National PBM Drug Monograph

**Aliskiren (Tekturna^®^)**

###### VA Pharmacy Benefits Management Service and the Medical Advisory Panel 

# *The purpose of VACO PBM-MAP drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.*

# [Executive Summary]{.underline}

-   **Indications:** Aliskiren (Tekturna^®^), a direct renin inhibitor,
    was approved by the FDA for the treatment of patients with
    hypertension (HTN).

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-   **Efficacy:** Treatment with aliskiren in published placebo and/or
    active-controlled trials of 4 to 13 weeks duration demonstrated a
    reduction in the primary endpoint of mean trough sitting diastolic
    blood pressure (DBP) in patients with mild to moderate essential
    HTN. Statistically significant reductions in DBP
    (placebo-subtracted) ranged from 2.0 to 5.4 mm Hg for aliskiren 150
    mg and 3.4 to 7.5 mm Hg with aliskiren 300 mg once daily. Reductions
    in systolic blood pressures (SBP) of 2.1 to 9.2 mm Hg and 5.0 to
    11.2 mm Hg were seen in patients receiving aliskiren 150 mg and
    300mg, respectively. In the aliskiren treatment groups,
    approximately 31-36% of patients receiving aliskiren 150 mg and 37
    to 42% of patients on 300 mg achieved blood pressure control
    (defined as BP \< 140/90 mm Hg) compared to 16 to 28% of patients in
    the placebo groups. In addition, it was reported that 38 to 59% and
    50 to 68% of patients responded to treatment (i.e., DBP \< 90 mm Hg
    and/or [\>]{.underline} 10 mm Hg reduction) with aliskiren 150 mg
    and 300 mg, respectively; these results compared to 21 to 48% of
    patients receiving placebo. In trials that included an active
    comparator, there was not a significant difference in DBP reduction
    with aliskiren 150 mg and irbesartan 150 mg (although the difference
    between aliskiren 300 mg and irbesartan 150 mg was significant), or
    with aliskiren 150 mg or 300 mg compared to losartan 100 mg. There
    was a slightly greater reduction in DBP with valsartan 160 mg and
    320 mg compared with aliskiren 150 mg that was statistically
    significant. The majority of combinations with aliskiren and
    hydrochlorothiazide were found to provide a significantly greater
    reduction in DBP compared to the respective monotherapy components.
    Combination therapy with aliskiren and valsartan was more effective
    at lowering blood pressure compared to treatment with either agent
    alone.

-   **Safety:** Aliskiren is generally well-tolerated. Discontinuation
    due to an adverse event was reported in 2.2% of patients receiving
    aliskiren compared to 3.5% on placebo. Angioedema has rarely been
    reported in patients receiving treatment with aliskiren. Symptomatic
    hypotension may occur in patients who may be sodium or volume
    depleted (e.g., in patients receiving diuretic therapy) upon initial
    therapy with aliskiren. It is recommended to correct the volume
    depletion prior to starting aliskiren; otherwise therapy should be
    initiated under close medical supervision. The most frequently
    occurring adverse events (reported in \> 1% of patients receiving
    aliskiren with similar or greater incidence in patients on placebo)
    included headache, nasopharyngitis, dizziness, fatigue, upper
    respiratory tract infection, back pain, and cough. One clinical
    trial comparing the tolerability of aliskiren and an
    angiotensin-converting enzyme inhibitor (ACEI) reported that cough
    occurred in 0.8% of patients on aliskiren compared to 1.7% of
    patients receiving lisinopril. As with the ACEIs and angiotensin II
    receptor antagonists (ARBs), product information for aliskiren
    contains a boxed warning for use in pregnancy. Administration of
    medications that act at the renin-angiotensin-aldosterone system
    (RAAS) during pregnancy has resulted in neonatal morbidity and
    mortality; therefore, aliskiren should be discontinued as soon as
    possible after a patient becomes pregnant.

-   **Laboratory Monitoring:** Since aliskiren acts at the RAAS,
    recommendations for monitoring serum potassium and kidney function
    should be similar as with other agents acting on the RAAS (e.g.,
    ACEIs, ARBs, aldosterone antagonists). The frequency of routine
    monitoring should take into consideration the patient's concomitant
    therapy and comorbid conditions. It is recommended that electrolytes
    and kidney function be routinely monitored in patients with diabetes
    mellitus receiving concomitant treatment with an ACEI due to an
    increase in serum potassium. In clinical trials of patients with
    essential hypertension, reports of increased potassium, blood urea
    nitrogen, and serum creatinine were similar to placebo. In addition,
    published results of comparison trials of aliskiren and an ACEI or
    ARB reported that blood chemistry levels remained normal in the
    majority of patients.

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-   **Dose:** The initial recommended total daily dose of aliskiren is
    150 mg administered once daily. The dose may be increased to 300 mg
    once daily after two weeks if the blood pressure goal is not
    achieved. Doses greater than 300 mg once daily did not provide
    additional blood pressure reduction but did increase the frequency
    of diarrhea. It is recommended that aliskiren be administered at a
    consistent interval in relation to meals as a high fat meal
    decreased the absorption of the drug; although, the clinical
    significance of this is unknown.

-   **Cost:** The monthly drug cost for therapy with aliskiren is
    \$18.90 to \$20.70, depending on the dose. The prices for other
    commonly recommended antihypertensive agents are approximately
    \$0.13 to \$0.35 per month for a thiazide diuretic; \$0.70 to \$4.85
    per month for an ACEI; and \$10.50 per month for a calcium channel
    blocker.

-   **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 should be considered in
    patients who are inadequately controlled or have a compelling
    indication for another drug class. As the long-term 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 VHA/DoD national clinical
    practice guidelines for the treatment of HTN, and that are available
    on the VA National Formulary.

National PBM Drug Monograph

**Aliskiren (Tekturna^®^)**

###### VA Pharmacy Benefits Management Service and the Medical Advisory Panel 

# 

# [Introduction]{.underline}^1-6^

Aliskiren (Tekturna^®^, Novartis Pharmaceuticals) is a direct renin
inhibitor that received FDA approval in the U.S. on March 5, 2007 for
the treatment of hypertension (HTN). Aliskiren may be used as
monotherapy or in combination with other antihypertensive
medications.^1,2^

Current national clinical practice guidelines recommend a thiazide-type
diuretic as first line therapy in most patients with uncomplicated HTN,
as monotherapy or in combination with other antihypertensive
agents.^3-5^ As most patients will require more than one
antihypertensive agent to control their blood pressure (BP), the
following drug classes may be considered in patients who are
inadequately controlled on or who are unable to tolerate a thiazide-type
diuretic: an angiotensin-converting enzyme inhibitor (ACEI), a
long-acting calcium channel blockers (CCB), or an angiotensin II
receptor antagonist (ARB) if ACEI intolerant.^3,4^ More recently, first
or second-line antihypertensive therapy with a beta-adrenergic blocker
as monotherapy has been questioned;^6^ although this class has been
shown to be beneficial in certain concomitant conditions (refer to table
below) and may also be considered as additional therapy. A number of
other antihypertensive agents are available for additional BP control,
although data are limited as to their beneficial effect on long term
morbidity and mortality. Consideration of an alternate or additional
antihypertensive class of medication should be based on positive outcome
data in patients with a compelling indication as outlined below.^3,4^

## Preferred Agents in Patients with Comorbidities^4^

+-------------------+---------------+--------------+------------------+
| **Condition**     | **Preferred   | **           | **Other agents** |
|                   | agents**      | Additional/A |                  |
|                   |               | lternative** |                  |
+-------------------+---------------+--------------+------------------+
| **Diabetes        | Thiazide-type | ARB          |                  |
| Mellitus (DM)**   | diuretic      |              |                  |
|                   |               | CCB          |                  |
|                   | > and/or ACEI |              |                  |
|                   |               | Βeta-blocker |                  |
+-------------------+---------------+--------------+------------------+
| **Systolic Heart  | ACEI          | ARB          | Diuretic (for    |
| Failure (HF)**    |               |              | volume overload) |
|                   | Beta-blocker  | Hydrala      |                  |
|                   |               | zine-Nitrate | LADHP            |
|                   |               |              |                  |
|                   |               | Aldosterone  |                  |
|                   |               | antagonist   |                  |
+-------------------+---------------+--------------+------------------+
| **Chronic Kidney  | ACEI          | Beta-blocker |                  |
| Disease (CKD)**   |               |              |                  |
|                   | ARB           | NCCB         |                  |
|                   |               |              |                  |
|                   | Diuretic      | LADHP        |                  |
|                   | (thiazide or  |              |                  |
|                   | loop, based   |              |                  |
|                   | on kidney     |              |                  |
|                   | function)     |              |                  |
+-------------------+---------------+--------------+------------------+
| **Post Stroke**   | Thiazide-type |              |                  |
|                   | diuretic      |              |                  |
|                   |               |              |                  |
|                   | and ACEI      |              |                  |
+-------------------+---------------+--------------+------------------+
| **Post Myocardial | Beta-blocker  | NCCB         | LADHP            |
| Infarction (MI)** |               |              |                  |
|                   | ACEI          | T            |                  |
|                   |               | hiazide-type |                  |
|                   |               | diuretic     |                  |
+-------------------+---------------+--------------+------------------+

## From the VHA/DoD Diagnosis and Management of Hypertension in the Primary Care Setting; Annotation M. Drug Treatment. Table 8. at [**http://www.oqp.med.va.gov/cpg/HTN04/htn_cpg/frameset.htm**](http://www.oqp.med.va.gov/cpg/HTN04/htn_cpg/frameset.htm) 

> ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin II
> receptor antagonist; CCB=calcium channel blocker; LADHP=long-acting
> dihydropyridine CCB; NCCB=nondihydropyridine CCB

## Pharmacology^1,2^ 

## 

Aliskiren is a direct renin inhibitor, thereby reducing plasma renin
activity (PRA). The renin-angiotensin-aldosterone system (RAAS) is a key
component in the regulation of blood pressure. Renin is secreted by the
kidney in response to a reduction in blood volume or kidney perfusion,
or to beta-adrenergic sympathetic stimulation. Renin is responsible for
the formation of angiotensin I, by cleaving angiotensinogen. Angiotensin
I is then converted by angiotensin-converting enzyme (ACE) to
angiotensin II, a potent vasoconstrictor. There is also an increase in
aldosterone secretion, resulting in sodium reabsorption. The result is
an increase in blood pressure. By inhibiting renin, the administration
of aliskiren results in a reduction of PRA, angiotensin I and
angiotensin II, thereby reducing blood pressure. In addition, aliskiren
blocks the response to the compensatory increase in renin levels that
occurs by disruption of the negative feedback loop with agents that
affect the RAAS.

Other agents that act at the RAAS that are frequently used for the
treatment of HTN include the ACEIs that block the formation of
angiotensin II by inhibition of ACE, the enzyme that converts
angiotensin I to angiotensin II, and that inhibit the breakdown of
bradykinin; and the ARBs that block the effects of angiotensin II at the
AT~1~ receptor. Effects mediated by the activation of AT~1~ receptors
are vasoconstriction (coronary, renal, cerebral), sodium retention
(aldosterone production), water retention (vasopressin release),
activation of sympathetic nervous system, constriction of the efferent
arteriole in the kidney, growth (remodeling and restructuring of vessel
walls, glomerular cells, and myocardium), inhibition of apoptosis (cell
death), and increases in platelet aggregation and thrombosis. Aliskiren
and the ARBs do not affect bradykinin, accumulation of which is thought
to be a factor in the development of cough and angioedema associated
with the ACEIs.

**[Pharmacokinetics]{.underline}^1,2^**

+------------+-----+-------+------------------+-----------------------+
| **Peak     | **t | **Me  | **Elimination**  | **Food Effect**       |
| Plasma     | ½** | tabol |                  |                       |
| Conce      |     | ism** |                  |                       |
| ntration** |     |       |                  |                       |
+------------+-----+-------+------------------+-----------------------+
| 1-3hrs     | 24  | CYP   | \~25% of         | [High fat             |
|            | hrs | 3A4   | absorbed dose    | meal]{.underline}:    |
|            |     |       |                  | AUC ↓ 71%; Cmax ↓ 85% |
|            |     |       | found unchanged  |                       |
|            |     |       | in urine         |                       |
+------------+-----+-------+------------------+-----------------------+

## 

## FDA Approved Indication(s) and Off-Label Uses^1,2^

Aliskiren is FDA approved for the treatment of patients with HTN.
Aliskiren may be used as monotherapy or in combination with other
antihypertensive agents. Clinical trials including patients with heart
failure, post myocardial infarction, left ventricular hypertrophy,
diabetes mellitus and proteinuria, diabetic nephropathy, and in the
elderly are ongoing or have recently been completed.

## 

## Current VA National Formulary Alternatives

+--------------+----------+--------------+------------+---------------+
| *            | *        | *            | **Beta-    | *             |
| *Thiazides** | *ACEIs** | *Long-Acting | blockers** | *Supplemental |
|              |          | CCBs**       |            | Agents\***    |
+--------------+----------+--------------+------------+---------------+
| Ch           | Be       | Amlodipine   | Atenolol   | Clonidine     |
| lorthalidone | nazepril |              |            |               |
|              |          | Felodipine   | Metoprolol | Doxazosin     |
| Hydroch      | C        |              |            |               |
| lorothiazide | aptopril | Nifedipine   | P          | Hydralazine   |
| (HCTZ)       |          |              | ropranolol |               |
|              | E        | Diltiazem    |            | Methyldopa    |
| Indapamide   | nalapril |              |            |               |
|              |          | Verapamil    |            | Minoxidil     |
| HCTZ         | Fo       |              |            |               |
| /triamterene | sinopril |              |            | Prazosin      |
|              |          |              |            |               |
|              | Li       |              |            | Reserpine     |
|              | sinopril |              |            |               |
|              |          |              |            | S             |
|              |          |              |            | pironolactone |
|              |          |              |            |               |
|              |          |              |            | Terazosin     |
+--------------+----------+--------------+------------+---------------+

\*ARBs are restricted to criteria for use and may be considered in
patients who are ACEI intolerant; alpha~1~-blockers are not recommended
as monotherapy for the treatment of HTN; loop diuretics are generally
not recommended for the treatment of HTN

## 

## Dosage and Administration^1,2^

**General Recommendations:** Aliskiren is administered once daily. It is
recommended that aliskiren be taken consistently with regard to mealtime
as high fat meals decreased absorption of the drug.

