National PBM Drug Monograph

**Nebivolol (Bystolic^®^)**

###### VHA Pharmacy Benefits Management Services and the Medical Advisory Panel 

# *The purpose of VHA 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 Documents will be placed in the Archive Section when the information is deemed to be no longer current.*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:** Nebivolol (Bystolic^®^), a third-generation
    cardioselective beta-blocker with L-arginine/nitric oxide-induced
    vasodilatory properties, was FDA-approved on December 17, 2007 for
    the treatment of mild-to-moderate hypertension (HTN) in adults as
    either monotherapy or in combination with other antihypertensive
    medications. Use of nebivolol in the management of any condition
    other than hypertension is currently an off-label indication in the
    U.S.

-   **Efficacy:** The safety and efficacy of nebivolol in the management
    of HTN has been assessed in three randomized, double-blinded,
    multi-center, placebo-controlled, 12-week monotherapy trials at
    doses ranging from 1.25mg to 40mg as part of the U.S. clinical
    development program (n=2,016 patients). Two of these trials studied
    a general hypertensive population with mean age of 54 years, 55%
    male, 26% black, 7% diabetic, and 6% genotyped as poor metabolizers
    (PMs). The third monotherapy trial exclusively studied 300 black
    patients with mean age of\
    51 years, 45% male, 14% diabetic, and 3% genotyped as PMs. Efficacy
    in reducing mean sitting systolic blood pressure/diastolic blood
    pressure (SBP/DBP) was similar across race and body mass index (BMI)
    (p\<0.001 for 5mg, 10mg, and 20mg; common dose across all trials).
    These three monotherapy randomized controlled trials (RCTs) enrolled
    375 patients ≥ 65 years of age. Distribution across all arms was as
    follows: placebo (n=30), 1.25mg (n=18), 2.5mg (n=18), 5mg (n=84),
    10mg (n=94), 20mg (n=84), 30/40mg (n=47). For the primary endpoint
    (least-squared (LS) mean reduction in trough sitting DBP, the 5mg
    dose approached statistical significance (p=0.053), while the 10mg
    and 20mg doses reached significance (p ≤ 0.002). Placebo effect for
    the elderly subgroup was much larger than for the younger subgroup
    (\< 65 years of age), which study authors attributed to small sample
    size. For the secondary endpoint of LS mean reduction in trough
    sitting SBP, no statistical significance was achieved in the elderly
    subgroup. A fourth placebo-controlled, U.S. trial demonstrated
    additional BP-lowering effects when nebivolol (5mg, 10mg, or 20mg
    daily) was administered concurrently with up to two other
    antihypertensive medications (ACEI, ARB, and/or thiazide diuretic).
    Nebivolol demonstrated efficacy across the following subgroups:
    black or non-black, BMI ≥ 30 or \< 30, age ≥ 65 years or \< 65
    years, male or female, and those with or without diabetes mellitus.
    The SENIORS trial evaluated the safety, efficacy, and tolerability
    of nebivolol in the management of heart failure (HF) in elderly
    patients. This was a randomized, prospective, multinational,
    multicenter, placebo-controlled, double-blinded, parallel-group
    study to evaluate the effects of nebivolol on mortality and
    hospitalization in 2,135 clinically stable elderly (≥ 70 years of
    age) HF patients (NYHA Functional Classes I-IV). Patients were
    randomized to placebo or nebivolol (1.25mg once daily titrated to
    10mg once daily over a 4-16 week period, as tolerated), with
    background HF therapy maintained. Patients were followed from 12 to
    39 months (average follow-up of 21 months). Treatment with nebivolol
    resulted in a statistically significant decrease in the primary
    endpoint (all-cause mortality or cardiovascular hospitalization) vs.
    placebo. The primary endpoint occurred in 332 (31.1%)
    nebivolol-treated patients vs. 375 (35.3%) placebo-treated patients
    (HR=0.86 95% CI 0.74-0.99; p=0.039). Nebivolol was generally
    well-tolerated. Bradycardia was the reason for study withdrawal in
    18 nebivolol-treated patients (11.1%) vs. 4 placebo-treated patients
    (2.6%); no analysis reported.

-   **Safety:** Nebivolol is generally well tolerated, with
    placebo-controlled studies demonstrating an adverse event-mediated
    discontinuation rate of 2.8% with nebivolol compared to 2.2% with
    placebo. Overall, the most common adverse events (AEs) contributing
    to discontinuation of nebivolol were headache (0.4%), nausea (0.2%),
    and bradycardia (0.2%). The most common AEs in the three monotherapy
    RCTs that were reported at an incidence of \>2% with nebivolol were
    headache, fatigue, dizziness, diarrhea, and nausea. In controlled
    and open-label trials of nebivolol conducted globally (\>5,300
    patients), the following AEs were reported at an incidence of ≥ 1%
    with nebivolol (Forest, Data on File): headache, fatigue, dizziness,
    diarrhea, nausea, bradycardia, asthenia, abdominal pain,
    hypercholesterolemia, hyperuricemia, paresthesias, and laboratory
    abnormalities (↑ BUN, ↑ uric acid, ↑ triglycerides, ↓ HDL-C, and ↓
    platelet-aggregation).

-   **Laboratory Monitoring:** Although there are currently no
    manufacturer recommendations for laboratory monitoring, studies have
    shown nebivolol to affect lipid and carbohydrate profiles, glucose
    tolerance, as well as platelet activity. In the placebo-controlled,
    monotherapy and add-on HTN trials, HDL-C was significantly decreased
    from baseline with nebivolol therapy compared to placebo. Reductions
    in HDL-C ranged from\
    0.383 mg/dL to 6.1 mg/dL with daily doses up to 40mg. The clinical
    implications of these changes are unknown. Statistically
    nonsignificant reductions in total cholesterol and LDL-C, as well as
    nonsignificant increases in triglycerides, were exhibited with
    nebivolol use. Treatment with nebivolol was associated with
    increases in serum glucose but was reported to be clinically
    insignificant in the HTN treatment trials reviewed. It is important
    to note that the effects of nebivolol on these parameters in these
    trials was only measured up to 9 months duration. In the SENIORS
    trial, increases in fasting serum glucose for nondiabetic patients
    were 0.54 mg/dL and 0.9 mg/dL for nebivolol and placebo,
    respectively. For diabetic patients, however, there were reductions
    in fasting serum glucose of 5.76 mg/dL and 1.98 mg/dL for nebivolol
    and placebo, respectively (no analysis reported). Although not
    statistically significant, nebivolol was associated with fewer cases
    of new-onset diabetes mellitus vs. placebo (1.8% nebivolol vs. 2.1%
    placebo).

-   **Dose:** The initial recommended dose of nebivolol for most
    patients is 5mg once daily, without regard to meals. The dose may be
    increased in 2-week intervals up to 40mg once daily, if BP goal is
    not achieved. Doses greater than 40mg daily are not likely to
    provide additional benefit and may increase risk of AEs. For
    patients with HF, mild-to-moderate hepatic dysfunction, and/or CrCl
    \< 30 mL/min, the recommended starting dose of nebivolol is 2.5mg
    once daily, with cautious upward titration. Nebivolol has not been
    studied in pediatric populations, severe hepatic dysfunction, or in
    hemodialysis/peritoneal dialysis patients.

-   **Cost:** The monthly drug cost per patient for nebivolol is
    currently flat-priced at \$30.90. In comparison, the monthly drug
    costs per patient for traditional beta-blockers used in the
    management of HTN are as follows:\
    \$0.15 - \$0.60 for atenolol, \$0.60 - \$2.40 for metoprolol
    tartrate, \$2.40 - \$6.00 for carvedilol, and \$7.20 - \$21.60 for
    labetalol. Likewise, the monthly drug costs per patient for
    traditional beta-blockers used in the management of HF are as
    follows: \$2.40 - \$6.00 carvedilol, \$3.60 - \$12.90 for metoprolol
    succinate, and \$8.70 - \$13.20 for bisoprolol.

-   **Place in Therapy:** A thiazide-type diuretic is recommended as
    initial therapy, either as monotherapy or in combination with other
    antihypertensive therapies, in the management of uncomplicated or
    essential HTN. Therapy with other antihypertensive drug classes
    should be considered based upon inadequate control of blood pressure
    or in patients who have compelling indications for use of other
    antihypertensive therapies. Due to the paucity of outcomes data
    regarding nebivolol's unique L-arginine/nitric oxide-induced
    vasodilatory properties, despite being on the European market for
    over a decade, it is recommended that nebivolol be reserved for
    patients with HTN who do not tolerate or are not adequately
    controlled with antihypertensive agents currently recommended per
    VHA/DoD National Clinical Practice Guidelines for the Pharmacologic
    Treatment of HTN and on the VA National Formulary (VANF). In
    addition, due to the paucity of data demonstrating superiority or
    equivalence of nebivolol over metoprolol succinate, bisoprolol and
    carvedilol (a third-generation beta-blocker with vasodilatory
    properties), nebivolol cannot be recommended for the treatment of
    heart failure.

National PBM Drug Monograph

**Nebivolol (Bystolic^®^)**

###### VHA Pharmacy Benefits Management Services and the Medical Advisory Panel 

# [ Introduction]{.underline} ^1-4^

Nebivolol (Bystolic, ^®^ Forest Pharmaceuticals) is a third-generation,
highly cardioselective, beta~1~-adrenergic receptor antagonist that was
first marketed for the treatment of hypertension (HTN) in Europe in
1997. It received subsequent approval in Europe in September 2005 for
the treatment of mild-to-moderate heart failure (HF) in elderly patients
≥ 70 years of age. Nebivolol recently received FDA approval in the U.S.
on December 17, 2007 for the treatment of HTN in adults as either
monotherapy or in combination with other antihypertensive medications.
Of note, no study to date has shown benefit of beta-blocker therapy for
all-cause mortality or cardiovascular morbidity and mortality when used
as monotherapy for uncomplicated or essential hypertension. Use of
nebivolol in the management of any condition other than HTN is currently
an off-label indication in the U.S.**\
**\
Beta-blockers are a heterogeneous class of antihypertensive agents that
differ with regard to several pharmacologic properties, including
beta~1~ / beta~2~ adrenergic receptor selectivity, lipophilicity vs.
hydrophilicity, membrane-stabilizing activity, intrinsic sympathomimetic
activity (ISA), and additional vasodilatory activity. This class is
generally divided into 3 categories or generations. First-generation
beta-blockers are considered beta~1~ / beta~2~ nonselective.
Second-generation beta-blockers are considered beta~1~ selective within
their respective therapeutic dosing ranges. Third-generation
beta-blockers are unique in their additional vasodilatory properties.
The table below categorizes the currently available oral beta-blockers
in the U.S. These pharmacologic differences may have clinical
implications. For example, beta~1~ / beta~2~ nonselective agents may
exacerbate asthma/coronary obstructive pulmonary disease (COPD), whereas
beta~1~ selective agents are not as likely to demonstrate this ancillary
effect. Also, third-generation, vasodilating beta-blockers may have a
lower risk of insulin resistance or impaired lipid and glucose
metabolism vs. non-vasodilating beta-blockers.

**Classification of Oral Beta-B**lockers Available in the U.S.

  -----------------------------------------------------------------------
  **I) First Generation: Nonselective beta~1~ and beta~2~ Blockade**

  \- Propranolol, Propranolol LA, Nadolol, Pindolol, Penbutolol, Timolol

  **II) Second Generation: Selective beta~1~ Blockade**

  \- Metoprolol Tartrate, Metoprolol Succinate, Atenolol, Bisoprolol,
  Acebutolol, Betaxolol

  **III)Third Generation: Nonselective beta~1~ and beta~2~ or Selective
  beta~1~ Blockade with Vasodilatation**

  Nonselective beta~1~ and beta~2~ Blockade with alpha~1~Vasodilatation

  \- Carvedilol, Labetalol

  Selective beta~1~ Blockade with L-arginine/Nitric Oxide (NO)-induced
  Vasodilatation

  \- Nebivolol
  -----------------------------------------------------------------------

The purposes of this drug monograph are to (1) summarize the available
evidence of the safety, efficacy, tolerability, and other relevant
pharmaceutical issues in evaluation of nebivolol for potential addition
to the VA National Formulary (VANF), (2) define any potential advantages
over current formulary alternatives, and (3) identify potential areas
for preferred use in the veteran population.

## 

## Pharmacology^1-4^  Nebivolol is a lipophilic, third-generation, highly cardioselective, beta~1~-adrenergic receptor antagonist with vasodilatory properties. Unlike other third-generation beta-blockers, such as carvedilol and labetalol, which cause vasodilatation via alpha~1~-mediated receptor antagonism, nebivolol is unique in that it causes peripheral vasodilatation via L-arginine/nitric oxide-induced release from endothelial cells and subsequent increased nitric oxide bioavailability in the endothelium. Nitric oxide (NO) is a major endothelium-derived vasodilatory compound that is also reported to have antithrombotic, antiproliferative, and anti-inflammatory effects as well as lead to decreased myocardial oxygen demands. 

##  Nebivolol is a racemic mixture of equal parts *d-* and *l-* nebivolol. The *d-*isomer is responsible for beta~1~-adrenergic receptor antagonism, while the *l-*isomer is primarily responsible for vasodilatation, with some contribution from the *d-*isomer. Nebivolol demonstrates beta~1~-receptor selectivity that is 321-fold higher than for the beta~2~-receptor at doses less than or equal to 10mg in extensive metabolizers (EMs), which is a majority of the population. Thus, it is the most cardioselective beta-blocker currently available. However, at daily doses \> 10mg or in poor metabolizers (PMs), it is reported to lose this potent cardioselectivity. Nebivolol is devoid of membrane-stabilizing activity, intrinsic sympathomimetic activity (ISA), and alpha~1~ antagonist properties at therapeutic concentrations.

**[Pharmacodynamics/Pharmacokinetics]{.underline}**^1-2^**[\
\
]{.underline}**The hemodynamic profile of nebivolol is different from
traditional beta-blockers in that it increases stroke volume (SV) while
reducing peripheral vascular resistance (PVR), which indicates
maintenance of left-ventricular (LV) function. Nebivolol has a neutral
effect on cardiac output (CO) and is not associated with acute decreases
in CO.

[\
]{.underline}Nebivolol demonstrates linear pharmacokinetics and
undergoes extensive first-pass metabolism, primarily via glucoronidation
and CYP2D6 hydroxylation, producing several active circulating
metabolites, including glucoronides and hydroxyl metabolites. As a
result of genetic polymorphisms in CYP2D6 activity, there are extensive
metabolizers (EMs) and poor metabolizers (PMs), with most of the
population being EMs. Plasma concentrations of the *d-*isomer increased
proportionately with dose in both EMs and PMs for doses up to 20mg
daily. Although the half-life of the *d-*isomer is \~12 hours in EMs and
\~19 hours in PMs, the drug is administered once daily due to the
beta-blocking activity of the active hydroxylated metabolites. The
clinical efficacy and safety profile observed in PMs was similar to that
of EMs in clinical trials. Thus, genetic differences in drug metabolism
have not shown to affect drug pharmacodynamics. Despite its high
lipophilicity, distribution of nebivolol in obese patients is limited,
with pharmacodynamic parameters unchanged. In-vitro studies have
demonstrated that at therapeutic concentrations, *d-* and *l-* nebivolol
does not inhibit nor induce any CYP450 metabolic pathways.

+-----------+-------------+----------+-----------------+---------------+
| **Peak    | **t½**      | **Meta   | **Elimination** | **Bioa        |
| Plasma    |             | bolism** |                 | vailability** |
| Concen    |             |          |                 |               |
| tration** |             |          |                 |               |
+-----------+-------------+----------+-----------------+---------------+
| 1.5 -     | \~12 hours  | Glucoron | \< 0.5 % of     | 96% in EMs\   |
| 4hrs in   | in EMs\     | idation\ | absorbed dose   | 12% in PMs\   |
| EMs and   | \~19 hours  | and      |                 | \~98%         |
| PMs       | in PMs      | CYP2D6   | found unchanged | a             |
|           |             | hydro    | in urine        | lbumin-bound\ |
|           |             | xylation |                 | No food       |
|           |             |          |                 | effects       |
+-----------+-------------+----------+-----------------+---------------+

## 

## FDA Approved Indication(s) and Off-Label Uses^1-2^  Nebivolol is FDA-approved for the treatment of HTN in adults as either monotherapy or in combination with other antihypertensive medications. Of note, no study to date has shown benefit of beta-blocker therapy for all-cause mortality or cardiovascular morbidity and mortality when used as monotherapy for uncomplicated or essential hypertension. Clinical trials including patients with HF and non-ischemic dilated cardiomyopathy have been completed. There are currently no published trials of nebivolol post-acute coronary syndrome (ACS). Use of nebivolol in the management of any condition other than HTN is currently an off-label indication in the U.S. 

**[Current VA National Formulary Alternatives in HTN or HF:\
]{.underline}**

+--------------+----------+--------------+------------+---------------+
| **Thiazide   | *        | *            | **Beta-    | *             |
| Diuretics**  | *ACEIs** | *Long-Acting | blockers** | *Supplemental |
|              |          | CCBs**       |            | Agents\***    |
+--------------+----------+--------------+------------+---------------+
| Ch           | Ben      | Amlodipine   | [HTN]{.u   | Clonidine     |
| lorthalidone | azepril\ |              | nderline}\ |               |
|              | Lis      | Felodipine   | C          | Doxazosin     |
| Hydroch      | inopril\ |              | arvedilol, |               |
| lorothiazide | C        | Nifedipine   | Atenolol   | Hydralazine   |
| (HCTZ)       | aptopril |              |            |               |
|              |          | Diltiazem    | Metoprolol | Methyldopa    |
| HCTZ/        | E        |              | Tartrate,  |               |
| triamterene\ | nalapril | Verapamil    | Pr         | Minoxidil     |
| Indapamide   |          |              | opranolol\ |               |
|              | Fo       |              | \          | Prazosin      |
|              | sinopril |              | [HF\       |               |
|              |          |              | ]{.u       | Reserpine     |
|              |          |              | nderline}C |               |
|              |          |              | arvedilol, | S             |
|              |          |              | Metoprolol | pironolactone |
|              |          |              | Succinate, |               |
|              |          |              | Bisoprolol | Terazosin     |
+--------------+----------+--------------+------------+---------------+

\*ARBs are restricted to criteria for use and may be considered in
patients who are ACEI intolerant; alpha-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]{.underline}\
Nebivolol should be administered once daily, without regard to meals.
For most patients, the recommended starting dose is 5mg once daily. The
dose may be titrated at 2-week intervals, if needed, up to 40mg daily. A
more frequent dosing regimen is not likely to be beneficial and may
increase risk of adverse events.

+-------+-------+--------------+--------------+-----------------------+
| *     | **In  | **Titration  | **Maximum    | **Comments**          |
| *Avai | itial | Interval**   | Dose**       |                       |
| labil | D     |              |              |                       |
| ity** | ose** |              |              |                       |
+-------+-------+--------------+--------------+-----------------------+
| 2     | 5mg   | Increase     | 40 mg once   | \- Starting dose of   |
| .5mg\ | once  | dosage at\   | daily        | 2.5mg is recommended  |
| 5mg\  | daily | 2-week       |              | in HF,                |
| 10mg\ | (see  | intervals    |              | mild-to-moderate      |
| uns   | comm  |              |              | hepatic dysfunction,  |
| cored | ents) |              |              | and CrCl \< 30        |
| ta    |       |              |              | mL/min, with cautious |
| blets |       |              |              | upward titration\     |
|       |       |              |              | - No dosage           |
|       |       |              |              | adjustment necessary  |
|       |       |              |              | in patients who are   |
|       |       |              |              | poor metabolizers\    |
|       |       |              |              | of CYP2D6             |
|       |       |              |              |                       |
|       |       |              |              | -Nebivolol has not    |
|       |       |              |              | been studied in       |
|       |       |              |              | severe hepatic        |
|       |       |              |              | dysfunction or in     |
|       |       |              |              | dialysis              |
+-------+-------+--------------+--------------+-----------------------+

**[Adverse Events]{.underline}**^1-4,\ 8-9^**[\
\
]{.underline}**Nebivolol is generally well tolerated, with
placebo-controlled studies demonstrating an adverse event-mediated
discontinuation rate of 2.8% with nebivolol compared to 2.2% with
placebo. Overall, the most common adverse events contributing to
discontinuation of nebivolol were headache (0.4%), nausea (0.2%), and
bradycardia (0.2%).

