The African American Study of Kidney Disease and Hypertension (AASK) Trial: What More Have We Learned?

Abstract

The final results of the African American Study of Kidney Disease and Hypertension (AASK) have shown that the angiotensin‐converting enzyme inhibitor ramipril was better than the β blocker metoprolol or the dihydropyridine calcium channel blocker amlodipine in slowing the rate of glomerular filtration rate decline in African American patients with mild to moderate renal insufficiency. Of note, there was no difference between the 92 mm Hg or less (lower group) and the 102–107 mm Hg (usual) mean arterial pressure groups as regards the secondary clinical composite end point. The secondary clinical composite end point in this study comprised a threshold drop of at least 50% or 25 mL/min in glomerular filtration rate, death, or reaching end‐stage renal disease. The final results from this study would suggest that reduction in blood pressure to levels below those currently advocated for cardiovascular risk reduction, although a clearly attainable goal in this population, does not provide readily identifiable benefits to African Americans with hypertensive nephrosclerosis. Importantly, this study provides the basis for the primary use of angiotensin‐converting enzyme inhibitors in an African American population with the characteristics of those studied in AASK. It remains to be determined if this represents a class effect for all angiotensin‐converting enzyme inhibitors.

The impact of hypertension on highly vascular organs such as the kidney can be particularly devastating. Irrespective of the genesis of hypertension (essential or secondary), the kidney becomes a target organ for hypertension‐related damage. Although the specific means by which hypertension produces renal structural damage is still open to conjecture, it is now well recognized that if hypertension goes untreated, renal failure develops, progresses, and reaches end‐stage with some regularity. Even with treatment there is no guarantee that the kidney is necessarily shielded. In addition, there remains ongoing debate as to the optimum blood pressure (BP) level for preservation of renal function and some question as to which antihypertensive medication (or medications) best preserves renal function.

Certain groups, including African Americans, appear to have increased susceptibility to hypertension as a cause of end‐stage renal disease (ESRD). ¹ , ² Several explanations have been proposed for this phenomenon, including ineffective treatment, renal damage antedating the inception of therapy, the existence of intrinsic renal processes refractory to conventional therapies, and the finding that daytime BP measurements often miss the more frequent nondipping nocturnal BP pattern of blacks. ³ Additional considerations relating to ESRD in African Americans have included familial clustering of the disease, ⁴ low birth weights (less than 2500 g), ⁵ higher systolic BP values, and a delay in the time to a formal renal failure evaluation. ⁶ The magnitude of this problem and the several unanswered questions surrounding the most effective treatment for hypertensive nephrosclerosis in African Americans prompted the African American Study of Kidney Disease and Hypertension (AASK). ⁷ , ⁸

STUDY DESIGN

The AASK trial was undertaken in self‐identified African Americans with hypertension, aged 18–70 years, with a glomerular filtration rate (GFR) between 20–65 mL/min per 1.73 m² and no other identifiable causes of renal insufficiency (Table I). Pertinent exclusion criteria in this trial included a known history of diabetes mellitus, a urinary protein to creatinine ratio of greater than 2.5, evidence of non‐BP‐related causes of chronic renal failure, clinical evidence of congestive heart failure, and active systemic illness.

Table I.

Baseline Study Characteristics in the African American Study of Kidney Disease and Hypertension (AASK) Trial

	Metoprolol (n=441)	Ramipril (n=436)	Amlodipine (n=217)
Age (years)	54.9±10.4	54.2±10.9	54.4±10.7
Female (%)	38.6	38.8	40.1
Blood pressure (mm Hg)	150±24/95±14	151±23.3/96±14.5	150±25.3/95.7±14.1
Serum creatinine (mg/dL)
Males	2.14±0.75	2.18±0.74	2.27±0.83
Females	1.80±0.55	1.76±0.59	1.76±0.59
Urine protein (g/day)
Males	0.63±1.11	0.61±1.01	0.57±0.99
Females	0.44±0.72	0.40±0.75	0.38±0.73
Antihypertensive use (%)
ACE inhibitors	34.2	39.9	41.5
β Blockers	30.4	25.9	28.1
CCB	64.6	62.8	61.3
DHP‐CCB	47.9	46.6	44.7
ACE=angiotensin‐converting enzyme; CCB=calcium channel blockers; DHP‐CCB=dihydropyridine CCB

