Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03001739 |
| Other study ID # |
20160920-9 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 1
|
| First received |
December 10, 2016 |
| Last updated |
December 20, 2016 |
| Start date |
December 2016 |
| Est. completion date |
July 2019 |
Study information
| Verified date |
December 2016 |
| Source |
Sir Run Run Shaw Hospital |
| Contact |
Ying-zhi Fang, MD |
| Phone |
+86 571 86006987 |
| Is FDA regulated |
No |
| Health authority |
China: Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
Aortic dissection (AD) aneurysm is a common catastrophic aortic disease in clinical setting.
Conservative therapy of heart rate and blood pressure control in the acute phase is the
essential treatment as guidelines recommended. Nevertheless, there is no unanimous optimal
target for blood pressure in patients with AD so far. The American Heart Association and the
Canadian Cardiovascular Society recommend the blood pressure should be controlled to lower
than 140/90mmHg, while for patients with diabetes or chronic renal failure, the blood
pressure target should be no less than 130/80 mmHg. Recently, the Japanese Circulation
Society recommended that the blood pressure should be controlled to no less than 130mmHg.
However, there was few large-scale, randomized, controlled studies reported on the effect of
different blood pressure control levels on the prognosis of patients with AD. Hence, the
intensive control of blood pressure to <120 mmHg, compared to <140 mmHg, may improve the
patients' outcome. Thus, in this study, the effect of intensive blood pressure control
(<120mmHg) with conventional blood pressure control (<140mmHg) on the prognosis of ABAD
patients will be compared, and to identify the therapeutic efficacy of intensive blood
pressure control on the ABAD patients.
Description:
Aortic dissection (AD) aneurysm is a common catastrophic aortic disease in clinical setting.
In the U.S., the prevalence is approximate 2.9-3.5 cases/100000 persons per year, with
recent evidence showing an increasing incidence of up to 14 cases per 100000 patients per
year. AD aneurysm can be classified into the types of Stanford A and B based on whether the
ascending aorta was being involved. For acute type B aortic dissection (ABAD), which is
generally accounted for one thirds of all aortic dissection and is especially more common
among Chinese due to the suboptimal control of blood pressure. Optimal treatment of ABAD
from symptom onset remains uncertain. Conservative therapy of heart rate and blood pressure
control in the acute phase is the essential treatment for patient without serious
complications such as concurrent mesenteric artery or lower limb arterial embolism. The
long-term survival of ABAD is still low though great improved in medication optimization and
surgical repair technique in the past decades. It was reported that 5-year and 10-year
survival rates for ABAD were 60% and 35% respectively. As the development of minimally
invasive techniques in recent years, the endovascular repair procedure has become a routine
procedure in the treatment of patient with ABAD, this rendered an improved prognosis with a
5-year survival rate close to 80%.
Hypertension is well known as the most common cause for AD. The statistics from
International Registry of Acute Aortic Dissection (IRAD) demonstrated that 72.1% of AD
patients had a history of hypertension. The hypertension may aggravate hematoma expansion
and results in serious consequences. Therefore, effectively blood pressure control may
alleviate the severe pain caused by acute AD and lessen the progression of arterial
dissection. The control of hypertension is the primary treatment for acute aortic
dissection, and should be maintained throughout the entire treatment. Currently, all
guidelines recommended to decline the transaortic pressure via controlling the heart rate
and blood pressure for AD patient in acute phase. Theoretically, to control the blood
pressure to the minimal level meeting the sufficient end-organ perfusion can decrease the
risk of vessel rupture as much as possible. Whereas, too much low blood pressure target may
increase the mortality of patients. Powell and his colleague found when the minimum blood
pressure increased by 10mmHg (vs. <70 mmHg, maximal to 120 mmHg) for AD patients, the risk
of death decreased by 12% (OR = 0.88, P <0.001).
Nevertheless, there is no unanimous optimal target for blood pressure in patients with AD so
far. The American Heart Association and the Canadian Cardiovascular Society recommend the
blood pressure should be controlled to lower than 140/90mmHg, while for patients with
diabetes or chronic renal failure, the blood pressure target should be no less than 130/80
mmHg. Recently, the Japanese Circulation Society recommended that the blood pressure should
be controlled to no less than 130mmHg. Hence, the intensive control of blood pressure to
<120 mmHg, compared to <140 mmHg, may improve the patients' outcome. Thus, in this study,
the effect of intensive blood pressure control (<120mmHg) with conventional blood pressure
control (<140mmHg) on the prognosis of ABAD patients will be compared.
Methods Study design and setting The study was a prospective randomized controlled trial
that will recruit a maximal of 360 patients in eight tertiary Chinese hospitals over 2
years. All patients with new diagnosed ABAD in the participating hospitals will be screened
for potential eligibility. The study was approved by the ethics committee of the hospitals
(20160920-9). Written informed consents will be signed by the patients or their legally
authorized representatives. The study was registered in the website of ClinicalTrial.gov .
Sites and patients Doctors from eight hospitals attended the kick-off meeting held in
Courtyard Marriott, Hangzhou, March 19th, 2016, and discussed the research protocol and
details. The amended research protocol was passed according to revised discussion results
and the agreement of all participating units. The methods of blood pressure measurement and
the apparatus used are unified. All hospitals will adopt similar non-invasive blood pressure
monitoring method and unified monitoring frequency to observe whether the blood pressure is
controlled within the target range in two groups. Likewise, the blood pressure target after
discharge was maintained at the same levels.
All patients with AD from the participating hospitals who conform to the following inclusion
and exclusion criteria will be randomized. Inclusion and exclusion criteria were shown in
other parts.
