Abstract
Primary aldosteronism (PA) is the most common secondary cause of hypertension. Patients with PA experience significant cardiovascular and other complications compared to patients with primary hypertension for the same degree of blood pressure control. Guidelines recommend screening all patients with resistant hypertension for PA.
Objective:
The objective of this study was to assess screening rate for PA among patients with apparent treatment resistant hypertension and to determine the rate of positive screening test result among the group screened.
Methods:
This is a retrospective chart review of electronic medical record data of all patients with hypertension and ≥18 years within a single health system in Minnesota from September 2018 – September 2020.
Results:
Out of 140,734 patients who were≥18 years with a diagnosis of hypertension, 13.4% (18,908) fulfilled the criteria for apparent treatment resistant hypertension after excluding those with congestive heart failure. Only 4.2% (795) of patients with apparent treatment resistant hypertension had screening for PA in our cohort. Of the 795 patients who had screening for PA, 16.9% (134) had a positive screening test result.
Conclusion:
The screening rate for PA among patients with resistant hypertension is low. Clinical and public health strategies directed at improving screening rate for PA are vital.
Introduction
Hypertension is defined as a blood pressure at or above 130/80 mm Hg, according to the 2017 hypertension guideline by the American College of Cardiology and the American Heart Association (1). Forty-five percent of adults (108 million people) in the United States have hypertension as defined by this guideline or are on blood pressure medications (2). Resistant hypertension is defined as above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes or any patient with hypertension on ≥4 antihypertensive medications. Apparent treatment resistant hypertension is used when one or more data elements that exclude pseudo-resistance such as medication dose, medication adherence or blood pressure measurement out-of-office are missing (3).
Guidelines recommend patients with resistant hypertension have a screening test for primary aldosteronism (PA) (3-4). Primary aldosteronism, a syndrome that results in autonomous hypersecretion of aldosterone from adrenal cortex, is the most common secondary cause of hypertension.4 Studies have shown that the prevalence of PA among patients with resistant hypertension ranges from 19%-22% (5-7). Patients with PA experience an increased burden of stroke, myocardial infarction, arrhythmias, other cardiovascular complications, and chronic kidney disease compared to patients with primary hypertension (8-12). Therefore, early diagnosis and treatment of patients with PA is crucial to prevent complications. Guidelines recommend using serum aldosterone to renin activity ratio (ARR) levels for screening of PA and the most accepted cutoff value is ARR of ≥30 in a setting of aldosterone concentration ≥ 10 ng/dL (3-4). Previous studies reported low screening rate for PA among high-risk populations (13-15). The 2016 Endocrine guideline in the management of PA and the hypertension management guideline published in 2017 have outlined the importance of screening patients with resistant hypertension for PA. This study was designed to assess if the practice of screening of patient with resistant hypertension for PA has changed over the recent years.
The study objectives were to assess the screening rate for PA among patients with apparent treatment resistant hypertension and to determine the rate of positive screening test result among this group.
Methods
This is a retrospective chart review of electronic medical record data of all patients with hypertension ≥18 years within a single health system in Minnesota. The study protocol was approved by the Institutional Review Board of the University of Minnesota. Patients ≥18 years who consented to the use of their electronic medical records for research purposes and who were diagnosed with hypertension between 9/1/2018 and 9/30/2020 were included. Patients who have not consented to research and patients with a diagnosis of congestive heart failure were excluded from the study as these groups are frequently on multiple blood pressure medications as part of treatment plan for heart failure.
Data was extracted by the informatics consulting service of the Clinical and Translational Science Institute of the University of Minnesota and was provided within the Academic Health Center Secure Data Environment (AHC-SDE), which gives researchers a secure environment in which to work with clinical data. All viewing and manipulation of the data took place within this secure environment. Only authorized research personnel were given permission to login to the shelter to view and analyze the requested data.
Patients with apparent treatment resistant hypertension were identified using the 2017 AHA/ACC definition of resistant hypertension, which included patients on three blood pressure medication classes and most recent BP pressure ≥ 130/80 or patients on ≥ 4 blood pressure medications were identified. The term apparent treatment resistant hypertension was used instead of resistant hypertension since pseudo-resistance causes including white coat hypertension, inaccurate measurement of blood pressure, medications adherence and other factors have not been excluded.
