RESEARCH PROTOCOL. Primary aldosteronism in general practice: organ damage, epidemiology and treatment (PAGODE)

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1 NL PAGODE RESEARCH PROTOCOL Primary aldosteronism in general practice: organ damage, epidemiology and treatment (PAGODE)

2 NL PAGODE PROTOCOL TITLE: Primary aldosteronism in general practice: organ damage, epidemiology and treatment Protocol ID NL Short title PAGODE Version 2 Date May 2014 Coordinating investigator/project Dr J Deinum leader from the department of Department of Internal Medicine, Internal Medicine Radboud university medical center, P.O. Box 9101, Internal Code 463, 6500 HB Nijmegen The Netherlands Tel.: Jaap.Deinum@radboudumc.nl Coordinating investigator/project Dr MCJ Biermans leader from the department of Department of Primary and Community Care Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Marion.Biermans@radboudumc.nl Principal investigator from the Dr J Deinum department of Internal Medicine Department of Internal Medicine, Radboud university (in Dutch: medical center, P.O. Box 9101, Internal Code 463, hoofdonderzoeker/uitvoerder 6500 HB Nijmegen vanuit de afdeling Algemeen The Netherlands Interne Geneeskunde) Tel.: Jaap.Deinum@radboudumc.nl

3 NL PAGODE Principal investigator from the department of Primary and Community Care (in Dutch: Hoofdonderzoeker/uitvoerder vanuit de afdeling Eerstelijnsgeneeskunde) Research leader from the department of Primary and Community Care Internist-researcher/advisor from the department of Internal Medicine General Practitionerresearcher/advisor from the department of Primary and Community Care Dr MCJ Biermans Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Dr TR Schermer Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Prof dr JWM Lenders Department of Internal Medicine, Radboud university medical center P.O. Box 9101, Internal Code 463, 6500 HB Nijmegen The Netherlands Tel.: Dr WJC de Grauw Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.:

4 NL PAGODE Junior researcher Junior researcher Statistician Data manager Drs SC Käyser Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Drs JHCC van Happen Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Mr JHJ Bor Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Mr HJG Peters Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.:

5 NL PAGODE Research assistant Sponsor (in Dutch: verrichter/opdrachtgever) Independent physician Laboratory site Pharmacy Ms L Peters-van Gemert Department of Primary and Community Care Radboud university medical center P.O. Box 9101, Internal Code 117, 6500 HB Nijmegen The Netherlands Tel.: Lea.Peters-vanGemert@radboudumc.nl Radboud university medical center Dr NP Riksen Department of Internal Medicine, Radboud university medical center, P.O. Box 9101, Internal Code 463, 6500 HB Nijmegen The Netherlands Tel.: Niels.Riksen@radboudumc.nl Stichting Huisartsenlaboratorium Oost (SHO) Florijnweg JP Velp Tel.: Not applicable

6 NL PAGODE PROTOCOL SIGNATURE SHEET Name Signature Date For non-commercial research, Head of Department: Prof dr WJJ AssendelftDepartment of Primary and Community Care, Radboud university medical center Coordinating investigator/ project leader from the department of Internal Medicine: Dr J Deinum Department of Internal Medicine, Radboud university medical center Coordinating investigator/project leader from the department of Primary and Community Care: Dr MCJ Biermans Department of Primary and Community Care Radboud university medical center

7 NL PAGODE TABLE OF CONTENTS 1. SUMMARY INTRODUCTION AND RATIONALE Primary aldosteronism Prevalence Organ damage OBJECTIVES STUDY DESIGN Study design Duration Setting Flowchart STUDY POPULATION Population (base) Selection criteria For consideration Sample size calculation TREATMENT OF SUBJECTS METHODS Study parameters/endpoints Main study parameter/endpoint Secondary study parameters/endpoints Study procedures Part 1: screening for PA Part 2: determining cardiovascular and renal damage Part 2: patients with increased ARR Part 2: patients with normal ARR Withdrawal of individual subjects Premature termination of the study SAFETY REPORTING Section 10 WMO event Adverse events and serious adverse events Follow-up of adverse events Data Safety Monitoring Board (DSMB) STATISTICAL ANALYSIS statistical analyses part statistical analyses part ETHICAL CONSIDERATIONS Regulatory statement Recruitment and consent Recruitment and consent part Recruitment and consent part

