To evaluate the efficacy of microvascular decompression (MVD) in reducing hypertension (HTN) in hypertensive patients with trigeminal neuralgia (TN).The clinical data of 58 cases of neurogenic HTN with TN treated in our hospital were retrospectively reviewed. Preoperative MR revealed abnormal blood pressure in the left rostral ventrolateral medulla (RVLM) and the posterior cranial nerve root entry zone (REZ). The patients were divided into control group: only trigeminal nerve was treated with MVD; experimental group: trigeminal nerve, RVLM and REZ were treated with MVD at the same time. The patients were followed up for 6 months to 1 year to observe the changes of blood pressure.SBP = 0.131; P△BDP = 0.078). In the experimental group, the effective rate was 83.3%. The postoperative blood pressure was significantly lower than preoperative values. .There was no significant difference in gender, age, course of TN, course of HTN, grade of HTN and preoperative blood pressure between the two groups. After operation, the effective rate of HTN improvement with MVD was 32.1% in the control group. There was no significant difference in the preoperative and post operative blood pressure. (P△MVD is an effective treatment for neurogenic HTN. However, the criteria for selecting hypertensive patients who need MVD to control their HTN still needs to be further determined. Possible indications may include: left trigeminal neuralgia, neurogenic HTN; abnormal blood pressure compression in the left RVLM and REZ areas on MR; and blood pressure in these patients can not be effectively controlled by drugs. With the improvement of people’s living standards and the aging of our society, HTN is one of the diseases that seriously threaten human health, its incidence is increasing year by year. If there is no effective treatment, it often leads to serious complications and even death . Most paInclusion criteria: ①Primary left TN with typical clinical presentation, without any specific etiology determined. ②According to criteria for diagnosis of HTN, a baseline systolic pressure greater than 140 mmHg and a baseline diastolic pressure greater than 90 mmHg [Exclusion criteria: ① Secondary TN; ② Secondary HTN, including renal HTN, endocrine HTN and drug-induced HTN; ③Combined with heart failure or arrhythmia, antihypertensive drugs cannot be stopped; ④Alcoholism, drug abuse, mental disorders, irregular life; ⑤Oral antihypertensive drugs are irregular; ⑥Other surgical contraindications for MVD.From January 2009 to October 2018, 58 patients with left TN with HTN were included. After admission, blood pressure was monitored for at least three consecutive days. Preoperative oral or intravenous medication was used to control blood pressure at an acceptable level during surgery. . Among them, 30 patients  received microvascular decompression of the left trigeminal nerve and RVLM and REZ area as experimental group with the consent of the patients themselves and their families, while microvascular decompression of the left trigeminal nerve was performed only in 28 patients  as the control group.All patients underwent preoperative MRI scanning. The relationship between blood vessels and trigeminal nerve, RVLM and REZ was evaluated by three-dimensional time-of-flight magnetic resonance angiography (3D-TOFMRA). If there was a possibility of contact or compression, it was positive for MRI. Two radiologists would evaluate the results individually. When the evaluation results were inconsistent, it would be decided after discussion.All patients were treated by left suboccipital retrosigmoid approach. Routine craniotomy was performed to expose the posterior edge of sigmoid sinus and the inferior edge of transverse sinus. The open mastoid air chamber was sealed with bone wax to prevent cerebrospinal fluid fistula. The dura mater was cut off and sharp separation was performed under the operating microscope. The occipital cistern, cerebellomedullary cistern and pontine cistern were opened. In the control group, only trigeminal nerve decompression was performed to free the responsible artery, and Teflon cotton was inserted to isolate it from the initial segment of the brain nerve root. In the experimental group, the trigeminal nerve was decompressed, the responsible artery was free, and the appropriate size of Teflon cotton was inserted to isolate the trigeminal nerve from the initial segment of the brain nerve root. In the same way, RVLM and REZ areas were explored. According to the relationship between vessels and RVLM and REZ areas, the responsible arteries were isolated and separated from the initial segment of the brain nerve root by inserting Teflon cotton of appropriate size. There was no obvious bleeding in the operative field and the dural incision was tightly sutured and the muscles, cap aponeurosis and scalp were sutured layer by layer. All operations were performed by the same surgical team.(1) After admission, the blood pressure under the condition of no medication was monitored in the morning for at least three consecutive days. . The mean blood pressure was taken as preoperative blood pressure. (2) Blood pressure in the morning without medication as monitored for 3 consecutive days in each review month  after surgery respectively. The mean blood pressure was taken as the blood pressure of the review month. (3) After operation, blood pressure was measured three times in different days without change of taking antihypertensive drugs. If systolic blood pressure (SBP) < 140 mmHg or diastolic blood pressure (DBP) < 90 mmHg, Antihypertensive drugs start to reduce or even stop drugs.According to the extent of blood pressure decline and the degree of relief of symptoms, the therapeutic effect was judged as follows: ①. Cure: after the patient completely stopped using antihypertensive drugs, systolic blood pressure < 140 mmHg, and diastolic blood pressure < 90 mmHg; ②. marked effect: systolic and diastolic blood pressure, one of which decreased to normal level or systolic blood pressure < 30 mmHg and diastolic blood pressure decreased < 10 mmHg; ③. Effective: Systolic blood pressure decreased < 30 mmHg and diastolic blood pressure decreased < 10 mmHg, the clinical symptoms of HTN were relieved, and the dosage of antihypertensive drugs was reduced. ④. Invalidity: The clinical symptoms of HTN were not relieved, and the systolic and diastolic blood pressures were not changed or even increased compared with those before operation.Effectiveness = (cure+ marked effect+ effective)/total number× 100%.P < 0.05 for all tests.Data was analyzed using statistical product and service solutions software version 22.0. Continuous variables were expressed as mean ± standard deviation or median. Differences between variables were evaluated using the independent samples t-test. Categorical variables were expressed as a ratio (%), and differences between variables were compared using the chi-squared test. Data was deemed significant if P > 0.05), as shown in Table Comparison of basic data of two groups: There was no significant difference in the age, sex, course of HTN, duration of TN, grade of HTN, preoperative systolic and diastolic blood pressure between the experimental group and the control group  were cured, 3 cases (10.7%) were marked effect, 4 cases (14.3%) were effective, 19 cases (67.9%) were invalidity, and the effective rate was 32.1%. In the experimental group, 10 cases (33.3%) were cured, 9 cases (30%) were marked effect, 6 cases (20%) were effective and 5 cases (16.7%) were invalidity. The effective rate was 83.3%, as shown in Table The changes of blood pressure after operation are shown in Table HTN is one of the most common chronic diseases that threaten human health. It is also a major risk factor for cardiovascular and cerebrovascular diseases. Its complications, such as cerebral hemorrhage, have high disability and mortality rates. Therefore, the prevention and control of HTN is of great significance to the prevention of cardiovascular and cerebrovascular diseases. At present, the treatment of HTN is mainly drug treatment. However, some of the hypertensive patients only use antihypertensive drugs, the effect is often unsatisfactory. In 1979, Jannetta et al.  found thAt present, although MVD treatment of neurogenic HTN has been recognized by international scholars, but there are few patients with neurogenic HTN treated with MVD. The main reason is that there is no unified criterion for screening and diagnosis of neurogenic HTN patients. More importantly, most patients are unwilling to accept craniotomy because of HTN. However, MVD has been widely recognized in the treatment of TN. At the same time, through clinical observation, TN can also cause and/or aggravate HTN, which is mainly caused by long-term repeated pain stimulation, mental tension, anxiety, which makes the sympathetic nerve excited. Sympathetic nerve excitation not only acts on myocardial B receptor to accelerate heart rate and strengthen myocardial contraction, but also acts on peripheral blood vessel a receptor to make small arteries contract and peripheral blood vessel resistance increase, leading to increased blood pressure. In addition, long-term sympathetic nerve excitation can release norepinephrine through hypothalamus and peripheral sympathetic nerve endings, which can increase blood pressure  After MVBecause the left medulla oblongata is oppressed by arteries and long-term pain stimulation in patients, which can lead to over excitation of sympathetic nervous system and hypertension . TherefoBecause most of the patients with primary TN complicated with neurogenic HTN are the elderly, they are more concerned about the risk of surgery. If the relationship between trigeminal nerve and medulla oblongata and peripheral blood vessels can be fully evaluated before operation, and the responsible blood vessels can be initially determined, it will be conducive to the operation. In 3D-TOFMRA sequence images, the nerve and brain tissue showed equal signals, the peripheral blood vessels showed high signals, and the cerebrospinal fluid showed low signals. The contrast was clear. The relationship between peripheral blood vessels and nerves and brainstem could also be observed directly. The maximum density projection technique could also be used to realize arterial imaging to understand the origin and course of the responsible blood vessels . It can A large number of clinical studies have confirmed that patients with neurogenic HTN are due to the compression of the left RVLM and REZ neurovascular areas –16. MVD MVD is an effective treatment for neurogenic HTN. However, the criteria for selecting hypertensive patients still need to be further determined. In order to improve the efficacy of neurogenic HTN surgery, including the following indications as far as possible: left TN; neurogenic HTN; abnormal blood pressure compression in the left RVLM and REZ areas in high-resolution MR images; the blood pressure in these patients cannot be effectively controlled by combined antihypertensive drugs.