+-------+-------+--------------+--------------+-----------------------+
| *     | **In  | **Titration  | **Maximum    | **Comments**          |
| *Avai | itial | Interval**   | Dose**       |                       |
| labil | D     |              |              |                       |
| ity** | ose** |              |              |                       |
+-------+-------+--------------+--------------+-----------------------+
| 150   | 150   | Increase to  | 300 mg once  | No dose adjustments   |
| mg    | mg    | 300mg once   | daily        | necessary in elderly, |
|       | once  | daily at 2   |              | or in patients with   |
| 300   | daily | weeks        | (↑ diarrhea  | renal or hepatic      |
| mg    |       | (85-90% of   | with higher  | impairment; caution   |
|       |       | response     | doses,       | in severe renal       |
| f     |       | seen by 2    | without      | disease due to        |
| ilm-c |       | weeks)       | improved BP  | limited data          |
| oated |       |              | control)     |                       |
|       |       |              |              |                       |
| ta    |       |              |              |                       |
| blets |       |              |              |                       |
+-------+-------+--------------+--------------+-----------------------+

**[Adverse Events]{.underline}^1,2,7,8^**

Aliskiren is generally well-tolerated. Discontinuation due to an adverse
event was reported in 2.2% of patients receiving aliskiren compared to
3.5% on placebo.

Two cases of angioedema with respiratory symptoms and two cases of
periorbital edema without respiratory symptoms were reported with
aliskiren in clinical trials (0.06% patients). Edema involving the face,
hands, or entire body was reported in 26 additional cases of patients
taking aliskiren (4 patients discontinued therapy). Edema (involving the
face, hands, or entire body) was reported in 0.4% of patients on
aliskiren compared to 0.5% of patients on placebo. There were no reports
of angioedema in the published comparison trials of aliskiren with an
ACEI or an ARB. The incidence of angioedema in patients taking an ACEI
is reported to be approximately 0.1-1.2%. There has also been a number
of published case reports of angioedema in patients treated with an ARB.
In approximately one third of these cases, the patients previously
experienced angioedema with an ACEI.

The manufacturer states that in comparison trials with an ACEI, the
incidence of cough with aliskiren was reported to be \~33%-50% of that
reported with the ACEIs. In a clinical trial comparing the tolerability
of aliskiren and lisinopril in patients with severe HTN, cough was
reported in 0.8% of patients in the aliskiren treatment group and in
1.7% of patients who received lisinopril.^7^ Another trial comparing
aliskiren to ramipril reported cough in 2.1% of patients on aliskiren,
4.7% of patients on ramipril, and 1.8% of the patients receiving
combination therapy with the two agents.^2^

Unpublished results from long-term studies of therapy (26 weeks) with
aliskiren reported serious adverse events in 1.9% of patients on
aliskiren compared to 1.4% of patients receiving ramipril.^2^ In another
unpublished long-term comparison trial (12 months duration) of over 1900
patients, it was reported that 5.1% of patients randomized to aliskiren
150 mg, 4.3% to aliskiren 300 mg, 5% on monotherapy, and 4.5% on
combination therapy with hydrochlorothiazide experienced serious adverse
events; including, cerebrovascular event (5 patients), acute myocardial
infarction (4 patients), HTN (3 patients), hypertensive crisis (3
patients). Six patients had a serious adverse event that was thought to
be drug-related (treatment group or adverse event not reported).
Discontinuations due to adverse events occurred in 5.9% of patients on
aliskiren 150 mg and 5.3% of patients randomized to treatment with
aliskiren 300 mg.^2^

Dose related increases in diarrhea have been reported in patients
overall at 300mg (2.3%), with rates in older patients ([\>]{.underline}
65 years) and females at the 150mg dose comparable to the 300mg dose in
men or younger patients. Two patients treated with aliskiren experienced
an episode of tonic-clonic seizures with loss of consciousness (one
patient was predisposed to seizures); treatment was discontinued in
these patients.

The most frequently occurring adverse events (reported in \> 1% of
patients receiving aliskiren with similar or greater incidence in
patients on placebo) included: headache, nasopharyngitis, dizziness,
fatigue, upper respiratory tract infection, back pain, cough. The
frequency of headache and nasopharyngitis reported in a pooled analysis
of 7,060 patients enrolled in seven randomized controlled trials is
shown in the table below (Novartis, Data on File;^2^ also refer to
reports of most frequently reported adverse events in the clinical trial
data compiled in Appendices 1-3).

+------------+------------------+-------------------+------------------+
| # Advers   | **Aliskiren 150  | **Aliskiren 300   | **Placebo        |
| e Event^a^ | mg (n=774), %**  | mg (n=768), %**   | (n=781), %**     |
+------------+------------------+-------------------+------------------+
| Headache   | 5.4              | 5.7               | 8.7              |
+------------+------------------+-------------------+------------------+
| Nasop      | 4.3              | 3.8               | 5.8              |
| haryngitis |                  |                   |                  |
+------------+------------------+-------------------+------------------+

## ^a^Data for aliskiren 75 mg and 600 mg not included in table 

Adverse events reported more frequently in patients on aliskiren
compared to placebo are shown below:

+-----------------------+--------------------+-------------------------+
| # Adverse Event^a^    | **Aliskiren, %**   | **Placebo, %**          |
+-----------------------+--------------------+-------------------------+
| Diarrhea              | 2.3^b^             | 1.2                     |
+-----------------------+--------------------+-------------------------+
| Cough                 | 1.1                | 0.6                     |
+-----------------------+--------------------+-------------------------+
| Rash                  | 1                  | 0.3                     |
+-----------------------+--------------------+-------------------------+
| Increased Uric Acid   | 0.4                | 0.1                     |
+-----------------------+--------------------+-------------------------+
| Gout                  | 0.2                | 0.1                     |
+-----------------------+--------------------+-------------------------+
| Kidney Stones         | 0.2                | 0                       |
+-----------------------+--------------------+-------------------------+

## ^a^Adverse events reported more frequently in patients on aliskiren compared to placebo 

^b^300mg aliskiren

**Laboratory Parameters:** Increases in blood urea nitrogen (BUN) or
serum creatinine (sCr) were similar in patients treated with aliskiren
(\< 7%) compared to those on placebo (6%). In general, published results
of comparison trials of aliskiren and an ACEI or ARB reported that blood
chemistry levels remained normal in the majority of patients. One trial
comparing the tolerability of aliskiren and the ACEI lisinopril in 183
patients with severe HTN reported one case of elevated potassium (\> 5.5
mEq/L) in the aliskiren treatment group and none treated with
lisinopril; approximately half the patients in each treatment group also
received hydrochlorothiazide. Compared to baseline, patients in the
aliskiren treatment group experienced a mean increase in sCr of 1.5
micromol/L (i.e., 0.017 mg/dl), with a mean decrease of 0.6 micromol/L
(i.e., 0.0068 mg/dl) in patients receiving lisinopril.^7^ In a
comparison trial of aliskiren and the ARB valsartan, an increase in
serum potassium to \> 5.5 mEq/L occurred in a similar proportion of
patients in the aliskiren and valsartan treatment groups (i.e., 2% in
each group), compared to 3% of patients receiving placebo, and 4% of
patients on combination therapy with aliskiren and valsartan. An
increase in serum potassium to [\>]{.underline} 6.0 mEq/L was reported
in 1% of patients in each of the monotherapy treatment groups as well as
in the placebo group; and 0.5% in patients treated with
aliskiren/valsartan combination therapy. An increase in sCr to \> 176.8
micromol/L (i.e., \> 2 mg/dl) was reported in 0.2% of patients on
aliskiren, 0.4% on valsartan, 0.9% on combination therapy, and 0% of
patients on placebo. According to data on file with the manufacturer,
2.2% of patients with HTN and DM treated with aliskiren 300mg
experienced an increase in potassium to \> 5.5 mEq/L compared to 2.6% of
patients receiving ramipril 10 mg, and 5.5% of patients on the
combination.^2^ As with other agents that act at the RAAS (e.g., ACEIs,
ARBs, aldosterone antagonists), it is recommended that kidney function
be monitored in patients where kidney function depends on the RAAS
(e.g., renal artery stenosis, volume depletion, severe heart failure)
and in patients with prior kidney dysfunction or diabetes mellitus.
Serum potassium should be monitored in patients receiving
potassium-sparing diuretics, potassium supplements, or other medications
that may increase serum potassium, and in patients with kidney
impairment, diabetes mellitus, or heart failure. The frequency of
routine monitoring should take into consideration the patient's
concomitant therapy and comorbid conditions. The manufacturer recommends
that electrolytes and kidney function be routinely monitored in patients
with DM receiving concomitant ACEIs due to an increase in serum
potassium (5.5% of patients as previously mentioned); this is compared
to 0.9% of patients with essential HTN who experienced an increase in
potassium \> 5.5 mEq/L on monotherapy (vs. placebo 0.6%).

Slight decreases in hemoglobin (0.08 g/dL) and hematocrit (0.16 volume
percent) were found in patients receiving aliskiren, with an increase in
the incidence of anemia compared to placebo (0.1% aliskiren; 0.3%
aliskiren 300mg; 0% placebo).

The effect of aliskiren on uric acid levels appears to be additive with
hydrochlorothiazide, increasing the risk for adverse events: elevated
uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and kidney stones (0.2%
vs. 0%).

Treatment with aliskiren was associated with an increase in creatine
kinase (CK) of \> 300% in \~ 1% of patients compared to 0.5% of patients
receiving placebo. There were five cases of increased CK levels reported
as adverse events in the clinical trials with aliskiren: one diagnosed
as myositis; one as subclinical rhabdomyolysis; three discontinued
treatment.

## 

# [Look-alike/Sound-alike Error Risk Potential]{.underline}

## 

As part of a pilot program, the VA PBM and Center for Medication Safety
queried a multi-attribute drug product search engine for similar
sounding and appearing drug names based on orthographic and phonological
similarities, as well as similarities in dosage form, strength and route
of administration.  By incorporating similarity scores as well as
clinical judgment, it was determined that the following drug names may
pose as potential sources of drug name confusion.

+-----------------+----------------------------------------------------+
| **Drug Name**   | **Potential Name Confusion**                       |
+-----------------+----------------------------------------------------+
| **Aliskiren     | Alkeran\* (2 mg tablets)                           |
| (generic)**     |                                                    |
|                 |                                                    |
| **150 mg, 300   |                                                    |
| mg tablets**    |                                                    |
+-----------------+----------------------------------------------------+
|                 | Aspirin (81 mg, 325 mg, 500 mg tablets)            |
+-----------------+----------------------------------------------------+
|                 | Eskalith (350 mg tablets and capsules; 450 mg CR   |
|                 | capsules)                                          |
+-----------------+----------------------------------------------------+
|                 | Visken (5 mg, 10 mg tablets)                       |
+-----------------+----------------------------------------------------+
| **Tekturna      | Ketek (400 mg tablets)                             |
| (brand)**       |                                                    |
|                 |                                                    |
| **150 mg, 300   |                                                    |
| mg tablets**    |                                                    |
+-----------------+----------------------------------------------------+
|                 | Sanctura (20 mg tablets)                           |
+-----------------+----------------------------------------------------+
|                 | Tarceva (25 mg, 100 mg, 150 mg tablets)            |
+-----------------+----------------------------------------------------+
|                 | Taztia XT (120 mg, 180 mg, 240 mg, 300 mg, 360 mg  |
|                 | capsules)                                          |
+-----------------+----------------------------------------------------+
|                 | Tetrex (250 mg capsules)                           |
+-----------------+----------------------------------------------------+

^\*^ Identified as a High Alert Medication per ISMP (i.e., special
precautions must be taken in the receipt, storage, distribution and
administration of these drugs)

## 

## Warnings^1,2^

## Fetal/Neonatal Morbidity and Mortality: The product information for aliskiren contains a Black Box Warning for use in pregnancy. Administration of medications that act at the RAAS during pregnancy has resulted in neonatal morbidity and mortality; therefore, aliskiren should be discontinued as soon as possible after a patient becomes pregnant. In patients where medications that affect the RAAS have been administered during the second or third trimester of pregnancy, hypotension, neonatal skull hypoplasia, anuria, kidney failure (reversible or irreversible), and death have occurred in the fetus. Deficiency in the amount of amniotic fluid (i.e., oligohydramnios) has been reported and was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Although not clear if related to the medication, premature birth, intrauterine growth retardation, and patent ductus arteriosus have been reported. In addition, data from an observational study in pregnant women receiving an ACEI in the first trimester reported an increase in the rate of fetal abnormalities compared to infants not exposed to ACEIs or other antihypertensive agents throughout pregnancy (refer to [**http://www.pbm.va.gov/ezminutes/EZ-MinutesApr-June06.pdf**](http://www.pbm.va.gov/ezminutes/EZ-MinutesApr-June06.pdf)). Patients receiving aliskiren should be instructed to discontinue the medication as soon as possible, and an alternative medication considered. Studies of aliskiren in pregnant rats did not appear to have an adverse effect on the fetus at daily doses up to 600 mg/kg (20 times the maximum recommended human dose), or in pregnant rabbits at daily doses up to 100 mg/kg (7 times the maximum recommended human dose). At daily doses of 50 mg/kg, there was an adverse effect on birth weight in pregnant rabbits. Aliskiren was also reported to be present in the placenta, amniotic fluid, and fetuses of pregnant rabbits. Aliskiren has not been studied in pregnant women. 

## 

**Angioedema:** Angioedema (occurring in the face, lips, tongue, glottis
and/or larynx, and extremities) has been reported in patients receiving
treatment with aliskiren. It is unknown if the incidence of angioedema
occurs more frequently in African American patients as has been seen
with the ACEIs. Angioedema occurring in the tongue and glottis/larynx
require prompt attention as there is a higher likelihood of airway
obstruction.

**Hypotension:** Symptomatic hypotension may occur in patients who may
be sodium or volume depleted (e.g., in patients receiving diuretic
therapy) upon initial therapy with aliskiren. It is recommended to
correct the volume depletion prior to starting aliskiren, otherwise
therapy should be initiated under close medical supervision. Significant
hypotension has been reported in 0.1% of patients with essential HTN
receiving monotherapy with aliskiren, and in \< 1% of patients on
aliskiren in combination with other antihypertensive medications.
Transient hypotension may occur and is not considered a contraindication
to therapy with aliskiren.

