PHARES Study: Management of Resistant Hypertension
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to assess the efficacy of two different treatment regimens for
      treating resistant hypertension previously uncontrolled with at least 3 antihypertensive
      treatments. The study hypothesis is that these two regimens (one based on increasing
      diuretics and the other based on increasing renin angiotensin system blockage) may not differ
      in terms of efficacy.
    

Detailed description: 
      Tested hypothesis: For essential resistant hypertension, a new regimen based on intensive RAS
      blockage is non inferior to the recommended regimen based on intensive sodium depletion.

      Primary objective: To demonstrate non-inferiority (i.e difference between the two regimen
      less than 5 mmHg for the mean day-time SBP at week 12)

        -  One treatment arm including irbesartan 300 mg, hydrochlorothiazide (HCTZ) 12.5mg,
           amlodipine 5 mg, ramipril 10mg and bisoprolol 10 mg

        -  One treatment arm including irbesartan 300 mg, HCTZ 12.5mg, amlodipine 5 mg,
           spironolactone 25 mg, furosemide 40 mg and amiloride 5 mg.

      Secondary objectives:

        -  To assess clinical and biological safety and efficacy of these regimen

        -  To evaluate predicted factors of controlled or uncontrolled BP

        -  To evaluate compliance to treatment

        -  To compare the cost of the different strategies

        -  To compare the two strategies in terms of endothelial function and left ventricular
           diastolic filling

      Study design:

        -  Period 1 from week-4 to week 0 : 4-week treatment for all patients with irbesartan 300
           mg, HCTZ 12.5mg, amlodipine 5 mg. At the end of this period, an ABPM will be performed:
           only patients with a mean day time SBP>135 and/or DBP>85 mmHg will be randomized for a
           further 3 months treatment

        -  Period 2 from week 0 to week 4: patients will be randomized in two groups, the first one
           receiving spironolactone 25mg and the second one receiving ramipril 5 mg as add-on
           therapy (on top of the previous tri-therapy).

        -  Period 3 from week 4 to week 8: Patients with BP controlled at week 4 (i.e mean home
           blood pressure measurement (HBPM) <135/85 mmHg at week 4) remain on the same treatment.
           For those uncontrolled (i.e. mean HBPM >135/85 mmHg at week 4), furosemide 20 mg will be
           added in the first group and ramipril will be titrated to 10 mg in the second group

        -  Period 4 from week 8 to week 10: Patients with BP controlled at week 8 (i.e. mean HBPM
           <135/85 mmHg at week 8) remain on the same treatment. For those uncontrolled (i.e. mean
           HBPM >135/85 mmHg at week 8), furosemide will be titrated to 40 mg in the first group
           and bisoprolol 5 mg will be added in the second group.

        -  Period 5 from week 10 to week 12 (end of the study): Patients with BP controlled at week
           10 (i.e mean HBPM <135/85 mmHg at week 10) remain on the same treatment. For those
           uncontrolled (i.e mean HBPM > 135/85 mmHg at week 10), amiloride 5 mg will be added to
           the previous treatment in the first group and bisoprolol will be titrated to 10 mg in
           the second group.

      Reasons for treatment discontinuation:

        -  Patient decision

        -  Informed consent withdrawal

        -  SBP>180 mmHg or <100 mmHg (HBPM) whatever the time during the trial

        -  Adverse events related to treatment or not
    

Intervention name(s): irbesartan, amlodipine and hydrochlorothiazide
Intervention type(s): Drug
Intervention description(s): irbesartan, amlodipine and hydrochlorothiazide
Intervention MeSH terms: Amlodipine; Hydrochlorothiazide; Irbesartan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Resistant hypertension; Combined diuretic therapy; Combined RAS blockers