Benazepril plus amlodipine should be used for initial treatment of hypertension instead of benazepril plus hydrochlorothiazide because it slows CKD progression to a greater extent, researchers concluded.

The finding is based on data from the randomized, double-blind ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial.

In the trial, which was conducted in the United States, Sweden, Norway, Denmark, and Finland, investigators randomly assigned 11,506 hypertensive patients who were at high risk for cardiovascular events to receive benazepril (20 mg) plus amlodipine (5 mg) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg) orally once a day. Cardiovascular morbidity and mortality were prespecified primary end points and CKD progression was a prespecified secondary end point.

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The trial, led by George L. Bakris, MD, Director of the Hypertensive Diseases Unit at the University of Chicago Pritzker School of Medicine was stopped early (after a mean follow-up of three years) because benazepril plus amlodipine was shown to be superior benazepril plus hydrochlorothiazide in decreasing the risk of cardiovascular morbidity and mortality (N Engl J Med. 2008;359:2417-2428) The new prespecified analysis, published in The Lancet (2010; published online ahead of print), examined the effects of the drug combinations on CKD progression.

Researchers defined CKD progression as the composite end point of a doubling of serum creatinine level or development of end-stage renal disease (ESRD), defined as an estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73 m2 or the need for dialysis.

After a mean follow-up of three years, 2% of patients who received benazepril plus amlodipine had CKD progression compared with 3.7% of those treated with benazepril plus hydrochlorothiazide, the investigators reported. This finding could not be explained by differences in BP control throughout the study, Dr. Bakris’ group noted.

The most frequent adverse event in patients with CKD was peripheral edema, which occurred in 33.7% of those treated with benazepril plus amlodipine and 16% of those who received benazepril plus hydrochlorothiazide. In non-CKD patients, dizziness, hypokalemia, and hypotension occurred more frequently in the benazepril plus hydrochlorothiazide group.

Study strengths included the use of prespecified CKD end points and the incorporation of ESRD as part of the definition of CKD progression, the authors noted. With respect to study limitations, they pointed out that the trial was not powered as a CKD outcome study and the early termination of the trial “probably diminished our ability to discern a significant difference in progression to end-stage renal disease or need for dialysis that might have occurred at a later timepoint as seen in studies with long-term follow-up.”

In an accompanying editorial, Hiddo Lambers Keerpink, MD, and Dick de Zeeuw, MD, of University Medical Center Groningen in Groningen, The Netherlands, wrote that the renal analysis of the trial “was needed to help to guide the best treatment of high-risk patients for the future.” The trial design and its interpretation, however, “should be more closely examined to verify the validity of the conclusions.”