Pharmacosurveillance and Pharmacogenetics of First-line Diuretics in Hypertension: The StayOnDiur Study
Condition: Essential Hypertension
MeSH terms: Hypertension; Essential Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      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
    

Detailed description: 
      Background and rationale

      Many comments have been issued about similarities and differences between 2003 American and
      European guidelines for the management of arterial hypertension (1,2), especially after the
      publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
      Trial (ALLHAT) study (3-5). Both guidelines agree that the majority of hypertensive patients
      require more than one medication to achieve optimal blood pressure control and, consistent
      with the most recent findings, the need of expensive, large clinical trials to demonstrate
      the superiority of one medication on another is probably over (3,6). What is clear now is
      that blood pressure must be optimally controlled to reduce risk of cardiovascular mortality
      and morbidity in population, no matter which combination of medications is used. Comparison
      between single medications is substantially academic and conceals the reality: in all trials,
      in most circumstances comparison is between combinations, more than single medications. In
      the Losartan Intervention for Endpoint Reduction Study (LIFE study) (6), for instance, there
      has been a comparison between the combination of losartan with low dose hydrochlorothiazide
      versus the combination of atenolol with the same diuretic.

      The difference between the seventh Joint National Committee (USA) on Prevention, Diagnosis
      and Management of Hypertension (JNC VII) and European Society of Cardiology (ESC) and
      European Society of Hypertension (ESH) 2003 guidelines, often presented as substantial, is in
      the priority that Americans still give to the diuretic therapy, consistent with the most
      waited results of the ALLHAT (3).

      The ALLHAT was a randomized, double-blind, multicenter clinical institutional trial, entirely
      sponsored by the National Heart, Lung, and Blood Institute (NHLBI) (3), and designed to
      determine whether occurrence of fatal or nonfatal coronary heart disease is lower for high
      risk hypertensive patients treated with amlodipine, lisinopril, doxazosin, or chlorthalidone.
      The protocol was also approved by an independent Review Committee external to the NHLBI (7).
      The ALLHAT recruited 9,000-15,000 participants/intervention arm (total: 33,357), and the
      follow-up was quite long (4-8 years). The doxazosin arm was closed prematurely because of
      higher mortality (8). Despite a number of important limitations of this study (4,9), the
      overall impact of its findings remains very high.

      The baseline characteristics of the ALLHAT participants were substantially similar in the 3
      arms completing the study. Chlortalidone was significantly more effective than both
      amlodipine and lisinopril in achieving optimal control of blood pressure at year 1 and year 2
      and more effective than lisinopril in blood pressure control at year 3, 4 and 5 (all
      p<0.001). Consistent with the better control of blood pressure, chlortalidone tended to
      provide a 10% more protection for combined fatal and non fatal coronary heart disease than
      lisinopril whereas protection was similar for amlodipine, though this protection was less
      evident than the superiority in controlling blood pressure. In fact, the difference in risk
      profile versus the lisinopril arm achieved statistical significance only for elderly and
      African-American participants.

      Another relevant finding from the ALLHAT concerns the incidence of congestive heart failure
      that was substantially less with chlortalidone than with either amlodipine or lisinopril.

      There are many recurrent criticisms to all trials showing the superiority of diuretics over
      other medications in controlling blood pressure. First of all, worsening of glucose
      metabolism, due to thiazide effects, is matter of concern (4,14-18). Also the ALLHAT authors
      report a higher incidence of diabetes in the diuretic group which, however, did not affect
      the outcome results (3). However, this concern is also sustained by recent evidence of the
      dangerous effect of incident diabetes in patients with arterial hypertension (15).

      One factor that might aggravate glucose metabolism during therapy with diuretics is the
      underestimated effect of hypokalemia, which interferes with glucose-stimulated insulin
      release, a condition that might be aggravated by association with beta-adrenergic block
      (19,20). Among other beneficial effects, including improvement in blood pressure control,
      correction of hypokalemia prevents or significantly reduces thiazide-induced hyperglycemia
      (21-24). It is possible that low-dose potassium-sparing diuretics by preventing hypokaleemia
      might also prevent metabolic effects of thiazide, at the same time enhancing the
      antihypertensive effects of thiazide (25), but, this hypothesis has never been tested in ad
      hoc trials.

