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...43 Appendix A: Standard blood assessment at hypertension...43 Appendix B: Diagnosing hypertension in general practice...44 Appendix C: Criteria for urgent referral...47 Appendix D: Risk table...48 Appendix E: Additional risk factors...49 Appendix F: Lifestyle counselling in hypertension...50 Appendix G: Information leaflet part Appendix H: Referral criteria for general practitioners at hypertension...54 Appendix I: Protocol sodium loading test...55 Appendix J: Letter and information leaflet part 2: patients with increased ARR...57 Appendix K: Letter and information leaflet part 2: patients with normal ARR...65 Appendix L: Declaration of Helsinki...72 Appendix M: Datamanagement plan PAGODE...77

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 Pulse Wave Velocity Serious Adverse Event Systolic Blood Pressure; in Dutch: Systolische Bloeddruk Centre for Medical Diagnostics; in Dutch: Stichting Huisartsenlaboratorium Oost SLT Sponsor 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 TC TRH WHO WMO 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

22 22 Diabetes mellitus Severe co-morbidity, which seriously interferes with diagnostic procedures or possible treatment 5.3 For consideration In case of newly diagnosed systolic blood pressure 200 mmhg the patient is referred for further evaluation. If a hypertensive crisis is excluded, the patient can be included in our study; In case of hypertension and subjective complaints (headache, visual disturbances, nausea, vomiting) the patients is referred for further evaluation. If a hypertensive crisis is excluded, the patient can be included in our study; In case of hypertension and cardiovascular symptoms (dyspnoea, thoracic pain) the patient is referred for further evaluation. If a cardiovascular event is excluded, the patient can be included in our study; In case of hypertension and cerebral complaints (reduced consciousness, neurologic symptoms), the patient is referred for further evaluation. If cerebral complications are excluded, the patient can be included in our study. See also appendix C for criteria of urgent referral. First, patients with high blood pressure that needed instant treatment, were treated with amlodipine 5 mg during their sodium loading test (Radboudumc protocol). However, in a recent published article the influence of amlodipine on a salt loading test is discussed: there is reason to assume that amlodipine might influence the result of the sodium loading test in some patients (false negative result) 2. In the future, when a patient complies to the inclusion criteria but needs immediate treatment, we will start treatment with diltiazem 200 mg daily. The use of diltiazem is also better supported by previous evidence 9, Sample size calculation Although previously presumed a rare condition (prevalence <1%), PA is now estimated to affect 6 to 20% of the hypertensive population. We assume a conservative estimate of 5% PA affected patients in the hypertensive population. We intent to include 4 controls for every PA patient. Based on a t-test, two sided, at α = 0.05, and 80% power, in part 2 to detect a medium effect size of 0.5 between PA patients and control group for each of the 7 primary outcomes we need to include 40 PA patients in the

23 23 study. Taking into account a dropout of 25% an estimated number of 54 PA patient has to be included. Therefore we need to enrol 1080 hypertensive patients in our study. In part I, to estimate the proportion of PA assuming 5% PA affected patients in the hypertensive population, with a confidence level of 95% and confidence limits of 5% +/- 1.3% we need to include 1079 hypertensive patients. It is our intention to enrol 1100 patients in our study. 6. TREATMENT OF SUBJECTS In part 1 of this study, we will examine the relation between the ARR and the blood pressure response to treatment in newly diagnosed hypertensive patients in general practice (objective 1.2). In other words: we will study the relation between the ARR and the response to usual care in general practice. In usual care, hypertensive treatment in general practice is done according to the following algorithm*: 1) The General Practitioner (GP) diagnosis hypertension according to the guidelines; 2) The GP sends the patient for a standard blood screening, analyzing glucose, lipids and renal function (appendix A); 3) The GP or Practice Nurse in General Practice (PNG) calculates cardiovascular risk depending on the degree of blood pressure, age, gender, the total cholesterol to HDL ratio, and smoking habits, based on the risk table Ten years risk on event or death by cardiovascular diseases of patients without cardiovascular diseases (appendixd): a) High risk (red areas in table): risk 20% to experience a cardiovascular event or die due to a cardiovascular disease in the next ten years, or an intermediate risk with additional risk factors (appendixe); b) Intermediate risk (yellow areas in table): risk 10-20% to experience a cardiovascular event or die due to a cardiovascular disease in the next ten years; c) Low risk (green areas in table): risk <10% to experience a cardiovascular event or die due to a cardiovascular disease in the next ten years. * Included patients will be diagnosed according to the current Dutch guideline in general practice, which is called the NHG-guideline Cardiovascular risk management. We mentioned a difference between this guideline and other national and international guidelines. According to the NHGguideline, hypertension is defined as a systolic blood pressure >140 mmhg. According to the Dutch Society of Internal Medicine, hypertension is defined as a systolic blood pressure of 140 mmhg. This is in accordance with international guidelines.

