Clinical trial NCT01267747: Prevalence of Primary Aldosteronism in Hypertensive Patients Presenting With Atrial Flutter or Fibrillation
Official title: Prospective Assessment of The Prevalence of Primary Aldosteronism in Hypertensive Patients Presenting With Atrial Flutter or Fibrillation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Atrial Fibrillation
Atrial Flutter
Aldosteronism
Keywords: Atrial fibrillation
Atrial Flutter
Primary Aldosteronism
Aldosterone Producing Adenoma
Lead sponsor: University Hospital Padova
Sponsor class: OTHER
First posted: 2010-12-28
Enrollment: 411
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Hypertensive patients presenting with atrial fibrillation or flutter

Brief summary: Primary objective of the PAPPHY Study is to establish the prevalence of primary aldosteronism (PA) in consecutive hypertensive patients referred for 'lone' paroxysmal, persistent or permanent atrial flutter or fibrillation (AFF).

Design: cohort multicenter prospective study. State-of-the-art criteria and guidelines were followed for case detection and management of both PA and of AF in all enrolled patients (Funder J. J Clin Endocrinol Metab 2008 and 2016; Kirchhof P. Eur Heart J 2011 and 2016).

Detailed description: A previous retrospective study documented a 12-fold increase of the risk of AFF in patients with primary aldosteronism (PA) as compared to subjects with primary (essential) hypertension (Milliez 2005). However, being retrospective this investigation could involve a selection bias and therefore is to be regarded as hypothesis-generating rather than a proof-of-concept study.

Hence, based on results of experimental studies, we hypothesize that in a proportion of hypertensive patients presenting with 'lone' PA could be the underlying cause of hypertension leading to AFF. If proven, this hypothesis would imply that an early diagnosis of PA might not only cure PA and hypertension but also prevent AFF in a non negligible number of hypertensive patients.

Primary objective is to establish the prevalence of PA in consecutive hypertensive patients referred for 'lone' paroxysmal, persistent or permanent AFF.

Study design: Prospective multicenter cohort study.

Sample size:

Based on the PAPY study experience and on available data from the literature concerning prevalence studies, we anticipated that the enrolment of at least 1000 consecutive patients will give conclusive evidence on PA prevalence in AFF patients.

Nothwithstanding a long enrolment period (from 2015 to 2018), we were unable to reach the calculated sample size and, therefore, the study was smaller than the size calculated when the PAPPHY study was conceived. In order not to introduce a time-dependent bias associated with an unduly long recruitment with associated changes in practice, it was decided to stop the study upon screening of 411 patients.

Data analysis. Data collection in a specific software, with the database securely stored and analyzed at the core laboratory of the Arterial Hypertension Unit at the University of Padova, Italy.

Experimental Procedures.

Baseline visit

* Clinic evaluation of the patient;
* Collection of demographic data and history;
* Measurement of blood pressure and heart rate;
* Scanning and storage of ECG documenting AFF;
* Echocardiography for measurement of left atrial and aortic diameters, left ventricular thickness and diameters, systolic and diastolic and transmitral Doppler flow velocity indexes;
* Clinical chemistry including serum ions, s-Creatinine, eGFR, HbA1c, microalbuminuria, TSH;
* Measurement of PRA and plasma aldosterone concentration (PAC), under baseline and after captopril challenge, if the patient is not assuming drugs interfering with the renin angiotensin system and eventually after correction of hypokalemia;
* Cardioversion if needed.

Diagnosis of PA in patients with a florid PA phenotype, i.e. a high aldosterone to renin ratio (ARR), e.g. \> 100 (in \[ng \*dl-1 \] \* \[ng \*ml-1 \* h-1\]) with no further tests, following the Endocrine Society guidelines (Funder J. J Clin Endocrinol Metab 2016) and based on compelling evidence that in these patients the specificity approaches 100%, and the false negative rate 0% (Maiolino G. J Am Heart Assoc 2017).

Exclusion of PA when ARR \< 26 and plasma aldosterone concentration (PAC) \< 15 ng \*dl-1 at the first or a repeated test. In all PA patients presenting with an ARR value in a grey area (i.e. between 26 and 100, and a PAC \> 15 ng \*dl-1) at the first and a repeated test after further 1 month wash-out, a confirmatory (captopril challenge) test to rule out false positive results (Funder J. J Clin Endocrinol Metab 2016).

At the end of this work-up, computed tomography and adrenal vein sampling in patients with biochemically confirmed PA for PA subtyping.

Diagnosis of aldosterone producing adenoma (APA) confirmed by biochemical cure, e.g. normalization of plasma renin activity (PRA) and aldosterone, after adrenalectomy.

The protocol of the study was revised in 2013 and then in 2015. Herein is reported the last approved version.

Eligibility criteria: Inclusion Criteria:

* Unequivocal evidence (by ECG, Holter ECG or medical charts) of AFF (paroxysmal, persistent or permanent) in patients with blood pressure \> 140/90 mmHg on at least 3 office measurements, or current use of anti-hypertensive drugs;
* Written informed consent.

Exclusion Criteria:

* Patient refusal to participate to the study;
* Moderate-severe valvular or congenital or myocardial heart disease;
* Current abnormal thyroid function;
* Chronic renal failure (sCreatinine \> 200 μM or eGFR \< 40 ml/min, calculated with MDRD formula);
* Hemochromatosis;
* Alcohol abuse;
* Acute coronary syndrome, or history of CABG, PTCA with/without stenting, acute myocardial infarction;
* Hepatitis C virus and/or B and/or HIV infection;
* Pheochromocytoma and other known secondary forms of arterial hypertension;
* Hemodynamic instability precluding withdrawal of drugs (e.g. β-blockers, ARBs, ACE-I, diuretics), interfering with PRA (or DRA) and aldosterone measurements.

Primary outcomes:
measure: Prevalence of PA in hypertensive patients referred for 'lone' atrial fibrillation.
timeFrame: 2015-2018
Secondary outcomes:
Other outcomes:
Locations:
city: Padova
country: Italy
facility: Department of Medicine - DIMED, University of Padova, Italy
city: Padova
country: Italy
facility: Department of Medicine - DIMED, University of Padova, Italy
Study officials:
affiliation: Department of Medicine -DIMED, University Hospital of Padova, Italy
name: Gian Paolo Rossi, MD, FAHA
role: STUDY_DIRECTOR
References:
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citation: Maiolino G, Rossitto G, Bisogni V, Cesari M, Seccia TM, Plebani M, Rossi GP; PAPY Study Investigators. Quantitative Value of Aldosterone-Renin Ratio for Detection of Aldosterone-Producing Adenoma: The Aldosterone-Renin Ratio for Primary Aldosteronism (AQUARR) Study. J Am Heart Assoc. 2017 May 21;6(5):e005574. doi: 10.1161/JAHA.117.005574.
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citation: Seccia TM, Letizia C, Muiesan ML, Lerco S, Cesari M, Bisogni V, Petramala L, Maiolino G, Volpin R, Rossi GP. Atrial fibrillation as presenting sign of primary aldosteronism: results of the Prospective Appraisal on the Prevalence of Primary Aldosteronism in Hypertensive (PAPPHY) Study. J Hypertens. 2020 Feb;38(2):332-339. doi: 10.1097/HJH.0000000000002250.