      The second concern about the use of diuretics is the risk of low therapeutic compliance of
      hypertensive patients, due to the diuretic effect and other hypokalemia-related side-effects
      (26,27). These few reports, however, contrast with the evidence that quality of life is
      improved by long term therapy with diuretics (28-30). The effort, therefore, should probably
      be direct toward persistence of initial treatment with diuretics, a goal that might be
      reached by improving the procedures of follow-up, for instance, as we have recently proposed,
      by implementing internet-based digital networks, connecting hypertension specialists with
      general practitioners (31). The Campania Salute (CS)network is a system that was set up in
      1995 by us (31). It is an italian regional network system aimed at improving the management
      of essential hypertension by integrating the activity of general practitioners (GPs) with
      hypertension specialists. This network includes about 12.000 hypertensive patients followed
      by 23 outpatient hypertensive clinics allocated in different Community Hospitals in the
      Campania Region and 60 GPs, homogeneously allocated in the regional area, referring to the
      Hypertension Clinic of Federico II University Hospital in Naples (coordinating centre). GPs
      were randomly selected among a pool of physicians referring their patients to the
      Hypertension Clinic at Federico II University. Through the CS system clinical data detected
      at each visit can be shared between the coordinating center and the peripheral units.Low-risk
      hypertensive patients continue their follow up in the peripheral units, whereas high-risk
      hypertensive patients are more closely followed up by the coordinating centre, which also
      evaluates target organ damage and associated diseases. Patients' information is shared
      through on-line access to the remote database, integrated by smartcards. The smartcard
      belongs to patients and contains his/her personal identification number (PIN). This PIN
      allows users to access the file of the patient stored in the database. Each physician has
      also his own PIN to access into the database, limited to his/her own patient files. Clinical
      data are upgraded at each visit by GPs and physicians of both peripheral centres and
      coordinator centre. Access to the remote database allows users to read all clinical and
      laboratory data, as well as tracking electrocardiography (ECG) and cardiac and vascular
      ultrasound images. In addition, the smartcard also works as portable database in which
      identification and clinical data are reported. By virtue of a central database, data of
      individual patients can be stored, updated and retrieved directly on-line by participants in
      the project. The restricted access to individual data requires the pre-assigned
      identification code of both the patient and the relevant remote units. The central database
      uses Wincare software (TSD Projects, Milan, Italy) which contains separate sheets for medical
      history, physical examination, biochemistry electrocardiography, cardiovascular ultrasound,
      other imaging tests and ambulatory blood pressure monitoring. The last update of an
      individual patient's record can also be downloaded and stored in the patient's personal
      smartcard. We started the CS project with the aim of obtaining a stronger interaction between
      GPs and hypertension clinics, by providing a direct link and accessible patients' records.
      Blood pressure control was improved with our referral system, since better overall results
      were obtained if the patient was followed within the network. Indeed, at the end of the
      observation period, 51% of patients in the CS group had a blood pressure below 140/90 mmHg, a
      percentage comparable to that of patients included in clinical trials.

      This follow-up strategy also allowed an active pharmacovigilance procedure, with side effects
      promptly reported to the GPs, which prevented the occurrence of difference in compliance
      among the various antihypertensive treatments. In addition, this kind of follow-up allowed by
      means of pharmacogenetic studies to demonstrate that the occurrence of side effects may be
      predicted from individual genotype (32). Indeed, we have recently reported that in patients
      bearing β2AR gene Glu27 variant or the β3AR gene Arg64 variant there was a larger occurrence
      of hypertriglyceridemia, alone or in combination with elevated cholesterol levels.
      Furthermore, the β2AR Glu27variant significantly associates with hypetriglyceridemia in a
      cumulative fashion. The risk of developing this side effect after β-blockade was four-fold
      higher in patients homozygous for the β2AR Glu27 variant than in β2AR27Gln allele. This
      result not only allowed the identification of patients at high risk to develop metabolic
      complications to chronic β-blockade treatment, but also contributed to elucidate the
      pathophysiological mechanisms which mediate these side effects, raising the possibility to
      prevent them.

      Objectives of the study

      This study has been designed to assess whether a follow-up strategy based on a strict
      cooperation between GPs and hypertension specialists allows the use of diuretics as
      first-line antihypertensive treatment with a persistence on assigned therapy equivalent to
      that achieved by using any other first line antihypertensive therapy. Assessment of safety
      and efficacy for controlling cardiovascular risk will be also performed as secondary
      endpoint. In fact, in contrast with trials comparing single-drug effects, this study compares
      two strategies of antihypertensive management, based on either real-word prescriptions or a
      regimen in which thiazide diuretics represent a forced first line antihypertensive therapy.
      If our hypothesis will be demonstrated diuretics might be suggested as an efficient and
      economic first line antihypertensive treatment, on which build up optimal antihypertensive
      therapy by adding other class drugs, in all patients, provided that the follow-up procedure
      is based on the proposed organization. This approach will be of great utility for the
      National Health Care System to reduce costs, since, a large part of the economic burden is
      related to the use of antihypertensive medications more expensive than thiazides, as first
      line agents, in particular so far only 40% of the hypertensive patients receive diuretics in
      their therapy.

