Lercanidipine in patients with chronic renal failure: the ZAFRA Study

Aim. To evaluate the safe use of a new calcium channel blocker, lercanidipine, in patients with chronic renal failure (CRF); the protective effect of calcium channel blocker on renal function in CRF patients previously treated with ACE inhibitors or angiotensin receptor blockers (ARB). Material and methods. The study included 203 CRF patients (creatinine >1,4 mg/dL for men, >1,2 mg/dL for women; or creatinine clearance <70 mL/min). All patients were receiving ACE inhibitors (63,4 %) or angiotensin II antagonist (36,6 %) therapy, but they had higher blood pressure than recommended for CRF (130/85 mmHg). No patients received diuretics. Patients were clinically evaluated 1, 3, and 6 months after starting treatment with lercanidipine. Urine and blood samples were taken during the examination. When needed, a third drug was added to the treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection. Results. 175 patients completed the study protocol (age 63,9±11,9 years, 52,9 % males and 47,1 % females). Blood pressure (BP) significantly decreased from 162±17/93±8.3 mm Hg to 132±12/78±6 mm Hg. 89,2 % of patients showed a significant BP reduction, and 58,1 % achieved optimal BP control (<130/85 mmHg). Seven patients (3,4 %) showed adverse effects. No single case of oedema was detected, and the prevalence of adverse effects related to vasodilatation was extremely low (3 patients, 1,48 %). Plasmatic creatinine did not change (1,9±0,5 baseline vs.1,9±0,6 mg/dL), but creatinine clearance increased at the end visit (41,8±16,0 baseline vs. 45,8±18,0 mL/min, p=0,019). Plasmatic cholesterol also decreased from 221±46 to 211±35 mg/dL (p=0,001). Conclusion: Lercanidipine showed a high antihypertensive effect in CRF patients. It had a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, assessed by creatinine clearance, was detected.

1. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996; 334: 13-8.

2. Rostand SG, Brunzell JD, Cannon RO, Victor RG. Cardiovascular complications in renal failure. J Am Soc Nephrol 1991; 2: 1053-8.

3. Shulman NB, Ford CE, HalL WO, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The hypertension detection and follow-up program cooperative group, Hypertension 1989, 13 (Suppl 5), Il80-93.

4. Samuelsson 0, Wilhelmsen L, Elmfeldt D, et al. Predictors of cardiovascular morbidity in treated hypertension: results from the primary preventive trial in Goteborg, Sweden. J Hypertens 1985; 3: 167-76.

5. Ruilope LM, Campo C, Rodriguez-Artalejo F, et al. Blood pressure and renal function: therapeutic implications. J Hypertens 1996; 14: 1259-63.

6. Mandhavan S, StockweII D, Cohen H, Alderman MH. Renal function during antihypertensive treatment. Lancet 1995; 345: 749-51.

7. Barrios V, Navarro A, Esteras A, et al. Antihypertensive efficacy and tolerability of lercanidipine in daily clinical practice. The ELYPSE study. Blood Pressure 2002; 11: 95-100.

8. Leonetti G, Magnani B, Pessina AC, et al., COHORT Study Group, Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives, Am J Hypertens 2002; 15: 932-40.

9. DiGiorgio LA, Orlandini F, Malasorna P, Zappa A. A doubleblind cross-over study of lercanidipine versus amlodipine in the treatment of mild-to-moderate essential hypertension. Curl Ther Res 1999; 60: 511-20.

10. Tobbe S, Epstein M. The use of calcium antagonists in the treatment of hypertensive persons with kidney disease. Curr Hypertcns Rep 2002; 4: 191-4.

11. Bitar R, Flores 0, Reverte M, et al. Beneficial effect of verapamil added to chronic ACE inhibitor treatment on renal function in hypertensive elderly patients. Int Ural Nephrol 2000; 32(2): 165-9.

12. Messerli FB. Calcium antagonists in hypertension: from hemodynamics to outcomes. Am J Hypertens 2002; 15 (Pt2): 945-75.

13. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Blood pressure lowering treatment trialists’ collaboration. Lancet 2000; 356: 1955-64.

14. Opie LI-I, Schall R. Evidence-based evaluation of calcium channel blocker for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. JACC 2002; 39: 315-22.

15. Lewis E, Huncksicker LG, Clarke WR, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-60.

16. Rengo F, Romis L. Activity of 1ercanidipine in double-blind comparison with nitrendipine in combination treatment of patients with resistant essential hypertension. J Cardiovasc Pharmacal 1997; 29(Suppl. 2): 554-8.