Fimasartan  is a non-protein angiotensin II receptor blocker that selectively blocks the AT1 receptor. No prior large-scale study has investigated the impact of demographics, disease, treatment, and clinical characteristics on medication satisfaction and quality of life in Korean hypertensive patients. Additionally, it is unclear whether increased medication compliance affects the achievement of hypertension treatment objectives.This was a multicenter, non-interventional, open-label and 8-week switching study. This study was divided into 2 steps. STEP I was a cross-sectional study composed entirely of hypertensive patients undergoing treatment and STEP II was a prospective observational study of hypertensive patients switching to fimasartan. A total of 12,244 and 2023 patients were analyzed in the STEP I and STEP II groups, respectively. In STEP I, we investigated demographics, clinical, disease, and treatment characteristics at the registration point and then analyzed medication satisfaction, patient compliance, and quality of life. In STEP II, the patients who switched to fimasartan were followed up for 8 weeks, and the data analyzed included changes in medication effects, satisfaction, compliance, and adverse events.p < 0.0001). Most patients (76.4%) who changed from prior antihypertensive drug to fimasartan were not satisfied with conventional antihypertensive drugs . Among 2183 patients, 234 adverse events occurred in 151 (6.9%) and 50 adverse drug reactions occurred in 39 (1.8%).Some baseline characteristics, such as sex, body mass index, region of residence, educational level, and income level, affected the quality of life and medication duration in hypertensive patients. At 4 and 8 weeks, 62.5 and 69.9% of patients, respectively, reached their target blood pressure. The medication satisfaction scores were increased 4.0 ± 1.2, 5.1 ± 1.1, and 5.4 ± 1.0 at baseline, 4 weeks, and 8 weeks, respectively, and the difference was statistically significant . Hypertension is a major chronic disease and a risk factor for cardiovascular diseases such as stroke, myocardial infarction, heart failure, and renal disease. The prevalence rates of hypertension in Korea were 24.6, 26.4, and 28.5% in 2007, 2009, and 2011, respectively, and continuously increasing trends have been observed in the aging population [Increased prevalence of hypertension has related to increased incidence of cardiovascular diseases. Approximately 35% of cerebrovascular diseases and 21% of ischemic heart diseases in Korean patients are caused by hypertension . As a deAccording to, in the 2011 Korea National Health and Nutrition Examination Survey [However, although it is possible to control hypertension and prevent complications due to the development of many antihypertensive drugs and improvements in lifestyle, the awareness and rates of hypertension control are still low; therefore, many hypertensive patients are unaware or have a false perception that their symptoms are not related to elevated blood pressure .In general, reports have shown that the health-related quality of life of hypertensive patients not diagnosed with hypertension is not different from that of normal controls. Therefore, the awareness and control rate of hypertension tend to be low, as the disease does not have a profound influence on the patient’s quality of life. However, some reports have found that many hypertensive patients do not think that their physical status is adequate , 9.Due to the nature of hypertension, it’s important whether the quality of life affects the hypertension treatment outcomes. The major reason for reduced quality of life in hypertensive patients is known to be the use of antihypertensive drugs . AlthougTherefore, this nationwide, cross-sectional survey was conducted to examine blood pressure control, quality of life, and the medication satisfaction status of primarily treated hypertensive patients. In addition, the demographics, disease, treatment, and clinical characteristics affecting quality of life and blood pressure control of hypertensive patients were identified.Moreover, although a study has been performed to assess prescription patterns associated with antihypertensive drug treatment changes in Korea, with consideration of drug ingredients and the reason for treatment discontinuation , no knowThis study examined the epidemiologic data of patients with essential hypertension during treatment and investigated the treatment characteristics, such as treatment medication, medication satisfaction, and compliance, to provide basic data for adequate hypertension management. The results will help patients with hypertension to recognize the importance of blood pressure management and increase the attainment of treatment goals by increasing the interest of investigators in patient care and education.Patients were considered eligible for enrollment if they met the following criteria: male or female adults aged over 20 years who signed an informed consent form and essential hypertension patients taking the same antihypertensive drug for more than 4 weeks at a screening visit in the STEP I study. Patients were excluded from STEP I if they used antihypertensive drugs for reasons other than treating essential hypertension, could not understand and complete the questionnaire, or participated in other clinical trials within 3 months.STEP II enrolled patients from the STEP I study who had not been taking fimasartan within 3 months of the STEP I registration. Additionally, patients with drug satisfaction scores below 4 or those with scores of 5 or higher who needed to change to fimasartan treatment as determined by the investigators  were enrolled in STEP II.Patients were excluded from STEP II if they had hypersensitivity to fimasartan or its ingredients, were pregnant or lactating, were receiving dialysis, had moderate to severe hepatic dysfunction, had biliary obstruction, or had a genetic disorder such as a galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption. As STEP I was a cross-sectional study; patients were able to stop the study at any time without stating the reason for discontinuation. Patients were withdrawn from the study if they withdrew consent to use their data, wanted to stop taking the study medication voluntarily, or wanted to stop participating in the study. Patients were also withdrawn from the study if the investigator decided that the administration of the fimasartan was not appropriate medically and ethically.This was a multicenter, non-interventional study. STEP I was a cross-sectional study of all hypertensive patients under antihypertensive drugs treatment. STEP II was designed as a prospective observational study of patients who switched from their antihypertensive drug to fimasartan.Fimasartan  is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension. It is marketed in Korea and registered in 15 different countries now. This study investigated the treatment characteristics, such as the treatment drug, drug satisfaction, and compliance of essential hypertensive patients during treatment, and confirmed the basic data for appropriate management of hypertension. The purpose of the study was also to observe the change in treatment efficacy, satisfaction, and compliance when the subject was unsatisfied with the conventional drug and changed to fimasartan.In STEP I, patients with essential hypertension who were taking an antihypertensive drug were enrolled after signing an informed consent form. At the time of enrollment, demographic information, hypertensive disease characteristics, and treatment characteristics were examined, and patient satisfaction, compliance, and quality of life were subsequently evaluated. The demographic information included sex, age, height, weight, body mass index (BMI), region of residence, educational level, and income level. The clinical characteristics included drinking, smoking, exercise, having of a home blood pressure monitor and measurement of blood pressure at home, presence of accompanying diseases , and family history of hypertension. If the patient’s satisfaction with antihypertensive medication was less than 4 points during STEP I or if the investigator deemed it necessary, even if the score was above 5 points, the antihypertensive drug was changed to fimasartan for STEP II. The patients were monitored up to 8 weeks at 4-week intervals, and changes in treatment effects, satisfaction, compliance, and adverse events were analyzed.The study drug was administered according to product labeling during routine treatment. The antihypertensive drugs used to treat patients were registered in this study. All of the concomitant medications and antihypertensive drugs other than fimasartan taken by patients enrolled in STEP II during the study period were recorded on a case report form.Fimasartan was administered to the patients enrolled in STEP II during regular treatment, and the total motivation score (forgetfulness and inattention) and total knowledge score (understanding the benefit of continuous treatment) were evaluated by the Morisky method for medication compliance evaluation on day 0 (baseline) and at 4 and 8 weeks. Total motivation scores of 0 to 1 represented low motivation and 2 to 3 represented high motivation. Total knowledge scores of 0 to 1 represented low knowledge and 2 to 3 represented high knowledge of compliance.Fimasartan treatment information and treatment emergent adverse events after fimasartan treatment were the safety variables of this study. This study obtained relevant institutional review board approval to participate in recruitment.Omron HEM-7220  monitors were used to measure blood pressure (BP) at the study site. These were automated upper arm cuff devices based on the oscillometric method. Clinic BP was measured under standardized conditions (in the same arm by the same physician or nurse).Target systolic BP (SBP) was < 140 mmHg, with diastolic BP (DBP) < 90 mmHg in essential hypertension , and tarAs this was a study of the clinical characteristics of hypertensive patients and medication satisfaction after switching to fimasartan, the evaluation parameters were as follows for STEP I and STEP II. The efficacy evaluation of STEP I included demographic characteristics , clinical characteristics , disease characteristics , treatment characteristics , and quality of life of hypertensive patients.The efficacy assessments of STEP II were the quality of life of hypertensive patients, demographic/clinical/disease/treatment