In controlled or open-labeled trials of nebivolol conducted globally,
which included \>5,300 patients, the following adverse events were
reported at an incidence of ≥1% with nebivolol (Forest, Data on File):
headache, fatigue, dizziness, diarrhea, nausea, bradycardia, asthenia,
abdominal pain, hypercholesterolemia, hyperuricemia, paresthesias, and
laboratory abnormalities (↑ BUN, ↑ uric acid, ↑ triglycerides, ↓ HDL
cholesterol, and ↓ platelet-aggregation).

A worldwide spontaneous reports registry captured the following
voluntarily-reported adverse events (note: due to the generation of
these reports from an unknown population size, the frequency of events
and a causal relationship to nebivolol treatment cannot be determined):
abnormal hepatic functioning (increases in AST, ALT, and bilirubin),
acute pulmonary edema, acute renal failure, second- and third-degree
atrioventricular block, bronchospasm, erectile dysfunction,
hypersensitivity reactions including urticaria, allergic vasculitis, and
rarely angioedema, myocardial infarction, pruritis, psoriasis,
Raynaud\'s phenomenon, peripheral ischemia/claudication, somnolence,
syncope, thrombocytopenia, various rashes and skin disorders, vertigo,
and vomiting.

Combined analysis of three, 12-week, placebo controlled, monotherapy
trials and treatment-emergent adverse events with an incidence ≥ 1% in
nebivolol-treated patients is shown in the table below. Adverse events
reported occurred at a higher frequency with nebivolol-treated patients
than with placebo-controlled patients.

+------------+----------+---------------+--------------+--------------+
| # Adv      | **P      | **Nebivolol   | **Nebivolol  | **Nebivolol  |
| erse Event | lacebo** | 5mg**         | 10mg**       | 20-40mg**    |
|            |          |               |              |              |
|            | **(n =   | **(n = 459),  | **(n = 461), | **(n = 677), |
|            | 285),    | %**           | %**          | %**          |
|            | %**      |               |              |              |
+------------+----------+---------------+--------------+--------------+
| Headache   | 6        | 9             | 6            | 7            |
+------------+----------+---------------+--------------+--------------+
| Fatigue    | 1        | 2             | 2            | 5            |
+------------+----------+---------------+--------------+--------------+
| Dizziness  | 2        | 2             | 3            | 4            |
+------------+----------+---------------+--------------+--------------+
| Diarrhea   | 2        | 2             | 2            | 3            |
+------------+----------+---------------+--------------+--------------+
| Nausea     | 0        | 1             | 3            | 2            |
+------------+----------+---------------+--------------+--------------+
| Insomnia   | 0        | 1             | 1            | 1            |
+------------+----------+---------------+--------------+--------------+
| Chest Pain | 0        | 0             | 1            | 1            |
+------------+----------+---------------+--------------+--------------+
| B          | 0        | 0             | 0            | 1            |
| radycardia |          |               |              |              |
+------------+----------+---------------+--------------+--------------+
| Dyspnea    | 0        | 0             | 1            | 1            |
+------------+----------+---------------+--------------+--------------+
| Rash       | 0        | 0             | 1            | 1            |
+------------+----------+---------------+--------------+--------------+
| Peripheral | 0        | 1             | 1            | 1            |
| Edema      |          |               |              |              |
+------------+----------+---------------+--------------+--------------+

**[Laboratory Parameters]{.underline}**^1-4,\ 8-9,\ 14^**[\
]{.underline}**\
Although there are no manufacturer recommendations for laboratory
monitoring with nebivolol therapy, studies have demonstrated nebivolol
to affect lipid and carbohydrate profiles, glucose tolerance, and
platelet activity.

In the placebo-controlled monotherapy and add-on trials of nebivolol for
HTN, HDL-C was significantly decreased from baseline to study end
compared to placebo. Reductions in HDL-C ranged from 0.383 mg/dL to 6.1
mg/dL for nebivolol doses up to 40mg daily. The clinical implications of
these changes in HDL-C are unknown. Statistically nonsignificant
reductions in total and LDL cholesterol, as well as nonsignificant
increases in triglycerides, were exhibited with nebivolol use. It is
important to note that the effects of nebivolol on these parameters in
these trials was only measured up to 9 months duration.

Treatment with nebivolol was associated with increases in serum glucose
but was reported to be clinically insignificant in the HTN treatment
trials reviewed. In the SENIORS trial, changes in fasting serum glucose
for nondiabetic patients were 0.54 mg/dL and 0.9 mg/dL for nebivolol and
placebo, respectively. For diabetic patients, there were reductions in
fasting serum glucose of 5.76 mg/dL and 1.98 mg/dL for nebivolol and
placebo, respectively. Although not statistically significant, nebivolol
was associated with fewer cases of new onset diabetes mellitus than
placebo (1.8% nebivolol vs. 2.1% placebo).

Nebivolol has been shown to directly inhibit platelet-aggregation, a
function thought to be modulated through its NO-inducing properties. In
a comparison trial of nebivolol vs. metoprolol on platelet aggregation,
nebivolol significantly decreased mean platelet volume (7.59 ± 0.78 fl
vs. 7.42 ± 0.74 baseline, p\<0.001) and plasma soluble P-selectin
concentrations (1.29 ± 0.46 ng/mL vs. 1.21 ± 0.36 ng/mL baseline,
p=0.002) at 6 months. Metoprolol treatment did not demonstrate any
significant reductions on these parameters. Despite these results, the
manufacturer does not consider nebivolol to possess any clinically
useful antiplatelet activity.

[**Look-alike/Sound-alike Error Risk Potential\
**\
]{.underline}The VA PBM and Center for Medication Safety is conducting a
pilot program which queries a multi-attribute drug product search engine
for similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength, and route of administration. Based on similar scores as well
as clinical judgment, the following drug names may be potential sources
of confusion:

+-----------------+----------------------------------------------------+
| **Drug Name**   | **Potential Name Confusion**                       |
+-----------------+----------------------------------------------------+
| **Nebivolol     | Metoprolol (25mg, 50mg, 100mg) tablet, Betaxolol   |
| (generic)**     | (10mg) tablet, Nadolol (40mg, 120mg) tablet,       |
|                 | Atenolol (25mg, 50mg, 100mg) tablet, Bisoprolol    |
| **2.5, 5, 10 mg | (5mg, 10mg) tablet, Labetolol (100mg) tablet,      |
| tablets**       | Timolol (10mg) tablet, Carteolol (2.5mg, 5mg)      |
|                 | tablet, Acebutolol (100mg, 200mg) capsule,         |
|                 | \*Propranolol (40mg) tablet, Carvedilol (25mg)     |
|                 | tablet, Penbutolol (20mg) tablet, Pindolol (10mg)  |
|                 | tablet, Nebupent vial for solution (inhalation)    |
+-----------------+----------------------------------------------------+
| **Bystolic      | Bisoprolol (5mg, 10mg) tablet, BiDil (37.5mg)      |
| (brand)**       | tablet, B-Scorbic tablet, Betoptic ophthalmic      |
|                 | drops                                              |
| **2.5, 5, 10 mg |                                                    |
| tablets**       |                                                    |
+-----------------+----------------------------------------------------+

^\*^ 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)

# 

# [Contraindications]{.underline}^1-2^[ ]{.underline}

Nebivolol is contraindicated in patients with severe bradycardia, heart
block (2^nd^ degree or greater), cardiogenic shock, decompensated
cardiac failure, sick sinus syndrome without pacemaker placement, or
severe hepatic dysfunction (Child-Pugh Score C).

**[Warnings]{.underline}**^1-2^[**\
**\
]{.underline}**Abrupt Cessation of Therapy:** Patients with coronary
heart disease (CHD) treated with beta-blockers should be informed that
abrupt discontinuation of therapy may result in severe exacerbations of
angina and the occurrence of myocardial infarction and ventricular
tachycardia. Patients without underlying cardiac disease should also be
cautioned regarding interruption or abrupt discontinuation of
beta-blocker therapy. Patients requiring discontinuation of nebivolol
should be monitored closely and instructed to reduce physical activity.
A tapering off regimen of 1-to-2 weeks is recommended, if possible. In
the event a patient develops worsening angina or acute coronary
sufficiency, nebivolol should be restarted.

**Cardiac Failure:** Nebivolol should be administered cautiously in
patients who have compensated HF. As beta-blockade may result in further
myocardial contractility depression and worsen severity of
decompensation, cessation of nebivolol therapy should be considered if
HF worsens.

**Angina and Acute Myocardial Infarction:** Nebivolol has not been
evaluated in patients with angina pectoris or acute myocardial
infarction (post-ACS). **\
**

**Anesthesia and Major Surgery**: Patients who are continued on
nebivolol therapy and require surgery should be monitored closely if
anesthetic agents with myocardial depression profiles, such as ether,
cyclopropane, and trichloroethylene, are to be used. Protracted severe
hypotension may result in patients when attempting to reverse the
beta-blocking effects of nebivolol with beta-agonists.\
\
**Bronchospastic Disease:** It is recommended that beta-blockers, in
general, not be used in patients with bronchospastic disease.

**Diabetes and Hypoglycemia:** Nebivolol should be used with caution in
patients with diabetes mellitus, especially in patients subject to
spontaneous hypoglycemia, as beta-blockers may mask some of the
manifestations of hypoglycemia, particularly tachycardia. It is unknown
whether nebivolol may potentiate insulin-induced hypoglycemia and delay
recovery of serum glucose.

**Thyrotoxicosis:** Clinical signs and symptoms of hyperthyroidism may
be masked in patients receiving beta-blocker therapy. Exacerbations of
the symptoms of hyperthyroidism or thyroid storm have been reported in
patients who abruptly discontinue beta-blocker therapy.

**Peripheral Vascular Disease:** Beta-blockers should be used with
caution in patients with peripheral vascular disease (PVD).
Beta-blockers have been shown to precipitate or aggravate symptoms of
arterial insufficiency.

**Non-dihydropyridine Calcium Channel Blockers:** Given the negative
chronotropic and inotropic properties of beta-blockers and
non-dihydropyridine calcium channel blockers (e.g. diltiazem and
verapamil), ECG and BP should be monitored closely, as concomitant use
may result in heart block.

**[Precautions]{.underline}**^1-2^**[\
]{.underline}**

**CYP2D6 Inhibitors:** Inhibition of CYP2D6 will likely lead to
increased plasma level of nebivolol, thus potentially requiring
dose-adjustment of nebivolol.

**Impaired Renal Function:** Caution and consideration for
dose-adjustment of nebivolol is recommended for patients with severe
renal impairment (CrCl \< 30 mL/min), as the apparent clearance of
nebivolol was decreased by 53% in this patient population. Nebivolol
should be used with caution in patients receiving
hemodialysis/peritoneal dialysis, as no formal studies have been
conducted in these patients.

**Impaired Hepatic Function:** Caution and consideration for
dose-adjustment of nebivolol is recommended for patients with moderate
hepatic impairment (Child-Pugh Score B), as *d*-nebivolol peak plasma
concentration increased 3-fold, AUC increased 10-fold, and apparent
clearance decreased by 86% in this patient population. Patients with
severe hepatic impairment (Child-Pugh Score C) were excluded from
studies; thus, nebivolol is considered contraindicated in this patient
population.

**Risk of Anaphylactic Reactions:** While taking beta-blocker therapy,
patients with a history of severe anaphylactic reactions may be more
reactive to repeat challenge and may be more likely not to respond to
usual doses of epinephrine. Alpha-blockers should be initiated prior to
beta-blocker therapy for patients with known or suspected
pheochromocytoma.

**Carcinogenesis/Mutagenesis/Impairment of Fertility:** Oral doses of
nebivolol up to 40mg/kg/day were studied in mice (5x the maximum
recommended human dose) and rats (10x the maximum recommended human
dose) over\
2 years. A statistically significant increase in the incidence of
testicular Leydig cell hyperplasia and adenomas was seen in mice
receiving nebivolol 40mg/kg/day. This was not thought to be clinically
relevant in humans, as it was determined to be an indirect leutenizing
hormone-mediated effect in mice. Rats receiving nebivolol did not
produce a tumorigenic effect. A randomized, double-blinded,
placebo-controlled study in human males demonstrated no significant
effect on ACTH-stimulated mean serum cortisol AUC0-120min, serum LH, or
serum testosterone with 6 weeks of nebivolol 10mg daily. In male rats
and mice, spermatogenesis was effected when nebivolol at doses 10 and 5
times the maximum recommended human dose (240mg/kg/day), respectively,
was given. Impaired fertility in rats was not reversible, while mice
demonstrated partial reversal. Nebivolol was shown to be non-genotoxic
when tested.

**Pregnancy:** Nebivolol is rated Pregnancy Category C. Nebivolol has
not been studied in pregnant women. Rats receiving 1.25mg/kg/day and
2.5mg/kg/day of nebivolol produced pups with decreased body weight. At
doses of 5mg/kg/day and higher (1.2x the maximum recommended human
dose), there was an increase in late fetal deaths and stillbirths. No
adverse effects on embryo-fetal viability, sex, weight, or morphology
was observed in pregnant rabbits when doses up to 20mg/kg/day (10x the
maximum recommended human dose) were administered.

**Labor and Delivery:** The risk vs. benefit of nebivolol to the fetus
should be evaluated prior to initiating therapy.

**Nursing Mothers:** It is unknown whether nebivolol is excreted in
human milk. Nebivolol and its active metabolites have been shown to
cross the placental barrier and have been detected in breast milk of
rats. Nebivolol is not recommended during human nursing due to potential
for beta-blocker adverse events in infants (e.g. bradycardia).

**Information for Patients:** Patients should be advised to consult a
physician with any difficulty in breathing or development of excessive
bradycardia or signs and symptoms of worsening HF, such as weight gain
or increased shortness of breath. Patients subject to spontaneous
hypoglycemia or diabetic patients receiving oral hypoglycemic agents
and/or insulin should be cautioned that beta-blockers may mask the signs
and symptoms of hypoglycemia, particularly tachycardia. Nebivolol should
be used with caution in these patients. It is unknown whether nebivolol
may potentiate insulin-induced hypoglycemia and delay recovery of serum
glucose.

**Demographics (Age):** The manufacturer reports no differences in
efficacy or incidence of adverse events between older patients (≥ 65
years of age) and younger patients. Nebivolol has not been studied in
pediatric patients.

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

Nebivolol should be used cautiously when administered with digitalis
glycosides and non-dihydropyridine calcium channel blockers (e.g.
diltiazem and verapamil), as concurrent use can increase risk of
bradycardia. Nebivolol should not be combined with other beta-blockers.
Patients receiving catecholamine-depleting therapy, such as reserpine or
guanethidine, should be closely monitored, as this may lead to excessive
reductions in sympathetic activity. If patients are receiving both
nebivolol and clonidine, nebivolol should be discontinued several days
prior to gradual tapering of clonidine.**[\
\
]{.underline}**Nebivolol is extensively hepatically metabolized by
CYP2D6 enzymes. Drugs that inhibit CYP2D6, including fluoxetine,
paroxetine, quinidine, and propafenone, may increase nebivolol plasma
levels. Nebivolol dose-adjustment may be warranted in patients receiving
CYP2D6 inhibitors or inducers based upon blood pressure (BP) response.
Administration of fluoxetine 20mg/day for 21 days prior to a single dose
of 10mg of nebivolol in 10 healthy adults resulted in an 8-fold increase
in AUC and 3-fold increase in Cmax for *d*-nebivolol. Coadministration
of 5mg of nebivolol with 400mg twice daily of cimetidine resulted in a
23% increase in plasma levels of *d*-nebivolol. The pharmacokinetics of
nebivolol were not affected by repeated administration of activated
charcoal. Sildenafil AUC and Cmax were decreased by 21% and 23%,
respectively, when concomitantly administered with nebivolol. The
effects on BP and HR were approximately the sum of the effects of
nebivolol and sildenafil.\
\
The manufacturer reports no clinically significant increases in the
pharmacokinetics of nebivolol when concomitantly administered with the
following: acetaminophen, acetylsalicylic acid, atorvastatin,
simvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin,
sildenafil, or tocopherol. No clinically significant changes in the
pharmacokinetics of digoxin or warfarin were observed when administered
with nebivolol. In addition, digoxin and warfarin did not produce
clinically significant changes in the plasma levels of *d-*nebivolol.

## Efficacy & Safety Measures in HTN^1-5,\ 7-9^ 

#### **Primary Endpoints**

#### Change in mean trough sitting DBP from baseline to study end 

#### **Secondary and Other Endpoints**

-   Change in mean trough sitting SBP from baseline to study end

-   Change in mean peak sitting SBP/DBP from baseline to study end

-   Change in mean trough and peak supine and standing SBP/DBP from
    baseline to study end

-   Responder rate (% of patients with mean sitting DBP \< 90mmHg at
    study end or absolute sitting DBP reduction of ≥10mmHg)hn mean
    trough SiDBPn antihypertensive therapies were allowed an additonal
    40mg is an independent predictor of CV outcome. 000

-   Mean 24-hour sitting SBP/DBP, as measured by ambulatory blood
    pressure monitoring (ABPM)

-   Safety and tolerability

+----+---+-----+--------+--------+--------+--------+---------+------+
| ## | # | #   | ##     | ##     | ## Neb | #      | ## Ne   | ##   |
|  T | # | # P | Nebivo |  Nebiv | ivolol | # Nebi | bivolol | Nebi |
| ri |   | lac | lol 1. | olol 2 |  5mg\* | volol  |  20mg\* | volo |
| al | n | ebo | 25mg\* | .5mg\* |        | 10mg\* |         | l 40 |
|    |   |     |        |        |        |        |         | mg\* |
+----+---+-----+--------+--------+--------+--------+---------+------+
| ## | # | ##  | ## -4  | ##     | ##     | ##     | #       | ##   |
|  W | # |  +2 | .4 / - |  -6.3  |  -5.9  |  -7.0  | # -6.5  | -9.5 |
| ei |   | .2  | 8.0 0. | / -8.5 | / -8.4 | / -9.2 | / -9.8  |  / - |
| ss | 9 | / - | 002; \ |        |        |        | \<0.001 | 11.2 |
| ,  | 0 | 2.9 | <0.001 | \      | \      | \      |         |  N/A |
| et | 9 |     |        | <0.001 | <0.001 | <0.001 |         |      |
|  a |   |     |        |        |        |        |         |      |
| l^ |   |     |        |        |        |        |         |      |
| 8^ |   |     |        |        |        |        |         |      |
+----+---+-----+--------+--------+--------+--------+---------+------+
| #  | # | ##  | ## \   | ## \   | ## -4. | ##     | #       | ## \ |
| #  | # |  -0 | -\-\-- | -\-\-- | 2 / -7 |  -3.5  | # -6.7  | -\-- |
| RC |   | .4  |        |        | .8 NS; | / -8.5 | / -9.1  |      |
| T  | 8 | / - |        |        |  0.002 |  NS; \ | \<0.001 |      |
| #2 | 0 | 4.6 |        |        |        | <0.001 |         |      |
|  o | 7 |     |        |        |        |        |         |      |
| n- |   |     |        |        |        |        |         |      |
| fi |   |     |        |        |        |        |         |      |
| le |   |     |        |        |        |        |         |      |
+----+---+-----+--------+--------+--------+--------+---------+------+
| #  | # | ##  | ## \   | ##     | ##     | ## -6  | #       | #    |
| #  | # |  -0 | -\-\-- | -1.9 / | -3.0 / | .4 / - | # -7.6  | # -7 |
| Sa |   | .4  |        |  -5.7  |  -7.7  | 8.9 0. | / -8.9  | .2 / |
| un | 3 | / - |        | 0.611; | 0.383; | 044; \ | 0.005;  |  -8. |
| de | 0 | 2.8 |        |  0.084 |  0.004 | <0.001 | \<0.001 | 3 0. |
| rs | 0 |     |        |        |        |        |         | 002; |
| ,  |   |     |        |        |        |        |         |  \<0 |
| et |   |     |        |        |        |        |         | .001 |
|  a |   |     |        |        |        |        |         |      |
| l^ |   |     |        |        |        |        |         |      |
| 9^ |   |     |        |        |        |        |         |      |
| \* |   |     |        |        |        |        |         |      |
| \* |   |     |        |        |        |        |         |      |
+----+---+-----+--------+--------+--------+--------+---------+------+
| #  | # | ##  | ##     | ##     | #      | #      | ##      | ##   |
| #  | # |  -0 |  \-\-- |  \-\-- | # -5.7 | # -3.7 | -6.3 /  |  \-\ |
| RC |   | .1  |        |        |  / -6. |  / -6. | -7.9 \< | -\-- |
| T  | 6 | / - |        |        | 6 \<0. | 8 \<0. | 0.015;  |      |
| #4 | 6 | 3.3 |        |        | 015; \ | 015; \ | \<0.001 |      |
|  o | 9 |     |        |        | <0.001 | <0.001 |         |      |
| n- |   |     |        |        |        |        |         |      |
| fi |   |     |        |        |        |        |         |      |
| le |   |     |        |        |        |        |         |      |
| \^ |   |     |        |        |        |        |         |      |
+----+---+-----+--------+--------+--------+--------+---------+------+