8 NL PAGODE 10.3 Objection by minors or incapacitated subjects Benefits and risks assessment, group relatedness Compensation for injury Incentives ADMINISTRATIVE ASPECTS AND PUBLICATION Handling and storage of data and documents Monitoring and Quality Assurance Amendments Annual progress report End of study report Public disclosure and publication policy Publication Authorship REFERENCES APPENDICES Appendix A: Standard blood assessment at hypertension Appendix B: Diagnosing hypertension in general practice Appendix C: Criteria for urgent referral Appendix D: Risk table Appendix E: Additional risk factors Appendix F: Lifestyle counselling in hypertension Appendix G: Information leaflet part Appendix H: Referral criteria for general practitioners at hypertension Appendix I: Protocol sodium loading test Appendix J: Letter and information leaflet part 2: patients with increased ARR Appendix K: Letter and information leaflet part 2: patients with normal ARR Appendix L: Declaration of Helsinki Appendix M: Datamanagement plan PAGODE... 78

9 9 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABI ABPM APA ARR ATC BAH BMI cm DBD DSMB egfr EMRs kg/m 2 GP HIS HDL HVZ ICC IRMA LDL MDRD METC mg mmhg mmol/l MRA NHG PA Pmol/l pmol/mu PNG Ankle-brachial index Ambulatory Blood Pressure Monitoring Aldosterone Producing Adenoma Aldosterone to Renin Ratio Anatomical Therapeutic Chemical Bilateral Adrenal Hyperplasia Body Mass Index centimetre Diastolic Blood Pressure; in Dutch: Diastolische Bloeddruk Data Safety Monitoring Board estimated Glomerular Filtration Rate Electronic Medical Records kilograms per meter squared General Practitioner General Practice Information System (in Dutch: Huisarts Informatie Systeem) High Density Lipoprotein Cardiovascular Diseases; in Dutch: Hart- en Vaatziekten Intracluster Correlation Coefficient Immunoradiometric assay Low Density Lipoprotein Modification of Diet in Renal Disease Medical Research Ethics Committee (MREC); in Dutch: Medisch Ethische Toetsing Commissie (METC) milligram millimetres of Mercury; in Dutch: millimeter kwik millimol per litre Mineralocorticoid Receptor Antagonist (spironolactone or eplerenone) Dutch Society of General Practitioners; in Dutch: Nederlands Huisartsen Genootschap Primary Aldosteronism Picomol per liter picomol per milli-unit; in Dutch: picomol per milli-eenheid Practice Nurse in General practice; in Dutch: POH, Praktijk Ondersteuner

10 10 van de Huisarts PWV SAE SBD SHO SLT Sponsor TC TRH WHO WMO Pulse Wave Velocity Serious Adverse Event Systolic Blood Pressure; in Dutch: Systolische Bloeddruk Centre for Medical Diagnostics; in Dutch: Stichting Huisartsenlaboratorium Oost Sodium Loading Test The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party Triglycerides Therapy Resistant Hypertension World Health Organization Medical Research Involving Human Subjects Act; in Dutch: Wet Medischwetenschappelijk Onderzoek met mensen

