Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03288181 |
Other study ID # |
2015-25 |
Secondary ID |
|
Status |
Completed |
Phase |
N/A
|
First received |
September 15, 2017 |
Last updated |
September 15, 2017 |
Start date |
October 5, 2015 |
Est. completion date |
June 15, 2016 |
Study information
Verified date |
September 2017 |
Source |
Tallahassee Research Institute, Inc. |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Patients with peripheral arterial disease often have walking impairment due to insufficient
oxygen supply to lower extremity skeletal muscle. In an aging rat model, we have previously
shown that daily calf muscle stretching improves endothelium-dependent dilation of soleus
muscle arterioles and blood flow during exercise. The effect of muscle stretching on
endothelial function and walking distance in patients with peripheral arterial disease is
unknown. We performed a prospective, randomized, non-blinded, crossover study in 13 patients
with stable symptomatic peripheral artery disease. Patients were randomized to undergo either
4 weeks of passive calf muscle stretching (ankle dorsiflexion splints applied 30 minutes/day,
5 days/week) followed by 4 weeks of no muscle stretching (control group) and vice versa.
Endothelium-dependent flow-mediated dilation and endothelium- independent
nitroglycerin-induced dilation of the popliteal artery and a 6 minute walk test were
evaluated at baseline and after each 4 week treatment interval. Patients crossed over to the
other treatment arm after 4 weeks and endothelium-dependent flow-mediated dilation and
endothelium- independent nitroglycerin-induced dilation of the popliteal artery and the 6
minute walk test were repeated.
Description:
This study is a prospective randomized, non-blinded, crossover trial conducted at Tallahassee
Memorial HealthCare, Tallahassee, FL, USA between October 2015 and May 2016. The Tallahassee
Memorial Healthcare Institutional Review Board and the Human Subject Committee at Florida
State University approved the study prior to initiation. Informed written consent was
provided by all patients prior to enrollment.
Study Patients The study sample consisted of patients with stable symptomatic PAD. Inclusion
criteria included reproducible claudication with walking associated with an ankle brachial
index of less than 0.90,15 and/or computed tomographic angiographic evidence of at least a
60% stenosis of the iliac, femoral, or popliteal artery deemed to be the source of
claudication. Individuals with critical limb ischemia or who had severe comorbid conditions
limiting their walking ability were excluded.
Study Design:
Participants were initially randomized to undergo either 4 weeks of passive stretching or 4
weeks of no stretching (control), respectively, followed by cross-over to the other
intervention. Patients were evaluated at baseline, after the first 4 weeks of initial
intervention (stretching or no stretching) and then again after 4wks following the cross-over
intervention (stretching or no stretching). Participants were taught how to apply a simple
dorsiflexion splint and during the 4 wks of daily stretching intervention and applied the
splint daily at home for 30 minutes/day, 5 days/week. Endothelium-dependent flow-mediated
dilation (FMD) and endothelium-independent nitroglycerin-induced dilation (NID) of the
popliteal artery (measured by doppler ultrasound) and a 6 minute walk test were evaluated at
baseline and after each 4 week treatment interval.
Muscle stretching Protocol. To passively stretch each patient's calf muscle, dorsiflexion
splints (Healwell Plantar Fasciitis Night Splint®, FLA Orthopedics, Charlotte, NC, USA) were
applied. Using the splint, ankle joints were kept at 15 degrees of dorsiflexion for 30
min/day, 5 days/wk, for the 4 week interval. The splint has a strap to adjust the angle of
the joint. Participants learned how to wear the splint correctly from a trained physical
therapist who initially fitted and adjusted the splint. Splints were sent home with the
patient and a physical therapist was available for questions by phone. Using the splint, both
the gastrocnemius and soleus muscles were effectively stretched. If participants complained
of pain during muscle stretching, the physical therapist assisted in adjusting the straps,
but efforts were made to maintain the angle of dorsiflexion.
Flow-mediated dilation of the popliteal artery. Vascular functional testing was performed in
a temperature controlled (72 degrees F), quiet and dark laboratory. To exclude the acute
effects of acute exercise or medicine on vascular endothelial function, participants were
asked to refrain from taking sildenafil, tadalafil and vardenafil for 48 hours prior to the
vascular assessment, and not to take carvedilol, cartelol labetalol, verapamil, diltiazem,
nifedipine, nicardipine, isradipine, felodipine and amlodipine for 24 hours prior to the
assessment. Participants were also asked to refrain from any form of exercise and not to eat
or drink for 3 hours prior to the assessment.