24 24 4) Every newly diagnosed hypertensive patient will receive lifestyle counselling independent of their score on the risk table (appendixf); 5) In case of an intermediate risk the GP or PNG will take additional risk factors into account to decide whether or not to start antihypertensive medication (appendix E); 6) In case of diabetes mellitus or rheumatoid arthritis the GP or PNG will add 15 years to the patient s age (increased vascular damage due to condition) to calculate an adequate risk. In general practice, every newly diagnosed hypertensive patient receives treatment according to the national guideline (NHG-guideline Cardiovascular risk management ). The GP or PNG calculates a cardiovascular risk profile and assesses additional risk factors of the individual patient, in order to decide which intervention (lifestyle counselling or/and medication) is appropriate. In part 1 of our study, we will examine the relation between the ARR at baseline, and the blood pressure response after 3 months of usual care using data from Electronic Medical Records (EMRs) in general practice. 7. METHODS 7.1 Study parameters/endpoints Main study parameter/endpoint Part 1: The primary outcome for objective 1.1 is: the proportion of patients with PA in newly diagnosed hypertensive patients screened at the SHO. The primary outcome for objective 1.2 is: the blood pressure measured in general practice after 3 months of treatment. Part 2: The primary outcome for objective 2 is: cardiovascular and renal damage in cases and controls, as measured by a) left ventricular mass index, b) intima-media thickness, c) pulsewave velocity, d) central aortic blood pressure, e) flow-mediated dilation, f) ankle-brachial index, g) and albuminuria.

25 Secondary study parameters/endpoints Part 1: In part 1, we will also study possible selection bias in the referral of patients to the SHO. Therefore, we defined the following two secondary outcomes: The proportion of newly diagnosed hypertensive patients screened at the SHO in newly diagnosed hypertensive patients in general practice. A description of patient characteristics and interpractice variation between the screened and unscreened group (i.e. newly diagnosed hypertensive patients who were not referred to the SHO). Furthermore, we will study the relation between the ARR and the target blood pressure (<140). This secondary outcome is defined as: The target blood pressure reached (<140 mmhg), measured in general practice after 3 months of treatment. Part 2: If possible, we will make a composite outcome of vascular and renal damage in part 2. The corresponding secondary outcome is defined as: A composite outcome based on the mean of the Z-scores of relevant outcomes of cardiovascular and renal damage. 7.2 Study procedures Part 1: screening for PA In part 1, general practices that have their laboratory tests analyzed by the SHO will be asked to participate in this study. Coded data (no names or addresses) from the EMR s of the included practices will be extracted at the end of the inclusion period (January 2016). The included practices will inform all their patients that data from their EMR will be extracted for scientific research, and they give them opportunity to object to the use of their data (opt out), which is in accordance with the code of conduct for health research (in Dutch: Gedragscode Gezondheidsonderzoek), in particular chapter 5. For the transfer of the data, an agreement will be signed by the included general practices and the Department of Primary and Community Care of the Radboud university medical

26 26 center, which states that the study will be performed according to the code of conduct for health research (in Dutch: Gedragscode Gezondheidsonderzoek) which has been approved by the data protection authorities for conformity with the applicable Dutch privacy legislation (in Dutch: College Bescherming Persoonsgegevens). Consecutive newly diagnosed hypertensive patients will be asked to participate in our study. Hypertension will be diagnosed according to the NHG-guideline (appendixb). An inventory blood assessment forms part of the usual diagnostic workup (appendix A), during this standard venipuncture an extra blood sample of 8 ml will be taken from all patients. All samples will be analyzed for ARR by the Centre of Medical Diagnostics in Velp (SHO). Renin will be assessed by the immunoradiometric assay (IRMA) of Diagnostic Systems Laboratories (DSL Active Renin IRMA), which measures active renin concentration. Aldosterone will be measured by radioimmunoassay of Siemens Medical Solutions Diagnostics. An aldosterone to renin ratio of 40 pmol/mu and/or an aldosterone 400 pmol/l will be interpreted as a normal ARR (absence of PA). Samples for ARR analysis will be taken from all patients. The patient s general practitioner will give oral and written information to all newly diagnosed hypertensive patients (appendix G). Patients can object to part 1 of the study (opt out). Also, patients have the possibility to participate in part 1 of the study without knowing their ARR result Part 2: determining cardiovascular and renal damage In part 2, all patients with PA will be asked to participate. The control group will consist of patients with newly diagnosed essential hypertension. Control patients are derived from two groups: patients with a normal ARR (ARR neg ) patients with deviating test results for ARR (ARR pos ) who are not diagnosed with PA (PA neg ) We will select control patients in such a way that the distribution of ARR neg and ARR pos in the control group in part 2 (160 patients) is equal to the distribution of ARR neg and ARR pos in PA neg patients in the study population in part 1 (1100 patients). To make a proper selection of patients with PA and controls from the study population in part 1 the researcher will have: online access to identification of the patient and the results of the laboratory tests of the SHO of PAGODE patients and

27 27 information from the GP (by telephone) of PAGODE patients. The code of conduct for health research (in Dutch: gedragscode gezondheidsonderzoek) article 6.1C describes the use of personal data i.e. medical information without explicit permission of the participants. This article is intended primarily to select a sample from a bigger population which makes it impossible to ask individual written consent. The most important requirements are described here: patients will have the opportunity to object to the use of their data and a confidentiality agreement for protection of confidential information (personal data) will be signed by principle investigators and the junior researchers. For each PA pos patient, four control patients will be selected at random from the study population in part 1. The control group will be stratified by sex, age, and 24-hour baseline blood pressure. We will use the following categories for stratification: age: / / / 80 years and older systolic blood pressure: / / mmhg. For practical purposes, systolic blood pressure as measured in general practice will be used for stratification. However, if the results of the 24h ABPM reveal that the patient falls into a different blood pressure category than previously classified, the ABPM will be considered the gold standard for stratification. For all patients that are included in part 2, we will record the following patients characteristics in order to describe the patient groups: Age Gender Smoking habits (past and current, in packyears) Alcohol (in units per day) Physical activity according to the Dutch Norm for Healthy Exercise (in Dutch: Nederlandse Norm Gezond Bewegen) (meets the norm/less than the norm/inactive/indistinct) Previous cardiovascular diseases (including pregnancy induced hypertension) Medication (current) Family history (especially cardiovascular diseases) Length Weight BMI Pre-eclampsia

