Unsatisfactory screening rates for Primary Aldosteronism in high risk patients

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Unsatisfactory screening rates for Primary Aldosteronism in high risk patients

https://doi.org/10.21203/rs.3.rs-3863491/v1

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The Endocrine Society (ES) guidelines recommend screening for primary aldosteronism (PA) in high risk hypertensive patients presenting with at least one of seven criteria (resistant HTN, hypokalemia, adrenal nodule etc.).

Although guidelines are clear and screening is simple, compliance rates among clinicians are extremely low. This results in underdiagnosis of early disease, leading to cadiovasculaer complications and extra-burden of advanced chronic kidney disease.

We aimed to evaluate the screening rates in the Nephrology and Hypertension clinics at Assuta Ashdod University Hospital, Israel.

Data on adult hypertensive patients was retrieved during January 2018 to December 2020. Included in the study were hypertensive patients who had at least one of the ES criteria for PA screening. Of all suitable patients, we compared those who were screened for PA to patients who were not screened. Univariate and multivariate cox regression analysis were used for comparison between groups.

Of 661 patients with HTN, 218 patients (33%) met the ES guidelines for PA screening. Forty-six of them (21.1%), were referred for screening. Advanced age and male gender were associated with lower screening referral rates. Odds ratio for age was 0.945 for every year (95% CI 0.915-0.975). There was a trend towards decreased referral rate in advanced kidney disease.

A 21% screening rate, suggests that many cases of PA are likely missed, more often in older patients.We therefore advocate for PA screening of all hypertensive patients, especially elderly patients with CKD, in whom clinicians’ awareness is low but the absolute risk is high.

Health sciences/Diseases/Endocrine system and metabolic diseases/Adrenal gland diseases

Health sciences/Diseases/Cardiovascular diseases/Hypertension

aldosterone

primary aldosteronism

secondary hypertension

guidelines

screening

What is known about the topic?	What this study adds?
Screening rates for PA according to the endocrine society guidelines are unsatisfactory	Screening rates for PA in a Hypertension Excellence Center are still low,albeit better than the rates achieved in other clinical settings
Primary hyperaldosteronism (PA) is a major cardiovascular and metabolic risk factor	Elderly patients, especially men with reduced GFR, who are at increased cardiovascular risk, are paradoxically less screened than others

Resistant hypertension (rHTN) accounts for 8.9–33% of diagnosed HTN cases according to different cohorts[1–4]. Primary aldosteronism (PA), comprises ~ 20% of cases of rHTN, and is the most common form of secondary HTN[3, 5].

The three hallmarks of PA are HTN, increased adrenal aldosterone secretion and suppressed renin secretion[6]. Aldosterone secretion in PA originates from either an adrenal adenoma or bilateral adrenal hyperplasia; treatment options in PA include either surgical adrenalectomy or targeted pharmacotherapy[7, 8].

The prevalence of PA is reported with wide variations in patients referred to specialized HTN units (1%-29.8%) and primary care clinics (3.2%-12.7%)[9], and correlates with severity of HTN, ranging from 2% in patients with grade I HTN[10] up to 20% among individuals with resistant HTN[11]. PA is a multi- faceted disease and has deleterious effects on the heart, blood vessels, kidneys, and the brain[12, 13]. It is therefore important to diagnose PA early, to properly control HTN and prevent end-organ damage.

The diagnosis of PA is performed in three phases: screening phase - case detection tests, confirmatory tests, and subtype evaluation tests [14, 15]. Unfortunately, there is no reliable clinical phenotype to guide clinicians as to which patients should be referred for PA testing. In efforts to conserve medical costs and limit the consequences of false-positive screening tests, the Endocrine Society (ES) guidelines recommend testing patients at high-risk for PA. These include: (i) patients with sustained BP above 150/100 mmHg on each of three measurements obtained on different days; (ii) patients with HTN resistant to three conventional antihypertensive drugs at maximal tolerated doses (including a diuretic) or controlled BP on four or more antihypertensive drugs (rHTN); (iii) hypertensive patients with spontaneous or diuretic-induced hypokalemia; (iv) hypertensive patients with adrenal incidentaloma; (v) hypertensive patients with obstructive sleep apnea (OSA); (vi) hypertensive patients with a family history of early onset HTN or cerebrovascular accident at a young age (< 40 years); and (vii) all hypertensive first-degree relatives of patients with PA[12].

