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The primary renal function analysis was based on a mixed effects model with random intercepts and random acute and chronic slopes. The mean acute, chronic, and total slopes were estimated by restricted maximum likelihood for each treatment group; total mean slopes were estimated as time-weighted averages of the acute and chronic slopes. The effects of the treatment interventions were estimated by appropriate contrasts of these mean slopes. The model included August 1, 2002 19 clinical center and the following prespecified baseline factors as covariates: proteinuria (expressed as the log transformed UP/Cr to account for positive skewness), history of heart disease, mean arterial pressure, gender, and age. Analyses of the clinical outcome events and other designated events were performed by Cox regression with adjustment for the same covariates as the analysis of GFR slope.

During the trial, members of the Steering Committee became aware of external clinical studies published after the initiation of the AASK that indicated a slowing of renal disease progression by ACEI in patients with elevated proteinuria, as well as studies suggesting DHP-CCBs may increase the level of proteinuria and not slow renal disease progression. Accordingly, an extension of the primary renal function model was analyzed which incorporated interaction terms between log baseline UP/Cr and each treatment group comparison. Subsequently, subgroup analyses were performed in participants with baseline UP/Cr above and below 0.22 (a value corresponding to ~300 mg/ day, which suggests the presence of microalbuminuria). The baseline UP/Cr 0.22 subgroup includes one-third of the study participants, with the remaining two-thirds belonging to the baseline UP/Cr 0.22 subgroup. The UP/Cr cut point of 0.22 was post-hoc but was selected independently of the AASK data.

Summary of AASK Interim Results: Among participants with proteinuria 300 mg/day, those assigned to ACEI had a 36% slower mean decline in GFR to three years (p0.006) and 48% reduced risk of the clinical endpoints vs. the DHP-CCB group (p =0.003). In the whole cohort, there was no significant difference in mean GFR decline from baseline to three years between treatment groups. However, ACEI group had a 38% reduced risk of clinical endpoints (p = 0.005), 36% slower mean decline in GFR after three months (p=0.002), and less proteinuria (p 0.001) than the DHP-CCB group. On the basis of these results, the AASK investigative group concluded that ACEI retards renal disease progression compared to DHP-CCB in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria (Agodoa, 2001).

Summary of AASK Main Results: Main results of the AASK trial were presented at the Annual Scientific Sessions of the American Heart Association on November 14, 2001. In brief, August 1, 2002 20 the presence of even small amounts of proteinuria at baseline (urinary protein to creatinine ratio [UP/C] of 0.22 or ~300mg of protein/day) was associated with rapid progression of kidney disease. In most analyses, the level of proteinuria also influenced the effects of AASK treatments. The separation of MAP between the low and usual BP groups was 10 mmHg, which is greater than that achieved in any previous trial. Still, those on the lower BP goal had similar renal disease progression as those on the usual goal.

For the comparison of medications, results were not definitive because the total GFR slopes and chronic slopes (3 months to end of follow-up) did not reach statistical significance in the same direction in all patients. However, important findings were evident. Blood pressures during follow-up were similar in the three randomized groups. Ramipril as compared to metoprolol reduced the rate of decline in GFR over 4 yrs by 25% and the rate of composite clinical events by 22% in all patients. In patients with baseline UP/C of 0.22, ramipril reduced the risk of clinical events by 46% as compared to amlodipine, while metoprolol reduced the risk of clinical events by 37% as compared to amlodipine. The analysis of GFR slope after 3 months favored metoprolol over amlodipine, while both the chronic and total GFR slopes were significantly better with ramipril as compared to amlodipine. In patients with UP/C 0.22, there was no suggestion of a benefit of metoprolol as compared to amlodipine.

In summary, a lower than usual BP goal was not associated with additional slowing of the progression of hypertensive renal disease in African Americans. Ramipril as compared to metoprolol appears to slow renal disease progression independent of protein level, while ramipril and metoprolol slow progression as compared to amlodipine in patients with baseline UP/C 0.22 (roughly ‘dipstick positive’ proteinuria).

Implications of AASK Trial Results for Cohort Study: The main results from AASK, in combination with published interim results, have implications for the AASK Cohort Study.

First, the incidence of clinical endpoints and the progression of kidney disease was high, even in the group that receive the most effective therapy. Specifically, in the ramipril group, the cumulative incidence of clinical outcomes was ~30% over 5 years, and the average annual decline in GFR (total mean slope) was 1.9 ml/min/1.73m2/yr. This documented decline in renal August 1, 2002 21 function, which is roughly twice the average age-associated decline in GFR in the general population (~1 ml/min/1.73m2/yr) highlights the importance of identifying factors other than blood pressure that predict, if not determine, progression of hypertensive kidney disease.





Second, of the three medications tested in AASK, ramipril had the most beneficial effects on kidney function. These results support provision of ramipril therapy to all participants in the AASK Cohort. Third, among patients with proteinuria, metoprolol appeared to be more renoprotective than amlodipine. Accordingly, beta-blocker therapy follows ramipril and diuretic therapy in the recommended treatment algorithm.

August 1, 2002 22 Section 5. DESIGN OF THE AASK COHORT Despite excellent blood pressure control and despite use of reno-protective

Overview:

antihypertensive medication, hypertension-related renal disease commonly progresses. The factors that determine the progression of this condition remain poorly understood. The overall objective of the AASK Cohort Study is to determine prospectively the long-term course of kidney function and risk factors for kidney disease progression in African-Americans with hypertension-related kidney disease that receive recommended antihypertensive therapy. A secondary objective is to determine the occurrence of cardiovascular disease and assess its risk factors in the setting of hypertension-related kidney disease.

The AASK Cohort Study is a prospective, observational study that is an extension of the AASK clinical trial. The AASK trial was a randomized, clinical trial that tested the effects of 3 different medications used as first line antihypertensive therapy (ramipril, metoprolol and amlodipine) and 2 levels of blood pressure control (usual control and more aggressive control). Of the 1,094 randomized participants in AASK, it is anticipated that 650-750 individuals who have not reached ESRD will enroll. In addition, those individuals who reached ESRD during the AASK trial will be invited to attend one visit for collection of DNA. Exposure data is collected annually. Exposures include environmental, genetic, physiologic, and socio-economic factors.

The primary renal outcome is a clinical outcome defined by doubling of serum creatinine, ESRD or death. Antihypertensive treatment recommended by current treatment guidelines will be provided to all participants who do not have ESRD. The ACE inhibitor, Ramipril, will be included in the antihypertensive regimen. While no difference in renal outcome was seen in participants randomized to the two BP levels in the AASK trail, current treatment guidelines recommend a BP goal 130/80 mmHg in those with CKD. Thus, this will be the treatment goal in the cohort. In this fashion, the cohort directly controls two of the major ‘known’ determinants of kidney disease progression (treatment of hypertension and use of reno-protective, antihypertensive medication) and therefore addresses research hypotheses in the setting of recommended antihypertensive care. We anticipate a minimum of 4 contacts and maximum of 6 contacts for BP control per patient per year. The anticipated duration of follow-up in the Cohort Study is 5 years (total of 9-12 years, including the period of the AASK trial).

–  –  –

The AASK Cohort Study provides the core infrastructure for epidemiologic investigations that elucidate potential risk factors for kidney disease progression. Data is collected and stored in a fashion that permits future analyses when preliminary evidence warrants such analyses and when resources become available. For instance, fingernail clippings for heavy metals and blood for inflammatory markers will be collected and stored; assays will not be performed immediately.

In contrast, ambulatory blood pressure is obtained at baseline in the cohort and then analyzed.

Timeline: Baseline data collection in the AASK Study commenced in February 1995 with the start of recruitment. Follow-up data collection in the trial ended on September 30, 2001.

