Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design

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Abstract

Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non-valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the ‘four corners criteria’ for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA.

Introduction

Primary aldosteronism (PA) is a common albeit often undetected curable cause of arterial hypertension.1 PA patients appear to be at increased risk of cardiovascular complications, including left ventricular hypertrophy, diastolic dysfunction, ‘flash’ pulmonary oedema myocardial infarction and stroke.2, 3 Moreover, they have a 12-fold increase of relative risk of atrial flutter or fibrillation (AFF), compared with primary (essential) hypertensive patients.4 Age, duration of hypertension and PA have been shown to be independent predictors of atrial fibrillation.4 Previously, in a report of six cases, AFF has been claimed to be an unusual presentation of PA.5, 6

Several mechanisms may account for the heightened excess risk of AFF in PA. Hypokalemia, an established risk factor for arrhythmia, is unlikely to be the only major causative factor for AFF, as it occurs in less than 50% of the patients with PA.1 Compelling evidence also indicates that PA induces left ventricular (LV) remodelling and hypertrophy inappropriate for the haemodynamic load, and also diastolic dysfunction causing left atrium dilatation.7 Left ventricular hypertrophy and atrial enlargement were found to be associated with persistent atrial fibrillation in the Framingham Heart Study.8 In the setting of a high sodium intake hyperaldosteronism was also found to cause cardiac fibrosis, partly independent of increased blood pressure; moreover, cardiac fibrosis is also a feature of human PA contributing to diastolic dysfunction, prolonged PQ interval and left atrial enlargement.9, 10, 11, 12 Hence, in PA, several factors may interact to increase the likelihood of re-entry mechanisms thereby setting the stage for development of hyperkinetic arrhythmias such as AFF.

The LIFE and the VALUE studies, in which losartan and valsartan reduced the incidence of atrial fibrillation compared with atenolol or amlodipine respectively,13, 14, 15 also suggested a role of excess aldosterone in this context. This may reflect angiotensin II AT1 receptor antagonism conferring a protective effect on the heart by blunting angiotensin II-dependent aldosterone secretion. Taken together, these findings suggest that reduction of LV end-diastolic pressure and left atrial stretch plus blunted collagen deposition following angiotensin II blockade contribute to prevention of AFF,16 a contention supported by the results of two meta-analyses.16, 17 Therefore, even though the evidence collectively supports an association of AFF with LV remodelling and hyperaldosteronism in hypertensive patients,4, 18 whether the prevalence of PA is high in hypertensive patients presenting with lone AFF remains unknown. Moreover, although AFF and PA may both be associated with an impaired quality of life (QOL),19 whether restoration of sinus rhythm and/or adrenalectomy may improve QOL20 remains uncertain.21

On the basis of this background we will prospectively document the prevalence of PA and the QOL in hypertensive patients presenting with lone AFF, using state-of-the-art criteria for the case detection of PA and following guidelines for the management of AFF.21

Objectives of the study

The primary and secondary goals of this study are summarized in Table 1.

Table 1 Primary and secondary goals of the PAPPHY Study

Methods

Study design

Prospective observational multicentre cohort study of consecutive hypertensive patients presenting at units (Internal Medicine, Cardiology, Endocrinology and so on) located in Europe that have consented or will consent to participate in the study. This will allow recruitment of a large sample, and therefore should produce hard data on the prevalence of PA in hypertensive patients presenting with AFF. To minimize the chances of selection bias data from participating centres will be analysed only if they have enroled at least 20 patients.

Sample size

On the basis of the experience of the PAPY Study and of the literature on prevalence studies,1,17,22,23 we estimate that a sample size of 1000 consecutive patients will provide solid data on PA prevalence in AFF patients.

Inclusion and exclusion criteria

The inclusion and exclusion criteria for the PAPPHY Study are listed in Table 2.

Table 2 Inclusion and exclusion criteria

Data analysis

Data will be collected on a specific form created by File-Maker (FileMaker Inc., Santa Clara, CA, USA) in a dedicated database hosted by a server in the core laboratory in Internal Medicine 4, Department of Medicine-DIMED, Padua, Italy. The principal investigator (PI) will be responsible for monitoring in real time the building up of the database, preservation of data integrity and statistical analysis.

Fulfilment of the inclusion criteria will be verified beforehand by allowing individual patient data to be entered only when the preliminary have been satisfied. A Clinical Events Committee will allocate patients to each diagnosis group.

Comparison of quantitative variables between groups will be performed by analysis of variance and post-hoc tests, or unpaired t-tests, as appropriate. Comparison of qualitative variables, such as AFF prevalence, and secondary end points distinguishing AFF/PA and AFF/non-PA patients will be performed using χ2-tests.