**[Clinical Trial Data in HTN\
\
]{.underline}Placebo-Controlled, Monotherapy (1 of 3 with Data on
File):** The safety and efficacy of nebivolol in HTN management has been
assessed in three randomized, double-blinded, multi-center,
placebo-controlled, 12-week monotherapy trials at doses ranging from
1.25mg to 40mg as part of the U.S. clinical development program (n=2,016
patients). Two of these trials studied a general hypertensive population
with mean age of 54 years, 55% male, 26% black, 7% diabetic, and 6%
genotyped as PMs. The third monotherapy trial exclusively studied 300
black patients with mean age of 51 years, 45% male, 14% diabetic, and 3%
genotyped as PMs. Efficacy in reducing mean sitting SBP/DBP was similar
across race and BMI (p\<0.001 for 5mg, 10mg, and 20mg; common doses
across all trials). These three monotherapy RCTs enrolled 375 patients ≥
65 years of age. Distribution across all arms was as follows: placebo
(n=30), 1.25mg (n=18), 2.5mg (n=18), 5mg (n=84), 10mg (n=94), 20mg
(n=84), 30/40mg (n=47). For the primary endpoint (least-squares (LS)
mean reduction in trough sitting DBP), the 5mg dose approached
statistical significance (p=0.053), while 10mg and 20mg doses reached
significance (p ≤ 0.002). Placebo effect for the elderly subgroup was
much larger than for the younger subgroup (\< 65 years of age), which
study authors attributed to small sample size. For the secondary
endpoint of LS mean reduction in trough sitting SBP, no statistical
significance was achieved in the elderly subgroup.\
\
**Combination Therapy (Data on File):** A fourth placebo-controlled,
U.S. trial demonstrated additional BP-lowering effects when nebivolol
(5mg, 10mg, or 20mg daily) was administered concurrently with up to two
other antihypertensive medications (ACEI, ARB, and/or thiazide
diuretic). Nebivolol's efficacy was demonstrated across the following
subgroups: black or non-black, BMI ≥ 30 or \< 30, age ≥ 65 years or \<
65 years, male or female, and those with or without diabetes mellitus.
Summary of change in SBP/DBP in these 4 U.S. clinical trials below:

\*Least-Square (LS) Mean Reductions in Trough SBP/DBP (mmHg) with
p-values vs. placebo

## \*\*Study exclusively enrolled black patients only \^ Study of nebivolol add-on therapy to 1 or 2 baseline antihypertensive therapies (thiazides, ACEIs, or ARBs)

**Long-Term Follow-up (Data on File):** An open-label, 9-month extension
study was conducted throughout 123 U.S. and European sites to evaluate
the long-term safety and efficacy of nebivolol in self-selected patients
who participated in the prior three U.S. monotherapy RCTs. Nebivolol's
antihypertensive effects (5mg, 10mg, or 20mg daily) were maintained or
increased with 9-months of treatment. In a 4-week run-out phase of this
trial, 18 patients were withdrawn from nebivolol monotherapy and
continued on placebo to assess for rebound hypertension. Mean sitting
SBP/DBP increased but did not return to baseline values. In addition, 13
of 18 patients (72.2%) remained classified as responders vs. 78.2% after
the extension phase of the trial (p=NS).

*For further details on the safety and efficacy results of these HTN
trials, refer to Appendices 1 and 2.*

#### **Efficacy & Safety Measures in HF**^1-4,\ 6,\ 10-16^** ** **Primary Endpoints**

-   Composite all-cause mortality or cardiovascular (CV) hospitalization
    (time to first event)

-   Change in Left Ventricular Ejection Fraction (LVEF) from baseline to
    study end

-   Change in NYHA Functional Class from baseline to study end

#### **Secondary and Other Endpoints**

-   CV mortality

-   CV hospitalization

-   Composite CV mortality and CV hospitalization

-   All-cause mortality

-   All-cause hospitalization

-   Composite all-cause mortality and all-cause hospitalization

-   Safety and tolerability

-   Dose-response relationship

-   Quality of Life (QOL)

**[Clinical Trial Data in HF\
]{.underline}**

**Comparator Studies in Heart Failure:** One randomized, prospective,
single-blinded, open-label, parallel-group,\
6-month Italian study^10^ compared the effects of nebivolol vs.
carvedilol on LV function in 70 Caucasian patients with NYHA Class II or
III HF and LVEF ≤ 40% (mean age 67 years; mean LVEF 34%). Patients were
randomized to one of the following (n=35 per arm): (a) carvedilol
3.125mg twice daily titrated to target 25mg twice daily if SBP \>110
mmHg and HR \>60 bpm, or (b) nebivolol 1.25mg daily titrated to target
5mg daily if SBP \>110 mmHg and HR \>60 bpm. Standard background therapy
with a loop diuretic, ACEI, and/or digitalis was continued, where
applicable. Carvedilol target dose was achieved in 77% of patients,
while nebivolol target dose was achieved in 83% of patients. Compared
with baseline, LVEF increased in both carvedilol arm (33% ± 6% to 37% ±
11%) and nebivolol arm (34% ± 7% to 38% ± 10%), with non-significant
between-group differences. NYHA Class improved slightly in both arms,
although only the carvedilol arm reached statistical significance
(p\<0.05). AEs occurred in 20% of carvedilol recipients and 26% of
nebivolol recipients, with 1 patient drop-out in each treatment arm. The
most common AEs in each arm were fatigue and dizziness.

Another randomized, prospective, double-blinded, parallel-group Greek
study^11^ compared the efficacy of nebivolol vs. carvedilol on LVEF and
exercise capacity in 72 patients with HF (NYHA Classes II-III,
nonischemic dilated cardiomyopathy). Following a titration phase to
target doses of 5mg daily of nebivolol and 25mg twice daily of
carvedilol, patients were followed for 12 months. LVEF was shown to
significantly increase at 3 and 12 months from baseline in both the
nebivolol and carvedilol arms (p\<0.05). An intergroup-analysis revealed
carvedilol was associated with a greater effect on LVEF at 3 months
(32.1% ± 34.9% vs. 15.3% ± 15.9%, mean difference -16.7 ± 16.5, p=0.04)
and 12 months (35.5% ± 31.9% vs. 20.7% ± 19.1%, mean difference -14.7 ±
6.4, p=0.002) compared with nebivolol. Exercise duration significantly
improved at 12 months in both the nebivolol arm (p=0.01) and carvedilol
arm (p=0.01), with no significant between-group differences (p=0.85). An
initial deterioration in exercise capacity was seen after 3 months in
nebivolol-treated patients but was not observed in carvedilol-treated
patients.

##  Although nebivolol was likely under-dosed in these two studies, they are currently the only published prospective comparator trials and helped to pave the way for the following two larger-scale, placebo-controlled, HF trials.

## 

## ENECA^12^ evaluated the safety, efficacy, and tolerability of nebivolol as add-on therapy vs. placebo in the management of HF in the elderly. This randomized, prospective, multicenter, placebo-controlled, double-blinded, parallel-group study evaluated the effects of nebivolol treatment (mean dose 7.2mg; 64.2% achieved target 10mg daily) on changes in LVEF from baseline, NYHA Functional Class, and health-related quality of life (HRQOL) in patients \> 65 years of age with NYHA Class II-IV HF and LVEF ≤ 35%. Improvement in LVEF was significantly greater in nebivolol-treated patients vs. placebo-treated patients (6.51% vs. 3.97%; p=0.027). A subgroup analysis revealed that nebivolol-treated males with no prior MI history or with heart rate \> 75 bpm demonstrated the highest relative improvement in LVEF. In terms of NYHA Functional Class changes, 33 patients in the nebivolol group improved by one class compared to 34 patients in the placebo group. The overall difference in functional status between the two groups was not statistically significant (p=0.835). Following 8 months of treatment, there was no difference in mean value of the sum score for the Minnesota Living with Heart Failure Questionnaire between nebivolol and placebo (-9.13% ± 13.78% vs. -11.01% ± 14.66% placebo; p=0.342). Bradycardia, hypotension, and dizziness were the most frequent drug-related AEs in patients treated with nebivolol. Nebivolol-treated patients (baseline: 76.90 ± 10.88bpm vs. 8 month: 67.08 ± 9.21bpm) had a significantly lower heart rate compared to placebo (baseline: 75.29 ± 9.96bpm vs. 8 month: 75.00 ± 9.62bpm), with p\<0.0001. 

## SENIORS^13-14^ evaluated the safety, efficacy, and tolerability of nebivolol in the management of HF in the elderly. This was a randomized, prospective, multinational, multicenter, placebo-controlled, double-blinded, parallel-group study to evaluate the effects of nebivolol on mortality and hospitalization in 2,135 clinically stable elderly (≥ 70 years of age) patients with NYHA Classes I-IV HF. Patients were randomized to placebo or nebivolol (1.25mg once daily titrated to 10mg once daily over a 4-16 week period, as tolerated) and were followed from 12 to 39 months (average follow-up 21 months). Background HF therapy was maintained, where applicable. Treatment with nebivolol resulted in a statistically significant decrease in the primary endpoint (all-cause death or CV hospitalization) vs. placebo. The primary endpoint occurred in 332 (31.1%) nebivolol-treated patients vs. 375 (35.3%) placebo-treated patients (HR=0.86; 95% CI 0.74-0.99; p=0.039). Nebivolol was generally well-tolerated. There was an increased incidence of bradycardia in nebivolol-treated patients (11.1% vs. 2.6% placebo). Bradycardia was the cause for study withdrawal in 18 nebivolol-treated patients and 4 placebo-treated patients (no statistical analysis reported). A post-hoc analysis of the SENIORS trial has been published.^16^ This non-prespecified analysis should be viewed as hypothesis-generating only and has been reviewed in *Appendix 4*.  *For further details on the safety and efficacy results of these HF trials, refer to Appendices 3 and 4. *

## Summary of Findings 

In reviewing the available safety and efficacy trials of nebivolol in
the management of HTN, it is important to keep the following in mind:

-   ACC/AHA guidelines no longer recommend beta-blockers as initial
    therapy for essential HTN

-   Blood pressure is a surrogate end point and does not always
    correlate with hard outcomes, such as CV morbidity and mortality or
    stroke. The effects of nebivolol on clinical outcomes in
    hypertensive patients have yet to be investigated.

In reviewing the available safety and efficacy trials of nebivolol in
the management of HF, it is important to keep the following in mind:

-   Compared with prior outcomes data from landmark beta-blocker trials
    in the management of HF across similar populations, it is unknown
    whether nebivolol demonstrates a similar risk reduction in
    mortality.

-   The majority of head-to-head comparison trials with nebivolol have
    focused on comparisons with atenolol rather than with carvedilol,
    which is another third-generation beta-blocker with vasodilatory
    properties. There are currently 2 small-scale comparison trials of
    nebivolol vs. carvedilol measuring surrogate endpoints, but a
    large-scale comparator outcomes trial has yet to be investigated.

**Acquisition Costs\***

+----------------------+--------+------------------+------------------+
| **Dose/Regimen**     | **Pr   | **Price          | **Pric           |
|                      | ice/Ta | /Patient/Month** | e/Patient/Year** |
|                      | blet** |                  |                  |
+----------------------+--------+------------------+------------------+
| Nebivolol 2.5mg to   | \$1.03 | \$30.90 (2.5 to  | \$375.95 (2.5 to |
| 40mg once daily      |        | 10mg)            | 10mg)            |
| (available as 2.5,   |        |                  |                  |
| 5, 10mg tablets)     |        | \$61.80 (20mg)   | \$751.90 (20mg)  |
|                      |        |                  |                  |
|                      |        | \$123.60 (40mg)  | \$1503.80 (40mg) |
+----------------------+--------+------------------+------------------+

##### \*Prices accurate per McKesson on 05192008

##### Price Comparison with Other Beta-Blockers on VANF

+--------------------------------+------------------+------------------+
| ## Drug                        | ####### **Price  | ####### **Pric   |
|                                | /Patient/Month** | e/Patient/Year** |
+--------------------------------+------------------+------------------+
| **HTN Management**             |                  |                  |
+--------------------------------+------------------+------------------+
| ## Ateno                       | \$0.15 - \$0.60  | \$1.83 - \$7.30  |
| lol 12.5mg -- 200mg once daily |                  |                  |
+--------------------------------+------------------+------------------+
| ## Metoprolol Tart             | \$0.60 - \$2.40  | \$7.30 - \$29.20 |
| rate 12.5mg -100mg twice daily |                  |                  |
+--------------------------------+------------------+------------------+
| ## Carvedi                     | \$2.40 - \$6.00  | \$29.20 -        |
| lol 3.125mg - 25mg twice daily |                  | \$70.00          |
+--------------------------------+------------------+------------------+
| **HF Management**              |                  |                  |
+--------------------------------+------------------+------------------+
| ## Carvedi                     | \$2.40 - \$6.00  | \$29.20 -        |
| lol 3.125mg - 25mg twice daily |                  | \$70.00          |
+--------------------------------+------------------+------------------+
| ## Metoprolol Succi            | \$3.60 - \$12.90 | \$43.80 -        |
| nate 12.5mg - 200mg once daily |                  | \$156.95         |
+--------------------------------+------------------+------------------+
| ## Biso                        | \$8.70 - \$13.20 | \$105.85 -       |
| prolol 2.5mg - 10mg once daily |                  | \$160.60         |
+--------------------------------+------------------+------------------+

##### \*Prices accurate per McKesson on 05192008

##### 

##### Cost-Effectiveness Analysis^17^ 

Currently, there is one published study, conducted by the manufacturer,
of an economic evaluation of nebivolol in the treatment of HTN, from the
healthcare provider prospective. This was a 6-week, post-marketing
surveillance study conducted in Germany, where 8,682 moderately
hypertensive, "real-world" patients (mean age 56.3 years) were started
on nebivolol 5mg/day monotherapy. Each patient was assumed to have at
least one Framingham risk factor. A baseline Framingham risk score was
calculated for each patient. Assuming treatment with nebivolol for\
\> 1-year period, the author determined the number of CV events that
would potentially be avoided, with applicable cost-containment values
presented in Euros. This study, however, is not a true
cost-effectiveness analysis, as it does not compare nebivolol to
alternative drug therapy. Thus, there is currently no cost-effectiveness
analysis data.

**[Conclusions\
]{.underline}**\
In clinical trials, nebivolol has demonstrated statistically significant
reductions in BP compared with placebo and has proven at least as
efficacious as other beta-blockers. However, there is currently no hard
outcomes data (i.e. mortality and CV risk), assessing nebivolol's unique
mechanism of L-arginine/NO-induced endothelial vasodilatation in the
treatment of HTN. Nebivolol demonstrates a statistically significant
benefit over placebo in the treatment of HF in the elderly. A
comparative outcomes trial specifically of nebivolol vs. carvedilol
(both third-generation beta-blockers with vasodilatory properties) has
yet to be investigated.

## Recommendations for Place in Therapy  A thiazide-type diuretic is recommended as initial therapy, either as monotherapy or in combination with other antihypertensive therapies, in the management of uncomplicated or essential HTN. Therapy with other antihypertensive drug classes should be considered based upon inadequate BP control or in patients who have compelling indications for use of other antihypertensive therapies. Due to the paucity of outcomes data regarding nebivolol's unique L-arginine/nitric oxide-induced vasodilatory properties, despite being on the European market for over a decade, it is recommended that nebivolol be reserved for patients with HTN who do not tolerate or are not adequately controlled with antihypertensive agents currently recommended per VHA/DoD National Clinical Practice Guidelines for the Treatment of HTN and on the VANF. In addition, due to the paucity of data showing superiority or equivalence of nebivolol with metoprolol succinate, bisoprolol and carvedilol (a third-generation beta-blocker with vasodilatory properties), nebivolol cannot be recommended for the treatment of heart failure.

## 

**[References\
]{.underline}**

1.  Bystolic^®^ (nebivolol) package insert. New York, NY: Forest
    Laboratories, Inc; 2007.

2.  Forest Pharmaceuticals U.S. Clinical Development and Medical
    Affairs. Submission of clinical and economic data supporting
    formulary consideration of: Bystolic^®^ (nebivolol). Formulary
    Submission Dossier. December 2007:1-108.

3.  de Boer RA, Voors AA, van Veldhuisen. Nebivolol: third generation
    β-blockade. *Expert Opin Pharmacother* 2007;8(10):1539-50.

4.  Moen MD, Wagstaff AJ. Nebivolol: a review of its use in the
    management of hypertension and chronic heart failure.
    *Drug*s2006;66(10):1389-1409.

5.  Diagnosis and Management of Hypertension in the Primary Care
    Setting. Washington, DC: VA/DoD Evidence-Based Clinical Practice
    Guideline Working Group, Veterans Health Administration, Department
    of Veterans Affairs and Health Affairs, Department of Defense,
    Updated August 2004. Office of Quality and Performance publication
    10Q-CPG/HTN-99. (Update 2004). Office of Quality and Performance
    publication 10Q-CPG/HTN-04. Available at
    [www.oqp.med.va.gov](http://www.oqp.med.va.gov/).

6.  The Pharmacologic Management of Chronic Heart Failure. Washington,
    DC: VA/DoD Evidence-Based Clinical Practice Guideline Working Group,
    Veterans Health Administration, Department of Veterans Affairs and
    Health Affairs,\
    Department of Defense, Updated August 2003. Office of Quality and
    Performance publication No. 00-0015. Available at
    [www.oqp.med.va.gov](http://www.oqp.med.va.gov/).

7.  Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension
    in the prevention and management of ischemic heart disease: a
    scientific statement from the American Heart Association Council for
    High Blood Pressure Research and the Councils on Clinical Cardiology
    and Epidemiology and Prevention. *Circulation* 2007; 115:2761-88.

8.  Weiss RJ, Weber MA, Carr AA, et al. A randomized, double-blind,
    placebo-controlled parallel-group study to assess the efficacy and
    safety of nebivolol, a novel β-blocker, in patients with mild to
    moderate hypertension. *Hypertens* 2007;9:\
    667-76.

9.  Saunders E, Smith WB, DeSalvo KB, et al. The efficacy and
    tolerability of nebivolol in hypertensive African American patients.
    *J Clin Hypertens* 2007;9(11):866-75.

10. Lombardo RM, Reina C, Abrignani MG, et al. Effects of nebivolol
    versus carvedilol on left ventricular function in patients with
    chronic heart failure and reduced left ventricular systolic
    function. *Am J Cardiovasc Drugs* 2006;6(4):259-63.

11. Patrianakos AP, Parthenakis FI, Mavrakis HE, et al. Comparative
    efficacy of nebivolol versus carvedilol on left ventricular function
    and exercise capacity in patients with nonischemic dilated
    cardiomyopathy: a 12-month study. *Am Heart J* 2005;150:985e9-e18.

12. Edes I, Gasior Z, and Wita K. Effects of nebivolol on left
    ventricular function in elderly patients with chronic heart failure:
    results of the ENECA study. *Eur J Heart Fail* 2005;7:631-9.

13. Shibata MC, Flather MD, Bohm M, et al. Study of the effects of
    nebivolol intervention on outcomes and rehospitalization in seniors
    with heart failure (SENIORS): rationale and design. *Intern J
    Cardiol* 2002;86:77-85.

14. Flathers MD, Shibata MC, Coats AJ, et al. Randomized trial to
    determine the effect of nebivolol on mortality and cardiovascular
    hospital admission in elderly patients with heart failure (SENIORS).
    *Eur Heart J* 2005;26:215-25.

15. McMurray J. Making Sense of SENIORS. *Eur Heart J* 2005;26:203-6.

16. Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and
    dose-related effects of nebivolol in elderly patients with heart
    failure: data from the study of the effects of nebivolol
    intervention on outcomes and rehospitalization in seniors with heart
    failure (SENIORS) trial. *Am Heart J* 2007;154:109-15.

17. Kaltwasser MT. Economic evaluation of nebivolol in the treatment of
    hypertension. *Am J Cardiovasc Drugs* 2005;5(5):\
    319-24.

