PHARES Study: Management of Resistant Hypertension

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

Inclusion criteria

• Primary hypertension
• Resistant hypertension defined by mean day-time SBP > 135 mmHg and DBP > 85 mmHg (determined with ABPM device) after a standardized 4-week regimen including irbesartan, amlodipine and HCTZ.

Exclusion criteria

• Secondary hypertension
• Unstable angina, history of stroke or coronary heart disease (coronary by-pass or angioplasty) in the previous 3 months
• History of cough with ACEi or gynecomastia with antialdosterones
• Heart failure (New York Heart Association [NYHA] III-IV)
• Contraindication to beta blockers because of bronchopathy or auriculoventricular block
• Diabetes mellitus (type 1 or 2) with HbA1C > 8%
• Renal failure with creatinine clearance < 40ml/min (COCKROFT evaluation)
• Arm circumference > 42 cm