Prevalence of Primary Aldosteronism in Hypertensive Patients Presenting With Atrial Flutter or Fibrillation (PAPPHY)

This study is currently recruiting participants.
Verified March 2014 by University Hospital Padova
Sponsor:
Information provided by (Responsible Party):
Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova
ClinicalTrials.gov Identifier:
NCT01267747
First received: December 27, 2010
Last updated: March 26, 2014
Last verified: March 2014

December 27, 2010
March 26, 2014
March 2011
March 2016   (final data collection date for primary outcome measure)
Prevalence of Primary Aldosteronism [ Time Frame: 2 years ] [ Designated as safety issue: No ]
The prevalence of Primary Aldosteronism, as assessed as Aldosterone Renin Ratio > 26 ng/dL/ng/mL h) and PAC > 15 ng/dL, will be prospectively assessed in consecutive hypertensive patients hospitalized for lone (non valvular), paroxysmal, persistent or permanent AFF, at Internal Medicine, Cardiology and Endocrinology Units.
Same as current
Complete list of historical versions of study NCT01267747 on ClinicalTrials.gov Archive Site
  • Echocardiographic and biochemical variables predicting Primary Aldosteronism. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The clinical, echocardiographic and biochemical markers that can predict the risk for atrial fibrillation or flutter will be identified in the hypertensive patients with/without Primary Aldosteronism.
  • Aldosterone-to-renin ratio (ARR) based on plasma renin activity (PRA) and also on the direct measurement of active renin (DRA) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The diagnostic usefulness of the aldosterone-to-renin ratio (ARR) based on either plasma renin activity (PRA) or the direct measurement of active renin (DRA) will be prospectively determined for diagnosing primary aldosteronism in patients with atrial fibrillation or atrial flutter.
  • ARR for identification of PA as a function of the presence/absence of AFF [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The hypothesis being tested here is the following: AFF, by increasing ANP and/o BNP, could blunt aldosterone secretion. Hence the ARR could be lowered by the concurrence of AFF and this could impede the detection of PA in hypertensive patients.
  • Recurrence or new onset AFF in hypertensive patients with/without PA [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The rate of recurrence or new onset AFF during follow-up will be prospectively determined in a cohort of hypertensive patients with/without PA as a function of specific treatment for the latter.
Same as current
Not Provided
Not Provided
 
Prevalence of Primary Aldosteronism in Hypertensive Patients Presenting With Atrial Flutter or Fibrillation
Prospective Assessment of The Prevalence of Primary Aldosteronism in Hypertensive Patients Presenting With Atrial Flutter or Fibrillation

Primary objective of the PAPPHY Study is to establish the prevalence of primary aldosteronism (PA) in consecutive hypertensive patients hospitalized for lone (non valvular), paroxysmal, persistent or permanent atrial flutter or fibrillation (AFF).

Secondary objectives are to identify:

  1. the clinical, echocardiographic and biochemical predictors of AFF in the hypertensive patients with/without PA;
  2. if AFF, by increasing ANP and/o BNP thereby conceivably blunting aldosterone secretion, can lower the ARR and impede PA detection.
  3. the usefulness of the aldosterone-to-renin ratio (ARR) based on plasma renin activity (PRA) and the direct measurement of renin (DRA) for diagnosing PA in patients with AFF.
  4. the rate of recurrence or new onset AFF during follow-up in a cohort of hypertensive patients with/without PA as a function of specific treatment for the latter.

Design: cohort multicenter prospective study. Sample size: 1000 consecutive patients.

Procedure At baseline cardiac function, arterial stiffness, and plasma renin activity (PRA), direct renin assay (DRA), plasma aldosterone (PAC) will be measured. Pharmacologic or direct current cardioversion (DCC) will be performed if indicated according to 2010 ESC guidelines.

PRA and PAC will be measured again 2 weeks after cardioversion to answer secondary aim b.

If ARR is > 26 and PAC > 15 ng/dL, adrenal vein sampling (AVS) will be performed in patients willing to undergo adrenalectomy to identify a lateralized PAC excess.

Follow-up will be aimed at assessing damage organ, occurrence of cardiovascular events and recurrence of AFF in patients with or without PA.

Demonstration of a higher prevalence of PA in the patients with AFF as compared to the general population of the hypertensive subjects will provide evidence for 1) a role of aldosterone excess in causing AFF and cardiac electric remodeling; 2) the usefulness of case detection of PA in hypertensive patients with AFF; 3) the predictors of AFF; 4) the outcome of specific treatment for PA on risk of incident and recurrent AFF.

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 (non valvular) 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 hospitalized for lone (non valvular), paroxysmal, persistent or permanent AFF.

