Comparison of 2 Beta Blocker Drugs on Peripheral Arterial Disease in Patients With High Blood Pressure

Peripheral arterial disease (PAD) affects up to an estimated 16-29% of men and women over
age 50, and is associated with increased cardiovascular morbidity and mortality.
Beta-blockers have been shown to reduce the risk of myocardial infarction and death in
patients with coronary artery disease (CAD) and are indicated for the treatment of
hypertension in patients with PAD. However, there is a theoretical risk that
antihypertensive therapy may decrease limb perfusion pressure and therefore exacerbate
symptoms of claudication or limb ischemia. Patients with CAD and concomitant PAD are less
likely to be prescribed beta-blockers, even though most patients are able to tolerate
antihypertensive therapy without worsening of symptoms.

The third generation beta-blocker, nebivolol, has vasodilating properties in addition to
beta-adrenergic blockade. This vasodilatory effect is mediated through the L-arginine-nitric
oxide-dependent pathway. Nitric oxide is a critical modulator of vascular disease with
effects that lead to vasodilatation, endothelial regeneration, inhibition of leukocyte
chemotaxis and inhibition of platelet adhesion. This combination of beta-blockade and
nitric oxide-dependent vasodilation may enhance effectiveness and tolerability of nebivolol
versus other beta-blockers in patients with hypertension, CAD or high-risk state, and PAD.

This study will be a pilot comparative effectiveness study to examine the effect of
nebivolol versus metoprolol succinate in patients with lower-extremity PAD and at least
moderate risk for CAD on PAD symptoms as measured by both functional and quality of life
measures.

Inclusion Criteria:

- Men and non-pregnant, non-lactating women 45 years of age or older

- Able to give informed consent and complete scheduled visits

- Mild-moderate bilateral lower extremity peripheral arterial disease as defined by an
ABI of 0.6-0.9. If a subject has baseline claudication symptoms, the symptoms must be
stable for the 3 months preceding enrollment.

- History of hypertension. Blood pressure at the screening visit must be ≤160/100 mmHg
and ≥100/60 mmHg for all subjects. If a subject is currently prescribed
beta-blocker therapy, BP at the screening visit must be ≤140/90 mmHg. In addition,
heart rate must be ≥55 beats per minute if currently prescribed a beta-blocker and
≤60 beats per minute if not currently prescribed a beta-blocker.

- At least moderate risk for CAD.

Exclusion Criteria:

- Participation in another clinical trial

- Ongoing ischemic (resting) limb pain, or lower extremity ulceration due to arterial
insufficiency, or an ABI indicating <0.6 indicating disease potentially requiring
revascularization

- History of limb or digit amputation due to arterial insufficiency

- Revascularization of peripheral vessels within the preceding 6 months

- Uncontrolled hypertension as defined by systolic blood pressure ≥160 mmHg or
diastolic blood pressure ≥100 mmHg

- Contraindication or allergy to beta blocker therapy

- History of myocardial infarction , coronary revascularization, or a cerebrovascular
event within the preceding 6 months

- Class III or IV angina

- Current or past history of New York Heart Association (NYHA) class III or IV heart
failure

- Inability to walk on a treadmill for any reason

- Regular use of nitroglycerin or nitrates including oral, transdermal ointment or
patch, or sublingual, translingual spray and/or combination agents containing
nitrates

- Active liver, pulmonary, infectious or inflammatory process

- History of malignancy within preceding 5 years (excluding basal or squamous cell skin
cancer)

- History of any other condition that, in the opinion of the investigators, renders it
unsafe for the subject to be enrolled