Pbm-map drug Monograph: Aliskiren




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Conclusions

In published, randomized, controlled clinical trials, treatment with aliskiren has been shown to reduce blood pressure when used as monotherapy and in combination with hydrochlorothiazide or valsartan in patients with mild to moderate HTN. In addition, the efficacy of aliskiren has been compared to treatment with an ARB, with comparable reductions in blood pressure. It is unknown if there is a therapeutic advantage of treatment with a direct renin inhibitor such as aliskiren, and the influence on plasma renin activity and renin concentration, compared to treatment with an ACEI or ARB. Combination therapy with aliskiren and an ARB or an ACEI has not been adequately studied in long-term clinical trials.


There are limited data on the long-term efficacy and tolerability of aliskiren in patients with HTN. The sustained efficacy of aliskiren was demonstrated in two unpublished trials; one open-label trial of 12 months and one randomized, active-controlled trial of 26 weeks duration in patients with essential HTN. The long-term effects of treatment with aliskiren on morbidity and mortality have yet to be established; as does the effect of aliskiren on outcomes in patients with other conditions such as heart failure, myocardial infarction, DM, or kidney disease.
Treatment with aliskiren was well-tolerated with the most frequently occurring adverse events including headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain, and cough. Complaints of cough were reported to be one third to one half that of treatment with an ACEI. There have been reports of angioedema with aliskiren but how this compares to treatment with an ACEI or ARB, or whether patients who previously experienced angioedema on an ACEI or ARB would be more likely to develop angioedema with aliskiren, is unknown at this time.

Recommendations for Place in Therapy

A thiazide-type diuretic is recommended as initial therapy, either as monotherapy or in combination with other antihypertensive agents, in patients with uncomplicated HTN. Therapy with other antihypertensive drug classes may be considered in patients who are inadequately controlled or have a compelling indication for another drug class (http://www.oqp.med.va.gov/cpg/HTN04/HTN_base.htm). As the long-term effects on morbidity and mortality of aliskiren has yet to be established, it is recommended that aliskiren be reserved for patients with HTN who do not tolerate or are not controlled on antihypertensive medications within the drug classes currently recommended as initial or alternative/supplemental therapy per the VHA/DoD national clinical practice guidelines for the treatment of HTN, that are available on the VA National Formulary (http://www.pbm.va.gov/NationalFormulary.aspx).


References





  1. Tekturna® (aliskiren) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2007 Mar.

  2. Novartis US Clinical Development and Medical Affairs. Submission of clinical and economic data supporting formulary consideration of: Tekturna® (aliskiren). Formulary Submission Dossier. March 16, 2007:1-175.

  3. Chobanian AV, Bakris GL, Black HR, et al. for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560-72.

  4. Diagnosis and Management of Hypertension in the Primary Care Setting. Washington, DC: VA/DoD Evidence-Based Clinical Practice Guideline Working Group, Veterans Health Administration, Department of Veterans Affairs , and Health Affairs, Department of Defense, November 1999. Office of Quality and Performance publication 10Q-CPG/HTN-99. (Update 2004). Office of Quality and Performance publication 10Q-CPG/HTN-04. Available at www.oqp.med.va.gov.

  5. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97.

  6. Lindholm LH, Carlberg B, Samuelsson O. Should  blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545-53.

  7. Strasser RH, Puig JG, Farsang C, Croket M, Li J, van Ingen H. A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension. J Hum Hypertens 2007; advance online publication, May 31, 2007 doi:10.1038/sj.jhh.1002220:1-8.

  8. Oparil S, Yarows SA, Patel S, Fang H, Zhang H, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007;370:221-9.

  9. 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;49:1157-63.

  10. Kushiro T, Itakura H, Abo Y, Gotou H, Terao S, Keefe DL. Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens Res 2006;29:997-1005.

  11. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012-8.

  12. Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003;42:1137-43.

  13. Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy and alone and in combination with valsartan. Am J Hypertens 2007;20:11-20.

  14. Villamil A, Chrysant SG, Calhoun D, Schober B, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007;25:217-26.

Contact person: Elaine M. Furmaga, PharmD, Clinical Pharmacy Specialist, VACO PBM Service



Appendix 1: Evidence Table (Placebo-controlled Monotherapy Trials)

Trial

Inclusion/Exclusion

Endpoints/Treatment

Results/Conclusions

Withdrawals/AEs


Oh et al, 20079
MC, R, DB, PC, DR
Korea, U.S.
n=672 (safety); 662 (ITT)
8 wks tx; 2 wks W/D

Supported by Novartis



Inclusion Criteria

Men and women > 18 yrs of age, essential HTN, mean sitting DBP > 95 mm Hg and < 110 mm Hg



Exclusion Criteria

Severe HTN (sitting DBP > 110 mm Hg); secondary HTN; serious cardiac or cerebrovascular disease;

type 1 DM or type 2 DM with HbA1c > 9%; any condition with potential to affect pharmacokinetics of the drug


Endpoints

Primary: antihypertensive efficacy (change in mean trough sitting DBP at end of study vs. baseline) of 150 mg, 300 mg, and 600 mg aliskiren vs. placebo

Secondary: change in mean trough sitting SBP at end of study vs. baseline; proportion responding to Tx (mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP vs. baseline) or BP control (BP < 140/90 mm Hg); 24-hr ABPM profiles (pt subset); TPR; dose response relationship; effects on PRA and RC (pt subset); safety and tolerability; effect of Tx W/D on BP, PRA, and RC
Wash-out Phase

W/D HTN Rx; 2 wk wash-out



Run-in Phase

2-4 wk SB placebo



Treatment Phase

Randomized to placebo or aliskiren 150 mg, 300 mg, or 600 mg once daily at ~ 8:00am for 8 wks (drug taken after evaluation on study visits)



Run-out Phase

2 wk W/D



Baseline (safety population): mean age 53yrs; 61.3% Caucasian; 61.6% male; mean sitting SBP/DBP 152.1/99.6 mm Hg


Tx

DBP*

P

SBP

Placebo

-4.9+0.64




-3.8+1.02

Aliskiren








150 mg/d

-10.3+0.63

<0.0001

-13.0+1.01

300 mg/d

-11.1+0.64

<0.0001

-14.7+1.02

600 mg/d

-12.5+0.64

<0.0001

-15.8+1.02
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