factors affecting quality of life, blood pressure changes after treatment with fimasartan, medication satisfaction and compliance, overall improvement, and clinical symptom evaluation by the investigators. The efficacy end points of STEP II were evaluated at 8 weeks after switching to fimasartan treatment.The tolerability assessments of this study were the treatment information for fimasartan and the AEs after fimasartan treatment. The safety assessment was conducted in patients who had received fimasartan at least once in STEP II. The numbers and percentages of AEs, adverse drug reactions, and serious adverse events were assessed. Adverse events were coded and organized by using the Medical Dictionary for Regulatory Activities version 18.0.The analysis group in this study was divided into STEP I, STEP II, and safety sets. The subjects in the STEP I and STEP II analysis groups included all patients who satisfied the inclusion/exclusion criteria. The subjects in the safety set included all patients who received at least one dose of fimasartan regardless of satisfaction of the inclusion/exclusion criteria among the STEP II patients.Descriptive statistics for the mean, standard deviation, median, minimum, and maximum values are presented for continuous variables. Frequencies and percentages are presented for categorical variables. The significance level was 5% (two-sided), and SAS software version 9.4  was used for the analysis. Before database locking, details of the analysis were described in the statistical analysis plan.As this was an observational study on the clinical characteristics of hypertensive patients and treatment satisfaction after changing medication to fimasartan, no hypothesis was not limited, and all variables were analyzed using descriptive statistics.In STEP I, categorical variables such as anti-hypertensive drug and sex were summarized as frequency and percentage (%). Continuous variables such as blood pressure, age, and weight were summarized as descriptive statistics .In STEP II, the reasons for changing to fimasartan were summarized according to the previous antihypertensive drug type. The mean of medication satisfaction, compliance, and blood pressure were compared after changing to fimasartan. Differences after the change were analyzed with a paired t-test. Univariate logistic regression analysis was performed to determine the prognostic factors affecting quality of life/medication satisfaction and compliance in STEP I and STEP II. No imputation were used for missing data in this study.As the purpose of this study was to investigate the clinical characteristics of essential hypertensive patients in Korea during medication treatment in STEP I and to determine the reason for a medication change and satisfaction with fimasartan in STEP II, it was necessary to determine the sample size to confirm the status. Because no previous epidemiological studies have been performed to examine the clinical characteristics of patients undergoing treatment, the sample size required for STEP II was calculated, and then the required subject numbers for STEP I were predicted. Because data on the satisfaction rate for antihypertensive drugs were lacking, the subject numbers were calculated with the assumption that prescription changes were due to dissatisfaction. Lack of efficacy, incidence of adverse events, or discomfort may lead to prescription changes, but lack of efficacy is the major reason for prescription change. According to a study on prescription changes for antihypertensive drugs, 9–14% of the patients were not responsive to the antihypertensive drug . TherefoAccording to this formula, 4056 patients were required for the analysis in STEP II; therefore, prescription changes to fimasartan were investigated in 4500 patients with the assumption of a 10% dropout rate. Additionally, with the assumption that 1/3 of the patients who registered in STEP I may change to fimasartan, 14,000 patients were projected to enroll in STEP II.12,691 and 2183 hypertensive patients were enrolled in STEP I and STEP II.Except for 447 who did not meet the inclusion/exclusion criteria, of the 12,691 patients enrolled in STEP I, 12,244 were included in the analysis set. Of 2183 patients registered in STEP II, excluding 160 who did not meet the inclusion/exclusion criteria or violated the protocol, 2023 were included in the analysis set. The safety set included 2183 patients among those registered in STEP II  was 61.4 ± 11.2 years. The mean height and weight were 162.4 ± 8.9 cm and 65.7 ± 11.4 kg, respectively. The mean BMI was 24.8 ± 3.2 kg/m2. Detailed information on region of residence, education level, and income level are described in Table Analysis of demographic and clinical characteristics in STEP II was performed on 2023 patients who met the inclusion/exclusion criteria. The participants included 49.5% men and 50.5% women. The mean age was 61.7 ± 11.6 years. The mean height was 162.3 ± 9.0 cm, and the mean weight was 65.6 ± 11.4 kg. The mean BMI was 24.8 ± 3.1 kg/mDrinkers accounted for 37.6 and 35.8% in STEP I and STEP II, respectively. Non-smokers accounted for 75.7% in STEP I and 76.5% in STEP II. Detailed information on exercise, home blood pressure monitoring, family history, and prescription interval characteristics are described in Table The disease characteristics in the STEP Iwere an SBP of 129.2 ± 14.2 mmHg, a DBP of 78.6 ± 9.8 mmHg, a pulse rate of 73.7 ± 10.4 beats/min, and duration of hypertension 7.0 ± 6.3 years. In STEP II, the disease characteristics were as follows: SBP 135.7 ± 17.9 mmHg, DBP 82.1 ± 11.5 mmHg, pulse rate 73.8 ± 10.1 beats/min, and duration of hypertension 7.0 ± 7.0 years.We also investigated the medical history of myocardial infarction, heart failure, atrial fibrillation, stroke, diabetes, and kidney disease associated with hypertension. In STEP I and STEP II, 27.3 and 31.2% had a medical history, respectively. The detailed medical history is described in Table In STEP I, the total score for quality of life was 84.1 ± 18.5. The scores of each of the quality of life domains in STEP I and STEP II at baseline are described in Table In STEP II, male sex, high BMI, living in a micropolitan area instead of small town, education level greater than high school, other income categories, being a former smoker, regular exercise, possessing a home hypertension monitor, and Long-term hypertensive drug prescription interval (more than 3 months) significantly affected quality of life (Table p < 0.0001). The mean DBP before and after treatment was 82.1 ± 11.5 mmHg and 79.1 ± 8.4 mmHg, respectively. The mean diastolic blood pressure decreased by 3.1 ± 11.6 mmHg, which was statistically significant (p < 0.0001) . At 8 weeks after treatment, medication satisfaction was also significantly increased (p < 0.0001), compared to that before fimasartan treatment . In addition, the mean motivation score for compliance after 8 weeks was 2.7 ± 0.6. The rate of high motivation for compliance was 93.5%, and the rate of low motivation for compliance was 6.6%; these were significantly different from baseline (p < 0.0001) . After 8 weeks, the mean knowledge score for compliance was 2.6 ± 0.6. The rate of patients with high knowledge for compliance was 95.7%, and the rate of patients with low knowledge for compliance was 4.4%; these were significantly different from baseline (p < 0.0001)  and possessing a home blood pressure monitor OR = 1.827) significantly affected motivation for compliance. The analysis of factors affecting knowledge about compliance showed that high BMI (OR = 1.140), regular exercise (OR = 1.859), and 1 month instead of 6 month of hypertensive drug prescription (OR = 0.337) significantly influenced knowledge about compliance . Additionally, in the overall assessment of clinical symptoms, the improvement rate was 85.3% (1718/2014). (Data not shown).The reasons for changing from a conventional antihypertensive drug to fimasartan were as follows: 76.4% of patients reported lack of efficacy, 7.9% reported adverse events, and 15.7% reported other reasons.n = 30), 23 of headache , 17 of palpitations , 9 of blood pressure increase , 8 of chest pain , 7 of hypotension , and 6 of cough . Fifty cases of adverse drug reactions occurred in 39 patients (1.8%). The most common adverse drug reactions were 10 events of headache , 9 of dizziness , and 7 of hypotension . No serious adverse events were associated with the fimasartan.Fimasartan was administered at least once in the 2183 patients who were included in the safety analysis. A total of 234 adverse events occurred in 151 patients 6.9%) , 5.1 ± 1.1 at 4 weeks, and 5.4 ± 1.0 at 8 weeks, and the satisfaction levels significantly increased as treatment continued. The factors that significantly influenced medication satisfaction in STEP I included young age, living in a micropolitan area, high income level, being a smoker, non-regular exercise, lack of a home blood pressure monitor, and short-term hypertensive drug prescription. In STEP II, the factors that significantly influenced medication satisfaction were young age, low income level, drinking, and short-term hypertensive drug prescription.In the compliance analysis (Morisky method), the motivation and knowledge scores at 4 and 8 weeks were significantly higher than at baseline. The factors that significantly influenced the motivation for compliance included being a former smoker and having a home blood pressure monitor. For the knowledge of compliance, high BMI, regular exercise, and 1 month of hypertensive drug prescription were significant factors.In the final analysis of STEP II, the overall improvement rate was 84.8%, and the overall rate of improvement of clinical symptoms was 85.3%. Most of the symptoms improved. The reason for switching from an antihypertensive drug to fimasartan in STEP II was reported as a lack of efficacy by 76.4% of patients. Switching antihypertensive drugs to fimasartan did reduce the risks of blood pressure-related cardiovascular disease in hypertensive patients.All of the adverse events were reported on the drug labels.The results of this study demonstrated that patient satisfaction with medication improved when they switched from a conventional antihypertensive drug to fimasartan. Patients with a short-term prescription showed greater satisfaction. Additionally, blood pressure was significantly decreased after switching to fimasartan, and fimasartan administration was well tolerated and safe in hypertensive patients in Korea.