1094 subjects were enrolled and randomized in this study between February, 1995 and September, 1998. Patients were followed for 3–6.4 years. On the recommendation of the data and safety monitoring board the amlodipine treatment arm was stopped in September, 2000, and these patients were provided open‐label medication. ⁹

This trial employed a 3×2 factorial design with patients randomized to a usual mean arterial pressure (MAP) goal of 102–107 mm Hg or to a low MAP goal of 92 mm Hg. ⁹ Patients were randomly assigned to one of three antihypertensive agents: a sustained‐release β blocker, metoprolol (50–200 mg/day; Toprol XL); an angiotensin‐converting enzyme (ACE) inhibitor, ramipril (2.5–10 mg/day; Altace); or a dihydropyridine calcium channel blocker (DHP‐CCB), amlodipine (5–10 mg/day; Norvasc). If BP did not reach the assigned goal with maximum tolerated doses of the blinded drug, additional open‐label drugs could be added in the following suggested order: furosemide, dox‐azosin, clonidine, hydralazine, or minoxidil (Level 2–5 medication).

The scheme for this study was an uneven block design with a 2:2:1 randomization ratio for metoprolol, ramipril, and amlodipine, respectively. Thus, 441 patients were assigned to metoprolol, 436 patients to ramipril, and 217 to amlodipine. This design was utilized because AASK pilot data found an early increase in GFR in the DHP‐CCB group compared with the ACE inhibitor and β blocker groups. ⁸ This early observation increased the statistical power for amlodipine, thereby reducing the number of subjects required in the DHP‐CCB group. GFR was measured by iothalamate clearance twice at baseline; thereafter, it was measured at 3 and 6 months and every 6 months for the remainder of the study. Serum and urinary levels of both creatinine and protein were measured semi‐annually. ⁹

ANALYSIS AND STATISTICAL METHODS

The primary analysis of renal function was through the rate of change of GFR and was presented as a GFR slope. This slope was determined in the early phase of the study during the first 3 months. Subsequently, it was determined per protocol at specified time points. Distinguishing early from later slope determinations is important, because antihypertensive therapy can acutely reset GFR, a process that differs substantially from the long‐term effects of antihypertensive therapy on progression of renal disease. The phenomenon of an acute change in GFR upon starting antihypertensive therapy is particularly prominent with ACE inhibitors. ¹⁰ The analytic plan determined both the mean chronic slope and the mean total slope from baseline to end of follow‐up, a computation which took into account both phases of GFR change. The mean total slope (includes both the acute and chronic phases) assesses the effect of interventions on renal function during the entire study period, while the chronic slope is not adulterated by acute hemodynamic changes and more accurately reflects long‐term disease progression.

The protocol also designated a main secondary clinical‐outcome analysis, based on the time from randomization to any of the following end points: 1) a confirmed reduction in GFR by 50% or by 25 mL/min from the mean of the two baseline GFR determinations; 2) the need for renal replacement treatment (ESRD); and 3) death. The clinical end point analysis was important in that it was the principal indicator of patient benefit, being based on events of clear clinical import. Finally, urinary protein excretion, expressed as the urine protein‐creatinine ratio (UP/Cr), was specified as a secondary outcome variable. As a matter of reference, UP/Cr correlates well with timed urine protein excretion determinations. ¹¹

OBSERVATIONS

The costs of managing hypertension, renal failure, and associated cardiovascular conditions in many industrialized countries are staggering. In the United States these problems are at their worst in the African American population. Of the disease‐state disparities found in the African American population, the onset and/or progression of renal failure to ESRD is one that is particularly demoralizing. ¹ Unfortunately, until recently, well‐accepted therapies for slowing renal failure progression—such as ACE inhibition or angiotensin‐receptor blockade—have not been formally studied in any significant number of African Americans with hypertension and renal disease. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Thus, many in the scientific community eagerly anticipated the results of the AASK study.

