Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02989428 |
| Other study ID # |
UAarhus170879 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 3, 2017 |
| Est. completion date |
September 1, 2018 |
Study information
| Verified date |
April 2018 |
| Source |
University of Aarhus |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The aim of this study is to establish whether patients with mild primary hyperparathyroidism
(PHPT) have an increased risk of cardiovascular diseases. The primary outcome is to determine
whether arterial stiffness and blood pressure will decrease in patients with mild PHPT
3-month after parathyroidectomy (PTX).
Description:
Background:
The cardiovascular manifestation of primary hyperparathyroidism (PHPT) has been debated in
many years. PHPT was once a highly symptomatic disease with severe symptoms. Today, the
clinical presentation of the disease is often asymptomatic or with few symptoms at diagnose.
This may be the reason why the literature regarding this area is conflicting. Studies have
observed an increased mortality cause by cardiovascular diseases (CVD) in moderate to severe
disease, whereas other studies with focus on mild disease observed no increased risk of
mortality. A shift in the clinical presentation of the disorder to a more asymptomatic
appearance makes it pivotal to investigate CVD risk in patients with PHPT before and after
surgery. Large-arterial stiffness is known to be a predictor of cardiovascular events and
all-cause mortality. Measurement of carotid-femoral pulse wave velocity (PWV) is considered
as the gold standard for non-invasive measurement of arterial stiffness. To date, only few
studies have investigated the relationship between PWV and PHPT. In three prospective studies
the authors reported a significant increase in PWV preoperative in PHPT patients compared to
controls. 6-month after parathyroidectomy two of the studies observed a significant decrease
in PWV, where one study observed a non-significant decrease. Another study by Ring et al
observed only a slightly, but significant increased PWV in PHPT patients compared to controls
and no changes after surgery at 1-year follow-up. However, a study by Tordjman et al observed
no differences in PWV among PHPT patients compared to controls. In addition, other studies
have explored the relationships between arterial stiffness and PHPT using either augmentation
index (AIx) or carotid intima-media thickness (IMT) as predictors for arterial stiffness.
Three studies with focus on AIx reported an increased AIx in PHPT patients, whereas two other
studies observed no increased AIx in PHPT patients compared to controls. Using the IMT
methods, two studies reported a significant increased IMT in PHPT patient preoperative
compared to controls and a significant decrease after parathyroidectomy. Furthermore, a study
by Walker et al observed an increased IMT in PHPT patients compared to controls but in a
subsequent follow-up study there was no changes in IMT after surgery. In contrast, one study
reported no differences in IMT in PTHP patients before and after surgery. Most research so
far has focussed on different methods for measurements of arterial stiffness which makes a
comparison among studies difficult. More research with focus on one of the methods is
necessary.
Another clinical aspect of PHPT is the increased prevalence of hypertension compared to the
general population. Previous research findings into parathyroidectomy's effect on
hypertension have been inconsistent and contradictory. Four studies reported no effect of
parathyroidectomy on preoperative hypertensive patients and in two studies they observed an
increased incidence in hypertension after surgery. However, in four other studies they
observed a significant postoperative reduction in systolic and diastolic BP among known
hypertensive patients at follow-up.
Nevertheless, much uncertainty still exists and more research investigating the relationship
between BP and arterial stiffness pre- and postoperative is required. PWV is considered the
gold standard for non-invasive measurements of arterial stiffness and a predictor for
cardiovascular events and all-cause mortality. It is therefore the best approach to assess
the association of PHPT and cardiovascular risk in combination with BP. In addition, until
now study design has been prospective with small population sizes. Therefore, we need to
perform a randomized controlled trial (RCT) comparing arterial stiffness and blood pressure
(BP) in patients with mild PHPT pre- and post-operative. This study will be the first
performed randomized controlled trial (RCT) investigating arterial stiffness and BP in
patients with PHPT. Hopefully, this study will be able to establish the cardiovascular risk
in patients with mild PHPT and have an influence on future international guidelines for
management of PHPT.
Aim:
The aim of this study is to establish whether patients with mild PHPT have an increased risk
of cardiovascular diseases. The primary outcome is to determine whether arterial stiffness
and BP will decrease in patients with mild PHPT 3-month after parathyroidectomy (PTX).
Arterial stiffness will be assessed as PWV and BP as sitting- and 24-hour BP. In addition,
the study will evaluate the effect of PTX on serum cholesterol and other markers of
cardiovascular risk.
Hypothesis:
1. Patients with PHPT have an increased cardiovascular risk assessed by BP, PP (central
pulse pressure) and arterial stiffness.
2. PWV, PP and BP in patients with PHPT will decrease 3-month after PTX.
Study design:
The study will be performed as a RCT enrolling patients with PHPT. Participants will be
assessed at baseline and subsequently randomized to one of two study groups, i.e., a group in
which PTX is performed as soon as possible ("early PTX group" [EPTX-group]) and a group in
which PTX is performed three months after study inclusion ("late PTX group" [LPTX-group]).
