Abstract
Primary aldosteronism (PA) is the most common cause of endocrine hypertension and is often underdiagnosed. This condition is associated with increased cardiovascular morbidity and mortality in comparison to age and blood pressure matched individuals with essential hypertension (EH). The diagnostic pathway for PA consists of three phases: screening, confirmatory testing, and subtyping. The lack of specificity in the screening step, which relies on the aldosterone to renin ratio, necessitates confirmatory testing. The Endocrine Society’s clinical practice guideline suggests four confirmatory tests, including the fludrocortisone suppression test (FST), saline suppression test (SST), captopril challenge test (CCT), and oral sodium loading test (SLT). There is no universally accepted choice of confirmatory test, with practices varying among centers. The SST and FST are commonly used, but they can be resource-intensive, carry risks such as volume overload or hypokalemia, and are contraindicated in severe/uncontrolled HTN as well as in cardiac and renal impairment. In contrast, CCT is a safe and inexpensive alternative that can be performed in an outpatient setting and can be applied when other tests are contraindicated. Despite its simplicity and convenience, the variability in captopril dose, testing posture, and diagnostic threshold limit its widespread use. This narrative review evaluates the diagnostic accuracy of the CCT across different populations, addresses controversies in its usage, and proposes recommendations for its use in the diagnosis of PA. Furthermore, suggestions for future research aimed at promoting the wider utilization of the CCT as a simpler, safer, and more cost-effective diagnostic test are discussed.
Introduction
Primary aldosteronism (PA), a syndrome of renin-independent aldosterone secretion from the adrenal glands, is classically characterized by hypokalemic hypertension (HTN) with suppressed plasma renin activity (PRA) or concentration (PRC). Previously considered a rare disorder, it is now established as the most common cause of endocrine HTN and the single most important cause of treatment-resistant hypertension.The prevalence of PA ranges from 4.6% to 13.0% in patients with uncomplicated HTN (1) and up to 30% in those with treatment-resistant HTN (2, 3). Despite its significance, PA remains an underdiagnosed condition due to misconceptions about its rarity, the absence of a typical clinical phenotype, and the perceived complexity of the diagnostic pathway.
PA is associated with a higher risk of stroke, nonfatal myocardial infarction, coronary artery disease, heart failure, and atrial fibrillation compared to blood pressure (BP) matched essential hypertension (4, 5). Patients with PA also display an increased prevalence of metabolic syndrome and diabetes (6, 7), osteoporotic fractures (8), and symptoms of depression with a reduced quality of life (9). When PA goes undetected, patients miss out on targeted treatment for excess mineralocorticoid receptor (MR) activation in the form of MR antagonists or even potentially curative adrenal surgery for those with unilateral aldosterone-producing adenomas (APA) (10).
The aldosterone-to-renin ratio (ARR) has been the most used indicator for PA screening since its utility was first demonstrated by Hiramatsu and colleagues in 1981 (11). The assay is effective in screening for PA with a sensitivity of up to 94% and a specificity of up to 65% but with a positive predictive value of only 34% (12, 13). The low specificity of ARR can result in false-positive screening in as many as 57–88% of patients (13).
Elevated ARR can occur in some primary hypertensive patients due to factors such as posture, high salt intake, or interfering medications that suppress renin production. These factors can increase the ARR to above-normal range even when the plasma aldosterone concentration is low or normal (14). False-positive ARRs can also occur during the luteal phase of the menstrual cycle in premenopausal women or in those using oral contraceptives (15) as well as in patients with advancing age or chronic kidney disease (16). Potassium levels also critically regulate aldosterone levels together with other factors (17). It is important to confirm an elevated ARR with additional testing unless the patient has florid biochemical features of PA including suppressed renin, high aldosterone concentration, and hypokalemia. Indeed, a recent meta-analysis of 31 datasets comprising 4242 patients found that pooled accuracy estimates (summary area under the operating characteristics curve (sAUROC)) did not differ between the screening ARR (0.95; 95% CI 0.92–0.98), CCT (0.92; 95% CI 0.88–0.97), and SST (0.96; 95% CI 0.94–0.99) for the diagnosis of unilateral PA, possibly due to their florid presentations (18).