**[Precautions]{.underline}^1,2^**

**Impaired Kidney Function:** Aliskiren should be used with caution in
the following patients: those with greater than moderate kidney
dysfunction (defined as serum creatinine [\>]{.underline} 1.7 mg/dL for
women and [\>]{.underline} 2.0 mg/dL for men, or estimated GFR \< 30
mL/min), on dialysis, with a history of nephrotic syndrome or
renovascular HTN; as these patients were not included in the clinical
trials with aliskiren.

**Hyperkalemia:** Patients with DM receiving therapy with an ACEI are
more likely to experience an increase in potassium levels when receiving
concomitant aliskiren. It is recommended that electrolytes and kidney
function be routinely monitored in this patient population.

**Carcinogenesis, Mutagenesis, Fertility Impairment:** Oral doses of
aliskiren of up to 1500 mg/kg/day were studied in rats (4 times the
maximum recommended human dose for 2 years) and mice (1.5 times the
maximum recommended human dose for 6 months). In both species, mucosal
epithelial hyperplasia was seen in the lower gastrointestinal tract at
dose up to 750 mg/kg/day. A colonic adenoma was seen in one rat and a
cecal adenocarcinoma in another rat; although, there was not a
statistically significant increase in tumor incidence with aliskiren.
Mucosal hyperplasia was also seen in the cecum or colon in rats at a
dose of 250 mg/kg/day, and at higher doses in studies of 4 and 13 weeks
duration. In male or female rats, fertility was not affected with
aliskiren at doses of up to 8 times the maximum recommended dose in
humans.

**Pregnancy:** Aliskiren is Pregnancy Category C for the first trimester
and Category D for the second and third trimesters (see Warnings).

**Nursing Mothers:** It is unknown if aliskiren is excreted in human
milk. The drug has been detected in the milk of lactating rats. Due to
the potential for adverse effects in the infant, it is recommended that
a decision be made to either discontinue nursing or the medication after
consideration of the risk vs. benefit of the drug for the mother.

**Drug Interactions:** It has been reported that the blood
concentrations of furosemide are significantly reduced when given in
combination with aliskiren; therefore, the clinical effects of
furosemide may be decreased after initiation of aliskiren.

**Patient Information:** *Pregnancy:* Women of child-bearing potential
should be informed of the risks to the fetus with administration of
medications that act at the RAAS during the second and third trimesters
(although not apparent in patients where the use was limited to the
first trimester), and should be instructed to inform their provider
immediately when pregnancy is detected. *Angioedema:* Patients should be
informed of the risk for angioedema at any time during treatment with
aliskiren, and to immediately report any signs of swelling in the face,
tongue, lips, or extremities, or any difficulty breathing or swallowing.

**Demographics (Age):** According to the manufacturer, the AUC of
aliskiren is increased in older patients (pharmacokinetics studied in
patients [\>]{.underline} 65 years of age); although, dose adjustment is
not necessary in this patient population. In clinical trials, 19% of
patients studied were [\>]{.underline} 65 years of age, with 3.4%
[\>]{.underline} 75 years of age. Safety and efficacy were reported to
be similar in these patients as in younger patients. Aliskiren has not
been studied in pediatric patients.

**[Drug Interactions]{.underline}^1,2^**

Aliskiren is metabolized by cytochrome (CYP) 3A4. Aliskiren does not
inhibit CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor does it induce CYP
3A4. Repeated concomitant administration of irbesartan decreased C~max~
aliskiren up to 50%. The C~max~ and AUC of aliskiren were increased
approximately 50% in patients receiving multiple concomitant doses of
artorvastatin. Concomitant administration of ketoconazole 200 mg twice
daily increased plasma levels of aliskiren by approximately 80%. The
manufacturer reports a decrease in C~max~ (\~50%) and in AUC (\~30%) of
furosemide when administered in combination with aliskiren. There was
not a clinically significant increase in aliskiren exposure or a
significant effect on the pharmacokinetics of the following medications
during concomitant administration: amlodipine, atenolol, celecoxib,
digoxin, furosemide, hydrochlorothiazide, metformin, ramipril, or
valsartan. There was not a significant increase in aliskiren with
concomitant administration of warfarin, although the manufacturer states
that the effect of aliskiren on the pharmacokinetics of warfarin has not
been evaluated in a controlled clinical trial.

## 

## Efficacy Measures^8-14^

#### 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 [\>]{.underline} 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 Data^7-14^

## 

## 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^ hydrochlorothiazide^14^), and in combination with other antihypertensive agents (e.g., valsartan,^8,13^ hydrochlorothiazide^14^) 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 trials^8-11,13,14^ 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 trials^8-11,13,14^ 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^

## 

+---------+----+-----------+-----------+-------+----------------------+
| #       | ## | #         | #         | ## Pl | ## Active Comparator |
| # Trial |  n | # Aliskir | # Aliskir | acebo |                      |
|         |    | en 150 mg | en 300 mg |       |                      |
+---------+----+-----------+-----------+-------+----------------------+
| ## Oh e | ## | ## -      | ## -      | ##    | ## NA                |
| t al^9^ |  6 | 10.3+0.63 | 11.1+0.64 |  -4.9 |                      |
|         | 62 |           |           | +0.64 |                      |
+---------+----+-----------+-----------+-------+----------------------+
| ## Kus  | ## | ## -      | ## -1     | ##    | ## NA                |
| hiro et |  4 | 7.75+0.76 | 0.72+0.75 | -3.26 |                      |
|  al^10^ | 55 |           |           | +0.75 |                      |
+---------+----+-----------+-----------+-------+----------------------+
| ## Gra  | ## | ## -      | ## -1     | ##    | ## -8.88+0.74        |
| dman et |  6 | 9.28+0.76 | 1.77+0.75 | -6.34 |  (irbesartan 150 mg) |
|  al^11^ | 52 |           |           | +0.75 |                      |
+---------+----+-----------+-----------+-------+----------------------+
| ## O    | #  | ## NA     | ## -9.0   | ##    | ## -9.               |
| paril e | #  |           |           |  -4.1 | 7 (valsartan 320 mg) |
| t al^8^ | 17 |           |           |       |                      |
|         | 76 |           |           |       |                      |
+---------+----+-----------+-----------+-------+----------------------+
| ##      | #  | ## -      | ## -      | ##    | ## -10.5+1.07; -1    |
| Pool et | #  | 10.3+0.62 | 12.3+0.62 |  -8.6 | 1.0+1.07; -11.3+1.05 |
|  al^13^ | 11 |           |           | +0.62 |                      |
|         | 23 |           |           |       | ## (valsartan 80     |
|         |    |           |           |       |  mg; 160 mg; 320 mg) |
+---------+----+-----------+-----------+-------+----------------------+
| ## Vill | #  | ##        | ## -      | ##    | ## -9.1+0.58; -      |
| amil et | #  | -8.9+0.59 | 10.3+0.60 |  -6.9 | 10.1+0.59; -9.4+0.61 |
|  al^14^ | 27 |           |           |       |                      |
|         | 52 |           |           |       | (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^

## In addition, one randomized controlled trial evaluated the tolerability of aliskiren in 183 patients with severe HTN (DBP \> 105 mm Hg and \< 120 mm Hg; mean BP 163/108 mm Hg at baseline). Although this was a tolerability trial, the authors reported similar efficacy with aliskiren-based compared to lisinopril-based treatment (SBP/DBP reduction of 20.0+15.3/18.5+8.7 mm Hg vs. 22.3+14.6/20.1+7.9 mm Hg, respectively). It was reported that 73.6% of patients on aliskiren were titrated from 150 mg to 300 mg and 65.5% were titrated from lisinopril 20 mg to 40 mg; 53.6% and 44.8% of patients had hydrochlorothiazide 25 mg added to their treatment regimen, respectively.^7^ 

#### 

#### In an unpublished trial of 8 weeks in over 800 patients with HTN and type 1 or 2 DM, treatment with a combination of aliskiren 300 mg and ramipril 10 mg resulted in a statistically significant reduction in DBP compared to either monotherapy (mean reduction 1.46 mm Hg and 2.07 mm Hg with combination vs. aliskiren or ramipril, respectively). The difference between aliskiren and ramipril monotherapy was not significant.^2^ 

## 

## Long-term Follow-up: The following results are data on file with the manufacturer but are included as they provide data on long-term treatment with aliskiren that are not available in the published literature. Unpublished data from over 1900 patients enrolled in an open-label extension trial evaluating the blood pressure lowering effects of one year of treatment with aliskiren showed that 85.6% and 86.2% of patients responded to treatment with aliskiren 150 mg and 300 mg, respectively (65.9% and 66.0% were controlled, respectively).^2^ Reduction from baseline in DBP was reported to be 13.5 mm Hg and 14.2 mm Hg in patients randomized to aliskiren 150 mg or 300 mg, respectively. The proportion of patients in the 150 mg treatment group who were up-titrated or those who received hydrochlorothiazide was not reported. Another trial (data on file) of 26 weeks with more than 800 patients randomized to aliskiren or ramipril reported treatment to be non-inferior (aliskiren reported to be superior to ramipril in the intent-to-treat population) for change from baseline in DBP; although the proportion of patients who were up-titrated or who received hydrochlorothiazide was not reported.^2^ The long-term effects of aliskiren on cardiovascular outcomes or mortality are not available in the published literature. 

##### Acquisition Cost

+-------------------+-----------+------------------+------------------+
| **Dose/Regimen**  | **Price   | **Price          | **Annual         |
|                   | /Tablet** | /Patient/Month** | Price/Patient**  |
+-------------------+-----------+------------------+------------------+
| Aliskiren 150 mg  | \$0.63    | \$18.90          | \$226.80         |
| once daily        |           |                  |                  |
+-------------------+-----------+------------------+------------------+
| ## Aliskiren      | ## \$0.69 | \$20.70          | \$248.40         |
| 300 mg once daily |           |                  |                  |
+-------------------+-----------+------------------+------------------+

***Price Comparison of Other Antihypertensive Medications***

+--------------------------------+------------------+------------------+
| ## Drug                        | ####### **Price  | ####### **Annual |
|                                | /Patient/Month** |  Price/Patient** |
+--------------------------------+------------------+------------------+
| ## Hydrochloro                 | \$0.13-\$0.35    | \$1.57-\$4.25    |
| thiazide 12.5-50 mg once daily |                  |                  |
+--------------------------------+------------------+------------------+
| ## L                           | \$0.70-\$4.85    | \$8.42-\$58.21   |
| isinopril 2.5-40 mg once daily |                  |                  |
+--------------------------------+------------------+------------------+
| ## Nifedipine extende          | \$10.50          | \$126.00         |
| d-release 30-60 mg once daily  |                  |                  |
+--------------------------------+------------------+------------------+

##### 

##### Cost-Effectiveness Analysis^2^

An economic evaluation was conducted by the manufacturer comparing the
incremental cost-effectiveness ratio (ICER) for treatment with aliskiren
vs. losartan (an ARB) or ramipril (an ACEI) in patients with Stage 1 HTN
(BP 140-159/90-99 mm Hg).^2^ The model was based on ability of the
medication to reduce SBP and estimation of cardiovascular event rates
and death associated with coronary heart disease and stroke, as
calculated using the Framingham risk equations. Cost was based on
hospitalizations as determined by DRG reimbursement, and daily average
medication cost using wholesale acquisition cost, national estimates of
daily average consumption and dose utilization, as well as taking into
consideration dispensing fees, patient co-payments, and medication
rebates.

According to the estimates and assumptions used in the model (i.e., 52
year old male, mean baseline SBP 150 mm Hg, mean baseline total
cholesterol 224 mg/dL and HDL 48 mg/dL, nonsmoker, and without history
of cardiovascular disease, DM, atrial fibrillation, or left ventricular
hypertrophy, with a time horizon of 10 years), the ICER were calculated
as follows: aliskiren vs losartan \$68,935/life years gained; aliskiren
vs ramipril \$48,145/life years gained. When sensitivity analyses were
performed for age and cardiovascular risk factors, the ICER tended to be
lower with the range as follows: aliskiren vs losartan \$20,444 (left
ventricular hypertrophy) to 44,202 (DM)/life years gained; aliskiren vs
ramipril \$10,716 (left ventricular hypertrophy) to 28,988 (DM)/life
years gained.

Limitations of the model included the use of change in SBP that was not
a primary endpoint of the clinical trials with aliskiren, and the use of
reductions in SBP from the manufacturer's package insert rather than
results from head-to-head comparison trials of aliskiren with losartan
(published data) and with ramipril (unpublished data on file). If the
model were modified based on cost estimates for the VA, the difference
in price of the medications used for comparison would be an important
factor in determining the ICER. In addition, the patient population of
the VA would also influence the ICER.

