Dual blockade of the renin-angiotensin-aldosterone system: Beyond the ACE inhibitor and angiotensin-II receptor blocker combination

American Journal of Hypertension

Volumn 22, Issue 10, 2009, Pages 1032-1040

  Bomback, Andrew S ^a   Toto, Robert ^b  

^a Columbia University College of Physicians and Surgeons ^*  (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDOSTERONE; ALISKIREN; AMLODIPINE; ANGIOTENSIN I; ANGIOTENSIN II; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTITHROMBOCYTIC AGENT; BENAZEPRIL; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; EPLERENONE; HYDROCHLOROTHIAZIDE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOSARTAN; PLACEBO; RAMIPRIL; RENIN; SPIRONOLACTONE; TELMISARTAN; VALSARTAN;

ACUTE KIDNEY FAILURE; ADD ON THERAPY; BLOOD PRESSURE REGULATION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHRONIC KIDNEY DISEASE; CLINICAL TRIAL; DIASTOLIC BLOOD PRESSURE; DRUG MEGADOSE; DRUG WITHDRAWAL; ELECTROLYTE BALANCE; FLUID BALANCE; HEART FAILURE; HEART INFARCTION; HEART LEFT VENTRICLE FAILURE; HUMAN; HYPERKALEMIA; HYPERTENSION; HYPOTENSION; KIDNEY DISEASE; KIDNEY DYSFUNCTION; KIDNEY FUNCTION; MONOTHERAPY; MORBIDITY; MORTALITY; OUTCOME ASSESSMENT; PLASMA RENIN ACTIVITY; PRIORITY JOURNAL; PROTEINURIA; RECOMMENDED DRUG DOSE; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; RISK REDUCTION; SINGLE DRUG DOSE; STROKE; SYNCOPE; SYSTOLIC BLOOD PRESSURE; UNSPECIFIED SIDE EFFECT;

ALDOSTERONE; AMIDES; ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANTIHYPERTENSIVE AGENTS; CARDIOVASCULAR DISEASES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG THERAPY, COMBINATION; FUMARATES; HUMANS; KIDNEY DISEASES; RECEPTORS, MINERALOCORTICOID; RENIN-ANGIOTENSIN SYSTEM;

EID: 70349440846     PISSN: 08957061     EISSN: None     Source Type: Journal    
DOI: 10.1038/ajh.2009.138     Document Type: Review

References (89)

1. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362:1527-1535.
2. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861-869. (Pubitemid 34940825)
3. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148:30-48.
4. Lewis EJ, Hunsicker LG, Bain R P, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456-1462.
5. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 2001; 135:73-87.
6. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-860.
7. Toto R, Palmer BF. Rationale for combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor treatment and end-organ protection in patients with chronic kidney disease. Am J Nephrol 2008; 28:372-380.
8. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep 2006; 8:409-412.
9. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC, Klein R. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009; 361:40-51.
10. Jorde U P, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, Hammer A, Sonnenblick EH, Le Jemtel TH. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000; 101: 844-846.
11. Forclaz A, Maillard M, Nussberger J, Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor? Hypertension 2003; 41:31-36.
12. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004; 66:1-9.
13. Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction. J R Soc Med 2001; 94:378-383. (Pubitemid 32738676)
14. Jensen C, Herold P, Brunner HR. Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov 2008; 7:399-410.
15. Wood JM, Maibaum J, Rahuel J, Grütter MG, Cohen NC, Rasetti V, Rüger H, Göschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P, Yamaguchi Y, Cumin F, Baum H P, Schnell CR, Herold P, Mah R, Jensen C, O'Brien E, Stanton A, Bedigian M P. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003; 308:698-705.
16. Fisher ND, Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 2005; 16:592-599.
17. Azizi M. Renin inhibition. Curr Opin Nephrol Hypertens 2006; 15:505-510.
18. Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006; 24:243-256.
19. Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998; 32:387-392.
20. Mooser V, Nussberger J, Juillerat L, Burnier M, Waeber B, Bidiville J, Pauly N, Brunner HR. Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol 1990; 15:276-282.
21. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000; 355: 637-645.
22. Rousseau MF, Gurné O, Duprez D, Van Mieghem W, Robert A, Ahn S, Galanti L, Ketelslegers JM. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J A m Coll Cardiol 2002; 40:1596-1601.
23. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, Parving HH. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006; 70:536-542.
24. van de Wal RM, Plokker HW, Lok DJ, Boomsma F, van der Horst FA, van Veldhuisen DJ, van Gilst WH, Voors AA. Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol 2006; 106:367-372.
25. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002; 39:E1-E8.
26. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293-302.
27. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:1429-1435.
28. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327:669-677.
29. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. 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 Med 2000; 342:145-153.
30. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362:772-776. (Pubitemid 37093917)
31. Maggioni A P, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002; 40:1414-1421.
32. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334:939-945.
33. Maillard M P, Würzner G, Nussberger J, Centeno C, Burnier M, Brunner HR. Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing. Clin Pharmacol Ther 2002; 71:68-76.
34. Juillerat L, Nussberger J, Ménard J, Mooser V, Christen Y, Waeber B, Graf P, Brunner HR. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 1990; 16:564-572. (Pubitemid 20368346)
35. Burgess E, Muirhead N, Rene de Cotret P, Chiu A, Pichette V, Tobe S. Supramaximal dose of candesartan in proteinuric renal disease. J Am Soc Nephrol 2009; 20: 893-900.
36. Schjoedt KJ, Astrup AS, Persson F, Frandsen E, Boomsma F, Rossing K, Tarnow L, Rossing P, Parving HH. Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 2009; 52:46-49.
37. Yu C, Gong R, Rifai A, Tolbert EM, Dworkin LD. Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection. J Am Soc Nephrol 2007; 18:750-759.
38. Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int 2005; 68:1190-1198.
39. Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R, Delles C. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol 2005; 16:3038-3045.
40. Berl T. Maximizing inhibition of the renin-angiotensin system with high doses of converting enzyme inhibitors or angiotensin receptor blockers. Nephrol Dial Transplant 2008; 23:2443-2447.
41. de Zeeuw D, Lambers-Heerspink H. Drug dosing for renoprotection: maybe it's time for a drug efficacy-safety score? J Am Soc Nephrol 2009; 20:688-689.
42. Hou F F, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, Guo ZJ, Jiang J P. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007; 18:1889-1898.
43. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni A P, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349:1893-1906. (Pubitemid 37409706)
44. Yusuf S, Teo S, Pogue KK, Dyal J, Copland L, Schumacher I, Dagenais H, Sleight G, Anderson P. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547-1559.
45. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100:1056-1064. (Pubitemid 29416231)
46. Latini R, Masson S, Wong M, Barlera S, Carretta E, Staszewsky L, Vago T, Maggioni A P, Anand IS, Tan LB, Tognoni G, Cohn JN. Incremental prognostic value of changes in B-type natriuretic peptide in heart failure. Am J Med 2006; 119:70.e23-70.e30.
47. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362: 767-771. (Pubitemid 37093916)
48. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667-1675.
49. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004; 141:693-704.
50. Phillips CO, Kashani A, Ko DK, Francis G, Krumholz HM. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007; 167:1930-1936.
51. Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail 2008; 14:181-188.
52. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006; 48:8-20.
53. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsärinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547-553.
54. Fried LF, Duckworth W, Zhang JH, O'Connor T, Brophy M, Emanuele N, Huang GD, McCullough PA, Palevsky PM, Seliger S, Warren SR, Peduzzi P. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy ( VA NEPHRON-D). Clin J Am Soc Nephrol 2009; 4:361-368.
55. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007; 3:486-492.
56. Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001; 29:13-21.
57. Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004; 47:1936-1939.
58. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003; 41:64-68.
59. Horita Y, Taura K, Taguchi T, Furusu A, Kohno S. Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton) 2006; 11:462-466.
60. Pitt B. "Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995; 9:145-149.
61. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709-717.
62. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309-1321.
63. Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, Ravid M. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study. Diabet Med 2004; 21:471-475.
64. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005; 28:2106-2112.
65. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, Parving HH. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005; 68:2829-2836.
66. van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, Boomsma F. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens 2006; 24:2285-2292.
67. Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1:256-262.
68. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006; 1: 940-951.
69. Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006; 70:2116-2123.
70. Tylicki L, Rutkowski P, Renke M, Larczynski W, Aleksandrowicz E, Lysiak-Szydlowska W, Rutkowski B. Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. Am J Kidney Dis 2008; 52:486-493.
71. Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N, Tsubakihara Y, Imai E, Shoji T. Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res 2008; 31:59-67.
72. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 2008; 51:199-211.
73. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351:543-551.
74. Bomback AS, Kshirsagar AV, Klemmer PJ. Renal aspirin: will all patients with chronic kidney disease one day take spironolactone? Nat Clin Pract Nephrol 2009; 5:74-75.
75. Brown MJ. Aliskiren. Circulation 2008; 118:773-784.
76. Azizi M, Ménard J, Bissery A, Guyenne T T, Bura-Rivière A, Vaidyanathan S, Camisasca R P. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol 2004; 15:3126-3133.
77. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007; 49:1157-1163.
78. Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003; 42:1137-1143.
79. Andersen K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens 2008; 26:589-599.
80. Villamil A, Chrysant SG, Calhoun D, Schober B, Hsu H, Matrisciano-Dimichino L, Zhang J. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007; 25:217-226.
81. Drummond W, Munger MA, Rafique Essop M, Maboudian M, Khan M, Keefe DL. Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy. J Clin Hypertens (Greenwich) 2007; 9:742-750.
82. Uresin Y, Taylor AA, Kilo C, Tschöpe D, Santonastaso M, Ibram G, Fang H, Satlin A. 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 Syst 2007; 8:190-198. (Pubitemid 351166266)
83. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370:221-229.
84. Sealey JE, Laragh JH. Aliskiren fails to lower blood pressure in patients who have either low PRA levels or whose PRA falls insufficiently or reactively rises. Am J Hypertens 2009; 22:112-121.
85. McMurray JJ, Pitt B, Latini R, Maggioni A P, Solomon SD, Keef DL, Ford J, Verma A, Lewsey J. Effect of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 2008; 1:17-24.
86. Solomon SD, Appelbaum E, Manning WJ, Verma A, Berglund T, Lukashevich V, Cherif Papst C, Smith BA, Dahlöf B. Effect of the 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.
87. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433-2446.
88. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Ghadanfar M, Weissbach N, Xiang Z, Armbrecht J, Pfeffer MA. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009; 24:1663-1671.
89. Egan BM, Basile JN, Rehman SU, Davis PB, Grob Iii CH, Riehle JF, Walters CA, Lackland DT, Merali C, Sealey JE, Laragh JH. Plasma renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial. Am J Hypertens 2009; 22:792-801.