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Original Research  n  Vascular

Jean-Philippe Mailhot, MD Manuela Traistaru, MD Gilles Soulez, MD Martin Ladouceur, PhD Marie-France Giroux, MD Patrick Gilbert, MD Ping Shi Zhu, MD Isabelle Bourdeau, MD Vincent L. Oliva, MD André Lacroix, MD Eric Therasse, MD

Purpose:

To assess the sensitivity and specificity for ratios of adrenal vein cortisol level (Ca) to peripheral vein cortisol level (Cp), adrenal vein aldosterone level (Aa) to peripheral vein aldosterone level (Ap), and combined cortisol and aldosterone levels (“combined ratio”) for the detection of successful adrenal vein catheterization (“selectivity”) in adrenal vein sampling (AVS) without adrenocorticotropic hormone (ACTH) injection at different cutoff values.

Materials and Methods:

This retrospective study was approved by the institutional review board, and informed consent was waived. AVS was performed in 160 consecutive patients (49 women and 111 men; mean age, 53.6 years) between December 1989 and January 2014. Cortisol and aldosterone levels were measured in samples from the adrenal veins and left iliac vein every 5 minutes, two times before (basal) and three times after intravenous cosyntropin (ACTH 1–24) injection. Selectivity was defined by Ca/Cp or Aa/Ap ratio of at least 5 in at least one sampling after ACTH administration. Sensitivity and specificity for the detection of selective adrenal vein catheterization were calculated for basal Ca/Cp ratio, Aa/Ap ratio, and combined ratios for three cutoff values reported in the literature. The McNemar test was used to assess differences in sensitivity and specificity to detect selective adrenal vein catheterization.

Results:

The sensitivity and specificity for the cutoff values of at least 3, at least 2, and at least 1.1 for the detection of AVS selectivity were respectively 50.4% and 100%, 70.8% and 100%, and 98.5% and 76.9% for Ca/Cp ratio; 61.3% and 100%, 70.8% and 100%, and 94.2% and 53.8% for Aa/Ap ratio; and 75.2% and 100%, 88.3% and 100%, and 99.3% and 46.2% for combined ratios (sensitivity at the 2 cutoff value: P , .0001 for combined ratio vs Ca/Cp ratio and for combined ratio vs Aa/Ap ratio).

Conclusion:

Basal combined ratio has the best sensitivity for the detection of AVS selectivity at all cutoff values, and for all ratios, the cutoff value of at least 2 has the best sensitivity for 100% specificity.

1

 From the Division of Interventional Radiology, Department of Radiology (J.P.M., M.T., G.S., M.F.G., P.G., V.L.O., E.T.), and Division of Endocrinology, Department of Medicine (P.S.Z., I.B., A.L.), Centre Hospitalier de l’Université de Montréal (CHUM), 3840 rue Saint-Urbain, Montréal, QC, Canada H2W 1T8; and Centre de Recherche du CHUM (CRCHUM), Montréal, QC, Canada (G.S., M.L.). Received October 14, 2014; revision requested November 24; revision received February 8, 2015; accepted March 10; final version accepted March 26. Address correspondence to E.T. (e-mail: [email protected]).

and Interventional Radiology

Adrenal Vein Sampling in Primary Aldosteronism: Sensitivity and Specificity of Basal Adrenal Vein to Peripheral Vein Cortisol and Aldosterone Ratios to Confirm Catheterization of the Adrenal Vein1

 RSNA, 2015

q

 RSNA, 2015

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1

VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

P

rimary aldosteronism is the most common, curable form of hypertension, accounting for 5%–11% of hypertensive patients (1,2). Treatment options in primary aldosteronism depend on whether excess aldosterone secretion is unilateral (aldosteroneproducing adenoma) or bilateral (bilateral adrenal hyperplasia, also known as idiopathic aldosteronism). Unilateral overproduction may be treated with unilateral laparoscopic adrenalectomy or, more recently, with radiofrequency ablation (3,4), whereas patients with bilateral adrenal hyperplasia usually undergo lifelong medical therapy, including mineralocorticoid receptor antagonists (5). Adrenal imaging cannot demonstrate all microadenomas and nodular hyperplasias or permit differentiation of nonsecreting incidentalomas from aldosterone-producing adenomas with confidence (6). Adrenal vein sampling (AVS) is the only test that allows

