1. Recent studies of ACE inhibition in renal disease
Content Points:
This slide presentation discusses recent clinical studies of ACE inhibition in patients with renal disease, which demonstrate that these agents improve outcomes in an expanding number of patient populations.
The African American Study of Kidney Disease (AASK) demonstrated a reduction of hypertensive renal disease progression with the ACE inhibitor ramipril in African Americans, a population previously considered to be less responsive to these agents.1
Jafar et al conducted a recent meta-analysis of patient data examining the efficacy of various ACE inhibitors for nondiabetic renal disease. The data show that progression of nondiabetic renal disease was slowed in patients who were treated with ACE inhibition as part of an antihypertensive regimen.2
The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that the ACE inhibitor ramipril was effective and safe in reducing the risk of cardiovascular (CV) events in high risk patients with mild renal insufficiency.3

2. AASK: Study design
Content Points:
AASK was designed to evaluate the impact of an ACE inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a b-blocker (metoprolol) on hypertensive renal disease progression.1
AASK was a randomized, double-blind, 3 x 2 factorial study conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease. Subjects had a glomerular filtration rate (GFR) of mL/min per 1.73m2.
Patients were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441). Other agents were added to achieve 1 of 2 blood pressure goals, low vs usual. Follow-up was 3 years.
The primary study outcome was the rate of change in GFR. The secondary outcome was a composite of >50% reduction in GFR, end-stage renal disease (ESRD), or death.
NOTE: This interim report on the AASK study is based on data obtained through September 2000 when the amlodipine arm of the study was terminated as recommended by the data and safety monitoring board. This action followed an interim analysis that showed a slower decline in mean GFR and a reduced rate of clinical endpoints in the ramipril and metoprolol groups, especially in participants with proteinuric nondiabetic kidney disease.
This report is limited to findings in the amlodipine and ramipril groups through September The ramipril vs metoprolol and low vs usual blood pressure comparisons are continuing.

3. AASK: Cumulative incidence of renal events and death
Content Points:
Participants randomized to the ramipril group experienced significant reductions in the risk of the important clinical outcomes: a marked decline in renal function (>50% decline in GFR), ESRD, or death when compared to those who were treated with amlodipine.1
After adjustment for covariates (protein-creatinine ratio, history of heart disease, mean arterial pressure, age, and sex) the ramipril group had a 38% lower risk for the clinical composite outcome (decline in GFR, ESRD, or death). The 95% confidence interval was 13%-56% (P = 0.005).
For the combined endpoints of ESRD or death, the ramipril group had a 41% reduction in risk (95% CI, 14%-60%, P = 0.007).

4. AASK: Rates of clinical events
Content Points:
This slide summarizes the rates of clinical events per person-year in the two treatment groups and the risk reductions with ramipril vs amlodipine after adjustment for prespecified covariates as required by the study’s analysis plan.1
The risk reductions with ramipril included: GFR events, 41% (P = 0.03); ESRD (dialysis), 44% (P = 0.01); GFR or ESRD, 38% (P = 0.01); ESRD or death, 41% (P = 0.007), and GFR, ESRD, or death (the prespecified clinical composite outcome), 38% (P = 0.005).
There was a 31% reduction in death (P = 0.31) with ramipril. This includes only deaths prior to ESRD, as three additional deaths occurred in each group after ESRD.

5. AASK: Mean change in GFR by baseline UP/Cr
Content Points:
This slide summarizes the changes in renal function in the ramipril and amlodipine groups according to baseline urine protein-to-creatinine ratio UP/Cr <0.22 vs UP/Cr >0.22.1
Among participants with a UP/Cr >0.22 (corresponding to proteinuria of >300 mg/d), the ramipril group had a 36% (2.02 mL/min per 1.73 m2/year) slower mean decline in GFR over 3 years.

