Pbm-map drug Monograph: Aliskiren




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AC=active-comparator; ABPM=ambulatory blood pressure monitoring; AE=adverse event; BP=blood pressure; CAD=coronary artery disease; CV=cardiovascular; d=day; DB=double-blind; DBP=diastolic blood pressure; DM=diabetes mellitus; ECG=electrocardiogram; GI=gastrointestinal; HA=headache; hr=hours; HTN=hypertension; ITT=intention to treat population; LV=left ventricular; min=minutes; n=number of patients; NR=not reported; PC=placebo-controlled; PG=parallel group; PRA=plasma renin activity; pt=patient; R=randomized; Rx=medication; SB=single-blind; SBP=systolic blood pressure; TPR=trough-to-peak ratio; Tx=treatment; W/D=withdrawal; wk=week; yrs=years


Appendix 3: Evidence Table (Monotherapy and Combination Therapy Parallel Group Trials)

Trial

Inclusion/Exclusion

Endpoints/Treatment

Results/Conclusions

Withdrawals/AEs


Oparil et al, 20078
MC, R, DB, PC, PG
Germany, Spain, U.S.
n=1797; 1776 (ITT)

8 wks


Funded by Novartis Pharmaceutical Corporation

Inclusion criteria

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 180 mm Hg at any time during the study were withdrawn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)

Abnormal labs: sCr > 176.8 micromo/L (n=1, aliskiren; n=2, valsartan; n=4, aliskiren/valsartan; n=0, placebo); K+ > 5.5 mEq/L (n=7, aliskiren; n=7, valsartan; n=18, aliskiren/valsartan; n=12, placebo); K+ > 6.0 mEq/L (n=4, aliskiren; n=5, valsartan; n=2, aliskiren/valsartan; n=6, placebo)




Pool et al, 200713
MC, R, DB, PC, PG
Denmark, France, Germany, Poland, U.S.
n=1123

8 wks


Supported by Novartis Pharma AG

Inclusion criteria

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



Completed Trial (ITT Analysis)

Aliskiren: 75 mg, 177/179 (98.9%); 150 mg, 177/178 (99.4%); 300 mg, 175/175 (100%)

Valsartan: 80 mg, 58/58 (100%); 160 mg, 58/59 (98.3%); 320 mg, 60/60 (100%)

Aliskiren/Valsartan: 75/80 mg, 60/60 (100%); 150/160 mg, 60/60 (100%); 300/320 mg, 58/58 (100%)

Valsartan/HCTZ: 160/12.5 mg, 58/59 (98.3%)

Placebo: 176/177 (99.4%)
Adverse Events

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)

Abnormal labs: sCr > 2 mg/dL (n=1, aliskiren 75 mg); K+ > 5.5 mEq/L (n=1, placebo; n=1, aliskiren 75 mg; n=1, aliskiren 300 mg; n=1, aliskiren/valsartan 150/160 mg; n=1, aliskiren/valsartan 300/320 mg)



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