Advances in Knowledge nn Detection of catheter selectivity with the ratio of adrenal vein aldosterone level (Aa) to peripheral vein aldosterone level (Ap) is similar to the ratio of adrenal vein cortisol level (Ca) to peripheral vein cortisol level (Cp) (70.8% at a cutoff value of 2). nn Combining basal Aa/Ap and Ca/Cp ratios improves the sensitivity for the detection of catheter selectivity (+17.5% and +24.8% at cutoff values of 2 and 3, respectively), with no loss of specificity in comparison to use of the Ca/Cp ratio alone. nn Compared with the selectivity cutoff value of 2, the cutoff value of 3 decreased the sensitivity for the detection of catheter selectivity (220.4% for Ca/ Cp, 29.5% for Aa/Ap, and 213.1% for combined ratios) with no improvement of specificity, while the cutoff value of at least 1.1 improved sensitivity at the cost of significantly reduced specificity for all three ratios. 2

differentiation of unilateral from bilateral forms of primary aldosteronism and is therefore accepted as a reference standard. For this reason, the Endocrine Society guidelines now advocate AVS to distinguish between these causes (7). Although some centers will forego AVS when adenomas are clearly visualized in combination with noninvasive testing, many others consider AVS mandatory, even in this setting. AVS first requires catheterization of both adrenal veins. Confirmation of adequate adrenal vein catheterization (“selectivity”) is essential before lateralization assessment of primary aldosteronism. Historically, this has been based on the cortisol concentration ratio in AVS compared with sampling from a peripheral vein (ratio of adrenal vein cortisol level [Ca] to peripheral vein cortisol level [Cp]). In one study, investigators highlighted the lack of uniformity in the way each center generates and interprets their data (8). Many of them relied only on baseline samplings without adrenocorticotropic hormone (ACTH) stimulation (nine of 20 centers). Ca/Cp ratio cutoff values to ascertain catheter selectivity also varied markedly in centers in which AVS was performed both with and without ACTH stimulation. Among centers in which AVS was undertaken without ACTH stimulation, most (.60%) considered a Ca/Cp selectivity cutoff value of at least 2; some centers (20%) adopted more permissive criteria (1.1 or 1.36), and others (20%) preferred

Implications for Patient Care nn Basal Ca/Cp ratios with cutoff values higher than 2 for the detection of catheter selectivity will result in a higher number of adrenal vein samplings (AVSs) that will be inappropriately discarded. nn Combining Aa/Ap and Ca/Cp ratios will improve sensitivity for the detection of catheter selectivity, resulting in an increased number of clinically useful AVSs and minimization of the need for repeat procedures.

Mailhot et al

more restrictive criteria (3.0) (6). Likewise, most centers use a selectivity index cutoff of 3–5 with ACTH stimulation (8). The rationale for using cortisol rather than aldosterone to assess catheter selectivity was based historically on the belief that, in the case of unilateral aldosterone hyperproduction, aldosterone secretion of the contralateral adrenal vein would be suppressed and therefore could not be used to assess selectivity (9). However, it was recently demonstrated that aldosterone secretion from the contralateral adrenal vein is not completely suppressed, as zona glomerulosa hyperplasia is often present, in addition to a dominant and lateralizing aldosterone-secreting adenoma (10). This bilaterally increased aldosterone secretion, despite suppression of the renin-angiotensin system, led to the hypothesis that the ratio of adrenal vein aldosterone level (Aa) to peripheral vein aldosterone level (Ap) might also be helpful in adrenal vein selectivity detection. The purpose of our study was to assess the sensitivity and specificity of basal Ca/Cp ratios, Aa/Ap ratios, and combined cortisol and aldosterone Published online before print 10.1148/radiol.2015142413  Content codes: Radiology 2015; 000:1–8 Abbreviations: Aa = adrenal vein aldosterone level ACTH = adrenocorticotropic hormone Ap = peripheral vein aldosterone level AVS = adrenal vein sampling Ca = adrenal vein cortisol level Cp = peripheral vein cortisol level Author contributions: Guarantor of integrity of entire study, E.T.; study concepts/ study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, J.P.M., M.T., M.F.G., P.S.Z., I.B., V.L.O., A.L., E.T.; clinical studies, M.T., G.S., M.F.G., P.G., I.B., A.L., E.T.; experimental studies, I.B., A.L.; statistical analysis, J.P.M., M.L., P.S.Z., V.L.O.; and manuscript editing, J.P.M., M.T., G.S., M.L., M.F.G., P.G., I.B., V.L.O., A.L., E.T. Conflicts of interest are listed at the end of this article.