Secondary objectives are to identify:

  1. the clinical, echocardiographic, and biochemical predictors of AFF in the hypertensive patients with/without PA;
  2. if AFF by increasing ANP and/or BNP, and thereby conceivably blunting aldosterone secretion, can lower the ARR and impede detection of PA;
  3. the usefulness of the aldosterone-to-renin ratio (ARR) based on either plasma renin activity (PRA) or the direct measurement of active renin (DRA) for diagnosing PA in patients with AFF;
  4. prospectively the rate of recurrence of AFF during follow-up in a cohort of hypertensive patients with/without PA after correction of PA with adrenalectomy or mineralocorticoid receptor antagonists and after pharmacological treatment of essential hypertension.

Study design: Prospective multicenter cohort study. Enrolment Sites: Internal Medicine, Cardiology, Endocrinology located all over Europe. These centers constitute the network of the PAPY (Primary Aldosteronism Prevalence in Hypertension) Study and the ENS@T (European Network for the Study of Adrenal Tumors).

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.

Data analysis. Data will be collected using a specific software; the database will be securely stored and analyzed at the core laboratory of the Clinica Medica 4-DMCS in Padova, Italy.

Experimental Procedures.

Baseline visit (visit 1)

  • 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;
  • Measurement of pulse wave velocity and ankle-brachial index with EcoDoppler for the assessment of regional arterial stiffness;
  • Clinical chemistry including serum ions, s-Creatinine, GFR calculated with MDRD formula, HbA1c, microalbuminuria, S-proBNP, ANP, TSH, and SNP identification;
  • 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 according to 2010 ESC guidelines. In patients assuming drugs interfering with the renin angiotensin-aldosterone system, such drugs will be withdrawn and therapy with verapamil, or diltiazem, or amiodarone will be started for heart rate control. α2 agonists will be added, if necessary, to achieve BP control.

Visit 2. If not performed at visit 1, PRA, DRA and PAC will be measured under both basal conditions and after the captopril challenge.

Visit 3. Two weeks after cardioversion, PRA, DRA and plasma aldosterone will be measured at baseline and after captopril challenge to calculate the ARR-P and ARR-D. If baseline ARR-P > 26 and PAC > 15 ng/dL, either before and/or after cardioversion, imaging of the adrenal gland with CT will be performed to exclude an adrenocortical carcinoma. The patients who are plausible candidates for general anesthesia and are willing to undergo adrenalectomy in case of detection of lateralized excess aldosterone production, will be offered AVS. If patients do no satisfy these criteria they will receive spironolactone or potassium canrenoate, alone or in combination with other antihypertensive medications as appropriate, in order to achieve target BP for their level of risk.

If ARR-P < 20 and PAC > 15 ng/dL under basal conditions, PA may be excluded and the patient will enter follow-up with no further investigation.

Visit 4. AVS will be used for diagnosis only if bilaterally selective (Selectivity Index > 1.1) and lateralization will be diagnosed if Lateralization Index > 2. In case of lateralized excess aldosterone production, adrenalectomy will be planned.

Follow-Up. Follow-up will be aimed at assessing damage organ, occurrence of cardiovascular events, including recurrence of AFF in patients with or without PA. Visits will be scheduled every 6 months for 2 years. BP, HR and biochemical parameters will be measured, and EKG and echocardiography will be recorded.

Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:

Venous blood will be withdrawn to measure

  • levels of ions (sodium, potassium, magnesium), creatinine, proBNP, and TSH in the serum, and
  • percent HbA1c levels, plasma aldosterone concentration (PAC), renin concentrations (DRA) and renin activity (PRA) in the plasma.

A venous blood specimen will be used to separate buffy coat for downstream identification of SNP associated with primary aldosteronism and development of atrial flutter or fibrillation.

Urine specimens will be collected to measure microalbuminuria.

Probability Sample

Hypertensive patients presenting with atrial fibrillation or flutter AFF) at primary care European clinics (Internal Medicine, Cardiology, Endocrinology).

  • Atrial Fibrillation
  • Atrial Flutter
  • Aldosteronism
Not Provided
Atrial fibrillation or flutter patients
Patients with atrial flutter or lone (non valvular), paroxysmal, persistent, or permanent atrial fibrillation consecutively admitted at Internal Medicine, Cardiology and Endocrinology Units.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1000
July 2016
March 2016   (final data collection date for primary outcome measure)

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.

Patients with resistant hypertension in whom antihypertensive drug treatment withdrawal/modifications will be considered unsafe will be investigated on treatment and, if necessary, submitted to AVS to exclude a lateralized cause of aldosterone excess. They will be analyzed as a separate group.

Both
18 Years to 75 Years
No
Contact: Gian Paolo Rossi, MD, FAHA 0039 049 8213 gianpaolo.rossi@unipd.it
Italy
 
NCT01267747
GPR-PAPPHY
Yes
Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova
University Hospital Padova
Not Provided
Study Director: Gian Paolo Rossi, MD, FAHA Department of Medicine -DIMED, University Hospital of Padova, Italy
University Hospital Padova
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP