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The AASK trial is extremely well positioned to accomplish this task. First, the AASK cohort is a unique, established cohort, one that could never be assembled again. Second, the AASK cohort is extremely well-characterized. Baseline data on many relevant exposures, including extensive medical history, detailed medication records and numerous laboratory measurements, are already available. A bank of biological specimens has already been established. A major ancillary study of genetic factors is underway. Third, the AASK cohort is enriched with March 25, 2004 10 individuals who have progressive renal disease. To date, over 150 individuals are on dialysis or have received a renal transplant. Hence, the cohort is well-positioned to characterize distinct phenotypes (progressors and non-progressors). If another 150 cases of ESRD occur in AASK over the next year, there will be a total of 300 ESRD cases, a number which vastly exceeds the number of ESRD cases from all causes in most population based cohort studies, few of which enrolled large numbers of African-Americans. Fourth, the additional follow-up of AASK participants should allow us to identify and characterize individuals with slow, but clinically important, renal disease progression. To date, ~15% of AASK participants who reached ESRD comprise a group of individuals with rapid disease progression. From the standpoint of prevention, the distinction between slow and rapid progressors is important because the largest fraction of hypertension-related ESRD likely occurs from slow rather than rapid progression of disease. Finally, the cohort is well-positioned to directly control, rather than statistically adjust for, two of the major known determinants of kidney disease progression, that is, treatment of hypertension and use of reno-protective, antihypertensive medication.

March 25, 2004 11 Section 4. AFRICAN AMERICAN STUDY OF KIDNEY DISEASE AND

HYPERTENSION (AASK) TRIAL

Background: The optimal strategy to prevent hypertension-related kidney failure is uncertain.

Two strategies that might be effective are (1) selection of antihypertensive medications that have reno-protective effects beyond blood pressure control and (2) aggressive blood pressure control beyond conventional recommendations.

Trials of angiotensin converting enzyme inhibitors (ACEI) in patients with diabetic and proteinuric non-diabetic kidney disease have documented significant benefits from ACEI. The impact of ACEI on progression of renal disease in African-Americans has been unknown since all published trials had too few African-Americans randomized to such agents. Although animal studies have demonstrated prevention of glomerulosclerosis by calcium channel blockers (CCB), human studies have not consistently confirmed their renoprotective effects. Likewise, preliminary evidence suggested that aggressive blood pressure control might retard the progression of renal disease (Klahr, 1994; Hebert, 1997; Toto, 1995).

In this setting, the African American Study of Kidney Disease and Hypertension (AASK) was designed to evaluate the impact on progression of hypertensive kidney disease of two different blood pressure (BP) goals and three treatment regimens initiated by a ß-blocker (BB, metoprolol); a dihydropyridine (DHP) CCB (amlodipine), or an ACEI (ramipril). Recruitment into the full-scale trial began in February 1995, with planned treatment through October 2001.

However, in September 2000, the amlodipine arm was terminated at the recommendation of the Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based on safety concerns that arose because interim analyses showed a slower mean GFR decline and a reduced rate of clinical endpoints (rapid decline in renal function, ESRD or death) in the ramipril and metoprolol groups relative to the amlodipine group in proteinuric participants. Participants originally assigned to amlodipine remained in the trial in order to test the effects of the blood pressure goals on renal disease progression. However, they were provided open label medication, typically ramipril, instead of amlodipine that was discontinued. On September 30, 2001, data collection in the AASK trial ended. Participants were provided blinded

–  –  –

Participants: Participants were self-identified African-American hypertensives (n=1,094), aged 18-70 years, with GFR between 20-65 ml/min/1.73m2, and no other identified causes of renal

insufficiency. Inclusion/exclusion criteria were as follows:

Inclusion Criteria for the AASK Randomized Trial:

• African-American men and women (including Black individuals born in the Caribbean, Africa, Canada, etc.)

• Age 18-70 years.

• Hypertension was defined as a sitting diastolic blood pressure of 95 mmHg or more.