6. AASK: Mean change in GFR by baseline GFR
Content Points:
This slide summarizes the change in GFR according to baseline GFR >40 vs <40.1
For participants with higher baseline GFR, the decline in GFR was faster in the ramipril group than in the amlodipine group (by 0.97 mL/min per 1.73 m2/year). In the group with lower baseline GFR, the decline in GFR was faster in the amlodipine group than in the ramipril group (by 1.6 mL/min per 1.73 m2/year).
The total change in GFR during the study did not differ significantly between the two treatment groups (P = 0.38). However, after adjusting for baseline variables, the ramipril group had a 36% slower mean decline in GFR after 3 months (P = 0.002) and less proteinuria (P < 0.001). The decline in GFR in the ramipril group was 1.15 mL/min per 1.73 m2/year slower than in the amlodipine group.
Related to this, there was also a 38% reduced risk of clinical outcomes in patients treated with ramipril (as discussed on the preceding slides).

7. AASK: % changes in proteinuria from baseline
Content Points:
During the first 6 months of the study, proteinuria declined by 20% in the ramipril group, while proteinuria increased by 58% in the amlodipine group. This difference between the groups was statistically significant (P < 0.01) and persisted throughout follow-up.1
The increase in proteinuria in the amlodipine group was significant for both the higher and lower baseline strata (UP/Cr <0.22 and UP/Cr >0.22).
The difference in UP/Cr change between the ramipril and amlodipine groups was greater in the group that had higher baseline proteinuria. However, the ramipril group with a baseline UP/Cr level <0.22 had a 56% lower rate of progression to proteinuria (UP/Cr >0.22) than the comparable group treated with amlodipine.
The importance of this treatment effect is suggested by the fact that patients with chronic renal failure who have severe proteinuria have been shown to progress more rapidly to ESRD.4
The risk reduction in clinical outcomes in the ramipril group in the AASK study was not significantly related to baseline proteinuria, but it was strongly influenced by the subgroup with baseline proteinuria UP/Cr >0.22 (approximately 300 mg/d), as 63% of the clinical events occurred in this group. Among participants with UP/Cr >0.22, the ramipril group had a 48% risk reduction (P = 0.003).

8. AASK: Conclusion and clinical implications
Content Points:
Conclusion: Initial antihypertensive therapy with ramipril, an ACE inhibitor, offers greater benefit in slowing deterioration of renal function than amlodipine, a calcium channel blocker, in patients with mild-to-moderate chronic renal insufficiency associated with hypertensive nephrosclerosis.1
This conclusion is based on three findings: Participants in the ramipril group, compared with the amlodipine group, had significant reductions in (1) the risk of important clinical outcomes, ie, marked decline of renal function, ESRD, or death; (2) mean chronic decline in GFR from 3 months postrandomization; and (3) proteinuria.
Clinical implications: These interim results of the AASK trial, as well as previous trials, support the use of an ACE inhibitor as initial therapy in a multidrug regimen in African Americans and whites with mild-to-moderate chronic renal insufficiency and proteinuria (as the levels were defined in the study).
These results provide further documentation extending the renoprotective effect of an ACE-inhibition-based regimen to African Americans with hypertensive renal disease, a population previously thought to be less responsive to these agents.

9. ACE inhibition slows the progression of nondiabetic renal disease: A meta-analysis of 11 trials
Content Points:
Investigators in the ACE Inhibition in Progressive Renal Disease Study Group performed a meta-analysis of 11 randomized controlled trials involving patients with nondiabetic renal disease.2 Their objective was to determine whether antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibition for the treatment of nondiabetic renal disease.
During a mean follow up of 2.2 years, the ACE inhibitor groups exhibited significantly greater decreases in systolic BP, diastolic BP, and urine protein excretion than the control groups.
The studies involved 1860 patients. Of these, 941 patients were randomly assigned to treatment with ACE inhibitors and 919 patients were controls. All baseline patient characteristics were balanced between the two groups.
Patients who received ACE inhibitors had a greater decline in blood pressure (top left). Mean systolic/diastolic blood pressures decreased 4.5/2.3 mm Hg more in the ACE inhibitor group than in the controls.
Patients who received ACE inhibitors also had a greater decrease (0.46 g/d more) in urinary protein excretion than the control group (top right). Urinary protein excretion remained relatively stable in the control group.
Kidney function was significantly better preserved in patients who received ACE inhibitors. ESRD developed in 7.4% of those taking ACE inhibitors compared with 11.6% of the control patients (P = 0.002). Doubling of baseline creatinine or ESRD occurred in 13% of the ACE inhibitor group vs 20.5% of the amlodipine group (P = 0.001).