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VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

ratios for the detection of catheter selectivity in AVS at different cutoff values.

Materials and Methods Study Population The institutional review board approved this retrospective study and waived informed consent. We included all consecutive patients referred to our center who (a) had biochemically proven primary aldosteronism, (b) underwent a unilateral adrenalectomy in the event that lateralization was confirmed, and (c) underwent AVS between December 1989 and January 2014. These patients were identified from an interventional radiology database, and their biochemical results were retrieved from the electronic health record of our medical center by a radiology resident (J.P.M.). There were 160 patients (49 women and 111 men; mean age 6 standard deviation, 53.6 years 6 12.1) who underwent a total of 170 AVS sessions. AVS was repeated in 10 patients in another separate session between 40 days and 9 years after the first attempt. These AVS sessions were repeated because they were nonselective on one or both sides (three cases), were inconclusive for lateralization despite adequate selectivity (one case), were technical failures (three cases), or had to be repeated for other reasons (three cases). Twenty AVS sessions were excluded—eight because they were a second AVS attempt, seven because of technically impossible catheterization of the right, left, or both adrenal veins, and five because of partial or absent information regarding biochemical tests. In total, 150 AVS sessions were included in the statistical analysis (Fig 1). Patients with proven primary aldosteronism were eligible if they agreed to undergo an eventual unilateral adrenalectomy in the event that lateralization was confirmed with AVS. The diagnosis of primary aldosteronism was established on the basis of increased plasma aldosterone to renin activity ratios (.550 pmol/L of aldosterone per ng/mL · hour of renin) and was confirmed with increased 24-hour

urinary aldosterone secretion (.38 nmol per day) after 3 days of high oral salt intake (.200 nmol per day) or abnormal aldosterone suppression after 2 L of 0.9% saline load (.280 pmol per liter) (7). Hypokalemia, if present, was systematically corrected with oral or intravenous potassium supplements to normalize blood potassium levels during investigation and the AVS procedure. Sodium intake was normalized at least 2 months before the scheduled AVS date, and medications were adjusted to prevent interference with patients’ native aldosterone production by the endocrinologists (A.L. and I.B.) involved in our study (11,12).

AVS Technique All 170 AVS procedures were performed by six fellowship-trained interventional radiologists, of whom four are authors of our study (M.F.G., with 13 years of experience; V.L.O., with 23 years of experience; G.S., with 24 years of experience; and E.T., with 22 years of experience), by following identical methods, with one of them (E.T.) undertaking 90% of the procedures. The same departmental protocol, with the same blood sample timing, was followed without modification for more than 25 years and is still in use, unchanged, in our center. The AVS technique has already been described in detail (13). Briefly, AVS procedures were performed via the bilateral femoral venous approach. The left adrenal vein was catheterized with a Simmons 5-F medium- or large-curve catheter (Cordis, Miami, Fla), and the right adrenal vein was catheterized with a Chuang 5-F catheter (Cook, Bloomington, Ind), a Simmons 5-F smallcurve catheter (Cordis), or a cobra 5-F medium-curve catheter (Cook). In all patients, the left adrenal vein catheter was inserted through a 6-F sheath, allowing simultaneous blood sampling of both adrenal veins and the left common iliac vein. The left iliac vein sheath provided easy and reliable venous access, with no risk of peripheral blood mixing with the adrenal vein outflow and without having to secure additional venous access. No sheath was used on the right

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Mailhot et al

Figure 1

Figure 1:  Flowchart of study population shows the number of repeated AVS procedures and the number of samplings excluded from analysis.