## 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>).

## 

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

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

+---+-----------+------------+------------------------+---------------+
| # | ### I     | ###        | #                      | ### Wi        |
| # | nclusion/ |  Endpoints | ## Results/Conclusions | thdrawals/AEs |
| # | Exclusion | /Treatment |                        |               |
|   |           |            |                        |               |
| T |           |            |                        |               |
| r |           |            |                        |               |
| i |           |            |                        |               |
| a |           |            |                        |               |
| l |           |            |                        |               |
+---+-----------+------------+------------------------+---------------+
| * | ##        | #########  | **Baseline** (safety   | **[Completed  |
| * | ####### I |  Endpoints | population): mean age  | Tx Phase of   |
| O | nclusion  |            | 53yrs; 61.3%           | Trial]{       |
| h | Criteria  | **         | Caucasian; 61.6% male; | .underline}** |
| e |           | Primary:** | mean sitting SBP/DBP   |               |
| t | Men and   | antihy     | 152.1/99.6 mm Hg       | *             |
| a | women     | pertensive |                        | *Aliskiren:** |
| l | [\>]{.u   | efficacy   |   ----------           | 150 mg,       |
| , | nderline} | (change in | - -------------------- | 162/172       |
| 2 | 18 yrs of | mean       | ------ ---------- ---- | (94.2%); 300  |
| 0 | age,      | trough     | ---------------------- | mg, 159/169   |
| 0 | essential | sitting    |   **Tx**      *        | (94.1%); 600  |
| 7 | HTN, mean | DBP at end | *DBP\***               | mg, 152/166   |
| ^ | sitting   | of study   |     **P**      **SBP** | (91.6%)       |
| 9 | DBP       | vs.        |                        |               |
| ^ | [\>]{.u   | baseline)  |   Placebo              | **Placebo:**  |
| * | nderline} | of 150 mg, |      -4.9[+]{.underlin | 135/165       |
| * | 95 mm Hg  | 300 mg,    | e}0.64               - | (81.8%)       |
|   | and \<    | and 600 mg | 3.8[+]{.underline}1.02 |               |
| M | 110 mm Hg | aliskiren  |                        | **[Adverse    |
| C |           | vs.        |   Aliski               | Events]{      |
| , | #         | placebo    | ren                    | .underline}** |
| R | ########  |            |                        |               |
| , |           | **Se       |                        | **Serious     |
| D | ##        | condary:** |   150 mg/d             | AEs:**        |
| B | ####### E | change in  |     -10.3[+]{.underlin | Aliskiren 150 |
| , | xclusion  | mean       | e}0.63   \<0.0001   -1 | mg (n=1); 300 |
| P | Criteria  | trough     | 3.0[+]{.underline}1.01 | mg (n=2); 600 |
| C |           | sitting    |                        | mg (n=1);     |
| , | Severe    | SBP at end |   300 mg/d             | none thought  |
| D | HTN       | of study   |     -11.1[+]{.underlin | to be         |
| R | (sitting  | vs.        | e}0.64   \<0.0001   -1 | tx-related;   |
|   | DBP       | baseline;  | 4.7[+]{.underline}1.02 | no deaths     |
| K | [\>]{.u   | proportion |                        |               |
| o | nderline} | responding |   600 mg/d             |   -           |
| r | 110 mm    | to Tx      |     -12.5[+]{.underlin | -------- ---- |
| e | Hg);      | (mean      | e}0.64   \<0.0001   -1 | --- --------- |
| a | secondary | sitting    | 5.8[+]{.underline}1.02 |               |
| , | HTN;      | DBP \< 90  |   ----------           |  **Tx**    ** |
| U | serious   | mm Hg      | - -------------------- | W/D   **Total |
| . | cardiac   | and/or     | ------ ---------- ---- |               |
| S | or        | [\>]{.     | ---------------------- |  AE**    AE** |
| . | cerebr    | underline} |                        |               |
|   | ovascular | 10 mm Hg   | \* Primary endpoint:   |   Placebo     |
| n | disease;  | decrease   | change from baseline   | 3.6%    43.0% |
| = |           | in DBP vs. | in mean trough sitting |   (n=16       |
| 6 | type 1 DM | baseline)  | DBP (mm Hg)            | 5)            |
| 7 | or type 2 | or BP      | [+]{.underline} SEM; P |               |
| 2 | DM with   | control    | value vs. placebo      |   150 mg      |
| ( | HbA~1c~   | (BP \<     |                        | 0.6%    40.1% |
| s | \> 9%;    | 140/90 mm  | Note: n for            |   (n=17       |
| a | any       | Hg); 24-hr | distribution of        | 2)            |
| f | condition | ABPM       | patients in ITT not    |               |
| e | with      | profiles   | provided               |   300 mg      |
| t | potential | (pt        |                        | 1.8%    46.7% |
| y | to affect | subset);   |                        |   (n=16       |
| ) | pharmac   | TPR; dose  | ----------- ---------- | 9)            |
| ; | okinetics | response   | ------ --------------- |               |
| 6 | of the    | rel        |   **Tx**               |   600 mg      |
| 6 | drug      | ationship; |  **Response\***   **BP | 1.2%    52.4% |
| 2 |           | effects on |                        |   (n=16       |
| ( |           | PRA and RC |          control\*\*** | 6)            |
| I |           | (pt        |                        |   -           |
| T |           | subset);   |   Placebo              | -------- ---- |
| T |           | safety and | 36.2%            20.3% | --- --------- |
| ) |           | tol        |                        |               |
|   |           | erability; |   Aliskir              | Most common   |
| 8 |           | effect of  | en                     | AEs included  |
| w |           | Tx W/D on  |                        | HA (aliskiren |
| k |           | BP, PRA,   |   150 mg/d             | (5.4-7.7% vs. |
| s |           | and RC     | 59.3%            35.9% | placebo 9.7%) |
| t |           |            |                        | and           |
| x |           | *          |   300 mg/d             | na            |
| ; |           | *[Wash-out | 63.3%            41.6% | sopharyngitis |
| 2 |           | Phase]{.un |                        | (aliskiren    |
| w |           | derline}** |   600 mg/d             | 1.8-3.6% vs.  |
| k |           |            | 69.3%            46.4% | placebo       |
| s |           | W/D HTN    |                        | 6.1%);        |
| W |           | Rx; 2 wk   | ----------- ---------- | diarrhea      |
| / |           | wash-out   | ------ --------------- | occurred in   |
| D |           |            |                        | 11.4% on      |
|   |           | **[Run-in  | \* Response: percent   | aliskiren 600 |
| S |           | Phase]{.un | of patients with mean  | mg (P\<.0001) |
| u |           | derline}** | sitting DBP \< 90 mm   | vs other tx   |
| p |           |            | Hg and/or              | groups        |
| p |           | 2-4 wk SB  | [\>]{.underline} 10 mm |               |
| o |           | placebo    | Hg decrease in DBP vs. |               |
| r |           |            | baseline; P \< 0.0001  |               |
| t |           | **         | vs. placebo            |               |
| e |           | [Treatment |                        |               |
| d |           | Phase]{.un | \*\* BP control: \<    |               |
| b |           | derline}** | 140/90 mm Hg; P \<     |               |
| y |           |            | 0.001 vs. placebo      |               |
| N |           | Randomized |                        |               |
| o |           | to placebo | > **ABPM (n=216)**:    |               |
| v |           | or         | > Significant          |               |
| a |           | aliskiren  | > reduction in DBP and |               |
| r |           | 150 mg,    | > SBP with all doses   |               |
| t |           | 300 mg, or | > vs. placebo; P \<    |               |
| i |           | 600 mg     | > 0.0001               |               |
| s |           | once daily | >                      |               |
|   |           | at \~      | > **PRA/RC vs.         |               |
|   |           | 8:00am for | > Baseline (n=270)**:  |               |
|   |           | 8 wks      | > PRA reduced with all |               |
|   |           | (drug      | > doses aliskiren      |               |
|   |           | taken      | > (75-81.1%) vs.       |               |
|   |           | after      | > increased with       |               |
|   |           | evaluation | > placebo (19.5%); RC  |               |
|   |           | on study   | > increased with all   |               |
|   |           | visits)    | > doses aliskiren      |               |
|   |           |            | > (51.5-228.5%) vs.    |               |
|   |           | **[Run-out | > minimal change (data |               |
|   |           | Phase]{.un | > NR) with placebo     |               |
|   |           | derline}** | >                      |               |
|   |           |            | > **Tx W/D (n=608)**:  |               |
|   |           | 2 wk W/D   | > DBP remained below   |               |
|   |           |            | > baseline (6.8 mm Hg  |               |
|   |           |            | > with 150 mg, 6.9 mm  |               |
|   |           |            | > Hg with 300 mg, 8.7  |               |
|   |           |            | > mm Hg with 600 mg)   |               |
|   |           |            | > vs. 5.3 mm Hg with   |               |
|   |           |            | > placebo at 2 wks     |               |
|   |           |            |                        |               |
|   |           |            | **[Study               |               |
|   |           |            | Conc                   |               |
|   |           |            | lusions]{.underline}** |               |
|   |           |            |                        |               |
|   |           |            | Short-term treatment   |               |
|   |           |            | (8 weeks) with         |               |
|   |           |            | aliskiren 150 mg, 300  |               |
|   |           |            | mg, and 600 mg         |               |
|   |           |            | significantly reduced  |               |
|   |           |            | mean sitting DBP       |               |
|   |           |            | compared to placebo in |               |
|   |           |            | patients with mild to  |               |
|   |           |            | moderate HTN with no   |               |
|   |           |            | demonstration of a     |               |
|   |           |            | rebound effect at 2    |               |
|   |           |            | wks                    |               |
+---+-----------+------------+------------------------+---------------+
| * | ##        | #########  | **Baseline** (mean):   | **[Completed  |
| * | ####### I |  Endpoints | age                    | Trial]{       |
| K | nclusion  |            | 51.6[+                 | .underline}** |
| u | Criteria  | **         | ]{.underline}9.9-53.3[ |               |
| s |           | Primary:** | +]{.underline}10.4yrs; | *             |
| h | 20 to 80  | antihy     | 72.5% male; duration   | *Aliskiren:** |
| i | yrs of    | pertensive | HTN 4.6-6.2 yrs; mean  | 75 mg,        |
| r | age,      | efficacy   | sitting SBP/DBP        | 110/115       |
| o | Japanese, | (change in | 152.7[+]{.             | (95.7%); 150  |
| e | essential | mean       | underline}11.8-155.6[+ | mg, 109/112   |
| t | HTN, mean | trough     | ]{.underline}11.1/99.4 | (97.3%); 300  |
| a | sitting   | sitting    | [+]{.underline}3.9-    | mg, 111/113   |
| l | DBP       | DBP at end | 99.6[+]{.underline}4.4 | (98.2%)       |
| , | [\>]{.u   | of study   | mm Hg                  |               |
| 2 | nderline} | vs.        |                        | **Placebo:**  |
| 0 | 90 mm Hg  | baseline)  |   ----------- -------  | 104/115       |
| 0 | and \<    | of 75 mg,  | ---------------------- | (90.4%)       |
| 6 | 110 mm Hg | 150 mg,    | ----- ---------- ----- |               |
| ^ | during    | 300 mg     | ---------------------- | **[Adverse    |
| 1 | run-in    | aliskiren  |                        | Events]{      |
| 0 | and       | vs.        | **Tx**      **n**   ** | .underline}** |
| ^ | [\>]{.u   | placebo    | DBP\***                |               |
| * | nderline} |            |     **P**      **SBP** | **Serious     |
| * | 95 mm Hg  | **Se       |                        | AEs:**        |
|   | and \<    | condary:** |   Placebo     115      | Aliskiren 75  |
| M | 110 mm Hg | change in  |    -3.26[+]{.underline | mg (n=1:      |
| C | at        | mean       | }0.75               -2 | AMI);         |
| , | baseline  | trough     | .85[+]{.underline}1.17 | aliskiren 150 |
| R | prior to  | sitting    |                        | mg (n=1:      |
| , | rando     | SBP at end |   Aliskiren            | death due to  |
| D | mization, | of study   |                        | psychiatric   |
| B | with \<   | vs.        |                        | drug OD);     |
| , | 10 mm Hg  | baseline;  |                        | placebo (n=3: |
| P | d         | proportion |   75 mg/d     115      | 1 cerebral    |
| C | ifference | responding |    -7.22[+]{.underline | infarction; 1 |
|   | between   | to Tx      | }0.75    0.0002     -8 | pancreatic    |
| J | mea       | (mean      | .57[+]{.underline}1.17 | CA; 1         |
| a | surements | sitting    |                        | infective     |
| p |           | DBP \< 90  |   150 mg/d    112      | enteritis)    |
| a | ##        | mm Hg      |    -7.75[+]{.underline |               |
| n | ####### E | and/or     | }0.76    \<0.0001   -8 |   -           |
|   | xclusion  | [\>]{.     | .72[+]{.underline}1.18 | -------- ---- |
| n | Criteria  | underline} |                        | --- --------- |
| = |           | 10 mm Hg   |   300 mg/d    113      |               |
| 4 | Severe    | decrease   |   -10.72[+]{.underline |  **Tx**    ** |
| 5 | HTN       | in DBP);   | }0.75   \<0.0001   -14 | W/D   **Total |
| 5 | (sitting  | dose       | .09[+]{.underline}1.18 |               |
|   | DBP       | response   |   ----------- -------  |  AE**    AE** |
| 1 | [\>]{.u   | re         | ---------------------- |               |
| 3 | nderline} | lationship | ----- ---------- ----- |   Placebo     |
| w | 110 mm Hg |            | ---------------------- | 3.5%    50.4% |
| k | and/or    | **Other:** |                        |               |
| s | SBP       | AEs (date  | \* Primary endpoint:   |   75 mg       |
|   | [\>]{.u   | of onset;  | change from baseline   | 1.7%    53.0% |
| I | nderline} | ranked     | in mean trough sitting |               |
| n | 180 mm    | mild,      | DBP (mm Hg)            |   150 mg      |
| v | Hg);      | moderate,  | [+]{.underline} SEM; P | 1.8%    51.8% |
| o | suspected | severe;    | value vs. placebo      |               |
| l | secondary | related to |                        |   300 mg      |
| v | or        | study      |   ---                  | 1.8%    54.9% |
| e | malignant | drug);     | -------- ------------- |   -           |
| m | HTN; type | labs       | --- -------- --------- | -------- ---- |
| e | 1 DM or   | (blood     |   **Tx**      **Respo  | --- --------- |
| n | type 2 DM | ch         | nse\***   **OR     **P |               |
| t | on        | emistries, |                        | Most common   |
| o | insulin   | h          |                        | AEs included  |
| f | or        | ematology, |       (95%     value** | na            |
| s | HbA~1c~   | ur         |                        | sopharyngitis |
| p | \> 8%;    | inalysis); |              CI)**     | (17.7-20.9%   |
| o | serious   | weight;    |                        | aliskiren vs. |
| n | cardiac,  | ECG;       |   Placebo     32/1     | 13.9%         |
| s | hepatic,  | compliance | 15 (27.8%)             | placebo) and  |
| o | renal or  | (drug      |                        | HA (2.6-5.3%  |
| r | cerebr    | taken      |   Aliskiren            | aliskiren vs. |
| n | ovascular | [\>]{.     |                        | 3.5% placebo) |
| o | disease;  | underline} |                        |               |
| t | c         | 70% of     |                        |   -           |
| r | linically | days per   | 75 mg/d     55/115 (47 | -------- ---- |
| e | si        | interview) | .8%)   2.52     0.0015 | ----- ------- |
| p | gnificant |            |                        | -- ---------- |
| o | a         | **[Run-in  |              (1.42,    |               |
| r | llergies; | Phase]{.un |                        |  **Tx**    ** |
| t | history   | derline}** |              4.46)     | WBC**   **ALT |
| e | of        |            |                        | **   **K^+^** |
| d | panc      | 4 wk SB    |                        |               |
|   | reatitis; | placebo    | 150 mg/d    54/112 (48 |   Placeb      |
|   | malignant |            | .2%)   2.60     0.0011 | o   1.7%      |
|   | tumors    | **         |                        |  2.6%      0% |
|   | within 5  | [Treatment |              (1.46,    |               |
|   | yrs;      | Phase]{.un |                        |   75 mg       |
|   | a         | derline}** |              4.62)     |   1.7%      4 |
|   | utoimmune |            |                        | .3%      1.7% |
|   | diseases; | Randomized |                        |               |
|   | anemia;   | to placebo | 300 mg/d    72/113 (63 |   150 mg      |
|   | gout;     | or         | .7%)   5.22     0.0001 |     0.9%      |
|   | hyperth   | aliskiren  |                        |  3.6%      0% |
|   | yroidism; | 75 mg, 150 |              (2.89,    |               |
|   | deh       | mg, or 300 |                        |   300 mg      |
|   | ydration; | mg once    |              9.42)     |     0.9%      |
|   | p         | daily      |   ---                  |  1.8%      0% |
|   | regnancy; | between    | -------- ------------- |   -           |
|   | treatment | 6:00am and | --- -------- --------- | -------- ---- |
|   | for       | 10:00am    |                        | ----- ------- |
|   | gastric   | [\>]{.     | \* Response: percent   | -- ---------- |
|   | or        | underline} | of patients with mean  |               |
|   | duodenal  | 30 min     | sitting DBP \< 90 mm   | WBC \> 50%    |
|   | ulcers;   | before     | Hg and/or              | baseline; ALT |
|   | receiving | meals for  | [\>]{.underline} 10 mm | [\>           |
|   | invest    | 8 wks      | Hg decrease in DBP; P  | ]{.underline} |
|   | igational | (drug      | value vs. placebo      | 150%          |
|   | drug      | taken      |                        | baseline;     |
|   | within 12 | after      | **[Study               | K^+^          |
|   | wks       | evaluation | Conc                   | [\>           |
|   |           | on study   | lusions]{.underline}** | ]{.underline} |
|   |           | visits)    |                        | 20% baseline  |
|   |           |            | > Short-term treatment |               |
|   |           | **[Run-out | > (8 weeks) with       |               |
|   |           | Phase]{.un | > aliskiren            |               |
|   |           | derline}** | > significantly        |               |
|   |           |            | > reduced BP (placebo  |               |
|   |           | 1 wk W/D   | > corrected decrease   |               |
|   |           |            | > SBP/DBP (mm Hg)      |               |
|   |           |            | > 5.7/4.0, 5.9/4.5,    |               |
|   |           |            | > 11.2/7.5 in the 75   |               |
|   |           |            | > mg, 150 mg 300 mg tx |               |
|   |           |            | > groups,              |               |
|   |           |            | > respectively) in     |               |
|   |           |            | > Japanese patients    |               |
|   |           |            | > with HTN, with       |               |
|   |           |            | > tolerability similar |               |
|   |           |            | > to placebo           |               |
+---+-----------+------------+------------------------+---------------+

