As every internist knows, getting patients' blood pressure under control often takes trial and error. Of the 108 million U.S. adults with hypertension, 45% of the adult population, many will develop apparent treatment-resistant hypertension, some as a result of primary aldosteronism.
Resistant hypertension is defined as above-goal elevated blood pressure despite the use of three or more classes of antihypertensive medication, commonly including a long-acting calcium-channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic, according to a 2018 American Heart Association (AHA) scientific statement. Patients with resistant hypertension also include those taking four or more classes of antihypertensives, irrespective of blood pressure level.
With this definition, the prevalence of apparent treatment-resistant hypertension in the U.S. is 19.7%, according to a study published in the February 2019 Hypertension. Despite receiving ongoing antihypertensive drug therapy, these individuals are at increased risk for target organ damage, morbidity, and mortality, the AHA statement said.
When it comes to potential causes, studies show that internists may be missing an important endocrine-related diagnosis. More than 20% of patients with resistant hypertension have primary aldosteronism, an underrecognized cause of hypertension and cardiovascular disease that occurs when the adrenal glands produce too much aldosterone, said Jordana B. Cohen, MD, MSCE, an assistant professor of medicine and epidemiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
Given this relatively high prevalence in patients with resistant hypertension, they should all be screened for primary aldosteronism, the AHA statement said. Similarly, a 2015 clinical practice guideline from the Endocrine Society recommends screening for primary aldosteronism in a broad population, including patients with resistant hypertension and those with hypertension and spontaneous or diuretic-induced hypokalemia, using the plasma aldosterone-to-renin ratio.
But most people with resistant hypertension or hypokalemia are never screened. Data from small, local health systems have suggested extremely low rates of primary aldosteronism testing (less than 3%) in patients with resistant hypertension, even though identifying and appropriately managing the condition has been linked to substantially lowering the risk of ischemic heart disease, atrial fibrillation, and end-stage kidney disease, said Dr. Cohen.
That's why she and her research colleagues said they were “disappointed but not surprised” to find an even lower rate of primary aldosteronism testing among U.S. veterans with resistant hypertension: 1.6%. Rates of testing were higher among patients seen by subspecialists who care for patients already diagnosed with primary aldosteronism (endocrinologists and nephrologists) compared with those seen by primary care clinicians or cardiologists, according to results published in the March 2021 Annals of Internal Medicine.
“We suspect that many of the providers who are not testing for primary aldosteronism may not be doing so because they are less familiar with the benefits of testing for primary aldosteronism in these patients, how to perform screening, how to interpret the results, and whether patients should be referred for confirmatory testing and further evaluation by a subspecialist,” she said.
From research to practice
One explanation for the underdiagnosis of primary aldosteronism is that new insights in the research world have not yet translated to clinical practice, said Anand Vaidya, MD, MMSc, who directs the Center for Adrenal Disorders at Brigham and Women's Hospital in Boston.
Primary aldosteronism (also known as Conn's syndrome) was first discovered in the 1950s by Jerome Conn, MD. It was first described in a patient with severe hypertension and hypokalemia and an aldosterone-secreting adenoma. This first case then guided the medical community's approach to the disease, which has been largely unchanged since the 1960s, Dr. Vaidya said.
“Like most diseases, the first description of something is usually the most severe, intense version … and the way it is currently taught in medical schools is the same way—almost undeterred—from that time,” he said.
However, research has demonstrated that primary aldosteronism is not simply a rare, severe disease. In fact, it manifests across a broad severity spectrum not unlike that of diseases internists routinely treat, such as hypercholesterolemia, said Dr. Vaidya, who is also an associate professor of medicine at Harvard Medical School in Boston.
“Instead of looking at it as a continuum, people defined different parts of the continuum as separate diseases, so it distracted the field away from recognizing the full spectrum,” he said. “It took several decades for us to circle back.”
But it's still taking time for medical education to catch up, said Richard Auchus, MD, PhD, a professor of internal medicine and pharmacology at the University of Michigan and section chief for endocrinology and metabolism at the Lieutenant Colonel Charles S. Kettles Department of Veterans Affairs Medical Center, both in Ann Arbor.
He said he's asked many medicine residents how many patients they've seen with primary aldosteronism, and they all say zero. “I say, ‘Well, how many of you have four patients with resistant hypertension?’ and they all raise their hands,” he said. “And I say, ‘Well, you have at least one patient with primary aldosteronism; you just haven't diagnosed it yet.’ … Just like anything else, if you don't think about it, if you don't screen for it, you won't find it.”
One physician who said a colleague “converted” him to the new understanding of primary aldosteronism about 10 to 15 years ago is Robert M. Centor, MD, MACP, past chair of the ACP Board of Regents, who has hosted three primary aldosteronism episodes on the podcast series “Annals On Call,” including a March 2021 interview with Dr. Cohen. He said there are three main problems with the old approach to the disease.
“No. 1, we were taught that it was unusual. No. 2, whether we were explicitly taught or implicitly, the thought was that it always causes hypokalemia, and it turns out that it doesn't always cause hypokalemia,” said Dr. Centor, who is also professor emeritus of general internal medicine at the University of Alabama at Birmingham. “And we didn't really have good tests for it for a long time, and the tests were complicated. The tests are better now.”
The higher the aldosterone-to-renin ratio, the more obvious the case. “If the renin is low, the aldosterone should be zero. But most of the time, it's not, and it can be anywhere from a little bit to a lot,” said Dr. Auchus. “And there's some arbitrary point where we cut it off and say, ‘Yeah, this is primary aldo,’ but aldosterone production below this value also contributes to hypertension.”
While the Endocrine Society guideline recommends using the plasma aldosterone-to-renin ratio to screen patients for primary aldosteronism, cutoff values for interpreting a positive test are variable.