side. Two side holes were manually created a few millimeters from the catheter tip to ease blood withdrawal. The distal tip of a 0.014-inch hydrophilic guide wire (Transend; Boston Scientific, Fremont, Calif) was positioned in the 5-F catheter through a “Y” hemostatic valve and advanced about 1–2 cm into the right adrenal vein. This stabilized it and eased blood sampling during AVS by preventing adrenal vein collapse during blood aspiration. Proper catheter positioning was verified by performing adrenal phlebography before the first venous sampling and after the last venous sampling. In addition, fluoroscopic spot-check verification of catheter and guide wire positioning was performed regularly between samplings. Blood samples were drawn simultaneously, with minimal negative pressure, from the adrenal veins and left iliac vein 5 minutes before, immediately before, and 5, 10, and 15 minutes after intravenous bolus injection of 250 mg of cosyntropin (Cortrosyn; Organon 3

VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

Mailhot et al

there were differences associated with the operators and/or techniques. All the statistical analyses were performed with R software and packages (R Foundation for Statistical Computing, Vienna, Austria) (14).

Figure 2

Results

Figure 2:  Schematic representation of the AVS sequence. Blood samples were drawn simultaneously from adrenal veins and the left iliac vein 5 minutes before, immediately before, and 5, 10, and 15 minutes after intravenous bolus injection of 250 mg of cosyntropin.

Pharmaceuticals, West Orange, NJ). Whether the catheter was really “selective” was only known a few weeks after the procedure when the AVS laboratory results were received. Therefore, catheters could not be repositioned during the procedure to account for the AVS selectivity results. Figure 2 summarizes the AVS sequence in our study. All 15 samples were then sent to the hospital biochemistry laboratory for cortisol and aldosterone measurement.

Definition of Selectivity Selectivity of adrenal venous cannulation was based on Ca/Cp ratio of at least 5 or Aa/Ap ratio of at least 5 in at least one of the three samplings after ACTH stimulation. A cutoff value of at least 5 was chosen because 80% of the centers in which AVS is performed with ACTH stimulation use Ca/Cp cutoff values of 5 or lower than 5 (8). We included the Aa/Ap ratio after ACTH stimulation in the definition of our reference standard, since one of the basal ratios studied (Ca/Cp or Aa/Ap) involved the use of aldosterone. Statistical Analysis Descriptive statistics were calculated for the mean cortisol and aldosterone concentration values and ratios (Ca/ Cp and Aa/Ap) for the right adrenal vein, left adrenal vein, and peripheral vein samplings, before and after ACTH stimulation. Comparisons of the mean concentration ratios were conducted by using the paired Student t 4

test after transforming for normality. Percentages of AVS selectivity detection were calculated for our reference standard (ie, Ca/Cp or Aa/Ap ratio  5 after ACTH stimulation) for the right adrenal vein, the left adrenal vein, and the whole examination (“selective” on both sides). Percentages of AVS selectivity detection were also calculated on the basis of basal Ca/Cp and Aa/Ap ratios for three commonly used cutoff values reported in the literature (ie, 1.1, 2, and 3) (8) and were compared by using the McNemar test. Sensitivity and specificity of the Ca/Cp and Aa/Ap ratios for the detection of AVS selectivity with basal samplings were calculated for the three different cutoff values. Sensitivity and specificity were calculated for the whole examination (both adrenal veins) for which global selectivity requires bilateral selectivity detection. Given that two repeated basal samplings were obtained (at t = 25 minutes and t = 0 minutes), all sensitivities and specificities were calculated for the mean value of the two basal samplings. Sensitivity and specificity percentages were compared by using the McNemar test. Variables with P values less than .05 were considered to indicate a statistically significant difference. Subgroup analyses were performed without the 10% of cases performed by operators other than the main operator and with half of the cases that occurred in each half of our study period to assess whether