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)**

+---+-----------+------------+-----------------------+----------------+
| # | ### I     | ###        | ##                    | ### W          |
| # | nclusion/ |  Endpoints | # Results/Conclusions | ithdrawals/AEs |
| # | Exclusion | /Treatment |                       |                |
|   |           |            |                       |                |
| T |           |            |                       |                |
| r |           |            |                       |                |
| i |           |            |                       |                |
| a |           |            |                       |                |
| l |           |            |                       |                |
+---+-----------+------------+-----------------------+----------------+
| * | ##        | #########  | **Baseline** (mean):  | **[ITT         |
| * | ####### I |  Endpoints | age                   | Analysis]      |
| G | nclusion  |            | 55.0[+]{.             | {.underline}** |
| r | Criteria  | **         | underline}12.5-57.1[+ |                |
| a |           | Primary:** | ]{.underline}12.0yrs; | **Aliskiren:** |
| d | Men and   | antihy     | 50.2% male; 76.8%     | 150 mg,        |
| m | women     | pertensive |                       | 127/127        |
| a | [\>]{.u   | efficacy   | Caucasian; mean       | (100%); 300    |
| n | nderline} | (change in | sitting SBP/DBP       | mg, 130/130    |
| e | 18 yrs of | mean       | 151.3[+]{.un          | (100%); 600    |
| t | age, mild | trough     | derline}11.1-152.8[+] | mg, 129/130    |
| a | to        | sitting    | {.underline}11.2/98.8 | (99.2%)        |
| l | moderate  | DBP at end | [+]{.underline}3.4-9  |                |
| , | essential | of study   | 9.4[+]{.underline}4.0 | **Placebo:**   |
| 2 | HTN (mean | vs.        | mm Hg                 | 130/131        |
| 0 | sitting   | baseline)  |                       | (99.2%)        |
| 0 | DBP       | of 150 mg, |   ---                 |                |
| 5 | [\>]{.u   | 300 mg,    | --------- ------- --- | *              |
| ^ | nderline} | 600 mg     | --------------------- | *Irbesartan:** |
| 1 | 95 mm Hg  | aliskiren  | --- ---------- ------ | 150 mg 133/134 |
| 1 | and \<    | vs.        | --------------------- | (99.3%)        |
| ^ | 110 mm    | placebo    |   **Tx                |                |
| * | Hg)       |            | **       **n**   **DB | **Discontinued |
| * |           | **Other:** | P\***                 | Tx (n=66)**:   |
|   | ##        | antihy     |    **P**      **SBP** | reported to be |
| M | ####### E | pertensive |                       | similar across |
| C | xclusion  | efficacy   |                       | Tx groups      |
| , | Criteria  | (DBP)      | Placebo      130      |                |
| R |           | aliskiren  | -6.34[+]{.underline}0 | **[Adverse     |
| , | Severe    | vs.        | .75               -5. | Events]        |
| D | HTN       | irbesartan | 29[+]{.underline}1.23 | {.underline}** |
| B | (sitting  | and        |                       |                |
| , | DBP       | irbesartan |   Aliskiren           | **Serious      |
| P | [\>]{.u   | vs.        |                       | AEs:** Placebo |
| C | nderline} | placebo;   |                       | (n=2:          |
| , | 110 mm Hg | change in  |                       | infective      |
| P | and/or    | mean       |   1                   | arthritis and  |
| G | SBP       | trough     | 50 mg/d     127     - | gout; LV       |
| , | [\>]{.u   | sitting    | 9.28[+]{.underline}0. | failure);      |
| A | nderline} | SBP and at | 76    0.004      -11. | irbesartan 150 |
| C | 180 mm    | end of     | 36[+]{.underline}1.25 | mg (n=2:       |
| ( | Hg);      | study vs.  |                       | bipolar        |
| i | secondary | placebo;   |   3                   | disorder;      |
| r | HTN; type | proportion | 00 mg/d     130     - | intervertebral |
| b | 1 DM or   | responding | 11.77[+]{.underline}0 | disc           |
| e | type 2 DM | to tx      | .75   \<0.0001   -15. | protrusion);   |
| s | with      | (mean      | 76[+]{.underline}1.23 | no deaths      |
| a | HbA~1c~   | trough     |                       | reported       |
| r | \> 8%;    | sitting    |   6                   |                |
| t | history   | DBP \< 90  | 00 mg/d     129     - |   --           |
| a | CV        | mm Hg and  | 11.5[+]{.underline}0. | ---------- --- |
| n | disease;  | SBP \< 140 | 75    \<0.0001   -15. | ---- --------- |
| ) | history   | mm Hg);    | 73[+]{.underline}1.23 |                |
|   | of        | dose       |                       | **Tx**       * |
| E | m         | response   |   Irbesartan          | *W/D   **Total |
| u | alignancy | rel        |                       |                |
| r | or other  | ationship; |                       |   AE**    AE** |
| o | life-th   | TPR;       |                       |                |
| p | reatening | effect of  |   1                   |   Placebo      |
| e | disease;  | Tx W/D on  | 50 mg/d     133     - |  2.3%    32.1% |
| , | any       | BP; AEs    | 8.88[+]{.underline}0. |                |
| U | medical   | (duration; | 74               -12. |   Aliskir      |
| . | or        | severity;  | 50[+]{.underline}1.21 | en             |
| S | surgical  | relation   |   ---                 |                |
| . | condition | to study   | --------- ------- --- |   150 mg       |
|   | with      | drug;      | --------------------- |  3.9%    26.8% |
| n | potential | outcome);  | --- ---------- ------ |                |
| = | to affect | compliance | --------------------- |   300 mg       |
| 6 | pharmac   |            |                       |  3.1%    36.2% |
| 5 | okinetics | *          | \* Primary endpoint:  |                |
| 2 | of the    | *[Wash-out | change from baseline  |   600 mg       |
|   | drug      | Phase]{.un | in mean trough        |  2.3%    33.1% |
| 8 |           | derline}** | sitting DBP (mm Hg)   |                |
| w |           |            | [+]{.underline} SEM;  |   Irbesar      |
| k |           | W/D HTN    | P value vs. placebo   | tan            |
| s |           | Rx; 2 wk   |                       |                |
|   |           | wash-out   | Aliskiren 150 mg vs.  |   150 mg       |
| S |           |            | irbesartan 150mg      |  2.2%    36.6% |
| u |           | **[Run-in  | (DBP, SBP; NS); DBP   |   --           |
| p |           | Phase]{.un | aliskiren 300 mg      | ---------- --- |
| p |           | derline}** | (P=0.005) and 600 mg  | ---- --------- |
| o |           |            | (P=0.01) vs.          |                |
| r |           | 2-4 wk SB  | irbesartan 150 mg     | All patients   |
| t |           | placebo    | (SBP; NS)             | included in    |
| e |           |            |                       | safety         |
| d |           | **         |   ------------ -      | analysis       |
| b |           | [Treatment | --------------- ----- |                |
| y |           | Phase]{.un | ------ -------------- | Most common    |
| N |           | derline}** |   **Tx**              | AEs included   |
| o |           |            |       **Response\***  | HA (2.4-6.2%   |
| v |           | Randomized |   **P vs.     **P vs. | aliskiren vs.  |
| a |           | to         |                       | 5.3% placebo,  |
| r |           | placebo,   |                   Pla | 3.0%           |
| t |           | aliskiren  | cebo**   Irbesartan** | irbesartan),   |
| i |           | 150 mg,    |                       | dizziness      |
| s |           | 300 mg,    |                       | (n=19 all tx   |
|   |           | 600 mg, or | Placebo      27/130 ( | groups),       |
|   |           | irbesartan | 20.8%)                | diarrhea (n=16 |
|   |           | 150mg once |                       | all tx groups) |
|   |           | daily at   |                       |                |
|   |           | 8:00am for | Aliskiren             |                |
|   |           | 8 weeks    |                       |                |
|   |           | (drug      |                       |                |
|   |           | taken      |                       |                |
|   |           | after      | 150 mg/d     48/127 ( |                |
|   |           | evaluation | 37.8%)   \<0.05       |                |
|   |           | on study   |                       |                |
|   |           | visits)    |   300 mg              |                |
|   |           |            | /d     65/130 (50.0%) |                |
|   |           | **[Run-out |    \<0.05      \<0.05 |                |
|   |           | Phase]{.un |                       |                |
|   |           | derline}** |   600 mg              |                |
|   |           |            | /d     59/129 (45.7%) |                |
|   |           | 3-4 d W/D  |    \<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              |                |
|   |           |            | Concl                 |                |
|   |           |            | usions]{.underline}** |                |
|   |           |            |                       |                |
|   |           |            | > 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             |                |
+---+-----------+------------+-----------------------+----------------+
| * | ##        | #########  | **Baseline** (mean):  | **[Completed   |
| * | ####### I |  Endpoints | age                   | Trial (ITT     |
| S | nclusion  |            | 50.7[+]{              | Analysis)]     |
| t | Criteria  | **         | .underline}10.9-55.9[ | {.underline}** |
| a |           | Primary:** | +]{.underline}8.9yrs; |                |
| n | Men and   | antihy     | 66.0% male; mean      | **Aliskiren:** |
| t | women 21  | pertensive | daytime ABPM SBP/DBP  | 37.5 mg, 39/45 |
| o | to 70 yrs | efficacy   | 152.6[+]{.            | (86.7%); 75    |
| n | of age,   | (change in | underline}9.7-156.2[+ | mg, 41/46      |
| e | mild to   | daytime    | ]{.underline}10.5/91. | (89.1%); 150   |
| t | moderate  | SBP by     | 1[+]{.underline}9.0-9 | mg, 41/44      |
| a | HTN       | ABPM at    | 6.5[+]{.underline}8.4 | (93.2%); 300   |
| l | (off-Tx   | end of     | mm Hg                 | mg, 40/47      |
| , | average   | study vs.  |                       | (85.1%)        |
| 2 | SBP by    | baseline)  |   ----------- ---     |                |
| 0 | ABPM      | of         | ---- ---------------- | **Losartan:**  |
| 0 | [\>]{.u   | aliskiren  | ---------- ---------- | 100 mg 36/44   |
| 3 | nderline} | 37.5 mg,   | ---------------- ---- | (81.8%)        |
| ^ | 140 mm    | 75 mg, 150 | --------------------- |                |
| 1 | Hg)       | mg, 300 mg |   *                   | **[Adverse     |
| 2 |           | **Other:** | *Tx**      **n**   ** | Events]        |
| ^ | ##        | antihy     | SBP\***               | {.underline}** |
| * | ####### E | pertensive |     **SBP\*\***       |                |
| * | xclusion  | efficacy   |           **DBP\*\*** | **Serious      |
|   | Criteria  | of         |                       | AEs:**         |
| M |           | aliskiren  |   Aliskiren           | Aliskiren 300  |
| C | Unable to | vs.        |                       | mg (n=2: chest |
| , | W/D       | losartan;  |                       | tightness/ECG  |
| R | me        | clinic     |                       | ischemic       |
| , | dications | sitting    |                       | changes;       |
| D | for HTN;  | and        |   37.5 mg/d   3       | collapsed      |
| B | secondary | standing   | 9      -0.4[+]{.under | /hypotensive); |
| , | or        | BP; dose   | line}11.7    -4.3[+]{ | losartan 100   |
| P | malignant | response   | .underline}17.8    -1 | mg (n=1: death |
| G | HTN; DM;  | rel        | .9[+]{.underline}10.5 | after ruptured |
| , | CAD; any  | ationship; |                       | left common    |
| A | medical   | aliskiren  |   75 mg/d     4       | iliac artery   |
| C | or        | levels and | 1      -5.3[+]{.under | aneurysm)      |
| ( | surgical  | PRA; AEs;  | line}11.3    -4.1[+]{ |                |
| l | condition | compliance | .underline}16.9    -0 |   -            |
| o | with      |            | .2[+]{.underline}12.4 | ---------- --- |
| s | potential | *          |                       | ---- --------- |
| a | to affect | *[Wash-out |   150 mg/d    4       |                |
| r | pharmac   | Phase]{.un | 1      -8.0[+]{.under |  **Tx**      * |
| t | okinetics | derline}** | line}11.0    -10.0[+] | *W/D   **Total |
| a | of the    |            | {.underline}17.0   -2 |                |
| n | drug      | W/D HTN    | .2[+]{.underline}10.0 |   AE**    AE** |
| ) |           | Rx; 1-4 wk |                       |                |
|   | #         | wash-out   |   300 mg/d    4       |   Aliski       |
| I | ########  |            | 7      -11.0[+]{.unde | ren            |
| r |           | **         | rline}11.0   -11.8[+] |                |
| e |           | [Treatment | {.underline}14.9   -5 |   37.5 mg      |
| l |           | Phase]{.un | .7[+]{.underline}11.0 |    4.4%    22% |
| a |           | derline}** |                       |   (n=45)       |
| n |           |            |   Losartan            |                |
| d |           | #########  |                       |                |
|   |           |  Randomize |                       |   75 mg        |
| n |           | d to alisk |                       |    6.5%    35% |
| = |           | iren 37.5  |                       |   (n=46)       |
| 2 |           | mg, 75 mg, |   100 mg/d    4       |                |
| 2 |           |  150 mg, 3 | 4      -10.9[+]{.unde |                |
| 6 |           | 00 mg, or  | rline}13.8   -11.4[+] |   150 mg       |
| ( |           | losartan 1 | {.underline}19.2   -5 |    0%      25% |
| s |           | 00mg once  | .5[+]{.underline}10.7 |   (n=44)       |
| a |           | daily 30 m |   ----------- ---     |                |
| f |           | in before  | ---- ---------------- |                |
| e |           | breakfast  | ---------- ---------- |   300 mg       |
| t |           | for 4 wks  | ---------------- ---- |    6.4%    23% |
| y |           |            | --------------------- |   (n=47)       |
| ) |           |            |                       |                |
| ; |           |            | \* Primary endpoint:  |                |
| 1 |           |            | change from baseline  |   Losart       |
| 9 |           |            | in mean daytime SBP   | an             |
| 7 |           |            | by ABPM (mm Hg)       |                |
| ( |           |            | [+]{.underline} SEM,  |   100 mg       |
| I |           |            | P=0.0002 for          |    6.8%    32% |
| T |           |            | dose-dependent        |   (n=44)       |
| T |           |            | analysis; reported    |                |
| ) |           |            | significant reduction |   -            |
|   |           |            | for 75 mg, 150 mg,    | ---------- --- |
| 4 |           |            | 300 mg and losartan   | ---- --------- |
| w |           |            | 100 mg; reported no   |                |
| k |           |            | significant           | Most common    |
| s |           |            | difference with       | AEs (n=NR)     |
|   |           |            | losartan 100 mg vs.   | included       |
| S |           |            | aliskiren 75 mg, 150  | fatigue or     |
| p |           |            | mg, 300 mg            | weakness, GI   |
| o |           |            |                       | disorders, HA  |
| n |           |            | \*\* Change from      |                |
| s |           |            | baseline in mean      |                |
| o |           |            | sitting BP (mm Hg)    |                |
| r |           |            | [+]{.underline} SD    |                |
| e |           |            |                       |                |
| d |           |            | > **PRA vs.           |                |
| b |           |            | > Baseline**: PRA     |                |
| y |           |            | > significantly       |                |
| S |           |            | > reduced with all    |                |
| p |           |            | > doses aliskiren     |                |
| e |           |            | > (55-83%) vs.        |                |
| e |           |            | > increased with      |                |
| d |           |            | > losartan (110%)     |                |
| e |           |            | >                     |                |
| l |           |            | > **Aliskiren         |                |
| P |           |            | > Levels**: Trough    |                |
| h |           |            | > plasma              |                |
| a |           |            | > concentrations      |                |
| r |           |            | > increased with      |                |
| m |           |            | > increasing doses    |                |
| a |           |            | > aliskiren           |                |
| A |           |            | >                     |                |
| G |           |            | > **Compliance (pill  |                |
|   |           |            | > count):** \> 95%    |                |
|   |           |            | > across Tx groups    |                |
|   |           |            |                       |                |
|   |           |            | **[Study              |                |
|   |           |            | Concl                 |                |
|   |           |            | usions]{.underline}** |                |
|   |           |            |                       |                |
|   |           |            | 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             |                |
+---+-----------+------------+-----------------------+----------------+