Randomization Blocked randomization was adopted and the intensive and conventional blood
pressure control treatments were allocated at random in a ratio of 1:1 in blocks of sizes of
4,6,8, and 10 to 360 subjects. The study is an open label trial. After investigators in each
participating centers screened the potential patients within 4 hours after acute onset, a
number from a pre-allocated envelope will be gotten and which denotes which group the
patient will be allocated to.
Treatments All the patients were admitted to ICU or general wards at the discretion of
doctors. Based on the guidelines of aortic management, all patients received analgesic
therapy and standard control of heart rate and blood pressure treatments. Intravenous
esmolol was used for continuous control of heart rates. Choice of intravenous
antihypertensive agents was at the discretion of the in charge physicians. After the
stabilization of the situation, the intravenous medications were shifted to the oral
treatments. The target blood pressure for the intensive and conventional groups were
<140mmHg and <120mmHg respectively. For most patients, they will undergo an endovascular
treatment approximate two weeks later.
Study endpoints The primary outcome is a composite in-hospital adverse outcome, including
death, permanent paraplegia or semi- paralysis during the hospitalization, and renal failure
requiring hemodialysis at discharge.
The secondary outcomes include the mortality in 6-month and 1-year, ICU length of stay,
total length of hospital stay, postoperative renal injury, and re- intervention.
Data collection Research coordinators of individual participating hospital will collect the
required data on the case report form. However, the data was de-named and special security
code was required to access the data. To facilitate the communications between
investigators, the case report form was written in Chinese. The primary research institute
is responsible for collecting and checking the data of all centers; and will contact the
co-investigators in various centers for checking or revising should they had any question.
The primary research institute has established an independent study quality control group to
implement the disposal plan for all unexpected circumstances that may occur.
Sample size calculation and interim analysis The primary outcome was a composite in-hospital
adverse outcome, including the death, stroke, permanent paraplegia or semi- paralysis during
the hospitalization, and renal failure requiring hemodialysis at discharge. Bashir et al
reported that the incidence of comprehensive nosocomial severe prognostic adverse events of
ABAD was 45.2%. Assume that the incidence of severe prognosis adverse event in comprehensive
hospital after intensive blood pressure control could be reduced to 30%, so a total of 322
subjects enrolled in the study are sufficient to find the difference statistically between
two groups through the appropriate software calculation under the power of 0.8 and at the
two-side test with α = 0.05. Considering a dropout rate of 10%, it is proposed to include
360 cases totally into the study. A formal interim analysis was conducted halfway during
study enrollment. The overall type I error was controlled using an O'Brien-Fleming spending
function, with a final significance level of 0.05 for the primary end point.
Statistical analysis Descriptive data were reported as either mean ± SD, median
(interquartile range) or number and percentage. With respect to the differences between two
groups, categorical variables were compared using chi-square analysis. Continuous variables
were compared using Independent Sample T test for normally distributed data and Mann-Whitney
U test for non-normally distributed data. For survival analyses, Kaplan-Meier estimates were
generated to assess differences between groups using the log-rank test, and expressed the
data as cumulative mortality curves. Statistical analysis was performed by using SPSS 16.0
(Chicago, Ill, USA) and PASS 11.0. Statistical significance was defined as a P value <0.05.
Discussion ABAD comprises approximately 30% of all aortic dissection cases. In contrast with
type A aortic dissection, patients with type B dissection are tend to be older, have higher
rates of atherosclerosis. Initial goals for acute aortic dissection management are directed
at control of blood pressure and heart rate, which subsequently limiting propagation of the
false lumen by controlling aortic shear stress. Whilst medical management has demonstrated
an in-hospital mortality rate less than 10%, post-discharge the acute type B aortic disease
continues to evolve eventually resulting in complicated type B disease. Moreover,
complicated acute type B aortic dissection shows even more striking mortality as high as
30%, particularly in the elderly. Poor control of blood pressure was believed to be one of
the main reasons for the progress of the type B aortic dissection into complications or even
the laceration extended to the ascending aorta. Dalsart and colleague demonstrated that a
systolic blood pressure more than 130 mmHg was associated with a bigger aortic enlargement
in type B aortic dissection (P=0.02) . In another study of 25 years follow-up in 252
patients who received repair of acute type A aortic dissection, patients who maintained a
systolic blood pressure <120 mm Hg had improved freedom from reoperation, compared to those
target blood pressure 120-140 mm Hg or >140 mm Hg. Hence, most guidelines recommended a
reasonable initial target for systolic blood pressure is between 100 and 120 mm Hg. However,
this target is based on the hypothesis that all the end-organs blood supply is not
compromised. Data from International Registry of Acute Aortic Dissection (IRAD) has shown
that approximately one quarter of patients presenting with acute type B aortic dissection
are followed into complicated category, including malperfusion of spinal arteries leading to
paresis, and paraplegia or malperfusion of visceral arteries leading to abdominal pain.
Thus, how to balance the decrease of blood pressure to the lowest amount and maintain
adequate end-organ perfusion is a challenge. Given vast majority patients with type B aortic
dissection had a history of hypertension, a too lower target of blood pressure may comprise
the cerebral perfusion or complicated organ perfusion, which consequently caused stroke or
other morbidity such as ischemic intestinal necrosis. On the other hand, a much strict blood
pressure target and sometimes constrain on the patients daily activities may aggravate
patients' worry, which inversely increased increase the blood pressure. Unfortunately, there
is no empirical data or trials to guide the optimal blood pressure target setting for
various patients. Hence, the study was designed to bridge the gap.
In conclusion, the investigators believe that the study will provide new insight into the of
blood pressure management of patients of acute Type B aortic dissection and subsequently
improve the outcomes.