After identification of patients with apparent treatment resistant hypertension during the study period, we assessed how many of these patients ever had laboratory measures for serum aldosterone and renin activity. Those who had at least one serum aldosterone level checked were considered screened. A positive test result was defined as ARR of ≥ 30 and an aldosterone level greater than or equal to 10. If more than one ARR was available for a patient, the highest ARR was taken. The rate of a positive screening test result was calculated from this group.
Statistical Methods
Primary outcomes of interest included rates of apparent treatment resistant hypertension, screening rates for PA and screening results for PA based on aldosterone and renin laboratory values. Secondary objectives included investigating the association between demographic/comorbidity variables and apparent treatment resistant hypertension/screening results. Demographics were summarized using descriptive statistics for all patients, by apparent treatment resistant hypertension, and by screening test result. Comorbidities were summarized by all patients and by apparent treatment resistant hypertension. To investigate the association between continuous variables and these groups, Student’s t-tests were used. Chi-square or Fisher’s exact tests were used for categorical variables. Blood pressure medication classes were summarized by apparent treatment hypertension. All reported p-values are two-sided and a significance level of 0.05 was used. Statistical analyses were performed using R (version 4.0.2, R Core Team).
Results
The total number of patients 18 years and older with a diagnosis of hypertension during the study period was 140,734. Mean age was 62, about 49% were female, and a majority were White (Table 1 & Central Illustration).
Table 1.
Demographics of patients with hypertension and apparent treatment resistant hypertension.
| Variable | All hypertension patients (N=140,734) |
Apparent treatment resistant hypertension patients (N=18,908) |
No apparent treatment resistant hypertension patients (N=121,826) |
P-value |
|---|---|---|---|---|
| Age at first diagnosis of hypertension | <0.001 | |||
| Number missing | 2 | 0 | 2 | |
| Mean (SD) | 61.8 (14.8) | 63.5 (14.2) | 61.6 (14.9) | |
| Sex, n (%) | 0.059 | |||
| Number missing | 16 | 0 | 16 | |
| Female | 69479 (49.4%) | 9215 (48.7%) | 60264 (49.5%) | |
| Male | 71239 (50.6%) | 9693 (51.3%) | 61546 (50.5%) | |
| Race, n (%) | <0.001 | |||
| Number missing | 6589 | 770 | 5819 | |
| White | 118162 (88.1%) | 15701 (86.6%) | 102461 (88.3%) | |
| Black | 8970 (6.7%) | 1530 (8.4%) | 7440 (6.4%) | |
| Other | 7013 (5.2%) | 907 (5.0%) | 6106 (5.3%) | |
| Ethnicity, n (%) | 0.737 | |||
| Number missing | 10605 | 1525 | 9080 | |
| Hispanic or Latino | 2022 (1.6%) | 265 (1.5%) | 1757 (1.6%) | |
| Not Hispanic or Latino | 128107 (98.4%) | 17118 (98.5%) | 110989 (98.4%) |
To investigate the association between continuous demographics and resistant hypertension, Student’s t-test was used. For categorical variables, Chi-square tests were used.
Central Illustration.
Out of all patients with a diagnosis of hypertension, 13.4% (18,908) fulfilled the criteria for apparent treatment resistant hypertension after excluding those with congestive heart failure; 9.2% (12,903) were on ≥ 4 blood pressure medications and 4.3% (6,005) were on 3 blood pressure medications and had a blood pressure ≥ 130/80. Mean age for patients with apparent treatment resistant hypertension was 64. The percentage of apparent treatment resistant hypertension among Whites and Blacks was 13.3% and 17.1%, respectively. Older age and black race were associated with apparent treatment resistant hypertension (both p<0.001) (Table 1).
Serum aldosterone level (screening rate for PA) was checked for 795 (4.2%) of patients out of 18,908 patients with apparent treatment resistant hypertension (Table 2). Of the 795 patients who had aldosterone level checked, 16.9% (134) had a positive screening test result as defined by ARR ≥ 30 and aldosterone lab ≥ 10. Screening rate for PA for patients with hypertension on ≥ 4 medications was 5.1% (653/12,903) and 18.1% (118/653) of this group had a positive screening test result.
