Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.
BACKGROUND
The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease.


METHODS
ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950.


RESULTS
The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.


CONCLUSIONS
Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent.


BACKGROUND
Novartis.
Bakris
George L
GL
Hypertensive Diseases Unit, Department of Medicine, University of Chicago-Pritzker School of Medicine, Chicago, IL 60637, USA. gbakris@gmail.com
Sarafidis
Pantelis A
PA
Weir
Matthew R
MR
Dahlöf
Björn
B
Pitt
Bertram
B
Jamerson
Kenneth
K
Velazquez
Eric J
EJ
Staikos-Byrne
Linda
L
Kelly
Roxzana Y
RY
Shi
Victor
V
Chiang
Yann-Tong
YT
Weber
Michael A
MA
D000368:Aged; D000419:Albuminuria; D017311:Amlodipine / Q000008:administration & dosage / Q000009:adverse effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000009:adverse effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D002121:Calcium Channel Blockers; D004232:Diuretics; D004338:Drug Combinations; D006852:Hydrochlorothiazide; D017311:Amlodipine; D003404:Creatinine; C044946:benazepril