11 11 1. SUMMARY Rationale: Primary aldosteronism (PA) is the most frequent form of secondary hypertension. It is caused by autonomous secretion of aldosterone, encompassing a group of disorders which is for more than 99% predominated by unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). Diagnosis of PA is relevant for two reasons: 1) independent of the level of blood pressure, hypertension due to autonomous aldosterone secretion causes more cardiovascular damage than essential hypertension; 2) PA requires specific treatment: adrenalectomy in case of APA and mineralocorticoid receptor antagonists (MRA) in case of BAH. Although previously presumed a rare condition (prevalence <1%), PA is now estimated to affect 6 to 20% of the hypertensive population. Given this high prevalence of PA, as well as the amount of cardiovascular damage and the available specific treatment, the question has been raised whether screening of PA should be introduced in Dutch general practice. To answer this important question, several issues with regard to PA need to be elucidated: 1) International studies report a prevalence of PA in general practice of 6-13%. Prevalence in the Dutch population is still unknown; 2) Up to now, the laboratory test for screening for PA, the aldosterone/renin ratio (ARR), is primarily used in secondary care. The relation between the ARR and outcomes in primary care is unknown; 3) Because of underdiagnosis of PA and long delay in diagnosis of PA after recognition of hypertension (mean eight years), data on characteristics of early diagnosed PA are lacking. Indications of early cardiovascular damage would strengthen the case of screening for PA and needs to be studied. Objectives: 1.1) to assess the proportion of patients with PA in newly diagnosed hypertensive patients 1 in Dutch general practice (part 1 of this study); 1.2) to study the relation between the ARR and the blood pressure response to treatment in newly diagnosed hypertensive patients in general practice (part 1 of this study); 2) to explore cardiovascular and renal damage in PA patients with newly diagnosed hypertension in comparison to a control group of patients with newly diagnosed essential hypertension, stratified by sex, age, and 24-hour baseline blood pressure (part 2 of this study). 1 Definition of newly diagnosed hypertensive patients: the patients are not previously diagnosed with hypertension and hitherto untreated with antihypertensive medication for hypertension.

12 12 Study design: cross-sectional study (objective 1.1), prospective cohort study (objective 1.2), case-control study (objective 2). Study population: 1100 adults with newly diagnosed hypertension in general practice Main study parameters/endpoints: Objective 1.1: the proportion of patients with PA in newly diagnosed hypertensive patients screened at the Stichting Huisartsenlaboratorium Oost (SHO). Objective 1.2: blood pressure measured in general practice after 3 months of treatment. Objective 2: cardiovascular and renal damage in cases and controls, as measured by a) left ventricular mass index, b) intima-media thickness, c) pulse-wave velocity, d) central aortic blood pressure, e) flow-mediated dilation, f) ankle-brachial index, g) and albuminuria. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: ln part 1 of the study all newly diagnosed hypertensive patients will extend their standard diagnostic blood examination with an additional blood sample to determine the aldosterone-renin ratio (ARR), this causes neither extra burden nor risk. In order to obtain a reliable estimate of the prevalence of PA, it is important to collect an ARR from every patient with newly diagnosed hypertension; Patients with an increased ARR will be referred to our hospital for a sodium loading test to confirm or exclude PA. This requires a visit to the hospital; the examination takes about 4,5 hours. In part 2, PA patients and controls will be asked to participate in additional examinations, which include a 24-hour blood pressure measurement, a cardiac ultrasound, five noninvasive vascular measurements, and a urine test. o The 24-hour blood pressure measurement requires two visits 24 hours apart to the general practice for fitting and removal of the 24-hour blood pressure monitor. This measurement is safe and painless, but can be a bit uncomfortable as some patients wake up at night as the cuff inflates. o The remaining examinations require at least a second visit to the hospital for PA patients and one visit for controls; all together this enhanced diagnostic workup will take 2 hours. These examinations encompass the following risks and burden: a. Left ventricular mass index by cardiac ultrasound: negligible risk, no pain; b. Intima-media thickness of carotid artery by ultrasound: negligible risk, no pain; c. Pulse wave velocity by Sphygmocor: negligible risk, no pain; d. Central aortic blood pressure by Sphygmocor: negligible risk, no pain;

13 13 e. Endothelial function by flow-mediated dilation of the brachial artery: negligible risk, uncomfortable feeling in arm during examination; f. Ankle-brachial index by Doppler ultrasound: negligible risk, no pain. g. Albuminuria by urine sample: negligible risk, no pain. Patients with an increased ARR may directly benefit to a large extent from participation, because if PA is diagnosed, they will not have the usual diagnostic delay of PA of eight years; Patients in the control group will benefit from participation at an individual level. The results of the diagnostic workup can be used as contributing factors in the assessment of their cardiovascular risk profile (NHG-guideline Cardiovascular risk management ).