For people in whom confirmation testing is required, the Endocrine Society’s clinical practice guideline recommends four confirmatory tests, including the fludrocortisone suppression test (FST), saline suppression test (SST), captopril challenge test (CCT), and oral sodium loading test (SLT) (Table 1) (11). Another confirmatory test recommended by the Japanese Endocrine Society is the furosemide upright posture test (19) (Table 1). Among the tests, FST is considered the most reliable, though its lengthy duration, cost, and complex protocol make it less practical for routine clinical use (20, 21, 22). The SST, especially when performed in the seated position, is a widely used and reliable alternative to the FST, with superior sensitivity and specificity compared to the SST in the supine position (23). The SLT is the least expensive option, but patient compliance with the 24-h urine collection can pose a challenge (21). Unfortunately, all of the aforementioned tests are contraindicated in patients who present with severe/uncontrolled HTN or with advanced cardiovascular complications such as congestive heart failure or renal insufficiency (Table 1) (24). In contrast, the CCT, as the only test not causing volume expansion or an increase in blood pressure, is safe for use in these patients and can be performed in an outpatient setting. Although it is the least time-consuming confirmatory test, it is not as widely used as the SST and SLT at present. In recent studies on the prevalence of PA from various centers in China, Italy, Australia, and the USA, the diagnosis of PA was primarily based on the SST or SLT (25, 26, 27, 28, 29, 30), although Xu et al. used either the SST or the CCT as a confirmatory test in their study of PA prevalence study in China (25).
Key features of confirmatory tests for PA diagnosis.
| Name of the test | Reliability (sensitivity and specificity) | Duration | Hospitalization | Complexity | Key limitation | Cost |
|---|---|---|---|---|---|---|
| Fludrocortisone suppression test (FST) | Most reliable test | 4 days | Yes | Relatively complex protocol | - Contraindicated in heart failure, renal insufficiency - Risk of hypokalemia |
Expensive |
| Saline suppression test (SST) | Reliable and widely used | 4 h | Day admission only | Less complex than FST | - Contraindicated in renal insufficiency or congestive heart failure and severe/uncontrolled HTN | Expensive |
| Salt loading test (SLT) | Variable | 4 days | No | Relatively complex | - Possible inaccuracy with urinary aldosterone measurement - Poor patient compliance with 24- h urine collection - Contraindicated in severe hypertension, kidney failure, cardiac arrhythmia, severe hypokalemia |
Inexpensive |
| Captopril challenge test (CCT) | Variable | 1–2 h | No | Simple and convenient | - Considerable heterogeneity regarding protocol, outcome parameter | Most inexpensive test |
| Furosemide upright test (FUT) | Variable | 2 h | Day admission only | Relatively less complex than FST, SST, and SLT | - Can be done in in renal insufficiency or congestive heart failure and severe/uncontrolled HTN - Not recommended by the Endocrine Society and not widely practiced |
Relatively inexpensive than SST, FST |
The selection of a confirmatory test varies across centers due to a lack of consensus regarding the most accurate and feasible option. A key factor contributing to the heterogeneity in confirmatory tests is the lack of gold standard for the diagnosis of bilateral forms of PA, unlike unilateral PA, which can usually be defined by surgical cure. Using one confirmatory test as the ‘gold-standard’ to determine the accuracy of a second test is flawed, as all of these tests have relatively arbitrary thresholds. Whilst there is no current international consensus on a preferred confirmatory test, the 2014 consensus statement from the Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2014) recommended CCT as the first choice because of its convenience and safety (19). Despite being a feasible and safe test, the diagnostic accuracy of the CCT remains uncertain, as highlighted in a systematic review and meta-analysis that showed significant variability in the procedures, interpretation, and validation of all confirmatory tests including the CCT (32). This review aims to examine the diagnostic accuracy of the CCT in various populations and address the controversies surrounding its use, with the goal of reevaluating the CCT as a useful tool for the diagnosis of PA.