The average of the last two of three consecutive readings on a random zero sphygmomanometer machine at any visit was used. Hypertensive participants on antihypertensive therapy needed only one qualifying clinic visit. Those not currently on medications at baseline qualified on each of two consecutive clinic visits.

• Reduced renal function, defined as a pre-randomization (G1 visit) I-iothalamate glomerular filtration rate between 20-65 ml/min/1.73m2.

• Willingness and ability to cooperate with the protocol.





Exclusion Criteria for the AASK Randomized Trial:

• History of malignant or accelerated hypertension within 6 months prior to study entry;

previous chronic peritoneal or hemodialysis or renal transplantation.

• Known secondary causes of hypertension.

• Any known history of diabetes mellitus type I and II, or fasting (8-12 hrs.) glucose 140 mg/dl on two occasions, or glucose 200 mg/dl on one occasion prior to randomization.

• A ratio of urinary protein (mg/dl) to creatinine (mg/dl) exceeding 2.5 in a 24-hour urine sample collected shortly before the initial GFR visit. (This ratio is used as an estimate of 2.5 g/day proteinuria without needing to factor for validity of the collection.)

• Clinical or renal biopsy evidence of any renal disease other than hypertensive August 1, 2002 13 nephrosclerosis. Persons with arteriographically documented renal arterial atherosclerotic disease less than 50% stenosis of the renal artery were considered eligible for the study if the PI at the center felt the disease was not clinically significant.

• History of drug abuse in the past 2 years, including narcotics, cocaine or alcohol ( 21 drinks per week).

• Serious systemic disease that might influence survival or the course of renal disease.

(Chronic oral steroid therapy was an exclusion, but steroid-containing nasal sprays were not. Inactive sarcoidosis was not an exclusion.)

• Clinical evidence of lead intoxication.

• Arm circumference 52 cm, which precluded measuring blood pressure with the "thigh" blood pressure cuff. Arm length such that if the cuff circumference extended into the antecubital space so that the cuff interfered with placement of the stethoscope over the brachial artery for blood pressure measurement.

• Clinical evidence of congestive heart failure, current or within the preceding six months. Ejection fraction below 35% measured by any method. Heart block greater than first degree or any other arrhythmia that contraindicated the use of any of the randomized drugs.

• Reactive airway disease, current or in the preceding six months requiring prescribed treatment for more than two weeks.

• Impairment or difficulty in voiding, precluding adequate urine collections.

• Intake of non-steroidal anti-inflammatory agents (NSAIDs) more than 15 days/month, excluding aspirin. Inability to discontinue NSAIDs or aspirin for 5 days prior to GFR measurement.

• History of severe adverse reaction to any of the randomized drugs required for use in the protocol or contraindication of their use.

• Pregnancy or likelihood of becoming pregnant during the study period; lactation.

• Serum potassium level 5.5 mEq/L at the SV2 and confirmed at G1 for those not on ACE inhibitors during Baseline, or serum potassium level 5.9 mEq/L at the SV2 and confirmed at G1 for those on ACE inhibitors during Baseline.

• Leukopenia 2,500/mm3 at SV2 and confirmed at the end of Baseline.

–  –  –

Participant enrollment began in August 1994 and ended in September 1998. Table 2 displays baseline characteristics of all randomized participants and characteristics of participants who are likely to enroll in the Cohort Study.

Core Design of the Trial: The AASK trial had a 3 X 2 factorial design (Table 1). Participants were randomized to a usual mean arterial pressure (MAP) goal of 102-107 mm Hg or to a low MAP goal of 92 mmHg, and to treatment with one of three antihypertensive study drugs, a sustained-release ß-blocker (BB), metoprolol (Toprol XL), an ACEI, ramipril (Altace), or the DHP-CCB, amlodipine (Norvasc). Doses were 50-200 mg/day, 2.5-10 mg/day, and 5-10 mg/day, respectively. If the BP goal was not achieved on the study drug, additional unmasked drugs were added in the following recommended order: furosemide, doxazosin, clonidine, hydralazine, and minoxidil. The dosage of each drug was increased to the maximum tolerated dose before the addition of a subsequent agent.