28 28 Snoring (not/light/heavy/unknown) Known with apnea syndrome (yes/no) Part 2: patients with increased ARR Newly diagnosed hypertensive patients with an increased ARR will be referred to the department of Internal Medicine of the Radboud university medical center. This referral is standard care (appendix H). In the medical centre patients will undergo an intravenous sodium loading test (appendix I). After the SLT patients will be asked to participate in part 2 of our study. All patients with a positive SLT and a random part of the patients with a negative SLT will be asked to participate. The patients will have an ABPM measured in general practice or in the centre for medical diagnostics (SHO) 3. They all have to come back for the following additional non-invasive examinations to determine cardiovascular and renal damage: a. Left ventricular mass index by cardiac ultrasoundb. Intima-media thickness of carotid artery by ultrasound c. Pulse wave velocity (PWV) by the Sphygmocor system. The pulse wave will be registered by tonometry at the level of the carotid artery and of the femoral artery: the distance between these two in cm is divided by the time lapse between the pulses at the two sites, which is defined as the PWV; d. Central aortic blood pressure by the Sphygmocor. Increased central aortic blood pressure has been implicated as a cause of excess cardiovascular morbidity and mortality in the presence of normal brachial blood pressure 50 ; e. Endothelial function will be measured by flow-mediated dilation. With a tourniquet the perfusion of the forearm will be interrupted for five minutes. After release of the tourniquet a post-ischemic flow increase will lead to increased shear stress of the brachial artery wall which causes vasodilation. The magnitude of vasodilation depends on endothelial function: the better the function, the wider the artery. Vasodilation is monitored by ultrasound and a wall-tracking video system; f. Ankle-brachial index (ABI) using Doppler ultrasound, is measured as the ratio of the ankle to brachial systolic blood pressure. g. Albuminuria will be assessed in a urine sample as albumin to creatinin ratio. 3 If in less than 4 months prior to the examinations in part 2 an ABPM was measured, the test does not have to be repeated if the settings were the same as those used in the PAGODE-study: daytime value between 9 a.m. and 8 p.m., nighttime value between 12 p.m. and 6 a.m. and the 24h time value measured over 24 hours.

29 29 Oral and written information will be given by the physician who performs the sodium loading test (appendix J). Patients can consider their participation for a maximum of one week. They can contact our independent physician. If a patient decides to participate, we try to perform these examinations at the same day of the cardiac ultrasound. All together this enhanced diagnostic workup will take 2 hours. Written informed consent is obligatory for inclusion Part 2: patients with normal ARR A random sample of newly diagnosed hypertensive patients with normal ARR will receive a letter with an information leaflet from their GP (appendix K). In the letter the GP will invite the patient to participate in extra examinations in the hospital for optimal assessment of cardiovascular status. In the letter is announced that we will contact the patient to evaluate their interest in participating. The extra examinations encompass: 1) ABPM 2) Cardiac ultrasound to measure left ventricular mass 3) Intima-media thickness of the carotid artery 4) Pulse wave velocity 5) Central aortic blood pressure 6) Flow-mediated dilation 7) Ankle-brachial index 8) Albuminuria Patients can consider their participation for a maximum of one week. They can contact our independent physician. The additional workup will take approximately 120 minutes. Patients not living in Nijmegen, who visit our medical centre because of participation in our study, will receive travel expenses. Written informed consent is obligatory for inclusion. 7.3 Withdrawal of individual subjects Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons or any of the following reasons: Withdrawal of informed consent Pregnancy After withdrawal, the patient will be referred back to the GP.

30 Premature termination of the study Because the describing character of our study (part 1 and 2) and the non-invasive diagnostic procedures (part 2), no interim analysis for early stopping will be included in this analysis. No additional risk for our subjects is to be expected, therefore no premature termination procedure is included in this study. 8. SAFETY REPORTING 8.1 Section 10 WMO event In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited METC if anything occurs, on the basis that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the accredited METC, except insofar as suspension would jeopardise the subjects health. The investigator will take care that all subjects are kept informed. 8.2 Adverse events and serious adverse events Adverse events and serious adverse events in this study will be related to the enhanced diagnostic procedures to detect early cardiovascular damage. However, all diagnostic procedures are non-invasive, well-known, very low-risk procedures. It is highly unlikely that these diagnostic procedures may cause any harm to our subjects. However, any adverse or severe adverse event will be reported according to the guidelines mentioned below. Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to diagnostic procedure (part 2). All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. A serious adverse event is any untoward medical occurrence: Results in death; Is life threatening (at the time of the event); Requires hospitalisation or prolongation of existing in patient s hospitalisation; Results in persistent or significant disability or incapacity; Is a congenital anomaly or birth defect;