Physiological basis for CCT
The CCT was first proposed to be useful in discriminating PA from essential hypertension (EH) by Corvol et al. in 1983 who reported a 100% sensitivity and specificity of the test for diagnosing an APA (33). The mechanism of the CCT lies in the inhibition of the conversion of angiotensin I to angiotensin II by the angiotensin-converting enzyme (ACE) through the administration of captopril. This decrease in angiotensin II and aldosterone production in individuals with a normal renin–angiotensin axis leads to an increase in renin release as a result of alterations in volume and salt status. In contrast, patients with autonomous production of aldosterone, as seen in PA, are thought to show little or no effect on aldosterone secretion or renin production with captopril administration, allowing for differentiation between PA and EH (34).
Protocols for CCT and outcome evaluation
The CCT is a simple and brief procedure, performed in an outpatient setting, that involves oral administration of a 25 or 50 mg captopril tablet followed by measurement of plasma aldosterone and renin at 0, 60, and/or 120 min post administration. Captopril is an inexpensive medicine that is widely available, including in low to middle-income countries, and used in hypertensive patients with negligible adverse effects. The CCT can be applied safely in patients with severe/uncontrolled HTN or with cardiovascular complications including congestive heart failure in whom other confirmatory tests are contraindicated.
However, its widespread adoption is challenged by the heterogeneity in drug dose, posture during testing, and timing of venesection (35). There is lack of consensus on the optimal timing for blood sampling after captopril challenge (11, 36, 37). The Japan Endocrine Society recommends blood sampling at 1 or 1.5 h after captopril challenge (37), the American Endocrine Society recommends 1 or 2 h (5), whilst the Working Group on Endocrine Hypertension of the European Society of Hypertension and the Italian Society of Arterial Hypertension recommends 2 h (36, 37, 38).
Xinyu Liu et al. conducted a retrospective analysis of 204 hypertensive patients suspected of having PA. Oral captopril challenge was administered at a dose of 50 mg (or 25 mg if systolic blood pressure was <120 mm Hg). Plasma aldosterone concentration and direct renin concentration were measured at 1 h and 2 h following captopril challenge using a chemiluminescence immunoassay (Liaison DiaSorin, Italy). The diagnostic performance of the 1-h aldosterone concentration was assessed by sensitivity and specificity, using the 2-h aldosterone concentration (11 ng/dL as the cutoff) as the reference. Receiver operating characteristic (ROC) curve analysis was also performed (39).
At a cutoff of 11 ng/dL, the sensitivity and specificity of using the 1-h aldosterone concentration to diagnose PA were 87.2% and 78.2%, respectively. A higher cutoff of 12.5 ng/mL increased specificity to 90% but decreased sensitivity to 75.5%. Conversely, a lower cutoff of 9.3 ng/mL increased sensitivity to 97.9% but decreased specificity to 65.4%. The authors concluded that when diagnosing PA with a captopril challenge, the 1-h aldosterone concentration cannot be used as a substitute for the 2-h aldosterone concentration (39).
There is also uncertainty in the optimal diagnostic outcome measure and threshold (Table 2). Some investigators advocate for an ARR >200 (pg/mL)/(ng/mL/h) (67 pmol/mU) at 1 or 2-h post captopril as a useful criterion for having the highest sensitivity, whereas other centers prefer post-captopril PAC cutoffs for the diagnosis of PA (Table 2) (35, 40). According to the Endocrine Society clinical practice guideline, a positive CCT is defined by a PAC after captopril (post-captopril PAC) that remains elevated at > 70% of baseline PAC (pre-captopril PAC) (11). The Japanese Endocrine Society proposes that PA can be diagnosed if any of the following criteria are met: ARR >200 (pg/mL)/(ng/mL/h) (67 pmol/mU), or PAC (pg/mL)/active renin concentration (mU/L) ratio >40, or PAC >120 pg/mL (332 pmol/L) at 60 or 90 min after captopril administration (41).