**Prepared:** June 2008; Jignesh Patel, PharmD, Lisa M. Rubin, PharmD,
Pharmacoeconomics and Formulary Management Residents; VA San Diego
Healthcare System

**Contact person:** Elaine Furmaga, PharmD, Clinical Pharmacy
Specialist, VHA PBM Services

# [Appendices ]{.underline}

A literature search was performed on PubMed/Medline (January 1966 to
March 2008) using the key search terms nebivolol and Bystolic. Reference
lists of review articles as well as the AMCP Dossier, provided by the
manufacturer, have been searched for relevant clinical trials. Studies
were included for review that met the following criteria: studies
performed in humans, studies available in the English language, studies
involving \> 60 patients, and studies that did not evaluate nebivolol
for the treatment of essential or uncomplicated hypertension, as current
guidelines in the U.S. do not recommend beta-blockers as first-line
therapy for this indication. For a collective review of these trials,
please refer to *Moen, et al* and *de Boer, et al* in reference section.
However, the 4 major randomized, placebo-controlled clinical trials that
evaluated nebivolol for essential HTN as part of the U.S. clinical
development program were reviewed. In addition, an open-label extension
study in the U.S. and Europe that evaluated the long-term safety and
efficacy of nebivolol in the treatment of essential HTN was reviewed.
The two major published trials evaluating nebivolol in the management of
HF were also reviewed.

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

+----+--------+-----------+---------------------------+---------------+
| #  | ### I  | ### E     | ### Results/Conclusions   | ### Wi        |
| ## | nclusi | ndpoints/ |                           | thdrawals/AEs |
|  T | on/Exc | Treatment |                           |               |
| ri | lusion |           |                           |               |
| al |        |           |                           |               |
+----+--------+-----------+---------------------------+---------------+
| *  | ####   | #         | [**Baseline               | **[Completed  |
| *W | #####  | ########  | (mean)**:]{.underline}    | TX Phase of   |
| ei | Inclus | Endpoints | 78.8% \< 65 yrs; 57%      | Trial:        |
| ss | ion Cr |           | male; 85.5% non-black;    | (777/909)]{   |
| ,\ | iteria | **P       | 9.7% diabetic; 43.9% BMI  | .underline}** |
| et |        | rimary:** | ≥ 30                      |               |
| a  | Men    | change in |                           | *             |
| l, | and    | mean      |   --------------- ---     | *Nebivolol:** |
| 20 | women  | trough    | ------------ --------- -- | 710/828       |
| 07 | ≥ 18   | SiDBP (24 | --------------- --------- | (85.7%); W/D  |
| ** | years  | +/- 2     |   **TX (mg/d)**           | ranged from   |
| ^8 | of age | hours     |  **T-SiDBP\***   **p**    | 10.2% to      |
| ^* | with   | from      |   **T-SiSBP\*\***   **p** | 19.9% across  |
| *\ | dia    | previous  |                           | arms          |
| ** | gnosis | morning   |   **Placebo*              |               |
|    | of     | dose)     | *     -2.9 ± 1.1          | **Placebo:**  |
| Mu | mild   | from      |        +2.2 ± 1.9         | 67/81         |
| lt | -to-mo | baseline  |                           | (82.7%);      |
| ic | derate | to day-84 |   **Nebivolo              | W/D=17.3%     |
| en | hypert |           | l**                       |               |
| te | ension | **Sec     |                           | **[Safety     |
| r, | (d     | ondary:** |                           | (W/D /        |
| pr | efined | changes   |   1.25                    | AEs)]{        |
| os | as     | in mean   |  -8.0 ± 1.1      \<0.001  | .underline}** |
| pe | SiDBP  | trough    |   -4.4 ± 1.9        0.002 |               |
| ct | ≥ 95   | SiSBP,    |                           | \- 382/828    |
| iv | mmHg   | mean peak |   2.5             -       | (46.1%) AEs   |
| e, | and ≤  | SiDBP and | 8.5 ± 1.1      \<0.001    | across        |
| ra | 109    | SiSBP     | -6.3 ± 1.9        \<0.001 | nebivolol     |
| nd | mmHg)  | (2-3      |                           | arms vs.      |
| om |        | hours     |   5               -       | 33/81 (40.7%) |
| iz | ####   | po        | 8.4 ± 1.0      \<0.001    | in placebo    |
| ed | #####  | st-dose), | -5.9 ± 1.6        \<0.001 | arm           |
| ,\ |        | and       |                           | (p=0.273;NS)\ |
| d  | ####   | responder |   10              -       | - 20mg and    |
| ou | #####  | rate (%   | 9.2 ± 0.9      \<0.001    | 40mg arms had |
| bl | Exclus | of        | -7.0 ± 1.6        \<0.001 | significantly |
| e- | ion Cr | patients  |                           | higher        |
| bl | iteria | with mean |   20              -       | incidence of  |
| in |        | SiDBP \<  | 9.8 ± 0.9      \<0.001    | AEs vs.       |
| de | Dia    | 90mmHg at | -6.5 ± 1.6        \<0.001 | placebo       |
| d, | gnosis | study end |                           | (p\<0.44 and  |
| p  | of     | or        |   40              -       | p\<0.009,     |
| la | sec    | absolute  | 11.2 ± 0.9     \<0.001    | r             |
| ce | ondary | SiDBP     | -9.5 ± 1.5        \<0.001 | espectively)\ |
| bo | or     | reduction |   --------------- ---     | - 2 of 11     |
| -c | mal    | of\       | ------------ --------- -- | serious AEs   |
| on | ignant | ≥ 10mmHg  | --------------- --------- | (abnormal     |
| tr | h      | hn mean   |                           | ECGs) in      |
| ol | yperte | trough    | \* Change from baseline   | nebivolol     |
| le | nsion, | SiDBPn    | in least-squares (LS)     | arms were     |
| d, | BMI ≥  | antihyp   | mean trough SiDBP (mmHg)  | considered    |
| pa | 35,    | ertensive | ± SEM\                    | possibly      |
| ra | b      | therapies | \*\*Change from baseline  | drug-related  |
| ll | roncho | were      | in least-squares (LS)     | but resolved  |
| el | spasm, | allowed   | mean trough SiSBP (mmHg)  | spontaneously |
| -g | bradyc | an        | ± SEM\                    | without study |
| ro | ardia, | additonal | Note: significant         | dis           |
| up | or     | 40mg is   | reductions in BP apparent | continuation. |
|    | other  | an        | by week 2 and sustained   | No deaths     |
| 70 | known  | in        | until study end           | reported in   |
| U. | cont   | dependent |                           | this study.\  |
| S. | raindi | predictor |   --------------- ---     | -Incidence of |
| s  | cation | of CV     | ------------- --------- - | AEs typically |
| it | to\    | outcome.  | --------------- --------- | associated    |
| es | beta-b | 0vs.      |   **TX (mg/d)**           | with          |
| (  | locker | baseline) |  **Response\***   **p**   | beta-blockers |
| Se | th     |           |    **T-SiHR\*\***   **p** | was low       |
| pt | erapy, | *         |                           | across all    |
| 20 | uncont | *[Run-In, |   **Placebo*              | nebivolol     |
| 01 | rolled | Wash-out  | *     24.7%               | arms: fatigue |
|  - | di     | Ph        |         +2.4 ± 1.1        | 3.6%, dyspnea |
| M  | abetes | ase]{.und |                           | 1.0%,         |
| ar | (HgA1c | erline}** |   **Nebivolo              | bradycardia   |
| ch | ≥      |           | l**                       | 0.7%,         |
| 2  | 10%),  | \-        |                           | erectile      |
| 00 | ACS    | 4-week,   |                           | dysfunction   |
| 3) | within | single    |   1.25                    | 0.2%, and     |
|    | past 6 | -blinded, |  45.8%            0.008   | depression    |
| Ef | m      | placebo   |    -1.4 ± 1.1       0.002 | 0.2%.         |
| fi | onths, | run-i     |                           |               |
| ca | HF,    | n/washout |   2.5             5       |   ---         |
| cy | clin   | phase.    | 0.0%            0.001     | --------- --- |
| &  | ically | Patients  |  -2.4 ± 1.1       \<0.001 | ---- -------- |
| Sa | signi  | p         |                           | -- ---------- |
| fe | ficant | reviously |   5               5       |   *           |
| ty | va     | on        | 0.3%            \< 0.001  | *TX**       * |
| in | lvular | antihyp   |  -4.9 ± 0.9       \<0.001 | *W/D   **SAEs |
| m  | heart  | ertensive |                           | **   **Total\ |
| il | di     | therapies |   10              5       |               |
| d- | sease, | were      | 3.6%            \< 0.001  |   AEs**       |
| mo | th     | allowed   |  -5.5 ± 0.9       \<0.001 |         AEs** |
| de | yroid, | an        |                           |               |
| ra | renal, | a         |   20              5       |   Pla         |
| te | or     | dditional | 9.6%            \<0.001   | cebo\     1   |
| H  | h      | 2-week    |  -7.9 ± 0.9       \<0.001 |      1        |
| TN | epatic | single    |                           |    33 (40.7%) |
|    | dysfun | -blinded, |   40              6       |   (n=81)      |
| n  | ction, | placebo   | 4.5%            \< 0.001  |               |
| =  | peri   | run-i     |  -8.9 ± 0.9       \<0.001 |               |
| 90 | pheral | n/washout |   --------------- ---     |               |
| 9\ | va     | period.   | ------------- --------- - |   Nebivolol   |
| IT | scular |           | --------------- --------- | \   22      1 |
| T/ | di     | **[\      |                           | 1         382 |
| LO | sease, | Treatment | \* % of patients with     |               |
| CF | preg   | P         | mean SiDBP \< 90 mmHg     | (n=828)       |
|    | nancy, | hase]{.un | and/or absolute SiDBP     |               |
| 84 | pr     | derline}\ | reduction                 |       (46.1%) |
| da | evious | **Placebo | [\>]{.underline} 10 mmHg  |   ---         |
| ys | ex     | daily     | vs. baseline; p value vs. | --------- --- |
|    | posure | (n=81)\   | placebo\                  | ---- -------- |
| S  | to     | Nebivolol | \*\*Change from baseline  | -- ---------- |
| up | nebi   | 1.25mg    | in mean trough sitting HR |               |
| po | volol, | daily     | (bpm) ± SEM; p value vs.  | Most common   |
| rt | or     | (n=83)\   | placebo                   | AEs (\> 2%)   |
| ed | conco  | Nebivolol |                           | amongst       |
| by | mitant | 2.5mg     | **-** Significant         | nebivolol     |
| B  | t      | daily     | reduction in peak SiDBP   | arms: HA      |
| er | herapy | (n=82)\   | at all doses vs. placebo  | (7.1% vs.     |
| te | with   | Nebivolol | (range -9.1 to -13.9 mmHg | 7.4%          |
| k, | at     | 5mg daily | vs. -5.9 mmHg placebo;    | placebo),     |
| n  | least  | (n=165)\  | p=0.005 for 1.25mg and    | fatigue (3.6% |
| ow | 1      | Nebivolol | p\<0.0001 for all other   | vs. 2.5%      |
| pa | proh   | 10mg      | doses) and in peak SiSBP  | placebo),     |
| rt | ibited | daily     | at all doses vs. placebo  | na            |
| of | medi   | (n=166)\  | (range -7.6 to -14.0 mmHg | sopharyngitis |
| M  | cation | Nebivolol | vs. -3.1 mmHg placebo;    | (2.9% vs.     |
| yl | that   | 20mg      | p=0.029 for 1.25mg,       | 7.4%          |
| an | may    | daily     | p=0.015 for 2.5mg, and    | placebo),     |
|    | have   | (n=166)\  | p\<0.001 for all other    | diarrhea      |
|    | af     | Nebivolol | doses)**[\                | (2.7% vs.     |
|    | fected | 40mg      | \                         | 2.5%          |
|    | blood  | daily     | ]{.underline}**           | placebo),     |
|    | pr     | (n=166)\  |                           | dizziness     |
|    | essure | \         | **[Study                  | (2.8% vs.     |
|    | (oral  | -         | C                         | 3.7%          |
|    | and    | patients  | onclusions]{.underline}** | placebo), and |
|    | opt    | s         |                           | increased CRP |
|    | halmic | tratified | Nebivolol is an effective | (2.7% vs.     |
|    | BBs,   | across    | therapy for               | 1.2%          |
|    | ABs,   | t         | mild-to-moderate          | placebo).     |
|    | ACEIs, | reatments | hypertension and is       | None were     |
|    | ARBs,  | arms      | well-tolerated, with low  | d             |
|    | CCBs,  | according | incidence of typical      | ose-related.\ |
|    | and    | to        | beta-blocker AEs          | \             |
|    | diur   | f         | (fatigue, depression,     | **[Lab        |
|    | etics) | ollowing: | erectile dysfunction) and | Parameters\   |
|    |        | BMI (≥ 30 | neutral effects on serum  | ]{.unde       |
|    |        | vs. \<    | glucose and LDL-C. Of     | rline}**HDL-C |
|    |        | 30),      | note, there were small    | significantly |
|    |        | diabetes  | differences in SBP        | decreased     |
|    |        | mellitus  | lowering effects from     | from baseline |
|    |        | (present  | 2.5mg to 20mg, while the  | to study end  |
|    |        | vs.       | effects on HR lowering    | vs. placebo   |
|    |        | absent),  | were larger and           | (-0.383 to    |
|    |        | race      | dose-related. The finding | -1.887 mg/dL  |
|    |        | (black    | of decreases in HDL-C may | across        |
|    |        | vs.       | warrant further           | dose-range;   |
|    |        | no        | investigation.            | p=0.005 for   |
|    |        | n-black), |                           | 1.25mg,       |
|    |        | sex (male |                           | p=0.17 for    |
|    |        | vs.       |                           | 2.5mg,        |
|    |        | female),  |                           | p\<0.001 for  |
|    |        | and age   |                           | all other     |
|    |        | (≥ 65     |                           | doses).       |
|    |        | years vs. |                           | Clinical      |
|    |        | \<        |                           | implications  |
|    |        | 65years)  |                           | of these      |
|    |        |           |                           | changes       |
|    |        | \- Only   |                           | unknown.      |
|    |        | the 40mg  |                           |               |
|    |        | arm       |                           |               |
|    |        | underwent |                           |               |
|    |        | titration |                           |               |
|    |        | (30mg     |                           |               |
|    |        | daily x2  |                           |               |
|    |        | weeks,    |                           |               |
|    |        | titrated  |                           |               |
|    |        | to 40mg   |                           |               |
|    |        | daily if  |                           |               |
|    |        | HR \> 55  |                           |               |
|    |        | bpm)\     |                           |               |
|    |        | \         |                           |               |
|    |        | - Trough  |                           |               |
|    |        | BP/HR     |                           |               |
|    |        | measured  |                           |               |
|    |        | on days   |                           |               |
|    |        | 0, 14,    |                           |               |
|    |        | 28, 56,   |                           |               |
|    |        | and 84.   |                           |               |
|    |        | Peak      |                           |               |
|    |        | BP/HR     |                           |               |
|    |        | measured  |                           |               |
|    |        | on days   |                           |               |
|    |        | 0, 28,    |                           |               |
|    |        | and 84.   |                           |               |
+----+--------+-----------+---------------------------+---------------+
| *  | ####   | #         | [**Baseline               | **[Completed  |
| *R | #####  | ########  | (mean)**:]{.underline}    | TX Phase of   |
| CT | Inclus | Endpoints | 81.8% \< 65 yrs; 53.5%    | Trial:        |
| #  | ion Cr |           | male; 87% non-black; 4.6% | (702/807)]{   |
| 2\ | iteria | **P       | diabetic; 40.1% BMI ≥ 30  | .underline}** |
| On |        | rimary:** |                           |               |
| -F | Men    | change in |   --------------- ---     | *             |
| il | and    | mean      | ------------ --------- -- | *Nebivolol:** |
| e* | women  | trough    | --------------- --------- | 641/732       |
| *^ | ≥ 18   | SiDBP (24 |   **TX (mg/d)**           | (87.6%); W/D  |
| 2^ | years  | +/- 2     |  **T-SiDBP\***   **p**    | from each arm |
|    | of age | hours     |   **T-SiSBP\*\***   **p** | unavailable   |
| Mu | with   | from      |                           |               |
| lt | dia    | previous  |   **Placebo*              | **Placebo:**  |
| ic | gnosis | morning   | *     -4.6                | 61/75         |
| en | of     | dose)     |        -0.4               | (81.3%);      |
| te | mild   | from      |                           | W/D=18.7%     |
| r, | -to-mo | baseline  |   **Nebivolo              |               |
| pr | derate | to day-84 | l**                       | **[Safety     |
| os | hypert |           |                           | (W/D /        |
| pe | ension | **Sec     |                           | AEs)]{        |
| ct | (d     | ondary:** |   5                       | .underline}** |
| iv | efined | changes   |     -7.8            0.002 |               |
| e, | as     | in mean   |      -4.2              NS | \- 311/732    |
| ra | SiDBP  | trough    |                           | (38.5%) AEs   |
| nd | ≥ 95   | SiSBP,    |   10                      | across        |
| om | mmHg   | mean peak |     -8.5            \<0.0 | nebivolol     |
| iz | and ≤  | SiDBP and | 01   -3.5              NS | arms vs.      |
| ed | 109    | SiSBP     |                           | 27/75 (36.0%) |
| ,\ | mmHg)  | (2-3      |   20              -       | in placebo    |
| d  |        | hours     | 9.1            \<0.001    | arm (p=NS)\   |
| ou | ####   | po        | -6.7              \<0.001 | - 20mg arm    |
| bl | #####  | st-dose), |   --------------- ---     | had           |
| e- |        | and       | ------------ --------- -- | significantly |
| bl | ####   | responder | --------------- --------- | higher        |
| in | #####  | rate (%   |                           | incidence of  |
| de | Exclus | of        | \* Change from baseline   | AEs vs.       |
| d, | ion Cr | patients  | in least-squares (LS)     | placebo       |
| p  | iteria | with mean | mean trough SiDBP (mmHg); | (p=0.028)\    |
| la |        | SiDBP \<  | SEM values unavailable\   | - 3 of 6      |
| ce | Dia    | 90mmHg at | \*\*Change from baseline  | serious AEs   |
| bo | gnosis | study end | in least-squares (LS)     | in nebivolol  |
| -c | of     | or        | mean trough SiSBP (mmHg); | arms were     |
| on | sec    | absolute  | SEM values unavailable\   | considered    |
| tr | ondary | SiDBP     | Note: significant         | possibly      |
| ol | or     | reduction | reductions in BP apparent | drug-related  |
| le | mal    | of\       | by week 2 and sustained   | and resulted  |
| d, | ignant | ≥ 10mmHg  | until study end           | in study      |
| pa | h      | hn mean   |                           | di            |
| ra | yperte | trough    |   --------------- -       | scontinuation |
| ll | nsion, | SiDBPn    | --------------- ------- - | (SOB, MI,     |
| el | BMI ≥  | antihyp   | --------------- --------- | ruptured AA). |
| -g | 35,    | ertensive |   **TX (mg/d)**           | No deaths     |
| ro | b      | therapies |    **Response\***   **p** | reported in   |
| up | roncho | were      |    **T-SiHR\*\***   **p** | this study.\  |
|    | spasm, | allowed   |                           | -Incidence of |
| 89 | bradyc | an        |   **Placeb                | AEs typically |
| U. | ardia, | additonal | o**     49.3%             | associated    |
| S. | or     | 40mg is   |         unavailable       | with          |
| s  | other  | an        |                           | beta-blockers |
| it | known  | in        |   **Nebivo                | was low       |
| es | cont   | dependent | lol**                     | across all    |
| (  | raindi | predictor |                           | nebivolol     |
| Se | cation | of CV     |                           | arms: fatigue |
| pt | to\    | outcome.  |   5                       | 3.8% and      |
| 20 | beta-b | 000vs.    |  66.0%            0.009   | bradycardia   |
| 01 | locker | baseline) |  -5.1             \<0.001 | 0.8%.         |
|  - | th     |           |                           | Incidences of |
| M  | erapy, | *         |   10                      | dyspnea,      |
| ar | uncont | *[Run-In, |  66.8%            0.005   | erectile      |
| ch | rolled | Wash-out  |  -6.5             \<0.001 | dysfunction,  |