Systolic and diastolic blood pressure was measured using an automatic brachial
sphygmomanometer applied to the upper arm after at least 10 min of quiet rest with the
patient seated in the vascular laboratory. Pulse rate was recorded. Participants then assumed
a prone position on a bed and a blood pressure cuff applied to the lower thigh of the most
symptomatic lower extremity. Using vascular ultrasound and Doppler (GE Vivid Q ultrasound
with 12L-RS Linear Vascular Probe, GE, Milwaukee, WI, USA), flow-mediated dilation of the
popliteal artery was measured in the following manner. The measurement was conducted on the
affected leg (leg with greater symptoms or lower ankle-brachial index). First, popliteal
artery diameter and blood flow velocity were recorded after resting for 10 min. A lower thigh
blood pressure cuff was then inflated up to 250 mmHg for 5 min. During the 5 min of arterial
occlusion, participants were asked to remain as still as possible. The blood pressure cuff
was then quickly deflated, and popliteal artery diameter and blood flow remeasured in the
same location for another 10 min. FMD was obtained by referencing the peak popliteal artery
diameter to the baseline measurement.
Endothelium-independent dilation of the popliteal artery. At least 30 min after the
assessment of FMD, nitroglycerin-induced dilation (NID) of the popliteal artery was also
assessed as a measure of endothelium-independent dilation. Baseline popliteal artery diameter
was recorded after resting for 10 min. The recording was done continuously for 10 min after
the administration of 400 µg of sublingual nitroglycerin (NTG, Wilshire, Atlanta, Georgia).
The peak diameter relative to baseline served as the measurement of endothelium-independent
dilatation.
Hemodynamic analyses. Vessel diameter and blood flow velocity were recorded at 30 Hz of
frequency, and converted into DICOM (DICOM, Rosslyn, VA, USA) format to perform further
analysis. Since peripheral arterial diameter and blood flow velocity vary during the cardiac
cycle,16 popliteal artery diameter was measured at the end of the diastolic phase (defined as
the point just before the popliteal arterial Doppler waveform rises). Blood flow velocity was
measured at the peak of the systolic phase. Using two-dimensional B mode images,
end-diastolic popliteal artery diameter and peak velocity were obtained from three
consecutive cardiac cycles, averaged and the same technique used to measure arterial diameter
for FMD and NID.
Six-minute Walk Test (6MWT) The Six-minute walk test (6MWT) was performed after vascular
function testing according to the American Thoracic Society guidelines.Using a straight 30m
corridor, participants were asked to walk back and forth over 6 minutes. Participants were
asked to report any symptoms, including leg pain or cramping, tiredness and/or chest
discomfort. Participants were allowed to rest if they felt it necessary and then asked to
resume walking as soon as able. Symptom-free walking distance was measured as the distance
covered without symptoms. Continuous walking distance was also measured as the distance
covered without stopping. Total 6-minute walking distance was measured as the distance
covered for 6 minutes. Immediately after the 6-minute walk, participants were seated and
again asked to report any chest and lower-extremity symptoms. Chest and lower-extremity
exertional symptoms were assessed using a modified borg scale. The modified borg scale is
scored from zero (no symptoms of exertion) to 10 (maximal sensation of symptoms).
Participants answered the chest and lower-extremity symptoms by indicating a number from zero
to 10. Systolic and diastolic blood pressure and heart rate were then measured at
approximately 1-min after 6-min walk termination.
Sample size calculation. The primary endpoint for which the sample size was derived was
popliteal artery FMD. From published data, we estimated that the FMD of popliteal artery
would improve by approximately 40% with muscle stretching. In a prior pilot study, we
observed a baseline FMD of 3.87% (standard deviation of 0.62%) in 13 patients with stable
PAD. Assuming an alpha of 0.05, and a cross-over design, we predicted that we would need at
least 12 patients per group to have 90% power to detect a 20% increase in FMD. Allowing for
an approximately 20% drop out rate (3 patients), the targeted sample size was adjusted to 15
in this study. However, recruitment was to continue until at least 12 patients were enrolled
and completed the protocol.
Statistical analysis. Baseline clinical characteristics are reported as means and standard
deviations. A histogram of vascular function and walking distance was made to assess their
distribution. If non-normal distribution was suggested by the histogram, a Kolmogorov-smirnov
test was performed to assess the distribution of obtained data. On the basis of the
distribution test, paired t-test (normal distribution) or Wilcoxon signed-rank test
(non-normal distribution) were used to compare between those data obtained after 4 weeks of
stretching and after 4 weeks of no stretching with a 2-sided level of significance of 0.05.
Data were presented as mean ± standard error.