Summary of the studies on the CCT.
| Name of the author/year/country | No. of subjects | Drugs withdrawal/duration | Dose of captopril | Timing of sampling | Comparator study | Post-CCT outcome parameter and diagnostic threshold | Outcome parameter and diagnostic threshold of comparator | AUC for PA detection | Sensitivity (CCT vs SST) | Specificity (CCT vs SST) |
|---|---|---|---|---|---|---|---|---|---|---|
| Kim JH, et al./2016/South Korea (44) | 64 | - MRA/ARB/ACEI/β-blocker discontinued for 2 weeks | 50 mg | 60 and 90 min | SST | - ARR: >20 ng/dL) (ng/mL/h) or - PAC: 13 ng/dL |
- PAC: ≥10 ng/dL | 0.956 | 98% | 78.6% |
| Liu B, et al./2020/China (35) | PA = 196 EH = 73 |
- Diuretics/(MRA) were withdrawn for 4 weeks - ACEIs, angiotensin-1/ARB, and β-blockers stopped for 2 weeks |
50 mg | 0 and 120 min | SST | - PAC: 11 ng/dL Cutoff for APA 11 ng/dL |
- PAC: 8 ng/dL | 0.88 AUC for APA: 0.96 |
73% vs 72% Sensitivity of CCT for APA 91% |
85% vs 86% |
| Lyons DF, et al./1983/USA (34)a,e | PA = 12 EH = 10 NC = 9 |
- ARB/ACEI/β-blocker discontinued 2 or more weeks - Spironolactone discontinued for at least 3 weeks |
25 mg | 0 and 120 min | SST | - PAC: 15 ng/dL or - ARR: 50 (ng/dL) (ng/mL/h) |
Not applicable | NA | NA | NA |
| Zhu KY, et al./2019/China (48) | PA = 110 EH = 163 NC = 40 |
- MRA discontinued for 4 weeks - β-Blockers, ACE inhibitor/ARB 2 weeks |
50 mg | 0 and 120 min | None | - Upright PRA <1.0 ng/mL/h or - ARR ≥20 ng/dL (ng/mL/h) or - PAC suppression >30% or - PAC: 13 ng/dL |
Not applicable | 0.754 | 70.1% | 72.4% |
| Okamoto R, et al./2018/Japan (46) | PA = 101 EH = 27 |
- Recruited patients only on calcium channel antagonists and/or alpha-blockers as antihypertensive drugs |
50 mg | 60 and 90 min | SST FUT |
- ARR >20 (ng/dL) (ng/mL/h) | - Post-SST PAC >6.0 ng/dL - Post-FUT: PRA <2.0 ng/mL |
0.832 | 80% vs 90% | 71.1% vs 90% |
| Song Y, et al./2017/China (31) | PA = 135 EH = 101 |
- Diuretics withheld for at least 4 weeks - β-Blockers, ARB/ACE inhibitor stopped for at least 2 weeks |
50 mg | 0 and 120 min | SST FST |
- PAC: 11 ng/dL | Post-SST PAC >8 ng/dL | 0.96 AUC for APA: 0.98 |
90% vs 85% | 90% vs 92% |
| Rossi E, et al./2007/Italy (40) | PA = 126 EH = 999 |
- MRA withdrawn for 6 weeks - ACEI/ARB/β-blocker discontinued for 2 weeks |
50 mg | 0 and 60 min | SST | - PAC: 13.9 ng/dL Cutoff for APA 13.9 ng/dL |
- Post-SST PAC 6.75 ng/dL | 0.769 AUC for APA: 0.765 |
69.6% vs 82.6% Sensitivity of CCT for APA 69.6% |
74% vs 75.1% Specificity of CCT for APA 74% |
| Kidoguchi S, et al./2019/Japan (45)b, d | PA = 71 | - ACEI/ARB/β-blocker/diuretics/MRA discontinued for 6 weeks |