14 14 2. INTRODUCTION AND RATIONALE 2.1 Primary aldosteronism Within the last 20 years, primary aldosteronism (PA) shifted from a rare cause of hypertension (<1% of the hypertensive population) into the most frequent cause of secondary hypertension, affecting 6 to 20% of all hypertensive patients 1-6. This range can be explained by the use of various definitions of PA, differences in patient selection (primary care, referral centres, degree of hypertension), other diagnostic procedures, and the current rediscovery of the normokalemic variant of primary aldosteronism leading to a higher vigilance for detection 7,8. In this study PA will be defined as a group of disorders in which aldosterone production is inappropriately high, relatively autonomous from the renin-angiotensin system, and nonsuppressible by sodium loading 9. The two major subtypes of PA are the aldosterone-producing adenoma (APA; 30-50% of the cases) and bilateral adrenal hyperplasia (BAH; 50-70% of the cases). Both causes of secondary hypertension require a different treatment of essential hypertension: APA is preferably treated by adrenal surgery (which results in reduction of blood pressure and normalization of possible hypokalemia), while BAH is treated with mineralocorticoid receptor antagonists (MRA). Signs suggestive of PA are hypokalemia (spontaneous or diuretic-induced),, and therapy resistant hypertension (defined as uncontrolled blood pressure despite intake of three antihypertensive drugs, ideally prescribed at optimal doses and one of which is a diuretic). However, pathognomonic clinical features are often lacking 10. This might be one of the reasons why diagnosis of PA is delayed by six (our own unpublished data) to eight 11 years. In the Netherlands the diagnosis and treatment of hypertension form part of the standard care of the general practitioner. However, diagnosing and treating PA is not standard (due to the need for additional investigations, e.g. CT-scan, and the possibility of surgical treatment if an APA is diagnosed). Based on the current Dutch guideline in general practice, which is called the NHG-guideline Cardiovascular risk management, only patients with hypertension and hypokalemia will be referred to diagnose or exclude PA (or, in treatment stage, therapy resistant hypertension). However, hypokalemia is only present in 9-37% of the patients with PA 12. Detection of PA in general practice can be done by blood assessment of the aldosterone-torenin ratio (ARR). Proposed in 1981 by Hiramatsu 13, the calculation of this ratio has proven less fluctuation than either aldosterone or renin 14. Although the ARR is considered a useful screening test for PA 15,16, cut-offs vary widely in literature due to different test characteristics

15 15 of ARR under different conditions 17. After a positive screening test a confirmatory test is mandatory for diagnosing PA. Detection of PA is relevant for three reasons: 1) Hypertension due to underlying autonomous aldosterone secretion causes more cardiovascular damage than essential hypertension. This cardiovascular damage is independent of the degree of hypertension 18,19 ; 2) PA requires a specific treatment: adrenalectomy in case of an APA 20-22, and mineralocorticoid receptor antagonists in case of BAH 23 ; 3) In case of an APA, delay in diagnosis may result in less response to adrenalectomy once the APA is finally diagnosed 24,25. In addition, detection of PA in general practice is relevant for three reasons: 1) Hypertension is almost invariably diagnosed in general practice; 2) Because of possible interference of antihypertensive medication with the ARR, screening of PA can be most easily done when diagnosing hypertension (when no antihypertensive medication is used yet). In addition, a wash-out period of antihypertensive medication in case of screening can be harmful; 3) Prevalence of PA in primary care is estimated to be 8 to 13% of all hypertensive patients 26, in therapy resistant hypertension a prevalence up to 23% is mentioned 27. At this moment, there are no data of PA in Dutch general practice. However, in view of the diagnostic delay, patients with PA are expected to receive inadequate medication for a prolonged period of time, in which cardiovascular damage due to unopposed aldosterone action can proceed. One of the main reasons to start this study is to find answers that can help us resolve the question of whether screening for PA in general practice should be introduced as a standard diagnostic procedure. For ethical justification of screening we aim to apply to the criteria of Wilson and Jungner (WHO 1968) 28 : 1) The condition sought should be an important health problem. 2) There should be an accepted treatment for patients with recognized disease. 3) Facilities for diagnosis and treatment should be available. 4) There should be a recognizable latent or early symptomatic stage. 5) There should be a suitable test or examination. 6) The test should be acceptable to the population. 7) The natural history of the condition, including development from latent to declared disease, should be adequately understood.