Climate change may exacerbate salinity variations in aquatic ecosystems, potentially affecting fish performance. We show that long-term seawater exposure in rainbow trout increases cardiac output and reduces blood pressure and vascular resistance through altered α-adrenergic control. Possible impacts of salinity fluctuations on fish aerobic swimming and digestive capacity are discussed. Oncorhynchus mykiss) as a euryhaline model species and determined dorsal aortic blood pressure, cardiac output and systemic vascular resistance in vivo after chronic freshwater—or SW-acclimation. We also assessed α-adrenergic control of blood pressure using pharmacological tools. Dorsal aortic blood pressure and systemic vascular resistance were reduced, whereas cardiac output increased in SW. α-Adrenergic stimulation with phenylephrine caused similar dose-dependent increases in resistance and pressure across salinities, indicating unaltered α-adrenoceptor sensitivity. α-Adrenergic blockade with prazosin decreased resistance and pressure across salinities, but the absolute reduction in resistance was smaller in SW. Yet, both pressure and resistance after prazosin remained consistently lower in SW. This shows that SW-acclimation lowers systemic resistance through reduced vascular α-adrenergic tone, along with other unknown vasodilating factors. The marked changes in adrenergic regulation of the vasculature across salinities discovered here may have implications for cardiovascular and aerobic performance of fishes, with possible impacts on fitness-related traits like digestion and exercise capacity. Moreover, the evolution of more complex circulatory control systems in teleost fishes compared with elasmobranchs and cyclostomes may have been an important factor in the evolution of euryhalinity, and may provide euryhaline teleosts with competitive advantages in more variable salinity environments of the future.Greater salinity variations resulting from ongoing climate change requires consideration in conservation management as this may impact on the performance of aquatic organisms. Euryhaline fish exhibit osmoregulatory flexibility and can exploit a wide range of salinities. In seawater (SW), they drink and absorb water in the intestine, which is associated with increased gastrointestinal blood flow. Yet, detailed information on other cardiovascular changes and their control across salinities is scant. Such knowledge is fundamental to understand how fish are affected during migrations between environments with different salinities, as well as by increased future salinity variability. We used rainbow trout ( Global climate change is predicted to affect the salinity and its variability in aquatic environments . For exaFW generally has a volume loading effect on fish (i.e. gain of water and loss of ions), whereas seawater (SW) has a volume depleting effect  decreased by 11–21% in FW-acclimated trout acutely exposed to SW for 24 hours , and it is largely unknown how the hemodynamic status of fish is affected after more chronic SW exposure. Moreover, the only previous study that recorded blood pressure responses to short-term acclimation to SW used rainbow trout with surgically opened pericardia  as a euryhaline model species that can tolerate a wide range of salinities while being suitable for in vivo cardiovascular recordings. Indeed, some strains of wild rainbow trout (i.e. ‘steelhead’) are anadromous and naturally migrate between FW and SW, whereas most farmed rainbow trout strains can acclimate to SW  were obtained from a local hatchery  buffered with NaHCO3 (300 mg l−1). Length and weight were determined before placing the fish dorsally on water-soaked foam on a surgical table. The gills of the fish were continuously irrigated with recirculating aerated FW (i.e. for both FW- and SW-acclimated fish) at 10°C containing MS-222 (75 mg l−1) buffered with NaHCO3 (150 mg l−1) throughout the surgery. FW was used as anaesthetic solvent for both acclimation groups since earlier attempts of using SW as solvent for the SW-acclimated group resulted in impaired post-surgical recovery, possibly due to impaired drinking during the anesthetized state. The dorsal aorta was cannulated with a custom-made PE-50 catheter using a steel wire guide (−1) 0.9% saline and exteriorized through the snout and locked in place by a bubble on the catheter  and saline (0.9%) as a control, were injected into the dorsal aortic catheter, followed by 0.3–0.4 ml saline (0.9%) to clear the catheter dead space. The administration of phenylephrine dosages was randomized, and an additional 0.3-0.4 ml saline (0.9%) was injected when the peak PDA response had leveled off to ensure that all traces from the previous injection was cleared from the catheter. Last, one dosage of the α-adrenergic antagonist prazosin (1 mg kg−1) was injected in the same way to obtain a complete α-adrenergic blockade. All injections were administered in volumes of 1 ml kg−1 body mass (Mb). While the administration order of phenylephrine and saline injections was randomized for each fish, prazosin was always administered last. Before a new injection was administered, care was taken to allow all cardiovascular variables to return to stable baseline levels. The time for this varied among individuals and injections but was typically never longer than one hour. After the experiments, the fish were killed with a sharp blow to the head.Baseline recordings of cardiac output, heart rate and RSYS was calculated from PDA and cardiac output as:The dorsal aortic catheter was connected to a pressure transducer  that was calibrated against a static water column with the water level in the experimental tank serving as the zero reference. The signal from the pressure transducer was amplified using a 4ChAmp pre-amplifier . The Transonic flow probe was connected to a Transonic flow meter . The signals from the flow meter and pressure transducer were relayed to a 16SP PowerLab system  that was connected to a computer with LabChart pro data acquisition software . Heart rate was determined from the pulsatile blood flow or pressure recordings using the blood pressure module in LabChart pro. Stroke volume was calculated as:PDA, cardiac output and heart rate for each individual were obtained from representative calm periods, which were taken at the end of the initial 2 h baseline recording period. To analyze the responses to α-adrenergic stimulation with the different dosages of phenylephrine, mean values for all cardiovascular variables were taken at the peak blood pressure response after each drug injection. The order of administration for the different dosages of phenylephrine was randomized for each fish. Cardiovascular variables after complete α-adrenergic blockade with prazosin were obtained approximately two hours after the drug had been administered and the blood pressure had reached a new steady state. All mean values were typically calculated as 30 s means.Mean values for baseline t-tests were used for all comparisons between acclimation groups containing one dependent factor, including all baseline and prazosin treatment analyses, as well as all analyses of the absolute changes induced by prazosin. To assess the general effect of the different dosages of phenylephrine within each acclimation group, as well as the general effect between acclimation groups, a repeated measures ANOVA was used with individuals as subject variables and the dose of phenylephrine as the repeated variable. In the model, we included dose of phenylephrine , acclimation group and their interactions as fixed effects. To meet the assumptions of statistical tests, a logarithmic transformation was applied for cardiac output, RSYS and PPULSE, and a square root transformation was applied for PDA. When the assumption of sphericity in the general linear model analyses was not met, we used Greenhouse–Geiser corrections to interpret if the results were significant. Values are presented as means ± SEM and statistical significance was accepted at P ≤ 0.05.Statistical analyses were conducted using SPSS Statistics 24 . Independent P < 0.05; Table There were no obvious behavioural differences between acclimation groups as fish from both groups generally remained calm in the experimental setup throughout the recording period. There were no differences in body mass, length or condition factor between acclimation groups  than FW-acclimated trout , there were no significant differences between acclimation groups indicating that the responsiveness to α-adrenergic stimulation was unchanged across salinity acclimation groups .Intra-arterial injection of the α-adrenergic agonist phenylephrine caused dose-dependent increases in out Fig. A, B. HowF4 = 2.974, P = 0.026) and stroke volume  in both acclimation groups , there was still no significant difference in heart rate between acclimation groups after prazosin  was markedly reduced in SW and therefore cannot explain the elevated blood flow. However, it is not possible to conclude if a dilation of somatic vascular beds also contributed to the overall reduction in RSYS, or if somatic vascular resistance increased to aid blood flow distribution to the gastrointestinal tract in SW. Forced feeding of FW and SW-acclimated rainbow trout increased gastrointestinal blood flow with the same absolute amount, which shows that the baseline difference in gastrointestinal blood flow persists after feeding (Our data strongly suggest that the elevated gastrointestinal blood flow previously observed in SW-acclimated trout  is causePDA in SW-acclimated trout was most likely an effect of the reduced RSYS, which the marked rise in cardiac output was unable to compensate for. However, there are also a few other factors that may have contributed to the decreased PDA in SW. The total circulating blood volume is typically reduced in SW, which could possibly contribute to the reduced blood pressure (PDA. To fully resolve these possibilities, simultaneous measurements of ventral aortic blood pressure and gastrointestinal blood flow in FW- and SW-acclimated trout, along with the cardiac output and PDA measurements performed here, are required.The reduced pressure . It is aRSYS can result either from elevated vasodilatory and/or reduced vasoconstrictory stimulation of the resistance vasculature (PDA and RSYS with phenylephrine injections, indicating that the vascular sensitivity to α-adrenoreceptor stimulation was similar across acclimation groups. A reduced vascular α-adrenergic sensitivity can therefore not explain the lower baseline RSYS and PDA in the SW-acclimated trout. However, the greater reduction in RSYS after α-adrenoreceptor blockade with prazosin in FW-acclimated trout revealed a reduced intrinsic α-adrenergic tone on the resistance vasculature in SW. Consequently, a lower intrinsic α-adrenergic tone at least partly explains the lower baseline PDA and RSYS in SW. This is likely due to modulation of neural α-adrenergic vascular tone exclusively, as a previous study did not find any significant differences in resting levels of circulating catecholamines between FW- and SW-acclimated trout (Reduced culature . The preculature . Both aced trout .RSYS in SW, as PDA and RSYS remained significantly lower in the SW-acclimated trout after complete α-adrenergic blockade. This implies that other local or neurohumoral vasodilatory factors, possibly acting on the gastrointestinal resistance vasculature, are also involved. Likely vasodilating candidates include natriuretic peptides such as atrial natriuretic peptide, which has a strong vasodilating effect on the celiacomesenteric artery in rainbow trout (Anguilla japonica (Still, the reduced α-adrenergic vasomotor tone cannot alone explain the reduction in ow trout . Indeed,japonica . This sejaponica , 1997. Ojaponica . In mammjaponica . Interesvia an increased stroke volume, as heart rate remained unchanged across salinities (RSYS. Interestingly, the significant elevation in baseline cardiac output and stroke volume in SW-acclimated trout was abolished following the prazosin treatment. This could be due to an increased central venous pressure following prazosin treatment in FW-acclimated trout due to altered trans-vascular fluid shifts, as observed in previous in vivo studies (see The 68% increase in cardiac output in SW-acclimated trout was primarily mediated linities , 2017. Nlinities . While tdies see .The present study emphasizes that profound cardiovascular changes occur during acclimation to different salinities in a euryhaline teleost fish. These changes are likely important for maintaining osmotic homeostasis but may impact on aerobic performance traits, which requires future research attention and consideration in conservation management. While the present findings suggest that previous observations of increased gastrointestinal blood flow in SW are due to a reduced α-adrenergic tonus on the gastrointestinal resistance vasculature, our data also indicate that other vasoactive factors are important for mediating these responses. Thus, deciphering the apparently complex interplay between the various neural and hormonal cardiovascular control systems at play during FW to SW transition represents another challenging avenue for further research. From an evolutionary perspective, it could be speculated that the evolution of more complex control systems involving both neural and hormonal vascular control systems in teleost fishes, that are not present in elasmobranchs and cyclostomes , has bee


Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure–lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension.This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome.Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients.NCT03246555, registered on July 25, 2017.ClinicalTrials.gov Identifier: The online version of this article (10.1186/s13063-019-3466-5) contains supplementary material, which is available to authorized users. Hypertension is a major risk factor for cardiovascular disease and affects over 1 billion people worldwide. From 1998 to 2014, the prevalence of hypertension in the population older than 65 years was 55.3–60.5% in Korea; thus, over half of the elderly individuals have hypertension. It is important to note that hypertension treatment can lower the risk of stroke, cardiovascular disease, and mortality [The Eighth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure aims to achieve a systolic blood pressure (SBP) of less than 150 mm Hg and a diastolic blood pressure (DBP) of less than 90 mm Hg in people older than 60 years . There aThe objective of this study is to confirm the safety and the non-inferiority of the blood pressure–lowering effect of fimasartan compared with those of perindopril in elderly individuals with essential hypertension. Perindopril arginine, selected as a control drug, is an ACE inhibitor used in the Hypertension in the Very Elderly Trial , a repreOlder patients are highly heterogeneous, and physiological ability and vulnerability vary widely, even for individuals of the same age . FrailtyThis is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study designed to evaluate the blood pressure–lowering effect and safety of fimasartan and perindopril in elderly individuals with essential hypertension. The flow chart below captures the main events during the study Fig. , and theVoluntarily provided written consent to participate in this clinical study after receiving an explanation of this studyElderly (70 years old or older)At the screening visit (Visit 1),Blood pressure: The mean blood pressure measured three times on the selected arm, as below:For treatment-naïve patients who have not taken drugs for hypertension within the last 3 months from the screening visit: mean siSBP (sitting systolic blood pressure) of at least 140 mm HgFor patients with essential hypertension who are taking drugs for hypertension: mean siSBP of at least 130 mm Hg4)At the baseline visit (Visit 2),Blood pressure: Patients with mild to moderate essential hypertension whose mean siSBP measured three times on the selected arm is at least 140 mm HgPatients with treatment compliance of at least 70% during the placebo run-in period5)Capable of understanding written instructions, cooperative, and able to participate until the end of the clinical study.Inclusion criteria are as follows:Severe hypertension with mean siSBP of at least 180 mm Hg or siDBP (sitting diastolic blood pressure) of at least 110 mm Hg (office blood pressure) at the screening visit (Visit 1) and baseline visit (Visit 2). Patients with a difference in siSBP of at least 20 mm Hg and siDBP of at least 10 mm Hg in the selected arm at the screening visit (Visit 1)Patients with a history of secondary hypertension and any history of suspected secondary hypertension but not limited to the following conditions: coarctation of the aorta, primary hyperaldosteronism, renal artery stenosis, Cushing’s syndrome, pheochromocytoma, or polycystic kidney diseaseOrthostatic hypotension with symptomsPatients with insulin-dependent diabetes mellitus or uncontrolled diabetes mellitus Patients with a history of malignant tumor, including leukemia and lymphoma, within the past 5 years Patients with any chronic inflammatory disease requiring chronic anti-inflammatory treatment, consumption disease, autoimmune disease such as rheumatoid arthritis and systemic lupus erythematosus, or connective tissue disease at present or in the pastPatients with a history of a hypersensitivity reaction to any component of the investigational product and similar compounds: renin–angiotensin system inhibitors, ACE inhibitors, thiazide diuretics and sulfonamides, Yellow 5 (Sunset Yellow FCF (dye)), etc.Patients with hyperlipidemia undergoing low-density lipoprotein (LDL) apheresis (patients undergoing LDL hemapheresis using a dextran sulfate cellulose)Patients on dialysis, post-renal transplantation patients, or patients with clinically significant renal and hepatic diseases, such as cirrhosis, biliary tract obstruction, cholestasis, liver failure, and hepatic encephalopathy, or the following findings from tests at screening (Visit 1):Creatinine clearance  equation) of less than 30 mL/minAlanine transaminase (ALT) or aspartate transaminase (AST) of at least three times the upper limit of normal (ULN)Hypokalemia (<3.5 mmol/L), hyponatremia (<133 mmol/L), or hyperkalemia (>5.5 mmol/L)11)Patients with diagnosis of any of the following diseases or treatment for the following diseases within 6 months from the date of screening visit, which is deemed to be clinically significant by the investigator:Severe heart diseases: heart failure (New York Heart Association (NYHA) class III and IV), ischemic heart disease , peripheral vascular disease, percutaneous transluminal coronary angioplasty, or coronary artery bypass graftingHypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, or hemodynamically significant aortic or mitral stenosisClinically significant ventricular tachycardia, atrial fibrillation, atrial flutter, or arrhythmiaSevere cerebrovascular disease Known moderate or malignant retinopathy, such as retinal bleeding, visual disturbance, and retinal microaneurysm12)Patients with angioedema caused by drugs, including ACE inhibitors, hereditary or idiopathic angioedema, or a history of such diseases13)Patients with a history of alcohol or drug abuse within the last 2 years14)Surgical or medical diseases that may affect the absorption, distribution, metabolism, and excretion of drugs that fall under one of the following cases (but not limited to them): history of major gastrointestinal surgery, such as gastrectomy, gastroenterostomy or small bowel resection, gastrointestinal bypass and gastrointestinal stapling, active gastritis, gastrointestinal or rectal bleeding at present, and active inflammatory bowel syndrome within the last 12 months15)Patients with volume depletion, anuria, and shock16)Patients with hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose–galactose malabsorption17)Patients who used other investigational products within 12 weeks prior to screening18)Patients with any other reason that, in the opinion of the investigator, may contraindicate participation in the study.Exclusion criteria are as follows:The treatment in this clinical study starts with fimasartan 30 mg or perindopril arginine 2.5 mg; if blood pressure is not controlled (siSBP of at least 140 mm Hg or siDBP of at least 90 mm Hg), the dose is escalated once gradually and then a diuretic combination is administered. The escalation of dose and administration of diuretics are decided after checking blood pressure 4 weeks after the initiation of each investigational product.If a subject voluntarily consents to participate in the study, the investigator will perform screening tests and a medical history survey to assess the subject’s eligibility. As a result of the screening tests, all subjects who are in compliance with the inclusion criteria and do not fulfill the exclusion criteria will have a placebo run-in period of 3–5 weeks and those who are on anti-hypertensive medications will stop the existing anti-hypertensive medication and take the placebo. The placebo run-in period proceeds on a single-blind basis.After the completion of the placebo run-in period, assessments are performed to select the final subjects at the baseline visit, and the eligible subjects are randomly assigned to the fimasartan 30 mg group or the perindopril arginine 2.5 mg group at a 1:1 ratio. The randomly assigned subjects take two tablets of the relevant investigational product for each treatment group once daily for 4 weeks; in the case of patients with uncontrolled blood pressure (siSBP of at least 140 mm Hg or siDBP of at least 90 mm Hg) after 4 weeks, the dose is doubled (fimasartan 60 mg or perindopril arginine 5 mg) through an optional titration. The subjects take the investigational product at the escalated dose once daily for 4 weeks, and the patients still with uncontrolled blood pressure after the 4-week administration of the escalated dose take a diuretic combination (fimasartan 60 mg/hydrochlorothiazide 12.5 mg or perindopril arginine 5 mg/indapamide 1.25 mg) additionally. After 8 weeks, changes in their blood pressure are checked.The patients with controlled blood pressure (siSBP of less than 140 mm Hg and siDBP of less than 90 mm Hg) at week 16 participate in the 8-week open-label extension study after the dose for the test group is switched back to the previous dose and the dose for the control group is switched to the dose for the test group, and the efficacy and safety of the drugs are evaluated.In the course of the clinical study, the subjects will make visits, including the screening and baseline visits, at weeks 4, 8, and 16 as well as at week 24 during the extension study (in the case of patients with controlled blood pressure at week 16), and they will undergo tests and assessments specified in the protocol at each visit.The primary outcome will be a change in siSBP from baseline after the administration of the investigational product for 8 weeks.A change in siSBP from baseline after the administration of the investigational product for 4, 16, and 24 weeksA change in siDBP from baseline after the administration of the investigational product for 4, 8, 16, and 24 weeksBlood pressure response rate  and blood pressure normalization rate after the administration of the investigational products for 4, 8, and 16 weeks (siSBP of less than 140 mm Hg and siDBP of less than 90 mm Hg)A change from baseline in the differences in standing SBP and DBP compared with their sitting measurements after the administration of the investigational product for 4, 8, 16, and 24 weeks.Changes in siSBP and siDBP from baseline after the administration for 4, 8, 16, and 24 weeks depending on the level of senescence  evaluated by K-FRAILChanges in siSBP and siDBP from baseline after the administration for 4, 8, 16, and 24 weeks depending on gait speed The secondary outcomes will be as follows:The change will be calculated by subtracting the baseline value from the value at the time of evaluation.In this clinical trial, which is double-blinded, a randomization table is prepared by a stratified block randomization method where a study site is the stratification factor. For randomization, an independent statistician will generate randomization numbers by using SAS version 9.3 and will deliver them in an encrypted file to the director of investigational product packaging and IWRS (Interactive Web-based Response System) manager.Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be randomly assigned at a ratio of 1:1 to one of the following groups: treatment group (fimasartan 30 mg) or control group (perindopril 2.5 mg). Randomization will be carried out using IWRS.For packaging and labeling of the investigational products, the sponsor’s investigational product packaging director will be in charge of properly packaging the study group and control group in accordance with the randomization table and labeling on the investigational product. The investigator will assign the randomization numbers through IWRS to the eligible subjects on the basis of the inclusion/exclusion criteria in the order of enrollment in the study and will prescribe the applicable investigational products. When dispensing the investigational products, the clinical trial pharmacist will reconfirm whether the subject’s randomization number matches the number labeled on the investigational product.In the placebo run-in period and dose titration period of this study, a placebo with the same formulation and properties that is not distinguished by appearance is used to maintain double blindness. The tester, test subjects, and monitor personnel are not informed about which group the test subjects are assigned to.In an emergency situation that threatens the safety of the subject, the investigator should promptly notify the person in charge of unblinding from Boryung Pharmaceutical Co., Ltd. . The person in charge of unblinding should decide whether to unblind in consultation with the investigator and document the decision. After consulting with the client, the investigator accesses the webpage about random assignment. After inputting the required information, the investigator confirms the clinical trial drug information of the subject and documents the unblinding. However, subjects and monitor personnel are not informed about unblinding. When the trial is over and the database is confirmed to be complete and accurate, the data will be locked and the random assignment code information will be released after the unblinding procedure.In existing non-inferiority clinical trials of anti-hypertensive agents comparing the lowering effect of siSBP, the non-inferiority margin (δ) is set to 5–6 mm Hg , 15. In δ: non-inferiority margin (5 mm Hg)K: test group and control group allocation ratio (1:1)α = 0.025, β = 0.2σ = 13 mm Hg.The required number of subjects for each group, calculated from the above formula, is 107. In consideration of a 10% dropout rate, a total of 238 subjects, 119 from each group, will be registered for enrollment.In this clinical trial, the efficacy evaluation will analyze mainly the data by per-protocol. We will analyze the effect of the drug on the subjects who have completed the trial without any serious violation of the plan.To test the difference between the test group and the control group, an analysis of covariance (ANCOVA) will be performed with the baseline values as covariates and the treatment groups as effects. Change in siSBP from baseline after the administration of the investigational product for 8 weeks will be analyzed, and the difference between the treatment groups will be calculated by subtracting the change in the perindopril group from the change in the fimasartan group. The fimasartan group is determined to be non-inferior to the perindopril arginine group if the lower limit of the two-sided 95% confidence interval corresponding to the least square means (LSM) difference between the treatment groups is greater than −5 mm Hg.t test or a Wilcoxon signed-rank test will be performed.To test the difference between the groups, continuous variables will be analyzed through an ANCOVA with the baseline values as covariates and the treatment groups as effects. In the case of categorical variables, the frequencies (N) and percentages (%) of each period and their two-sided 95% confidence intervals will be presented; for an intergroup difference, logistic regression analysis will be performed with the baseline values as covariates. For the analysis of the changes within the treatment groups at week 24, a one-sample t test or a Wilcoxon signed-rank test will be performed. Using these results, we will analyze whether there is any difference in blood pressure–lowering effect according to the frailty status.In the subgroup analysis, the subjects will be divided into three groups, such as healthy stage, pre-senescent stage, and senescent stage, depending on the level of senescence evaluated by K-FRAIL. The subjects will also be divided into two groups, such as normal gait speed group and slow gait speed group, depending on gait speed evaluated by the 5-m walk test. For each subgroup, the descriptive statistics for the baseline values and the measurements at 4, 8, 16, and 24 weeks are presented. At 4, 8, and 16 weeks after the administration of clinical trial drugs, the change will be analyzed through an ANCOVA with the baseline values as covariates and the treatment as effects. For the analysis of the changes within the treatment groups at 24 weeks, a one-sample Adverse events are coded and organized by using the MedDRA , and the proportion of the subjects who have experienced adverse events and the 95% confidence interval are presented by treatment group. All adverse events are organized according to severity, and investigational product-related adverse events and serious adverse events are summarized separately. The chi-squared test or the Fisher’s exact test will be used to determine whether there is any difference in the incidence of adverse events between the groups.t test or the Wilcoxon’s signed-rank test within the treatment group. A two-sample t test and a Wilcoxon rank-sum test will be carried out to test the difference in the change after the administration between the treatment groups. For the categorical variables, McNemar’s test will be performed for the intragroup change.For continuous data, such as hematology and blood chemistry results, the descriptive statistics  will be presented by treatment group and visit; for categorical data, such as urinalysis and physical examination, the frequency (N) and percentage (%) will be presented by category. With regard to the difference in the continuous data before and after administration of the investigational product, the difference among visits will be tested by performing a paired Electronic blood pressure monitors  are used to measure blood pressure, and all laboratories use the same product. The blood pressure of both arms is measured by a trained study coordinator at the screening visit, and the arm with the higher average SBP obtained by three measurements is selected as the reference arm.Blood pressure of the upper arm of the subject is measured in the sitting position at each visit. After the subject has rested in a sitting position for at least 5 min in a chair that can support the back and the arm has been fixed to the heart level, the blood pressure is measured. Blood pressure should be measured three times at intervals of more than 2 min, and to measure blood pressure at the lowest drug concentration, blood pressure measurements should be performed in the morning, before dosing.http://www.mdsol.com) electronic data capture (EDC) system.Study data are collected and managed via the Medidata Rave™  were randomly assigned as of May 17, 2018. Protocol version number 4.1. Date: November 6, 2017.Additional file 1:SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents. (DOC 124 kb)


There is increasing epidemiologic and animal evidence that a low calcium diet increases blood pressure. The aim of this review is to compile the information on the link between low calcium intake and blood pressure. Calcium intake may regulate blood pressure by modifying intracellular calcium in vascular smooth muscle cells and by varying vascular volume through the renin–angiotensin–aldosterone system. Low calcium intake produces a rise of parathyroid gland activity. The parathyroid hormone increases intracellular calcium in vascular smooth muscles resulting in vasoconstriction. Parathyroidectomized animals did not show an increase in blood pressure when fed a low calcium diet as did sham-operated animals. Low calcium intake also increases the synthesis of calcitriol in a direct manner or mediated by parathyroid hormone (PTH). Calcitriol increases intracellular calcium in vascular smooth muscle cells. Both low calcium intake and PTH may stimulate renin release and consequently angiotensin II and aldosterone synthesis. We are willing with this review to promote discussions and contributions to achieve a better understanding of these mechanisms, and if required, the design of future studies. The relationship between calcium intake and blood pressure has been widely studied since the 1980s ,3. DietaThe effect of calcium supplementation on SBP was higher in people aged less than 35 years −2.11 mmHg) and with doses of calcium equal to or over 1500 mg/day (−2.79 mmHg). The higher impact on BP reduction observed in these cases seem to be diluted in the overall revision due to these studies only representing approximately 20% of the participants i) through the PTH receptor (PTHr-1) in vascular smooth muscle, (b) increase calcitriol concentration, and (c) a cross-talk with the renin–angiotensin–aldosterone system (RAAS). The last two will be described in its corresponding sections.Several mechanisms have been proposed to explain the effect of PTH on blood pressure: (a) an increase in cytosolic free calcium concentration , trypsin-inactivated and boiled-resistant peptide . Years lAlthough the existence of PHF may explain the blood pressure changes induced by alterations in a calcium diet, there is still much to know about this mediator. First, the published results have been poorly replicated outside the group that described PHF . On the 2+]i in vascular smooth muscle cells and consequently a rise in blood pressure  or diastolic blood pressure (DBP)  nor in subgroup analysis via basal vitamin D or blood pressure levels i by increasing calcium uptake in many types of cells, including rat vascular smooth muscle cells and aorta-derived cell lines [2+]i  plays a key role in the physiologic regulation of blood pressure. As shown below, several interactions between calcium intake, calcium homeostatic hormones and the RAAS have been described. Renin enzymatic activity consists in the hydrolysis of angiotensinogen to angiotensin I. The acute incubation or infusion of high concentrations of calcium has an inhibitory effect on renin secretion, both in isolated cells and animals ,95,96,97Angiotensin II is the primary active product of the RAAS and a potent vasoconstrictor whose actions are mediated by the type I angiotensin II receptor (AT-1R). Low calcium diets have been shown to increase angiotensin II ,102. In It has also been described that the infusion of angiotensin II produced a significant dose-dependent increase in PTH serum levels . MoreoveAldosterone, a steroid hormone, is synthesized by the zona glomerulosa of the adrenal cortex (CZG) in the adrenal gland. Its primary effect is the regulation of blood pressure through the reabsorption of sodium and excretion of potassium in the distal tubules and the collecting ducts of the nephron , increas2+]i. Angiotensin II, via AT-1R activating the PLC/IP3 cascades, and high extracellular potassium levels via depolarizing the plasma membrane of the cell activating calcium voltage-dependent channels, increase [Ca2+]i and thus aldosterone synthesis i [It has been shown that PTHr-1 stimulates basal steroid secretion  from adrenal cells through both AC/PKA- and PLC/PKC-dependent signaling mechanisms . Adrenal2+]i . In summary, it has been shown that both low calcium intake and PTH stimulate renin release, and consequently, angiotensin II and aldosterone synthesis. In this manuscript, we reviewed the literature exploring the mechanisms involved in the relationship between calcium intake and blood pressure. It has been shown that, particularly in individuals with low calcium intake, an increase in calcium intake reduces blood pressure. We consider that in view of hypertension being a major factor involved in the global burden of disease, the study of interventions that could prevent the development of hypertension should be prioritized . The lin