Experimental procedure

Initial evaluation

The procedure used for recruitment, clinical management and ascertainment of PA will be according to current recommendations,21, 24 with slight modifications, as summarized in the study algorithm (Figure 1). During AFF, atrial and ventricular stretch are likely to increase release of the natriuretic peptides ANP and BNP, which potently inhibit aldosterone secretion. It is therefore conceivable that the presence of AFF can lower aldosterone secretion and the aldosterone-to-renin ratio (ARR), thereby increasing the false negative rate. To investigate this hypothesis the screening test will be performed, whenever possible, when the patients are in AFF, and then repeated after restoration of sinus rhythm. A within-patient comparison of plasma aldosterone concentration (PAC), plasma renin, and the ARR will therefore be undertaken, with simultaneously measured levels of natriuretic peptides, in the presence and absence of AFF.

Figure 1
figure1

Flow-chart of the study. Eligible patients will be adult hypertensive patients with EKG evidence of paroxysmal, persistent or permanent AFF. After physical examination, assessment of cardiac function and correction of hypokalemia, if the patient is not taking drugs interfering with the RAAS, PRA, DRA and PAC will be measured at baseline and after captopril challenge. The ARR will be calculated to screen for PA. If the duration of AFF is <48 h, the patient will undergo pharmacological cardioversion or DCC. After 4 weeks, screening for PA will be performed again after conversion to sinus rhythm, to determine whether ARR may be affected by concomitant AFF, and therefore whether the diagnostic accuracy of ARR may be challenged by AFF. If an appropriate withdrawal of the drugs interfering with the RAAS is needed and duration of AFF <48 h requires immediate cardioversion, PRA, DRA and PAC will be measured after restoration of sinus rhythm. If the patient is taking drugs interfering with the RAAS, screening for PA will be done after withdrawal of these drugs and treatment with verapamil, or diltiazem and doxazosin to control heart rate and blood pressure.

Logistic organization

This study has two major important features (Figure 2):

  1. a)

    Centralization of data collection: each investigator will be responsible for the input of their data in the database that will be centrally managed and monitored in real time. Besides the need to fulfil inclusion and exclusion criteria, the data collection form has filters to censor input of aberrant or incoherent values. This will exclude the need for post-hoc deletion of mistaken or gross outlier entries. Any difficulty in work-up and/or management of clinical cases will be discussed between the participating and the coordinating centres.

  2. b)

    Centralized measurement of the analytes will be undertaken for variables, such as plasma renin activity (PRA), serum aldosterone and proBNP, for which there is non negligible inter-laboratory variability, to avoid localized methodological bias.

Figure 2
figure2

PRA, DRA and PAC will be measured twice, that is before and after cardioversion in those patients who are not taking drugs interfering with the RAAS, and who not require immediate cardioversion according to the 2010 ESC guidelines as detailed in the legend to Figure 1.21 Hence, ARR values calculated before and after cardioversion will allow estimation of ARR performance for case detection of PA in hypertensive patients with concurrent AFF. If biochemical diagnosis of PA is done and adrenal venous sampling indicated, adrenal vein sampling will allow detection of lateralized excess aldosterone production, if present, and adrenalectomy to be offered. All patients will be followed up for 2 years starting 1 month after treatment and then at 6-month intervals. Any change in drugs, occurrence of death or cardiovascular events will be recorded, and cardiac and vascular remodelling assessed.

The diagnostic strategy includes the following steps:

  1. 1

    collection of demographic data via the link https://fm.dmcs.unipd.it;

  2. 2

    measurement of blood pressure and heart rate;

  3. 3

    evidence of AFF at electrocardiogram (EKG);

  4. 4

    echocardiography to identify exclusion criteria at enrolment and after restoration of sinus rhythm, to gather information on LV diameter and wall thickness, aortic diameter and trans-mitral Doppler flow velocity indices of diastolic function.

  5. 5

    clinical chemistry (Table 3);

    Table 3 Biochemical measurements to be performed at enrolment and follow-up visits
  6. 6

    assessment of QOL;

  7. 7

    measurement of the pulse wave velocity as a marker of arterial stiffness;

  8. 8

    correction of hypokalemia, if present;

  9. 9

    measurement of ANP, proBNP, serum and urinary ions.

Depending on the onset of AFF and the on-going treatment with drugs affecting the renin-angiotensin-aldosterone system (RAAS), patients will be allocated into four subgroups. Given that diuretics, β-blockers, clonidine and monoxidine can impair case detection of PA,25 they will be withdrawn before measuring PRA and PAC (Table 4). ACE-inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) will be allowed when strictly necessary to achieve BP control. Under treatment with these agents the finding of low PRA and high PAC is strongly suggestive of PA; further testing will therefore be undertaken (see below, case detection).