Table 2.
Summary of screening rate of patients with apparent treatment resistant hypertension for PA by number of blood pressure medication classes and blood pressure goals and positive screening test result rate.
| Variable | n (%) | |
|---|---|---|
| Screened for PA (at least one aldosterone lab value available) | Positive test result (ARR ≥ 30 and serum aldosterone ≥ 10 | |
| Patients with hypertension with BP ≥130/80 and on 3 Blood pressure medications or patients on ≥ 4 blood pressure medications (N=18,908) | 795/18,908 (4.2%) | 134/795 (16.9%) |
| Patients with hypertension with BP ≥140/90 and on 3 Blood pressure medications or patients on ≥ 4 blood pressure medications (N=14,513) | 693/14,513 (4.8%) | 124/693 (17.9%) |
| Patients with hypertension on ≥ 4 blood pressure medications (N=12,903) | 653/12,903 (5.1%) | 118/653 (18.1%) |
Table 3 summarizes the relationship between screening result (after excluding 64 without a renin value) and demographic variables. Positive screening test result was significantly associated with male sex and black race (p=0.009 and 0.002, respectively).
Table 3.
Summary of screening rate of patients with apparent treatment resistant hypertension for PA and positive screening test result rate for those who had the screening test by demographics.
| Variable | Screened for PA (N=795) |
Positive screening test result (N=134) |
Negative screening test result (N=597) |
P-value |
|---|---|---|---|---|
| Age at first diagnosis of hypertension | 0.640 | |||
| Mean (SD) | 57.7 (14.7) | 58.2 (13.4) | 57.5 (14.9) | |
| Sex, n (%) | 0.009 | |||
| Female | 420 (52.8%) | 57 (42.5%) | 328 (54.9%) | |
| Male | 375 (47.2%) | 77 (57.5%) | 269 (45.1%) | |
| Race, n (%) | 0.002 | |||
| Number missing | 40 | 15 | 21 | |
| White | 624 (82.6%) | 86 (72.3%) | 490 (86.1%) | |
| Black | 95 (12.6%) | 25 (21.0%) | 59 (10.2%) | |
| Other | 36 (4.8%) | 8 (6.7%) | 27 (4.7%) | |
| Ethnicity, n (%) | 0.104 | |||
| Number missing | 83 | 21 | 57 | |
| Hispanic or Latino | 18 (2.5%) | 6 (5.3%) | 12 (2.2%) | |
| Not Hispanic or Latino | 694 (97.5%) | 107 (94.7%) | 528 (97.8%) | |
| Apparent treatment resistant hypertension group, n (%) | 0.050 | |||
| Patients on 3 hypertension medications and BP≥130/80 | 142 (17.9%) | 16 (11.9%) | 114 (19.1%) | |
| Patients on ≥ 4 medications | 653 (82.1%) | 118 (88.1%) | 483 (80.9%) |
To investigate the association between continuous demographics and screening result, Student’s t-test was used. For categorical variables, Chi-square or Fisher’s exact tests were used.
There was a significant association between the diagnosis of coronary heart disease, chronic kidney disease, OSA, stroke, and apparent treatment resistant hypertension (all p<0.001, Table 4).
Table 4.
Comparison of chronic complications by apparent treatment resistant hypertension.
| Variable | All hypertension patients (N=140,734) |
Apparent treatment resistant hypertension patients (N=18,908) |
No apparent treatment resistant hypertension patients (N=121,826) |
P-value |
|---|---|---|---|---|
| Any comorbidity, n (%) | 50847 (36.1%) | 9395 (49.7%) | 41452 (34.0%) | <0.001 |
| CHD, n (%) | 20221 (14.4%) | 4116 (21.8%) | 16105 (13.2%) | <0.001 |
| CKD, n (%) | 18141 (12.9%) | 4119 (21.8%) | 14022 (11.5%) | <0.001 |
| Stroke, n (%) | 8215 (5.8%) | 1443 (7.6%) | 6772 (5.6%) | <0.001 |
| Obstructive sleep apnea (OSA), n (%) | 19061 (13.5%) | 3456 (18.3%) | 15605 (12.8%) | <0.001 |
To investigate the association between comorbidities and resistant hypertension. Chi-square test were used.