Unfortunately, these guidelines are often not followed by clinicians[7]. For example, two large cohort studies demonstrated low percentage (3% or less) of PA screening in patients with rHTN[16] and HTN with hypokalemia or OSA[17]. Other studies found that over more than three decades, patients were not tested for PA at the time of HTN diagnosis, but rather only after irreversible target organ damage developed[14, 18, 19]. These findings raise serious doubts regarding the effectiveness and relevance of the ES guidelines.

In this study we aimed to estimate the compliance rate for PA screening in eligible patients at the Nephrology & Hypertension Institute of the Assuta Ashdod University Hospital, a European Society of Hypertension (ESH) Excellence Center, and evaluate the parameters which were associated with the decision to refer patients for testing.

All hypertensive patients who had a BP measurement of ≥ 140/90 during two or more different clinic visits, who were over the age of 18 years and visited the Nephrology & Hypertension Clinics at Assuta Ashdod University Hospital Hypertension Excellence Center between January 2018 and December 2020 were included in our retrospective cohort study. Patients with missing relevant data were excluded.

We obtained patients’ demographics, clinical information and medications from existing electronic medical records (EMR) systems. The demographic and clinical information consisted of age, comorbidities, systolic and diastolic blood pressure measurements, relevant family history, as well as lab results (electrolytes, endocrine tests, etc.)

We then looked only at those hypertensive patients who had criteria compatible for PA screening (at least one out of the seven ES subgroups mentioned above) and compared the group which was screened for PA to those who were not screened according to multiple demographic and clinical parameters. Clinically relevant variables, which were significantly different between groups, were introduced into a cox regression multivariate analysis.

Descriptive statistics in terms of mean, SD, median and percentiles were calculated for all parameters in the study. Differences in continuous parameters between groups were calculated using T-test or Mann Whitney U test whenever needed. Fisher Exact test or Pearson Chi square were used for categorical variables. Logistic regression model with odds ratio and 95% confident interval (CI) was used to determine the effect of independent parameters associated with screening vs. not screening patients for PA. Parameters were selected for the multivariable logistic regression model based on their level of significance in the univariate analysis. Additional parameters which had clinical importance were also included in the multivariable logistic regression model. A p value of < 0.05 was considered significant. SPSS software, version 25 was used for all statistical analysis.

The study was approved by the Assuta Ashdod Hospital’s IRB and waved the need for informed consent.

Of 661 hypertensive patients, 218 were eligible for PA screening according to the ES Guidelines. Of those, only 46 patients (21.1%) were referred for screening. Demographic and clinical characteristics of patients who were either screened or not screened for PA are shown in Table 1.

The specific criteria of patients suitable for PA screening are shown in Figure 1. Resistant HTN was the most common indication in both groups (over 50%). A linear regression analysis demonstrated that suitable patients who were not referred for screening, were older (age 70.8±12.2 compared to 59.1± 15.8, p<0.001). Male patients were less likely to be referred for screening: 124/172 (72%) of those not screened were men, compared to 26/46 (56.5%) of those who were screened (p=0.05). Patients not referred for screening also had lower albumin levels (3.74g/dL compared to 4.01g/dL, p=0.001) and borderline higher serum creatinine (2.36mg/dL compared to 1.77mg/dL; p=0.06).

A multivariable model was created according to the linear regression analysis for predicting the probability for referral to PA screening. Variables selected for our model were gender, age, diabetes mellitus, creatinine level and albumin level (Table 2).

The probability of being referred for screening was substantially higher for women (odds ratio=3.68, p=0.003 and 95%CI=1.54-8.8) and for each 1g/dL increase in albumin level (odds ratio=3.09, p=0.038 and 95%CI=1.064-8.980). Older age was associated with lower chances of referral (odds ratio=0.943 for each year, p<0.001 and 95%CI=0.913-0.975) (Table 2). Renal function (as assessed by plasma creatinine and eGFR levels) and the existence of diabetes mellitus were not statistically significant in the multivariate analysis.

When age was analyzed according to Youden index and area under the curve (ROC model), patients under the age of 64.5 years were found to have a five times higher chance of being referred for PA screening – 20/159 patients (12.6%) under the age of 64.5 were referred for screening, vs. 26/50 (44.1%) of those over the age of 64/5 years (p <0/001). A new multivariable model according to this age cutoff was created which demonstrated a higher likelyhood for PA screening referral in patients under the age of 64.5 (odds ratio of 4.89, p<0.001 and 95%CI=2.072-11.55). (Table 3)

Of 218 hypertensive patients eligible for PA screening, 46 (21%) were in-fact referred for screening. Based on a multivariable model, older male patients were less likely to be referred for PA screening.

