Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Monticone S, D Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 017; published online Nov 9.

2 Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis Silvia Monticone *, Fabrizio D Ascenzo *, Claudio Moretti, Tracy Ann Williams, Franco Veglio, Fiorenzo Gaita, Paolo Mulatero 7 Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova, 101, Torino, Italy (Silvia Monticone, MD; Tracy Ann Williams, PhD; Prof Franco Veglio, MD; Paolo Mulatero, MD). 8 9 Division of Cardiology, Department of Medical Sciences, University of Torino, Corso Dogliotti 1, 101, Torino, Italy (Fabrizio D Ascenzo, MD; Claudio Moretti, MD; Prof. Fiorenzo Gaita, MD) Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany (Tracy Ann Williams, PhD) 1 * Equal contribution 1 Corresponding author: 1 1 Paolo Mulatero, MD, Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Via Genova, 101, Torino, Italy. 1 paolo.mulatero@unito.it 17 Phone: Fax: Word count: summary 0; manuscript,8 (excluding references, figure legends and tables) 19 Key words: aldosterone, primary aldosteronism, target organ damage, cardiovascular events 0 1

3 Study Diagnosis of hypertension Diagnosis of heart failure Diagnosis of diabetes mellitus Diagnosis of metabolic syndrome Curione M., 01 1 n.a. n.app. n. app. Patients with diabetes were According to ATPIII excluded Fallo F., 00 According to the WHO-ISH 1999 n.app. According to the report of the expert According to ATPIII Guidelines 1 committee on the diagnosis and classification of diabetes mellitus Fischer E., 01 n.a. n.app WHO diagnostic criteria for diabetes mellitus 0 According to IDF criteria Alberti et al., 009. Hanslik G., 01 n.a. n.app. MEPHISTO patients: I) when subjects reported a respective physician s diagnosis; II) had an HbA1c >.%; III) fasting serum glucose concentrations >7.0 mmol/l or IV) a According to IDF criteria Alberti et al., 009. For SHIP1, this definition had to be adapted to compensate for the nonfasting blood sampling conditions. When subjects fulfilled at least three positive OGTT result ( h serum out of five diagnostic criteria, the glucose concentration >11.1 mmol/l). SHIP1 patients: I) when subjects reported a respective physician s MetS was present. These criteria include a waist circumference >9 cm in men or >80 cm in women; diagnosis; II) had an antidiabetic treatment or fasting HbA1c >.%; III) non-fasting glucose serum glucose concentrations >11.1 >. mmol/l (MEPHISTO) or nonfasting glucose mmol/l or IV) intake of antidiabetic >8 mmol/l (SHIP1); HDL-cholesterol medication. >1.0 mmol/l in men or >1. mmol/l in women; lipidlowering treatment or fasting triglycerides >1.7 mmol/l (MEPHISTO), or non-fasting triglycerides >. mmol/l (SHIP1); antihypertensive treatment, or systolic blood pressure >10 mmhg, or diastolic blood pressure >8 Iacobellis G., 010 According to the 007 ESH/ESC guidelines for the management of arterial hypertension 17 mmhg. n.app. n.app. According to ATPIII

4 Matrozova J., 009 n.a. n.app. According to the American Diabetes n.app. Association guideline Monticone S., According to the 007/01 HF requiring hospitalization According to ADA guideline 01 According to ATPIII ESH/ESC guidelines for the management of arterial hypertension 17,18 Mulatero P., 01 8 According to the 007 ESH/ESC HF requiring hospitalization According to ADA guideline 01 n.app. guidelines for the management of arterial hypertension 17 Murata M., n.a. HF requiring hospitalization ADA Executive summary, 01 n.app. Prejbisz A., According to the 007 ESH/ESC guidelines for the management of arterial hypertension 17 n.app. According to the 007 ESH/ESC guidelines for the management of arterial hypertension 17 According to ATPIII Reincke M., Blood pressure 10 / 90 mm Hg and / or current use of antihypertensive drugs n.app. Savard S., 01 1 n.a. Pulmonary congestion, decompensated heart failure, or exertional dyspnea associated with a left ventricular ejection fraction on echocardiography <% by the - dimensional method Known history of diabetes mellitus at the time of diagnosis of PA Somloova Z., n.a. n.app. n.a. According to the IDF criteria Alberti et al Takeda R., n.a. n.a. n.app. n.app. Widimsky J., n.a. n.app. According to ADA guideline 000 n.app. Supplemental Table S1. Criteria adopted for the diagnosis of hypertension, heart failure, diabetes mellitus and metabolic syndrome across studies. n.a. = not available; n.app. = not applicable; ESC = European Society of Hypertension; ESC = European Society of Cardiology; ADA = American Diabetes Association; ATPIII = Adult Treatment Panel III; HF = heart failure; OGTT = oral glucose tolerance test; IDF = International Diabetes Federation; PA = primary aldosteronism; WHO = World Health Organization; ISH = International Society of Hypertension n.a. n.app. n.app.