31 31 All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that approved the protocol, within 15 days after the sponsor has first knowledge of the serious adverse reactions. SAEs that result in death or are life threatening should be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the report. 8.3 Follow-up of adverse events All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. 8.4 Data Safety Monitoring Board (DSMB) No DSMB was installed in this study, because this study is not concerned with interventions that are expected to be harmful to the patient, with a life-threatening disease, with a legally incapable population, nor with the need for an interim-analysis for early stopping. 9. STATISTICAL ANALYSIS The following analyses will be performed. 9.1 Statistical analyses part 1 1.1a Primary outcome: the proportion of patients with PA in newly diagnosed hypertensive patients screened at the SHO Analyses: the number of patients with PA confirmed by a positive SLT divided by the number of newly diagnosed hypertensive patients screened at the SHO 1.1b Secondary outcome 1: the proportion of newly diagnosed hypertensive patients screened at the SHO in newly diagnosed hypertensive patients in general practice

32 32 Analyses: the number of newly diagnosed hypertensive patients screened at the SHO divided by all newly diagnosed hypertensive patients in the Electronic Medical Records (EMRs) of the general practices 1.1c Secondary outcome 2: description of patient characteristics and interpractice variation between the screened and unscreened group Analyses: descriptive analyses of age, sex, blood pressure, and comorbidity of the screened and unscreened group. Measure of interpractice variation (ICC). 1.2a Primary outcome: blood pressure measured in general practice after 3 months of treatment Analyses: multilevel multivariate regression analyses with blood pressure after 3 months as dependent variable, the ARR as independent variable, and the following covariates: age, sex, baseline blood pressure, variables from the SHO (lipids, glucose, egfr), and variables from the EMRs of the general practices (comorbidity and type of treatment (lifestyle advice (no medication) and various groups of medication). The following groups of medication (ATC codes) will be considered: antiadrenergic agents, centrally acting (C02A*) alpha-adrenoreceptor antagonists (C02CA*) and serotonin antagonists (C02KD*) diuretics (C03* without potassium sparing agents (C03D*)) potassium sparing agents (C03D* without aldosterone antagonists (C03DA*) Aldosterone antagonists (C03DA*) beta blocking agents (C07*) calcium channel blockers (C08*) ace-inhibitors, plain (C09A*) and ace-inhibitors, combinations (C09B*) angiotensin II antagonists, plain (C09C*) and angiotensin II antagonists, combinations (C09D*) Renin-inhibitors (C09XA*) Other antihypertensives (C02B*, C02CC*, C02D*, C02K* without C02KD*, C02L*, C02N* Dependent on the size of the groups, groups might be combined in the final analyses. 1.2b Secondary outcome 1: target blood pressure reached (<140 mmhg), measured in general practice after 3 months of treatment Analyses: multilevel logistic regression analyses with presence/absence of target blood pressure reached as dependent variable, the ARR as independent variable, and the following covariates: age, sex, baseline blood pressure, variables from the SHO (lipids, glucose,

33 33 egfr), and variables from the EMRs of the general practices (comorbidity and type of treatment (lifestyle (no medication) and various groups of medication (Anatomical Therapeutic Chemical (ATC) codes)). 9.2 Statistical analyses part 2 Descriptive analyses Description of patient characteristics of the PA and the control group including the variables mentioned in and the various laboratory measurements. 2.1 Primary outcomes: o Left ventricular mass index o Intima-media thickness of the carotid artery o Pulse wave velocity o Central aortic blood pressure o Flow-mediated dilation o Ankle-brachial index o Albuminuria Analyses: multivariate regression analyses for each of these outcomes, corrected for age, sex and 24h baseline blood pressure. 2.2 Secondary outcome (if the exploratory analyses reveal relevant outcomes): composite outcome based on the mean of the Z-scores of relevant outcomes of cardiovascular and renal damage. Analyses: multivariate regression analyses with the mean of the Z-scores of the relevant outcomes as the dependent variable and age, sex, and 24h blood pressure as covariates. 10. ETHICAL CONSIDERATIONS 10.1 Regulation statement The study will be conducted according to the declaration of Helsinki (appendix L) and has been approved by the regional independent medical ethical committee Nijmegen-Arnhem in accordance with the Medical Research Involving Human Subjects Act (WMO). Changes in the study will not take place until approval of the independent medical ethical committee Nijmegen-Arnhem. Part 2 will not start until patient s informed consent procedures have been completed.

34 Recruitment and consent The oral and written information as well as the informed consent forms should be in a language fully comprehensible by the patient. By dating and signing the informed consent form, the patient confirms his informed consent. Conversely, the GP/PNG/investigating physician by signing confirms his/her commitment to the protocol Recruitment and consent part 1 Patients will be recruited by the professional that diagnoses hypertension, which is in general practice the GP or the PNG. Patients will be given oral and written information (appendix G). If patients need time to consider their participation, they can do this for one week. They can contact our independent physician. Samples for ARR analysis will be taken from all patients who do not object to participate in the study (opt out). Also, knowledge of the ARR test result is by opt-out procedure : without objection patients will be informed about their test result. Patients who object to know their ARR result will not be informed, a note will be made in their medical record: they will not automatically be referred for further testing if their ARR is elevated, nor will they be approached to be a control. All ARR results will be stored in a coded way for the calculation of the proportion of PA. All patients will receive a unique number without any personally identifiable data. Source documents from SHO, EMR s in general practice and the Radboud university medical center record will be electronically saved in a validated database. The key to the identification code will be safeguarded by the two principle investigators and the two junior researchers Recruitment and consent part 2 Patients with an increased ARR will be recruited after the sodium loading test. They will be given oral and written information (appendix J). If they decide to participate, we try to perform the additional workup the same day as the patient s cardiac ultrasound is planned. Patients can consider their participation for one week. They can contact our independent physician. Patients not living in Nijmegen, who visit our medical centre because of the additional workup, will receive travel expenses. Written informed consent is obligatory to participate. A sample of patients with normal ARR will receive a letter and an information leaflet from their GP (appendix K). In the letter the GP will invite the patient to participate in additional examinations and treatment in the hospital. In the letter is announced that we will contact the patient to evaluate their interest in participating. From this pool of patients we will match patients with newly diagnosed essential hypertension to patients with PA