Table 4 Drugs requiring wash out before measurement of PRA and aldosterone levels

Subgroup 1: patients with AFF onset <48 h and not taking any drugs affecting the RAAS will receive prophylaxis of thromboembolism with low molecular weight heparin. After PRA and PAC at baseline are measured and ARR calculated, they will undergo cardioversion, either pharmacological or by direct current (DCC), within 48 h of AFF onset. PRA and PAC at baseline and after captopril challenge will be measured again after 4 weeks of sinus rhythm to recalculate ARR. Urinary steroids (tetrahydrocortisone, tetrahydrocortisol and allotetrahydro-cortisol) will be measured at the same time.

Subgroup 2: patients not taking drugs affecting the RAAS with onset of AFF unknown or >48 h. After the presence of AFF is confirmed, plasma and urine will be collected for measurement of steroid, and of PRA, PAC and ARR (under baseline and after captopril challenge). Low molecular weight heparin and oral anticoagulants will be administered to prevent thrombo-embolism, and elective DCC will be planned to take place after 3 weeks. No cardioversion will be undertaken if AFF is permanent and/or there is marked left atrial dilatation (left atrial volume index (biplane method) 40 ml m−2)26 given the high risk of AFF recurrence.27, 28, 29 The mandatory 3-week period of anticoagulation before cardioversion can be shortened if trans-oesophageal echocardiogram (TOE) shows no left atrial or left atrial appendage thrombus.21 Urinary steroids, as well as PRA and PAC at baseline and after captopril challenge, will be determined after 4 weeks of sinus rhythm, and ARR calculated.

Subgroup 3: patients taking drugs affecting the RAAS with AFF onset <48 h. After being given LMWH, patients will undergo pharmacological cardioversion or DCC within 48 h of the onset of AFF. Drugs listed in Table 4 will be withdrawn and, if necessary, verapamil or diltiazem and/or doxazosin given to control blood pressure. After 4 weeks of sinus rhythm, PRA and PAC at baseline and after captopril challenge will be measured, as well as urinary steroid levels.

Subgroup 4: patients taking drugs listed in Table 4 with AFF onset unknown or >48 h will receive prophylaxis of thromboembolism, as described above, and treatment with verapamil/ diltiazem/doxazosin until elective DCC. Measurement of PRA and PAC at baseline and after captopril challenge, and of urinary steroids, will be performed after appropriate wash out and 4 weeks of sinus rhythm.30

Case detection of PA

  • (A) PA will be excluded if baseline ARR <26 and PAC <15 ng dl−1. No further search of PA will be made in these patients.

  • (B) PA will be diagnosed if baseline ARR >100. Further testing by computed tomography and adrenal vein sampling will be planned to identify the PA subtype.

  • (C) In patients with a baseline ARR between 26 and 100 and a PAC <15 ng dl−1, PRA and PAC will be measured again under both baseline conditions and after captopril challenge 1 month later to re-estimate the ARR.1 Investigation to identify the PA subtype, as described above, will be restricted to the patients with a confirmed abnormal ARR at the second determination.

  • (D) In patients on ACE-I or ARBs, the diagnosis of PA will be regarded as highly likely if PRA is suppressed, for example <1 μg l−1 h−1 and PAC is elevated, for example >15 ng dl−1. In these patients, if required and is feasible, PRA and PAC for calculation of ARR will be measured again after withdrawal of ACE-I and ARBs for 3 weeks. The diagnosis will then be made according to points A–C. If withdrawal of ACE-I and ARBs is not feasible, or unsafe, and the patients seek surgical cure of PA, they will undergo computed tomography and adrenal vein sampling as described for patients at point B.

We will use the cutoff ARR values of 26 ng dl−1 μg−1 l−1 h−1 and 27.3 ng mIU−1 for PA screening for PRA and DRA. The first value was established by the PAPY Study1 and the latter in a study investigating the accuracy of ARR with DRA as denominator.31

Diagnostic criteria for PA subtype

The diagnosis of APA will be made on the four corner criteria.1 This is feasible only in those who are candidates for laparoscopic adrenalectomy under general anaesthesia and seek surgical cure of PA. Patients with a biochemical diagnosis of PA not satisfying these criteria will be considered to have idiopathic hyperaldosteronism and will be assigned to medical treatment with a mineralocorticoid receptor antagonist plus other antihypertensives as needed.