–  –  –

The Usual Goal (MAP 102 to 107 mmHg) corresponds to a blood pressure of approximately 140/90 mmHg and reflects traditional blood pressure recommendations. The Low Goal of MAP

–  –  –

A randomization scheme that resulted in a 2:2:1 (metoprolol:ramipril:amlodipine) ratio was used because AASK pilot data revealed an early increase in GFR in the DHP-CCB group compared to the ACEI and BB groups. This increased the projected statistical power for the DHP-CCB vs.

BB comparison, allowing a smaller sample size for the amlodipine group. Study drug assignment but not BP goal was double masked.

–  –  –

August 1, 2002 17 Data Collection: At each visit, three consecutive seated blood pressures were measured using a Hawksley MKII random zero sphygmomanometer after at least 5 min rest, with the mean of the last two readings calculated. All personnel measuring blood pressures were centrally trained and certified annually. During the six-month period following randomization, antihypertensive drugs were adjusted at monthly protocol and interim visits to achieve the BP goal. Subsequent protocol visits occurred at two-month intervals. GFR was assessed by 125I-iothalamate clearance at baseline twice, then at 3, 6 and every six months thereafter. Serum and urine creatinine and urine protein were measured by a central laboratory at 6 month intervals. Specimens of blood and urine from each annual visit were stored. Fasting lipid profiles and quality of life measurements were collected annually. Throughout follow-up, adherence by pill count was assessed at each protocol visit; medication usage, both antihypertensive agents and other medications, was collected at each visit.

Trial Outcome Variables: The primary analysis of renal function was based on the rate of change in GFR (GFR slope). GFR slope was determined separately over the first three months after randomization (acute phase) and during the remainder of follow-up (chronic phase), because previous studies indicated that drug interventions could result in acute changes in GFR that differ from long-term effects on renal disease progression. The analytic plan called for determining both i) the mean chronic slope, and ii) the mean total slope from baseline to end of follow-up, including both phases, and for inferring a definitive beneficial effect on renal function of an intervention that significantly reduces the magnitude of both the chronic and total mean slopes. The mean total slope assesses the effect of interventions on renal function during the study period, while the chronic slope is interpreted as the parameter more likely to reflect long-term disease progression.

The protocol also designated a secondary clinical-outcome analysis, based on the time from randomization to any of the following endpoints: i) a confirmed reduction in GFR by 50% or by 25-ml/min/1.73m2 from the mean of the two baseline GFRs, ii) ESRD, defined as need for renal replacement therapy, or iii) death. The clinical endpoint analysis was identified as the principal assessment of patient benefit. In contrast to the analysis of GFR slope, which addresses the mean drug effect on renal function in all patients including those with little or no GFR decline,

–  –  –

Conduct of the Trial: Trial results have high internal validity as measured by adherence to interventions and retention of participants. On average, a 10 mmHg separation in MAP between the low and usual MAP goals was achieved throughout the follow-up period. After the initial 6 month titration period, the average MAP was 93.7 in the low MAP group and 103.7 in the usual MAP group. The average number of medications used to achieve the low MAP goal was 3.1; the corresponding number for the usual MAP group was 2.4. The percent of participant visits without cross-over to the other 2 drug groups was 92.0% in the BB group, 89.6% in the ACEI group, and 93.1% in the CCB group.

Retention of participants was excellent. As of October 17, 2001, vital status was known on 1,082 (99%) of randomized participants. Over the course of the trial, 103 persons died, and another 159 (14%) reached ESRD. Of the remaining 820 participants who were eligible for a close-out GFR, 733 (89%) had a close-out measurement. A poll of trial participants about possible participation in the cohort study suggests that ~ 675 participants will enroll in the AASK cohort, not including the ESRD patients who will be asked to provide DNA.

Analysis Plan of the Trial: The protocol specified three primary comparisons (ACEI vs.

beta-blocker, DHP-CCB vs. beta-blocker, and low vs. usual MAP goal). The ACEI vs.

DHP-CCB comparison was designated as a secondary rather than a primary comparison because the DHP-CCB and ACEI interventions were expected to produce acute slopes in opposite directions, complicating the comparison of these two groups.



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