10. Risk for ESRD or combined outcome according to baseline urinary protein excretion
Content Points:
The study found a significant interaction between the degree of baseline urinary protein excretion and the effect of ACE inhibition on outcome, that is progression to ESRD and the combined outcome of a doubling of baseline serum creatinine concentration or ESRD.2 The risk for both outcomes was greater at higher levels of baseline urinary protein excretion than at lower levels.
The risk for renal disease progression was lower in the ACE inhibitor group than in the control group at all urinary protein excretion levels and the difference between groups was greater at higher levels of baseline urinary protein excretion.
The findings in this meta-analysis are compatible with previous studies that have shown a more rapid progression to ESRD in patients with severe proteinuria.4
The statistical power and duration of the follow up (mean 2.2 years) precluded conclusions about the effect of ACE inhibitors in patients with urine protein excretion of <0.5 g/d.

11. Relative risk adjusted for treatment effect on BP and proteinuria: ACEI group vs control
Content Points:
Although patients who received ACE inhibitors had greater decreases in both blood pressure and urinary protein excretion, these effects did not explain the benefit to the kidney. Statistical adjustments for these treatment effects demonstrated that risk reductions for ESRD or the combined outcome of doubling of serum creatinine concentration or ESRD persisted after they were excluded.2
After adjusting for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion, the relative risks in the ACE inhibitor group were 0.69 (95% CI, ) for ESRD and 0.70 (95% CI, ) for the combined outcome of doubling of the baseline serum creatinine concentration or progression to ESRD.
These findings suggest that the beneficial effects of ACE inhibition in patients with nondiabetic renal disease are mediated by factors that are not directly related to reduction in blood pressure and urinary protein excretion.

12. Conclusion and clinical implications
Content Points:
Conclusion: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease.2 (The effects are similar to the effects in diabetic renal disease.)
The benefits of ACE inhibitors are mediated by factors in addition to decreasing blood pressure and urinary protein excretion and are greater in patients with proteinuria.
Clinical implications: ACE inhibitors help prevent worsening of kidney disease that is unrelated to diabetes. Therefore, ACE inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria, and possibly for those without proteinuria.
Because the effects in patients with nondiabetic renal disease are similar to the effects in patients with diabetic renal disease, the authors suggest that “ACE inhibitors should be the antihypertensive agents of first choice in nondiabetic renal disease, as they are in diabetic renal disease.”

13. HOPE subgroup analysis: Baseline characteristics of patients with and without renal insufficiency
Content Points:
Clinicians are often reluctant to use ACE inhibitors in patients with renal insufficiency. This post hoc subgroup analysis of HOPE data was undertaken to determine whether mild renal insufficiency increases CV risk and whether ramipril decreases that risk.3
The HOPE study was a randomized, double-blind trial that included men and women at least 55 years of age from 267 centers. The study participants had objective evidence of vascular disease (CHD, stroke, or peripheral vascular disease) or diabetes combined with another CV risk factor. The main exclusion criteria were heart failure, intolerance to ACE inhibitors or vitamin E, a serum creatinine concentration >2.3 mg/dL or dipstick positive proteinuria (>1+).
The subgroup analysis involved 980 patients with mild renal insufficiency (serum creatinine concentration >1.4 mg/dL) and 8307 participants with normal renal function (serum creatinine concentration <1.4 mg/dL). Patients with a baseline serum creatinine concentration >2.3 mg/dL were excluded.
Compared with patients who had no evidence of renal insufficiency, patients with renal insufficiency were older, more likely to be male, and had a higher prevalence of diabetes, CHD, peripheral vascular disease, hypertension, and low HDL-cholesterol. Systolic blood pressure and urine albumin level, as well as waist-to-hip ratio, were also higher in this group.