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)**

+---+-----------+------------+-----------------------+----------------+
| # | ### I     | ###        | ##                    | ### W          |
| # | nclusion/ |  Endpoints | # Results/Conclusions | ithdrawals/AEs |
| # | Exclusion | /Treatment |                       |                |
|   |           |            |                       |                |
| T |           |            |                       |                |
| r |           |            |                       |                |
| i |           |            |                       |                |
| a |           |            |                       |                |
| l |           |            |                       |                |
+---+-----------+------------+-----------------------+----------------+
| * | ##        | #########  | **Baseline** (mean):  | **[Completed   |
| * | ####### I |  Endpoints | age 51.9-52.6yrs; 61% | Trial (ITT     |
| O | nclusion  |            | male; 75% White, 16%  | Analysis)]     |
| p | criteria  | **         | Black; mean sitting   | {.underline}** |
| a |           | Primary:** | SBP/DBP               |                |
| r | Men and   | antihy     | 152.8[+]{.und         | **Aliskiren:** |
| i | women     | pertensive | erline}12.2-154.2[+]{ | 430/437        |
| l | [\>]{.u   | efficacy   | .underline}12.7/100.1 | (98.4%)        |
| e | nderline} | (change in | [+]{.underline}4.0-10 |                |
| t | 18 yrs of | mean       | 0.4[+]{.underline}4.2 | **Valsartan:** |
| a | age,      | trough     | mm Hg                 | 453/455        |
| l | stage 1   | sitting    |                       | (99.6%)        |
| , | to 2      | DBP at end |                       |                |
| 2 | essential | of study   |  -------------------- | **Aliskire     |
| 0 | HTN (mean | vs.        | - ------- ----------- | n/Valsartan:** |
| 0 | sitting   | baseline)  |  ---------- --------- | 438/446        |
| 7 | DBP       | of 300 mg  |   **Tx**              | (98.2%)        |
| ^ | [\>]{.u   | aliskiren  |     **n**   **DBP\*** |                |
| 8 | nderline} | and 320 mg |    **P**      **SBP** | **Placebo:**   |
| ^ | 95 mm Hg  | valsartan  |                       | 455/459        |
| * | to \< 110 | vs.        |   Placebo             | (99.1%)        |
| * | mm Hg)    | c          |        455     -4.1   |                |
|   | were      | ombination |                  -4.6 | **[Adverse     |
| M | eligible  | aliskiren  |                       | Events]        |
| C | for       | /valsartan |   Aliskiren           | {.underline}** |
| , | en        | 300/320 mg |                       |                |
| R | rollment; |            |                       | **Serious      |
| , | patients  | **Se       |                       | AEs:**         |
| D | with DBP  | condary:** |   300 mg/d            | aliskiren      |
| B | [\>]{.u   | change in  |       430     -9.0    | (n=8; 1 death  |
| , | nderline} | mean       |      \<0.0001   -13.0 | due to MI);    |
| P | 90 mm Hg  | trough     |                       | valsartan      |
| C | by 8hr    | sitting    |   Valsartan           | (n=6; 1 sudden |
| , | daytime   | SBP at end |                       | death due to   |
| P | ABPM at   | of study   |                       | arte           |
| G | end of    | vs.        |                       | riosclerosis); |
|   | run-in    | baseline;  |   320 mg/d            | alisk          |
| G | phase     | proportion |       453     -9.7    | iren/valsartan |
| e | were      | responding |      \<0.0001   -12.8 | (n=3); placebo |
| r | eligible  | to Tx      |                       | (n=5)          |
| m | for       | (mean      |   Aliskiren/V         |                |
| a | rand      | sitting    | alsartan              |   -----------  |
| n | omization | DBP \< 90  |                       | ---------- --- |
| y |           | mm Hg or   |                       | ---- --------- |
| , | ##        | [\>]{.     |   300/320 mg/d        |   **Tx**       |
| S | ####### E | underline} |       438     -12.2   |              * |
| p | xclusion  | 10 mm Hg   |      \<0.0001   -17.2 | *W/D   **Total |
| a | criteria  | decrease   |                       |                |
| i |           | in DBP);   |  -------------------- |                |
| n | History   | BP control | - ------- ----------- |   AE**    AE** |
| , | of severe | (mean      |  ---------- --------- |                |
| U | CV or     | sitting    |                       |   Place        |
| . | cerebr    | DBP \< 90  | \* Primary endpoint:  | bo             |
| S | ovascular | mm Hg and  | change from baseline  |    3.4%    37% |
| . | disease;  | SBP \< 140 | in mean trough        |                |
|   | other     | mm Hg);    | sitting DBP (mm Hg);  |   Al           |
| n | life-th   | change     | P value vs. placebo;  | iskiren        |
| = | reatening | from       | P\< 0.0001 for        |                |
| 1 | medical   | baseline   | aliskiren/valsartan   |                |
| 7 | c         | in 24hr    | vs. each component as |   300 m        |
| 9 | ondition; | ABPM; PRA, | monotherapy)          | g              |
| 7 | patients  | RC, PAC    |                       |    1.7%    34% |
| ; | with      |            |   ------------        |                |
| 1 | sitting   | **Other:** | --------- ----------- |   Va           |
| 7 | DBP       | Change in  | ----- --------------- | lsartan        |
| 7 | [\>]{.u   | DBP and    |   **Tx**              |                |
| 6 | nderline} | SBP at 4   |             **Respons |                |
| ( | 110 mm Hg | wks;       | e\***   **Control\*** |   320 m        |
| I | or SBP    | safety and |                       | g              |
| T | [\>]{.u   | to         |                       |    5.0%    37% |
| T | nderline} | lerability | Placebo               |                |
| ) | 180 mm Hg | (AEs,      |  30%              16% |   Al           |
|   | at any    | h          |                       | iskiren/Valsar |
| 8 | time      | ematology, |   Aliskiren           | tan            |
| w | during    | blood      |                       |                |
| k | the study | chemistry, |                       |   300/3        |
| s | were      | urine, VS, |                       | 20 mg          |
|   | withdrawn | physical   | 300 mg/d              |    3.4%    35% |
| F |           | condition, |  53%              37% |   -----------  |
| u |           | weight)    |                       | ---------- --- |
| n |           |            |   Valsartan           | ---- --------- |
| d |           | *          |                       |                |
| e |           | *[Wash-out |                       | Most common    |
| d |           | Phase]{.un |                       | AEs included   |
| b |           | derline}** | 320 mg/d              | HA (3%         |
| y |           |            |  55%              34% | aliskiren vs.  |
| N |           | W/D HTN    |                       | 5% valsartan,  |
| o |           | Rx; 1-2 wk |   Aliskiren/Valsarta  | 4%             |
| v |           | wash-out   | n                     | aliski         |
| a |           |            |                       | ren/valsartan, |
| r |           | **[Run-in  |                       | 9% placebo),   |
| t |           | phase]{.un | 300/320 mg/d          | n              |
| i |           | derline}** |  66%              49% | asopharyngitis |
| s |           |            |   ------------        | (4% aliskiren  |
| P |           | 3-4 wk SB  | --------- ----------- | vs. 4%         |
| h |           | placebo    | ----- --------------- | valsartan, 3%  |
| a |           |            |                       | aliski         |
| r |           | **         | \* Response: percent  | ren/valsartan, |
| m |           | [Treatment | of patients with mean | 2% placebo),   |
| a |           | phase]{.un | sitting DBP \< 90 mm  | dizziness (2%  |
| c |           | derline}** | Hg or                 | aliskiren vs.  |
| e |           |            | [\>]{.underline} 10   | 2% valsartan,  |
| u |           | #          | mm Hg decrease in     | 2%             |
| t |           | ######## R | DBP; BP control: mean | aliski         |
| i |           | andomized  | sitting DBP \< 90 mm  | ren/valsartan, |
| c |           | to placebo | Hg and SBP \< 140 mm  | 2% placebo)    |
| a |           | , aliskire | Hg                    |                |
| l |           | n monother |                       | Abnormal labs: |
| C |           | apy (150 m | > **ABPM (n=354)**:   | sCr \> 176.8   |
| o |           | g), valsar | > Combination         | micromo/L      |
| r |           | tan monoth | > significantly more  | (n=1,          |
| p |           | erapy (160 | > effective than      | aliskiren;     |
| o |           |  mg), or c | > either monotherapy  | n=2,           |
| r |           | ombination | > (P\<0.0001); each   | valsartan;     |
| a |           |  aliskiren | > monotherapy         | n=4,           |
| t |           |  and valsa | > significantly more  | aliski         |
| i |           | rtan (150/ | > effective than      | ren/valsartan; |
| o |           | 160 mg) on | > placebo (P\<0.0001) | n=0, placebo); |
| n |           | ce daily f | >                     | K^+^ \> 5.5    |
|   |           | or 4 wks;  | > **PRA:** Aliskiren  | mEq/L (n=7,    |
|   |           | doses were | > significantly       | aliskiren;     |
|   |           |  then doub | > decreased PRA and   | n=7,           |
|   |           | led for an | > valsartan           | valsartan;     |
|   |           |  additiona | > significantly       | n=18,          |
|   |           | l 4 wks Tx | > increased PRA from  | aliski         |
|   |           |            | > baseline compared   | ren/valsartan; |
|   |           |            | > to placebo;         | n=12,          |
|   |           |            | > aliskiren/valsartan | placebo); K^+^ |
|   |           |            | > combination         | \> 6.0 mEq/L   |
|   |           |            | > significantly       | (n=4,          |
|   |           |            | > reduced PRA vs.     | aliskiren;     |
|   |           |            | > placebo             | n=5,           |
|   |           |            | >                     | valsartan;     |
|   |           |            | > **RC:**             | n=2,           |
|   |           |            | > Aliskiren/valsartan | aliski         |
|   |           |            | > significantly       | ren/valsartan; |
|   |           |            | > increased RC vs.    | n=6, placebo)  |
|   |           |            | > 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              |                |
|   |           |            | Concl                 |                |
|   |           |            | usions]{.underline}** |                |
|   |           |            |                       |                |
|   |           |            | 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            |                |
+---+-----------+------------+-----------------------+----------------+
| * | ##        | #########  | **Baseline** (mean):  | **[Completed   |
| * | ####### I |  Endpoints | age                   | Trial (ITT     |
| P | nclusion  |            | 56.1[+                | Analysis)]     |
| o | criteria  | **         | ]{.underline}12.2yrs; | {.underline}** |
| o |           | Primary:** | 55.9% male; 92.1%     |                |
| l | Men and   | antihy     | Caucasian; trough     | **Aliskiren:** |
| e | women     | pertensive | mean sitting SBP/DBP  | 75 mg, 177/179 |
| t | [\>]{.u   | efficacy   | 152.4[+]{.under       | (98.9%); 150   |
| a | nderline} | (change in | line}12.58-154.5[+]{. | mg, 177/178    |
| l | 18 yrs of | mean       | underline}10.57/98.6[ | (99.4%); 300   |
| , | age, mild | trough     | +]{.underline}3.01-99 | mg, 175/175    |
| 2 | to        | sitting    | .4[+]{.underline}3.78 | (100%)         |
| 0 | moderate  | DBP at end | mm Hg                 |                |
| 0 | essential | of study   |                       | **Valsartan:** |
| 7 | HTN (mean | vs.        |   ---------           | 80 mg, 58/58   |
| ^ | sitting   | baseline)  | ------------ -------  | (100%); 160    |
| 1 | DBP       | of 75 mg,  | --------------------- | mg, 58/59      |
| 3 | [\>]{.u   | 150 mg,    | ----- --------- ----- | (98.3%); 320   |
| ^ | nderline} | 300 mg     | --------------------- | mg, 60/60      |
| * | 95 mm Hg  | aliskiren  |   **Tx**              | (100%)         |
| * | and \< 10 | vs.        |            **n**   ** |                |
|   | mm Hg     | placebo    | DBP\***               | **Aliskire     |
| M | d         |            |     **P**     **SBP** | n/Valsartan:** |
| C | ifference | **Se       |                       | 75/80 mg,      |
| , | between   | condary:** |   Placebo             | 60/60 (100%);  |
| R | last 2    | change in  |                176    | 150/160 mg,    |
| , | mea       | mean       |   -8.6[+]{.underline} | 60/60 (100%);  |
| D | surements | trough     | 0.62              -10 | 300/320 mg,    |
| B | of 3-4 wk | sitting    | .0[+]{.underline}0.96 | 58/58 (100%)   |
| , | placebo   | SBP at end |                       |                |
| P | run-in)   | of study   |   Alis                | **Val          |
| C |           | vs.        | kiren                 | sartan/HCTZ:** |
| , | ##        | baseline;  |                       | 160/12.5 mg,   |
| P | ####### E | efficacy   |                       | 58/59 (98.3%)  |
| G | xclusion  | of         |                       |                |
|   | criteria  | aliskiren  |   75 mg/d             | **Placebo:**   |
| D |           | /valsartan |                177    | 176/177        |
| e | Severe    | c          |   -10.3[+]{.underline | (99.4%)        |
| n | HTN       | ombination | }0.62             -12 |                |
| m | (sitting  | vs.        | .1[+]{.underline}0.96 | **[Adverse     |
| a | DBP       | respective |                       | Events]        |
| r | [\>]{.u   | m          |   150 mg/             | {.underline}** |
| k | nderline} | onotherapy | d              177    |                |
| , | 110 mm Hg | and with   |   -10.3[+]{.underline | **Serious      |
| F | or SBP    | vals       | }0.62             -12 | AEs:** 0.7%    |
| r | [\>]{.u   | artan/HCTZ | .1[+]{.underline}0.95 | (n=8 overall); |
| a | nderline} | c          |                       | 1 death        |
| n | 180 mm    | ombination |   300 mg/             | reported       |
| c | Hg);      |            | d              175    | (placebo)      |