35 35 by sex, age and 24h baseline blood pressure. Patients can consider their participation for one week. They can contact our independent physician. Patients not living in Nijmegen, who visit our medical centre because of participation in our study, will receive travel expenses. Written informed consent is obligatory in order to participate Objection by minors or incapacitated subjects Minors and incapacitated subjects will not participate in this study Benefits and risks assessment, group relatedness In part 1 of the study all newly diagnosed hypertensive patients will give an extra blood sample at their standard diagnostic blood examination. Patients can object to participate in part 1 of the study (opt out). Also, knowledge of the test result is by opt-out procedure : patients who object to know their ARR result will not be informed, a note will be made in their medical record. In part 2 patients with an increased ARR will be referred to our hospital for further evaluation, which is standard diagnostic care. In part 2 a sample of patients without PA will be asked to participate in additional diagnostic examinations. This group will be our matched control group. The extended diagnostic workup is well-known, non-invasive and the risks are negligible. However, the ischemic and post-ischemic phase of the measurement of endothelial function by flow-mediated dilation is uncomfortable, though not harmful. It is expected that patients with newly diagnosed hypertension and PA will directly benefit from participation. This is because the average time to diagnose PA is eight years (time from the diagnosis of hypertension to the detection of PA), while in this study we will diagnose PA within one month, which will result in timely, definitive and adequate therapy. It is expected that patients with newly diagnosed essential hypertension will benefit from participation at an individual level. They will undergo additional diagnostic tests. The results of this diagnostic workup can be used in the assessment of their cardiovascular risk profile according to the NHG-Guideline Cardiovascular risk management Compensation for injury The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 of the WMO. The sponsor (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for

36 36 Clinical Research in Humans of 23th June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study ,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research; ,-- (i.e. three million five hundred thousand Euro) for death or injury for all subjects who participate in the Research; ,-- (i.e. five million Euro) for the total damage incurred by the organisation for all damage disclosed by scientific research for the Sponsor as verrichter in the meaning of said Act in each year of insurance coverage. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study. Because we don t consider any risk in part 1 of our study, we have asked dispensation for part 1 of this study to the regional independent medical ethical committee Nijmegen-Arnhem. This dispensation is approved. For part 2 of this study an insurance is provided Incentives Patients not living in Nijmegen, will receive a compensation in travel expenses if they visit our clinic because of study purposes only. Patients that visit our clinic because of standard diagnostic purposes, will not receive travel expenses. Patients will not receive any remuneration for participation. 11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 11.1 Handling and storage of data and documents All study findings will be stored in a computer database and handled strictly confidentially. This database will be constructed and managed according to the Dutch Data Protection Act (in Dutch: Wet Bescherming Persoonsgegevens) and the code of conduct for health research (in Dutch: Gedragscode Gezondheidsonderzoek). All patients names will be kept secret, with identification by number only. The database will be accessible to the principal investigators and those employees actively involved in the study. The key to the identification code will be safeguarded by the principle investigators and the two junior researchers. Coded data will be kept after closure of the study and can only be used for ancillary studies after strict approval of the principal investigators. Anonymized data can be given to other organizations for academic research (for instance Cochrane reviews), consensus development, or other projects.

37 37 The remaining body materials at the SHO, i.e. the remaining blood that was used to determine the ARR, will be destroyed by the SHO. Remaining body materials in the Radboudumc, consisting of blood or possible urinary samples will be preserved for possible follow-up studies in a coded form in accordance with the code of conduct for responsible use of human tissue for medical research (in Dutch: Code Goed Gebruik van lichaamsmateriaal). All subjects will be asked permission before preservation. All subjects will be asked permission for future contact. The medical ethical commission will be consulted in case of future research that may lead to chance findings and before the body materials are used in future research that is not part of the current study. They will decide whether renewed subject permission is requisite Monitoring and Quality Assurance The risk classification of this study is: negligible risk. Monitoring of the study will be done by independent, colleague researchers. Data will be stored in ProMISe, a validated datamanagement system. Appendix M describes the datamanagement plan. Both principal investigators (dr. Deinum and dr. Biermans), the research leader (dr. Schermer), and the PhD student on this project (drs. Käyser) followed the Basic course in Regulations and Organisation for Clinical researchers (BROK) Amendments Amendments are changes made to the research after a favourable opinion by the accredited METC has been given. All amendments will be notified to the METC that gave approval. A substantial amendment is defined as an amendment to the terms of the METC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: The safety or physical or mental integrity of the subjects of the trial; The scientific value of the trial; The conduct or management of the trial; or The quality or safety of any intervention used in the trial. All substantial amendments will be notified to the METC and to the competent authority. Nonsubstantial amendments will not be notified to the accredited METC and the competent authority, but will be recorded and filed by the sponsor.