14. HOPE: Mild renal insufficiency increases the risk of CV events
Content Points:
Renal insufficiency was an important predictor of the CV events in all patients, as well as for the ramipril and placebo groups separately. The effect of renal insufficiency on the primary outcome (CV death, MI, or stroke) was independent of known CV risks and treatment.3 The cumulative incidence of CV death, MI, or stroke was significantly higher in all patients with renal insufficiency than in those without (22% vs 15%, P < 0.001).
An analysis of the relationship between the incidence of the primary outcome and renal insufficiency showed that both an elevated serum creatinine and microalbuminuria were highly significant independent renal risk factors for the aggregate primary outcome of CV death, MI, or stroke, with a hazard ratio of 1.4 and 1.6 respectively (P < 0.001).
Patients with renal insufficiency had a significantly increased risk for CV events, total mortality, and hospitalizations for heart failure. The rates of CV death, all-cause mortality, and hospitalizations for heart failure were approximately twice as high in patients with renal insufficiency than in those without.

15. HOPE: Rate of primary outcome (CV death, MI, or stroke) by baseline serum creatinine quartile
Content Points:
Analysis of the group risk for the primary outcome clearly showed that as serum creatinine concentration increases, so does CV risk. The incidence of the primary outcome increased significantly with each quartile of serum creatinine concentration (P < for the linear trend of the hazard ratio across quartiles).3
The HOPE study included hypertensive as well as normotensive patients. Therefore, the HOPE data extend current knowledge by demonstrating a continuous relationship between serum creatinine levels and CV outcomes in hypertensive as well as in normotensive patients.

16. MICRO-HOPE: Effect of ACE inhibition on renal and CV outcomes in type 2 diabetes
Content Points:
MICRO-HOPE, a substudy of HOPE, included 3577 patients with diabetes and 1 other CV risk factor (hypertension or on antihypertensive treatment, dyslipidemia, smoking, or microalbuminuria) who were randomly assigned to ACE inhibition (rampril 10 mg) or placebo.5 Findings in MICRO-HOPE demonstrated that in people with diabetes, ramipril helped prevent CV events and overt nephropathy, which was a main outcome of the study.
The risk for overt nephropathy was reduced by 24% after 4.5 years of follow-up (P = 0.027). Ramipril lowered the risk of nephropathy in those who did and did not have baseline microalbuminuria.
In addition, the CV benefits included significant reductions of 22% in MI (P = 0.01), 33% in stroke (P = 0.007), and 37% in CV death (P = ). The combined outcome (MI, stroke, and CV death) was reduced by 25%.
Ramipril also was associated with significant reductions in the albumin-creatinine ratio at 1 year (P = 0.02) and at the end of the study (P = 0.001). In participants without baseline microalbuminuria, the risk of new microalbuminuria was reduced by 9%.
Clinical implication: The treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