| 2  | di     | Ph        |                           | and           |
| 00 | abetes | ase]{.und |   20                      | depression    |
| 3) | (HgA1c | erline}** |  68.9%            0.002   | unavailable.  |
|    | ≥      |           |  -7.2             \<0.001 |               |
| Ef | 10%),  | \-        |   --------------- -       |   ---         |
| fi | ACS    | 4-week,   | --------------- ------- - | --------- --- |
| ca | within | single    | --------------- --------- | ---- -------- |
| cy | past 6 | -blinded, |                           | -- ---------- |
| &  | m      | placebo   | \* % of patients with     |   *           |
| Sa | onths, | run-i     | mean SiDBP \< 90 mmHg     | *TX**       * |
| fe | HF,    | n/washout | and/or absolute SiDBP     | *W/D   **SAEs |
| ty | clin   | phase.    | reduction                 | **   **Total\ |
| in | ically | Patients  | [\>]{.underline} 10 mmHg  |               |
| m  | signi  | p         | vs. baseline; p value vs. |   AEs**       |
| il | ficant | reviously | placebo\                  |         AEs** |
| d- | va     | on        | \*\*Change from baseline  |               |
| mo | lvular | antihyp   | in mean trough sitting HR |   Pla         |
| de | heart  | ertensive | (bpm); SEM values         | cebo\     4   |
| ra | di     | therapies | unavailable               |      1        |
| te | sease, | were      |                           |    27 (36.0%) |
| H  | th     | allowed   | **-** Significant         |   (n=75)      |
| TN | yroid, | an        | reduction in peak SiDBP   |               |
|    | renal, | a         | at all doses vs. placebo  |               |
| n  | or     | dditional | (range -10.5 to -12.2     |               |
| =  | h      | 2-week    | mmHg vs. -7.0 mmHg        |   Nebivolol   |
| 80 | epatic | single    | placebo; p\<0.0001 for    | \   18      6 |
| 7\ | dysfun | -blinded, | all doses) and in peak    |           311 |
| IT | ction, | placebo   | SiSBP at 10mg and 20mg    |               |
| T/ | peri   | run-i     | doses only vs. placebo    | (n=732)       |
| LO | pheral | n/washout | (range -9.5 to -10.7 mmHg |               |
| CF | va     | period.   | vs. -4.7 mmHg placebo;    |       (38.5%) |
|    | scular |           | p=0.004 for 10mg and      |   ---         |
| 84 | di     | **[       | p\<0.001 for 20mg)\       | --------- --- |
| da | sease, | Treatment | **[\                      | ---- -------- |
| ys | preg   | P         | ]{.underline}**           | -- ---------- |
|    | nancy, | hase]{.un |                           |               |
| S  | pr     | derline}\ | **[Study                  | Most common   |
| up | evious | **Placebo | C                         | AEs (\> 2%)   |
| po | ex     | daily     | onclusions]{.underline}** | amongst       |
| rt | posure | (n=75)\   |                           | nebivolol     |
| ed | to     | Nebivolol | Nebivolol is an effective | arms: HA      |
| by | nebi   | 5mg daily | therapy for               | (7.7%),       |
| B  | volol, | (n=244)\  | mild-to-moderate          | fatigue       |
| er | or     | Nebivolol | hypertension and is       | (3.8%),       |
| te | conco  | 10mg      | well-tolerated, with low  | na            |
| k, | mitant | daily     | incidence of typical      | sopharyngitis |
| n  | t      | (n=244)\  | beta-blocker AEs          | (3.7%). None  |
| ow | herapy | Nebivolol | (fatigue, depression,     | were          |
| pa | with   | 20mg      | erectile dysfunction) and | dose-related. |
| rt | at     | daily     | neutral effects on serum  | Placebo       |
| of | least  | (n=244)\  | glucose and LDL-C. The    | values        |
| M  | 1      | \         | finding of decreases in   | unavailable.\ |
| yl | proh   | -         | HDL-C may warrant further | \             |
| an | ibited | patients  | investigation.            | **[Lab        |
|    | medi   | s         |                           | Parameters\   |
|    | cation | tratified |                           | ]{.unde       |
|    | that   | across    |                           | rline}**HDL-C |
|    | may    | t         |                           | decreased     |
|    | have   | reatments |                           | from baseline |
|    | af     | arms      |                           | to study end  |
|    | fected | according |                           | vs. placebo   |
|    | blood  | to        |                           | across all    |
|    | pr     | f         |                           | doses,        |
|    | essure | ollowing: |                           | reaching      |
|    | (oral  | BMI (≥ 30 |                           | significance  |
|    | and    | vs. \<    |                           | for 10mg and  |
|    | opt    | 30),      |                           | 20mg arms     |
|    | halmic | diabetes  |                           | only (-2.76   |
|    | BBs,   | mellitus  |                           | to -2.62      |
|    | ABs,   | (present  |                           | mg/dL,        |
|    | ACEIs, | vs.       |                           | respectively; |
|    | ARBs,  | absent),  |                           | p-values      |
|    | CCBs,  | race      |                           | unavailable). |
|    | and    | (black    |                           | Clinical      |
|    | diur   | vs.       |                           | implications  |
|    | etics) | no        |                           | of these      |
|    |        | n-black), |                           | changes       |
|    | ####   | sex (male |                           | unknown.      |
|    | #####  | vs.       |                           |               |
|    |        | female),  |                           |               |
|    |        | and age   |                           |               |
|    |        | (≥ 65     |                           |               |
|    |        | years vs. |                           |               |
|    |        | \<        |                           |               |
|    |        | 65years)\ |                           |               |
|    |        | \         |                           |               |
|    |        | - Trough  |                           |               |
|    |        | BP/HR     |                           |               |
|    |        | measured  |                           |               |
|    |        | on days   |                           |               |
|    |        | 0, 14,    |                           |               |
|    |        | 28, 56,   |                           |               |
|    |        | and 84.   |                           |               |
|    |        | Peak      |                           |               |
|    |        | BP/HR     |                           |               |
|    |        | measured  |                           |               |
|    |        | on days   |                           |               |
|    |        | 0, 28,    |                           |               |
|    |        | and 84.   |                           |               |
+----+--------+-----------+---------------------------+---------------+
| *  | ####   | #         | [**Baseline               | **[Completed  |
| *S | #####  | ########  | (mean)**:]{.underline}    | TX Phase of   |
| au | Inclus | Endpoints | 88.3% \< 65 yrs; 45.3"%   | Trial:        |
| nd | ion Cr |           | male; 100% black; 14.3%   | (259/300)]{   |
| er | iteria | **P       | diabetic; 52.0% BMI ≥ 30; | .underline}** |
| s, |        | rimary:** | mean SiSBP/SiDBP          |               |
| et | Black  | change in | 151.4/100.8 mmHg          | *             |
| a  | men    | mean      |                           | *Nebivolol:** |
| l, | and    | trough    |   --------------- --      | 218/251       |
| 2  | women  | SiDBP (24 | ------------- --------- - | (86.9%); W/D  |
| 00 | ≥ 18   | +/- 2     | ---------------- -------- | from each arm |
| 7* | years  | hours     |   **TX (mg/d)**           | as follows:   |
| *^ | of age | from      |  **T-SiDBP\***   **p**    | 2.5mg (n=7);  |
| 9^ | with   | previous  |   **T-SiSBP\*\***   **p** | 5mg (n=9);    |
|    | dia    | morning   |                           | 10mg (n=4);   |
| Mu | gnosis | dose)     |   **Placebo*              | 20mg (n=5);   |
| lt | of     | from      | *     -2.8 ± 2.1          | 40mg (n=8)    |
| ic | mild   | baseline  |        -0.4±3.8           |               |
| en | -to-mo | to day-84 |                           | **Placebo:**  |
| te | derate |           |   **Nebivolo              | 41/49         |
| r, | hypert | **Sec     | l**                       | (83.7%);      |
| pr | ension | ondary:** |                           | W/D=16.3%     |
| os | (d     | changes   |                           |               |
| pe | efined | in mean   |   2.5                     | **[Safety     |
| ct | as     | trough    | -5.7 ± 2.1      0.084; NS | (W/D / AEs)\  |
| iv | SiDBP  | SiSBP,    |  -1.9 ± 3.7        0.611; | ]{.           |
| e, | ≥      | mean peak |                           | underline}**- |
| ra | 95mmHg | SiDBP and |                           | 113/251       |
| nd | and ≤  | SiSBP     |                        NS | (45.0%) AEs   |
| om | 109    | (2-3      |                           | across        |
| iz | mmHg)  | hours     |   5                       | nebivolol     |
| ed |        | po        | -7.7 ± 2.1      0.004     | arms vs.      |
| ,\ | ####   | st-dose), |  -3.0 ± 3.7        0.383; | 19/49 (38.8%) |
| d  | #####  | and       |                           | in placebo    |
| ou | Exclus | responder |                           | arm (p=0.474; |
| bl | ion Cr | rate (%   |                        NS | NS)\          |
| e- | iteria | of        |                           | - No          |
| bl |        | patients  |   10                      | dose-related  |
| in | Dia    | with mean |  -8.9 ± 2.0      \<0.001  | trends in     |
| de | gnosis | SiDBP \<  |   -6.4 ± 3.6        0.044 | incidence of  |
| d, | of     | 90mmHg at |                           | AEs was       |
| p  | sec    | study end |   20                      | noted.\       |
| la | ondary | or        |  -8.9 ± 2.1      \<0.001  | - 1 of 4      |
| ce | or     | absolute  |   -7.6 ± 3.7        0.005 | serious AEs   |
| bo | mal    | SiDBP     |                           | in nebivolol  |
| -c | ignant | reduction |   40                      | arms was      |
| on | h      | of\       |  -8.3 ± 2.0      \<0.001  | considered    |
| tr | yperte | ≥ 10mmHg  |   -7.2 ± 3.5        0.002 | possibly      |
| ol | nsion, | vhn mean  |   --------------- --      | drug-related  |
| le | BMI ≥  | trough    | ------------- --------- - | and resulted  |
| d, | 40,    | SiDBPn    | ---------------- -------- | in study      |
| pa | b      | antihyp   |                           | di            |
| ra | roncho | ertensive | \* Change from baseline   | scontinuation |
| ll | spasm, | therapies | in least-squares (LS)     | (cerebral     |
| el | bradyc | were      | mean trough SiDBP (mmHg)  | hemorrhage).  |
| -g | ardia, | allowed   | ± SEM\                    | No deaths     |
| ro | or     | an        | \*\*Change from baseline  | reported in   |
| up | other  | additonal | in least-squares (LS)     | this study.\  |
|    | known  | 40mg is   | mean trough SiSBP (mmHg)  | -Incidence of |
| 39 | cont   | an        | ± SEM\                    | AEs typically |
| U. | raindi | in        | Note: significant         | associated    |
| S. | cation | dependent | reductions in BP apparent | with          |
| s  | to\    | predictor | by week 2 and sustained   | beta-blockers |
| it | beta-b | of CV     | until study end           | was low       |
| es | locker | outcome.  |                           | across all    |
| (N | th     | 0s.       |   --------------- ---     | nebivolol     |
| ov | erapy, | baseline) | ------------- --------- - | arms: fatigue |
| 20 | uncont |           | --------------- --------- | 2.8%,         |
| 01 | rolled | *         |   **TX (mg/d)**           | bradycardia   |
|  - | di     | *[Run-In, |  **Response\***   **p**   | 0.4%,         |
| Au | abetes | Wash-out  |    **T-SiHR\*\***   **p** | decreased     |
| gu | (HgA1c | Ph        |                           | libido 0.4%   |
| st | ≥      | ase]{.und |   **Placebo*              | and dyspnea   |
| 2  | 10%),  | erline}** | *     26.5%               | 0.4%.         |
| 00 | ACS    |           |         -2.4 ± 2.7        | Incidence of  |
| 3) | within | \-        |                           | depression    |
|    | past 6 | 4-week,   |   **Nebivolo              | and erectile  |
| Ef | m      | single    | l**                       | dysfunction   |
| fi | onths, | -blinded, |                           | unavailable.  |
| ca | HF,    | placebo   |                           |               |
| cy | clin   | run-i     |   2.5             36.     |   ---         |
| &  | ically | n/washout | 7%            NS        - | --------- --- |
| Sa | signi  | phase.    | 4.4 ± 2.6       0.240; NS | ---- -------- |
| fe | ficant | Patients  |                           | -- ---------- |
| ty | va     | p         |   5               58.     |   *           |
| in | lvular | reviously | 0%            0.002     - | *TX**       * |
| St | heart  | on        | 3.9 ± 2.6       0.369; NS | *W/D   **SAEs |
| ag | di     | antihyp   |                           | **   **Total\ |
| es | sease, | ertensive |   10                      |               |
| I- | th     | therapies |  58.8%            \<0.001 |   AEs**       |
| II | yroid, | were      |    -7.2 ± 2.5       0.008 |         AEs** |
| H  | renal, | allowed   |                           |               |
| TN | or     | an        |   20                      |   Pla         |
|    | h      | a         |  64.0%            \<0.001 | cebo\     0   |
| n  | epatic | dditional |    -5.9 ± 2.6       0.009 |      0        |
| =  | dysfun | 2-week    |                           |    19 (38.8%) |
| 30 | ction, | single    |   40              5       |   (n=49)      |
| 0\ | peri   | -blinded, | 6.9%            \<0.001   |               |
| IT | pheral | placebo   |  -7.8 ± 2.6       \<0.001 |               |
| T/ | va     | run-i     |   --------------- ---     |               |
| LO | scular | n/washout | ------------- --------- - |   Nebivolol   |
| CF | di     | period.   | --------------- --------- | \   6       4 |
|    | sease, |           |                           |           113 |
| 84 | preg   | **[       | \* % of patients with     |               |
| da | nancy, | Treatment | mean SiDBP \< 90 mmHg     | (n=251)       |
| ys | pr     | P         | and/or absolute SiDBP     |               |
|    | evious | hase]{.un | reduction                 |       (45.0%) |
| S  | ex     | derline}\ | [\>]{.underline} 10 mmHg  |   ---         |
| up | posure | **Placebo | vs. baseline; p value vs. | --------- --- |
| po | to     | daily     | placebo\                  | ---- -------- |
| rt | nebi   | (n=49)\   | \*\* Change from baseline | -- ---------- |
| ed | volol, | Nebivolol | in mean trough sitting HR |               |
| by | or     | 2.5mg     | (bpm)                     | Most common   |
| B  | conco  | daily     |                           | AEs (\> 2%)   |
| er | mitant | (n=49)\   | **-** Significant         | amongst       |
| te | t      | Nebivolol | reduction in peak SiDBP   | nebivolol     |
| k, | herapy | 5mg daily | at all doses vs. placebo  | arms: HA      |
| n  | with   | (n=50)\   | (range -8.6 to -12.3 mmHg | (5.6% vs.     |
| ow | at     | Nebivolol | vs. -3.8 mmHg placebo;    | 4.0%          |
| pa | least  | 10mg      | p=0.008 for nebivolol     | placebo),     |
| rt | 1      | daily     | 2.5mg; p\<0.0001 for all  | dizziness     |
| of | proh   | (n=51)\   | other doses) and in peak  | (3.6% vs. 0%  |
| M  | ibited | Nebivolol | SiSBP at 5mg and up only  | placebo),     |
| yl | medi   | 20mg      | vs. placebo (range -10.6  | arthralgia    |
| an | cation | daily     | to -12.2 mmHg vs. -3.0    | (3.6% vs.     |
|    | that   | (n=50)\   | mmHg placebo; p=0.011 for | 2.0%),        |
|    | may    | Nebivolol | 5mg; p=0.005 for 10mg;    | diarrhea      |
|    | have   | 40mg      | p=0.002 for 20mg and      | (3.2% vs.     |
|    | af     | daily     | 40mg)                     | 2.0%),        |
|    | fected | (n=51)\   |                           | fatigue (2.8% |
|    | blood  | \         | **[Study                  | vs. 0%        |
|    | pr     | -         | C                         | placebo),     |
|    | essure | patients  | onclusions]{.underline}** | na            |
|    | (oral  | s         |                           | sopharyngitis |
|    | and    | tratified | Nebivolol is an effective | (2.4%) vs. 0% |
|    | opt    | across    | therapy for               | placebo, and  |
|    | halmic | t         | mild-to-moderate          | UTI (2.4% vs. |
|    | BBs,   | reatments | hypertension (Stages      | 0% placebo).  |
|    | ABs,   | arms      | I-II) in blacks and is    | None were     |
|    | ACEIs, | according | well-tolerated, with low  | d             |
|    | ARBs,  | to        | incidence of typical      | ose-related.\ |
|    | CCBs,  | f         | beta-blocker AEs          | \             |
|    | and    | ollowing: | (fatigue, depression,     | **[Lab        |
|    | diur   | BMI (≥ 30 | erectile dysfunction).    | Parameters\   |
|    | etics) | vs. \<    | The finding of            | ]{.           |
|    |        | 30),      | nonsignificant increases  | underline}**N |
|    |        | diabetes  | in serum glucose was      | onsignificant |
|    |        | mellitus  | generally not associated  | increases in  |
|    |        | (present  | with adverse metabolic    | serum glucose |
|    |        | vs.       | effects. Of note, mean BP | and           |
|    |        | absent),  | changes with the 40mg     | triglycerides |
|    |        | race      | dose were numerically     | across all    |
|    |        | (black    | less compared with the    | doses,        |
|    |        | vs.       | 10mg and 20mg doses. The  | including     |
|    |        | no        | finding of decreases in   | placebo.**[\  |
|    |        | n-black), | HDL-C may warrant further | \             |
|    |        | sex (male | investigation.            | ]{.unde       |
|    |        | vs.       |                           | rline}**HDL-C |
|    |        | female),  |                           | decreased     |
|    |        | and age   |                           | from baseline |
|    |        | (≥ 65     |                           | to study end  |
|    |        | years vs. |                           | across all    |
|    |        | \<        |                           | doses,        |
|    |        | 65years)\ |                           | including     |
|    |        | \         |                           | placebo:      |
|    |        | - Trough  |                           | placebo -0.8  |
|    |        | BP/HR     |                           | mg/dL; 2.5mg  |
|    |        | measured  |                           | nebivolol     |
|    |        | on days   |                           | -3.2 mg/dL;   |
|    |        | 0, 14,    |                           | 5mg nebivolol |
|    |        | 28, 56,   |                           | -5.2 mg/dL;   |
|    |        | and 84.   |                           | 10mg          |
|    |        | Peak      |                           | nebivolol     |
|    |        | BP/HR     |                           | -1.4 mg/dL;   |
|    |        | measured  |                           | 20mg          |
|    |        | on days   |                           | nebivolol     |
|    |        | 0, 28,    |                           | -3.9 mg/dL;   |
|    |        | and 84.   |                           | 40mg          |
|    |        |           |                           | nebivolol     |
|    |        |           |                           | -6.1 mg/dL.   |
|    |        |           |                           | These HDL-C   |
|    |        |           |                           | reductions    |
|    |        |           |                           | did not       |
|    |        |           |                           | appear        |
|    |        |           |                           | dose-related  |
|    |        |           |                           | and were only |
|    |        |           |                           | significant   |
|    |        |           |                           | from placebo  |
|    |        |           |                           | at 40mg dose  |
|    |        |           |                           | (p=0.03).     |
|    |        |           |                           | Clinical      |
|    |        |           |                           | implications  |
|    |        |           |                           | of these      |
|    |        |           |                           | changes       |
|    |        |           |                           | unknown.      |
+----+--------+-----------+---------------------------+---------------+

