Early Mineralocorticoid Receptor Antagonist Therapy for Low-Renin Essential Hypertension (EMERALD)

Participants will receive stepped antihypertensive treatment starting with eplerenone 50 mg orally once daily. Treatment will be intensified as needed by sequentially adding amlodipine 5 mg once daily, increasing eplerenone to 50 mg twice daily, increasing amlodipine to 5 mg twice daily, adding hydrochlorothiazide 12.5 mg once daily, adding doxazosin 4 mg once daily, and increasing hydrochlorothiazide to 25 mg once daily. Participants taking two antihypertensive drugs before washout will generally start with eplerenone plus amlodipine. Treatment adjustments will depend on blood pressure, tolerability, and safety assessments, with a target seated office blood pressure below 140/90 mmHg. Treatment will continue for 24 weeks.

Eplerenone will be administered orally at 50 mg once daily as the initial treatment in the experimental arm. The dose may be increased to 50 mg twice daily according to the prespecified treatment algorithm, blood pressure response, tolerability, serum potassium, and kidney function. Treatment will continue for 24 weeks, with dose reduction or interruption when clinically indicated.

Participants will receive stepped antihypertensive treatment starting with telmisartan 40 mg orally once daily. Treatment will be intensified as needed by sequentially adding amlodipine 5 mg once daily, increasing telmisartan to 80 mg once daily, increasing amlodipine to 5 mg twice daily, adding hydrochlorothiazide 12.5 mg once daily, adding doxazosin 4 mg once daily, and increasing hydrochlorothiazide to 25 mg once daily. Participants taking two antihypertensive drugs before washout will generally start with telmisartan plus amlodipine. Treatment adjustments will depend on blood pressure, tolerability, and safety assessments, with a target seated office blood pressure below 140/90 mmHg. Treatment will continue for 24 weeks.

Telmisartan will be administered orally at 40 mg once daily as the initial treatment in the active comparator arm. The dose may be increased to 80 mg once daily according to the prespecified treatment algorithm, blood pressure response, and tolerability. Treatment will continue for 24 weeks, with dose reduction or interruption when clinically indicated.

Change in mean daytime systolic blood pressure, measured in mmHg by 24-hour ambulatory blood pressure monitoring, from baseline to Week 12. Mean daytime systolic blood pressure is the average of all valid daytime systolic readings. A valid recording requires at least 70% of scheduled readings, including at least 20 daytime readings and 7 nighttime readings. Change is calculated as the Week 12 value minus the baseline value; a negative value indicates a reduction in blood pressure.

Change in seated office systolic blood pressure, measured in mmHg, from baseline to each assessment. Measurements are obtained after at least 5 minutes of seated rest using a standardized upper-arm blood pressure monitor.

Change in seated office diastolic blood pressure, measured in mmHg, from baseline to each assessment. Measurements are obtained after at least 5 minutes of seated rest using a standardized upper-arm blood pressure monitor.

Percentage of participants with seated office systolic blood pressure below 140 mmHg and diastolic blood pressure below 90 mmHg at each assessment.

Percentage of participants with a reduction from baseline in office systolic blood pressure of at least 10 mmHg, a reduction in office diastolic blood pressure of at least 5 mmHg, or achievement of office blood pressure below 140/90 mmHg.

Cumulative number of antihypertensive treatment adjustments per participant, including dose increases, addition of a drug, and discontinuation of a drug.

Time, measured in weeks from randomization, to the first study visit at which seated office systolic blood pressure is below 140 mmHg and diastolic blood pressure is below 90 mmHg.

Mean systolic blood pressure, measured in mmHg, calculated from all valid readings during 24-hour ambulatory blood pressure monitoring at each assessment.

Mean diastolic blood pressure, measured in mmHg, calculated from all valid readings during 24-hour ambulatory blood pressure monitoring at each assessment.

Mean systolic blood pressure, measured in mmHg, calculated from all valid nighttime readings during ambulatory blood pressure monitoring at each assessment.

Mean diastolic blood pressure, measured in mmHg, calculated from all valid nighttime readings during ambulatory blood pressure monitoring at each assessment.

Mean diastolic blood pressure, measured in mmHg, calculated from all valid daytime readings during ambulatory blood pressure monitoring at each assessment.

Total antihypertensive medication burden required to achieve office blood pressure below 140/90 mmHg, expressed in World Health Organization defined daily dose equivalents. For each drug, the prescribed daily dose is divided by its defined daily dose, and the resulting values are summed across drugs.

Change in echocardiographically measured left ventricular mass indexed to body surface area, expressed in g/m².

Change in left atrial volume indexed to body surface area, measured by echocardiography and expressed in mL/m²

Change in urinary albumin-to-creatinine ratio, calculated by dividing urinary albumin concentration by urinary creatinine concentration

Change in plasma aldosterone concentration, measured using a standardized chemiluminescent immunoassay.

Change in direct renin concentration, expressed in mU/L and measured using the DiaSorin LIAISON chemiluminescent immunoassay

Change in the ratio of plasma aldosterone concentration to direct renin concentration