Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency

1. Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency Adrienne Trustman, MD EBM Journal Club February 1, 2006

2. Background ACE Inhibitors (ACE-I) are known to slow the progression of kidney disease in patients with mild to moderate renal insufficiency (Cr <3.0) both with and without diabetes There is evidence that ACEIs slow progression in diabetic patients with more advanced disease (Cr>3.0) Physicians are reluctant to use ACE-Is in patients with creatinine > 3.0 due to concern that serum creatinine or serum potassium will rise Many believe that the benefit of ACE-Is is primarily due to its effect on blood pressure control

3. Background, continued Non-diabetic patients with advanced chronic kidney disease have previously been left out of randomized-controlled trials of ACE-Inhibitors Thus, the risk-benefit profile of ACE-Inhibitors in this population is poorly defined Prior to this study, the authors completed a small, open-label, prospective study of patients with advanced chronic renal insufficiency which demonstrated that Benazepril may have renal benefits

4. What would you do? 64 year old African American female with history of hypertension, chronic kidney disease, obesity is a new patient in your clinic. She is taking metoprolol and HCTZ and her blood pressure is 128/75 at her first appointment. You get screening labs and find that her creatinine is 3.1mg/dl. Should you start and ACE Inhibitor?

5. Study Objective To determine whether benazepril could slow the progression of renal dysfunction in patients without diabetes with advanced renal insufficiency

6. Study Design Randomized, placebo controlled, double-blinded Conducted at the Nanfang Hospital Renal Division, a center of kidney disease care in southern China Blinded adjudicating committee determined when patients met endpoints and evaluated for patient safety Study period of 3 years chosen on basis of previous trials with similar patient populations

7. Patients 486 consecutive patients were screened 422 patients were chosen based on the inclusion/exclusion criteria All patients were Chinese Ages ranged from 18 to 70 years No ACE-I or ARB for >6 weeks before screening

8. Inclusion Criteria Serum creatinine of 1.5-5.0 mg/dl Cr clearance of 20-70ml/min/1.73m^2 Nondiabetic renal disease Persistent proteinuria (0.3 g/d for 3+ months, without UTI or overt heart failure)

9. Exclusion Criteria Immediate need for dialysis Current treatment with corticosteroids, NSAIDS or immunosuppressive drugs Renovascular disease MI or stroke in year preceding trial Connective tissue disease Obstructive uropathy

10. Treatment Patients divided into 2 groups Group 1: patients with Cr 1.5-3.0 mg/dl Group 2: patients with Cr 3.1-5.0 mg/d All patients received Benazepril 10 mg qd for 4 weeks under close observation of BP, serum Cr, and serum K Dose then increased to bid for 4 weeks If Cr increased less than 30% and K remained below 5.6 and no adverse events reported, pts continued BP controlled with usual meds to <130/80

11. Treatment Continued After the run-in phase, Benazepril was discontinued for 3 weeks During this period, patients received antihypertensive therapy as required to maintain BP <130/80 Then, all patients in group 1 received Benazepril 10 mg bid Patients in group 2 were randomized to receive either placebo or Benazepril 10 mg bid Blinded physician saw each patient every 2 weeks times 2 then every 3 months to assess for endpoints or adverse events

12. Treatment Continued All patients advised to reduce salt intake to 5-7 g/d, to eat 0.5-0.7g of protein/kg body weight/d, and to restrict potassium rich food intake Dietary compliance assessed by evaluating daily urinary urea and chloride excretion

13. Outcome Measures Primary efficacy measure: time to any of 3 events: doubling of serum Cr, end-stage renal disease (requiring dialysis or transplantation), or death Secondary outcomes: changes in rate of urinary protein excretion, progression of renal disease (assessed by reciprocal of serum Cr), glomerular filtration rate, and Cr clearance

14. Statistical Analysis Sample size was estimated before the study using data from their preliminary study Primary and secondary endpoints were analyzed according to the intention to treat principle A Cox regression model was used to determine the hazard ratio for the primary endpoint

15. Enrollment Flow Chart

16. Baseline Characteristics of Patient Groups

17. Baseline Characteristics of Patient Groups

18. Primary Outcomes In group 2, 41% of Benazepril patients reached a primary endpoint and 60% of placebo patents reached a primary endpoint (p=0.003) This is a 43% overall risk reduction Decrease in risk remained significant after adjustment for differences in mean arterial pressure (p=0.009) Intention to treat analysis of individual components showed 51% reduced risk of doubling creatinine and 40% reduced risk of end-stage renal disease

19. Primary Outcomes

20. Blood Pressure

21. Secondary Outcomes Level of proteinuria was reduced in Benazepril group compared with placebo (52% vs. 20%, p<0.001) Rate of decline in renal function in Benazepril group by 23% compared to placebo (p=0.02) assessed by reciprocal of serum creatinine level Decline of GFR reduced by 24% in Benazepril group: 6.8 vs. 8.8 ml/min/1.73m�/year (p=0.006)

22. Safety 1 patient in Benazepril group 2 died of pneumonia with normal K and BPs No significant differences in numbers of nonfatal cardiovascular events between the 3 groups Hyperkalemia (defined as serum K >/=6.0) occurred in 11 (5%) of group 2, 6 in benazepril group and 5 in placebo group -8 treated with dietary modification and diuretics -3 withdrew from the study -follow up serum K in group 2 were higher in benazepril group but never by more than 0.5 mmol/L (p=0.001)

23. Discussion: Overview This study clearly demonstrates that benazepril offers renal protection in patients with advanced, non-diabetic kidney disease and well-controlled BP The risk of doubled creatinine or end stage renal disease is reduced by 43% in 3.4 years Thus need to treat about 2 patients for about 3 years to prevent one patient from this endpoint Benefit of benazepril was independent of changes in blood pressure

24. Discussion: Safety Similar incidence of major adverse events in the 2 subgroups Non-significant trend toward higher frequency of hyperkalemia in group with more advanced renal disease

25. Comments Patient population is fairly similar to ours except that it is limited to Chinese patients and the proportion of types of renal disease may not be representative those seen here Efficacy of benazepril for individual etiologies of renal disease is not identified and study is not powered to evaluate

26. Comments Risks of hyperkalemia may be minimized in this population due to close follow up, diet instruction on lowering potassium intake, and adherence to care plan Dosing in this study is bid, but we usually dose benazepril qd, which is supposed to allow for K clearance overnight

27. Back to our new patient� Would you start benazepril for this patient based on this study?

28. Reference Hou FF, et al. Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency. N Engl J Med 2006;354:131-40.