Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the ‘escape’ phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete ‘upstream’ inhibition of the renin—angiotensin—aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13—17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.
Alderman, M.H., Madhavan, S., Ooi, W.L., Cohen, H., Sealey, J.E. and Laragh, J.H. ( 1991) Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med324: 1098-1104.
2.
Andersen, K., Weinberger, M.H., Egan, B., Constance, C.M., Ali, M.A., Jin, J. et al. (2008) Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens26: 589-599.
3.
Andersen, K., Weinberger, M.H., Egan, B., Constance, C.M., Ali, M.A., Jin, J. et al. (2007) Aliskiren-based therapy lowers blood pressure more effectively than ramipril-based therapy in patients with hypertension: a 6-month, randomized, double-blind trial. J Am Coll Cardiol49(Suppl A): A371.
Campbell, D.J., Woodward, M., Chalmers, J.P., Colman, S.A., Jenkins, A.J., Kemp, B.E. et al. (2005) Prediction of myocardial infarction by N-terminal-pro-B-type natriuretic peptide, C-reactive protein, and renin in subjects with cerebrovascular disease. Circulation112: 110-116.
6.
Carter, B.L., Ernst, M.E. and Cohen, J.D. ( 2004) Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension43: 4-9.
7.
Cohen, J. ( 1988) Statistical Power Analysis for the Behavioural Sciences , 2nd edn, Lawrence Erlbaum Associates : Hillsdale, NJ.
8.
Duprez, D.A., Davis, P. and Botha, J. ( 2008) The AGELESS study: The effect of aliskiren versus ramipril alone or in combination with hydrochlorothiazide and amlodipine in patients 65 years of age with systolic hypertension (abstract 4423). Circulation118: 886-887.
9.
Duprez, D.A., Munger, M.A., Botha, J., Keefe, D.L. and Charney, A.N. ( 2009) Aliskiren for geriatric lowering of systolic hypertension: a randomized controlled trial. J Hum Hypertens. Advance online publication 24 December 2009; doi: 10.1038/jhh.2009.107.
10.
Gradman, A.H., Schmieder, R.E., Lins, R.L., Nussberger, J., Chiang, Y. and Bedigian, M.P. ( 2005) Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation111: 1012-1018.
11.
Gregoire, G., Derderian, F. and Le Lorier, J. ( 1995) Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias?J Clin Epidemiol48: 159-163.
12.
Haynes, R.B., Wilczynski, N., McKibbon, K.A., Walker, C.J. and Sinclair, J.C. ( 1994) Developing optimal search strategies for detecting clinically sound studies in MEDLINE. J Am Med Inform Assoc1: 447-458.
13.
Julius, S., Kjeldsen, S.E., Weber, M., Brunner, H.R., Ekman, S., Hansson, L. et al. (2004) Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet363: 2022-2031.
14.
McAuley, L., Pham, B., Tugwell, P. and Moher, D. ( 2000) Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? Lancet356: 1228-1231.
15.
McMurray, J.J.V., Pitt, B., Latini, R., Maggioni, A.P., Solomon, S.D., Keefe, D.L. et al. (2008) Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail1: 17-24.
16.
Meisel, S., Shamiss, A. and Rosenthal, T. ( 1994) Clinical pharmacokinetics of ramipril. Clin Pharmacokinet26: 7-15.
17.
Oparil, S., Yarows, S.A., Patel, S., Fang, H., Zhang, J. and Satlin, A. ( 2007) Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet370: 221-229.
18.
Palatini, P., Jung, W., Shlyakhto, E., Botha, J., Bush, C. and Keefe, D.L.(2010) Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study. J Hum Hypertens24: 93-103.
19.
Parving, H.H., Persson, F., Lewis, J.B., Lewis, E.J. and Hollenberg, N.K. ( 2008) Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med358: 2433-2446.
20.
Sever, P.S., Gradman, A.H. and Azizi, M.(2009) Managing cardiovascular and renal risk: the potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst10: 65-76.
21.
Solomon, S.D. ( 2008) Effect of the direct renin inhibitor aliskiren, either alone or in combination with losartan, compared to losartan, on left ventricular mass in patients with hypertension and left ventricular hypertrophy: the Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY) trial. In: Proceedings of the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March-April 2008.
22.
Staessen, J.A., Li, Y. and Richart, T. ( 2006) Oral renin inhibitors. Lancet368: 1449-1456.
23.
Staessen, J.A., Wang, J.G. and Thijs, L. ( 2001) Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet358: 1305-1315.
24.
Stanton, A., Jensen, C., Nussberger, J. and O’Brien, E. ( 2003) Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension42: 1137-1143.
25.
Strasser, R.H., Puig, J.G., Farsang, C., Croket, M., Li, J. and van Ingen, H. ( 2007) A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension. J Hum Hypertens21: 780-787.
26.
Turnbull, F. ( 2003) Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet362: 1527-1535.
27.
Urata, H., Kinoshita, A., Misono, K.S., Bumpus, F.M. and Husain, A. ( 1990) Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem265: 22348-22357.
28.
Uresin, Y., Taylor, A., Kilo, C., Tschöpe, D., Santonastaso, M., Ibram, G. et al. (2006) 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 Hypertens24(Suppl 4): 82.
29.
Uresin, Y., Taylor, A.A., Kilo, C., Tschope, D., Santonastaso, M., Ibram, G. et al. (2007) Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst8: 190-198.
30.
van de Wal, R.M., Plokker, H.W., Lok, D.J., Boomsma, F., van der Horst, F.A., van Veldhuisen, D.J. et al. (2006) Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol106: 367-372.
31.
Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G. and Reboldi, G. ( 2008) The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manag4: 971-981.
32.
Verdecchia, P., Staessen, J.A., Angeli, F., de Simone, G., Achilli, A., Ganau, A. et al. (2009) Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trialLancet374: 525-533.
33.
Villamil, A., Chrysant, S.G., Calhoun, D., Schober, B., Hsu, H., Matrisciano-Dimichino, L. et al. (2007) Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide . J Hypertens25: 217-226.
34.
Vrijens, B., Vincze, G., Kristanto, P., Urquhart, J. and Burnier, M. ( 2008) Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ336: 1114-1117.
35.
Weir, M., Bush, C., Zhang, J., Keefe, D. and Satlin, A. ( 2006) Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Eur Heart J27(Suppl): 299.
36.
Wood, J.M., Schnell, C.R., Cumin, F., Menard, J. and Webb, R.L. ( 2005) Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. J Hypertens23: 417-426.
37.
Yusuf, S., Sleight, P., Pogue, J., Bosch, J., Davies, R. and Dagenais, G. ( 2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med342: 145-153.
38.
Zhao, C., Vaidyanathan, S., Yeh, C.M., Maboudian, M. and Armin Dieterich, H. ( 2006) Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus. Clin Pharmacokinet45: 1125-1134.
