'Brand New' Data on Aldosterone in Hypertension a 'Tough Sell' to PCPs

Mitchel L. Zoler, PhD

October 02, 2020

Dr Jun Yang (right) and her father. Dr Yang

Jun Yang, MBBS, had watched as her father, who had battled hypertension for decades, ended up on four medications that still couldn't bring his blood pressure to a healthy level. The cardiovascular endocrinologist then ran some tests, and soon thereafter her father had his blood pressure optimized on just one targeted medication.

Yang's father was found to have a hormonal condition known as primary aldosteronism (PA) as the cause of his hypertension.

It turns out that PA is not as rare as once thought.

An eye-catching report in Annals of Internal Medicine this spring of an unexpectedly high prevalence of primary aldosteronism among a diverse cross-section of U.S. patients with hypertension has raised issues that could dramatically change the way doctors in America, and elsewhere, assess and manage high blood pressure.

Foremost is the question of whether primary care physicians – the clinicians at the front line for diagnosing and initially treating most patients with hypertension – will absorb and act on this new evidence. For them, aldosteronism doesn't automatically come to mind when they see high numbers on a BP monitor, and yet this latest research found that up to a third of all 726 patients in the study who were diagnosed with hypertension and with high urinary salt levels had PA.

That translates to a roughly three- to fivefold increase over standard prevalence estimates, and is a "game changer" for how clinicians should approach hypertension management and PA diagnosis going forward, said John W. Funder, MD, in an editorial accompanying the Annals study.

Long considered relatively uncommon, hypertension driven by an excess of the hormone aldosterone, often because of an adenoma on the adrenal gland, is not the same as conventional "essential" hypertension. The former benefits from early diagnosis because its treatment is completely different – close to half of all PA patients can be treated definitively and quickly with surgical removal of an adenoma from one side of the adrenal gland.

For other PA patients, who have bilateral adrenal hyperplasia that is impossible to resolve surgically, treatment with drugs called mineralocorticoid receptor antagonists (MRAs), such as spironolactone, is needed because they target the hormonal cause of the high BP.

But what usually happens is that a patient with PA is mistakenly diagnosed with essential hypertension, in which the classic approach to treatment is to start with one regular antihypertensive drug, and add on further ones from different drug classes if blood pressure is not adequately controlled. When patients are taking three drugs, without adequate control, they are labeled as having "resistant hypertension."

But in the case of PA, none of these conventional antihypertensives work, and the process of continuing to monitor and add different drugs wastes time, during which patients deteriorate.

"We need to change the culture of waiting for hypertension to be resistant and have patients riddled with end-organ damage," due to years of persistently high BP and excess aldosterone "before we look for a secondary cause" like PA, declared Yang, of Hudson Institute of Medical Research and Monash University in Melbourne, during an interview.

So early diagnosis and prompt treatment of PA is key.

In addition to boosting the public health importance of early PA detection in hypertensive patients, the new up-sized PA prevalence numbers throw a spotlight on primary care physicians (PCPs) as key players who will need to apply the findings to practice on a public health scale.

These novel results create a need for "new guidelines, and a radically revised game plan with the key role of PCPs" emphasized in future management of patients with hypertension, said Funder, a professor of medicine at Monash University, in a second recent editorial in Hypertension.

Dr Robert Carey

"Buy-in by PCPs is essential," agrees Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville, and a coauthor of the new study.

But he too acknowledges that this presents a major challenge. PCPs and internists, who diagnose a lot of hypertension, are "not used to thinking about aldosterone," he said in an interview, encapsulating the key problem faced by proponents of earlier and more widespread PA assessment.

This dilemma looms as a "huge public health issue," Carey warned.

'We're a Long Way From Getting' PCPs to Buy into PA Screening

Will PCPs grow more comfortable with screening patients for PA themselves, or might they become more willing to refer hypertensive individuals for assessment at an expert center?

One skeptic is Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg. The finding about high PA prevalence in patients with hypertension "is brand new, [and] the message needs to get to PCPs," he said. But, "We're a long way from getting it" to them. "I don't know how to do that. It will be a tough sell."

In addition, repositioning MRAs as an earlier option for many hypertensive patients won't be easy either, because "we'll never have outcome-trial data for MRAs," given that they are now generic drugs, he noted.

"No clinical trial data show [MRAs] are first-line drugs," said Feldman, who explained that, instead, MRAs are considered "go-to drugs" for patients with treatment-resistant hypertension, a niche therapeutic area. Results from the PATHWAY-2 trial published 5 years ago in Lancet showed "spironolactone was clearly the most effective treatment for the condition," according to the report authors.

But even among patients with resistant hypertension, screening for PA dramatically lags despite being enshrined in guidelines.

Dr Jordana B. Cohen

"PCPs should start checking aldosterone-to-renin ratios [a widely used PA screen] in all patients with resistant hypertension or hypertension with hypokalemia, and then refer patients to specialists for testing and management," said Jordana B. Cohen, MD, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia.

But recent studies of U.S. patient populations with clinical characteristics that meet existing criteria for PA screening showed that just 1%-2% of these individuals underwent an initial PA assessment, she noted, citing reports in the journals Surgery and Hypertension.

"We need to prioritize improving screening in these high-risk patients," she stressed in an interview.

This illustrates that, in some respects, the new prevalence numbers are beside the point, because PA has been going unscreened and overlooked far too often even in the context of historical, lower prevalence rates, said Yang.

"The key point is that approximately 1 in 10 people with hypertension, and even more with resistant hypertension, have a form of the disease that is worse than essential hypertension but is routinely missed at present" and is also highly treatable.

"Evidence for the need for increased awareness of PA has been building for 2 decades," stressed Yang, who has coauthored several commentaries and reviews that have bemoaned PA's underappreciated status.

Interest in Partnering With PCPs on Guidance Grows

One potential solution is to have endocrinologists and hypertension specialists' partner with PCPs to come up with diagnostic and management recommendations. Both Funder and Carey are opinion leaders regarding the role of aldosterone in hypertension, and both were coauthors of the 2016 Endocrine Society guideline for PA assessment and management published in the Journal of Clinical Endocrinology & Metabolism, with Funder chairing the writing panel.

Now approaching its fifth year in effect, this guideline is "due for revision," and "my hope is that we'll be able to partner with one or more PCP organizations to come up with a version of the guideline targeted to PCPs," Carey said.

He voiced interest in working on this with the American College of Physicians, which represents U.S. internal medicine physicians, and the American Academy of Family Physicians.

"We definitely need a partnership and educational efforts to get the word out from these organizations and not from a specialty society," said Carey.

Funder said he has submitted a proposal to the Endocrine Society for a guidelines update he would chair with Carey's assistance and with a diverse writing group that includes PCPs. Carey said that ideally this panel would write and release a revised guideline in 2021.

"Several of us are chomping at the bit to get this done," he noted.

But participation by the ACP and AAFP remains uncertain as of September 2020. When approached about this, an ACP spokesperson said the organization had no comment. A spokesperson for the AAFP said, "It's too early to tell if we will partner with any other organizations to develop guidelines specific to excess aldosterone, and how such guidelines might be received by our members."

Recent history shows little cooperation between ACP, AAFP, and what might be termed the U.S. hypertension "establishment." For example, when the American College of Cardiology and the American Heart Association released their most recent essential hypertension management guidelines in Hypertension in 2018, it was never adopted by ACP or AAFP.

The latter two organizations continue to endorse a higher BP threshold for diagnosing hypertension, and higher treatment targets set by alternative expert panels to those of the AHA/ACC.

Collaboration Feasible, Although PCPs Overworked

Carey hopes that this episode will not preclude agreement over PA screening.

"I think it is still possible to partner with [the ACP and AAFP]," he observed, adding that he believes high PA prevalence among hypertensive patients and its consequences when unrecognized is "noncontentious."

But he acknowledges that other, substantial hurdles also exist, notably the "overwhelming workload" that American PCPs already face.

David O'Gurek, MD, a family and community medicine physician at the Lewis Katz School of Medicine of Temple University in Philadelphia, agrees that a revamped approach to PA screening developed cooperatively between PCPs and specialists is an important goal and potentially feasible despite prior disagreements. "There has to be room for collaboration," he said, but also emphasized the need for developing policies based on a systematic evidence review and a focus on patient-centered outcomes.

"We're certainly missing patients with PA, but there needs to be greater clarity and standardization about the most appropriate screening approach and cutoff level" for flagging patients who need specialized assessment, O'Gurek said in an interview.

The current endocrinology literature also shows that experts remain divided on how best to accomplish this.

And some hypertension specialists question whether existing evidence is conclusive enough to warrant revised guidelines.

Cohen, the nephrologist and hypertension researcher, said that, while the recent prevalence report in Annals of Internal Medicine is "intriguing, hypothesis-generating information that suggests we are missing many cases of hyperaldosteronism in routine care," she nevertheless believes that "we need additional data to be able to truly understand the breadth and implications of the findings."

William C. Cushman, MD, a hypertension management specialist at the University of Tennessee Health Science Center in Memphis, agrees.

Changing existing practice guidelines "really need randomized, controlled trials demonstrating a difference in long-term outcomes, ideally major cardiovascular outcomes," that result from broader PA screening, he said.

Carey concurs that more evidence is needed to confirm the Annals report, but is confident this evidence will be in hand by the time a guideline-revision panel meets in 2021.

Australian Model of PCPs Screening for PA Could Be Implemented in US

An example of what might be possible when PCPs, endocrinologists, and hypertension specialists work together to make PA screening more accessible can be found in Melbourne, at the Endocrine Hypertension Service of Monash Health, in association with the Hudson Institute of Medical Research.

Dr William Cushman

This began operating in July 2016, cofounded by Yang, whose experiences with her own father made her sensitive to the issue.

The service's aim is to "address the underdiagnosis of PA, and to offer a streamlined diagnostic service for patients with hypertension," with an "extensive outreach program" targeted to regional PCPs that, among other messages, encourages them to screen patients for PA when blood pressures exceed 140/90 mm Hg.

During its first 3 years of operation, the service saw 267 patients, with PA diagnosed in 135 and ruled out in 73 patients.

Notably, the proportion of these patients referred from PCPs jumped from 21% of 70 patients during the first year of operation to 47% of 70 patients during year 2, and 52% of 127 patients during the third year, ending in July 2019, said Yang, who continues to help run the service.

During the first year, a scant 3% of referred patients had recently diagnosed hypertension, but this rose to 14% during the second year, and to 19% during the most recent year with data available.

The median duration of diagnosed hypertension among referred patients fell from 11 years during year 1, to 7 years during year 3.

Service clinicians diagnosed 37 patients with unilateral adenomas, and removed them from 23 patients with four more awaiting surgery and the remaining 10 opting instead for medical management. Another 95 patients went on therapy with an MRA, and during the most recent year studied all patients who began an MRA regimen had a partial or complete clinical response.

Carey said the "creative program represents a model for implementation in U.S. practice.

Funder, Carey, Feldman, Yang, Cohen, and O'Gurek had no relevant disclosures. Cushman has been a consultant to Novartis, received personal fees from Sanofi, and research funding from Eli Lilly.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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