HTN=hypertension; ITT=intention-to-treat; BMI=body mass index; ACS=acute
coronary syndrome; HF=heart failure; SiDBP=sitting diastolic blood
pressure; SiSBP=sitting systolic blood pressure; SiHR=sitting heart
rate; BBs=beta blockers; ABs=alpha blockers;
ACEIs=angiotensin-converting enzyme inhibitors;
ARBs=angiotensin-receptor blockers; CCBs=calcium channel blockers;
BPM=beats per minute; W/D=withdrawals; AEs=adverse events; SEAs=serious
adverse events; HA=headache; SOB=shortness of breath; MI=myocardial
infarction; AA=aortic aneurysm; UTI=urinary tract infection;
LDL-C=low-density lipoprotein cholesterol

**Appendix 2: Evidence Table (Placebo-Controlled Monotherapy with Active
Background HTN Trials)**

+----+--------+-----------+----------------------------+---------------+
| #  | ### I  | ### E     | ### Results/Conclusions    | ### Wi        |
| ## | nclusi | ndpoints/ |                            | thdrawals/AEs |
|  T | on/Exc | Treatment |                            |               |
| ri | lusion |           |                            |               |
| al |        |           |                            |               |
+----+--------+-----------+----------------------------+---------------+
| *  | #      | #         | **[Baseline                | **[Completed  |
| *R | ###### | ########  | (mean):]{.underline}**     | TX Phase of   |
| CT | ## Inc | Endpoints | 84.6% \< 65 yrs; 55.0%     | Trial:        |
| #  | lusion |           | male; 29.4% black;14.1%    | (598/669)]{   |
| 4\ |  Crite | **P       | diabetic; mean BMI = 29.7; | .underline}** |
| On | ria Me | rimary:** | mean trough sitting        |               |
| Fi | n and  | change in | SBP/DBP = 146/96 mmHg;     | *             |
| le | women  | mean      | mean trough sitting HR =   | *Nebivolol:** |
| ** | ≥ 18 y | trough    | 74 bpm                     | 45            |
| ^2 | ears o | SiDBP (24 |                            | 2/502(90.0%); |
| ^* | f age  | +/- 2     | **Percent of patients      | W/D from each |
| *\ | with d | hours     | receiving add-on therapy   | arm as        |
| ** | iagnos | from      | in each treatment group**  | follows: 5mg  |
|    | is of  | previous  |                            | arm (n=16),   |
| Mu | mild-t | morning   |   -------------- -----     | 10mg arm      |
| lt | o-mode | dose)     | -------- -------------- -- | (n=18), 20mg  |
| ic | rate h | from      | ------------ ------------- | arm (n=16)    |
| en | yperte | baseline  |   **Add-on TX**  **P       |               |
| te | nsion  | to day-84 | lacebo**   **Nebivolol\    | **Placebo:**  |
| r, | (defin |           | **Nebivolol\   **Nebivolol | 146/167       |
| pr | ed as  | ####      |                            | (87.4%)       |
| os | SiDBP  | ##### Sec |                   5**      | W/D=12.6%     |
| pe | ≥ 95mm | ondary: c |        10**           20** |               |
| ct | Hg and | hanges in |                            | **[Safety     |
| iv |  ≤ 109 |  mean tro |   **Diuretic**             | (W/D / AEs)\  |
| e, |  mmHg) | ugh SiSBP |    43.1%         42.9%     | ]{.           |
| ra |        | , mean pe |       45.8%          43.4% | underline}**- |
| nd | ####   | ak SiDBP  |                            | 202/502       |
| om | #####  | and SiSBP |   **ACEI**                 | (40.2%) AEs   |
| iz |        |  (2-3 hou |    49.1%         50.0%     | across        |
| ed | #####  | rs post-d |       48.8%          49.4% | nebivolol     |
| ,\ | #### E | ose), res |                            | arms vs.      |
| d  | xclusi | ponder ra |   **ARB**                  | 65/167        |
| ou | on Cri | te (% of  |    34.7%         31.0%     | (38.9%) in    |
| bl | teria  | patients  |       32.1%          30.7% | placebo arm   |
| e- |        | with mean |                            | (p=0.763;     |
| bl | Dia    |  SiDBP \< |   **ACEI + AR              | NS).\         |
| in | gnosis |  90mmHg o | B** 0%            1.2%     | -No           |
| de | of     | r absolut |        0%             0.6% | dose-related  |
| d, | sec    | e SiDBP r |                            | trends in     |
| p  | ondary | eduction  |   **ACEI +                 | incidence of  |
| la | or     | of ≥ 10mm |    13.8%         13.1%     | AEs of any    |
| ce | mal    | Hg)hn mea |       14.9%          11.4% | strength were |
| bo | ignant | n trough  |   Diureti                  | noted.\       |
| -c | h      | SiDBPn an | c**                        | - 4 of 7      |
| on | yperte | tihyperte |                            | serious AEs   |
| tr | nsion, | nsive the |                            | occurred in   |
| ol | BMI ≥  | rapies we |   **ARB +                  | nebivolol     |
| le | 35,    | re allowe |    13.2%         10.1%     | arms, of      |
| d, | b      | d an addi |       13.7%          13.3% | which none    |
| pa | roncho | tonal 40m |   Diureti                  | were          |
| ra | spasm, | g is an i | c**                        | considered    |
| ll | bradyc | ndependen |                            | possibly      |
| el | ardia, | t predict |                            | drug-related. |
| -g | or     | or of CV  |   **None**                 | There was 1   |
| ro | other  | outcome.  |     0%            0.6%     | death         |
| up | known  | 000 vs. b |        1.8%           1.8% | reported in   |
|    | cont   | aseline,  |   -------------- -----     | this study    |
| 96 | raindi | and mean  | -------- -------------- -- | (75-yr old    |
| U. | cation | 24-hour S | ------------ ------------- | female died   |
| S. | to\    | iDBP and  |                            | of cardiac    |
| s  | beta-b | SiSBP, as |   --------------- -        | arrest in     |
| it | locker |  measured | -------------- --------- - | nebivolol 5mg |
| es | th     |  by ABPM  | ---------------- --------- | arm;          |
| (O | erapy, |           |   **TX (mg/d)**            | considered    |
| ct | uncont | *         |    **T-SiDBP\***   **p**   | remotely      |
| 20 | rolled | *Other:** |    **T-SiSBP\*\***   **p** | related to    |
| 02 | di     | safety    |                            | drug          |
|  - | abetes | and       |   **Placeb                 | therapy).\    |
| O  | (HgA1c | tol       | o**     -3.3               | -Incidence of |
| ct | ≥      | erability |         -0.1               | AEs typically |
| 2  | 10%),  |           |                            | associated    |
| 00 | ACS    | *         |   **Nebivo                 | with          |
| 3) | within | *[Run-In, | lol**                      | beta-blockers |
|    | past 6 | Wash-out  |                            | was low       |
| Ef | m      | Phase\    |                            | across all    |
| fi | onths, | ]{.unde   |   5                        | nebivolol     |
| ca | HF,    | rline}**- |  -6.6            \<0.001   | arms:         |
| cy | clin   | 2-week ±  |  -5.7              \<0.015 | bradycardia   |
| &  | ically | 3 day     |                            | 0.8%,         |
| Sa | signi  | single    |   10                       | decreased     |
| fe | ficant | -blinded, |  -6.8            \<0.001   | libido 0.4%,  |
| ty | va     | placebo   |  -3.7              \<0.015 | and           |
| as | lvular | run-i     |                            | depression    |
| ad | heart  | n/washout |   20                       | 0.2%.         |
| d- | di     | phase for |  -7.9            \<0.001   | Incidences of |
| on | sease, | patients  |  -6.3              \<0.015 | fatigue,      |
| t  | th     | p         |   --------------- -        | dyspnea, and  |
| he | yroid, | reviously | -------------- --------- - | erectile      |
| ra | renal, | on        | ---------------- --------- | dysfunction   |
| py | or     | antihyp   |                            | unavailable   |
| in | h      | ertensive | \* Change from baseline in |               |
| m  | epatic | therapies | least-squares (LS) mean    |   ---         |
| il | dysfun |           | trough SiDBP (mmHg); SEM   | --------- --- |
| d- | ction, | **[       | values unavailable\        | ---- -------- |
| mo | peri   | Treatment | \*\*Change from baseline   | -- ---------- |
| de | pheral | P         | in least-squares (LS) mean |   *           |
| ra | va     | hase]{.un | trough SiSBP (mmHg); SEM   | *TX**       * |
| te | scular | derline}\ | values unavailable\        | *W/D   **SAEs |
| H  | di     | **Placebo | Note: significant          | **   **Total\ |
| TN | sease, | daily     | reductions in BP apparent  |               |
|    | preg   | (n=167)\  | by week 2 and sustained    |   AEs**       |
| n  | nancy, | Nebivolol | until study end            |         AEs** |
| =  | or     | 5mg daily |                            |               |
| 66 | pr     | (n=168)   |   --------------- -        |   Pla         |
| 9\ | evious |           | --------------- ---------  | cebo\     4   |
| IT | ex     | Nebivolol | ---------------- --------- |      3        |
| T/ | posure | 10mg      |   **TX (mg/d)**            |    65 (38.9%) |
| LO | to     | daily     |    **Response\***   **p**  |   (n=167      |
| CF | neb    | (n=168)\  |     **T-SiHR\*\***   **p** | )             |
|    | ivolol | Nebivolol |                            |               |
| 84 |        | 20mg      |   **Placeb                 |               |
| da |        | daily     | o**     41.3%              |   Nebivolol   |
| ys |        | (n=166)\  |          -3.0              | \   21      4 |
|    |        | -add-on   |                            |           202 |
| S  |        | therapy   |   **Nebivo                 |               |
| up |        | to stable | lol**                      | (n=502)       |
| po |        | regimen   |                            |               |
| rt |        | of\       |                            |       (40.2%) |
| ed |        | 1 to 2 of |   5                        |   ---         |
| by |        | the       |  53.0%            0.028    | --------- --- |
| B  |        | f         |   -7.3             \<0.001 | ---- -------- |
| er |        | ollowing: |                            | -- ---------- |
| te |        | ACEI,     |   10                       |               |
| k, |        | ARB,      |  60.1%            0.001    | Most common   |
| n  |        | and/or    |   -7.6             \<0.001 | AEs (\> 2%)   |
| ow |        | thiazide  |                            | amongst       |
| pa |        | diuretic  |   20                       | nebivolol     |
| rt |        |           |  65.1%            \<0.001  | arms: HA      |
| of |        | -Trough   |   -10.6            \<0.001 | (5.0% vs.     |
| M  |        | BP/HR     |   --------------- -        | 2.4%          |
| yl |        | measured  | --------------- ---------  | placebo),     |
| an |        | on days   | ---------------- --------- | fatigue (3.6% |
|    |        | 0, 14,    |                            | vs. 2.4%      |
|    |        | 42, and   | \* % of patients with mean | placebo), UTI |
|    |        | 84. Peak  | SiDBP \< 90 mmHg and/or    | (3.2% vs.     |
|    |        | BP/HR     | absolute SiDBP reduction   | 3.6%          |
|    |        | measured  | [\>]{.underline} 10 mmHg   | placebo),     |
|    |        | on days   | vs. baseline; p value vs.  | dizziness     |
|    |        | 0, 42,    | placebo\                   | (2.4% vs.     |
|    |        | and 84\   | \*\* Change from baseline  | 1.8%          |
|    |        | -ABPM     | in mean trough sitting HR  | placebo), and |
|    |        | measured  | (bpm); SEM values          | na            |
|    |        | using     | unavailable                | sopharyngitis |
|    |        | device    |                            | (2.2% vs.     |
|    |        | c         | **-** Significant          | 1.2%          |
|    |        | alibrated | reductions in both peak    | placebo).     |
|    |        | to within | SiDBP (up to -13.6) and    | None were     |
|    |        | 5 mmHg of | SiSBP (up to -13.3) from   | d             |
|    |        | the mean  | baseline at all doses vs.  | ose-related.\ |
|    |        | of 3 DBP  | placebo (p\<0.001 for both | \             |
|    |        | measures\ | SiDBP and SiSBP). All      | **[Lab        |
|    |        | -At       | doses significantly        | Parameters\   |
|    |        | baseline  | decreased mean 24-hour     | ]{.unde       |
|    |        | and day   | ABPM (p\<0.001 for SiDBP;  | rline}**HDL-C |
|    |        | 84,       | p\<0.005 for SiSBP)        | decreased     |
|    |        | 24-hour   |                            | from baseline |
|    |        | ABPM      | **[Study                   | to study end  |
|    |        | measured  | Conclusions]{.underline}** | across all    |
|    |        | every 20  |                            | doses: (mean  |
|    |        | minutes   | Nebivolol once daily       | decrease from |
|    |        | from      | add-on therapy is an       | -1.3 to -2.5  |
|    |        | 0600-2200 | effective, safe, and       | mg/dL;\       |
|    |        | and every | well-tolerated therapy for | p values      |
|    |        | 30        | mild-to-moderate           | unavailable). |
|    |        | minutes   | hypertension despite       | No            |
|    |        | from      | therapy with at least 1    | dose          |
|    |        | 2200-0600 | but not more than 2 of     | -relationship |
|    |        |           | ACEI, ARB, and/or thiazide | reported.     |
|    |        |           | diuretic. Nebivolol        | Clinical      |
|    |        |           | provided greater decreases | implications  |
|    |        |           | in mean 24-hour ABPM       | of these      |
|    |        |           | (SiDBP and SiSBP) vs.      | changes       |
|    |        |           | placebo at all studied     | unknown.      |
|    |        |           | doses. Finding of          |               |
|    |        |           | decreases in HDL-C may     |               |
|    |        |           | warrant further            |               |
|    |        |           | investigation.             |               |
+----+--------+-----------+----------------------------+---------------+
| *  | ####   | #         | **[Baseline                | **[Completed  |
| *R | #####  | ########  | (mean):]{.underline}**     | TX Phase of   |
| CT | Inclus | Endpoints | 83.1% \< 65 yrs; 53.4%     | Trial:        |
| #  | ion Cr |           | male; 76.7% nonblack; 6.3% | 832/845       |
| 5\ | iteria | **P       | diabetic;\                 | (90.0%)]{     |
| On |  Men a | rimary:** | 42.0% BMI ≥ 30; mean       | .underline}** |
| F  | nd wom | change in | trough sitting SBP/DBP =   |               |
| il | en ≥ 1 | mean      | 152/99 mmHg; mean trough   | **[Safety     |
| e* | 8 year | trough    | sitting HR = 73 bpm        | (W/D / AEs)\  |
| *^ | s who  | SiDBP (24 |                            | ]{.           |
| 2^ | succes | +/- 2     |   ------------ ---         | underline}**- |
|    | sfully | hours     | --------- ---------------  | 4             |
| Mu |  compl | from      | ------- ------------------ | 61/845(54.6%) |
| lt | eted 1 | previous  |   **TX**       *           | AEs across    |
| in |  of th | morning   | *%          **T-SiDBP\***  | all arms      |
| at | e 3 RC | dose)     |   **p**   **Response\*\*** | (compared     |
| io | Ts fro | from      |                Patients**  | with 45.0%,   |
| na | m Appe | baseline  |                            | 46.1%, and    |
| l, | ndix 1 | (end of   |                            | 42.5% in      |
|    |        | feeder    |   Neb                      | feeder        |
| m  | ####   | trial) to | ivolol    71.8%        -12 | trials)\      |
| ul | #####  | end of    | .3, -14.6,\  p=S     78.2% | \             |
| ti |        | extension |   Mono         (n=607)     | - 2 of 17     |
| ce | #####  | phase     |   -15.0, -15.0             | SEAs were     |
| nt | #### E | (6-month  |                            | considered    |
| er | xclusi | or        |   Neb                      | trea          |
| ,\ | on Cri | 9-month)  | ivolol\   24.4%        -5. | tment-related |
| pr | teria  |           | 0, -7.1,\    p=S     65.5% | (impotence    |
| os |        | **Sec     |   + Diuretic   (n=206)     | and severe    |
| pe | Dia    | ondary:** |   -10.7, -12.0             | RUQ pain).    |
| ct | gnosis | changes   |                            | There were no |
| iv | of     | in mean   |   Neb                      | deaths        |
| e, | sec    | trough    | ivolol\   2.5% (n=21)  N/A | reported in   |
| op | ondary | SiSBP,    |              N/A     40.0% | this study.   |
| en | or     | mean peak |   + CCB                    |               |
| -l | mal    | SiDBP and |                            |   ---         |
| ab | ignant | SiSBP     |                            | --------- --- |
| el | h      | (2-3      |   Neb                      | ---- -------- |
| ,\ | yperte | hours     | ivolol\   1.3% (n=11)  N/A | -- ---------- |
| p  | nsion, | po        |              N/A     72.2% |   *           |
| ar | BMI ≥  | st-dose), |   + Other                  | *TX**       * |
| al | 40,    | responder |                            | *W/D   **SAEs |
| le | b      | rate,     |   ------------ ---         | **   **Total\ |
| l- | roncho | defined   | --------- ---------------  |               |
| gr | spasm, | in 2      | ------- ------------------ |   AEs**       |
| ou | bradyc | ways: (a) |                            |         AEs** |
| p, | ardia, | % of      | \* Change from baseline in |               |
| 9  | or     | patients  | least-squares (LS) mean    |   Nebivolol   |
| -m | other  | with mean | trough SiDBP (mmHg) on     | \   31\*    1 |
| on | known  | SiDBP\    | days 28,91,182,and 273;    | 7         461 |
| th | cont   | \< 90mmHg | SEM values unavailable\    |               |
| e  | raindi | or        | \*\*% of patients with     | (n=845)       |
| xt | cation | absolute  | mean SiDBP \< 90 mmHg      |               |
| en | to\    | SiDBP     | and/or absolute SiDBP      |       (54.6%) |
| si | beta-b | reduction | reduction [\>]{.underline} |   ---         |
| on | locker | of ≥      | 10 mmHg vs. baseline       | --------- --- |
|    | th     | 10mmHghn  | [or]{.underline} SiDBP     | ---- -------- |
| 1  | erapy, | mean      | \<90 mmHg at study end     | -- ---------- |
| 23 | uncont | trough    |                            |               |
| U. | rolled | SiDBPn    | \- Reductions in trough    | AEs with the  |
| S. | di     | antihyp   | SiSBP and peak SiDBP and   | highest       |
| a  | abetes | ertensive | SiSBP were significant and | incidences    |
| nd | (HgA1c | therapies | similar across all arms.   | were HA       |
| Eu | ≥      | were      |                            | (5.4%),       |
| ro | 10%),  | allowed   | -Overall, 74.0% of         | fatigue       |
| pe | ACS    | an        | patients responded to      | (4.6%), URTI  |
| an | within | additonal | therapy. Only 1.1% of      | (3.9%),       |
| s  | past 6 | 40mg is   | patients required rescue   | arthralgia    |
| it | m      | an        | medication during the      | (3.8%),       |
| es | onths, | in        | 9-month trial.\            | na            |
| (M | HF,    | dependent | \                          | sopharyngitis |
| ar | clin   | predictor | **[4-Week                  | (3.7%), and   |
| ch | ically | of CV     | Run-Out]{.underline}**     | dizziness     |
| 20 | signi  | outcome.  |                            | (3.5%)\       |
| 02 | ficant | 000 vs.   | \- 18 patients were        | \             |
|  - | va     | baseline, | withdrawn from nebivolol   | \*26 of 31    |
| Se | lvular | and (b) % | monotherapy and continued  | W/D in        |
| pt | heart  | of        | on placebo to assess for   | nebivolol     |
| 2  | di     | patients  | rebound hypertension\      | monotherapy   |
| 00 | sease, | with mean | - SiDBP and SiSBP          | arm\          |
| 3) | th     | trough    | increased over the 4-weeks | \             |
|    | yroid, | SiDBP \<  | but did not return to      | **[Lab        |
| Ef | renal, | 90mmHg at | baseline values\           | Parameters\   |
| fi | or     | study end | - 72.2% were still         | ]{.und        |
| ca | h      |           | classified as responders   | erline}**Mean |
| cy | epatic | *         | (78.2% were responders in  | serum glucose |
| &  | dysfun | *Other:** | extension phase; p=NS)\    | levels        |
| Sa | ction, | safety    | - There were no reported   | increased     |
| fe | peri   | and       | withdrawal rebound         | from baseline |
| ty | pheral | tol       | effects. There was 1       | in the        |
| in | va     | erability | reported SEA               | nebivolol     |
| m  | scular |           | (spontaneously resolving   | monotherapy   |
| il | di     | **[       | episode of vertigo)        | arm on day    |
| d- | sease, | Treatment |                            | 182 (mean     |
| mo | preg   | P         | **[Study                   | change +3.26  |
| de | nancy, | hase]{.un | Conclusions]{.underline}** | mg/dL). This  |
| ra | pr     | derline}\ |                            | change was    |
| te | evious | **No      | Long-term use of nebivolol | not reported  |
| H  | ex     | placebo   | 5mg to 20mg once daily     | as clinically |
| TN | posure | arm\      | remained effective in      | significant,  |
|    | to     | Nebivolol | patients with              | however.      |
| n  | nebi   | mo        | mild-to-moderate           |               |
| =  | volol, | notherapy | hypertension with or       |               |
| 8  | or     | x 28      | without adjunctive         |               |
| 45 | conco  | days\     | diuretic and/or CCB        |               |
| to | mitant | (         | therapy. Results indicate  |               |
| ta | t      | 5mg,10mg, | that the majority of       |               |
| l\ | herapy | or 20mg;  | patients who responded     |               |
| IT | with   | dose      | initially to nebivolol     |               |
| T/ | at     | based     | continued to respond with  |               |
| LO | least  | upon      | extended therapy duration. |               |
| CF | 1      | SiDBP,    | Rebound hypertension did   |               |
|    | proh   | SiHR, and | not appear to be of        |               |
| 2  | ibited | previous  | concern with nebivolol     |               |
| 73 | medi   | trial     | discontinuation. Of note,  |               |
| da | cation | dose)\    | it is interesting that     |               |
| ys | that   | \         | serum glucose increased    |               |
|    | may    | -After 28 | significantly in the       |               |
| S  | have   | days,     | nebivolol monotherapy arm, |               |
| up | af     | nonr      | but not in the thiazide    |               |
| po | fected | esponders | diuretic adjunct arms.     |               |
| rt | blood  | (mean     |                            |               |
| ed | pr     | SiDBP ≥   |                            |               |
| by | essure | 90 mmHg)  |                            |               |
| B  | (oral  | received  |                            |               |
| er | and    | adjunct:\ |                            |               |
| te | opt    | -         |                            |               |
| k, | halmic | thiazide  |                            |               |
| n  | BBs,   | /         |                            |               |
| ow | ABs,   | t         |                            |               |
| pa | ACEIs, | hiazide + |                            |               |
| rt | ARBs,  | tri       |                            |               |
| of | CCBs,  | amterene\ |                            |               |
| M  | and    | -         |                            |               |
| yl | diur   | am        |                            |               |
| an | etics) | lodipine\ |                            |               |
|    |        | - other\  |                            |               |
|    |        | \         |                            |               |
|    |        | - Trough  |                            |               |
|    |        | BP/HR     |                            |               |
|    |        | measured  |                            |               |
|    |        | on days 0 |                            |               |
|    |        | (last day |                            |               |
|    |        | of feeder |                            |               |
|    |        | trial),   |                            |               |
|    |        | 28, 91,   |                            |               |
|    |        | 182, and  |                            |               |
|    |        | 273. Peak |                            |               |
|    |        | BP/HR     |                            |               |
|    |        | measured  |                            |               |
|    |        | on days   |                            |               |
|    |        | 0,        |                            |               |
|    |        | 91,182,   |                            |               |
|    |        | and 273   |                            |               |
|    |        |           |                            |               |
|    |        | *         |                            |               |
|    |        | *[Run-Out |                            |               |
|    |        | Phase\    |                            |               |
|    |        | ]{.unde   |                            |               |
|    |        | rline}**- |                            |               |
|    |        | 4-week    |                            |               |
|    |        | follow-up |                            |               |
|    |        | of        |                            |               |
|    |        | mo        |                            |               |
|    |        | notherapy |                            |               |
|    |        | patients  |                            |               |
|    |        | to assess |                            |               |
|    |        | for       |                            |               |
|    |        | rebound   |                            |               |
|    |        | (days 7,  |                            |               |
|    |        | 14, 28).  |                            |               |
|    |        | Doub      |                            |               |
|    |        | le-blind, |                            |               |
|    |        | rand      |                            |               |
|    |        | omization |                            |               |
|    |        | (2:1) of  |                            |               |
|    |        | placebo   |                            |               |
|    |        | and       |                            |               |
|    |        | nebivolol |                            |               |
+----+--------+-----------+----------------------------+---------------+

