Pharmacosurveillance and Pharmacogenetics of First-line Diuretics in Hypertension: The StayOnDiur Study - Full Text View

Sponsor:	Federico II University
Collaborator:	Agenzia Italiana del Farmaco
Information provided by:	Federico II University
ClinicalTrials.gov Identifier:	NCT00408512

Purpose

Background: The use of thiazide diuretics in the treatment of hypertension (HT) is widely considered a first line treatment, given the efficacy and low cost of this class of drugs. This indication is not unanimous, because thiazides can cause metabolic alterations and other side effects increasing cardiac and cerebrovascular risk, which reduce compliance to treatment and increase health care system cost. However, large intervention trials in HT suggest that the improvement in cardiovascular prognosis of HT patients depends more on follow-up procedures than on type of drug used. Furthermore, the investigators have documented improved compliance to antihypertensive therapy by implementing cooperation between general practitioners (GPs) and HT specialists.

Objectives: In a multicenter, open label randomized study the investigators will compare the persistence on therapy of thiazides versus other treatments, as a first line antihypertensive therapy, in a clinical setting characterized by a strict cooperation between GPs and HT specialist. The investigators will also analyse candidate genes with impact on drug-induced metabolic alterations to elucidate the pathophysiology of these phenomena.

Methods: 260 GPs will recruit 2600 hypertensive patients with indication to pharmacological treatment and randomise them to starting treatment with chlortalidone (12.5 to 25 mg daily, 1300 pts) or a GP decided single drug (excluding thiazides) or combination therapy at highest tolerated dose. In both groups any other class of antihypertensive drugs can be added over time in order to achieve blood pressure control (<140/90 mmHg). Follow-up will last 2 years. Blood sample and urine analyses, carotid and cardiac ultrasound will be performed at baseline and scheduled time points. Genotyping will be performed by sequencing. Data will be collected and stored using a web based centralized Case Report Form (CRF) Expected results: Results will highlight whether a follow-up strategy based on tight cooperation between GPs and HT specialists can allow the use of thiazides as first line antihypertensive therapy without any negative effect on persistence, adherence and efficacy of the treatment. These data can be used to reduce total burden of the Health Care System in HT by replacing more expensive drugs with diuretics in the 50% of hypertensive patients, who do not receive this class of drugs. Furthermore, the pharmacogenetic approach may clarify the pathophysiological mechanisms of drug-induced metabolic side effects

Condition	Intervention	Phase
Essential Hypertension	Drug: thiazides Procedure: Non thiazidic treatment	Phase IV

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	Increasing Stay-on-therapy in Hypertensive Patients Treated With First-line Diuretics: An Active Pharmacosurveillance and Pharmacogenetic Study.

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: High Blood Pressure

U.S. FDA Resources

Further study details as provided by Federico II University:

Primary Outcome Measures:

Persistance and adherence to treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
changes in markers of preclinical cardiovascular disease [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Changes in global cardiovascular risk based on the ESH/ESC table of risk [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

genetic mechanism of adverse events in response to treatment with thyazides [ Time Frame: 20 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	2500
Study Start Date:	December 2006
Study Completion Date:	March 2010
Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Thiazides Thiazidic diuretic	Drug: thiazides Up to 25 mg per day
Active Comparator: Non Tiazidic Non tiazidic diuretic treatment: Any other therapy can be considered in this arm: example: CCB, BB, ACEi, ARB	Procedure: Non thiazidic treatment Amximum tolerated dosage as indicated from the label

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Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Hypertensive patients will be 18 to 75-year old.
Eligible patients will be asked for written informed consent and thereafter referred to the identified Hypertension Specialist Centre located in their areas, for end-organ damage evaluation by echocardiography, carotid ultrasound and urine dip-stick.
Eligible patients are required to have stage Ic or II essential hypertension, and to be previously untreated or poorly controlled. They will be selected by GPs participating into the study. Similar to untreated patients, those with poor control of blood pressure under multiple-drug therapy will start treatment with one single drug, which will be titrated to the highest dose before adding subsequent medications, based on the GP's judgement.
Hypertension will be defined according to 2003 ESH/ESC guidelines (1). Blood and urine tests will be performed, according to guidelines for Hypertension Management For General Practitioners (GP) of the Regione Campania (see BURC number 11, 18/02/2002). This screening includes cell blood counts (CBCs), serum creatinine, sodium, potassium, uric acid, total cholesterol, triglycerides, HDL-cholesterol, glucose, urine analysis and EKG. LDL will be calculated starting from the total cholesterol, triglyceride and HDL-cholesterol.

Exclusion Criteria:

Omen in fertile age not using recognized contraceptive methods, or pregnant or nursing will be excluded from the protocol, since the use of many antihypertensive drugs is contraindicated in pregnancy and lactation.
Patients will be excluded when presenting with documented coronary or cerebrovascular events in the previous 6 months, NYHA class higher than 1
History of congestive heart failure
Secondary hypertension
Cancer disease
Renal disease (serum creatinine >2 mg/dl)
Liver cirrhosis or severe dysfunction, or any other health problem that may interfere with the projected 2 year follow-up.

Data will be stored in an electronic database located in the Coordinating Centre, to which GPs may have access for uploading data on a daily base, using personal, encrypted, login and password. These data will be stored in the central database. After local echocardiographic evaluation, patients showing left ventricular Ejection Fraction < 45% will be excluded from the study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00408512

Locations

Italy
Ambulatorio Ipertensione e Unità Coronarica Federico II University
Napoli, Italy, 80131

Sponsors and Collaborators

Federico II University

Agenzia Italiana del Farmaco

Investigators

Study Director:

Bruno Trimarco, MD

Federico II University, Dipartimento di medicina Clinica Scienze Cardiovascoalri ed Immunologiche

More Information

Additional Information:

website of the High Blood Pressure Outpatient Clinic and UTIC of "Federico II" University of Naples This link exits the ClinicalTrials.gov site

Publications:

Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003 Nov;16(11 Pt 1):925-30.

Responsible Party:	Bruno Trimarco, Federico II University
ClinicalTrials.gov Identifier:	NCT00408512 History of Changes
Other Study ID Numbers:	FARM5STRH9 AIFA
Study First Received:	December 6, 2006
Last Updated:	June 24, 2011
Health Authority:	Italy: Ethics Committee; Italy: Ministry of Health; Italy: National Bioethics Committee; Italy: National Institute of Health; Italy: National Monitoring Centre for Clinical Trials - Ministry of Health; Italy: The Italian Medicines Agency

Keywords provided by Federico II University:

treatment
adverse events
adherence
gene
polymorphism

Additional relevant MeSH terms:

Hypertension
Vascular Diseases
Cardiovascular Diseases
Diuretics

Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012