Direct renin inhibitor aliskiren in the treatment of cardiovascular and renal diseases

Česká verzia

Authors: K. Horký
Authors place of work: II. interní klinika kardiologie a angiologie 1. lékařské fakulty UK a VFN Praha, přednosta prof. MU Dr. Aleš Linhart, DrSc.
Published in the journal: Vnitř Lék 2010; 56(2): 120-126
Category: Reviews

Summary

The role of renin‑angiotensin‑aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE‑inhibitors (ACEI), AT₁‑receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre‑treatment levels (‘escape’ phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin‑angiotensin cascade – i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non‑peptide, orally long‑term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose‑dependent manner (75– 600 mg/ den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide‑induced RAAS activation. Once daily administration of the drug leads to longer than 24- hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT₁‑blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna^® and combination formulation TekturnaHCl^®, respectively) and shortly after that in European Union as Rasilez^®. In the Czech Republic, aliskiren (Rasilez^®) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150– 300 mg per day on 1. 8. 2009. It is recommended as monotherapy or in combination with other antihypertensives to treat conditions with elevated PRA, including PRA elevation following diuretic, ACEI or ARB administration. Aliskiren might be used in patients who do not tolerate ACEIs as well as in patients in whom angiotensin II participates in the pathogenesis of their diseases. Renoprotective properties leading to a reduction in proteinuria and delaying renal failure progression were observed in patients with diabetic as well as non‑diabetic nephropathy. The drug is the subject to similar precautions and contraindications as ACEIs and ARBs, i.e. pregnancy and bilateral renal artery stenosis. To make meaningful conclusions about the so far positive contribution of this new treatment class and its broad applicability for the therapy of hypertension and other cardiovascular diseases, it will be imperative to assess its long‑term effects on morbidity and mortality as well as to compare these agents with other RAAS blockers in long‑term clinical studies; this represents a research effort for another 7– 8 years.

Key words:
renin inhibitors – antihypertensive activity – organoprotective effects – preliminary study results – the role in hypertension treatment

Zdroje

1. Tigerstedt R, Bergman R. Niere und Kreislauf. Scand Arch Physiol 1898: 8: 223– 271.

2. Azizi M, Ménard J. Combined blockade of the renin‑angiotensin system with angiotensin‑converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004: 109: 2492– 2499.

3. Stanton A, Jensen C, Nussberger J et al. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003: 42: 1137– 1143.

4. O’Brien E, Barton J, Nussberger J et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin‑converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007: 49: 276– 284.

5. Shafig MM et al. Oral direct renin inhibition: Premise, promise, and potential limitation of a new antihypertensive drug. Am J Med 2008: 121: 265– 271.

6. Ménard J, Boger RS, Mayse DM et al. Dose‑dependent effects of the renin inhibitor zankiren‑ HCl after a single orgal dose in mildly sodium‑ depleted normotensive subjects. Circulation 1995; P1: 330– 338.

7. Azizi M. Renin inhibition. Curr Opin Nephrol Hypertens 2006: 15: 505– 510.

8. Staessen JA, Li V, Richart T. Oral renin inhibitors. Lancet 2006: 368: 1449– 1456.

9. Widimský J jr, Slíva S. Aliskiren. Farmakoterapie 2009: 5: 17– 23.

10. Villamil A, Chrysant S, Calhoun D et al. The novel renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. J Clin Hypertens 2006; 8 (Suppl A): A100.

11. Parving HH, Persson F, Lewis JB et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. NEJM 2008: 358: 2433– 2446.

12. Gradman AH, Schmieder RE, Lins RT et al. Aliskiren, a novel orally active renin inhibitor, provides dose‑dependent antihypertensive efficacy and placebo‑like tolerability in hypertensive patients. Circulation 2005: 111: 1012– 1018.

13. Nussberger J, Aubert JF, Bouzourene K et al. Renin inhibition by aliskiren prevents atherosclerosis progression. Comparison with irbesartan, atenolol, and amlodipin. Hypertension 2008: 51: 1306– 1311.

14. Sever PS, Gradman AH, Azizi M. Managing cardiovascular and renal risk: the potential of direct renin inhibition. J Renin‑Angiotensin‑Aldosterone System 2009; 10: 68– 76.

15. Nguyen G, Delarue F, Burcklé C et al. Pivotal role of the renin/ prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417– 1427.

16. Ichihara A, Kaneshiro Y, Takemitsu T et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47: 894– 900.

17. Ayalasomayajula S, Yeh ChM, Vaidyanathan S et al. Effects of Aliskiren, a direct renin inhibitor, on cardiac repolarization and conduction in healthy subjects. J Clin Pharmacol 2008; 48: 799– 811.

18. McMurray JJV, Pitt B, Latini R et al. Effects of Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure. Heart Failure (ALOFT) 2008; 1: 17– 24.

19. Souček M, Fráňa P, Plachý M et al. Aliskiren. Remedia 2008; 18: 266– 272.

20. Solomon SD, Appelbaum E, Manning WJ et al. Effect of direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation 2009: 119: 530– 537.

21. Ingelfinger JR. Aliskiren and dual therapy in type 2 diabetes mellitus. NEJM 2008; 358: 2503– 2505.

22. Uresin Y, Taylor A, Kilo C et al. Aliskiren, a novel renin inhibitor, has greater BP lowering than ramipril and additional BP lowering when combined with ramipril in patients with diabetes and hypertension. J Hypertens 2006; 24 (Suppl 4): S82.

23. Duprez D, Davis P, Botha J. The AGELESS Study: The effect of aliskiren vs ramipril alone or in combination with hydrochlorothiazide and amlodipine in patients > 65 years of age with systolic hypertension. Presented at the American Association Scientific Session 2008: 11th November 2008.

24. Oparil S, Yarrows S, Pater S et al. The direct renin inhibitor aliskiren in combination with valsartan provides additional blood pressure‑lowering effects compared with either agent alone in patients with hypertension. J Clin Hypertens 2007; 9 (Suppl A): A174.

25. Gradman AH, Schmieder RE, Lins RL et al. Aliskiren, a novel orally effective renin inhibitor, provides dose‑dependent antihypertensive efficacy and placebo like tolerability in hypertensive patients. Circulation 2005; 111: 1012– 1018.

26. Horký K. Představuje inhibitor reninu aliskiren nové výhledové možnosti v léčbě kardiovaskulárních onemocnění? Vnitř Lék 2007; 53: 364– 370.