The tricky part is establishing the lower end of the range, said Dr. Vaidya. To avoid missing any cases, he uses and recommends a liberal approach (at the expense of more false positives) that defines a positive screen as an aldosterone level of 5 ng/dL or higher in the context of a low renin level and hypertension. The alternative is to have a more conservative approach: screening fewer people at the highest risk. “You won't test a lot—but when you do, you're more likely to identify true cases—but it will come at the expense of more false negatives,” he said.
Because medications such as ACE inhibitors and ARBs can falsely lower plasma aldosterone levels, the gold standard is to withdraw them for several weeks before screening. However, in many cases, the aldosterone-to-renin ratio can still be confidently interpreted despite the effect of continued medications, the Endocrine Society guideline said. The exception would be mineralocorticoid receptor antagonists (MRAs) like spironolactone, which block aldosterone production and need to be stopped temporarily to perform initial testing. (That being said, patients with primary aldosteronism often have low renin despite taking MRAs.)
Dr. Vaidya recommended taking a pragmatic approach to screening, rather than stopping all drugs before testing. “I think anybody with resistant hypertension and hypokalemia should have a measurement of renin and aldosterone at any time on any medication at that moment,” he said. “In other words, we are missing 99% of the opportunities, so if you ever think of primary aldosteronism, test for it right then and there. Don't miss your chance.”
Generally speaking, the aldosterone level is going to be higher in a patient who has an aldosterone-producing adenoma, which can help clinicians decide whether to try medical treatment or refer for confirmatory testing and further evaluation that might direct surgical treatment, said Dr. Auchus.
“This is a high-yield, simple blood test that you can do whenever the patient's in clinic. … For internists, the real message is that you should screen more broadly and you should probably not refer most of those people on,” Dr. Auchus said. “But if you thought to screen them, they should probably at least be taking an MR antagonist.”
Easy, low-cost treatments
Only 13% of patients ultimately started MRA therapy in Dr. Cohen's recent Annals study, even though MRAs are recommended in about 70% of patients with treatment-resistant hypertension. Testing for primary aldosteronism was associated with a fourfold higher likelihood of starting an MRA, regardless of the results of testing.
“Providers often state that they prefer to empirically treat patients with mineralocorticoid receptor antagonists rather than test for primary aldosteronism. Our study showed that this does not tend to happen even if this is providers' intention,” said Dr. Cohen. The results showed that there are plenty of missed opportunities for appropriate MRA treatment for patients with treatment-resistant hypertension, including those who don't have primary aldosteronism with an MRA as the fourth agent, she said.
Dr. Centor, who spends about three months out of the year on the wards as an academic hospitalist, said that “If I'm teaching this, the big lead is that we are underusing spironolactone or eplerenone, which are the two aldo antagonists that we have available right now, in hypertensive patients and that we should be going to them much more often.”
Spironolactone works well, is widely known, and is very inexpensive, but it has the unfortunate side effect of gynecomastia, he said. “This happened to my patient. He was well controlled on spironolactone, but then he got gynecomastia, so they switched him to eplerenone, and eplerenone is about half as strong as spironolactone,” Dr. Centor said. “So whatever the dose was of spironolactone, you have to use about twice as much of eplerenone.”
Aldosterone and many of the sex hormones, such as estrogen, progesterone, and cortisol, are very similar, so spironolactone's anti-androgen effect may not occur in isolation, noted Dr. Vaidya. “There is cross-reactivity to spironolactone, and it can create estrogenic side effects,” he said. “So what that practically means is in men, at higher doses, it can cause gynecomastia, breast growth, and that's not really a reversible phenomenon.”
This side effect usually occurs at doses of 50 mg/d or higher, and older men are more vulnerable, said Dr. Auchus, adding that while postmenopausal women usually don't have any side effects, those who are premenopausal can get breast tenderness and vaginal spotting, and it can't be used without a birth control pill in reproductive-age women.
In almost all men, Dr. Vaidya tries to prescribe eplerenone rather than spironolactone unless it becomes unaffordable, whereas he typically prescribes women spironolactone. While eplerenone isn't as cheap as spironolactone, it is available as a generic. A 60-day prescription of generic eplerenone tablets (50 mg/d) costs about $1 to $2 per day, according to GoodRx.
The biggest mistake clinicians make when they prescribe spironolactone is that they give too much, cautioned Dr. Auchus. To avoid side effects and maintain effectiveness, he recommended using 12.5 to 25 mg a day, and twice as much for eplerenone.
“I usually start people—no matter what their blood pressure is, no matter how high the aldosterone—on 12.5 mg [of spironolactone] a day, a half of a 25 [mg] pill a day, and I don't reassess for four to six weeks because it takes some time for it to have its full effect,” Dr. Auchus said. “So if you just start low, take your time, you usually won't run into trouble, and you'll be amazed at how much blood pressure reduction you get.”
Patients who respond well to an MRA can potentially be switched to MRA monotherapy or an MRA plus one other medicine, and in some cases, surgical management of an aldosterone-producing adenoma can improve or cure hypertension, said Dr. Auchus. “When surgery is guided with adrenal vein sampling, the hypertension is cured in one-third and improved in half of patients,” he said. “So even if we don't cure the blood pressure, if we can turn somebody with uncontrollable resistant hypertension into somebody with controllable, garden-variety hypertension, that's total success.”
Primary care internists should refer these patients when they don't feel comfortable treating them, but testing for primary aldosteronism and starting MRA therapy is definitely in their wheelhouse, said Dr. Vaidya.
“I think this is bread-and-butter internal medicine. In fact, one of the reasons screening and diagnosis is very low is that this begins at the internal medicine primary care level,” he said. “If they don't suspect it and test for it, it never gets to the subspecialists.”