38 Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments End of study report The investigator will notify the accredited METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patient s last visit to the hospital in part 2. In case the study is ended prematurely, the investigator will notify the accredited METC, including the reasons for the premature termination. Within one year after the end of the study, the investigator will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC Public disclosure and publication policy Publication This protocol will be registered in a public registry as required by the International Committee of Medical Journal Editors, as a condition for consideration for publication. The results of the present study will be published in international journals and presented at medical conferences around the world. The results will be available for the development of wellfounded (Dutch) guidelines on diagnosis and treatment of primary aldosteronism in general practice and to authorities and policymakers that decide on allocation of financial resources to primary care and/or hospitals. Disputes between participants on the interpretation of study results should not delay the publication of these results. In case of a continued disagreement, the discussion should be pursued by means of correspondence to the journal involved. None of the parties has a veto and all parties should solve problems in mutual consultation Authorship To qualify for authorship, an investigator should have made a substantial contribution to the study and take public responsibility for the content. Authorship credit will be based on the following criteria, as recommended by the International Committee of Medical Journal Editors (2013) 53 : 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND

39 39 2. Drafting the work or revising it critically for important intellectual content; AND 3. Final approval of the version to be published; AND 4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All those designated as authors should meet all four criteria for authorship, and all who meet the four criteria should be identified as authors. Those who do not meet all four criteria should be acknowledged.

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41 Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008; 168(1): Sawka AM, Young WF, Thompson GB, Grant CS, Farley DR, Leibson C, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med. 2001; 135(4): Harris DA, Au-Yong I, Basnyat PS, Sadler GP, Wheeler MH. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2003; 29(5): Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World journal of surgery. 2005; 29(2): Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study. British journal of clinical pharmacology. 1999; 48(5): Streeten DH, Anderson GH, Jr., Wagner S. Effect of age on response of secondary hypertension to specific treatment. Am J Hypertens. 1990; 3(5 Pt 1): Celen O, O'Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism. Archives of surgery (Chicago, Ill : 1960). 1996; 131(6): Funder JW. Primary aldosteronism: are we missing the wood for the trees? Horm Metab Res. 2012; 44(3): Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapyresistant hypertension: a clue to efficient treatment. Journal of hypertension. 2004; 22(11): Andermann A, Blancquaert I, Beauchamp S, Déryc V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bulletin of the World Health Organization. 2008; 86(4): Sywak M, Pasieka JL. Long-term follow-up and cost benefit of adrenalectomy in patients with primary hyperaldosteronism. Br J Surg. 2002; 89(12): Jansen PM, Boomsma F, van den Meiracker AH. Aldosterone-to-renin ratio as a screening test for primary aldosteronism--the Dutch ARRAT Study. The Netherlands journal of medicine. 2008; 66(5): Letavernier E, Peyrard S, Amar L, Zinzindohoue F, Fiquet B, Plouin PF. Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma. Journal of hypertension. 2008; 26(9): Perschel FH, Schemer R, Seiler L, Reincke M, Deinum J, Maser-Gluth C, et al. Rapid screening test for primary hyperaldosteronism: Ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays. Clinical chemistry. 2004; 50(9): Ahmed AH, Gordon RD, Taylor PJ, Ward G, Pimenta E, Stowasser M. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men? The Journal of clinical endocrinology and metabolism. 2011; 96(2): E Pizzolo F, Raffaelli R, Memmo A, Chiecchi L, Pavan C, Guarini P, et al. Effects of female sex hormones and contraceptive pill on the diagnostic work-up for primary aldosteronism. Journal of hypertension. 2010; 28(1): Kerstens MN, Kobold AC, Volmer M, Koerts J, Sluiter WJ, Dullaart RP. Reference values for aldosterone-renin ratios in normotensive individuals and effect of changes in dietary sodium consumption. Clinical chemistry. 2011; 57(11): Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008; 371(9628): Young WF, Jr. Primary aldosteronism: management issues. Ann N Y Acad Sci. 2002; 970: Seiler L, Rump LC, Schulte-Monting J, Slawik M, Borm K, Pavenstadt H, et al. Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication. European Journal of Endocrinology. 2004; 150(3):

42 Hannemann A, Friedrich N, Ludemann J, Volzke H, Rettig R, Peters J, et al. Reference intervals for aldosterone, renin, and the aldosterone-to-renin ratio in the populationbased Study of Health in Pomerania (SHIP-1). Horm Metab Res. 2010; 42(6): Schwartz GL, Chapman AB, Boerwinkle E, Kisabeth RM, Turner ST. Screening for primary aldosteronism: implications of an increased plasma aldosterone/renin ratio. Clinical chemistry. 2002; 48(11): Rocha R, Stier CT. Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab. 2001; 12(7): Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero GR, Palatini P, et al. Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension. 1996; 27(5): Mulatero P, Veglio F, Pilon C, Rabbia F, Zocchi C, Limone P, et al. Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. The Journal of clinical endocrinology and metabolism. 1998; 83(7): Gordon RD. Mineralocorticoid hypertension. Lancet. 1994; 344(8917): Freedland KE, Mohr DC, Davidson KW, Schwartz JE. Usual and unusual care: existing practice control groups in randomized controlled trials of behavioral interventions. Psychosom Med. 2011; 73(4): ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288(23): Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Singledrug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993; 328(13): Attwood S, Bird R, Burch K, Casadei B, Coats A, Conway J, et al. Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedipine. Journal of hypertension. 1994; 12(9): Borm GF, Fransen J, Lemmens WA. A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007; 60(12): Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113(9): Borm GF, van der Wilt GJ, Kremer JAM, Zielhuis GA. A generalized concept of power helped to choose optimal endpoints in clinical trials. J Clin Epidemiol. 2007; 60: Ferriss JB, Brown JJ, Fraser R, Haywood E, Davies DL, Kay AW, et al. Results of adrenal surgery in patients with hypertension, aldosterone excess, and low plasma renin concentration. Br Med J. 1975; 1(5950): International Committee of Medical Journal Editors. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Updated December O'Brien E, Atkins N, Stergiou G, Karpettas N, Parati G, Asmar R, et al. European Society of Hypertension International Protocol revision 2010 for the validation of blood pressure measuring devices in adults. Blood Press Monit. 2010; 15(1): Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension. 2002; 40(6): Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013; 45(9):