Table 1 shows mean cortisol and aldosterone concentrations, as well as mean Ca/Cp and Aa/Ap values before and after ACTH stimulation. Before and after ACTH stimulation, Aa/Ap values were all significantly higher than Ca/Cp values (P , .0002). Ratios also increased significantly after ACTH stimulation bilaterally for both Aa/Ap (P , .0001) and Ca/ Cp (P , .0001), with a mean increment of 8.0 for cortisol and 4.5 for aldosterone. Left and right adrenal vein Ca/Cp and Aa/Ap ratios were not significantly different, either before or after ACTH stimulation (all P  .16). According to the definition of selectivity (ie, Ca/Cp or Aa/Ap ratio  5 after ACTH stimulation), 137 of 150 AVS procedures (91.3%) were selective, 138 of 150 (92.0%) were on the right side, and 149 of 150 (99.3%) were on the left side. Although phlebographies of nonselective AVS were all prospectively believed to have been obtained in the adrenal vein, retrospectively they could have also been renal capsular or sushepatic or obtained in other retroperitoneal veins. We did not identify a common imaging pattern for these veins. Tables 2 and 3 show AVS selectivity detection on the basis of basal Ca/Cp and Aa/Ap ratios. Selectivity detection decreased substantially for both basal Ca/Cp and Aa/Ap ratios between the cutoff values of at least 1.1 and 2 and basal Ca/Cp ratios between the cutoff values of at least 2 and 3. Bilateral selectivity according to Ca/Cp and Aa/Ap were not significantly different at all three cutoff values. With a cutoff value of at least 2, Ca/Cp and Aa/Ap ratios were concordant for selectivity (either both 2 or both ,2) in 110 of 150 samplings (73.3%). The effects of three different ratios and cutoff values on sensitivity and specificity for the detection of selectivity are reported in Tables 4 and 5. With

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Mailhot et al

Table 1 Mean Cortisol and Aldosterone Values and Ratios for Right Adrenal, Left Adrenal, and Left Common Iliac Vein (Peripheral) Samplings before and after Intravenous ACTH Stimulation Before ACTH Stimulation Parameter

25 min

Cortisol level (nmol/L)   Right adrenal vein   Left adrenal vein   Peripheral vein Aldosterone level (pmol/L)   Right adrenal vein   Left adrenal vein   Peripheral vein Mean ratio  Right Ca/Cp  Left Ca/Cp  Right Aa/Ap  Left Aa/Ap

0 min

After ACTH Stimulation 5 min

10 min

15 min

2300 6 4855 2217 6 3985 291 6 172

2001 6 4505 2261 6 4723 278 6 159

19 749 6 13 252 17 349 6 9624 329 6 150

25 854 6 21 349 22 572 6 17 454 445 6 130

24 984 6 20 265 22 734 6 24 950 505 6 125

31 826 6 76 681 19 927 6 39 684 639 6 495

34 695 6 85 377 22 270 6 47 653 614 6 476

147 434 6 248 203 149 233 6 227 301 741 6 528

178 582 6 296 485 186 293 6 325 298 1299 6 3513

178 713 6 308 854 182 179 6 276 257 1276 6 757

7.6 6 10.5 7.1 6 9.6 50.0 6 81.1 32.0 6 52.9

7.0 6 9.6 7.8 6 12.4 59.8 6 123.2 34.3 6 57.2

75.5 6 69.6 63.0 6 43.1 262.7 6 360.0 240.5 6 297.2

61.2 6 47.1 53.7 6 37.6 193.0 6 240.0 195.2 6 248.9

50.8 6 38.2 45.6 6 38.3 157.0 6 203.9 148.7 6 155.3

Note.—Data are means 6 standard deviations.

Table 2 AVS Selectivity Based on Basal Ca/Cp and Aa/Ap Ratios Cutoff Value and Side Cutoff value  1.1   Right side   Left side   Both sides Cutoff value  2   Right side   Left side   Both sides Cutoff value  3   Right side   Left side   Both sides

Basal Ca/Cp Ratio (%)

Basal Aa/Ap Ratio (%)

P Value

91.3 (137/150) 98.7 (148/150) 90.0 (135/150)

86.0 (129/150) 99.3 (149/150) 86.0 (129/150)

.31 ..99 .58

72.0 (108/150) 74.0 (111/150) 64.7 (97/150)

78.0 (117/150) 85.3 (128/150) 64.7 (97/150)

.14 .02 ..99

54.7 (82/150) 54.7 (82/150) 46.0 (69/150)

74.0 (111/150) 79.3 (119/150) 56.0 (84/150)

.00002* .000003* .04

Note.—Numbers in parentheses are the data used to calculate the percentages. * P , .05 after Bonferonni correction.

higher cutoff values, sensitivity decreased for all three ratios, between at least 1.1 and at least 2 and between at least 2 and at least 3. However, specificity increased only when the cutoff value was raised from at least 1.1 to at least 2 and remained at 100% thereafter for the three ratios. Sensitivity of the Ca/Cp ratio was not statistically different from the Aa/Ap ratio at all three cutoff values. Sensitivity of the combined ratio was always better than with the Ca/Cp ratio alone or the Aa/Ap ratio alone.