Follow-up

Follow-up will assess the outcomes of adrenalectomy or medical treatment on PRA, PAC, serum K+, and blood pressure, and will detail cardiac and vascular damage, occurrence of death and/or cardiovascular events, including recurrence of AFF in patients with or without PA. Visits will be scheduled 1 month after surgery/medical treatment, and then every 6 months for 2 years.

Ethical consideration

The study was approved by the local Ethics Committee on 16 December 2010, and has been registered at clinicaltrials.gov (Identifier: NCT01267747).

Discussion and expected results

This prospective study will progress from an enlarged collaborative research network of investigators, proven successful in the PAPY Study,1 and in the European Network for the Study of Adrenal Tumours, and thus likely to achieve its end points (Table 5). Achievement of its primary objective—establishing the prevalence of PA in hypertensive patients presenting with lone, paroxysmal, persistent or permanent AFF—will provide highly relevant information with a major impact on clinical practice. Currently the finding of lone AFF in a hypertensive patient does not automatically raise the question of whether this can be due to long-standing undetected PA, unless some clues (hypokalemia or resistant hypertension) are present. The demonstration that the prevalence of PA in patients with AFF is higher than in hypertensive subjects, in general, might increase the case detection of PA and thereby allow targeted treatment of this condition.

Table 5 Primary and secondary end points

We also expect to achieve more accurate identification of the predictors of AFF, better understanding of the mechanisms of AFF, identification of the effect of specific treatment of PA, that is adrenalectomy or mineralocorticoid receptor antagonists, alone or with other antihypertensive agents, on the rate of recurrence of AFF. Ancillary information will be the identification of the impact of lone AFF and/or PA on QOL and of the effects of correction of PA and/or sinus rhythm restoration. In addition to these aims, the feasibility of replacing the measurement of PRA with the direct measurement of active renin (DRA) in screening for PA, as suggested by several recent studies,31, 32, 33 will also be tested. This might be of particular interest in the subgroup of hypertensive patients with AFF who receive treatments for AFF that might interfere with renin synthesis34 and/or renin measurement,34 and could be exposed to altered sympathetic afferents and increased ANP and BNP release from stretched atria. Whether these mechanisms alter renin secretion, and differentially affect the PRA- and DRA-based assessment of renin levels is a further issue that may become clear.

Participating centres and core laboratory

In order to enrol and randomize the 1000 patients needed to provide significant power, the study will start within the Italian Society of Arterial Hypertension (SIIA), and will be then extended to all European centres that wish to participate. Each centre will be required to recruit at least 20 eligible patients.

A ‘core laboratory’ at Padua will (1) adjudicate eligible patients based on EKG and echocardiography; (2) confirm the diagnosis of PA; (3) confirm the diagnosis of lateralized excess aldosterone production at adrenal vein sampling.

Direct feedback between the core laboratory and the participating centres will allow validation of the diagnosis of PA in real time.

Critical event committee

Gian Paolo Rossi (PI), Diego Miotto, Teresa Maria Seccia, Loira Leoni.

Echocardiography committee

Gian Paolo Rossi (PI), Maria Lorenza Muiesan, Maurizio Cesari.

Participating centres

Gian Paolo Rossi, Teresa M Seccia, Valentina Gallina, Maurizio Cesari, Martino Pengo, Fabio Ragazzo, Loira Leoni, University of Padua;

Anna Belfiore, Internal Medicine, University of Bari;

Giampaolo Bernini, Internal Medicine, University of Pisa;

Francesco Cipollone, Internal Medicine, University of Chieti;

Santina Cottone, Giuseppe Andronico, Internal Medicine, University of Palermo;

Claudio Ferri, Internal Medicine, University of L'Aquila;

Gilberta Giacchetti, Endocrinology, University of Ancona;

Guido Grassi, Internal Medicine, University of Milan;

Claudio Letizia, Internal Medicine, University of Rome;

Massimo Mannelli, Gabriele Parenti Endocrinology, University of Florence;

Franco Mantero, Endocrinology, University of Padua;

Alberto Morganti, Internal Medicine, University of Milan;

Maria Lorenza Muiesan, Damiano Rizzoni, Internal Medicine, University of Brescia;

Ermanno Rossi, Internal Medicine, University of Reggio Emilia;

Massimo Volpe, Cardiology, University La Sapienza, Rome, and IRCCS Neuromed, Pozzilli.

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Correspondence to G P Rossi.

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Rossi, G., Seccia, T., Gallina, V. et al. Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design. J Hum Hypertens 27, 158–163 (2013) doi:10.1038/jhh.2012.21

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Keywords

  • aldosteronism
  • atrial fibrillation
  • high blood pressure
  • plasma renin

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