43 APPENDICES Appendix A Standard blood assessment at hypertension (copied from NHG-guideline Cardiovascular risk management ) Lipidenspectrum o TC o HDL o TC/HDL ratio o LDL o triglyceriden Glucosegehalte Serumcreatininegehalte met (via de MDRD-formule) geschatte glomerulaire filtratiesnelheid (egfr)

44 44 Appendix B Diagnosing hypertension in general practice (copied from NHG-guideline Cardiovascular risk management ) Bloeddrukbepaling De bloeddruk kent een aanzienlijke spontane variatie in de tijd. Daarom dient de hoogte van de bloeddruk te worden vastgesteld op basis van meerdere metingen, gedurende een wat langere periode. Bij een licht verhoogde bloeddruk (SBD mmhg) kunnen de metingen over een periode van enkele maanden worden verspreid, om zodoende zo nauwkeurig mogelijk een indruk te krijgen over de gemiddelde bloeddruk van de patiënt. Bij alarmsignalen zoals een sterk verhoogde bloeddruk (SBD >180 mmhg), tekenen van eindorgaanschade of een ongunstig cardiovasculair risicoprofiel, zal echter bij voorkeur gedurende een korte periode worden gemeten (weken of dagen). In het algemeen geldt dat de diagnose hypertensie gebaseerd moet zijn op meerdere bloeddrukmetingen op meerdere dagen. Bij zeer ernstig verhoogde bloeddruk (>200 mmhg) kan de diagnose worden gesteld op basis van drie metingen tijdens één consult. Stress, lichamelijke klachten (waaronder pijn of overgangsklachten) en sommige medicatie, voedingsstoffen of genotsmiddelen kunnen leiden tot (voorbijgaande) hoge bloeddruk. Een na verloop van tijd opnieuw gemeten bloeddruk kan dan normaal blijken. Indien de hoge bloeddruk persisteert, dienen de bloeddrukverhogende middelen zo mogelijk te worden vermeden. De mate waarin deze middelen bloeddrukverhogend werken, is zeer variabel: in de meeste gevallen treedt geringe of geen bloeddrukverhoging op, maar soms ernstig of extreem. Ouderen en patiënten met diabetes of chronisch nierfalen zijn gevoeliger voor de bloeddrukverhogende effecten van NSAID s dan anderen. Bloeddrukmeting in de dagelijkse praktijk In de dagelijkse praktijk wordt de bloeddruk gemeten door een arts, doktersassistente, verpleegkundige of praktijkondersteuner in de huisartsenpraktijk of in het ziekenhuis (spreekkamerbloeddrukmeting) of door de patiënt zelf thuis (thuisbloeddrukmetingen). Men spreekt van ambulante bloeddrukmetingen bij automatische herhaaldelijke metingen (bijvoorbeeld elk halfuur) over een bepaalde periode (bijvoorbeeld 24 uur) buiten de setting van de kliniek of huisartsenpraktijk. Uit vergelijkend onderzoek blijkt dat de uitkomst van spreekkamermetingen gemiddeld 10/7 mmhg hoger ligt dan de uitkomst van gestandaardiseerde metingen. Het is daarom raadzaam om bij grensgevallen de bloeddruk nog eens over te meten op optimaal gestandaardiseerde wijze. De uitkomst van spreekkamermetingen liggen gemiddeld ook hoger dan de gemiddelde uitkomst van ambulante en thuismetingen. Zie noot 14 voor een beschrijving van de indicaties, meetmethoden en -protocollen. Noot 14 (richtlijnen) Gestandaardiseerde spreekkamerbloeddrukmeting Laat de patiënt enkele (±5) minuten zitten in een rustige omgeving. Creëer een ontspannen situatie en zorg ervoor dat de patiënt comfortabel zit (benen niet over elkaar geslagen, geen vuist maken). Zorg ervoor dat de arm waaraan gemeten wordt, wordt ondersteund. Gebruik een standaard manchet met een rubberen luchtblaas van 12 tot 13 cm breed en ongeveer 35 cm lang en beschik over een grotere en een kleinere manchet/luchtblaas voor respectievelijk dikke en dunne armen (de luchtblaas dient minimaal 80% van de arm te omvatten, maar niet dubbel te zitten). De kleine manchet/luchtblaas kan ook worden gebruikt voor kinderen. Zorg ervoor dat de manchet zich bevindt ter hoogte van het hart, halverwege het sternum, ongeacht de positie van de patiënt. Meet ten minste 2 keer met een tussenpoos