Specificity of the combined ratio (100%) was identical to the two other ratios for the cutoff values of at least 2 and at least 3 and was lower than for the two other ratios for the cutoff value of at least 1.1, although it was not statistically significant. With a cutoff of at least 2, the combined ratio appropriately indicated selectivity in 24 of 97 additional AVS procedures (24.7%) in comparison to the Ca/Cp ratio alone.

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There were no statistically significant differences in sensitivity and specificity of the different ratio and cutoff values when comparing the first half of AVS procedures to the second half of AVS procedures performed in our study and when comparing AVS performed by all operators versus only by the main operator.

Discussion Our study demonstrates the utility of the basal combined ratio to assess the selectivity of AVS performed without ACTH stimulation. This combined ratio improves catheterization selectivity detection at cutoff values of at least 2 and at least 3 compared with the basal Ca/ Cp ratio alone. Accuracy improvement of the combined ratio over the Ca/Cp ratio alone was due to greater sensitivity (of 17.5% and 24.8%, respectively, at cutoff values of 2 and 3) with no loss of specificity (100%). Given that specificity was 100% and sensitivity of Ca/Cp and Aa/Ap ratios was not statistically different, improvement of selectivity detection of the combined ratio was mainly attributed to the fact that basal Aa/Ap and Ca/Cp ratios did not allow selectivity in exactly the same patients, explaining why both ratios were concordant in only 72.1% of cases. 5

VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

Aldosterone hypersecretion from one adrenal vein should have suppressed renin-angiotensin and thus aldosterone secretion from the contralateral adrenal vein, resulting in lower catheterization selectivity detection for the Aa/Ap ratio in comparison to the Ca/Cp ratio. However, our study shows that, in fact, sensitivity of Aa/Ap and Ca/Cp ratios for catheterization selectivity detection was not statistically different (70.8% for both Aa/Ap and Ca/Cp ratios at a cutoff value  2) and that suppression was not significant enough to impair selectivity detection of the Aa/Ap ratio. Our study also suggests that the selectivity cutoff value of at least 2 offers

the best compromise between sensitivity and specificity among the three main cutoff values (1.1, 2, and 3) reported in the literature, offering the best sensitivity for 100% specificity. A selectivity cutoff of at least 3 will decrease catheterization selectivity detection sensitivity without improving specificity, while a selectivity cutoff of at least 1.1 will enhance sensitivity at the cost of significant loss of specificity. Although ACTH stimulation increases the Ca/Cp and Aa/Ap ratios and therefore improves catheterization selectivity detection, almost 50% of centers (8) prefer basal AVS because they fear that ACTH stimulation may affect

Table 3 P Values for Differences in AVS Selectivity for Basal Ca/Cp and Aa/Ap Ratios with Varying Cutoff Levels Cutoff and Side Cutoff between 1.1 and 2   Right side   Left side   Both sides Cutoff between 2 and 3   Right side   Left side   Both sides

Mailhot et al

P Value for Ca/Cp Cutoff Values

P Value for Aa/Ap Cutoff Values

.00000004* .000000003* .0000000004*

.00006* .00001* .000000002*

.0000009* .0000002* .0000003*

.04 .008 .00087*

* P , .05 after Bonferonni correction.