The results of the AASK study emerged in two primary publications. ⁹ , ¹⁹ The first of these publications ⁹ was an interim report and was prompted by adverse renal findings in the amlodipine limb of this study, which led to the premature stoppage of this treatment. ¹³ This early halt to the amlodipine arm of the AASK trial occurred following careful deliberation by an independent data safety monitoring board. The second publication ¹⁹ represented the final dataset, which then included all data relevant to metoprolol as well as the findings of the usual vs. the low BP randomization groups. In the AASK study 155 patients in the β blocker treatment group reached an end point; only 126 on the ACE inhibitor did during the full follow‐up period. Roughly equal numbers in the two BP groups reached an end point, 167 in the usual and 173 in the low goal groups.

The following are several quotes taken from a National Institutes of Health press release dated November 20, 2002 titled “Kidney Disease and Hypertension in African Americans—ACE Inhibitor Protects Kidneys, Ultra‐Low BP Provides No Added Benefit.” These quotes show the level of enthusiasm for several of the findings, which emerged from the AASK study. “We were surprised that the lower BP level didn't have more of an effect on the kidney,” said coauthor Dr. Lawrence Agodoa, who specializes in kidney diseases at the National Institutes of Health. “But the good news is that we have a new tool—the ACE inhibitor—to improve the health of a large number of African Americans and others who have this type of kidney disease.”“People who have kidney disease of hypertension and any protein in the urine should be given the benefit of an ACE inhibitor, unless the drug is contraindicated, along with a diuretic,” said Agodoa, who sits on the Joint National Committee and heads the National Institute of Diabetes & Digestive & Kidney Diseases Office of Minority Health Research Coordination. “And anyone who also has heart disease or diabetes, as so many do, should try to reach the JNC goal of 130/85 mm Hg.”

The AASK trial is the first of its kind in the African American population and provides a unique array of information relating to hypertensive nephrosclerosis in this population. Like many good studies, as many questions arise as are answered and the AASK study is no different in this regard. Several of these questions are answered in the succeeding comments.

Did Those Patients Randomized to the Lower BP Group Reach Target BP and Did They Do Better?

AASK showed that while high BP may be more severe and therefore more difficult to control in African Americans, its control is feasible. Only 20% of patients entered the study with BP levels below the target of 140/90 mm Hg for a general population. Within 14 months, close to 80% of people in the low‐goal group (MAP, 92 mm Hg) and nearly 42% in the usual‐goal group (MAP, 102–107 mm Hg) had lowered pressures to 140/90 mm Hg. Achieved BP averaged 128±12/78±8 mm Hg in the lower BP group and 141±12/85±7 mm Hg in the usual BP group (Table II). A mean separation in BP of approximately 10 mm Hg was maintained throughout the majority of the study. In the primary analysis the mean GFR slope from baseline through 4 years did not differ significantly between the lower BP group (−2.21±0.17 mL/min per 1.73 m² per year) and the usual BP group (−1.95±0.17 mL/min per 1.73 m² per year) (Figure 1) and the lower BP goal did not significantly reduce the rate of the clinical composite outcome.

Table II.

Antihypertensive Therapy and Blood Pressure During Follow‐Up (SBP/DBP)