A 21% screening rate in a Hypertension Excellence Center, although better than previously published[16, 17], suggests that many cases of PA are likely missed. Mulatero et al. found that the adherence rate to the guidelines was 13%[20], while other studies had even lower adherence rates of less than 5%[16, 17, 19, 21]. Jaffe et al.[16] for example, demonstrated a screening rate of only 2.1% (98/4660) in eligible patients with rHTN. Younger patients were more likely to be screened possibly due to higher systolic and diastolic BP values. Even patients with hypokalemia in a large cohort of 37,000 hypertensive patients were screened at a rate of only 2.7% [17]. Notably, hospitalized hypertensive patients with hypokalemia were 2.5 times more likely to be screened than patients seen in the clinic. Charoensri et al.[21] implemented a best practice advisory in order to increase PA screening rates at their academic center outpatient clinics. Interestingly, even after implementing the intervention, screening rates reached only 14%. PA screening rates in our study were significantly higher (21.1%) than those described in other studies, suggesting a possible positive impact of a dedicated academic Hypertension Excellence Center. Nevertheless, screening rates are still far from satisfying given the potentially deleterious effects of undiagnosed and untreated autonomous production of aldosterone[12, 13].

Similar to the findings in our study, other studies have shown that females are referred for screening more often than males[16, 17, 21–23]. Data from the Centers for Disease Control and Prevention (CDC) suggest that compared with men, women are 33% more likely to visit a doctor, and 100% better at maintaining screening and preventive care[24], which could serve as a possible explanation for the higher PA screening rates observed in women[22]. Akasaka et al.[25] demonstrated that hypertensive women with hyperaldosteronism, due to unilateral aldosterone producing adenoma (APA) as well as bilateral adrenal hyperplasia, were younger than men with APA, possibly explained by more active screening of women.

Similar to other studies, in our study, older age was negatively associated with the rate of PA screening[17, 21].. This finding may be attributed to several reasons:First, Aldosterone-Renin ratio (ARR) as the most prevalent screening tool has been shown to have reduced accuracy in the aged population[26], and some age related adjustments for cutoffs have been suggested[26, 27]. The interpretation of screening test results is therefore more challenging for referring physicians, and may lead to lower refreal rates for screening. Second, hyperaldosteronism can also be the result of aldosterone-producing cell clusters (APCC),. As a result, lateralization in aldosterone secretion is not always present on adrenal vein sampling (AVS)[28, 29]. The incidence of APCC has been shown to correlate with older age in patients who had no evidence of APA [30]. In such cases the most appropriate treatment would be a mineralocorticoid receptor antagonist (MRA)[31, 32], Third, the preferred treatment method for PA in younger adults (< 35 years old) is often surgical[33]. Older patients usually have multiple comorbidities and in the rare case of APA, referral for surgery (may be associated with higher risks[34]. Specifically, we demonstrated that patients older than 64.5 were less likely to be referred for testing. Studies comparing the outcomes of adrenalectomy for APA in older ( > = 65yo) vs. younger (< 65yo) patients demonstrated worse outcomes for older patients with regards to GFR decline, hyperkalemia and load of antihypertensive medications post asurgery[31, 35].

Lastly, hyperaldosteronism in the elderly responds well to MRA, with fewer side effects compared to the young. Spironolactone is still the most prevalent MRA in use, and given its high percentage of hormonal influences, older males can probably tolerate spironolactone better than younger patients[32]. Surprisingly, despite low screening rates for APA in the elderly, only a small fraction of these patients with rHTN are empirically treated with an MRA [36], either due to fear of side effects, or a more lenient approach for higher BP values in the elderly. A more liberal screening approach will enhance medical treatment of rHTN in the elderly, including use of the highly effective MRAs currently at our disposal.

A possible explanation for the lower referral rates of patients with lower eGFR level, could be that clinicians tend to attribute HTN to the accompanying CKD, especially in the elderly [16, 37, 38]. In such circumstances, other possible etiologies for HTN including renovascular HTN or PA are often overlooked, correlating with the findings in our study[39]

In conclusion, we found that even in a dedicated, Nephrology oriented, HTN excellence center, screening rates for PA are insufficient in general, and especially low in older male patients and in those with renal dysfunction.