45 45 van 1 tot 2 minuten en meet vaker als er een duidelijk verschil is tussen de metingen. Neem het gemiddelde van de (laatste) 2 waarden. Bij auscultatoire meting zijn van de korotkoff-tonen fase I en V bepalend voor de systolische, respectievelijk de diastolische bloeddruk. Meet de eerste keer aan beide armen om eventuele verschillen door perifeer vaatlijden te onderkennen. Bij een verschil geldt de arm met de hoogste bloeddrukwaarde als representatief voor de systemische bloeddruk. Bij atriumfibrilleren is het aangewezen om ten minste 3 keer te meten en te middelen; oscillometrische apparaten geven vaak een foutmelding bij sterke irregulariteit of inaequaliteit. Protocollaire thuisbloeddrukmeting Gebruik een gevalideerde meter die via het International Protocol van de Working Group for Blood Pressure Measurement van de European Society of Hypertension, een voldoende beoordeling heeft gekregen 54, deze meters zijn te vinden, met instructies voor de patiënt, op hoge_bloeddruk/bloeddrukmetingthuis. Polsmeters worden niet aanbevolen. Auscultatoire meetmethoden worden niet aanbevolen voor metingen door de patiënt zelf. Demonstreer de meting en instrueer de patiënt als volgt: o meet in rustige omstandigheden, na 5 minuten rust genomen te hebben; o verricht geen inspanning, rook niet en drink geen koffie gedurende 30 minuten voorafgaand aan de meting; o meet de bloeddruk bij voorkeur in zittende houding met de rug ondersteund; o zorg ervoor dat de arm ondersteund is en breng de manchet aan op harthoogte; o zorg ervoor dat de benen niet zijn gekruist (zitten met beide voeten op de grond); o meet bij voorkeur aan de niet-dominante arm, tenzij er een (herhaaldelijk gemeten) aanzienlijk verschil is tussen de beide armen (>10 mmhg SBD en/of 5 mmhg DBD); dan dient er altijd aan de arm met de hoogste bloeddruk te worden gemeten. Geef een registratieformulier mee waarop in 4 kolommen datum, tijdstip, bloeddruk en bijzonderheden kunnen worden vermeld. Laat de patiënt dagelijks s morgens en s avonds 2 keer de bloeddruk meten gedurende 5 tot 7 dagen. Laat bij de interpretatie de gemeten bloeddrukwaarden van de eerste dag weg. o Klinische interpretatie wordt gebaseerd op de gemiddelde bloeddrukwaarden en de streefwaarden uit onderstaande tabel. o Metingen met de conventionele auscultatoire meter en de automatische oscillometer van de patiënt kan soms verrassend grote verschillen aantonen tussen de meters. De auscultatoire meter geldt dan als referentie. Corrigeer zo nodig de thuis gemeten bloeddrukwaarden op basis van een vergelijkende meetserie. 24-uurs ambulante bloeddrukmeting Gebruik een meter die gevalideerd is volgens het protocol van de Working Group for Blood Pressure Measurement van de European Society of Hypertension een voldoende beoordeling heeft gekregen 54 ( Stel de meter in op tussenpozen van maximaal 30 minuten; Instrueer patiënten normale activiteiten te ondernemen (maar geen maximale inspanning) en tijdens metingen de arm waaraan gemeten wordt te strekken en stil te houden; Vraag de patiënt om een dagboek bij te houden om opvallende gebeurtenissen te noteren, met vermelding van het precieze tijdstip van die gebeurtenis, ook notatie van de duur en de kwaliteit van de slaap is van belang; Accepteer geen 24-uursmetingen met >30% mislukte meetpunten.

46 46 Tabel bij AppendixB, noot 14. Streefwaarden afhankelijk van de meetmethoden van de bloeddruk Meetmethode Streefwaarde systolische bloeddruk Spreekkamer Thuis, protocollair Ambulant, 24 uur 140 mmhg (bij 80-plussers mmhg) 135 mmhg 130 mmhg

47 47 Appendix C Criteria of urgent referral (copied from NHG-guideline Cardiovascular risk management ) Spoedonderzoek naar het bestaan van orgaanschade is geïndiceerd bij: Een SBD >200 mmhg, tenzij de patiënt hier in het verleden reeds mee bekend was; Een SBD 200 mmhg, maar recente objectieve sterke bloeddrukstijging; Hypertensie met klachten als hoofdpijn, visusstoornissen, misselijkheid of braken; Aanwijzingen voor cardiovasculaire complicaties, zoals dyspnoe, pijn op de borst of pijn tussen de schouderbladen; Aanwijzingen voor cerebrale complicaties, zoals veranderde gemoedstoestand, verlaagd bewustzijn, neurologische uitvalsverschijnselen, verwardheid of convulsies; Aanwijzingen voor (acuut) hartfalen; Graad-III of -IV-hypertensieve retinopathie.

48 48 Appendix D Risk table (copied from NHG-guideline Cardiovascular risk management )

49 49 Appendix E Additional risk factors (copied from NHG-guideline Cardiovascular risk management) Bij aanvullende risicofactoren zoals een belaste familieanamnese, lichamelijke inactiviteit, obesitas of vermindering van nierfunctie, is het risico hoger dan in de tabel aangegeven. Slechts in de categorie patiënten bij wie het 10-jaarsrisico tussen de 10 en 20% valt, wegen deze aanvullende risicofactoren mee bij de keuze om al dan niet met medicamenteuze behandeling te starten.

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