Baseline data in the cohort phase began in April 2002. Follow-up data collection will end 5 years later. Table 3 displays these key dates.

–  –  –

Population: Participants in the AASK Cohort will include all participants in the AASK trial who are not on renal replacement therapy. If participants develop ESRD during the cohort phase, they will continue to be followed. (In addition, those individuals who have already been March 25, 2004 24 placed on renal replacement therapy during the AASK trial will be invited for one visit at which DNA is collected; otherwise, because these participants reached ESRD at variable intervals before the start of the cohort and because there would be the potential for extreme selection bias, further data will not be collected.) Table 2 in Section 4 displays characteristics of all randomized participants in AASK as well as the subset of participants who were active in follow-up and who are likely to enroll in the Cohort Study.

Inclusion Criteria: The only inclusion criteria for the AASK Cohort is prior randomization in the AASK Study and provision of informed consent, specific for the Cohort Study. In this fashion, the Cohort will retain those participants who subsequently developed diabetes and other illnesses that might lead to renal disease and participants who moved away from a local clinical center. While such participants would have been excluded from the trial, their inclusion in the Cohort study is appropriate both to describe the long-term progression of kidney disease and its complications and to minimize the potential for bias.

Recruitment: Upon the conclusion of the AASK trial, each participant is invited to participate in the Cohort Study. The primary benefits of the AASK Cohort study include provision of antihypertensive medications (which will be free of charge) and routine management of hypertension. There are no major risks associated with participation in the Cohort Study.

Contact Pattern and Data Collection Elements: The purpose of the study visits are to collect exposure data, ascertain clinical outcomes and manage antihypertensive therapy. Data collection for exposures are collected at baseline and annually thereafter. Management of antihypertensive therapy occur at baseline and every 6 months and at an additional 2-4 visits per patient per year.

For those requiring just 2 additional visits (total of 4 visits each year), the visit interval will be quarterly. The basic nomenclature for the data collection visits is “C” followed by a number that corresponds to months after enrollment (e.g., C0, C0.1, C3, C6, C9, C12, C15, C18, etc.).

Additional blood pressure management visits may occur in between these visits. Note that during the baseline visit window (C0), participants are asked to have a second serum creatinine measure (labeled the C0.1 serum creatinine); baseline creatinine is the average of two serum creatinine measurements labeled C0 and C0.1. Clinical outcomes are ascertained at each contact.

March 25, 2004 25 The types of data to be collected include questionnaire responses (exposures and clinical event surveillance), blood pressure, weight, electrocardiogram, blood, urine and finger nails clippings.

Ambulatory blood pressure monitoring and echocardiography are obtained at baseline and every other year (total of 3 times). At the 2 semi-annual data collection visits and 2 other visits, hypertension management occurs. An additional 2 visits may be required to achieve blood pressure control. While participants are encouraged to receive their antihypertensive medical care through the AASK Cohort, some persons may decide not to accept such care. In this case, they are asked just to attend the semi-annual data collection visits.

For those persons who have not reached ESRD, Table 4 of this section displays the data collection items and procedures by visit during the first two years. The pattern of data collection items and visits during all subsequent years will be similar to that of year 2, except that ambulatory blood pressure monitoring and echocardiography occurs every other year.

For those persons who reach ESRD during the Cohort Study, Table 5 of this section displays the data collection items and procedures by visit during the first two years. Data collection visits occur once each year. Again, the pattern of data collection items and visits during all subsequent years are similar to that of year 2 except that the echo will occur every other year. These post ESRD data collection visits occur at the same time the routinely scheduled cohort visits would have occurred.

For those persons who reached ESRD before enrolling in the Cohort Study, there will be one visit at which blood will be collected for DNA.

–  –  –

*Visit schedule will follow original schedule set during pre-ESRD phase. For example, the initial visit will occur at the time when the yearly data collection for the Cohort would have occurred.



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