50 mg | 0 and 90 min (supine) | FUT SST |
- ARR >200 (pg/mL) (ng/mL/h) or - PAC >12 ng/dL or - PAC suppression >30% |
- FUT: PRA <2.0 ng/mL/h - SST: 6 ng/dL |
Not applicable | Not applicable | Not applicable |
| Westerdahl C, et al./2011/Sweden (43)c, e | PA = 14 EH = 32 NC = 16 |
- β-Blockers, diuretics, ACEI/ARB withdrawn for 2 weeks | 25 mg | 0 and 120 min | FST | - ARR: >130 pmol/mIU | - PAC: 225 pmol/L | 0.664 | Not applicable | Not applicable |
| Nanba K, et al./2012/Japan (47)d | PA = 57 EH = 63 |
- ACEI/ARB/β-blocker stopped for 2 weeks - MRA stopped for 3 weeks |
50 mg | 0, 60, and 90 min | FUT, SST | - ARR: 20 (ng/dL) (ng/mL/h) at 60 or 90 min |
- Post-FUT PRA <2 ng/mL/h - Post-SST PAC: 6 ng/dL |
0.784 AUC for APA: 0.784 |
85% vs 65% Sensitivity of CCT for APA:55.3% |
94.4% vs 100% Specificity of CCT for APA: 94.4% |
| Mulatero P/2007/Italy (42) | PA = 11 | - ACEI/ARB/β-blocker stopped for 3 weeks - Diuretics for 6 weeks - Spironolactone for 8 weeks for |
50 mg | 0 and 120 min | SST, FST | - PAC: PRA > (30 ng/dL) (ng/mL/h) or - PAC 8.5 ng/dL |
- Post-SST PAC: 5 ng/dL | 90% (SST) | 84% (SST) | |
| Mohsen Agharazii/2001/Japan (49) | PA = 44 | - MRA discontinued for 6 weeks - Beta-blocker for 1 week - None were getting ACEI/ARB |
25 mg | 0 and 120 min | SAL | - PAC: 8.5 ng/dL | - Post-SAL PAC: 8.5 ng/dL | 97% vs 100% | Not applicable |
aThe study selected patients who previously had done SST; however, the CCT was not compared with SST later. The results looked at a positive rate of criterion; 70.4%, 64.8%, and 54.9% for criterion 1, criterion 2, and criterion 3, respectively, for PA diagnosis; bThe study selected patients who previously had done SST; however, the CCT was not compared with SST later. It looked for the post-CCT cutoff of ARR and PAC for diagnosis of PA, being 50 and 15 ng/dL, respectively; CThe study selected patients who previously had done FST; however, the CCT was not compared with FST later. It looked at the AUC for the post-CCT cutoff of ARR for diagnosis of PA; dThe CCT was done in a recumbent position in these two studies; in all the other studies the CCT was done in a sitting condition; eAll the studies except these two were performed under condition of controlled salt intake.
APA, aldosterone-producing adenoma; ARR, aldosterone–renin ratio; AUC, area under the curve; CCT, captopril challenge test; EH, essential hypertension; FST, fludrocortisone suppression test; FUT, furosemide upright test; NC, normal control; PA, primary aldosteronism; PAC, plasma aldosterone concentration, SST, saline suppression test.