	Blood Pressure Goal Intervention		Drug Intervention
	Lower	Usual	Ramipril	Amlodipine	Metoprolol
MAP, mean (SE), mm Hg†	95(8)	104 (7)	100 (9)	99 (8)	100 (9)
SBP, mean (SE), mm Hg†	128 (12)	141 (12)	135 (14)	133 (12)	135 (13)
DBP, mean (SE), mm Hg†	78 (8)	85 (7)	82 (9)	81 (8)	81 (9)
Visits with MAP in goal, %†	51.6	39.2	44.1	48.9	44.7
Visits with MAP of <107 mm Hg†	81.3	64.3	71.5	76.5	72.0
Visits with SBP/DBP of <140/90, %†	68.6	35.5	51.2	54.9	50.8
Visits with SBP/DBP of <125/75, %†	24.7	6.2	16.2	14.4	14.9
Visits with assigned primary drug, %‡	81.7	80.1	76.8	83.4	83.6
Visits with high dose, %‡	62.8	45.0	53.5	54.6	53.6
Visits with crossover to one of other two classes, %‡	9.3	8.1	10.9	6.4	7.6
Total no. of drug classes, mean (SE)‡	3.04 (1.14)	2.39 (1.18)	2.66 (1.23)	2.65 (1.24)	2.79 (1.15)
Visits with level 2 (furosemide), %‡	82.2	66.6	74.0	70.8	76.4
Visits with level 3 (doxazosin), %‡	55.2	34.4	42.0	46.3	46.6
Visits with level 4 (clonidine), %‡	40.5	27.3	34.4	34.4	33.1
Visits with level 5 (minoxidil), %‡	34.9	22.7	27.5	24.1	32.3
Protocol visits held, %	90.3	87.5	88.0	88.7	89.8
MAP=mean arterial pressure; SBP/DBP=systolic/diastolic blood pressure; †blood pressure summaries include visits after 3 months and exclude glomerular filtration rate visits; ‡Medication summaries include all visits starting at month 1 and are censored as of September 22, 2000, for the calcium channel blocker (amlodipine) group only.

Figure 1.

Mean changes in glomerular filtration rate (GFR) according to the two blood pressure goal interventions (A) and the three drug treatment randomization groups (B). The number of patients with GFRs at years 0, 1, 2, 3, 4, and 5 in all treatment groups combined were 1094, 953, 837, 731, 469, and 262, respectively. Reprinted with permission from JAMA. 2002;288:2421–2431. ¹⁹

Comments. The fact that the low BP group did not fare better than the usual BP treatment group was surprising. However, it does not diminish the importance of maintaining BP in a range suggested by current guidelines. This BP finding can be interpreted in several ways but should not be used as the basis for abandoning efforts at tight BP control in this population. However, these data do suggest that once BP reaches a certain threshold value (which may vary according to the cause of the nephropathy), additional factors assume added significance in adverse renal and clinical outcomes in patients with kidney disease resulting from hypertension. Inspection of the study data did show a trend favoring the lower BP goal in participants with higher baseline proteinuria. The AASK study was not powered to detect differences in the rate of myocardial infarction, stroke, or death. With this in mind, there was no evidence of differences in the rates of these events between the two randomized BP groups.

How Did Metoprolol Fare in This Study?

The metoprolol treatment limb was comparable to the amlodipine‐and ramipril‐based regimens in the number of additional drugs required to reach goal BP. Moreover, although treatment with ramipril was significantly better than amlodipine it was not better than metoprolol in the mean chronic GFR slopes in patients with a baseline UP/Cr >0.22 (300 mg protein/day) (Figure 2). GFR declined faster in the amlodipine than the metoprolol group during the chronic phase of the study. In the entire cohort, after adjusting for prespecified baseline covariates, ramipril was associated with a risk reduction in the time of progression to the following clinically relevant end points as compared with amlodipine: 41% risk reduction for the combination of ESRD or death, and 38% risk reduction for the combination of GFR events, ESRD, or death. The risk reduction for ramipril vs. metoprolol was 22% for the clinical composite end point of a GFR event, ESRD, or death. There was no significant difference between the amlodipine and the metoprolol groups in the main clinical composite outcome. However, the metoprolol group had a significantly lower risk for ESRD or death and for ESRD alone.

Figure 2.