17. Morisco C, Trimarco B. Efficacy and tolerability of lercanidipine in comparison to and in combination with atenolol in patients with mild to moderate essential hypertension in a double blind controlled study. J Cardiovasc Pharmacol 1997; 29(Suppl. 2): S54-8.

18. Barbagallo M, Barbagallo G. Sangiorgi, Efficacy and tolerability of lercanidipine in monotherapy in elderly patients with isolated systolic hypertension. Aging Clin Exp Res 2000; 12: 375-9.

19. Messerli FI-I. Vasodilatory edema: a common side effect of antihypertensive therapy. Am J Hypertens 2001: 14: 978-9.

20. Hanson L, Lindholm LH, Ekbom T, et al. STOP-IIypertension-2 study group, Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity. The Swedish trial in old patients with hypertension-2 study. Lancet 1999; 354: 1751-6.

21. Messerli FB, Oparil S, Feng Z. Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonists (either nifedipine 01’ amlodipine) versus high-dose calcium nntagonists monotherapy for systemic hypertension. Am J Cardiol 2000; 86: 1182-7.

22. Parving RH. The impact of hypertension and antihypertensive treatment on the course and prognosis of diabetic nephropathy. J Hypertens 1990; 8: 5187-91.

23. Peterson JE, Adler S, Burkart LM, et al. Blood pressure control, proteinuria and the progression of renal disease: the modification of diet in renal disease study. Ann Intern Med 1995; 123: 754-62.

24. Toto RD, Mitchell NC, Smith RO. “Strict” blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Kidney Int 1995; 48: 851-9.

25. Gansevoort RT, Sluiter WJ, Hemrnelder MH, et al. Antiproteinuric effect of blood pressure lowering agents: a metaanalysis of comparative trials. Nephrol Dial Transplant 1995; 10: 1963-74.

26. MaId DD, Ma IZ, Louis TA, Kasiske BL. Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Meet 1995; 155: 1073-80.

27. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different anti-hypertensive drugs in human diabetic nephropathy: an updated metaanalysis. Nephrol Dial Transplant 1995; 10(Suppl. 9): 39-45.

28. National High Blood Pressure Education Program Working Group on Hypertension and Renal Disease, 1995 Update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med 1996; 156: 1938-47.

29. Brenner BM, Cooper ME, de Zeeuw D, et al. Effect of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-9.

30. Parving III-I, Lehnert I-I, Brochner-Mortenscn I, et al. For the study group Irbesartun in patients with type 2 diabetes and microalbumlnuria. N Engl J Med 2001; 345: 870-8.

31. Kesteloot H, Joossens IV. On the determinants of the creatinine clearnnce: a population study. J Hum Hypertens 1996; 10: 245-9.

32. Lemann J, Bidani A, Bain RP. Collaborative Study Group, Use or serum creatinine to estimate glomerular filtration rate in health and curly diabetic nephropathy. Am J Kidney Dis 1990; 16: 236-43.

33. Voyaki SM, Staesscn JA, Thijs L, et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators, Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. J Hypertens 2001; 19: 511-9.

34. Bakris GL, Mangrum A, Copley JE, et al. Effect of calcium channel or B-blockade on the progression of diabetic nephropathy in African Americans. Hypertension 1997; 29: 744-50.

35. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the international nifedipine GITS study: intervention as a goal in hypertension treatment (INSIGHT). Lancet 2000; 356: 366-72.

36. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: 2719-28.

37. Epstein M. Calcium antagonists and renal protection: emerging perspecti Yes. J Hypertens 1998; J8(Suppl. 4): S17-25.

38. Sabbatini M, Leonardi A, Testa R, et al. Effect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats. Hypertension 2000; 35: 775-9.

39. Schultz P, Raij L. Inhibition of human mesangial cell proliferation by calcium channel blockers. Hypertension 1990; 15(Suppl. 1): 76-80.

40. Hebert LA, Bain RP, Venne D, et al. Collaborative Study Group, Remission of nephrotic range proteinuria in type I diabetes. Kidney Int 1994; 46: 1688-93.

41. Bakris GL, Williams B. ACE inhibitors and calcium antagonists alone or combined: is there a difference on progression of diabetic renal disease? J Hypertens 1995; 13 (Suppl 2): S95-101.

42. Bakris GL, Weir MR, DeQuattro V, et al. Effects of an ACE inhibitor/calcium antagonists combination on proteinuria in diabetic nephropathy. Kidney lnt 1998; 54: 1283-9.

43. The effects of an ACE inhibitor and a calcium antagonists on the progression of renal disease: the nephross study. Nephrol Dial Transplant 2001; J6: 2158-66.