      Finally, the pharmacogenetic study is focused on characterization of polymorphisms of
      candidate genes associated to development of metabolic side effects of diuretics, to help
      understanding of mechanisms underlying these adverse events. This kind of information will
      help to prevent the occurrence of adverse events by the use of adeguate combination
      treatment, thus resulting in the further reduction of the cost of antihypertensive treatment
      due to the reduction of the number of patients that discontinue therapy for occurrence of
      adverse events.

      Study design

      This is a multicenter, open label, randomized study to compare the effects of an
      antihypertensive strategy using a thiazide diuretic as first-line, versus the use as initial
      therapy of other antihypertensive treatments. All the analyses will be performed by personel
      blinded to treatment. The study will be performed in collaboration with the Società Italiana
      Medicina Generale (SIMG), Sezione Campania, and the Società Italiana Ipertensione Arteriosa
      (SIIA), Sezione Campania.

      Study population. The recruitment phase will last 8 months. During this period 2600 patients
      will be enrolled, in the offices of 260 GPs' with documented previous experience in
      controlled studies, performed according to recommendations of Good Clinical Practice, and
      availability to access to Internet. Selected GPs will be trained to the use of the web-based
      database on which they will store the required information of patients participating into the
      study. This training period will last a week and will be supervised by the coordinator's
      center. Exemplificative print outs of the web-based CRF are available for evaluation on the
      web site www.campaniasalute.it.

      GPs are required: 1) to record a full medical history, including smoking and drinking habits,
      based on a pre-defined clinical record; 2) to collect demographic and anthropometric measures
      (height, weight, waist circumference at the iliac crest); 3) to perform a complete physical
      exam. At baseline and at each visit thereafter, seated office blood pressure will be measured
      in triplicate using a manual sphygmomanometer according to international guidelines.
      Measurements will be rounded to the closest 2 mmHg interval.

      Inclusion criteria: Hypertensive patients will be 18 to 75-year old. 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 Bollettino Ufficiale Regione Campania, number
      11, 18/02/2002, allegato A). 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. Women 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. 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.
      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.

      Eligible patients will be asked for blood sampling for genomic DNA analysis and then
      randomised by the coordinating centre to either diuretics or other treatment. This latter
      will be decided by the GPs. Randomization will be organized in permuted blocks of 10 patients
      for each GP, half of which will be assigned to diuretics. The randomization code will be
      communicated to the referring GP by e-mail.

      Blood samples for genetic analysis and signed informed consents will be sent to the
      coordinating centre for storage. Blood samples will be coded and anonymously processed for
      genetic analysis by the Department of Pharmacology of FEDERICO II University of Naples. The
      data resulting from this analysis will be stored in the patient CRF page.

      Intervention: Drugs will be administered orally. GPs should use chlortalidone (12.5-25 mg
      daily) in the arm with compulsive thiazide diuretic as first line. In the alternative arm,
      GPs may choose any appropriate single-drug (excluding thiazide diuretic) or combination
      therapy, as first-line, at the tolerated dose.

      After randomization, patients will be evaluated monthly at the GPs' office, for therapy
      adjustment, to achieve blood pressure normalization (i.e Systolic Blood pressure >140 mmHg,
      and Diastolic Blood pressure >90 mmHg). In the thiazide arm, if blood pressure normalization
      is not achieved not even with the maximal dose, it will be possible to add any other classes
      of antihypertensive drugs. Once blood pressure normalization is achieved, GPs will monitor
      blood pressure once every 2 months, at the renewal of the drug prescription. Blood pressure
      values will be stored in the central database. At each visit, GPs will record drug therapy,
      including concomitant medications, evaluate the compliance to assigned antihypertensive
      regimen, and monitor and record adverse events by reporting all data in the CRF. After two
      years from randomization, patients will be checked for blood and urine tests and referred to
      the Hypertension Specialist Centre for echocardiography, carotid ultrasounds and urine
      dip-stick. This data will be stored in the central database.

      Information retrieval: At each visit, the GPs will record drug therapy, including concomitant
      medications, will evaluate the compliance to the assigned antihypertensive medications by
      pill count, and will monitor and record adverse events by reporting all data in the CRF.

      Pre clinical cardiovascular disease will be assessed by echocardiography and carotid
      ultrasonography. All ultrasound exams will be sent to the Reading Center at Federico II
      University Hospital and will be processed, according to procedures described in the annex.