Mean change in glomerular filtration rate (GFR) by randomized group for proteinuria subgroups according to the two blood pressure goal interventions (B and D) and the three drug treatment randomization groups (A and C). A urinary protein/creatinine ratio corresponds approximately with proteinuria of 300 mg/day. For the 2‐slope model, the results of the comparison of amlodipine with metoprolol and ramipril differed significantly depending on the level of baseline proteinuria for the acute slope (p=0.002 and p<0.01, respectively) and total slopes (p=0.21 and p=0.24, respectively). The results of the blood pressure comparison differed significantly depending on the level of baseline proteinuria for the acute slope (p=0.008) and total slopes (p=0.004) but not for the chronic slope (p=0.16). Reprinted with permission from JAMA. 2002;288: 2421–2431.19

Comments. These findings speak favorably for β blocker therapy in reducing BP in this patient population, but probably not as monotherapy. Beta blockers, like several other drug classes, reduce BP much better when given together with a diuretic, as was the case in the AASK study. Metoprolol therapy was effective in reducing proteinuria, which is important to consider in light of the increased emphasis on reducing proteinuria as one of the management steps in progressive renal disease (Figure 3). This study did not determine the effect on proteinuria of combining a β blocker with either an ACE inhibitor or a CCB. Metoprolol is a hepatically cleared β blocker; thus, it would not be expected to accumulate with repeat dosing in the setting of progressive renal disease. This may, in part, explain its good tolerance in this study. Renally cleared β blockers, such as atenolol, would be expected to accumulate with repeat dosing. This is a circumstance where concentration‐dependent β blocker side effects would be more likely.

Figure 3.

Percentage change in proteinuria by randomization group. Shown are the estimated percentage changes in the urine protein/creatinine ratio (geometric mean [SE]) from baseline throughout follow‐up by blood pressure and drug intervention. Reprinted with permission from JAMA. 2002;288:2421–2431. ¹⁹

How Did the Study Drugs Impact Proteinuria in the AASK Study?

Proteinuria (geometric mean of the UP/Cr ratio) increased by 58% in amlodipine‐treated patients and declined during the first 6 months of the study by 14% and 20% in the metoprolol and ramipril groups, respectively (Figure 3). Moreover, during the first 6 months of the study proteinuria decreased by 17% in the lower BP group and actually increased by 7% in the usual BP group. These treatment group differences were maintained throughout the study. Follow‐up proteinuria was only slightly lower in the ramipril treatment group when compared with the metoprolol group when total change was computed over 4 years.

Comments. It is not surprising that the reduction in protein excretion was BP dependent in this study. The antiproteinuric effect of BP reduction is well established. The fact that the antiproteinuric effect of the metoprolol regimen was comparable to that in the ramipril group is biologically plausible and points to the usefulness of any agent interfering with renin‐angiotensin‐aldosterone axis activity in lessening proteinuria. Of note, the change of urine protein excretion became less significant with time for both the ramipril and metoprolol treatment groups. The basis for this waning of the antiproteinuric effect with ramipril and metoprolol can only be speculated on but may relate to progression of the underlying disease having produced the proteinuria in the first place. It is of interest that prior recommendations as to a beneficial effect of ACE inhibition in both diabetic and nondiabetic renal insufficiency targeted higher levels of protein excretion as the threshold where a renoprotective effect is demonstrated. This analysis of the AASK dataset suggests a significantly lower threshold of proteinuria for an ACE inhibitor benefit but cannot define the specific break point per se.

How Many BP Medications Were Required in the AASK Study?

Between all three treatment limbs there was neither a difference in the number of antihypertensive medications prescribed nor a difference in the number of patients receiving the maximum titrated dose of ramipril, metoprolol, or amlodipine. Participants at or below MAP goal received an average of 2.7 and 3.5 agents in the usual MAP goal and the low MAP goal groups, respectively (Table II). The AASK participants above MAP goal were prescribed, on average, a greater number of agents than those participants at or below goal MAP. ²⁰

Comments. It comes as no great surprise that multiple medications were required to achieve BP control in the participants in the AASK trial. Hypertension as is seen in the black hypertensive with nephrosclerosis can prove quite difficult to treat. What is important about the AASK study is that goal MAP, even if arbitrarily set at a very low value, can be reached with a sequenced addition of medications that are readily available; thus, the addition of a loop diuretic, a peripheral α antagonist, clonidine, and minoxidil can get a patient to goal. It is noteworthy, that in the lower and usual BP groups, minoxidil was being given at 34.9% and 22.7% of the visits, respectively. There was a slightly lower use of minoxidil in the amlodipine group than in the metoprolol group, which may relate to the greater potency of amlodipine. However, minoxidil was a level 5 add‐on in this study, and its addition should have occurred at a time when any residual differences in BP lowering between amlodipine and metoprolol had diminished substantially; that is, when a diuretic had been added.