Diagnostic accuracy of CCT compared to other confirmatory tests
The diagnostic accuracy of the CCT varies among studies with older studies conducted on Caucasian populations showing disappointing results whilst recent studies in East Asian populations show more promising results. A study by Mulatero et al. compared the diagnostic accuracy of the CCT with the FST in 98 Italian patients and reported that the CCT produced false-positive or false-negative results in 36% (4 out of 11) of these patients whilst the SST and FST produced concordant results. The diagnostic threshold for the CCT was plasma aldosterone/plasma renin activity ratio >30 (ng/dL) (ng/mL/h) (101 pmol/mU) or plasma aldosterone concentration >8.5 ng/dL (>235 pmol/L) at 2 h post captopril (42). The discrepancy between the tests may be caused by the relatively low diagnostic threshold of post-saline plasma aldosterone concentration at 5 ng/dL (139 pmol/L) in comparison to the higher CCT cutoff (42). Westerdahl et al. showed that the range of ARR in primary hypertensive patients overlapped with the range of the ARR in the PA patients in 88% of cases at 120 min after captopril, with a mean post-captopril ARR of 43 pmol/mIU in primary hypertension and 81 pmol/mIU in PA. They argued that the post-captopril ARR was only marginally better than basal ARR as a confirmatory test. However, this study had some limitations including poor age matching of the healthy control and hypertensive patients, the use of a lower dose of captopril than most other studies, and the use of post-CCT ARR as the only outcome measure (43).
The PAPY study reported that, although the plasma aldosterone concentration after the CCT and the SST were equally helpful in APA (based on the four corners criteria) diagnosis, the accuracy of the CCT following 50 mg oral captopril was inferior to that of the SST in patients with a sodium intake of less than 130 mEq/d (equivalent to 7.6 g of dietary NaCl) because of renin–angiotensin system activation (40). Overall, the accuracy of the SST as reflected by the AUC (0.853) was higher than that of the CCT (0.765, P = 0.054) and the sensitivity and specificity of SST were 82.6% (95% CI 0.68–0.98) and 75.1% (95% CI 0.68-0.81), and that of CCT were 69.6% (95% CI 0.54–0.82) and 74% (95% CI 0.67–0.80). This study was done prospectively on patients with newly detected mild hypertension, whereas other studies recruited patients with preexisting or long-standing hypertension. Moreover, the prespecified ARR of 40 (ng/dL) (ng/mL/h) (135 pmol/mU) used in the PAPY study for the screening of PA was higher than in other studies using a cutoff of 20 (ng/dL) (ng/mL/h) (67 pmol/mU) (34, 44, 45, 46). According to the study, the sensitivity and specificity of ARR ≥35 (ng/dL) (ng/mL/h) (117 pmol/mU) were 95.4% and 28.3% at baseline, compared with 100% and 67.9% 2 h after captopril. Using post-captopril ARR ≥35 (ng/dL) (ng/mL/h) (117 pmol/mU) as screening and confirmation by the SST, a PA prevalence of 6.3% was found among 1046 consecutive Italian patients with normal renal function (27, 40).
More recently, the CCT has been reported to be as accurate as the SLT and/or SST in confirming PA in a number of studies mostly from East Asia (31, 35, 44, 45, 46, 47). Nanba et al. performed a complex evaluation of three tests (SST, CCT, and the furosemide upright test (FUT)) in 120 Japanese patients who tested positive for PA by ARR. The CCT and FUT showed similar positive rates (90%) for confirmation of PA, whereas the SST showed lower levels (65%) than either the CCT or FUT. Given the similar results of CCT and FUT and the low sensitivity of SST, the authors proposed that one test (CCT or FUT) should be sufficient to confirm the diagnosis of PA. This retrospective study design was prone to selection bias as patients with severe hypertension, cardiovascular complications including congestive heart failure, or untreated hypokalemia were not subjected to SST. On the other hand, the relatively high dietary salt intake in the Japanese population could have affected SST results in his study (47).