Follow-up will be performed 3 months after PTX in the EPTX-group and after 3 months of
observation in the LPTX-group. All enrolled participants will undergo PWV, PP, BP and blood
samples at baseline and at 3-month follow-up. Since women are affected by the disease
substantially more often than men are, the randomization will be performed as a bloc
randomization with 4 participants in each bloc. In each bloc two participants will be
randomized to either EPTX or LPTX. With a minimum of 80 participants (see statistic section
for power calculation) enrolling in the study 20 blocs will be created. Four of the blocs
will be allocated to the men in the study. The first man included will start with the
randomization number 64 and then the following men will be given numbers up to 80. If the men
included in the study are an unequal number, a bloc with a mix of women and men will be
constructed. Because of the inclusion criteria in the intention to treat analysis (see below)
more than 80 people will be included to calculate for drop outs. The same principle for bloc
randomization as describe above will be followed creating additional blocs with four
participants in each. If more than 16 men are included they will continue receiving numbers
from 81. For the likelihood to demonstrate an effect of PTX on the cardiovascular risk in
PHPT patients, the analysis will be restricted only to the population that obtain a normal
p-calcium after PTX.
Aarhus University Hospital is the primary center for diagnostic and treatment of PHPT in the
Region of Central Denmark. Hence, all referred patients with possible PHPT will be contacted
during their hospital visit. Participants fulfilling the diagnostic criteria for PHPT will be
asked for participation in the project.
PHPT is defined as elevated p-calcium of minimum 3 measurements and parathyroid hormone in
the upper one-third of or above the reference range.
Measurements:
Questionnaires: Height and weight will be measured on all participants. Additional
information about each participant will be collected through interview/questionnaires which
concerns: previous and current diseases, history of fractures, smoking status, consumption of
alcohol and use of medications. Medications covers all prescribed medication, calcium and
vitamin-D supplementation and natural medicine. Regarding females we will collect information
about age at menarche, pregnancy, labour, menopause, and previous and current use of hormonal
contraceptives.
For assessment of quality of life all participants will be asked to fill out 36-Item Short
Form Survey (SF-36) either in written form or online at baseline and at 3-month follow-up.
Blood pressure: After 5 minutes of rest in sitting position BP will be measured in both right
and left upper arm. Recorded BP will be measured in the arm with the lowest BP with three
following measurement performed with 2 minutes rest in between. The average of the last 2
measurement will be recorded. Furthermore, a 24-hour BP measurement will be performed on each
participant in the non-dominant arm.
Tonometry: In a supine position after 10 minutes of rest PP and PWV are assessed using the
SphygmoCor system (AtCor Medical, cuff-based system) with applanation tonometry. The test
will be performed on fasting participants in the morning both at baseline and at follow up to
avoid diurnal variation. A cuff is placed around right thigh while measurements will be
performed on the right carotid arterial. The carotid-femoral PWV is estimated as the distance
traveled divided by transit time. A minimum of 2 readings are performed and where there is
more than 0.5 m/s difference in the two measurements a three one is performed.
Biochemistry: Blood samples will be collected in the morning fasting, through a venepuncture,
at baseline and at 3-month follow-up. The concentrations of albumin, total and ionized
calcium, creatinine, hbA1C, total cholesterol, LDL, HDL, triglycerides, P-PTH, P-25(OH)D will
subsequent be determine. Plasma will be frozen down for later analysis of apolipoprotein
(Apo-A and Apo-B), high-sensitive CRP, interleukin-6, TNF-alfa, VCAM-1, fibrinogen, von
Willebrand factor and CD40L.
Statistic:
The difference between the two groups will be assessed using either a paired t-test or
Mann-Whitney U-test depending on distribution for continuous variables. Pearson's
correlations coefficient will be used to determine relationships between variables.
Multiple-linear regression analysis with PWV, PP and BT as the dependents variables will be
performed adjusting for age, BP, height, smoking status, BMI, anti-hypertensive medications
and hyperlipidaemia. With a sample size of 40 participants in each group the study has an 84
% power to detect a significant difference in PWV of 1 m/s between treatment and control
groups. This is under the assumptions that a healthy person have a mean PWV of 8.4 m/s and a
standard deviation of 1.5 m/s. Assuming a mean arterial blood pressure of 91 (±8) mm Hg, a
sample size of 40 participants in each group will allow for a 80 % statistical power to
detect a between group difference of 5 mm Hg (p<0.05).
Since the analysis only will be restricted to the participants in the EPTX group obtaining
normal p-calcium, we will aim to recruit 80-100 participants.
Ethical aspects:
The study is performed under the current guidelines developed in the Helsinki-declaration
concerning research with humans. Participants will be informed orally and in written about
the project's aim, execution and possible side effects. The project is entirely voluntarily
and the participants can withdraw their consent anytime during the study, without any
reasons. It will not affect their ongoing and future treatments if a participants decide to
withdraw. Only participants given full consent orally and in written will be enrolled in the
study.
The waiting period for a PTX operation at the Aarhus University Hospital is normally 2-3
month and therefore the enrolled participants in the control group will maximum wait an extra
2-4 week. As PHPT most often is a disease which develops over several years, postponement of
the treatment by surgery for a few weeks in the LPTX-group is not presumed to carry any risk
for the participants.