Finally, the literature is replete with statements that suggest that ACE inhibitor monotherapy is not as effective in hypertensive African Americans as in whites. This has influenced clinical prescription practice such that hesitancy exists to use these drugs as monotherapy in hypertensive African Americans. This hesitancy also appears to carry over to the use of ACE inhibitors in this population as part of a multi‐drug regimen. The findings from the AASK trial should dispel this myth. As the AASK trial demonstrated, when an ACE inhibitor is used in combination with a diuretic and other agents, BP control is achieved and maintained and renoprotection is readily evident.

What Was the Distribution of Adverse Events in the AASK Study?

The number of patients reporting adverse events was similar in both of the BP treatment groups. The rate of angioedema and cough was highest in the ramipril‐treated group. Hyperkalemia occurred in three patients in the ramipril and one patient in the metoprolol randomization group.

Comments. Cough and angioedema are not unexpected side effects with an ACE inhibitor. ²¹ Of note, angioedema also occurred in patients receiving either amlodipine or metoprolol. This may represent either a background rate of angioedema in the study population, unrelated to treatment, or a phenomenon of over reporting. Investigators were blinded to the primary study drug being given; accordingly, since in theory anyone could have been receiving ramipril it is certainly reasonable to presume that there was a heightened awareness for upper airway and oropharyngeal symptoms and thus a possibility of over reporting symptoms that otherwise might be disregarded in day‐to‐day practice. The virtual absence of hyperkalemia with ramipril therapy likely related to two factors: first, the majority of ramipril‐treated patients were receiving the loop diuretic furosemide, which reduces the risk of hyperkalemia; and second, the fact that hypertensive nephrosclerosis is not a form of progressive renal disease characterized by a high rate of hyperkalemia (as is the case for diabetic nephropathy). ²²

What Are the Implications of Ramipril in the AASK Study Relative to the Concept of Class Effect?

Ramipril was the only ACE inhibitor employed in the AASK study and angiotensin‐receptor blocker therapy was not permitted. In the AASK study the findings are indisputable that an ACE inhibitor‐based regimen can effectively reduce BP in a patient cohort notoriously resistant to treatment response; i.e., the African American with hypertensive nephrosclerosis. Patients remained on treatment with ramipril during 76.8% of visits and 53.5% of the visits were ones where the 10 mg dose of ramipril was in use.

Comments. How then does this relate to other ACE inhibitors? The concept of class effect is most easily conceptualized when ACE inhibitors are being evaluated in how well they reduce BP. In the instance of chronic renal failure and/or congestive heart failure it is reasonable to presume that the positive cardiac and renal benefits of an ACE inhibitor are to be found with any of the compounds in this class. However, the sticking point in each of these two diseases resides in what represents comparable doses among the various ACE inhibitors. The issue of comparable doses of an ACE inhibitor is nowhere more confusing than in the chronic renal failure population. This is the case because the majority of the ACE inhibitors on the US market undergo predominant if not exclusive renal clearance; ²³ thus, they are subject to varying degrees of systemic accumulation when administered to the patient with renal disease. Ramipril is one such ACE inhibitor whose clearance is mainly renal; trandolapril and fosinopril are the two ACE inhibitors that are equally renally/hepatically cleared. ²⁴

The positive effects of ramipril on clinical composite outcomes in the AASK study could be viewed as being a function of BP reduction, an antiproteinuric effect, a direct ACE inhibitor effect, and an effect relative to the specific blood levels of ramiprilat, the active diacid of ramipril. The blood levels of ramiprilat can be expected to importantly influence the duration and tissue‐specific level of ACE inhibition. It can be presumed that the blood levels of ramiprilat were not constant during the course of this study, and increased as the renal failure progressed. There would be no way to replicate this particular pharmacologic experiment. Accordingly, ramipril should remain the preferred ACE inhibitor in this patient population until other ACE inhibitors are studied under similar circumstances.

