Men and women > 18 yrs of age, stage 1 to 2 essential HTN (mean sitting DBP > 95 mm Hg to < 110 mm Hg) were eligible for enrollment; patients with DBP > 90 mm Hg by 8hr daytime ABPM at end of run-in phase were eligible for randomization
Exclusion criteria
History of severe CV or cerebrovascular disease; other life-threatening medical condition; patients with sitting DBP > 110 mm Hg or SBP > 180 mm Hg at any time during the study were withdrawn
Endpoints
Primary: antihypertensive efficacy (change in mean trough sitting DBP at end of study vs. baseline) of 300 mg aliskiren and 320 mg valsartan vs. combination aliskiren/valsartan 300/320 mg
Secondary: change in mean trough sitting SBP at end of study vs. baseline; proportion responding to Tx (mean sitting DBP < 90 mm Hg or > 10 mm Hg decrease in DBP); BP control (mean sitting DBP < 90 mm Hg and SBP < 140 mm Hg); change from baseline in 24hr ABPM; PRA, RC, PAC
Other: Change in DBP and SBP at 4 wks; safety and tolerability (AEs, hematology, blood chemistry, urine, VS, physical condition, weight)
Wash-out Phase
W/D HTN Rx; 1-2 wk wash-out
Run-in phase
3-4 wk SB placebo
Treatment phase
Randomized to placebo, aliskiren monotherapy (150 mg), valsartan monotherapy (160 mg), or combination aliskiren and valsartan (150/160 mg) once daily for 4 wks; doses were then doubled for an additional 4 wks Tx
Baseline (mean): age 51.9-52.6yrs; 61% male; 75% White, 16% Black; mean sitting SBP/DBP 152.8+12.2-154.2+12.7/100.1+4.0-100.4+4.2 mm Hg
Tx
n
DBP*
P
SBP
Placebo
455
-4.1
-4.6
Aliskiren
300 mg/d
430
-9.0
<0.0001
-13.0
Valsartan
320 mg/d
453
-9.7
<0.0001
-12.8
Aliskiren/Valsartan
300/320 mg/d
438
-12.2
<0.0001
-17.2
* Primary endpoint: change from baseline in mean trough sitting DBP (mm Hg); P value vs. placebo; P< 0.0001 for aliskiren/valsartan vs. each component as monotherapy)
Tx
Response*
Control*
Placebo
30%
16%
Aliskiren
300 mg/d
53%
37%
Valsartan
320 mg/d
55%
34%
Aliskiren/Valsartan
300/320 mg/d
66%
49%
* Response: percent of patients with mean sitting DBP < 90 mm Hg or > 10 mm Hg decrease in DBP; BP control: mean sitting DBP < 90 mm Hg and SBP < 140 mm Hg
ABPM (n=354): Combination significantly more effective than either monotherapy (P<0.0001); each monotherapy significantly more effective than placebo (P<0.0001)
PRA: Aliskiren significantly decreased PRA and valsartan significantly increased PRA from baseline compared to placebo; aliskiren/valsartan combination significantly reduced PRA vs. placebo
RC: Aliskiren/valsartan significantly increased RC vs. baseline compared to placebo, as did aliskiren and valsartan alone
PAC: Aliskiren/valsartan significantly reduced PAC vs. baseline compared to placebo, as did valsartan alone; aliskiren monotherapy did not significantly affect PAC
Wk 4 Endpoint: Combination significantly more effective (DBP and SBP) than either monotherapy or placebo (P<0.0001 for all except DBP combination vs. valsartan P=0.004); each monotherapy significantly more effective (DBP and SBP) than placebo (P<0.0001)
Study Conclusions
Short-term treatment (8 weeks) with the combination of aliskiren 300 mg and valsartan 320 mg once daily significantly reduced mean sitting DBP from baseline compared to either monotherapy or placebo in patients with mild to moderate HTN, with safety and tolerability similar to placebo
Completed Trial (ITT Analysis)
Aliskiren: 430/437 (98.4%)
Valsartan: 453/455 (99.6%)
Aliskiren/Valsartan: 438/446 (98.2%)
Placebo: 455/459 (99.1%)
Adverse Events
Serious AEs: aliskiren (n=8; 1 death due to MI); valsartan (n=6; 1 sudden death due to arteriosclerosis); aliskiren/valsartan (n=3); placebo (n=5)
Tx
W/D AE
Total AE
Placebo
3.4%
37%
Aliskiren
300 mg
1.7%
34%
Valsartan
320 mg
5.0%
37%
Aliskiren/Valsartan
300/320 mg
3.4%
35%
Most common AEs included HA (3% aliskiren vs. 5% valsartan, 4% aliskiren/valsartan, 9% placebo), nasopharyngitis (4% aliskiren vs. 4% valsartan, 3% aliskiren/valsartan, 2% placebo), dizziness (2% aliskiren vs. 2% valsartan, 2% aliskiren/valsartan, 2% placebo)
Men and women > 18 yrs of age, mild to moderate essential HTN (mean sitting DBP > 95 mm Hg and < 10 mm Hg difference between last 2 measurements of 3-4 wk placebo run-in)
Exclusion criteria
Severe HTN (sitting DBP > 110 mm Hg or SBP > 180 mm Hg); secondary HTN; type 1 DM or type 2 DM with HbA1c > 8%; pregnancy or breastfeeding; history of severe cardiac or cerebrovascular disease; history of severe or 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 75 mg, 150 mg, 300 mg aliskiren vs. placebo
Secondary: change in mean trough sitting SBP at end of study vs. baseline; efficacy of aliskiren/valsartan combination vs. respective monotherapy and with valsartan/HCTZ combination
Other: proportion responding to Tx (mean sitting DBP < 90 mm Hg or > 10 mm Hg decrease in DBP); BP control (mean sitting DBP < 90 mm Hg and SBP < 140 mm Hg); dose response relationship; safety and tolerability (duration/severity of AEs, relation to study drug)
Wash-out Phase
W/D HTN Rx
Run-in phase
3-4 wk SB placebo
Treatment phase
Randomized to placebo, aliskiren monotherapy (75 mg, 150 mg, 300 mg), valsartan (80 mg, 160 mg, 320 mg), combination aliskiren and valsartan (75/80 mg, 150/160 mg, 300/320 mg), or combination valsartan and HCTZ (160/12.5 mg) once daily at 8:00am (without regard to meals) except on day of study visit
Baseline (mean): age 56.1+12.2yrs; 55.9% male; 92.1% Caucasian; trough mean sitting SBP/DBP 152.4+12.58-154.5+10.57/98.6+3.01-99.4+3.78 mm Hg
Tx
n
DBP*
P
SBP
Placebo
176
-8.6+0.62
-10.0+0.96
Aliskiren
75 mg/d
177
-10.3+0.62
-12.1+0.96
150 mg/d
177
-10.3+0.62
-12.1+0.95
300 mg/d
175
-12.3+0.62
<0.001
-15.0+0.96
Valsartan
80 mg/d
58
-10.5+1.07
-11.2+1.65
160 mg/d
58
-11.0+1.07
<0.05
-15.5+1.65
320 mg/d
60
-11.3+1.05
<0.05
-16.5+1.62
Aliskiren/Valsartan
75/80 mg/d
60
-11.8+1.05
<0.01
-14.5+1.62
150/160 mg/d
60
-12.1+1.05
<0.01
-16.6+1.62
300/320 mg/d
58
-12.9+1.07
<0.001
-18.0+1.65
Valsartan/HCTZ
160/12.5 mg/d
58
-13.5+1.07
<0.001
-18.9+1.65
* Primary endpoint: change from baseline in mean trough sitting DBP (mm Hg) + SEM; P value for placebo-corrected change (<0.001 vs. placebo; < 0.05 and < 0.01 vs. aliskiren 150 mg)
Tx
Response*
Control*
Placebo
48.3%
27.8%
Aliskiren
75 mg/d
59.9%
36.2%
150 mg/d
59.3%
30.5%
300 mg/d
68.0%
42.3%
Valsartan
80 mg/d
55.2%
37.9%
160 mg/d
65.5%
46.6%
320 mg/d
63.3%
41.7%
Aliskiren/Valsartan
75/80 mg/d
75.0%
43.3%
150/160 mg/d
66.7%
36.7%
300/320 mg/d
75.9%
50.0%
Valsartan/HCTZ
160/12.5 mg/d
79.3%
55.2%
* Response: percent of patients with mean sitting DBP < 90 mm Hg or > 10 mm Hg decrease in DBP; BP control (mean sitting DBP < 90 mm Hg and SBP < 140 mm Hg)
Dose Response (DBP): Demonstrated with aliskiren 75 mg to 300 mg
Study Conclusions
Short-term treatment (8 weeks) with aliskiren 300 mg once daily significantly reduced mean sitting DBP compared to placebo in patients with mild to moderate HTN, with safety and tolerability similar to placebo; there was a slight reduction in DBP with combination therapy compared to the respective monotherapy components of aliskiren and valsartan
Serious AEs: 0.7% (n=8 overall); 1 death reported (placebo)
Tx
W/D AE
Total AE
Placebo
3.4%
32.2%
Aliskiren
75 mg
2.8%
35.2%
150 mg
1.7%
33.1%
300 mg
1.7%
28.6%
Valsartan
80 mg
0%
32.8%
160 mg
3.4%
28.8%
320 mg
5.0%
30.0%
Aliskiren/Valsartan
75/80 mg
0%
33.3%
150/160 mg
1.7%
26.7%
300/320 mg
3.4%
31.0%
Valsartan/HCTZ
160/12.5 mg
0%
22.0%
Most common AEs included HA (4.0-8.4% aliskiren vs. 3.4-5.2% valsartan, 8.5% placebo), fatigue (2.2-3.9% aliskiren vs. 0-6.8% valsartan, 2.3% placebo), back pain (1.1-2.2% aliskiren vs. 0-5.0% valsartan, 1.1% placebo), diarrhea (0.6-2.9% aliskiren vs. 0-1.7% valsartan, 1.7% placebo)