| e | secondary | **Other:** |   -12.3[+]{.underline |                |
| , | HTN; type | proportion | }0.62   \<0.001   -15 |   -----------  |
| G | 1 DM or   | responding | .0[+]{.underline}0.96 | ---------- --- |
| e | type 2 DM | to Tx      |                       | ---- --------- |
| r | with      | (mean      |   Vals                |   **Tx**       |
| m | HbA~1c~   | sitting    | artan                 |              * |
| a | \> 8%;    | DBP \< 90  |                       | *W/D   **Total |
| n | pregnancy | mm Hg or   |                       |                |
| y | or        | [\>]{.     |                       |                |
| , | breas     | underline} |   80 mg/d             |   AE**    AE** |
| P | tfeeding; | 10 mm Hg   |                58     |                |
| o | history   | decrease   |   -10.5[+]{.underline |   Placebo      |
| l | of severe | in DBP);   | }1.07             -11 |                |
| a | cardiac   | BP control | .2[+]{.underline}1.65 |  3.4%    32.2% |
| n | or        | (mean      |                       |                |
| d | cerebr    | sitting    |   160 mg/             |   Al           |
| , | ovascular | DBP \< 90  | d              58     | iskiren        |
| U | disease;  | mm Hg and  |   -11.0[+]{.underline |                |
| . | history   | SBP \< 140 | }1.07   \<0.05    -15 |                |
| S | of severe | mm Hg);    | .5[+]{.underline}1.65 |   75 mg        |
| . | or        | dose       |                       |                |
|   | life-th   | response   |   320 mg/             |  2.8%    35.2% |
| n | reatening | rel        | d              60     |                |
| = | disease;  | ationship; |   -11.3[+]{.underline |   150 mg       |
| 1 | any       | safety and | }1.05   \<0.05    -16 |                |
| 1 | medical   | to         | .5[+]{.underline}1.62 |  1.7%    33.1% |
| 2 | or        | lerability |                       |                |
| 3 | surgical  | (duratio   |   Alis                |   300 mg       |
|   | condition | n/severity | kiren/Valsartan       |                |
| 8 | with      | of AEs,    |                       |  1.7%    28.6% |
| w | potential | relation   |                       |                |
| k | to affect | to study   |                       |   Va           |
| s | pharmac   | drug)      |   75/80 m             | lsartan        |
|   | okinetics |            | g/d            60     |                |
| S | of the    | *          |   -11.8[+]{.underline |                |
| u | drug      | *[Wash-out | }1.05   \<0.01    -14 |   80 mg        |
| p |           | Phase]{.un | .5[+]{.underline}1.62 |                |
| p | #         | derline}** |                       |  0%      32.8% |
| o | ########  |            |   150/160             |                |
| r |           | W/D HTN Rx |  mg/d          60     |   160 mg       |
| t |           |            |   -12.1[+]{.underline |                |
| e |           | **[Run-in  | }1.05   \<0.01    -16 |  3.4%    28.8% |
| d |           | phase]{.un | .6[+]{.underline}1.62 |                |
| b |           | derline}** |                       |   320 mg       |
| y |           |            |   300/320             |                |
| N |           | 3-4 wk SB  |  mg/d          58     |  5.0%    30.0% |
| o |           | placebo    |   -12.9[+]{.underline |                |
| v |           |            | }1.07   \<0.001   -18 |   Al           |
| a |           | **         | .0[+]{.underline}1.65 | iskiren/Valsar |
| r |           | [Treatment |                       | tan            |
| t |           | phase]{.un |   Vals                |                |
| i |           | derline}** | artan/HCTZ            |   75/80 m      |
| s |           |            |                       | g              |
| P |           | #          |                       |  0%      33.3% |
| h |           | ######## R |                       |                |
| a |           | andomized  |   160/12.             |   150/160      |
| r |           | to placebo | 5 mg/d         58     |  mg            |
| m |           | , aliskire |   -13.5[+]{.underline |  1.7%    26.7% |
| a |           | n monother | }1.07   \<0.001   -18 |                |
| A |           | apy (75 mg | .9[+]{.underline}1.65 |   300/320      |
| G |           | , 150 mg,  |   ---------           |  mg            |
|   |           | 300 mg), v | ------------ -------  |  3.4%    31.0% |
|   |           | alsartan ( | --------------------- |                |
|   |           | 80 mg, 160 | ----- --------- ----- |   Va           |
|   |           |  mg, 320 m | --------------------- | lsartan/HCTZ   |
|   |           | g), combin |                       |                |
|   |           | ation alis | \* Primary endpoint:  |                |
|   |           | kiren and  | change from baseline  |   160/12.      |
|   |           | valsartan  | in mean trough        | 5 mg           |
|   |           | (75/80 mg, | sitting DBP (mm Hg)   |  0%      22.0% |
|   |           |  150/160 m | [+]{.underline} SEM;  |   -----------  |
|   |           | g, 300/320 | P value for           | ---------- --- |
|   |           |  mg), or c | placebo-corrected     | ---- --------- |
|   |           | ombination | change (\<0.001 vs.   |                |
|   |           |  valsartan | placebo; \< 0.05 and  | Most common    |
|   |           |  and HCTZ  | \< 0.01 vs. aliskiren | AEs included   |
|   |           | (160/12.5  | 150 mg)               | HA (4.0-8.4%   |
|   |           | mg) once d |                       | aliskiren vs.  |
|   |           | aily at 8: |   ------------        | 3.4-5.2%       |
|   |           | 00am (with | --------- ----------- | valsartan,     |
|   |           | out regard | ----- --------------- | 8.5% placebo), |
|   |           |  to meals) |   **Tx**              | fatigue        |
|   |           |  except on |             **Respons | (2.2-3.9%      |
|   |           |  day of st | e\***   **Control\*** | aliskiren vs.  |
|   |           | udy visit  |                       | 0-6.8%         |
|   |           |            |   Pl                  | valsartan,     |
|   |           |            | acebo               4 | 2.3% placebo), |
|   |           |            | 8.3%            27.8% | back pain      |
|   |           |            |                       | (1.1-2.2%      |
|   |           |            |   Aliskiren           | aliskiren vs.  |
|   |           |            |                       | 0-5.0%         |
|   |           |            |                       | valsartan,     |
|   |           |            |   75                  | 1.1% placebo), |
|   |           |            |  mg/d               5 | diarrhea       |
|   |           |            | 9.9%            36.2% | (0.6-2.9%      |
|   |           |            |                       | aliskiren vs.  |
|   |           |            |   15                  | 0-1.7%         |
|   |           |            | 0 mg/d              5 | valsartan,     |
|   |           |            | 9.3%            30.5% | 1.7% placebo)  |
|   |           |            |                       |                |
|   |           |            |   30                  | Abnormal labs: |
|   |           |            | 0 mg/d              6 | sCr \> 2 mg/dL |
|   |           |            | 8.0%            42.3% | (n=1,          |
|   |           |            |                       | aliskiren 75   |
|   |           |            |   Valsartan           | mg); K^+^ \>   |
|   |           |            |                       | 5.5 mEq/L      |
|   |           |            |                       | (n=1, placebo; |
|   |           |            |   80                  | n=1, aliskiren |
|   |           |            |  mg/d               5 | 75 mg; n=1,    |
|   |           |            | 5.2%            37.9% | aliskiren 300  |
|   |           |            |                       | mg; n=1,       |
|   |           |            |   16                  | alisk          |
|   |           |            | 0 mg/d              6 | iren/valsartan |
|   |           |            | 5.5%            46.6% | 150/160 mg;    |
|   |           |            |                       | n=1,           |
|   |           |            |   32                  | alisk          |
|   |           |            | 0 mg/d              6 | iren/valsartan |
|   |           |            | 3.3%            41.7% | 300/320 mg)    |
|   |           |            |                       |                |
|   |           |            |   Aliskiren/Valsarta  |                |
|   |           |            | n                     |                |
|   |           |            |                       |                |
|   |           |            |   75                  |                |
|   |           |            | /80 mg/d            7 |                |
|   |           |            | 5.0%            43.3% |                |
|   |           |            |                       |                |
|   |           |            |   15                  |                |
|   |           |            | 0/160 mg/d          6 |                |
|   |           |            | 6.7%            36.7% |                |
|   |           |            |                       |                |
|   |           |            |   30                  |                |
|   |           |            | 0/320 mg/d          7 |                |
|   |           |            | 5.9%            50.0% |                |
|   |           |            |                       |                |
|   |           |            |   Valsartan/HCTZ      |                |
|   |           |            |                       |                |
|   |           |            |                       |                |
|   |           |            |   16                  |                |
|   |           |            | 0/12.5 mg/d         7 |                |
|   |           |            | 9.3%            55.2% |                |
|   |           |            |   ------------        |                |
|   |           |            | --------- ----------- |                |
|   |           |            | ----- --------------- |                |
|   |           |            |                       |                |
|   |           |            | \* Response: percent  |                |
|   |           |            | of patients with mean |                |
|   |           |            | sitting DBP \< 90 mm  |                |
|   |           |            | Hg or                 |                |
|   |           |            | [\>]{.underline} 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              |                |
|   |           |            | Concl                 |                |
|   |           |            | usions]{.underline}** |                |
|   |           |            |                       |                |
|   |           |            | 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             |                |
+---+-----------+------------+-----------------------+----------------+
| * | ##        | #########  | **Baseline** (mean):  | **[Completed   |
| * | ####### I |  Endpoints | age 53.5-55.5yrs;     | Trial (ITT     |
| V | nclusion  |            | 49.2-60.5% male;      | Analysis)]     |
| i | criteria  | **Co-      | Race: 83.2-88.7%      | {.underline}** |
| l |           | Primary:** | Caucasian; Ethnicity: |                |
| l | Men and   | antihy     | 23.3-31.3%            | **Aliskiren:** |
| a | women     | pertensive | Hispanic/Latin; mean  | 75 mg, 183/184 |
| m | [\>]{.u   | efficacy   | sitting SBP/DBP       | (99.5%); 150   |
| i | nderline} | (change in | 1                     | mg, 183/185    |
| l | 18 yrs of | mean       | 52.7-154.6/98.4-100.0 | (98.9%); 300   |
| e | age, mild | trough     | mm Hg                 | mg, 180/183    |
| t | to        | sitting    |                       | (98.4%)        |
| a | moderate  | DBP at end |   ----                |                |
| l | essential | of study   | ---------------- ---- | **HCTZ:** 6.25 |
| , | HTN (mean | vs.        | --- ----------------- | mg, 194/194    |
| 2 | sitting   | baseline)  | --------- ----------- | (100%); 12.5   |
| 0 | DBP       | of 75 mg,  | ------------- ------- | mg, 188/188    |
| 0 | [\>]{.u   | 150 mg,    | -- ------------------ | (100%); 25 mg, |
| 7 | nderline} | 300 mg     |   **                  | 173/176        |
| ^ | 95 mm Hg  | aliskiren  | Tx**               ** | (98.3%)        |
| 1 | and \<    | vs.        | n**   **DBP\***       |                |
| 4 | 110 mm Hg | placebo    |             **P**     | **Ali          |
| ^ | after 2   | and the    |                 **SBP | skiren/HCTZ:** |
| * | wks       | antihy     | **   **Response^\#^** | 75/6.25 mg,    |
| * | placebo   | pertensive |                       | 187/188        |
|   | run-in)   | efficacy   |   Placebo             | (99.5%);       |
| M |           | of         |          192     -6.9 | 75/12.5 mg,    |
| C | ##        | c          |                       | 189/193        |
| , | ####### E | ombination |                       | (97.9%); 75/25 |
| R | xclusion  | aliskiren  |       -7.5      45.8% | mg, 186/186    |
| , | criteria  | with HCTZ  |                       | (100%);        |
| D |           | vs.        |   Aliskir             | 150/6.25 mg,   |
| B | Severe    | m          | en                    | 173/176        |
| , | HTN       | onotherapy |                       | (98.3%);       |
| P | (sitting  |            |                       | 150/12.5 mg,   |
| C | DBP       | **Se       |                       | 184/186        |
| , | [\>]{.u   | condary:** |                       | (98.9%);       |
| P | nderline} | change in  |   75 mg/d             | 150/25 mg,     |
| G | 110 mm Hg | mean       |          183     -8.7 | 187/188        |
|   | and/or    | trough     | [+]{.underline}0.59   | (99.5%);       |
| 2 | SBP       | sitting    |   \<0.05              | 300/12.5 mg,   |
| 1 | [\>]{.u   | SBP at end |       -9.4      51.9% | 180/181        |
| 3 | nderline} | of study   |                       | (99.5%);       |
| c | 180 mm    | vs.        |   150 mg/d            | 300/25 mg,     |
| e | Hg);      | baseline   |          183     -8.9 | 173/173 (100%) |
| n | history   | of the     | [+]{.underline}0.59   |                |
| t | secondary | primary    |   \<0.05              | **Placebo:**   |
| e | HTN; type | endpoint   |       -12.2     51.9% | 192/195        |
| r | 1 DM or   | co         |                       | (98.5%)        |
| s | type 2 DM | mparisons; |   300 mg/d            |                |