Zhu et al. found that the CCT had a relatively high sensitivity of 94% (95% CI 0.88–0.97) and specificity of 99.4% (95% CI 0.96–0.99) in diagnosing PA in 313 Chinese subjects, with a post-captopril ARR cutoff of 20 (ng/dL)/(ng/mL/h) (67 pmol/mU) (48). Liu et al. reported similar diagnostic accuracy for SST and CCT in over 200 Chinese patients. When the post-saline and post-captopril PAC were set at 8.5 ng/dL (235 pmol/L) and 11 ng/dL (305 pmol/L), respectively, the sensitivity and specificity of SST were 72% (95% CI 0.65–0.78) and 86% (95% CI 0.76–0.93), and that of CCT were 73% (95% CI 0.67–0.80) and 85% (95% CI 0.75–0.92) (35). In the CONPASS study, Song et al. compared SST and CCT to FST as the reference test in 236 Chinese patients with PA and EH (31). The optimal cutoff of PAC post-captopril was also set at 11 ng/dL (305 pmol/L), resulting in a sensitivity of 90% (95% CI 0.84–0.95) and a specificity of 90% (95% CI 0.83–0.95), which is comparable to the SST (with the PAC post-saline cutoff set at 8 ng/dL or 221 pmol/L) (31). This study had some important strengths including its prospective design, standardization of the procedures of screening and confirmation according to the Endocrine Society Guidelines, and using the FST as the reference test to simultaneously assess the diagnostic accuracy of the SST and CCT (31).
The only study comparing the CCT with the SLT was conducted by Agharazii et al. in a Caucasian population. The study found a significant correlation between the PAC of salt-loaded patients (mean of 08:00 h and noon results) and the PAC 2 h after captopril administration (r = 0.8, P < 0.01) (49). The optimal plasma aldosterone concentration post captopril and post-salt loading were found to be 8.5 ng/dL (240 pmol/L) for both tests with a sensitivity of 100% and 97%, respectively. However, specificity could not be calculated due to the low number of patients without PA (49).
A recent systematic review and meta-analysis compared the diagnostic efficacy of the SST, CCT, and FST in 26 studies involving 3686 patients. The findings revealed that the CCT has similar efficacy to the SST, with a pooled sensitivity and specificity of 87% (95% CI 0.84–0.89) and 85% (95% CI 0.82–0.87), respectively, for the CCT and 84% (95% CI 0.81–0.86) and 87% (95% CI 0.85–0.89), respectively, for the SST. FST had a similar sensitivity of 87% (95% CI 0.66–0.97) and a higher specificity of 95% (95% CI 0.82–0.99) compared to the CCT, and the FST had a similar sensitivity of 87% (95% CI 0.66–0.97) and a higher specificity of 95% (95% CI 0.82–0.99) compared to the CCT and SST (50). However, this systematic review did not examine the impact of ethnicity or geographic location on the outcomes of the confirmatory tests.
The disparities in the diagnostic accuracy of the CCT between Caucasian and Asian populations are intriguing. Whilst higher salt intake in Asian countries has been proposed to impact the captopril response, a study by Zhu et al. found no relationship between 24-h urinary sodium excretion and post-captopril aldosterone response (48). On the other hand, genetic differences may play a role. Cytochrome P450 family 2 subfamily C member 9 or CYP2C9*1*3 is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. The CYP2C9*1*3 genotype, which has been associated with reduced aldosterone response to captopril (51), has been described in 4% of Chinese and Japanese populations in contrast to Caucasian populations, which tend to harbor different CYP2C9 alleles (52).
Other factors that may contribute to differences between the studies include sample size, study design, reference standard, screening criteria, and outcome measure, as well as selection bias. For example, whereas hypokalemia accounted for 9–37% of patients with PA in the Caucasian trials (53), it affected 75.7% to 81% of patients in the Asian trials (31, 35). This may reflect more severe disease in the Asian cohorts enabling a higher degree of accuracy with the CCT. Of all the studies that evaluated the CCT, the PAPY (26) and CONPASS (31) studies were prospectively conducted with rigorous criteria and a large number of subjects. Both studies administered a 50 mg oral dose of captopril and measured aldosterone and renin concentrations with either radioimmunoassay (PAPY study) or automated chemiluminescence immunoassays (CONPASS study) (18, 19). The outcome measure of aldosterone concentration (29, 34, 35) provided greater diagnostic accuracy than the ARR (43, 46, 47) at 2 h post captopril.
