TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD
“If we knew what we were doing, it wouldn’t be called research.”
Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).22–26
African American Study of Kidney Disease and Hypertension (AASK)
The African American Study of Kidney Disease and Hypertension (AASK),22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.
AASK examined the effects of two levels of blood-pressure control:
- Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
- Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).
In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:
- The ACE inhibitor ramipril (Altace)
- The sustained-release beta-blocker metoprolol succinate (Toprol XL)
- The calcium channel blocker amlodipine (Norvasc).
To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m2. They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.22
AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.
At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.23 In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.
However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.
Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.
AASK cohort phase
After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.24
During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.
In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).24
Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.
The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study25 included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.
At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,25 with no racial or ethnic differences in its renoprotective effect.
Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.
To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)26 enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.
In a secondary analysis, patients were stratified by GFR:
- Normal (> 90 mL/min/1.73 m2; n = 8,126)
- Mild reduction (60–89 mL/min/1.73 m2; n = 18,109)
- Moderate-severe reduction (< 60 mL/min/1.73 m2; n = 5,662).
In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.
Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.