16 16 8) There should be an agreed policy on whom to treat as patients. 9) The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. 10) Case-finding should be a continuing process and not a once and for all project. Criterion 1 states that The condition sought should be an important health problem. One argument to meet this criterion is knowledge of the prevalence of PA in general practice. According to foreign studies the prevalence of PA is estimated to be 6-13%. Prevalence in Dutch general practice is still unknown, and needs to be studied. As to criteria 2 to 10, screening can be justified as well Prevalence In this study, the general practitioner will inform all newly diagnosed hypertensive patients about an additional measurement of blood that will be taken during the standard laboratory screening (appendix A). Out of this sample aldosterone and renin will be measured in order to calculate the aldosterone to-renin ratio (ARR). Because of the relevance of the ARR determination and the negligible risk, we suppose that patients will not refuse the ARR measurement. In 2008 the Endocrine Society proposed a cut-off value of the ARR of 91 pmol/mu. However, recent (not yet published) results of the ARRAT-study 30 showed that a cut-off value of 91 pmol/mu has a sensitivity of 53% (specificity 94%). They calculated that to achieve a sensitivity >90% the cut-off value should be lowered to 21 pmol/mu (specificity 55%). A lower cut-off value corresponds with several studies 19,31,32. However, in current literature there is no agreement on the ARR cut-off value. One of the problems in determining a sensible cut-off value is the risk of a high percentage of false-negative or false-positive results. Especially women have a risk of a false-positive result: they are at risk to have higher ARR because of assumed hormonal influences 33,34. Fortunately, the confirmatory test is not influenced by sex differences 35. To minimize the risk of false-positive results (women using oral contraceptives, women using hormonal suppletion therapy, patients with low renin hypertension) only an increased ARR in combination with an increased aldosterone will be used as a positive screening result 1, The results of the ARRAT-study and the reference values of healty individuals taken into account 35,39, in the PAGODE-study we choose a relatively low ARR cut-off value of >40 pmol/mu in combination with an increased aldosterone of >400 pmol/mu. We consider these to be reasonable cut-off values, especially because a screening test is designed to maximize

17 17 sensitivity 40. In addition, because of the relevance of diagnosing PA, we need to approximate a negative predictive value of 100%. Due to its limited specificity an elevated ARR in combination with an increased aldosterone by itself is not enough to diagnose PA: confirmatory testing by demonstrating nonsuppressible aldosterone secretion is mandatory for diagnosing PA. In our study we will use the intravenous sodium loading test (SLT) in confirming or excluding PA: in case of primary aldosteronism the autonomous secretion of aldosterone results in inadequate suppression of aldosterone after sodium infusion (figure 1). Figure 1. Part 1, screening for PA 2.3 Organ damage Recent literature shows that patients with primary aldosteronism experience more cardiovascular events than patients with essential hypertension 41. These events encompass stroke, non-fatal myocardial infarction, atrial fibrillation and renal dysfunction, and occur independently of the level of blood pressure. As reducing aldosterone production leads to improved cardiovascular outcome, it is assumed that the hormone aldosterone plays an independent role in the occurrence of cardiovascular complications 18,19,42. The classical presentation of PA with clinical clues like hypokalemia and therapy resistant hypertension might be absent in the initial phase of PA. Likewise, it is unknown whether cardiovascular damage is already present in the early stage of PA. In part 2 of this study we will compare cardiorenovascular damage in patients with newly diagnosed hypertension and PA to patients with newly diagnosed essential hypertension. We will perform a number of