RCTs=randomized-controlled trials; ABPM=ambulatory blood pressure
monitoring; BMI=body mass index; SiHR=sitting heart rate; SiDBP=sitting
diastolic blood pressure; SiSBP=sitting systolic blood pressure;
W/D=withdrawals; AEs=adverse events; HA=headache; URTI=upper respiratory
tract infection; UTI=urinary tract infection; BBs=beta blockers;
ACEIs=angiotensin-converting enzyme inhibitors;
ARBs=angiotensin-receptor blockers; CCBs=calcium channel blockers

**Appendix 3: Evidence Table (Placebo-Controlled Monotherapy with Active
Background HF Trials)**

+-----+--------+--------+---------------------------------+-----------+
| ### | ### I  | ### E  | ### Results/Conclusions         | ### Withd |
|  Tr | nclusi | ndpoin |                                 | rawals/AE |
| ial | on/Exc | ts/Tre |                                 |           |
|     | lusion | atment |                                 |           |
+-----+--------+--------+---------------------------------+-----------+
| *   | ####   | #      | [**Baseline                     | **[       |
| *Ed | #####  | ###### | (mean)**:]{.underline} 72.0     | Completed |
| es, | Inclus | ## End | years; 70.2% male; 99.3%        | TX Phase  |
| et  | ion Cr | points | Caucasian; BMI 26.1; 24.6%      | of Trial: |
| al, | iteria |        | diabetic;\                      | (         |
| 2   |        | **Prim | 52.2% NYHA II; 45.5% NYHA III;  | 136/260)\ |
| 005 | Hospit | ary:** | mean dose 7.2mg nebivolol;      | ]{.und    |
| **^ | alized | change | 64.2% reached target 10mg dose  | erline}** |
| 12^ | pa     | in     |                                 |           |
| **\ | tients | LVEF   | **Primary Outcome**: Change in  | **Neb     |
| **( | or     | from   | LVEF from baseline              | ivolol:** |
| ENE | outpa  | ba     |                                 | 124/134   |
| CA) | tients | seline | +-------+--------+----------+   | (92.5%);  |
|     | \> 65  | of     | | *     | **LVEF | **%      |   | W/D=7.5%  |
| Mul | yrs    | add-on | | *Tx** | I      | Change** |   |           |
| tic | old,   | neb    | |       | mprove |          |   | **P       |
| ent | NYHA   | ivolol | |       | ment** |          |   | lacebo:** |
| er, | Class  | t      | +-------+--------+----------+   | 112/126   |
| ra  | II-IV  | herapy | | *     | 3.97%  | 19.2 ±   |   | (88.9%);  |
| ndo | HF,    |        | | *Plac | ±      | 41.0     |   | W/D=11.1% |
| miz | stable | **\    | | ebo** | 9.20%  |          |   |           |
| ed, | cl     | Second | |       |        |          |   | **[Safety |
| dou | inical | ary:** | | (n    |        |          |   | (W/D /    |
| ble | c      | change | | =126) |        |          |   | A         |
| -bl | ourse, | in     | +-------+--------+----------+   | Es)]{.und |
| ind | LVEF   | NYHA   | | **N   | 6.51%  | 35.7 ±   |   | erline}** |
| ed, | ≤35%,  | func   | | ebivo | ±      | 57.6     |   |           |
| pro | and 2  | tional | | lol** | 9.15%  |          |   | \- 81/134 |
| spe | wk     | s      | |       |        |          |   | (60.5%)   |
| cti | m      | tatus; | | (n    |        |          |   | AEs in    |
| ve, | inimum | QOL;   | | =134) |        |          |   | nebivolol |
| p   | of     | hos    | +-------+--------+----------+   | group     |
| lac | stable | pitali | |       | p=0.27 | p=0.008  |   | vs.\      |
| ebo | meds   | zation | +-------+--------+----------+   | 78/126    |
| -co | for HF | rate;  |                                 | (61.9%)   |
| ntr | (      | safety | Mean ± SD; p value vs. placebo  | placebo   |
| oll | ACEIs, |        |                                 | group     |
| ed, | ARBs,  | **[Tre | **Secondary Outcomes:** Change  | (p=0.899; |
| pa  | diur   | atment | in NYHA Functional Status       | NS)       |
| ral | etics, | P      |                                 |           |
| lel | and/or | hase]{ | <table>                         | \- 152    |
| gr  | digi   | .under | <colgroup>                      | different |
| oup | talis) | line}\ | <col style="width: 28%" />      | types of  |
|     |        | **P    | <col style="width: 17%" />      | AEs       |
| 70  | ####   | lacebo | <col style="width: 24%" />      | reported; |
| ce  | #####  | (      | <col style="width: 29%" />      | overall,  |
| nte | Exclus | n=126) | </colgroup>                     | 360 AEs   |
| rs\ | ion Cr |        | <tbody>                         | reported  |
| P   | iteria | Neb    | <tr class="odd">                | in both   |
| ola |        | ivolol | <td><strong>NYHA Class          | groups    |
| nd, | #####  | (      | Status</strong></td>            |           |
| H   | #### A | n=134) | <td>                            | \- 54 AEs |
| ung | cute c |        | <p><strong>Placebo</strong></p> | thought   |
| ary | oronar | \-     | <                               | to be     |
|     | y synd | 1.25mg | p><strong>(%)</strong></p></td> | dru       |
| E   | rome;  | Daily  | <td><p                          | g-related |
| ffi | MI w/i | x7     | ><strong>Nebivolol</strong></p> | (40       |
| cac | n last | days;  | <                               | nebivolol |
| y/S |  3 mon | dose   | p><strong>(%)</strong></p></td> | and 14    |
| afe | ths; P | d      | <t                              | placebo). |
| ty, | TCA or | oubled | d><strong>p-value</strong></td> | Most      |
| Add |  CABG  | every  | </tr>                           | common    |
| -on | surger | 2      | <tr class="even">               | dru       |
| t   | y with | weeks  | <td>Improved 2 Classes</td>     | g-related |
| her | in las | if SBP | <td>3 (2.4)</td>                | AEs were  |
| apy | t mont | \> 110 | <td>2 (1.5)</td>                | bra       |
|     | h; obs | mmHg   | <td>NS; p=0.835</td>            | dycardia, |
| n = | tructi | and HR | </tr>                           | hyp       |
| 260 | ve or  | \> 60  | <tr class="odd">                | otension, |
|     | hypert | bpm up | <td>Improved 1 Class</td>       | and       |
| 280 | rophic | to     | <td>34 (27.0)</td>              | d         |
| d   |  cardi | target | <td>33 (24.6)</td>              | izziness. |
| ays | omyopa | dose   | <td>NS; p=0.835</td>            |           |
|     | thy; h | 10mg   | </tr>                           |   ------- |
| Spo | emodyn | daily\ | <tr class="even">               | ----- --- |
| nso | amical | \      | <td>Remained Stable</td>        | ------- - |
| red | ly rel | -      | <td>67 (53.2)</td>              | --------- |
| by  | evant  | neb    | <td>81 (60.4)</td>              |   **TX*   |
| B   | congen | ivolol | <td>NS; p=0.835</td>            | *       * |
| erl | ital o | admini | </tr>                           | *SAEs**   |
| in- | r valv | stered | <tr class="odd">                |  **Total\ |
| Che | ular h | as     | <td>Worsened 1 Class</td>       |           |
| mie | eart d | a      | <td>1 (0.8)</td>                |           |
| AG  | isease | djunct | <td>2 (1.5)</td>                |           |
|     | ; tach | t      | <td>NS; p=0.835</td>            |     AEs** |
|     | yarrhy | herapy | </tr>                           |           |
|     | thmia  | with   | </tbody>                        |           |
|     | resist | backg  | </table>                        | Placebo   |
|     | ant to | round, |                                 |     26    |
|     |  thera | open   | Intention-to-treat (ITT)        |       174 |
|     | py (\> | -label | protocol                        |           |
|     | 100/mi | ACEIs, |                                 |           |
|     | n); br | ARBs,  | **Change in QOL:** No           | Nebivolol |
|     | adycar | diur   | statistical difference between  | \   22    |
|     | dia (H | etics, | from baseline to end of follow  |       186 |
|     | R\<50/ | and/or | up between treatment groups     |   (n=828  |
|     | min);  | digi   | (p=0.342)                       | )         |
|     | beta-b | talis. |                                 |           |
|     | locker |        | **Hospitalization Rates:** No   |   ------- |
|     |  thera | -LVEF  | statistical difference in mean  | ----- --- |
|     | py wit | me     | time to first hospitalization,  | ------- - |
|     | hin 4  | asured | nebivolol 15.92 days vs.        | --------- |
|     | weeks  | on     | placebo 15.77 days (p=0.507)    |           |
|     | of tri | days   |                                 | Most      |
|     | al; in | 0, 14, | **Kaplan-Meier Survival         | common    |
|     | tolera | 84,    | Curves:** No statistical        | dru       |
|     | nce or | 198,   | difference between nebivolol    | g-related |
|     |  hyper | and    | 67.47% vs. placebo 52.89%       | AEs       |
|     | sensit | 280.   | (p=0.696).                      | (\>2%)    |
|     | ivity  | NYHA   |                                 | among     |
|     | to neb | cl     | **[Study                        | nebivolol |
|     | ivolol | assifi | Conclusions]{.underline}**      | group: HF |
|     |        | cation |                                 | worsening |
|     |        | eva    | Nebivolol as add-on therapy     | (7.5% vs. |
|     |        | luated | significantly improved LV       | 9.2%      |
|     |        | at all | function in patients \> 65      | placebo), |
|     |        | study  | years with signs of HF and      | ve        |
|     |        | v      | cardiomyopathy. Nebivolol was   | ntricular |
|     |        | isits. | found to be safe and generally  | ta        |
|     |        | QOL    | well-tolerated.                 | chycardia |
|     |        | me     |                                 | (2.7% vs. |
|     |        | asured |                                 | 4.0%      |
|     |        | on     |                                 | p         |
|     |        | days   |                                 | lacebo),\ |
|     |        | 0, 14, |                                 | A-fib     |
|     |        | 0, 84, |                                 | (2.2% vs. |
|     |        | 198,\  |                                 | 4.6%      |
|     |        | and    |                                 | placebo). |
|     |        | 280.   |                                 |           |
|     |        |        |                                 |           |
|     |        | ####   |                                 |           |
|     |        | #####  |                                 |           |
+-----+--------+--------+---------------------------------+-----------+
| *   | ####   | #      | **[Baseline                     | **[       |
| *Fl | #####  | ###### | (mean):]{.underline} mean age   | Completed |
| ath | Inclus | ## End | 76.1 years; median age 75.2     | TX Phase  |
| er, | ion Cr | points | years; 36.9% male; 64.5% LVEF ≤ | of        |
| et  | iteria |        | 35%; mean sitting SBP/DBP       | Trial:\   |
| al\ |        | **Prim | 139/80.6 mmHg; diabetes 26.1%;  | 1,        |
| 2   | Pa     | ary:** | NYHA Class I 2.9%; Class II     | 582/2,128 |
| 005 | tients | com    | 56.4%; Class III 38.7%; Class   | (74.      |
| **^ | ≥ 70   | posite | IV 2%; prior MI 43.8%; prior    | 3%)]{.und |
| 14^ | years  | all    | CABG 9.2%; prior PCTA 3.8%;     | erline}** |
|     | old    | -cause | concurrent diuretic 85.7%;      |           |
| (   | with   | mor    | concurrent ACEI 82.2%;          | **[Safety |
| SEN | h      | tality | concurrent ARB 6.7%; concurrent | (W/D /    |
| IOR | istory | or CV  | aldosterone antagonist 27.6%;   | A         |
| S)\ | of HF  | hos    | concurrent digitalis 39.4%**    | Es)]{.und |
| Mul | and at | pitali |                                 | erline}** |
| tin | least  | zation |   --                            |           |
| ati | 1 of   | (time  | --------------- --------------  | \-        |
| ona | the    | to     | ------------ --------- -------- | 285/1,067 |
| l,\ | foll   | first  |                                 | (26.7%)   |
| m   | owing: | event) |                    **Nebivolol\ | premature |
| ult | docu   |        |    **Placebo\   **HR (95% **p** | W/D for   |
| ice | mented | **     |                     (n = 1,     | reasons   |
| nte | ho     | Second | 067)**  (n =         CI)\***    | other     |
| r,\ | spital | ary:** |                                 | than      |
| ran | adm    | CV     |         1,061)**                | death in  |
| dom | ission | mort   |                                 | nebivolol |
| ize | within | ality, |   **Primary                     | arm vs.   |
| d,\ | pr     | CV     |                                 | 261/1,061 |
| d   | evious | hosp   |   Outcome**                     | (24.6%)   |
| oub | 12     | italiz |                                 | premature |
| le- | months | ation, |                                 | W/D for   |
| bli | with   | com    |                                 | reasons   |
| nde | dis    | posite |  Composite         332 (31.1%)  | other     |
| d,\ | charge | CV     |    375 (35.3%)  0.86      0.039 | than      |
| p   | dia    | mor    |   all-cause                     | death in  |
| ros | gnosis | tality |                      (0.74 -    | placebo   |
| pec | of HF, | or CV  |   mortality or CV               | arm       |
| tiv | and/or | hosp   |                      0.99)      |           |
| e,\ | docu   | italiz |   hospitalization               | -AEs with |
| pl  | mented | ation, |                                 | the       |
| ace | LVEF   | all    |                                 | highest   |
| bo- | ≤35%   | -cause |                                 | i         |
| con | within | mort   |  \*Unadjusted      332 (31.3%)  | ncidences |
| tro | pr     | ality, |    375 (35.3%)  0.85      0.034 | were:     |
| lle | evious | all    |   analysis                      | worsening |
| d,\ | 6      | -cause |                      (0.74 -    | HF (24.0% |
| pa  | months | hosp   |                                 | vs. 25.0% |
| ral |        | italiz |                      0.99)      | placebo); |
| lel | ####   | ation, |                                 | dizziness |
| -gr | #####  | com    |   **Secondary                   | excluding |
| oup | Exclus | posite |                                 | vertigo   |
|     | ion Cr | all    |   Outcomes**                    | (15.6%    |
| 160 | iteria | -cause |                                 | vs. 13.4% |
| c   |        | mor    |                                 | placebo); |
| ent | New    | tality |   CV                            | [br       |
| ers | drug   | or     |  mortality      123 (11.5%)     | adycardia |
| f   | t      | all    | 145 (13.7%)  0.84      0.17; NS | (11.1%    |
| rom | herapy | -cause |                                 | vs. 2.6%  |
| 10  | for HF | hosp   |                      (0.66 -    | plac      |
| c   | within | italiz |                                 | ebo);]{.u |
| oun | 6      | ation\ |                      1.07)      | nderline} |
| tri | weeks  | \      |                                 | A. fib    |
| es\ | prior  | -Hos   |   CV                            | (7.3% vs. |
| (Cz | to     | pitali |                 256 (24.0%)     | 7.0%      |
| ech | ra     | zation | 276 (26.0%)  0.90      0.20; NS | placebo); |
| Rep | ndomiz | d      |   hospitalization               | HA (5.8%  |
| ubl | ation; | efined |                      (0.76 -    | vs. 4.9%  |
| ic, | change | as     |                                 | placebo); |
| F   | in CV  | adm    |                      1.06)      | L         |
| ran | drug   | ission |                                 | ower-limb |
| ce, | t      | of at  |                                 | edema     |
| Ge  | herapy | least  |  Composite CV      305 (28.6%)  | (5.2% vs. |
| rma | within | 24     |    350 (33.0%)  0.84      0.027 | 2.3%      |
| ny, | 2      | hours\ |   mortality or CV               | placebo)\ |
| Hu  | weeks  | -CV    |                      (0.72 -    | \         |
| nga | prior  | hos    |   hospitalization               | - Authors |
| ry, | to     | pitali |                      0.98)      | did not   |
| Ita | ra     | zation |                                 | present   |
| ly, | ndomiz | d      |   Al                            | st        |
| Net | ation; | efined | l-cause         169 (15.8%)     | atistical |
| her | HF due | as     | 192 (18.1%)  0.88      0.21; NS | analyses  |
| lan | pri    | those  |   mortality                     | on AE     |
| ds, | marily | for    |                      (0.71 -    | outcomes  |
| Ro  | to     | c      |                                 |           |
| man | va     | ardiac |                      1.08)      |           |
| ia, | lvular | r      |                                 |           |
| Spa | heart  | easons |   Al                            |           |
| in, | di     | (wor   | l-cause         359 (33.6%)     |           |
| Uk  | sease; | sening | 364 (34.3%)  0.96      0.47; NS |           |
| rai | cont   | HF,    |   hospitalization               |           |
| ne, | raindi | ACS)   |                      (0.82 -    |           |
| and | cation | or     |                                 |           |
| U.  | or     | other  |                      1.10)      |           |
| K.) | pr     | CV     |                                 |           |
|     | evious | causes |                                 |           |
| **\ | intol  |        | Composite         408 (38.2%)   |           |
| **S | erance | **[Tre |   443 (41.8%)  0.90      0.082; |           |
| ept | to     | atment |   all-cause                     |           |
| 200 | beta   | Phase\ |                    (0.78 -   NS |           |
| 0 - | bl     | ]{.u   |   mortality or                  |           |
| Nov | ockers | nderli |                      1.02)      |           |
| 2   | (      | ne}**- |   all-cause                     |           |
| 003 | asthma | P      |                                 |           |
|     | or     | lacebo |   hospitalization               |           |
| Eff | b      | arm    |                                 |           |
| ica | roncho | (      |   --                            |           |
| cy/ | spasm, | n=1,06 | --------------- --------------  |           |
| Saf | 2^nd^  | 1)**[\ | ------------ --------- -------- |           |
| ety | or     | ]{.u   |                                 |           |
| in  | 3^rd^  | nderli | \*Results reported as Hazards   |           |
| e   | degree | ne}**- | Ratios (HR) adjusted for        |           |
| lde | heart  | Neb    | pre-specified variables:        |           |
| rly | block  | ivolol | gender, age (\< median 75.2     |           |
| pa  | w      | arm    | years vs.\                      |           |
| tie | ithout | (n=1   | ≥ median 75.2 years), and LVEF  |           |
| nts | pac    | ,067): | (≤35% vs. \>35%). Age and LVEF  |           |
| w   | emaker | neb    | considered as continuous        |           |
| ith | in     | ivolol | variables.\                     |           |
| /wi | -situ, | 1.25mg | \                               |           |
| tho | sick   | daily  | - ARR=4.2%; RRR=11.9%; Risk     |           |
| ut\ | sinus  | ti     | Reduction=14%; NNT=24 (over 21  |           |
| ↓   | syn    | trated | months)\                        |           |
| L   | drome, | up to  | - Kaplan-Meier survival Curve   |           |
| VEF | HR \<  | target | (time to event) shows           |           |
| (ad | 60     | 10mg   | divergence after \~6 months\    |           |
| ded | bpm,   | dose   | \                               |           |
| to  | or SBP | (or    | - Pre-specified risk-factor     |           |
| st  | \< 90  | max    | variables: gender, age (\<      |           |
| and | mmHg); | imally | median 75.2 years vs. ≥ median  |           |
| ard | c      | tol    | 75.2 years), LVEF (≤35% vs.\    |           |
| HF  | urrent | erated | \>35%), diabetes, prior MI. No  |           |
| th  | use of | dose)  | individual variable altered the |           |
| era | beta   | via    | effects of nebivolol on the     |           |
| py) | blo    | d      | primary outcome (p=NS).         |           |
|     | ckers; | ose-do |                                 |           |
| n = | signi  | ubling | \- Mean Titration Dose:         |           |
| 2,  | ficant | every  | nebivolol arm: 7.7mg (± 3.6mg   |           |
| 128 | h      | 1-2    | SD); 68% reached target 10mg;   |           |
| (IT | epatic | weeks  | placebo arm: 8.5mg (± 3.1mg\    |           |
| T)\ | or     | over   | SD); 80% reached target 10mg.   |           |
| \   | renal  | 4-to-1 | Authors did not report reasons  |           |
| 1-y | dysfun | 6-week | for certain % not reaching      |           |
| ear | ction; | do     | target dose.\                   |           |
| mi  | cer    | se-tit | \                               |           |
| nim | ebrova | ration | - In a pre-specified cohort     |           |
| um\ | scular | p      | analysis of patients \> 75 and  |           |
| fol | events | eriod\ | \< 85 years (n=459 or 43.0%     |           |
| low | within | -      | nebivolol arm; n=482 or 45.4%   |           |
| -up | pr     | Maint  | placebo arm) HR=0.91            |           |
| (m  | evious | enance | (0.74-1.13) for primary         |           |
| ean | 3      | period | endpoint. For patients \> 85    |           |
| 1   | m      | 12-29  | years, HR=1.32 (0.73-2.37) for  |           |
| .75 | onths, | months | primary endpoint, with no       |           |
| yea | on     | with 4 | differences between nebivolol   |           |
| rs) | PCTA   | month  | treatment and placebo for CV    |           |
|     | or     | visit, | hospitalization (p=0.95).\      |           |
| Spo | c      | 6      | \                               |           |
| nso | ardiac | month  | - In a post-hoc cohort analysis |           |
| red | s      | visit, | for age \< 75.2 years and LVEF  |           |
| by  | urgery | and    | ≤ 35%, which is a similar       |           |
| Me  | wait   | then   | population studied in prior     |           |
| nar | -list; | every  | landmark trials, (n=342 or      |           |
| ini | other  | 3      | 32.0% nebivolol arm; n=342 or   |           |
| Ri  | major  | months | 32.2% placebo arm), HR=0.62     |           |
| cer | m      | there  | (0.42-0.91; p=0.014) for        |           |
| che | edical | after\ | all-cause mortality, which is   |           |
| SpA | cond   | \      | not significantly different     |           |
|     | itions | **[R   | from composite HR=0.65 from     |           |
|     | likely | un-Out | prior trials.                   |           |
|     | to ↓   | Phase\ |                                 |           |
|     | su     | ]{.u   | **[Study                        |           |
|     | rvival | nderli | Conclusions]{.underline}**      |           |
|     | thro   | ne}**- |                                 |           |
|     | ughout | 4-to-7 | Nebivolol is well-tolerated and |           |
|     | study  | week   | effective in reducing CV        |           |
|     | period | do     | mortality and morbidity in HF   |           |
|     |        | wn-tit | patient ≥ 70 years of age,      |           |
|     | **     | ration | regardless of LVEF. Additional  |           |
|     | [Study | tre    | studies are needed comparing    |           |
|     | R      | atment | the long-term benefits of       |           |
|     | ationa | phase  | nebivolol with those of         |           |
|     | le]{.u | (open  | carvedilol (COPERNICUS),        |           |
|     | nderli | label) | metoprolol succinate            |           |
|     | ne}**\ |        | (MERIT-HF), and bisoprolol      |           |
|     | Prior  |        | (CIBIS-II).                     |           |
|     | la     |        |                                 |           |
|     | ndmark |        |                                 |           |
|     | HF     |        |                                 |           |
|     | trials |        |                                 |           |
|     | did    |        |                                 |           |
|     | not    |        |                                 |           |
|     | suffic |        |                                 |           |
|     | iently |        |                                 |           |
|     | study  |        |                                 |           |
|     | pa     |        |                                 |           |
|     | tients |        |                                 |           |
|     | ≥ 70   |        |                                 |           |
|     | years  |        |                                 |           |
|     | with   |        |                                 |           |
|     | pre    |        |                                 |           |
|     | served |        |                                 |           |
|     | LVEF   |        |                                 |           |
|     | \>     |        |                                 |           |
|     | 35%.   |        |                                 |           |
|     | S      |        |                                 |           |
|     | ENIORS |        |                                 |           |
|     | trial  |        |                                 |           |
|     | thus   |        |                                 |           |
|     | f      |        |                                 |           |
|     | ocused |        |                                 |           |
|     | on     |        |                                 |           |
|     | these  |        |                                 |           |
|     | pa     |        |                                 |           |
|     | tients |        |                                 |           |
|     | with   |        |                                 |           |
|     | longer |        |                                 |           |
|     | fol    |        |                                 |           |
|     | low-up |        |                                 |           |
|     | (mean  |        |                                 |           |
|     | fol    |        |                                 |           |
|     | low-up |        |                                 |           |
|     | du     |        |                                 |           |
|     | ration |        |                                 |           |
|     | of 21  |        |                                 |           |
|     | mo     |        |                                 |           |
|     | nths). |        |                                 |           |
+-----+--------+--------+---------------------------------+-----------+