lateralization assessment. However, this implies that a significant number of AVS procedures are unduly regarded as nonselective and interpreted as inconclusive or repeated. The different cutoff values to detect selectivity in nonstimulated and stimulated AVS varied markedly. In earlier studies, investigators did not mention any means to confirm correct catheter positioning in the adrenal veins while performing AVS (15–18). Different Ca/ Cp cutoff values have since been introduced arbitrarily, with each group proposing their own values. In two studies (19,20), investigators explored the performance of different cutoff values on the proportion of selective AVS in nonstimulated conditions, and both of them supported the choice of low Ca/ Cp cutoff values (eg, 1.1). However, one of these studies did not include a reference standard in the detection of selectivity, and the investigators merely calculated the number of “selective” catheterizations by varying cutoff values of the Ca/Cp ratio (20). In the other study, investigators produced receiver operating characteristic curves to assess the performance of different cutoff values for selectivity (ie, 1.1, 1.25, 1.50, and 1.75) compared with a reference standard that consists of a ratio to correctly detect the lateralization

Table 4 Sensitivity and Specificity in the Detection of Bilateral Selectivity by Using Basal Ca/Cp Ratio, Basal Aa/Ap Ratio, and Basal Combined Ratio with Varying Cutoff Values

Ratio and Cutoff Value Ca/Cp ratio   1.1   2   3 Aa/Ap ratio   1.1   2   3 Combined ratio   1.1   2   3

6

Sensitivity

Specificity

No. of True-Negative Findings

No. of False-Positive Findings

No. of False-Negative Findings

No. of True-Positive Findings

Value (%)

95% Confidence Interval

Value (%)

95% Confidence Interval

10 13 13

3 0 0

2 40 68

135 97 69

98.5 70.8 50.4

94.8, 99.8 62.4, 78.3 41.7, 59.0

76.9 100 100

46.2, 95.0 75.3, 100 75.3, 100

7 13 13

6 0 0

8 40 53

129 97 84

94.2 70.8 61.3

88.8, 97.4 62.4, 78.3 52.6, 69.5

53.8 100 100

25.1, 80.8 75.3, 100 75.3, 100

6 13 13

7 0 0

1 16 35

136 121 102

99.3 88.3 75.2

96.0, 100 81.7, 93.2 66.3, 81.5

46.2 100 100

19.2, 100 75.3, 100 75.3, 100

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VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

Table 5 P Values for Differences in Sensitivity and Specificity in the Detection of Bilateral Selectivity for Basal Ca/Cp Ratio, Basal Aa/Ap Ratio, and Basal Combined Ratio with Varying Cutoff Values Parameter Ca/Cp ratio between 1.1 and 2 Aa/Ap ratio between 1.1 and 2 Combined ratio between 1.1 and 2 Ca/Cp ratio between 2 and 3 Aa/Ap ratio between 2 and 3 Combined ratio between 2 and 3 Comparison between combined ratio and Ca/Cp ratio with a cutoff of 1.1 Comparison between combined ratio and Ca/Cp ratio with a cutoff of 2 Comparison between combined ratio and Ca/Cp ratio with a cutoff of 3 Comparison between combined ratio and Aa/Ap ratio with a cutoff of 1.1 Comparison between combined ratio and Aa/Ap ratio with a cutoff of 2 Comparison between combined ratio and Aa/Ap ratio with a cutoff of 3

P Value for Sensitivity

P Value for Specificity

.0000000004* .000000002* .000008* .0000003* .0009* .00004* .07

.25 .04 .02 ..99 ..99 ..99 .13

.000003*

..99

.00000003*

..99

.03

..99

.000003*

..99

.00006*

..99

* P , .05 after Bonferonni correction. On the basis of 12 comparisons, significance was set at ,.0042.

of an aldosterone-producing adenoma that was proven surgically, pathologically, or by means of postmedical treatment evolution (19). The choice of these authors is questionable, however, since there is no clear link between correct catheter positioning and their reference standard. To our knowledge, ours is the first study to use concentration ratios obtained after ACTH stimulation as the reference standard to assess selectivity against which basal AVS can be compared to calculate the diagnostic performance of different cutoff values. Methods of selectivity confirmation, such as ACTH stimulation, cone-beam computed tomography (CT) (21–23), or real-time cortisol assays (24,25), are essential for efficient diagnosis of successful adrenal catheterization. However, these methods may not always be available. Additionally, cortisol assays will increase the procedure time while waiting for the results, and cone-bean CT will increase the radiation expose. Therefore, it is unclear whether these methods should be used systematically or only when there is a doubt about