5 Study Fallo F., 00 Milliez P., 00 7 Monticone S., Savard S., 01 1 Criteria to define left ventricular hypertrophy Cornell voltage duration product (>,0 mm*ms) or Sokolow-Lyon criteria (> 8 mv) on electrocardiogram LVMI > 1 g/m (male) or > 110 g/m (female) LVMI 0 g/m.7 and LVMI 11 g/m (male) or 9 g/m (female) LVMI 0 g/m.7 (male) or 7 g/m.7 (female) and LVMI 11 g/m (male) or 9 g/m (female) Tanabe A., LVMI 1 g/m 1 Supplemental Table S. Criteria adopted to define left ventricular hypertrophy. LVMI = left ventricular mass index.

6 Study Exclusion criteria Abad-Cardiel M., 01 9 Diagnosis of PA not in agreement with the ES 9,0 / JES 1 guideline (confirmatory testing not performed) Born-Frontsberg E., Gaddam K., Hidaka T., 01 Janota T., 199 Lee H.H., 01 Liao M.T., 01 Lin Y.H., 011a Lin Y.H., 011b 7 Lin Y.H., 01 8 Litchfield W.R., Nishimura M., Rossi G.P., Rossi G.P., 1997 Rossi G.P., 1998 Rossi G.P., 00 Prevalence of cardio and cerebrovascular comorbidities was analyzed in patients with hypokalemic and normokalemic PA. Lack of patients affected by EH as control group. Diagnosis of PA not in agreement with the ES guideline 9,0 Echocardiographic parameters were compared between patients affected by APA and patients affected by BAH. Lack of patients affected by EH as control group. Diagnostic criteria for PA not available Duplicate report Duplicate report Duplicate report Duplicate report Duplicate report Prevalence of cerebrovascular complication was explored in patients affected by GRA. Lack of patients affected by EH as control group. Prevalence of cardiovascular complications was explored in patients affected by APA. Lack of patients affected by EH as control group. Duplicate report Duplicate report Duplicate report Duplicate report Shigematsu Y., 1997 Diagnosis not in agreement with the ES 9,0 /JES 1 guidelines

7 Su M.-Y. M, 01 Tsioufis C., Echocardiographic parameters were evaluated in PA patients and age matched healthy (not hypertensive) volunteers. Patients with essential hypertension were used as control group, but PA and EH patients were matched also for LVMI Yoshihara F., Diagnosis not in agreement with the ES 9,0 /JES 1 guidelines 1 Supplemental Table S. Excluded studies and criteria for exclusion ES = Endocrine Society; JES = Japan Endocrine Society; PA = aldosterone producing adenoma; BAH = bilateral adrenal hyperplasia; MetS = metabolic syndrome; LVMI = left ventricular mass index; GRA = Glucocortcoid Remediable Aldosteronism; EH = essential hypertension;

8 Study Type of matching Parameters of matching Catena C., 007 Clinical Age, gender, BMI, duration of hypertension Catena C., 008 Clinical Age, gender, BMI, duration of hypertension Fisher E., 01 Clinical Age, BMI Goldkorn R., 00 Clinical Age, gender, blood pressure Hanslick G., 01 Clinical Age, gender, BMI, blood pressure Kozakova M., 00 7 Clinical Age, gender, BMI, blood pressure Matrozova J., 009 Clinical Age, gender Milliez P., 00 7 Clinical Age, gender, blood pressure Muiesan M.L., Clinical Age, gender, blood pressure Mulatero P., 01 8 Clinical Age, gender, BMI, duration of hypertension, blood pressure, smoking habits, comorbidity for type diabetes mellitus Reincke M., Clinical Age, gender, blood pressure Reincke M., 01 Clinical Age, gender, BMI, blood pressure Savard S., 01 1 Clinical Age, gender, blood pressure Somlova Z., Clinical Age Takeda R., Clinical Age, gender Widimsky J., Clinical Age, BMI Supplemental Table S. Type of matching and parameters of matching of the included studies. BMI = body mass index. 7

9 Parameter,88 patients with PA 9,8 patient with EH (n of studies / n of patients) Age (years) [8-] [-] (/1,1) Female gender (%) 8 [-] [1-9] (8/1,99) Diabetes mellitus (%) 17 [1-1] 1 [9-17] (10/8,87) Hyperlipidemia (%) 1 [-] 9 [-] (11/9,80) BMI (Kg/m ) 8 [-] [1-9] (18/9,97) Duration of hypertension (years) (1/8,1) 8.8 [.-10.7] 7. [.7-9.8] Supplemental Table S Baseline features of included patients. Data are reported as median and [IQR] or as percentage

