Prognosis of adrenalectomy guided by computed tomography versus adrenal vein sampling in patients with primary aldosteronism: A systematic review and meta‐analysis

Abstract Adrenal vein sampling (AVS) is recommended to be the gold standard for patients with unilateral subtypes of primary aldosteronism to clinical diagnosis and surgery therapy. However, it is uncertain whether AVS is better for prognosis than computed tomography (CT), which is the most widely used. Pubmed, Embase, and Cochrane Library were searched for articles with no start date restriction. The last search was conducted on Jun 15, 2021. Eligible studies compared the distinct subtypes of primary aldosteronism by AVS with CT (as a control group) and reported the prognosis at follow‐up. Evaluation of cohort studies referred to Newcastle ‐ Ottawa Quality Assessment Scale, and randomized controlled trials referred to Updated Cochrane Collaboration tool. A random‐effect model or fixed‐effect model was chosen according to the heterogeneity test. All processes were performed following the PRISMA 2020 statement. Eleven studies were identified, including 1325 patients based on AVS and 907 patients based on CT. Compared with patients guided by CT, patients who underwent AVS had an increased possibility of complete biochemical success (odds ratio [OR] 2.78, 95% CI 1.88–4.12) and a decreased chance of absent biochemical success (OR 0.23, 95% CI 0.13–0.40) at follow‐up. Nevertheless, the rate of complete clinical success (OR 1.09, 95% CI 0.89–1.35) and absent clinical success (OR 0.96, 95% CI 0.68–1.33) had no significant difference. Therefore, distinguishing subtypes by AVS for early treatment may be crucial since it can promote biochemical improvement.

reverse target organ damage. 8 To choose optimal clinical management, correctly dividing primary aldosteronism into unilateral or bilateral subtypes is the key factor. 9 Surgery is indicated for unilateral subtypes, and lifelong use of mineralocorticoid antagonists is suitable for patients with bilateral subtypes. 9 There are two main methods to distinguish the subtypes of primary aldosteronism, adrenal vein sampling (AVS) and computed tomography (CT).
CT is widely used to distinguish unilateral from bilateral primary aldosteronism in clinical practice, yet it can be misleading. A systematic review asserted that 14.6% of patients are diagnosed as unilateral by CT while AVS diagnose as bilateral. 10 The adenoma showed by CT on the contrary side occupies 3.9%, which will lead to the wrong removal of the contralateral adrenal. 10 AVS is an invasive way to detect both adrenal glands' secretory function, 11 which is considered the gold standard for determining the laterality of primary aldosteronism.
Endocrine Society guidelines recommend that patients with primary aldosteronism should undergo AVS unless meeting the following conditions at the same time: age < 35 years old, spontaneous hypokalemia, significantly increased aldosterone concentration, and imaging showing adrenal cortical adenomas. 9 However, some current evidence has cast uncertainty of the benefits after adrenalectomy by AVS. 12 In 2016, a randomized diagnostic trial in 92 patients (46 used CT and 46 used AVS) found no significant difference in blood pressure control and biochemical improvement at 1-year follow-up. 13 But recently, two international multicenter cohort studies showed patients after AVS classification 14 could obtain a better prognosis, reflected in a higher rate of cure of hypertension and a decreased likelihood of achieving complete biochemical success. 15 Therefore, the results of the prognosis of adrenalectomy guided by CT versus AVS in patients with primary aldosteronism are highly heterogeneous. All single-center studies have fewer than 50 patients in at least one group.
Given the high morbidity of primary aldosteronism and the life-long severe consequences caused by the wrong resection, it is necessary to conduct a systematic review and meta-analysis including all published cohort studies and randomized controlled trials to explore clinical and biochemical benefits after adrenalectomy among patients with unilateral primary aldosteronism classified under CT and AVS guidance.

Identification and selection criteria
Pubmed, Embase, and Cochrane Library were searched for relevant articles using terms associated with primary aldosteronism and adrenalectomy (eg, "hyperaldosteronism" "primary aldosteronism" or "Conn syndrome", and the following terms: "surgery" or "adrenalectomy") from inception to January 21, 2021. A traceability search on the references of reviews and related documents of each included study was conducted. The last search was conducted on June 15, 2021, and a new study was discovered, but it was a duplicate report, so no new studies were included. 16  Quality Assessment Scale. 17 The Updated Cochrane Collaboration tool was used to assess the eligible randomized controlled trial's methodological quality (Table S2). 18 Any disagreements in abstracted data and assessment quality were adjudicated by a third reviewer (Y.Q.).

Outcomes
The outcomes for the analysis included the rate of complete, partial, And the other condition, normalization of the aldosterone-to-renin ratio, could be replaced, in patients with a raised aldosterone-to-renin ratio post-surgery, by suppressed aldosterone secretion in a confirmatory test. Absent biochemical success refers to persistent hypokalemia or persistent increased aldosterone-to-renin ratio, or both, as well as failure to suppress aldosterone secretion in the post-surgery confirmatory test. Besides, partial success lies between complete and absent.
The definitions of clinical and biochemical success in this study were summarized in Table S3.

Data analysis and synthesis
Categorical variables are reported as n/N (%). Continuous variables were expressed as mean (SD) or median (IQR). For the data that cannot be directly included in the meta-analysis, data conversion was carried out according to Luo and coworkers 20 and Wan and coworkers. 21 Mantel-Haenszel method for categorical variables and Inverse-Variance method for continuous variables calculated the odds ratio with 95% confidence interval (95% CI). Heterogeneity was assessed. When I 2 ≥ 75%, a random-effect model was applied; otherwise, a fixed-effect model was used. Subgroup analysis was conducted according to whether AVS is performed with guidance by CT results, and the detailed criteria were shown in Table S4. Sensitivity analysis was conducted using a random-effect model, excluding the studies with the largest sample size, high-risk bias studies, and the randomized controlled trial. Funnel plots were used to check for research publication bias.
The systematic review and meta-analysis was performed following the PRISMA 2020 statement. 22 All analyses did with Revman 5.3.
p < 0.05 was considered statistically different, based on the two-tailed test.

Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author Y.Q. had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Study characteristics
Eleven studies [13][14][15][23][24][25][26][27][28][29][30] were included in the analysis (detailed literature search described in Figure 1), including 1325 primary aldosteronism patients who underwent adrenalectomy guided by AVS and 907 patients guided by CT. Characteristics of the studies meeting the criteria and included in the final meta-analysis were in Tables 1 and   S5. There were one randomized controlled trial and ten cohort studies. Two cohort studies were at high risk of bias, and others were low or moderate risks (Table S2). Six of the seven items in the Updated Cochrane Collaboration tool for the randomized controlled trial were low risks, so the overall evaluation was low.

Clinical outcomes
The rate of clinical success was shown in
Only one study reported the aldosterone-renin ratio at followup and found that patients guided by AVS had a significantly lower ratio compared with patients guided by CT. Among three studies that reported the plasma renin activity, one large-sample study reported AVS-guided patients had higher activity than CT-guided patients, while the other two small-sample studies found no difference (Table S6).

Sensitivity analyses
Sensitivity analysis was conducted using a random-effects model for clinical and biochemical success rates, and there were no statistical changes in the six indicators ( Figure S3) Figure S3).

Reporting biases
No obvious bias was found for the four main indicators: complete clinical success, absent clinical success, complete biochemical success, and absent biochemical success ( Figure S4).  AVS can directly detect the bilateral adrenal glands' function and is defined as the gold standard by the guidelines. Therefore, if treatment is given based on the correct diagnosis, better benefits should be obtained. Our results also suggest that it has a clear benefit for biochemistry, but we did not find its clinical benefit. There are two aspects of possible reasons.

DISCUSSION
On the one hand, the technique and interpretation criteria of AVS are challenging. 31 The absence of ACTH stimulation will increase intubation failure, 32 and using ACTH stimulation will increase the misdiagnosis rate of AVS. 33 Different judgment standards about selectivity index and lateralization index will also affect AVS results. 34 Besides, for some patients with severe or refractory hypertension, AVS may be performed without withdrawn drug interference, thereby reducing the accuracy of diagnosis. 35 Moreover, even if AVS diagnosed patients with unilateral hypersecretion, its internal differences can also affect the outcome of the operation. For example, if AVS shows suppression of the contralateral adrenal gland secretion, there will be a higher possibility of cure of the hypertension 36 and develop to hyperkalemia 37 after unilateral adrenalectomy. An adrenal nodule on preoperative imaging referred to improved blood pressure control and preserved renal function after adrenalectomy guided by AVS. 38 On the other hand, the control of blood pressure is affected by many factors, so the corresponding benefit may not be seen. Complete biochemical success demonstrates a correct diagnosis of unilateral primary aldosteronism and total resection of the pathological adrenal gland. 19 Although high BMI can increase plasma aldosterone levels because of the positive feedback relationship between the secre-tion of adipokines leptin and aldosterone, 39 the biochemical result may still be the best indicator to show the value of AVS. The lack of clinical remission may attribute to not only inappropriate distinguish but also a complication with essential hypertension or chronic kidney disease or subclinical hypercortisolism, 40 long duration of hypertension, as well as male sex, elderly patients, KCNJ5 mutation carriers, 41 etc. Proye and coworkers reported that the prevalence of hypertension was almost the same in postoperative patients as the prevalence of essential hypertension in a random population of the same age. 42 Moreover, the PASO study also reported that the median time for the duration of hypertension was 5 years in patients with complete clinical success after surgery, while 10 years in those with partial or absent clinical success. 19 Nevertheless, regardless of whether blood pressure and antihypertension drugs improvement, correction of excessive aldosterone and increasing renin concentration themselves reduced risk for cardiovascular events, mortality, 43 and renal damage, 44 by inhibiting mineralocorticoid receptor activation. Current studies also suggested that partial or total adrenalectomy may have a different impact on the prognosis of primary aldosteronism. 45,46 Among included studies, only two studies have reported whether unilateral adrenalectomy was partial or complete 13,15 and one patient of partial adrenalectomy was performed at the patient's request, 13 therefore needing further studies to explore the impact of surgical procedure on the prognosis of primary aldosteronism.
As an imaging examination method, CT is difficult to find microade- included. After excluding the randomized controlled trial, there was no effect on the overall results, but more randomized controlled trials are still needed to provide stronger evidence.
In conclusions, AVS classification can promote the postoperative biochemical improvement of patients with primary aldosteronism, but it has not been proved beneficial to the advancement of clinical conditions, suggesting the necessity to focus not only on clinical outcomes but also biochemical outcomes when evaluating the prognosis of adrenalectomy in patients with primary aldosteronism. Meanwhile, this study will be meaningful for the popularity of AVS in the future.
To obtain a more reliable conclusion in the future, researchers need a stricter diagnosis and treatment process for the primary aldosteronism, standard AVS operation, uniform CT parameters, strict follow-up, and classification results.

ACKNOWLEDGMENTS
We appreciate the collaboration and would like to thank Professor Tao Xu from Peking University People's Hospital for his support in the preparation of this manuscript.

CONFLICT OF INTEREST
The authors declared no conflict of interest.