      Monitoring of the study: All data will be reported on a specifically designed electronic
      clinical research form (CRF) (see web site: www.campaniasalute.com), and will be transferred
      to the Coordinating Center for data storage and analysis. The Steering Committee will appoint
      a Data Coordinating Committee to evaluate all CRFs on a continuous way to ensure quality and
      objectivity of the analysis performed by trained professionals. In order to monitor for
      patient security, GPs will be asked to actively monitor periodically for adverse events, by
      asking patients at the time of drug prescription renewal for the occurrence of symptoms or
      signs that can be related to aggravation of their condition or adverse events of therapy. In
      selected cases, GPs can refer the patients to the Hypertension Specialist Centre for eventual
      instrumental and or blood and urinary analyses. Adverse events will be reported in the
      digital CRF.

      Sample size estimate: The main outcome to be tested is whether persitance on therapy of an
      antihypertensive regimen based on diuretics as first choice is equivalent to that obtained in
      a free regimen using any other antihypertensive medication as first choice (equivalence
      study).

      As secondary outcomes, reduction of left ventricle (LV) mass and carotid intima-media
      thickness will be evaluated as markers of preclinical cardiovascular disease, under the
      hypothesis that improvement of end-organ damage under diuretic-based treatment will not be
      different from the treatment based on other antihypertensive medications (equivalence). The
      reduction of the ESH/ESC risk-score will also be evaluated, under the same equivalence
      hypothesis. Sample size was primarily estimated for the primary outcome, but afterward tested
      on power also on secondary outcomes. See Annex for details

      Organizational characteristics: The study will be governed by a Steering Committee chaired by
      the Principal Investigator (Prof. Bruno Trimarco). The study will be performed as a
      collaborative effort of 260 general practitioners (with previous experience in scientific
      initiatives), specialist centers (Community Hospitals and University Hospitals in which
      specialized evaluation of hypertension related organ damage is routinely evaluated). The
      Department of Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, division of
      Coronary Intensive Care Unit and High Blood Pressure Center will act as a Coordinating
      Center, run by Professor Trimarco, PI. The central database will be stored at this center,
      and the other specialist centers and GPs will have remote access to it through encrypted
      login and password. The web-based access to the database has already been implemented at the
      Coordinating Center, within the Campania Salute Project, a regional network of Community
      Hospitals and GPs.

      Echocardiograms and carotid ultrasounds will be performed at the Federico II University
      Hospital or in peripheral centers, under a standardized protocol, which will be distributed
      in an electronic format (CD-ROM). All studies will be directly transmitted through the
      Internet to the Reading Center.

      Feasibility: The Principal Investigator, Bruno Trimarco, has a long and extensive experience
      in running trials of antihypertensive treatment and management of hypertension (see CV). As
      Director of the Coordinating Institution he will personally assure full support of the
      institution facilities, and of professional help in monitoring and statistics.

      The Ultrasound Reading Center has wide experience in centralized reading of studies on LV
      hypertrophy and function as well as in studies on arterial structure and has been involved in
      a number of international multicenter trials (35,40). The Reading Center is provided of 4
      work stations for echocardiographic reading and 2 for carotid ultrasound, with high level of
      security for preservation of data and privacy. All echocardiograms will be classified with a
      reception number which will join the recruitment number of the participant (every
      participants will have 2 identification numbers in addition to the number of identification
      document).

      Timing: The study will last 3 years. The first eigth months will be spent for recruitment and
      randomization. The follow-up will last 2 years. Analysis of data will be performed ad
      interim, as soon as the last recruited patient completes the intermediate evaluation after
      one year of follow-up. Final main analysis will be performed right after the conclusion of
      follow-up of the last recruited patient. A number of analysis concerning secondary end-points
      and including every ancillary study that might be proposed from the Steering Committee or the
      participating Hypertension Specialist Centres, will be implemented thereafter.

      Ethical aspects. We have tried to minimize possible therapy related side effects to those
      that are usually observed in the practical clinic. Indeed, all treatments and dosages are
      those that are usually adopted by general practitioner for the daily practice. Therefore, we
      do not expect any additional risk for patients that are enrolled in the study. The
      complications that are associated to thiazide treatment will be prevented by the use of
      maximal doses that are in the low range of therapeutic effect, and close to the regimen that
      currently used in daily practice. As for intromission in the private sphere of the patients,
      the data will be nominally entered in the database by the physician using a login/password
      protected web-based 32bit encrypted connection, and available only for this research purposes
      after given informed consent by the patients.
    

Intervention name(s): thiazides; Non thiazidic treatment
Intervention type(s): Drug; Procedure
Intervention description(s): Up to 25 mg per day; Amximum tolerated dosage as indicated from the label
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: treatment; adverse events; adherence; gene; polymorphism