Diuretics, beta blockers, ACEI/ARB and calcium channel blockers were the most prescribed anti-hypertensives and 12.2% of patients (2,307/18,908) with apparent treatment resistant hypertension were on mineralocorticoid antagonists (Spironolactone or Eplerenone). (Supplemental Material Table 1). Medication list for all patient with apparent treatment resistant hypertension was reviewed.
Discussion
In this single center, large-scale retrospective study, we found that screening rate for PA among patients with apparent treatment resistant hypertension is low (4.2%). Our study looked at recent data between 2018-2020 and the findings showed that screening of patients with resistant hypertension for PA is low despite clear guidance from guidelines (3-4).
Raising awareness on the importance of screening among providers and simplifying screening procedures might be an important step in closing the gap. Screening for PA traditionally required discontinuing antihypertensive medications which is potentially risky particularly for patients on multiple anti-hypertensive medications. However, studies have shown that screening and confirmatory tests for PA can be done without discontinuing most anti-hypertensive medications (16-18). Theoretically, some anti-hypertensive medications can cause potentially false negative test result but not false positive therefore initial testing can be performed without discontinuing medications (19). Patients with a positive screening test results undergo further confirmatory tests. PA secondary to unilateral disease is surgically treated and mineralocorticoid antagonists (Spironolactone or Eplerenone) are the mainstay of treatment for bilateral disease or unilateral disease when surgery is not performed. Spironolactone has been shown to be effective in treating resistant hypertension outside of treatment of PA (20) and current guidelines recommend adding Spironolactone in the treatment of resistant hypertension (1-3). We assessed if use of Spironolactone for the treatment of resistant hypertension contributed for the low screening rate for PA. In our cohort, only about 12% of patients with apparent treatment resistant hypertension were on Mineralocorticoid Antagonists (Spironolactone or Eplerenone).
The positive screening test result for PA was 16.9%. Clinical studies have reported PA prevalence ranging from 19-22% among patients with resistant hypertension (5-7). Our study showed that the screening rate for PA among patients with resistant hypertension has not improved in recent years. Patients with untreated PA experience significant cardiovascular and chronic kidney disease complications irrespective of blood pressure control (8-12). About 30-40% of patients with PA treated surgically are cured from hypertension (21-22). A short duration of hypertension, absence of vascular remodeling or chronic kidney disease are the strongest predictors of cure of hypertension, (21) emphasizing the importance of early diagnosis and treatment. The authors call for clinical and public health strategies directed to improve screening rate for PA among patients with resistant hypertension.
Limitations of the study
Our study has multiple limitations, many of which are common to observational and database studies. The study was conducted using EMR data from a single health system, which limits generalizability of the outcome. Medication list was extracted from EMR data for each study participant; however, medication compliance or prescribed dose of each medication was not assessed. Similarly, blood pressure readings for each participant were extracted from EMR, however, assessment of blood pressure measurement techniques or out-of-office blood pressure measurement were not conducted. Therefore, we used the term apparent treatment resistant hypertension in our study since potential pseudo-resistance causes mentioned above have not been excluded. We do not believe that this played a role in overestimating the number of patients with resistant hypertension. The prevalence of resistant hypertension in our cohort was 13.4%; previously done clinic-based studies have reported 15% to 18% (23-25) and clinical studies have reported much higher prevalence rate (26-28).
Supplementary Material
Acknowledgment:
The authors would like to thank the Informatics Consulting Service of the Clinical and Translational Science Institute of the University of Minnesota.
Research reported in this publication was supported by NIH grant P30 CA77598 utilizing the Biostatistics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations/Definitions
- AHA
American Heart Association
- ACC
American College of Cardiology
- Resistant hypertension
above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes or any patient with hypertension on ≥4 antihypertensive medications. Apparent treatment RH is used when one or more data elements that exclude pseudo-resistance are missing: medication dose, medication adherence or out-of-office BP.
- BP
Blood pressure
- PA
Primary aldosteronism
- ARR
Aldosterone to renin activity ratio
- ACE-I
Angiotensin converting enzyme inhibitor
- ARB
Angiotensin receptor blocker
- MCA
Mineralocorticoid antagonist
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