Pbm-map drug Monograph: Aliskiren




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Efficacy Measures8-14




Primary Endpoints


  • Change from baseline in mean trough sitting diastolic BP (DBP) with aliskiren vs. placebo (5 trials)9-11,13,14 and/or vs. combination therapy including aliskiren (2 trials)8,14

  • Change from baseline in daytime systolic BP (SBP) by ambulatory blood pressure monitoring (ABPM) (1 trial)12

Secondary and Other Endpoints


  • Change from baseline in mean trough sitting SBP with aliskiren vs. placebo, active comparator, or combination therapy including aliskiren

  • Proportion responding to treatment (mean sitting DBP < 90 mm Hg and/or > 10 mm Hg decrease in DBP vs. baseline; mean trough sitting DBP < 90 mm Hg and SBP < 140 mm Hg)

  • BP control (< 140/90 mm Hg)

  • Change from baseline in 24-hr ABPM

  • Dose response relationship

  • Effect of treatment withdrawal on BP

  • Aliskiren levels; effects on PRA and renin concentrations; plasma aldosterone concentrations

  • Trough-to-peak ratio

  • Safety and tolerability

  • Adherence



Clinical Trial Data7-14

The efficacy of aliskiren in reducing blood pressure in patients with mild to moderate HTN has been compared to placebo,9-11 other antihypertensive medications (e.g., irbesartan,11 losartan,12 valsartan,8,13 hydrochlorothiazide14), and in combination with other antihypertensive agents (e.g., valsartan,8,13 hydrochlorothiazide14) in published, randomized controlled trials of 4 to 13 weeks duration (Refer to Appendices 1 to 3 for details). The change in mean trough sitting DBP at the end of the study compared to baseline was the primary endpoint in all these trials8-11,13,14 except for one that evaluated the change in daytime SBP by ABPM at the end of the study vs. baseline.12




Monotherapy and Active Controlled Trials: Results of the primary endpoint (i.e., change from baseline in mean trough sitting DBP) as reported for the approved doses of aliskiren (i.e., 150 mg and 300 mg) in six published randomized controlled trials8-11,13,14 are compiled for comparison below. Treatment with aliskiren 150 mg and 300 mg produced a statistically significant reduction from baseline in mean trough sitting DBP compared to placebo.8-11,13,14 Trials including an active comparator also demonstrated a statistically significant reduction in DBP compared to placebo. In addition, an evaluation of BP reduction (DBP unless otherwise specified) with aliskiren at the approved doses of 150 mg and 300 mg and the active comparator obtained the following results (where NS=no statistically significant difference; > refers to a greater BP reduction that was statistically significant): aliskiren 150 mg vs. irbesartan 150 mg (NS);11 aliskiren 300 mg > irbesartan 150 mg;11 aliskiren 150 mg and 300 mg vs. losartan 100 mg (NS; daytime SBP by ABPM);12 valsartan 160 mg and 320 mg > aliskiren 150 mg.14

Trial

n

Aliskiren 150 mg

Aliskiren 300 mg

Placebo

Active Comparator

Oh et al9

662

-10.3+0.63

-11.1+0.64

-4.9+0.64

NA

Kushiro et al10

455

-7.75+0.76

-10.72+0.75

-3.26+0.75

NA

Gradman et al11

652

-9.28+0.76

-11.77+0.75

-6.34+0.75

-8.88+0.74 (irbesartan 150 mg)

Oparil et al8

1776

NA

-9.0

-4.1

-9.7 (valsartan 320 mg)

Pool et al13

1123

-10.3+0.62

-12.3+0.62

-8.6+0.62

-10.5+1.07; -11.0+1.07; -11.3+1.05

(valsartan 80 mg; 160 mg; 320 mg)

Villamil et al14

2752

-8.9+0.59

-10.3+0.60

-6.9

-9.1+0.58; -10.1+0.59; -9.4+0.61


(hydrochlorothiazide 6.25 mg; 12.5 mg; 25 mg)

Results of primary endpoint: change from baseline in mean trough sitting DBP (mm Hg) + SEM (when available)



Combination Therapy: One study that evaluated the effect of aliskiren alone (75 mg, 150 mg, 300 mg) and in combination with hydrochlorothiazide (6.25 mg, 12.5 mg, 25 mg) in 2,752 patients with HTN reported a greater reduction in DBP with combination therapy compared to treatment with either agent alone at 8 weeks (there was a significant reduction with all combination therapies compared to either monotherapy except for aliskiren/hydrochlorothiazide 150/6.25 mg and 75/12.5 mg).14 Results of another 8 week trial of 1,776 patients with HTN receiving aliskiren 150 mg (titrated after 4 weeks to 300 mg) or valsartan 160 mg (titrated after 4 weeks to 320 mg) compared to the combination, demonstrated that combination therapy was more effective at lowering blood pressure than either agent alone.8 In an 8 week trial evaluating the combination of aliskiren and valsartan, there was a small numeric reduction in DBP with combination therapy compared to the respective monotherapy components of aliskiren and valsartan, that was statistically significant for aliskiren/valsartan 150/160mg compared to aliskiren 150 mg alone.13

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