they say the preoperative use of mineralocorticoid receptor antagonist in patients awaiting unilateral adrenalectomy for the treatment of unilateral primary aldosteronism did not increase the risk of hyperkalemia, renal function deterioration or an excessive decrease in blood pressure in the first weeks after surgery. The authors then go on to make another statement which I'll quote them where they say pre treatment with mineralocorticoid receptor antagonists was associated with a higher rate of definitive biochemical cure at follow up greater than six months. They then go on to reiterate what Salilos told us already, which is that there were no other differences found between these two groups. June, I want to get your input here again because I'm really interested on this finding. We're going to go back to what we talked about before. Is that the decision to treat a patient with a mineralocorticoid receptor antagonist, that was not random. So there was some reason the clinician was choosing to treat a patient. That's one point that I'd like to make. And then the other one is that these differences didn't show up until after six months from the surgery. So could you give us some insight considering those two things, that non random selection for who gets treated and then also that the differences are showing up greater than six months after surgery?
- [30:15]
C
Yes. So that's a good question because the choice of Mr. Antagonist was not random. Patients with more florid hyperaldosteronism are much more likely to be pre treated in order to manage their hypertension and hypokalemia without pre treating with an Mr. Antagonist. Some of these patients with unilateral disease may require 10 to 20 potassium supplements a day and they're not small tablets while waiting for surgery. So it's a great benefit for the patients if they are pretreated in those with quite severe disease. At our endocrine hypertension service, we typically treat patients with Mr. Antagonist to fully unsuppress their renin before surgery because it serves as a physiological indicator that the aldosterone excess is adequately blocked such that the kidney can start making renin again. This should then enable activation of the renin angiotensin system and allow production of aldosterone from the contralateral gland. In my mind, it's not just the pre treatment that's important, it's also the dose of the MRI antagonist and whether renin is unsuppressed that will determine whether the patient has adequate aldosterone production following adrenalectomy. And so in this particular study I note that in the table 2 plasma renin activity is much the same between the Mr. Antagonist pretreated or non pretreated group. And similarly the renin concentration was also not significantly different. So these suggest that the Mr. Antagonist dose used for pre treatment was perhaps not sufficient to rescue the patient from post operative hypoaldosteronism, which may explain why the occurrence of hypoaldosteronism was much the same between the pretreated and the non treated groups in that immediate post operative period. Furthermore, the dose of spironolactone used, I note, was about 50 milligrams per day, which isn't really enough for people with unilateral pa. In my experience and reported by others, those with unilateral PA generally require a much higher dose of spironolactone to fully treat the condition. Unlike for bilateral PA where 50mg per day may be sufficient, the median dose was also only 50mg per day for pleurino, which is a drug that's only half as potent as spironolactone. So that's even less sufficient for adequate sort of aldosterone blockade. Now as for the higher chance of a biochemical cure, that is probably because the MRA treated group has more severe disease and so higher likelihood of having unilateral disease in the first place. Given that half the cohort did not have adrenal van sampling before proceeding to surgery, there is a pretty high risk of performing adrenalactolemy in people with bilateral adrenal disease. And this risk of operating in bilateral disease is much lower in the group that was MRA pretreated because they had more severe disease to start with. And so I think that's why there was no difference in the early post operative period. But the difference in biochemical cure at beyond six months.
- [33:30]
A
And June's done a really nice job of illustrating how a selection bias would work. And even if you can't quantify it or Identify exact data that connects it. The clinician choosing to do something always tells us important information. And it is possible that if indeed a selection bias is what's driving the outcomes here is that what we have learned is that the clinician deciding that somebody has more severe disease and so needs to be started on a mineralocorticoid receptor antagonist is that perhaps that's what's driving the outcome here. Always hard to know, but certainly something that we need to keep in mind whenever we're looking at observational studies. There's a few different ways to try to understand how valid they are. And one of the criteria that's been around for many, many decades is the Hill criteria. The Hill criteria, there's quite a few of them, ways to assess them. But it's important that you consider the biological plausib of any findings that you see. And for that reason it is quite traditional for authors in their discussion to try to explain whenever they have an observation, when they've made a finding to try to explain why that would make sense based on an underlying mechanism. It's often speculative and the authors do exactly that. They speculate on a possible mechanism and they suggest that it's possible that long term blockade of the mineralocorticoid receptor could be driving some of the differences that we see here, even well after the mineralocorticoid receptor antagonist has been withdrawn. So June, I saw that it didn't totally make sense to me, but I'm not an adrenal expert and you are. So thoughts on that as far as a potential mechanism that could explain the differences that the authors are finding here?
- [35:07]
C
I think the mechanism for the difference is probably more likely to be due to the selection bias in the first place that the MRA treated group more likely to have a severe and unilateral disease and therefore they appear to have a higher chance of biochemical cure. I'm not sure about this mechanism that long term blockade of the minocorticoid receptor can lead to a biochemical cure, particularly because these people are Pre treated with Mr. Antagonist, presumably for a relatively short period of time while waiting for surgery. Although I couldn't find the exact duration of Mr. Antagonist use in this study. And in my experience, even people who have been taking Mr. Antagonist for many years will still have recurring primary aldosteronism if they stop treatment. I mean, we don't do that very often in practice, but in recent months there are, you know, newer treatment options available for primary aldosteronism that's in clinical trials. So I'VE actually had to wash out a few patients from their Mr. Antagonists in preparation for a trial and their previous disease definitely comes back. I think the mechanism is more likely to be related to that selection bias mentioned earlier.
