Pbm-map drug Monograph: Aliskiren




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ABPM=ambulatory blood pressure monitoring; AE=adverse event; ALT=alanine aminotransferase; AMI=acute myocardial infarction; BP=blood pressure; CA=cancer; CI=confidence interval; d=day; DB=double-blind; DBP=diastolic blood pressure; DM=diabetes mellitus; DR=dose-ranging study; HA=headache; HTN=hypertension; ITT=intention to treat population; K+=potassium; OD=overdose; n=number of patients; NR=not reported; OR=odds ratio; PC=placebo-controlled; PRA=plasma renin activity; R=randomized; RC=renin concentration; Rx=medication; SB=single-blind; SBP=systolic blood pressure TPR=trough-to-peak ratio; Tx=treatment; WBC=white blood cell count; W/D=withdrawal; wk=week; yrs=years

Appendix 2: Evidence Table (Monotherapy with Active Comparator Trials)

Trial

Inclusion/Exclusion

Endpoints/Treatment

Results/Conclusions

Withdrawals/AEs


Gradmanet al, 200511
MC, R, DB, PC, PG, AC (irbesartan)
Europe, U.S.
n=652
8 wks

Supported by Novartis



Inclusion Criteria

Men and women > 18 yrs of age, mild to moderate essential HTN (mean sitting DBP > 95 mm Hg and < 110 mm Hg)


Exclusion Criteria

Severe HTN (sitting DBP > 110 mm Hg and/or SBP > 180 mm Hg); secondary HTN; type 1 DM or type 2 DM with HbA1c > 8%; history CV disease; history of malignancy or other life-threatening disease; any medical or surgical 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, 600 mg aliskiren vs. placebo

Other: antihypertensive efficacy (DBP) aliskiren vs. irbesartan and irbesartan vs. placebo; change in mean trough sitting SBP and at end of study vs. placebo; proportion responding to tx (mean trough sitting DBP < 90 mm Hg and SBP < 140 mm Hg); dose response relationship; TPR; effect of Tx W/D on BP; AEs (duration; severity; relation to study drug; outcome); compliance

Wash-out Phase

W/D HTN Rx; 2 wk wash-out



Run-in Phase

2-4 wk SB placebo



Treatment Phase

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



Run-out Phase

3-4 d W/D



Baseline (mean): age 55.0+12.5-57.1+12.0yrs; 50.2% male; 76.8%

Caucasian; mean sitting SBP/DBP 151.3+11.1-152.8+11.2/98.8 +3.4-99.4+4.0 mm Hg




Tx

n

DBP*

P

SBP

Placebo

130

-6.34+0.75




-5.29+1.23

Aliskiren











150 mg/d

127

-9.28+0.76

0.004

-11.36+1.25

300 mg/d

130

-11.77+0.75

<0.0001

-15.76+1.23

600 mg/d

129

-11.5+0.75

<0.0001

-15.73+1.23

Irbesartan













150 mg/d

133

-8.88+0.74




-12.50+1.21

* Primary endpoint: change from baseline in mean trough sitting DBP (mm Hg) + SEM; P value vs. placebo

Aliskiren 150 mg vs. irbesartan 150mg (DBP, SBP; NS); DBP aliskiren 300 mg (P=0.005) and 600 mg (P=0.01) vs. irbesartan 150 mg (SBP; NS)




Tx

Response*

P vs. Placebo

P vs. Irbesartan

Placebo

27/130 (20.8%)







Aliskiren










150 mg/d

48/127 (37.8%)

<0.05




300 mg/d

65/130 (50.0%)

<0.05

<0.05

600 mg/d

59/129 (45.7%)

<0.05

<0.05

Irbesartan










150 mg/d

45/133 (33.8%)







* Response: percent of patients with mean trough sitting DBP < 90 mm Hg and SBP < 140 mm Hg

Dose Response (DBP and SBP): Demonstrated with aliskiren 150 mg and 300 mg (P<0.001)

TPR (2, 4, 6 hr): Aliskiren 150 mg (0.69, 0.53, 0.63), 300 mg (0.94, 0.80, 0.74), 600 mg (0.92, 0.68, 0.78); irbesartan 150 mg (0.63, 0.51, 0.50)

Tx W/D (Wk 8.5 vs. baseline): Higher DBP and SBP for aliskiren 150 mg (35.6%), 300 mg (15.1%), 600 mg (22.2%), placebo (35.8%), and irbesartan 150 mg (30.8%)

Study Conclusions

Short-term treatment (8 weeks) with aliskiren 150 mg, 300 mg, and 600 mg once daily significantly reduced mean sitting DBP compared to placebo in patients with mild to moderate HTN, with similar BP reduction with aliskiren 150 mg vs. irbesartan 150 mg; safety and tolerability of aliskiren similar to irbesartan and placebo




ITT Analysis

Aliskiren: 150 mg, 127/127 (100%); 300 mg, 130/130 (100%); 600 mg, 129/130 (99.2%)

Placebo: 130/131 (99.2%)

Irbesartan: 150 mg 133/134 (99.3%)

Discontinued Tx (n=66): reported to be similar across Tx groups
Adverse Events

Serious AEs: Placebo (n=2: infective arthritis and gout; LV failure); irbesartan 150 mg (n=2: bipolar disorder; intervertebral disc protrusion); no deaths reported


Tx

W/D AE

Total AE

Placebo

2.3%

32.1%

Aliskiren







150 mg

3.9%

26.8%

300 mg

3.1%

36.2%

600 mg

2.3%

33.1%

Irbesartan







150 mg

2.2%

36.6%

All patients included in safety analysis

Most common AEs included HA (2.4-6.2% aliskiren vs. 5.3% placebo, 3.0% irbesartan), dizziness (n=19 all tx groups), diarrhea (n=16 all tx groups)





Stanton et al, 200312
MC, R, DB, PG, AC (losartan)
Ireland
n=226 (safety); 197 (ITT)
4 wks

Sponsored by Speedel Pharma AG



Inclusion Criteria

Men and women 21 to 70 yrs of age, mild to moderate HTN (off-Tx average SBP by ABPM > 140 mm Hg)


Exclusion Criteria

Unable to W/D medications for HTN; secondary or malignant HTN; DM; CAD; any medical or surgical condition with potential to affect pharmacokinetics of the drug





Endpoints

Primary: antihypertensive efficacy (change in daytime SBP by ABPM at end of study vs. baseline) of aliskiren 37.5 mg, 75 mg, 150 mg, 300 mg Other: antihypertensive efficacy of aliskiren vs. losartan; clinic sitting and standing BP; dose response relationship; aliskiren levels and PRA; AEs; compliance

Wash-out Phase

W/D HTN Rx; 1-4 wk wash-out



Treatment Phase

Randomized to aliskiren 37.5 mg, 75 mg, 150 mg, 300 mg, or losartan 100mg once daily 30 min before breakfast for 4 wks



Baseline (mean): age 50.7+10.9-55.9+8.9yrs; 66.0% male; mean daytime ABPM SBP/DBP 152.6+9.7-156.2+10.5/91.1+9.0-96.5+8.4 mm Hg


Tx

n

SBP*

SBP**

DBP**

Aliskiren










37.5 mg/d

39

-0.4+11.7

-4.3+17.8

-1.9+10.5

75 mg/d

41

-5.3+11.3

-4.1+16.9

-0.2+12.4

150 mg/d

41

-8.0+11.0

-10.0+17.0

-2.2+10.0

300 mg/d

47

-11.0+11.0

-11.8+14.9

-5.7+11.0

Losartan













100 mg/d

44

-10.9+13.8

-11.4+19.2

-5.5+10.7

* Primary endpoint: change from baseline in mean daytime SBP by ABPM (mm Hg) + SEM, P=0.0002 for dose-dependent analysis; reported significant reduction for 75 mg, 150 mg, 300 mg and losartan 100 mg; reported no significant difference with losartan 100 mg vs. aliskiren 75 mg, 150 mg, 300 mg

** Change from baseline in mean sitting BP (mm Hg) + SD


PRA vs. Baseline: PRA significantly reduced with all doses aliskiren (55-83%) vs. increased with losartan (110%)

Aliskiren Levels: Trough plasma concentrations increased with increasing doses aliskiren

Compliance (pill count): > 95% across Tx groups
Study Conclusions

Short-term treatment (4 weeks) with aliskiren 75 mg, 150 mg, and 300 mg once daily was effective in reducing mean SBP by ABPM in patients with mild to moderate HTN, with similar BP reduction vs. losartan 100 mg; treatment with aliskiren was well tolerated



Completed Trial (ITT Analysis)

Aliskiren: 37.5 mg, 39/45 (86.7%); 75 mg, 41/46 (89.1%); 150 mg, 41/44 (93.2%); 300 mg, 40/47 (85.1%)

Losartan: 100 mg 36/44 (81.8%)
Adverse Events

Serious AEs: Aliskiren 300 mg (n=2: chest tightness/ECG ischemic changes; collapsed/hypotensive); losartan 100 mg (n=1: death after ruptured left common iliac artery aneurysm)


Tx

W/D AE

Total AE

Aliskiren







37.5 mg (n=45)

4.4%

22%

75 mg (n=46)

6.5%

35%

150 mg (n=44)

0%

25%

300 mg (n=47)

6.4%

23%

Losartan







100 mg (n=44)

6.8%

32%

Most common AEs (n=NR) included fatigue or weakness, GI disorders, HA

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