Hypertension, Peripheral Artery Disease
Conditions
Brief summary
This is a 26-week, prospective double-blind, randomized pilot trial of nebivolol versus an active control, metoprolol succinate, in patients with established lower-extremity peripheral artery disease, hypertension, and at least moderate risk for coronary artery disease.
Detailed description
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.
Interventions
DRUGnebivolol
Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing).
DRUGMetoprolol succinate
Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing).
Sponsors
Forest Laboratories
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 ankle-brachial index (ABI measurement 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Walking Time (PWT) | Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks. | Change in peak walking time (PWT) is measured in seconds. The PWT is defined as when walking on a treadmill cannot continue due to maximal leg pain, resulting in the discontinuation of the treadmill test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Claudication Onset Time (COT) | Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks. | Change in measurement of claudication onset time (COT). The COT is defined as the time when a patient first experienced pain walking during a treadmill test. |
| Walking Impairment Questionnaire (WIQ) - Change Calf Pain | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. | Change in calf pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. |
| Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. | Change in buttock pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. |
| Ankle-brachial Index (ABI) | Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks | Change in measurement of Ankle-brachial index (ABI). The ABI is the ratio of the blood pressure measured in the lower legs to the blood pressure measured in the arms. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. | Change in speed score as captured by the Walking Impairment Questionnaire (WIQ) speed score subscale. In the walking speed component, the degree of difficulty walking is ranked on a 0 to 4 scale where speed is assessed for each of the following speeds: at the following speeds: 1, slowly; 2, average speed; 3, quickly; or 4, running or jogging 1 block. Zero represents the inability to walk the specified speed, and 4 represents no difficulty. The items on the subscale are weighted according to the difficulty of the task. The speed score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. | Change in stairs score as captured by the Walking Impairment Questionnaire (WIQ) stairs subscale. This scale item asks the subject to describe the degree of difficulty climbing one, two, or three flights of stairs in the past week. A flight of stairs is defined as 14 steps. A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, 5) Unable to Do, or 6) Didn Do for Other Reasons. The items on the subscale are weighted according to the difficulty of the task. The stairs score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. | Change in distance score as captured by the Walking Impairment Questionnaire (WIQ) distance score subscale. The degree of difficulty in the walking of specific distances is ranked on a 0 to 4 Likert scale, in which 0 represents the inability to walk the distance and 4 represents no difficulty. A Likert scale is an ordinal scale of consecutive, equidistant, numerical values (ie, 0 to 4). The distances assessed in the WIQ range from walking indoors around the home to walking 5 blocks (1500 feet). The items on the subscale are weighted according to the difficulty of walking. The distance score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol nebivolol 1 to 4 capsules daily
nebivolol: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing). | 9 |
| Metoprolol Succinate metoprolol 1 to 4 capsules daily
Metoprolol succinate: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). | 8 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Nebivolol | Total | Metoprolol Succinate |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 8 | 66 years STANDARD_DEVIATION 8 | 65 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment United States | 9 participants | 17 participants | 8 participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 8 |
| serious Total, serious adverse events | 2 / 9 | 0 / 8 |
Outcome results
Primary
Peak Walking Time (PWT)
Change in peak walking time (PWT) is measured in seconds. The PWT is defined as when walking on a treadmill cannot continue due to maximal leg pain, resulting in the discontinuation of the treadmill test.
Time frame: Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks.
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Peak Walking Time (PWT) | 110.4 seconds | Standard Deviation 89.7 |
| Metoprolol Succinate | Peak Walking Time (PWT) | -19.4 seconds | Standard Deviation 110.8 |
p-value: 0.039Wilcoxon (Mann-Whitney)
Secondary
Ankle-brachial Index (ABI)
Change in measurement of Ankle-brachial index (ABI). The ABI is the ratio of the blood pressure measured in the lower legs to the blood pressure measured in the arms.