Recommendation for a standard protocol for CCT
The main variations in the CCT procedure and interpretation include the dose of captopril used, timing of post-captopril sample collection, outcome measure, and diagnostic threshold. With regards to dose and timing, the lowest plasma concentration of angiotensin II (53) occurs between 60 and 90 min following the oral administration of a single dose of captopril. Considering the half-life of plasma aldosterone is 20 min, a 60–90% decline in its concentration resulting from maximal inhibition of angiotensin-converting enzyme is anticipated to occur 2 h post captopril (54). All except one of the centers used a 50 mg oral dose of captopril, without adverse effects such as hypotension or hyperkalemia, and the sampling was done in a seated position to allow adjustment of the renin–angiotensin–aldosterone axis to posture (Table 2). The SHRIMP study in Japan avoided the inclusion of patients on interfering antihypertensive medications (mineralocorticoid receptor antagonists, diuretics, angiotensin-converting enzyme inhibitors) and recruited patients only on calcium channel antagonists and/or alpha-blockers as antihypertensive drugs (44). All other studies discontinued interfering antihypertensive medications for two to six weeks and in most of them, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was withdrawn for at least 2 weeks (15, 28, 31, 35, 44, 45, 47, 48, 49).
We, therefore, recommend that following discontinuation of interfering medication for 2–6 weeks, a 50 mg captopril tablet should be given on an empty stomach (to maximize absorption) when the patient had been upright (sitting, standing, or walking) for at least 2 h after waking. During sampling at baseline and 2-h post captopril, the patient should remain seated for 5–15 min before the blood draw (31, 33). With regard to the outcome measure and optimal diagnostic threshold, there is significant variability among the different centers (Table 2). The most commonly used parameter for PA diagnosis is the post-captopril PAC, with the threshold variably set from 8.5 ng/dL (235 pmol/L) to 13.9 ng/dL (385 pmol/L) (27, 31, 33). The largest studies, i.e. Rossi’s PAPY for Caucasians and Zhu et al., Song et al., and Liu et al. for Asians, all provide post-captopril PAC thresholds between 300 and 385 pmol/L (31, 35, 40, 48). The diagnostic thresholds may be influenced by age, gender, antihypertensive medications, individual response to ACE inhibition and the assay method. It has been well shown that LC-MS/MS (liquid chromatography–tandem mass spectrometry) yields lower results that RIA/IA, requiring clinicians to adopt a lower cutoff. This would suggest that it may be necessary for different centers to establish their own population and assay technique-based diagnostic thresholds for the optimal interpretation of the CCT. However, as there are only a handful of well-designed prospective studies on CCT, it might be too early to establish such diagnostic thresholds.
Conclusion
It has been established that PA is a prevalent disorder, affecting one in ten people with hypertension. To effectively diagnose PA, a simple, convenient, and cost-effective confirmatory test is required. The CCT presents itself as an underutilized yet promising option. Recent studies, especially from Asia, have reported a comparable diagnostic accuracy between the CCT and other confirmatory tests. The cost-effectiveness of the CCT, with the use of inexpensive and easily accessible captopril tablets, and the convenience of venesection in an outpatient pathology laboratory make it a favorable diagnostic tool. Unlike the SST or FST, intravenous infusions and intensive monitoring are not necessary, and blood pressure rise is not a concern. This makes the CCT an accessible option, particularly in regional areas or low- to middle-income countries where access to inpatient testing is limited. However, further studies are needed to address areas of uncertainty, such as the differing diagnostic accuracy in different ethnic groups where head-to-head comparisons of the CCT with other confirmatory tests in diverse populations will be required. This will aid in determining the populations in which the CCT is the preferred confirmatory test for PA.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
Dr Sharmin Jahan is a master’s student at Monash University, Clayton, Victoria, Australia. She is a recipient of the Monash Graduate Scholarship and Monash International Tuition Scholarship. The Hudson Institute is supported by the Victorian Government’s Operational Infrastructure Scheme.
Author contribution statement
Dr Jun Yang is a senior editor of Endocrine Connections. Dr Jun Yang was not involved in the review or editorial process for this paper, on which she is listed as an author.
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