Conclusion

Where does the AASK trial take the practicing clinician? It should be clear from the AASK trial data that ACE inhibitor therapy is important in the African American patient with hypertensive nephrosclerosis and that in this type of patient, particularly when dip‐stick positive proteinuria is present, a DHP‐CCB should not be the primary drug therapy (Table III). Considerable circumstantial evidence has been amassed over the past several years that would suggest that DHP‐CCB treatment, without accompanying ACE inhibitor or angiotensin receptor blocker treatment, carries a risk of increasing proteinuria and/or accelerating the progression of renal disease despite substantially reducing BP. ²⁵ The AASK study supports these conclusions. The AASK study does not answer the question of whether the superimposition of an ACE inhibitor or an angiotensin receptor blocker protects from the negative renal effects of a DHP‐CCB.

Table III.

Key Points

Treatment with ramipril was significantly better than amlodipine but not metoprolol in the change in mean chronic GFR slopes in patients with a baseline UP/Cr >0.22 (300 mg protein/day). GFR declined faster in the amlodipine than the metoprolol group during the chronic phase of the study.

In the entire cohort, after adjusting for prespecified baseline covariates, ramipril was associated with a risk reduction in the time of progression to the following clinically relevant end points compared with amlodipine: 41% risk reduction for the combination of ESRD or death, and 38% risk reduction for the combination of GFR events, ESRD, or death. The risk reduction for ramipril vs. metoprolol was 22% for the clinical composite end point of a GFR event, ESRD, or death. There was no significant difference between the amlodipine and the metoprolol groups in the main clinical composite outcome. However, the metoprolol group had a significantly lower risk for ESRD or death and for ESRD alone.

The reduction in risk of the combined end points of ESRD, death, or GFR was influenced heavily by the subgroup of patients with baseline proteinuria; this subgroup contributed 63% of the events, although it represented only 33% of the cohort.

Treatment with amlodipine increased proteinuria by 58% in the first 6 months, whereas metoprolol and ramipril decreased proteinuria by 14% and 20%, respectively. The rate at which UP/Cr <0.22 progressed to >0.22 was 56% lower in the ramipril‐treated group than in the amlodipine group. Moreover, during the first 6 months of the study proteinuria increased by 7% in the usual BP group and decreased by 17% in the lower BP group. These treatment group differences were maintained throughout the study.

At the end of the follow‐up, there was no difference in the decline of GFR among patients with no baseline proteinuria or a GFR of at least 40 mL/min per 1.73 m2, which was related to the fact that those in the amlodipine treatment group experienced an acute rise in GFR shortly after beginning therapy. The same finding was observed in comparing metoprolol to amlodipine.

GFR=glomerular filtration rate; ESRD=end‐stage renal disease; UP/Cr=urine protein‐creatinine ratio

Should all African American renal failure patients with hypertensive nephrosclerosis be precluded from therapy with amlodipine or similar DHP‐CCBs? The answer to this is probably no, since DHP‐CCBs remain important tools in the control of stage 2 or 3 hypertension, a very common form of hypertension in the African American. The data from the AASK trial indicate that for patients without proteinuria and therefore who are at lower risk, treatment with amlodipine carried minimal if any risk. Close to three drugs were required to achieve goal BP in the AASK trial participants, and DHP‐CCBs can be of particular utility in achieving such tight BP control. An alternative, but untested, approach from an outcomes viewpoint may be to employ non‐DHP‐CCBs, such as verapamil or diltiazem, with which either alone or together with ACE inhibitors the potential exists for more favorable renal interactions. ²⁶