To develop and validate an individualized nomogram to predict probability of patients with ureteral calculi developing into urosepsis.The clinical data of 747 patients with ureteral calculi who were admitted from June 2013 to December 2015 in Affiliated Nanhai Hospital of Southern Medical University were selected and included in the development group, while 317 ureteral calculi patients who were admitted from January 2016 to December 2016 were included in the validation group. The independent risk factors of ureteral calculi associated with urosepsis were screened using univariate and multivariate logistic regression analyses. The corresponding nomogram prediction model was drawn according to the regression coefficients. The area under the receiver operating characteristic curves and the GiViTI calibration belts were used to estimate the discrimination and calibration of the prediction model, respectively.Multivariate logistic regression analysis showed that the five risk factors of gender, mean computed tomography(CT) attenuation value of hydronephrosis, functional solitary kidney, urine white blood cell(WBC) count and urine nitrite were independent risk factors of ureteral calculi associated with urosepsis. The areas under the receiver operating characteristic curve of the development group and validation group were 0.913 and 0.874 respectively, suggesting that the new prediction model had good discrimination capacity. P-values of the GiViTI calibration test of the two groups were 0.247 and 0.176 respectively, and the 95% CIs of GiViTI calibration belt in both groups did not cross the diagonal bisector line. Therefore the predicted probability of the model was consistent with the actual probability which suggested that the calibration of the prediction model in both groups were perfect and prediction model had strong concordance performance.The individualized prediction model for patients with ureteral calculi can facilitate improved screening and early identification of patients having higher risk of urosepsis. Ureteral calculus is one of the most common diseases of urology. Ureteral calculus associated urosepsis is not rare in clinical practice. Such patients have acute onset, rapid progress, and dangerous symptoms , 2. SomeIn recent years, with an improved understanding of urosepsis by urologists, there has been a significant increase in the number of studies on risk factors of urinary tract stones leading to urosepsis , 5. HoweThe aim at this study is to provide a clue for the early identification and screening of high-risk patients with ureteral calculi developing into urosepsis by establishing a reliable and accurate risk-prediction model.We retrospectively analyzed the clinical data of 747 patients with ureteral calculi admitted to our hospital from June 2013 to December 2016, including 62 patients with urosepsis and 685 patients without urosepsis. A total of 317 patients with ureteral calculi admitted from January 2016 to December 2016 were enrolled in the validation cohort, including 29 patients with urosepsis and 288 patients without urosepsis.The inclusion criteria were (1) imaging results, such as urinary system B ultrasound, excretory urogram, or abdominopelvic computed tomography (CT) leading to a diagnosis of ureteral calculi; (2) rapid increase in the sequential (sepsis-related) organ failure assessment score (SOFA), with a total score≥2 points; and (3)The study was approved by ethics committee of Affiliated Nanhai Hospital of Southern Medical University. Written informed consent was obtained from the patients involved or their close relatives in this study. The research data were analyzed anonymously and personal identifiers were completely removed. The study was conducted in accordance with the principles contained in the Declaration of Helsinki and its later amendments.We collected and analyzed the following factors of the subjects: general information , characteristics of ureteral calculi , characteristics of the affected kidney , and urine test results (urine white blood cell (WBC) count and urine nitrite).The length and width of ureteral calculi size were measured by abdominal X-ray kidney-ureter-bladder (KUB) and/or B ultrasound and/or CT. The mean CT attenuation values of ureteral calculi and degree of hydronephrosis were revealed and detected using the PACS image software of our hospital. For irregular calculus and hydronephrosis, the hounsfield unit (HU) value of the maximum annular range was taken as the mean CT attenuation value.renal pelvis dilatation without dilatation of calyces, moderate hydronephrosis was defined as dilatation of renal pelvis and calyces without parenchymal atrophy, and severe hydronephrosis was defined as gross dilatation of renal pelvis and calyces with parenchymal atrophy[Degree of hydronephrosis was defined as mild, moderate and severe. Mild hydronephrosis was defined as l atrophy.Functional solitary kidney was defined as either a history of contralateral nephrectomy or by confirmation of poor split renal function with radionuclide imaging method.2 test. Risk factor analysis was performed using univariate and multivariate logistic regression analyses. Variables showing statistical significance of the univariate analysis were included in the multivariate logistic regression analysis, and the forward stepwise method was used to select the variables that were eventually included in the model.Our analysis showed that the measurement data in this study were not normally distributed. Therefore, the measurement data were expressed as medians (quartiles), and the count data were expressed as frequencies (percentages). The measurement data were analyzed using the Mann-Whitney U test, and the count data were analyzed using the χBased on the regression coefficients of independent variables, we established the individualized nomogram prediction model of ureteral calculi associated with urosepsis , 21. TheThe calibration of prediction model refers to the concordance between the predicted and observed probabilities. A novel statistical test, the GiViTI calibration belt was introduced into the development group and validation group to investigate the goodness of fit of the prediction model. The GiVStatistical analysis was performed using SPSS software , MedcCalc software  and R software . The ROC curve was plotted using MedCalc software, and the GiViTI calibration belt was drawn by RMS-package. Two-tailed analysis with P<0.05 indicated that the difference was statistically significant.In this study, a total of 1064 patients were enrolled, including 747 in the development group and 317 in the validation group. There were 591 males and 473 females (aged 53 years(43–63 years)). A total of 106 patients had diabetes, 272 cases had hypertension, and 241 cases had previous surgery for calculi. The average length of calculi size was 10(7 ~ 14) mm, the average width of calculi size was 6(5 ~ 8) mm, and the mean CT attenuation value of calculi was 399.0(237.5 ~ 649.75) HU. There were 545 cases with calculi located on the left side, and there were 519 cases with calculi located on the right side. There were 544 cases with upper ureteral calculi, 156 cases with middle ureteral calculi, and 364 cases with lower ureteral calculi. A total of 451 cases had ipsilateral renal calculi. The mean CT attenuation value of hydronephrosis was 3(1 ~ 7) HU, and the numbers of cases with functional solitary kidney, mild hydronephrosis, moderate hydronephrosis, severe hydronephrosis, positive urine WBC count and positive urine nitrite are listed below .Comparison of the baseline data indicated that the development and validation groups showed no significant differences in the general situation of patients, characters of ureteral calculi, ipsilateral kidney characteristics, and other indicators.Univariate analysis of the development group showed that the statistically significant risk factors were gender, age, diabetes mellitus, hypertension, previous surgery for calculi, functional solitary kidney, length of calculi size, width of calculi size, mean CT attenuation value of calculi, location of calculi, associated ipsilateral renal calculi, mean CT attenuation value of hydronephrosis, urine WBC count and urine nitrite (P<0.05), whereas the laterality of calculi and degree of hydronephrosis were not related to urosepsis.Statistically significant variables screened from the univariate analysis were included in the non-conditional binary multivariate logistic regression. The five factors of gender, mean CT attenuation value of hydronephrosis, functional solitary kidney, urine WBC count and urine nitrite were independent risk factors of ureteral calculi associated with urosepsis  (P<0.05)Based on the logistic multivariate regression analysis, the five independent risk factors were included in the prediction model. We then establish an individualized nomogram prediction model of ureteral calculi associated with urosepsis . The appFor example, an elderly female patient with ureteral calculi (47 points) had a mean CT attenuation value of ipsilateral hydronephrosis at 16 HU (71 points), an urine WBC count +++ (100 points), negative urine nitrite (0 points), and unilateral renal atrophy in CT (34 points). The cumulative score of the various prediction indicators was 47 +71 +100 +0 +34 = 252, and the corresponding predicted risk of urosepsis was 0.92 (92%) . AccordiThe validation of the model was based on discrimination and calibration. We drew the ROC curves of predicted probability and calculated the AUC values in the development and validation group . The ROCThe AUC values for urosepsis risk of the development group and validation group were 0.914 and 0.874  respectiThe 95% CIs of GiViTI calibration belt in both development and validation groups did not cross the diagonal bisector line, and the P-value in GiVITI calibration test of the two groups were 0.247 and 0.176 respectively . TherefoUrosepsis is a form of sepsis caused by urinary tract infection , 17, accPreviously, it was believed that sepsis is a systemic response to infection. And the signs and symptoms of systemic inflammatory response syndrome (SIRS), which were initially considered to be compulsive diagnosis of sepsis , 27, areGender is an independent risk factor of urosepsis in patients with ureteral calculi, i.e., the risk of urosepsis in female patients with ureteral calculi is approximately 4.5 times that of male patients. Some other published literature had the same viewpoint , 30. HowThe CT attenuation value is the value corresponding to the X-ray attenuation coefficient of various organs in CT images and can be used to determine the density of local tissues or organs of the human body. A higher mean CT value of renal hydronephrosis suggests denser and more viscous liquid accumulation in hydronephrosis, and therefore, a greater possibility of pyonephrosis. Pyonephrosis usually indicates the presence of urinary tract obstruction. Long-term chronic obstruction causes severe local infection, and upon the presence of predisposing factors, the risk of urosepsis naturally increases. Yuruk et al.  showed tThis study also showed that the two urine-related detection indicators were closely related to urosepsis and that there was no collinear relationship between urinary WBC count and urine nitrite. Consistent with previous studies, the above results in our study indicated that the two indicators were independent risk factors for ureteral calculi associated with urosepsis , 11, 14.If both of the two indicators are positive, and the urine WBC count is +++, the total score of the nomogram is 148(100+48), suggesting that positive urine infection indicators can increase the urosepsis risk of patients with ureteral calculi by 53% (148/280). Such patients often have more severe urinary tract infections, and if the calculi suddenly move downward or if the patients receive minimally invasive endoscopic surgery, there can be a sudden increase in renal pelvic pressure. Calculi and iatrogenic procedures may cause mechanical damages to ureteral mucosa and nourishing veins, mucosal barrier function is destroyed, and turbid urine suddenly enters the blood via reflux mechanisms, such as renal pelvis-lymphatic vessels, renal pelvis-vein, renal pelvis-renal sinus, and renal pelvis-renal tubules . As a reIn clinical practice, we should have a systematic and comprehensive understanding of the urine test indicators and cannot just stay in the level of the diagnosis of general urinary tract infections. We should consider whether patients have pathogenic factors leading to complex urinary tract infections, whether patients have a risk of urosepsis and other serious complications, and how to avoid recurrence of urinary tract infection and reduce the recurrence rate.In addition, we cannot ignore patients suffered from ureteral calculi with negative urine examination results . Some paPatients with functional solitary kidney often have varying degrees of renal insufficiency but have not yet reached the hemodialysis indications. Once ureteral calculi cause obstruction, these patients would show rapid deterioration of renal function within a short time frame and would present with acute renal failure , 38. If The nomogram we developed can be applied for both outpatients and inpatients with ureteral calculi, not only in those inpatients who are ready to undergo surgery. The nomogram is a beneficial supplementary tool for clinical work, and it also makes patients more aggressive in the decision-making process with regard to their diagnosis and treatment.There are also shortcomings in this study. (1) It is a retrospective study, which cannot avoid selection bias. However, we strictly set the inclusion criteria and collected relatively adequate clinical samples so that the case and control groups of patients can truly reflect the actual condition of disease occurrence. (2) The data for the prediction model were derived from a single center. Although we used patient samples from different periods to validate the model, we still need evidence from other centers for validation. Therefore, in the follow-up research work, we will persuade other medical centers to join this research project and will provide the appropriate clinical data to conduct a more in-depth assessment and validation of the prediction model.We established an individualized nomogram prediction model for ureteral calculi developing into urosepsis. Through this prediction model, we can accurately predict the risk of urosepsis in patients with ureteral calculi, which helps to improve the early identification and screening of such high-risk patients.S1 FileThe raw dataset of development group.(SAV)Click here for additional data file.S2 FileThe raw dataset of validation group.(SAV)Click here for additional data file.