Time frame: Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Ankle-brachial Index (ABI) | 0.03 Ankle-Brachial Index | Standard Deviation 0.14 |
| Metoprolol Succinate | Ankle-brachial Index (ABI) | 0.06 Ankle-Brachial Index | Standard Deviation 0.11 |
p-value: 0.585Wilcoxon (Mann-Whitney)
Secondary
Claudication Onset Time (COT)
Change in measurement of claudication onset time (COT). The COT is defined as the time when a patient first experienced pain walking during a treadmill test.
Time frame: Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks.
Population: Final measurements of COT in the metoprolol succinate group excludes one subject who did not experience claudication while walking during the treadmill test, and one subject who withdrew consent prior to the end of the study, therefore, only 6 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Claudication Onset Time (COT) | 155.7 seconds | Standard Deviation 217.5 |
| Metoprolol Succinate | Claudication Onset Time (COT) | 148.7 seconds | Standard Deviation 173.1 |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Walking Impairment Questionnaire (WIQ) - Change Calf Pain
Change in calf pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain.
Time frame: Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Walking Impairment Questionnaire (WIQ) - Change Calf Pain | 25 units on a scale | Standard Deviation 28 |
| Metoprolol Succinate | Walking Impairment Questionnaire (WIQ) - Change Calf Pain | 10.7 units on a scale | Standard Deviation 40.5 |
p-value: 0.363Wilcoxon (Mann-Whitney)
Secondary
Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain
Change in buttock pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain.
Time frame: Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain | -8.3 units on a scale | Standard Deviation 12.5 |
| Metoprolol Succinate | Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain | 14.3 units on a scale | Standard Deviation 19.7 |
p-value: 0.017Wilcoxon (Mann-Whitney)
Secondary
Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score
Change in distance score as captured by the Walking Impairment Questionnaire (WIQ) distance score subscale. The degree of difficulty in the walking of specific distances is ranked on a 0 to 4 Likert scale, in which 0 represents the inability to walk the distance and 4 represents no difficulty. A Likert scale is an ordinal scale of consecutive, equidistant, numerical values (ie, 0 to 4). The distances assessed in the WIQ range from walking indoors around the home to walking 5 blocks (1500 feet). The items on the subscale are weighted according to the difficulty of walking. The distance score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100.
Time frame: Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score | 13.52 units on a scale | Standard Deviation 27.37 |
| Metoprolol Succinate | Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score | 28.28 units on a scale | Standard Deviation 31.18 |
p-value: 0.476Wilcoxon (Mann-Whitney)
Secondary
Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score
Change in speed score as captured by the Walking Impairment Questionnaire (WIQ) speed score subscale. In the walking speed component, the degree of difficulty walking is ranked on a 0 to 4 scale where speed is assessed for each of the following speeds: at the following speeds: 1, slowly; 2, average speed; 3, quickly; or 4, running or jogging 1 block. Zero represents the inability to walk the specified speed, and 4 represents no difficulty. The items on the subscale are weighted according to the difficulty of the task. The speed score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100.
Time frame: Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.
Population: One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. One patient in the nebivolol group failed to complete the items in the WIQ speed score subscale, therefore, only 8 patients were included in the analysis for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score | 21.88 units on a scale | Standard Deviation 30.08 |
| Metoprolol Succinate | Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score | -6.83 units on a scale | Standard Deviation 35.34 |
p-value: 0.17Wilcoxon (Mann-Whitney)
Secondary
Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score
Change in stairs score as captured by the Walking Impairment Questionnaire (WIQ) stairs subscale. This scale item asks the subject to describe the degree of difficulty climbing one, two, or three flights of stairs in the past week. A flight of stairs is defined as 14 steps. A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, 5) Unable to Do, or 6) Didn Do for Other Reasons. The items on the subscale are weighted according to the difficulty of the task. The stairs score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100.
Time frame: Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.
Population: Four people in the nebivolol group and 1 person in the metoprolol group did not complete the items in the Stairs WIQ subscale therefore they were excluded from the analysis. One person in the metoprolol succinate group withdrew consent before the end of the study so they were also excluded from the final analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score | 21.67 units on a scale | Standard Deviation 37.2 |
| Metoprolol Succinate | Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score | 24.31 units on a scale | Standard Deviation 38.77 |
p-value: 0.595Wilcoxon (Mann-Whitney)