- [36:22]
A
The authors then go on to point out that with long term follow up the overall biochemical cure was 76% and they suggest that that might be related to the infrequent use of adrenal vein sampling. Then the authors describe some limitations, several of which we've covered already, but I'll list all the ones that they point out. They first of all mentioned that there were varied treatment strategies between the centers. The second point that they make is that there were some missing details around blood pressure renin and MRA data. Immediately pre op they point out that they did not have any information on medication compliance. And then finally they point out a selection bias. We've talked about that several times already and they readily acknowledge that that could easily be a major part of what's going on here. The authors then conclude their work and they first of all give a summary where they say preoperative treatment with mineralocorticoid receptor antagonists is useful and safe in patients with primary aldosteronism awaiting adrenalectomy. They then mention as an area of possible further study of further investigation is needed to define the optimal dosing period and to identify predictors of definitive surgical cure in patients with unilateral primary aldosterone. So where I'd like us to end is where we typically do is trying to consider whether this should change our practice. Before we get to that specific point, I do want us to think about the quality of this report overall. So, Salila, let's start with you. What are your thoughts about the quality of this report?
- [37:49]
B
So I think that, you know, it was a large study and as many of us that work at adrenal centers can attest to, it's hard to get a big denominator of patients to evaluate. And so I think the fact that there were so many patients involved does give us good information to think about. And like many observational studies, it may lead to more questions than actually a change in practice. So it is interesting to see and maybe reiterates what we already thought is that patients who have unilateral disease benefit greatly from adrenalectomy. The other thing that I found interesting is that I think to me, this does support the use of AVs because it may explain some of the results in terms of why the pretreated group may have done Better is because they had more severe disease and unilateral disease. And it would be good to sort that out with adrenal vein sampling so that even in the non pretreated if there were patients who had unilateral disease, they likely would have benefited from adrenalectomy in that setting as well. So I think this was an interesting study that has some good observational data, but maybe more studies are more evaluation is needed prior to changing practice based on it.
- [38:58]
A
Yes, Alila had a similar thought about AVs, particularly with the author's last comment about the need to identify predictors of definitive surgical cure in patients with unilateral disease. And I thought, well I think probably AVS would would fit the bill for that as long as it's we're in a setting where that can be used consistently. All right, June, thoughts from you just on the quality of this report overall.
- [39:18]
C
Yeah, I really applaud the authors for collecting so much data and focusing on important clinical topic because there is so much variation in the perioperative management of patients with primary aldosteronism. They recognize the main limitation which is the absence of unrandomised nature, but that can't be helped. But the absence of information on renin blood pressure and potassium immediately before surgery because that would have been really useful to determine if the Mr. Antagonist given pre treatment actually achieved its main purpose of unsuppressing renin and waking up the contralateral gland. Furthermore, knowing the blood pressure and potassium immediately pre op would also help the authors determine if having treatment was really helpful from the patient's perspective. Were the patients more stable with better blood pressure and less inconvenienced by the high burden of potassium requirement. Another limitation, or perhaps area that could have been discussed a bit more is the inclusion of histopathology data and the histaldo classification. It took me a while to figure out why the authors may have wanted to include that information because I couldn't get it very clearly from the introduction or the discussion. Perhaps they were looking at the impact of Mr. Antagonists pre treatment aldosterone synthase expression. Perhaps there would have been a difference in aldosterone synthase expression in those who are pretreated versus no pretreated. Perhaps those with, you know, a healthy contralateral gland that should have been suppressed and therefore not expressing aldosterone synthase. Maybe that's woken up by the Mr. Antagonist pre treatment and that shows up in the surgical specimen. But this wasn't very clearly clarified in the sort of aims or the introduction. So would I be interesting to know more about that?
- [41:21]
A
Now we'll end where we usually do with actually thinking about changing our practice. Salila, let's start with you. For your practice with your patients or for endocrinologists at large. Do you see this report changing anything that we do?
- [41:35]
B
Yeah, I think one of the main take homes for me is that it sometimes confusion about whether it's okay to keep a patient on spironolactone or plurinone before they have surgery. And I think that this shows that it's, you know, with even with having AVS or proceeding with surgical intervention that staying on spironolactone and a perinone during the surgery and is safe both in the operative and the post operative setting. And so I think that that's an important thing to consider. So I found that to be useful and I think it's also helpful to see how AVS is managed in different settings and when different resources are available and to consider how to manage patients if they're not able to have AVs.
- [42:20]
A
June, let's end with you. Same question. Should we change our practice based on these results?
- [42:25]
C
Well, I think the study reassures us that it's quite Safe to prescribe Mr. Antagonists before surgery for patients with unilateral primary aldosteronism. It may not quite convince the reader that Mr. Antagonist use will reduce the rate of post operative hypoaldosteronism or fluorocortisone requirement, but that's due to the limitations mentioned earlier. So for sure I think we need another study that has more biochemical and clinical data that's immediately pre surgery available to help inform guidelines on Mr. Antagonist use pre surgery.
- [43:00]
A
And with that I would like to thank Salila Kira and June Yang for joining me for this month's edition of Endocrine Feedback Loop. I learned a great deal and know that you all did as well. Please join us again next month. And now you're in the loop. This has been Endocrine Feedback Loop. Endocrine Feedback Loop is brought to you by the Endocrine Society with Production Oversight by Brandy Brown. If you want to like and subscribe, you can find us on Apple, Spotify or wherever you get your podcast. We'd love to hear your feedback on this episode or the podcast itself. Please email us@podcastren.org Endocrine Feedback Loop is a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.