Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension:  a prospective, randomized, open blinded endpoint study.
OBJECTIVE
To compare two drug regimens to treat resistant hypertension.


METHODS
In a prospective, randomized, open blinded endpoint study, 167 patients with mean baseline daytime ambulatory blood pressure 135 mmHg or more and/or 85 mmHg or more, despite 4 weeks' treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day and amlodipine 5 mg/day, were randomized to sequential nephron blockade (group 1, n = 85) or sequential renin-angiotensin system blockade (group 2, n = 82). First, spironolactone 25 mg/day in group 1 or ramipril 5 mg/day in group 2 were added for 4 weeks. Treatment was increased at weeks 4, 8 or 10 if home blood pressure was 135 mmHg or more and/or 85 mmHg or more by sequentially administering furosemide 20 mg/day, furosemide 40 mg/day and amiloride 5 mg/day in group 1, or ramipril 10 mg/day, bisoprolol 5 mg/day and bisoprolol 10 mg/day in group 2. The primary endpoint was change in systolic daytime ambulatory blood pressure at week 12.


RESULTS
At week 12, the mean between-group difference in daytime ambulatory blood pressure was 10/4 mmHg (95% confidence interval: 7-14/2-7; P < 0.001/P = 0.0014) in favour of the group 1. The blood pressure goal (daytime ambulatory blood pressure <135/85 mmHg) was achieved in 58% in the group 1 and 20% in the group 2 (P < 0.0001). Discontinuation for drug-related adverse events was low (group 1, n = 7; group 2, n = 6).


CONCLUSIONS
In patients with resistant hypertension, sequential nephron blockade induces a large and well tolerated reduction in blood pressure via a progressive increase in sodium depletion, and is more effective than sequential renin-angiotensin system blockade.
Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. guillaume.bobrie@egp.aphp.fr
Guillaume
G
Bobrie
Michael
M
Frank
Michel
M
Azizi
Séverine
S
Peyrard
Pierre
P
Boutouyrie
Gilles
G
Chatellier
Stéphane
S
Laurent
Joël
J
Menard
Pierre-François
PF
Plouin
D000293:Adolescent; D000328:Adult; D000368:Aged; D000584:Amiloride / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D017298:Bisoprolol / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004351:Drug Resistance / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005665:Furosemide / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D009399:Nephrons / Q000187:drug effects* / Q000378:metabolism; D011446:Prospective Studies; D017257:Ramipril / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013148:Spironolactone / Q000627:therapeutic use*; D055815:Young Adult
D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000584:Amiloride; D005665:Furosemide; D017257:Ramipril; D017298:Bisoprolol