17. Recently completed studies of ARBs in patients with type 2 diabetes and renal disease
Content Points:
Recently completed clinical trials address the previously unanswered questions of whether angiotensin II receptor blockers (ARBs) delay the progression of diabetic nephropathy or reduce proteinuria in patients with type 2 diabetes.
The Irbesartan Diabetic Nephropathy Trial (IDNT) included 1715 patients with type 2 diabetes, hypertension and nephropathy followed up for a mean of 3.6 years.6 Irbesartan reduced the composite outcome of ESRD, doubling of baseline serum creatinine concentration, and death by 20% vs placebo and by 23% vs amlodipine. The effect was independent of blood pressure reduction. There were no differences between treatment modalities in a composite of CV outcomes or death.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) assessed the effect of losartan in 1513 patients with type 2 diabetes and nephropathy.7 Patients also received conventional antihypertensive therapy (excluding ACE inhibitors) as needed. The ARB reduced the risk of the composite outcome of ESRD, doubling of serum creatinine concentration, and death by 16% compared with placebo. Losartan had no impact on death or on CV morbidity and mortality in a composite analysis of events.
The Irbesartan Microalbuminuria and Type 2 Diabetes Study (IRMA-2) assessed the effect of irbesartan (150 mg or 300 mg daily) vs placebo in 590 patients with type 2 diabetes, hypertension, and microalbuminuria.8 In the 2-year study, significantly fewer patients assigned to both irbesartan doses had progression to nephropathy. The renoprotective effect of irbesartan was independent of its hypotensive effect. This study did not assess the impact of treatment on CV outcomes.
Clinical implications:
These studies confirm that drugs inhibiting the renin-angiotensin system have a renoprotective effect in patients with type 2 diabetes.9 This observation supports findings in MICRO-HOPE, a substudy of the HOPE trial,3,5 and those of earlier studies of ACE inhibition in patients with diabetes and renal disease.10-15
MICRO-HOPE included 3577 patients with type 2 diabetes and one other risk factor, including 1160 patients with baseline microalbuminuria (serum creatinine concentration >1.4 mg/dL). In MICRO-HOPE, ACE inhibition (ramipril) attenuated an increase in proteinuria and was associated with a significant 24% decline in overt nephropathy. In addition, ACE inhibition provided protection against CV events and death.5,9
The HOPE study showed that ACE inhibition reduced CV risk in patients with and without mild renal insufficiency and in both diabetic and nondiabetic patients.3

18. HOPE: ACE inhibition reduces CV risk in patients with and without renal insufficiency
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Ramipril significantly reduced the high CV risk associated with mild renal insufficiency (serum creatinine concentration >1.4 mg/dL). The risk reduction with treatment was at least as great in the patients with renal insufficiency as in those without.3
For CV mortality, all-cause mortality, and heart-failure related hospitalization, the risk reduction was significantly greater in patients with mild renal insufficiency than in those with normal renal function.
Ramipril was equally safe and effective in reducing CV disease in this subgroup of HOPE patients with mild renal insufficiency.

19. HOPE: ACEI reduces CV events in patients w/wo renal insufficiency and diabetes or hypertension
Content Points:
Hypertension and diabetes are important confounders when the effects of renal insufficiency on outcomes are analyzed. The HOPE subgroup analysis demonstrated that the impact of mild renal insufficiency on primary and secondary outcomes was similar among nondiabetic and normotensive subgroups as compared with diabetic and hypertensive subgroups.3
The benefits of ramipril treatment for prevention of CV death, MI, or stroke in subgroups with and without renal insufficiency were similar in patients that had a history of diabetes or hypertension and those that did not.
The risk reductions with ramipril ranged between 52% for diabetic patients with renal insufficiency to 18% for normotensive patients without renal insufficiency.

20. HOPE: Conclusions and clinical implications
Content Points:
Conclusions: The analysis establishes mild renal insufficiency as a new risk factor for future CV events in patients with other risk factors for CV disease. The risk associated with mild renal insufficiency was substantial and independent of other risk factors.3
Ramipril reduced CV events significantly in patients with mild renal insufficiency without increasing adverse outcomes.
Clinical implications: The findings of this study demonstrate that ACE inhibitors reduce the high rates of CV diseases in patients with renal insufficiency. Therefore, ACE inhibitors should not be withheld simply because of a moderate elevation in serum creatinine concentration.