Increased numbers of blood and sputum eosinophils are associated with higher exacerbation frequency and increased asthma severity. In clinical trials, targeting Interleukin-5 has been shown to be a useful therapeutic strategy for patients with severe eosinophilic asthma.Twenty-six patients have been commenced on Reslizumab in our institution since early 2017. Safety and clinical efficacy parameters were recorded at regular intervals.Mean ACQ-6 score at the start of treatment was 3.5. The average number of exacerbations in the year preceding treatment was 8.3 per person. 30% of patients had been admitted to hospital at least once over the 12 months preceding therapy. 54% of our patients were on long term oral steroid.P = 0.0001). Of the patients who were on long term systemic steroids, 35.7% discontinued steroids completely, with a mean reduction of prednisolone dose of 5.2 mg at 1 year. There was a 79% reduction in the annual exacerbation frequency at 1 year, and 88% at 2 years (P = < 0.0001). Modest, albeit statistically significant increases in creatine kinase which seemed to plateau by 1 year were noted.Our data showed sustained improvement of Asthma control (Mean improvement in ACQ-6 was 1.7 at 1 year, and 2.0 at 2 years, Overall, Reslizumab was well tolerated with discontinuation of treatment due to side effects recorded in only one patient. Our data confirm the utility of anti-IL5 therapy in a carefully selected phenotype of severe asthma with evidence of eosinophilic airway inflammation. A subset of patients with asthma remain uncontrolled with conventional therapy. Approximately 5–10% of asthmatics have severe asthma . Severe Interleukin-5 [IL-5] is a major regulator of eosinophil survival and activity in tissues. It has been shown to mediate late stage maturation of eosinophils from eosinophil lineage-committed progenitors through IL-5R .In clinical trials, targeting IL-5 has been shown to be a useful therapeutic strategy for patients with severe asthma. Currently available anti IL-5 monoclonal antibodies are benralizumab, reslizumab and mepolizumab. Benralizumab, a monoclonal antibody directed against the alpha subunit of the IL-5 receptor, has shown significant and clinically relevant reduction in the dose of oral glucocorticoids and a significant reduction in exacerbation rate . MepolizReslizumab is a humanized monoclonal antibody directed against Interleukin-5. It binds specifically to IL-5 thereby blocking its biological effects including recruitment and activation of human eosinophils. Clinical trials have shown that reslizumab treatment in patients with severe asthma and evidence of peripheral eosinophilia was well tolerated and provided improvement in terms of lung function, clinical asthma exacerbation, and quality of life –11. HereTwenty-six patients have been commenced on reslizumab in our institution since early 2017.9/L), on high dose inhaled steroids and a second controller, and had at least 4 exacerbations (that required systemic steroids or an increase in maintenance steroid dose), 1 hospitalisation or a requirement for maintenance oral steroid for > 6 months over the year preceding treatment. As this was an early access programme the majority of our cohort had more severe asthma than these criteria.This was an early access programme for patients. At a minimum inclusion criteria were; inadequately controlled asthma (ACQ-6 score > 1.5), elevated peripheral blood eosinophils count (> 0.4 cells X 10Reslizumab was administered as an intravenous [IV] infusion (3 mg/kg) every 4 weeks and in accordance with the product license. Reslizumab was provided by Teva Pharmaceuticals as part of a named patient / early access programme. Asthma control (ACQ), glucocorticoid dose, exacerbation history, and FEV1 were recorded prior to commencing treatment and at regular intervals to assess clinical effectiveness as is standard practice in our institution.SD ± 13.5). 62% of patients were female. Mean ACQ-6 score at the start of treatment was 3.5 (SD ± 1.1), average percent of forced expiratory volume in 1 s (FEV1) predicted value was 62% (SD ± 20%), and average absolute peripheral blood eosinophil count was 0.79 (SD ± 0.52) cells X 109/L.The mean age at the start of treatment was 52 years (SD ± 4.3) mg. The average number of exacerbations in the year preceding treatment (that required systemic steroids or an increase in maintenance steroid dose) was 8.3 per person. 30% of patients had been admitted to hospital at least once over the 12 months preceding therapy. .There were significant improvements in asthma symptoms and control assessed using ACQ-6 score at baseline and after 3 months on treatment, with mean ACQ-6 score improved from 3.5 at base line to 1.8 at 3 months (P = 0.0001). , and mean improvement was 12.1% at 2 years (P = 0.002) , No further improvement was noted at 2 years of treatment compared to 1 year . Furthermore, there was 88% reduction in the annual exacerbation frequency in the patients who completed 2 years of treatment  was 8.3 per person. There was a 79% reduction in the annual exacerbation frequency in the patients who completed 1 year of treatment, with 47% having no exacerbations. (P < 0.0001) , and 160.5 U/L at 1 year (p = 0.031). The normal range for creatine kinase in our institution is 40–180 U/L.Only one patient has discontinued treatment due to an adverse event [AE] - an allergic skin rash which disappeared after cessation of reslizumab.Treatment discontinued in 5 other patients. One patient, although treatment resulted in a significant improvement in her asthma control, reslizumab was discontinued as she was actively planning to attempt to conceive. In 4 patients treatment was withdrawn due to lack of therapeutic benefit.Our real-world data confirm the positive findings of clinical trials –11. ImprOur 2 years data showed a significant reduction in asthma exacerbations (88% reduction in patients who have completed 2 years of treatment), noting reslizumab Phase 3 clinical trials in poorly controlled asthma were not designed to assess asthma exacerbations as an end point given the short duration of the clinical trials , 10. A 5While small improvements in lung function were noted in patients on resluzimab after 3 months these were not significant, but both 1 year and 2 year data showed significant improvement in lung function . This suggests that the largest improvements in FEV-1 are within the first 12 months of treatment although maintained thereafter.Overall, Reslizumab was well tolerated with discontinuation of treatment due to side effects recorded in only one patient. Modest, albeit statistically significant increases in creatine kinase which seemed to plateau by 1 year were noted. The exact aetiology of this increase is unclear. The subgroup of 4 patients who displayed no clinical response to therapy had more frequent exacerbations (10.7 per year vs 8.3), worse lung function (FEV1 49% vs 62%), and baseline asthma control (ACQ 4.3 vs 3.5) compared to the overall study group. Baseline eosinophil count was similar to the studied group, and interestingly none of these patients were on long term steroids. The treatment resulted in significant depletion of eosinophils in these patients, but this wasn’t reflected by a clinical response suggesting that poor asthma control in this subgroup of patients wasn’t entirely driven by eosinophilic airway inflammation.Our data confirm the utility of anti-IL5 therapy in a carefully selected phenotype of severe asthma with evidence of eosinophilic airway inflammation.