Our findings have important clinical implications, as PA while being a treatable and often curable disease, carries a high risk for cardiovascular and other comorbidities [12]. Long standing and undiagnosed hyperaldosteronism increases this risk even further. We therefore suggest revisiting our screening protocols: we advocate for screening of all patients with HTN for PA, at least once, as early as possible. Such practice will improve detection rates and appropriate treatment of PA in general, and particularly for higher risk elderly population.

Data availability statement:

All data related to this study is available in the manuscript

Acknowlendgments:

The authors thank Ronit Leiba, MA, for assistance with statistical analysis

Author contribution:

AAK, HRSG, MH, AL – manuscript writing

HRSG, NNN – data collection

VR, ZK – review and commentary

Ethical approval:

The study was approved by Assuta Ashdod University Hospital IRB

Competing interests:

Non of the authors have any conflict of interest

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Table 1 : Clinical characteristics of hypertensive patients eligible for PA screening

	Not referred for PA screening N=172	Referred for PA screening N=46	P value
Female Male	48 (28%) 124 (72%)	20 (43.5%) 26 (56.5%)	P=0.05
Age	70.8±12.2	59.1±15.8	P<0.001
Atrial fibrillation	39 (22.7%)	6 (13.0%)	P=0.22
Diabetes mellitus	106 (61.6%)	18 (39.1%)	P=0.007
HTN	172 (100%)	46 (100%)	Na
Hyperlipidemia	80 (46.5%)	17 (37.0%)	P=0.32
Heart Failure	30 (17.5%)	5 (10.9%)	P=0.37
Ischemic Heart Disease	50 (29.1%)	8 (17.4%)	P=0.13
GOUT	16 (9.3%)	0	P=0.027
Cerebrovascular disease	24 (14.0%)	3 (6.5%)	P=0.21
Smoking None Yes Past	N=171 137 (80%) 16 (9%) 18 (11%)	N=46 38 (83%) 6 (13%) 2 (4%)	P=0.36
Last Clinic SBP 1	147.3±21.04; n=148	150.2±19.3; n=32	P=0.47
Last Clinic DBP 1	75.66±14.3; n=146	77.5±14.09;n=31	P=0.51
Creatinine(mg/dl)	2.36±1.87	1.77±1.53	P=0.062
*eGFR 1=<30 2=31-59 3=>60	N=155 57 (36.8%) 50 (32.3%) 48 (31.0%)	N=40 10 (25%) 7 (17.5%) 23 (57.5%)	P=0.19 P=0.08 P=0.003
Uric acid (mg/dL)	7.23±3.84	6.38±1.84	p=0.19
Urea (mg/dL))	82.56±50.15	60.76±39.9	p=0.005
Na (mmol/L)	139.2±4.52	139.5±3.15	P=0.65
K (mmol/L)	4.45±0.69	4.35±0.67	P=0.37
Hemoglobin (mg/dl)	11.9±2.28	12.7±2.2	P=0.04
Albumin (gr/dL)	3.74±0.54	4.07±0.46	P=0.001

^{HTN, hypertension;eGFR,estimated glomerular filtration rate.}

Table 2: multivariable model - Odds of sending eligible patients for PA screening

Variable		P value	Odds ratio	95% C.I
Variable		P value	Odds ratio	Lower	Upper
	Female Gender	.003	3.682	1.539	8.811
	Age	<.001	0.943	.913	.975
	Diabetes mellitus	.563	1.288	.546	3.039
	Creatinine (mg/dL)	.814	.971	.757	1.244
	Albumin (g/L)	.038	3.091	1.064	8.980

Table 3. Age cuttoff for PA screening referral

A. Youden index of age cuttof for PA screening referral

			group		Total
			Not referred	referred	Total
Age64.5	age <64.5	Count	33	26	59
	age <64.5	% within Age64.5	55.9%	44.1%	100.0%
	age >=64.5	Count	139	20	159
	age >=64.5	% within Age64.5	87.4%	12.6%	100.0%
Total		Count	172	46	218
Total		% within Age64.5	78.9%	21.1%	100.0%

B. Association of patient comorbidities with PA screening

Variable		p-value	Odds ratio	95% C.I.
Variable		p-value	Odds ratio	Lower	Upper
	Gender female vs. male	.005	3.577	1.481	8.641
	DM	.559	1.292	.548	3.047
	Cr	.946	1.008	.791	1.285
	Alb	.012	3.925	1.345	11.451
	Age 64.5	<.001	4.893	2.072	11.557

There is NO conflict of interest to disclose.

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Unsatisfactory screening rates for Primary Aldosteronism in high risk patients

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