MEDICATIONS: ACE INHIBITOR DRUG EFFECTIVE IN SLOWING PROGRESSION OF HYPERTENSIVE KIDNEY DISEASE

June 6, 2001 — For patients with kidney disease due to high blood pressure, treatment with a type of drug known as an ACE inhibitor offers greater benefit in slowing the progression of the disease than using a calcium channel blocker drug, according to an article in the June 6 issue of The Journal of the American Medical Association.

Lawrence Y. Agodoa, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health in Bethesda, Md., and colleagues with the African American Study of Kidney Disease and Hypertension (AASK) Study Group, are conducting a randomized, double-blind trial to compare the effects of three drugs used to treat high blood pressure (BP) on the progression of hypertensive renal (kidney) disease. The drugs are ramipril, an angiotensin-converting enzyme (ACE) inhibitor; amlodipine, a calcium channel blocker (CCB); and metoprolol, a beta blocker.

ACE inhibitors (ACEI) block an enzyme in the body that helps produce a substance that causes blood vessels to constrict. As the ACEI causes blood vessels to relax, blood pressure is lowered. Calcium channel blockers block the entry of calcium into cells, also leading to relaxation of blood vessels and lower blood pressure. Amlodipine is a type of CCB known as a dihydropyridine (DHP). Beta-blockers block the action of adrenaline and can relieve stress on the heart muscle. They are used in the treatment of angina (chest pain due to a lack of oxygen in the heart muscle), high blood pressure, and irregular heartbeat.

The AASK Study includes 1,094 African-Americans, aged 18 to 70, with hypertensive renal disease, who enrolled in the study between February 1995 and September 1998. According to background information cited in the article, the risk of end-stage renal disease (ESRD, a disease that leaves a patient with insufficient kidney function to support life and requires dialysis treatment for patient survival) due to hypertension is 20-fold greater for African-Americans than for whites.

The portion of the study reported in this issue of JAMA, in which patients were randomly assigned to receive amlodipine, was stopped early, in September 2000, at the recommendation of the data and safety monitoring board. The recommendation to halt that portion of the study was based primarily on results that indicated that patients with baseline proteinuria (too much protein in the urine, which may be a sign of kidney damage) had significantly slower decline in kidney function with ramipril compared with amlodipine. The ramipril and metoprolol treatment groups are continuing.

A total of 217 study participants were randomly assigned to receive amlodipine (5 to 10 milligrams per day); 436 were assigned to receive ramipril (2.5 to 10 milligrams per day); and 441 were assigned to receive metoprolol (50 to 200 milligrams per day), with other agents added to achieve one of two blood pressure goals. The authors measured the change in the glomerular filtration rate (GFR, a measure of the kidneys' ability to filter and remove waste products), as well as a composite index of three clinical end points: reduction of GFR to a specific level, ESRD or death.

"Among participants with a urinary protein to creatinine ratio greater than 0.22, the ramipril group had a 36 percent slower mean [average] decline in GFR over three years and a 48 percent reduced risk of the clinical end points vs. the amlodipine group," the authors write.

"In the entire cohort, there was no significant difference in mean [average] GFR decline from baseline to three years between treatment groups. However, compared with the amlodipine group, after adjustment for baseline covariates, the ramipril group had a 38 percent reduced risk of clinical end points, a 36 percent slower mean [average] decline in GFR after three months, and less proteinuria," they continue.

"Interim results of the AASK trial, taken together with previous trials, support the use of an ACEI as initial therapy in a multi-drug regimen over a DHP-CCB-based regimen in participants with mild-to-moderate chronic renal insufficiency and levels of proteinuria defined in this report," the authors assert.

"These results further provide documentation extending the renoprotective action of an ACEI-based regimen to African-Americans with this disorder, a population previously thought to be less responsive to these agents," they write.

The authors point out that the evidence is less conclusive for participants with hypertension without proteinuria and those at low risk for progressive kidney disease.

"Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to participants without proteinuria," they conclude.

Editor's Note: This study was funded under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases, and in part by general clinical research center grants from the National Institutes of Health. Study drugs and some financial support were provided by Pfizer Inc., Astra-Zeneca Pharmaceuticals and King Pharmaceuticals Inc.

In an accompanying editorial, Vasilios Papademetriou, M.D., of the Department of Cardiology, Veterans Affairs Medical Center in Washington, D.C., suggests that data from the study reported by the AASK Study Group can be interpreted in one of two ways.

"Either the ACEI, ramipril, exerted a strong renal protective effect, particularly in patients with baseline proteinuria, or the calcium channel blocker (CCB), amlodipine, exerted a detrimental effect. A beneficial effect from ACEI therapy is the most likely explanation," he writes.

"The alternative hypothesis, that amlodipine exerted a detrimental effect on renal function, is plausible but less likely. Such an association could b established only if a parallel study group had been treated with agents known to have neutral renal effects to reach a similar BP level goal," he suggests. "A placebo control arm would have helped address this issue, but inequalities in BP levels would have to be taken into account and ethical concerns would prohibit leaving patients untreated."

"Based on current evidence, it is reasonable to adhere to the recommendations of the Joint National Committee VI and initiate drug therapy in low-risk patients with low-dose diuretics. For patients at higher risk, or for patients with renal impairment and proteinuria, treatment should include an ACEI with a diuretic to achieve a target BP. If needed, CCBs can be added to the regimen to optimize BP control," he concludes.

Editor's Note: Dr. Papademetriou has received grants for research studies and honoraria for speaking engagements from several pharmaceutical companies, including Merck, Astra Zeneca, KOS and Bohringer Ingleheim.