10 Biochemical parameters (n of studies / n of patients) Serum creatinine (µmol/l) (9/909) Serum K + (meq/l) (7/0) PRA (ng/ml/h),88 patients with PA 79. [ ]. [.1-.] 0. [0.1-0.] (10/1) 1 Aldosterone (pmol/l) (/,07) - serum (1/99) - plasma (/,97) 89 [09-1,188] 9 [-1100] Supplemental Table S. Baseline features of PA patients. Data are reported as median and [IQR]

11 Evaluated Features Number of studies (%) Multicenter 1 (9) Prospective 10 () Selection bias: - Low - Medium - High - Unclear Attrition bias: - Low - Medium - High - Unclear Adjudication bias: - Low - Medium - High - Unclear (9) 0 () 0 (0) 8 () 8 (91) (9) 0 (0) 0 (0) 0 (0) (9) 8 (91) 0 (0) Supplemental Table S7. Qualitative evaluation of studies. 10

12 SUPPLEMENTAL FIGURES Supplemental figure S1. Random effect analysis to analyse the difference of proportion of females between EH and PA. 11

13 Supplemental figure S. Meta-regression analysis for stroke, showing that the proportion of females in the studies did not impact significantly the results

14 Supplemental figure S. Meta-regression analysis for CAD, showing that the proportion of females in the studies did not impact significantly the results

15 7 Supplemental figure S. Forest plot of the odds ratio of stroke in patients with PA and EH, including exclusively the studies in which blood pressure was a matching criterion. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH)

16 Supplemental figure S. Forest plot of the odds ratio of atrial fibrillation in patients with PA and EH, including exclusively the studies in which blood pressure was a matching criterion. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH). 7 1

17 Supplemental figure S. Forest plot of the odds ratio of heart failure in patients with PA and EH, including exclusively the studies in which blood pressure was a matching criterion. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH). 7 1

18 Supplemental figure S7. Forest plot of the odds ratio of coronary artery disease in patients with PA and EH, including exclusively the studies in which blood pressure was a matching criterion. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH)

19 7 Supplemental figure S8. Forest plot of the odds ratio of stroke in patients with PA and EH, after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH). 18

20 Supplemental figure S9. Forest plot of the odds ratio of CAD in patients with PA and EH, after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH). 19

21 Supplemental figure S10. Forest plot of the odds ratio of AF in patients with PA and EH, after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH). 0

22 Supplemental figure S11. Forest plot of the odds ratio of diabetes in patients with PA and EH. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in odds ratio between patients with PA and patients with EH). 1

23 Supplemental figure S1. Forest plot of the odds ratio of metabolic syndrome in patients with PA and EH. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in odds ratio between patients with PA and patients with EH).

24 Supplemental figure S1. Forest plot of the odds ratio of diabetes in patients with PA and EH, after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH).

25 Supplemental figure S1. Forest plot of the odds ratio of MetS in patients with PA and EH, after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in the odds ratio between patients with PA and patients with EH).

26 Supplemental Figure S1. Forest plot of left ventricular mass indexed to height (g/m.7 ) in patients with PA and EH. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups.

27 Supplemental figure S1. Forest plot of left ventricular mass indexed to body surface area (g/m ) in patients with PA and EH. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups.

28 Supplemental figure S17. Forest plot of intraventricular septum (mm) in patients with PA and EH. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups. 7

29 Supplemental figure S18. Forest plot of posterior wall (mm) in patients with PA and EH. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups. 8

30 Supplemental figure S19. Forest plot of the odds ratio left ventricular hypertrophy in patients with PA and EH. Central squares of each horizontal line represent the odds ratio for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line indicates the odds ratio of 1.0 (which indicates no differences in odds ratio between patients with PA and patients with EH). 7 9

31 Supplemental figure S0: Forest plot of left ventricular mass index (g/m.7 ) in patients with PA and EH including exclusively the studies in which blood pressure was a matching criterion. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups

32 Supplemental figure S1: Forest plot of left ventricular mass index (g/m.7 ) in patients with PA and EH after subdivision in prospective and retrospective studies. Central squares of each horizontal line represent the mean difference for each study. Horizontal lines indicate the range of the 9% confidence interval and the vertical line at zero indicates no difference between groups. 1

33 Supplemental figure S. Forest plot of comparison of the odds ratio of stroke in APA and BAH patients compared to EH patients (above) and in APA vs. BAH (below).

34 Supplemental figure S. Forest plot of comparison of the odds ratio of CAD in APA and BAH patients compared to EH patients (above) and in APA vs. BAH (below).

35 Supplemental figure S. Forest plot of comparison of the odds ratio of AF in APA and BAH patients compared to EH patients (above) and in APA vs. BAH (below).

36 Supplemental figure S. Funnel plot for risk of stroke (right) and CAD (left). The plots represent the visual graphical assessment of publication bias.

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