Intensive Blood PRessure Control in Patients With Acute Type B AortIc Dissection
Intensive Blood PRessure Control in Patients With Acute Type B AortIc Dissection
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.
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.
Inclusion Criteria:

 -  Newly diagnosed patients with Stanford type B acute aortic dissection and systolic
 blood pressure>160mmHg

 Exclusion Criteria:

 -  Age <18 years,

 -  In pregnancy,

 -  Diagnosis of aortic dissection was made 48 hours or more prior,

 -  Dissection due to aortic intramural hematoma or penetrating atherosclerotic ulcer,

 -  With history of previous surgical or interventional endovascular treatment for aortic
 diseases,

 -  With traumatic aortic injury,

 -  With history of cerebrovascular accident, brain surgery, chronic renal insufficiency,
 and mesenteric vascular thrombosis or dissection,

 -  AD patient concomitant with new cerebral infarction, or ischemic mesenteric artery or
 lower limb arteries which requiring urgent surgical interventions,

 -  With obvious contraindications for antihypertensive therapy, such as severe carotid
 stenosis, cerebral infarction in acute phase ,

 -  Pathogenesis of the dissection was due to congenital aortic hypoplasia, such as Marfan
 syndrome, connective tissue diseases.