P-179: The safety and efficacy of supramaximal doses of candesartan cilexetil (160mg) in chronic renal disease patients naīve to angiotensin receptor blockade therapy

• Published in: American journal of hypertension Vol. 16; no. S1; p. 103A
• Main Authors: Weinberg, Adam J., Haneiwich, Renee, Weinberg, Marc S.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2003
• Subjects: antihypertensive drugs; clinical trials; Renin-angiotensin-aldosterone
• ISSN: 0895-7061; 1879-1905; 1941-7225
• DOI: 10.1016/S0895-7061(03)00344-3

We examined the effect of supramaximal doses of candesartan cilexetil (SDCC), 160mg, in 10 patients with chronic renal disease (CRD; proteinuria > 500mg%, serum creatinine <3mg%) and hypertension in diabetic (D) and non-diabetic (ND) subjects to establish the safety and efficacy of high dose therapy to achieve maximal blockade of the renin-angiotensin-system (RAS). Despite aggressive blood pressure (BP) control, progression of CRD still occurs in both D and ND renal diseases. Blockade of the circulating (BP dependent effects) and tissue (BP independent effects) RAS has been identified as one of the most important strategies to limit the progression of chronic renal disease. However, the optimal doses of angiotensin converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARBs), as well as optimal therapeutic dosing intervals needed are not known. Furthermore, there may be a subset of patients where even higher doses of ACE-I or ARBs may be required to obtain maximal reduction in proteinuria. For this reason, we evaluated the safety and efficacy of SDCC in 10 hypertensive subjects (57.4 ± 15.3 yrs; 9) with CRD (creatinine clearance rates: 29–83 ml min−1) and proteinuria. After screening and washout periods, patients were titrated from 16mg of CC for 2 weeks, to 64mg for 2 wks, and to 160mg of CC for 4 wks. All subjects had never started or were ever prescribed an ARB for therapy. Patients on ACEI therapy were washed out for 4 wks. Data was compared during the screening period and following one month of SDCC, 160 mg. The mean serum creatinine was 2.0±0.6 mg% and did not change during the study (NS). Serum potassium levels were 4.8 mEql−1 at baseline and 5.0 mEql−1 at 160 mg (NS). After 4 wks at 160 mg of candesartan, 24 h urinary protein excretion was reduced by 31.7±37%from 4.7 to 3.3 g day −1 (p=0.027). Creatinine clearance rates were similar (p>0.05) at baseline (57±16 ml min−1) and at 160 mg CC (50±25 ml min−1). There was a significant reduction in SBP from 134 to 124 mmHg (p=0.04) while the DBP dropped from 84 to 76mmHg (p=0.02). In summary, SDCC (160mg) was associated with no significant adverse effects. However, SDCC lowered SBP, DBP and urinary 24 hour urinary protein excretion. Future investigations are warranted to evaluate the use of supramaximal doses of ARBs for more complete blockade of the tissue RAS to maximize renal protective effects.