NYHA=New York Heart Association; QOL=quality of life; HF=heart failure;
LVEF=left ventricular ejection fraction; ACS=acute coronary syndrome;
ACEIs=angiotensin-converting enzyme inhibitors; ARBs=angiotensin
receptor blockers; PTCA=percutaneous transluminal coronary angioplasty;
CABG=coronary artery bypass graft; BMI=body mass index; MI=myocardial
infarction; W/D=withdrawals; SAEs=serious adverse events; A-fib=atrial
fibrillation

**Appendix 4: Evidence Table (Retrospective, Post-Hoc Analysis of the
SENIORS Trial in HF)**

+-----+--------+-----------+-----------------------------+------------+
| ### | ### I  | ### E     | ### Results                 | ### C      |
|  Tr | nclusi | ndpoints/ |                             | onclusions |
| ial | on/Exc | Treatment |                             |            |
|     | lusion |           |                             |            |
+-----+--------+-----------+-----------------------------+------------+
| **D | ####   | #         | [**Baseline                 | **[Study   |
| obr | #####  | ########  | (mean)**:]{.underline} mean | Conclu     |
| e,\ | Patien | Endpoints | age 76.1 years; median age  | sions]{.un |
| et  | t Popu |           | 75.2 years; 36.9% male;     | derline}** |
| al, | lation | **P       | 64.5% LVEF ≤ 35%; mean      |            |
| 2   |        | rimary:** | sitting SBP/DBP 139/80.6    | Nebivolol  |
| 007 | Pa     | composite | mmHg; diabetes 26.1%; NYHA  | is well    |
| **^ | tients | all-cause | Class I 2.9%; Class II      | tolerated  |
| 16^ | who    | mortality | 56.4%; Class III 38.7%;     | in elderly |
| **\ | succes | or CV     | Class IV 2%; prior MI       | patients   |
| **  | sfully | hospit    | 43.8%; prior CABG 9.2%;     | with HF.   |
|     | partic | alization | prior PCTA 3.8%; concurrent | Nebivolol  |
| Po  | ipated | (time to  | diuretic 85.7%; concurrent  | at target  |
| st- | in the | first     | ACEI 82.2%; concurrent ARB  | dose of    |
| hoc | S      | event)    | 6.7%; concurrent            | 10mg       |
| an  | ENIORS |           | aldosterone antagonist      | sig        |
| aly | Trial  | **Sec     | 27.6%; concurrent digitalis | nificantly |
| sis | (Ap    | ondary:** | 39.4%                       | reduces    |
| of  | pendix | CV        |                             | the        |
| S   | 3)     | m         | **Primary Outcome**:        | primary    |
| ENI |        | ortality, | Composite all-cause         | endpoint   |
| ORS | #####  | CV        | mortality and CV            | (risk of   |
|     | ####   | hospita   | hospitalization             | all-cause  |
| 160 | Inclus | lization, |                             | mortality  |
| c   | ion Cr | composite | +------+--------+------+    | or CV      |
| ent | iteria | CV        | | **   | **%**  | **HR |    | hospit     |
| ers |        | mortality | | Tx** |        | \*** |    | alization) |
| f   | Pa     | or CV     | +------+--------+------+    | compared   |
| rom | tients | hospita   | | **P  | 34.7   |      |    | to         |
| 10  | ≥ 70   | lization, | | lace |        |      |    | placebo.   |
| c   | years  | all-cause | | bo** |        |      |    | Patients   |
| oun | old    | m         | |      |        |      |    | unable to  |
| tri | with   | ortality, | | (n=1 |        |      |    | tolerate a |
| es\ | h      | all-cause | | 030) |        |      |    | m          |
| (Cz | istory | hospita   | +------+--------+------+    | aintenance |
| ech | of HF  | lization, | | *    |        |      |    | dose of    |
| Rep | and at | composite | | *Neb |        |      |    | nebivolol  |
| ubl | least  | all-cause | | ivol |        |      |    | had 2x the |
| ic, | 1 of   | mortality | | ol** |        |      |    | risk of    |
| F   | the    | or        | +------+--------+------+    | all-cause  |
| ran | foll   | all-cause | | 0    | 52.7   | 1.95 |    | mortality  |
| ce, | owing: | hospit    | | mg - |        |      |    | or CV      |
| Ge  | docu   | alization | | ID   |        | (1.  |    | hospit     |
| rma | mented |           | |      |        | 38 - |    | alization. |
| ny, | ho     | **Patient | | (n   |        | 2    |    |            |
| Hu  | spital | Stratifi  | | =74) |        | .75) |    |            |
| nga | adm    | cation:** | +------+--------+------+    |            |
| ry, | ission |           | | 1.25 | 31.7   | 0.88 |    |            |
| Ita | within | Patients  | | /2.5 |        |      |    |            |
| ly, | pr     | in the    | | mg - |        | (0.  |    |            |
| Net | evious | nebivolol | | LD   |        | 64 - |    |            |
| her | 12     | arm were  | |      |        | 1    |    |            |
| lan | months | s         | | (n=  |        | .20) |    |            |
| ds, | with   | tratified | | 142) |        |      |    |            |
| Ro  | dis    | into 4    | +------+--------+------+    |            |
| man | charge | groups    | | 5    | 29.8   | 0.73 |    |            |
| ia, | dia    | according | | mg - |        |      |    |            |
| Spa | gnosis | to the    | | MD   |        | (0.  |    |            |
| in, | of HF, | dose      | |      |        | 52 - |    |            |
| Uk  | and/or | achieved  | | (n=  |        | 1    |    |            |
| rai | docu   | by the    | | 127) |        | .02) |    |            |
| ne, | mented | end of    | +------+--------+------+    |            |
| and | LVEF   | the       | | 10   | 27.8   | 0.75 |    |            |
| U.  | ≤35%   | titration | | mg - |        |      |    |            |
| K.) | within | phase:    | | HD   |        | (0.  |    |            |
|     | pr     |           | |      |        | 63 - |    |            |
| Tol | evious | \-        | | (n=  |        | 0    |    |            |
| era | 6      | I         | | 688) |        | .90) |    |            |
| bil | months | ntolerant | +------+--------+------+    |            |
| ity |        | to any    |                             |            |
| and | ####   | dose - ID | \*Hazard Ratios (95%        |            |
| dos | #####  | (0mg,     | Confidence Interval) -      |            |
| e-r | Exclus | n=74)     | adjusted for age, sex,      |            |
| ela | ion Cr |           | heart rate, SBP, DBP,       |            |
| ted | iteria | \- Low    | creatinine, HTN, MI, prior  |            |
| e   |        | dose - LD | CABG, prior PTCA,           |            |
| ffe | New    | (1.       | aldosterone antagonists,    |            |
| cts | drug   | 25/2.5mg, | antiarrhythmics, and        |            |
| su  | t      | n=142)    | calcium channel             |            |
| bst | herapy |           | antagonists.                |            |
| udy | for HF | \- Medium |                             |            |
| of  | within | dose - MD | **Secondary** Composite of  |            |
| S   | 6      | (5mg,     | all-cause mortality         |            |
| ENI | weeks  | n=127)    | Composite of CV mortality   |            |
| ORS | prior  |           | or                          |            |
|     | to     | \- High   |                             |            |
| No  | ra     | dose - HD | **Outcomes:** or all-cause  |            |
| sp  | ndomiz | (10mg,    | hospitalization CV          |            |
| ons | ation; | n=688)    | hospitalization             |            |
| ors | change |           |                             |            |
| hip | in CV  |           | <table>                     |            |
| ind | drug   |           | <colgroup>                  |            |
| ica | t      |           | <col                        |            |
| ted | herapy |           | style="width: 25%" />       |            |
|     | within |           | <col                        |            |
|     | 2      |           | style="width: 16%" />       |            |
|     | weeks  |           | <col                        |            |
|     | prior  |           | style="width: 22%" />       |            |
|     | to     |           | <col                        |            |
|     | ra     |           | style="width: 12%" />       |            |
|     | ndomiz |           | <col                        |            |
|     | ation; |           | style="width: 22%" />       |            |
|     | HF due |           | </colgroup>                 |            |
|     | pri    |           | <tbody>                     |            |
|     | marily |           | <tr class="odd">            |            |
|     | to     |           | <                           |            |
|     | va     |           | td><strong>Tx</strong></td> |            |
|     | lvular |           | <td><strong>%</strong></td> |            |
|     | heart  |           | <t                          |            |
|     | di     |           | d><strong>HR*</strong></td> |            |
|     | sease; |           | <td><strong>%</strong></td> |            |
|     | cont   |           | <t                          |            |
|     | raindi |           | d><strong>HR*</strong></td> |            |
|     | cation |           | </tr>                       |            |
|     | or     |           | <tr class="even">           |            |
|     | pr     |           | <td><p><                    |            |
|     | evious |           | strong>Placebo</strong></p> |            |
|     | intol  |           | <p>(n=1030)</p></td>        |            |
|     | erance |           | <td>41.1</td>               |            |
|     | to     |           | <td></td>                   |            |
|     | beta   |           | <td>32.4</td>               |            |
|     | bl     |           | <td></td>                   |            |
|     | ockers |           | </tr>                       |            |
|     | (      |           | <tr class="odd">            |            |
|     | asthma |           | <td><str                    |            |
|     | or     |           | ong>Nebivolol</strong></td> |            |
|     | b      |           | <td></td>                   |            |
|     | roncho |           | <td></td>                   |            |
|     | spasm, |           | <td></td>                   |            |
|     | 2^nd^  |           | <td></td>                   |            |
|     | or     |           | </tr>                       |            |
|     | 3^rd^  |           | <tr class="even">           |            |
|     | degree |           | <td><p>0mg - ID</p>         |            |
|     | heart  |           | <p>(n=74)</p></td>          |            |
|     | block  |           | <td>62.2</td>               |            |
|     | w      |           | <td><p>2.11</p>             |            |
|     | ithout |           | <p>(1.54 - 2.89)</p></td>   |            |
|     | pac    |           | <td>48.6</td>               |            |
|     | emaker |           | <td><p>2.30</p>             |            |
|     | in     |           | <p>(1.61 - 3.30)</p></td>   |            |
|     | -situ, |           | </tr>                       |            |
|     | sick   |           | <tr class="odd">            |            |
|     | sinus  |           | <td><p>1.25/2.5mg -         |            |
|     | syn    |           | LD</p>                      |            |
|     | drome, |           | <p>(n=142)</p></td>         |            |
|     | HR \<  |           | <td>43.0</td>               |            |
|     | 60     |           | <td><p>1.04</p>             |            |
|     | bpm,   |           | <p>(0.79 - 1.36)</p></td>   |            |
|     | or SBP |           | <td>28.9</td>               |            |
|     | \< 90  |           | <td><p>0.86</p>             |            |
|     | mmHg); |           | <p>(0.62 - 1.19)</p></td>   |            |
|     | c      |           | </tr>                       |            |
|     | urrent |           | <tr class="even">           |            |
|     | use of |           | <td><p>5mg - MD</p>         |            |
|     | beta   |           | <p>(n=127)</p></td>         |            |
|     | blo    |           | <td>37.8</td>               |            |
|     | ckers; |           | <td><p>0.77</p>             |            |
|     | signi  |           | <p>(0.57 - 1.04)</p></td>   |            |
|     | ficant |           | <td>29.1</td>               |            |
|     | h      |           | <td><p>0.75</p>             |            |
|     | epatic |           | <p>(0.53 - 1.06)</p></td>   |            |
|     | or     |           | </tr>                       |            |
|     | renal  |           | <tr class="odd">            |            |
|     | dysfun |           | <td><p>10mg - HD</p>        |            |
|     | ction; |           | <p>(n=688)</p></td>         |            |
|     | cer    |           | <td>33.9</td>               |            |
|     | ebrova |           | <td><p>0.78</p>             |            |
|     | scular |           | <p>(0.66 - 0.92)</p></td>   |            |
|     | events |           | <td>25.1</td>               |            |
|     | within |           | <td><p>0.73</p>             |            |
|     | pr     |           | <p>(0.60 - 0.88)</p></td>   |            |
|     | evious |           | </tr>                       |            |
|     | 3      |           | </tbody>                    |            |
|     | m      |           | </table>                    |            |
|     | onths, |           |                             |            |
|     | on     |           | \*Hazards Ratio (95%        |            |
|     | PCTA   |           | Confidence Interval) --     |            |
|     | or     |           | adjusted for age, sex,      |            |
|     | c      |           | heart rate, SBP, DBP,       |            |
|     | ardiac |           | creatinine, HTN, MI, prior  |            |
|     | s      |           | CABG, prior PTCA,           |            |
|     | urgery |           | aldosterone antagonists,    |            |
|     | wait   |           | antiarrhythmics, and CCBs.  |            |
|     | -list; |           |                             |            |
|     | other  |           | **Kaplan-Meier Survival     |            |
|     | major  |           | Curves:** Beneficial        |            |
|     | m      |           | effects of high dose and    |            |
|     | edical |           | medium dose nebivolol       |            |
|     | cond   |           | therapy appeared early and  |            |
|     | itions |           | were constant throughout    |            |
|     | likely |           | follow up. Patients         |            |
|     | to ↓   |           | intolerant to any dose of   |            |
|     | su     |           | nebivolol had a higher risk |            |
|     | rvival |           | of developing primary       |            |
|     | thro   |           | outcome event.              |            |
|     | ughout |           |                             |            |
|     | study  |           |                             |            |
|     | period |           |                             |            |
+-----+--------+-----------+-----------------------------+------------+

NYHA=New York Heart Association; HF=heart failure; LVEF=left ventricular
ejection fraction; CV=cardiovascular; PTCA=percutaneous transluminal
coronary angioplasty; CABG=coronary artery bypass graft; HR=heart rate;
LD=low-dose; ID=intermediate-dose; HD=high-dose; MI=myocardial
infarction; SBP=systolic blood pressure; DBP=diastolic blood pressure