adequate adrenal catheterization, especially for experienced interventionists. The limitations of our study include its retrospective design and the low number of nonselective samplings, which precluded the assessment of optimal cutoff values. Indeed, contrary to previous investigations that showed successful bilateral AVS rates of 63%– 78% (26–28), our study has a bilateral selective AVS rate of 91.8%, which limits the statistical significance of the comparisons of specificity. The number of nonselective AVS procedures was low in the left adrenal vein because, contrary to the right adrenal vein, the left adrenal vein has relatively constant and easily recognizable anatomy that can be differentiated from other surrounding veins. A cutoff value between at least 1.1 and at least 2 could still offer a better compromise between sensitivity and specificity but, given the low number of nonselective AVS procedures in our study, assessment of this point would not be robust with our data. Therefore, receiver operating characteristic curves of sensitivity and specificity for

Radiology: Volume 000: Number 0—   2015  n  radiology.rsna.org

Mailhot et al

the detection of AVS selectivity have not been calculated because there were relatively few nonselective AVS procedures in our study, so wide variations of sensitivity and specificity would be based on only a few samples. Another limitation of our study is the long study period, which could introduce uncontrolled biases. However, there were no variations in the AVS protocol since the beginning of our study period. Improved operator experience over the years may change the prevalence of selective (vs nonselective) AVS but should not change the sensitivity and specificity of the test, as demonstrated in our subgroup analyses. The definition of selectivity based on a ratio of at least 5 after ACTH stimulation is also arbitrary but corresponds to a cutoff value already accepted in the literature (8), and it is difficult to argue that the catheter could be somewhere other than in the adrenal vein with such a ratio. In addition, in our study, all three samples after ACTH stimulation had concordant Ca/Cp ratio (either ,5 or .5) in 96.5% (95% confidence interval: 91.7%, 98.7%) of the AVS procedures on the right side and in 95.2% (95% confidence interval: 93.45%, 99.55%) of the AVS procedures on the left side. Given that significant variation between the samples may also be due to physiological variation in the cortisol secretion, it is therefore unlikely that catheters could have been dislodged between different samplings. On the other hand, some selective AVS findings may have been considered nonselective because the ratio was lower than 5. Finally, since our criteria for assessing selectivity included the basal Aa/Ap ratio, we also chose to include the Aa/Ap ratio after ACTH stimulation in the definition of the reference standard, although the assessment of selectivity does not traditionally include the Aa/Ap ratio after ACTH stimulation. However, using only the cortisol ratio or only the aldosterone ratio as a reference standard may have led to missed selectivity detection that would then erroneously affect sensitivity and specificity assessment of basal AVS selectivity. In conclusion, the results of our study suggest that the selectivity cutoff 7

VASCULAR AND INTERVENTIONAL RADIOLOGY: Adrenal Vein Sampling in Primary Aldosteronism

value of 2 offers the best compromise between sensitivity and specificity among the three main cutoff values (1.1, 2, and 3) reported in the literature. It also shows that, in primary aldosteronism, the adrenal vein opposite to the one with a dominant source of excess aldosterone is often not completely suppressed, and its residual secretion is sufficient for selectivity detection. Indeed, combination of the aldosterone ratio (Aa/Ap) with the cortisol ratio (Ca/Cp) significantly improved catheterization selectivity detection of basal AVS at cutoff values of at least 2, with no decrease in specificity. Centers in which AVS is performed without ACTH may benefit from combination of the cortisol and aldosterone ratio to improve their AVS selectivity detection. Disclosures of Conflicts of Interest: J.P.M. disclosed no relevant relationships. M.T. disclosed no relevant relationships. G.S. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: author received grants from Siemens Medical, Bracco Diagnostics, and CAE; author received patent licensing from Cook Medical. Other relationships: disclosed no relevant relationships. M.L. disclosed no relevant relationships. M.F.G. disclosed no relevant relationships. P.G. disclosed no relevant relationships. P.S.Z. disclosed no relevant relationships. I.B. disclosed no relevant relationships. V.L.O. disclosed no relevant relationships. A.L. disclosed no relevant relationships. E.T. disclosed no relevant relationships.

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