18 18 non-invasive diagnostic tests to measure cardiorenovascular status, which may elucidate detrimental effects of aldosterone in the early stage of PA. 3. OBJECTIVES This study encompasses two different parts. Part 1 Primary objective 1.1: to assess the proportion of patients with PA in newly diagnosed hypertensive patients in Dutch general practice. Secondary objective 1.2: to study the relation between the ARR and the blood pressure response to treatment in newly diagnosed hypertensive patients in general practice. Part 2 Primary objective 2: to explore cardiovascular and renal damage in PA patients with newly diagnosed hypertension in comparison to a control group of patients with newly diagnosed essential hypertension, stratified by sex, age, and 24h baseline blood pressure. Cardiovascular and renal damage will be based on the following parameters: a) left ventricular mass index b) intima-media thickness c) pulse wave velocity d) central aortic blood pressure e) flow-mediated dilation f) ankle-brachial index g) albuminuria 4. STUDY DESIGN 4.1 Study design In part 1, a cross-sectional design is used to study objective 1.1 (proportion of PA patients), while a prospective cohort design is used to assess objective 1.2 (the relation between the ARR and the blood pressure response to treatment). In part 2, a case-control design is used to study objective 2 (cardiovascular and renal damage in PA patients and controls).

19 Duration The study has started in August We aim to finish the inclusion within two years and 4 months. Timeline: August 2013 up to and including July 2014: recruiting and visiting practices, setting up vascular parameter detection. August 2013 up to and including December 2015: inclusion of patients. 1 July 2016: end of study. 4.3 Setting Newly diagnosed hypertensive patients in general practices that have their laboratory tests analyzed by the SHO. All patients with increased ARR will be referred to the department of Internal Medicine of the Radbouduniversity medical center. 4.4 Flowchart

20 20 5. STUDY POPULATION 5.1 Population (base) Patients 18 years with newly diagnosed hypertension in general practice. No distinction will be made regarding gender or ethnicity, because no differences in clinical course or response to treatment between these groups are to be expected in primary aldosteronism. 5.2 Selection criteria Inclusion criteria for objective 1.1 (proportion of PA patients) Newly diagnosed hypertensive patients (according to the NHG-guideline Cardiovascular risk management, appendixb) 18 years ARR assessment For referred patients: written informed consent Exclusion criteria for objective 1.1 (proportion of PA patients) Use of antihypertensive medication 2 with the exception of: a) use of escape medication: amlodipine in the past or diltiazem in the present b) use of antihypertensive medication that started after the diagnosis and can be stopped before the SLT takes place c) antihypertensive medication during pregnancy in the past. Hypertensive crisis Systolic blood pressure > 200 mmhg or diastolic blood pressure > 120 mmhg Heart failure class II, III or IV (according to the New York Heart Association) Renal failure (egfr of <45 ml/min) Pregnancy or breastfeeding Diabetes mellitus Severe co-morbidity, which seriously interferes with diagnostic procedures or possible treatment 2 Definition of antihypertensive medication (ATC codes): antihypertensives (C02*), diuretics (C03*), beta blocking agents (C07*), calcium channel blockers (C08*), agents acting on the renin-angiotensin system (C09*).

21 21 Inclusion criteria for objective 1.2 (relation ARR- blood pressure response) Newly diagnosed hypertensive patients (according to the NHG-guideline Cardiovascular risk management, appendix B) 18 years ARR assessment Exclusion criteria for objective 1.2 (relation ARR blood pressure response) None Inclusion criteria for objective 2 (cardiovascular and renal damage) group A Newly diagnosed hypertensive patients (according to the NHG-guideline Cardiovascular risk management, appendix B) 18 years AberrantARR, defined as an aldosterone >400 pmol/l in combination with an ARR >40 pmol/mu Positive sodium loading test Written informed consent Inclusion criteria for objective 2 (cardiovascular and renal damage) group B Newly diagnosed hypertensive patients (according to the NHG-guideline Cardiovascular risk management, appendixb) 18 years Abberrant ARR and negative sodium loading test OR normal ARR Written informed consent Exclusion criteria for objective 2 (cardiovascular and renal damage), group A and B Use of antihypertensive medication 2 with the exception of: a) use of escape medication: amlodipine in the past or diltiazem in the present b) use of antihypertensive medication that started after the diagnosis and can be stopped before the cardiovascular and renal measurements take place c) antihypertensive medication during pregnancy in the past. Hypertensive crisis Systolic blood pressure > 200 mmhg or Diastolic blood pressure > 120 mmhg Heart failure class II, III or IV (according to the New York Heart Association) Renal failure (egfr of <45 ml/min) Pregnancy or breastfeeding