| w | with      | proportion |          180     -10. | **[Adverse     |
| o | HbA~1c~   | responding | 3[+]{.underline}0.60  | Events]        |
| r | [\>]{.u   | to tx      |   [\<]{.underline}0.0 | {.underline}** |
| l | nderline} | (mean      | 001   -15.7     63.9% |                |
| d | 9%;       | sitting    |                       | **Severe       |
| w | pregnancy | DBP \< 90  |   HCTZ                | AEs/Serious    |
| i | or        | mm Hg      |                       | AEs:**         |
| d | breas     | and/or     |                       | 0.             |
| e | tfeeding; | [\>]{.     |                       | 5-3.9%/0-2.6%; |
|   | any       | underline} |                       | 1 death        |
| n | medical   | 10 mm Hg   |                       | (              |
| = | or        | decrease   |   6.25 mg/d           | aliskiren/HCTZ |
| 2 | surgical  | in DBP);   |          194     -9.1 | 150/25 mg) due |
| 7 | condition | BP control | [+]{.underline}0.58   | to thoracic    |
| 7 | with      | (mean      |   \<0.05              | trauma from    |
| 6 | potential | sitting    |       -11.0     53.6% | MVA            |
| ; | to affect | DBP \< 90  |                       |                |
| 2 | pharmac   | mm Hg and  |   12.5 mg/d           |   ------       |
| 7 | okinetics | SBP \< 140 |          188     -10. | ---------- --- |
| 5 | of the    | mm Hg);    | 1[+]{.underline}0.59  | ---- --------- |
| 2 | drug      | dose       |   [\<]{.underline}0.0 |   **Tx         |
| ( |           | response   | 001   -13.9     60.6% | **           * |
| I |           | rel        |                       | *W/D   **Total |
| T |           | ationship; |   25 mg/d             |                |
| T |           | safety and |          173     -9.4 |                |
| ) |           | to         | [+]{.underline}0.61   |   AE**    AE** |
| ; |           | lerability |   \<0.05              |                |
| 2 |           | of         |       -14.3     59.0% |   Pl           |
| 7 |           | m          |                       | acebo          |
| 6 |           | onotherapy |   Aliskir             |  3.6%    44.0% |
| 2 |           | and        | en/HCTZ\*\*           |                |
| ( |           | c          |                       |   Aliskiren    |
| s |           | ombination |                       |                |
| a |           | therapy;   |                       |                |
| f |           | PRA and RC |                       |   75           |
| e |           |            |   75/6.25 mg/d        |  mg            |
| t |           | *          |          187     -10. |  0.5%    37.5% |
| y |           | *[Wash-out | 8                     |                |
| ) |           | Phase]{.un |   \<0.05              |   15           |
|   |           | derline}** |       -14.3     61.5% | 0 mg           |
| 8 |           |            |                       |  0%      37.3% |
| w |           | W/D HTN    |   75/12.5 mg/d        |                |
| k |           | Rx; 1 wk   |          189     -11. |   30           |
| s |           | wash-out   | 1                     | 0 mg           |
|   |           |            |                       |  4.4%    39.2% |
| I |           | **[Run-in  |       -15.6     63.5% |                |
| n |           | phase]{.un |                       |   HCTZ         |
| v |           | derline}** |   75/25 mg/d          |                |
| o |           |            |          186     -11. |                |
| l |           | 2-4 wk SB  | 5                     |   6.           |
| v |           | placebo    |   \<0.05              | 25 mg          |
| e |           |            |       -17.3     70.4% |  1.0%    38.7% |
| m |           | **         |                       |                |
| e |           | [Treatment |   150/6.25 mg/        |   12           |
| n |           | phase]{.un | d        173     -10. | .5 mg          |
| t |           | derline}** | 4                     |  0.5%    42.0% |
| o |           |            |                       |                |
| f |           | Randomized |       -15.3     58.4% |   25           |
| s |           | to         |                       |  mg            |
| p |           | placebo,   |   150/12.5 mg/        |  2.3%    41.6% |
| o |           | aliskiren  | d        184     -11. |                |
| n |           | m          | 9                     |   Aliskiren/H  |
| s |           | onotherapy |   \<0.05              | CTZ            |
| o |           | (75 mg,    |       -17.6     69.6% |                |
| r |           | 150 mg,    |                       |   75           |
| n |           | 300 mg),   |   150/25 mg/d         | /6.25 mg       |
| o |           | HCTZ (6.25 |          187     -12. |  1.6%    34.6% |
| t |           | mg, 12.5   | 7                     |                |
| r |           | mg, 25 mg) |   \<0.05              |   75           |
| e |           | or         |       -19.5     71.1% | /12.5 mg       |
| p |           | c          |                       |  3.7%    39.5% |
| o |           | ombination |   300/12.5 mg/        |                |
| r |           | aliskiren  | d        180     -13. |   75           |
| t |           | and HCTZ   | 9                     | /25 mg         |
| e |           | (all dose  |   \<0.05              |  2.2%    41.4% |
| d |           | co         |       -19.8     80.6% |                |
|   |           | mbinations |                       |   15           |
|   |           | except 300 |   300/25 mg/d         | 0/6.25 mg      |
|   |           | mg/6.25    |          173     -14. |  4.0%    37.9% |
|   |           | mg) once   | 3                     |                |
|   |           | daily      |   \<0.05              |   15           |
|   |           |            |       -21.2     76.9% | 0/12.5 mg      |
|   |           |            |   ----                |  2.2%    39.1% |
|   |           |            | ---------------- ---- |                |
|   |           |            | --- ----------------- |   15           |
|   |           |            | --------- ----------- | 0/25 mg        |
|   |           |            | ------------- ------- |  3.2%    44.1% |
|   |           |            | -- ------------------ |                |
|   |           |            |                       |   30           |
|   |           |            | \* Primary            | 0/12.5 mg      |
|   |           |            | endpoint:s: change    |  1.7%    45.3% |
|   |           |            | from baseline in mean |                |
|   |           |            | trough sitting DBP    |   30           |
|   |           |            | (mm Hg)               | 0/25 mg        |
|   |           |            | [+]{.underline} SEM;  |  2.9%    41.0% |
|   |           |            | P value vs. placebo;  |   ------       |
|   |           |            | \*\* change from      | ---------- --- |
|   |           |            | baseline in mean      | ---- --------- |
|   |           |            | sitting BP (mm Hg)    |                |
|   |           |            | [+]{.underline} SEM   | Most common    |
|   |           |            | vs. component         | AEs included   |
|   |           |            | monotherapy; P value  | HA (5.5-7.1%   |
|   |           |            | vs. component         | aliskiren vs.  |
|   |           |            | monotherapy           | 6.2-8.0% HCTZ, |
|   |           |            |                       | 13.5% placebo) |
|   |           |            | ^\#^ Response:        | and            |
|   |           |            | percent of patients   | n              |
|   |           |            | with mean sitting DBP | asopharyngitis |
|   |           |            | \< 90 mm Hg and/or    | (1.7-4.9%      |
|   |           |            | [\>]{.underline} 10   | aliskiren vs.  |
|   |           |            | mm Hg decrease in DBP | 3.1-4.8% HCTZ, |
|   |           |            |                       | 5.2% placebo); |
|   |           |            | > **BP Control:**     | incidence of   |
|   |           |            | > Significant with    | hypokalemia    |
|   |           |            | > aliskiren 300 mg    | with HCTZ      |
|   |           |            | > vs. placebo (46.7   | decreased with |
|   |           |            | > vs. 28.1%;          | combination    |
|   |           |            | > P=0.0001); all      | aliskiren      |
|   |           |            | > combinations        |                |
|   |           |            | > (except             |                |
|   |           |            | > aliskiren/HCTZ      |                |
|   |           |            | > 75/6.25 mg)         |                |
|   |           |            | > significant vs.     |                |
|   |           |            | > placebo (P\<0.02);  |                |
|   |           |            | > trend toward        |                |
|   |           |            | > improved BP control |                |
|   |           |            | > with combination    |                |
|   |           |            | > therapy             |                |
|   |           |            | > (37.4-59.5%) vs.    |                |
|   |           |            | > either monotherapy  |                |
|   |           |            | > (aliskiren          |                |
|   |           |            | > 29.0-46.7%; HCTZ    |                |
|   |           |            | > 32.5-37.8%)         |                |
|   |           |            | >                     |                |
|   |           |            | > **Dose Response     |                |
|   |           |            | > (DBP)**:            |                |
|   |           |            | > Demonstrated with   |                |
|   |           |            | > aliskiren           |                |
|   |           |            | >                     |                |
|   |           |            | > **PRA**: Decreased  |                |
|   |           |            | > with aliskiren 75   |                |
|   |           |            | > mg (54.2%), 150 mg  |                |
|   |           |            | > (65.1%), and 300 mg |                |
|   |           |            | > (57.6%); increased  |                |
|   |           |            | > with HCTZ 6.25 mg   |                |
|   |           |            | > (3.5%), 12.5 mg     |                |
|   |           |            | > (44.7%), and 25 mg  |                |
|   |           |            | > (71.9%); placebo    |                |
|   |           |            | > (0.7% increase);    |                |
|   |           |            | > decreased with      |                |
|   |           |            | > combination         |                |
|   |           |            | > aliskiren/HCTZ      |                |
|   |           |            | > (46.1-63.5%)        |                |
|   |           |            | >                     |                |
|   |           |            | > **RC**: Increased   |                |
|   |           |            | > with aliskiren (75  |                |
|   |           |            | > mg, 164%; 150 mg,   |                |
|   |           |            | > 192%; 300 mg,       |                |
|   |           |            | > 348%), also         |                |
|   |           |            | > increased with HCTZ |                |
|   |           |            | > 25 mg (108%);       |                |
|   |           |            | > increase with HCTZ  |                |
|   |           |            | > 6.25 mg (10%) and   |                |
|   |           |            | > 12.5 mg (26%) less  |                |
|   |           |            | > than placebo (30%)  |                |
|   |           |            |                       |                |
|   |           |            | **[Study              |                |
|   |           |            | Concl                 |                |
|   |           |            | usions]{.underline}** |                |
|   |           |            |                       |                |
|   |           |            | > Short-term          |                |
|   |           |            | > treatment (8 weeks) |                |
|   |           |            | > with aliskiren 75   |                |
|   |           |            | > mg, 150 mg, and 300 |                |
|   |           |            | > mg once daily       |                |
|   |           |            | > significantly       |                |
|   |           |            | > reduced mean        |                |
|   |           |            | > sitting DBP         |                |
|   |           |            | > compared to placebo |                |
|   |           |            | > (only 150 mg and    |                |
|   |           |            | > 300 mg significant  |                |
|   |           |            | > when adjusted for   |                |
|   |           |            | > multiple            |                |
|   |           |            | > comparisons) in     |                |
|   |           |            | > patients with mild  |                |
|   |           |            | > to moderate HTN,    |                |
|   |           |            | > with a significant  |                |
|   |           |            | > reduction in DBP    |                |
|   |           |            | > with all            |                |
|   |           |            | > combination         |                |
|   |           |            | > therapies compared  |                |
|   |           |            | > to either           |                |
|   |           |            | > monotherapy (except |                |
|   |           |            | > for aliskiren/HCTZ  |                |
|   |           |            | > 150/6.25 mg and     |                |
|   |           |            | > 75/12.5 mg)         |                |
+---+-----------+------------+-----------------------+----------------+

AE=adverse event; BP=blood pressure; CV=cardiovascular; d=day;
DB=double-blind; DBP=diastolic blood pressure; DM=diabetes mellitus;
HA=headache; HCTZ=hydrochlorothiazide; hr=hours; HTN=hypertension;
ITT=intention to treat population; MI=myocardial infarction; MVA=motor
vehicle accident; n=number of patients; NR=not reported; PAC=plasma
aldosterone concentration; PC=placebo-controlled; PG=parallel group;
PRA=plasma renin activity; R=randomized; RC=renin concentration;
Rx=medication; SB=single-blind; SBP=systolic blood pressure;
Tx=treatment; VS=vital signs; W/D=withdrawal; wk=week; yrs=years