Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

BACKGROUND: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. METHODS: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. RESULTS: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. CONCLUSIONS: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Cardio-ankle vascular index for predicting cardiovascular morbimortality and determinants for its progression in the prospective advanced approach to arterial stiffness (TRIPLE-A-Stiffness) study.

BACKGROUND: The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression. METHODS: TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81-4.69) years. FINDINGS: Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03-1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10-1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542-0.654) and 8.30 (c-index 0.565; 0.512-0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI. INTERPRETATION: The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments. FUNDING: International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.

When Pulmonary Arterial Hypertension may be Associated with Portal Hypertension: A Case Report of Two Different Hepatic Disorders in One Patient with Pulmonary Hypertension.

BACKGROUND: pulmonary arterial hypertension (PAH) is a rare complication of hepatic diseases with portal hypertension that, however, has a significant influence on prognosis. We present a mini-review of how to diagnose and treat it based on a clinical case. CASE PRESENTATION: in early childhood, a patient had portal hypertension associated with cavernous transformation of the portal vein. It was successfully treated by reno-splenic surgery. At the age of 20 years, this patient experienced increased dyspnea at minimal physical activity after the hepatic biopsy due to a hepatocellular adenoma. The examination in the specialized unit showed PAH, which was evaluated as associated with portal hypertension (PAH-PoH). The specific two-drug combination therapy was started with prominent improvement in patient's state. Successful surgical tumor treatment was provided some months later. The practical and clinical approaches to the diagnosis and treatment of PAH-PoH are discussed. It was emphasized that not all patients with portal hypertension have pulmonary hypertension, which needs to be treated. A lot of evidence gaps exist in management of these patients. CONCLUSION: all patients, even with past history of portal hypertension, should be monitored closely and screened for PAH earlier, for better results of treatment.

"The impact of statins addind to the fixed combination antihypertensive therapy on the arterial stiffness in patients with moderate and severe hypertension".

Aim: The objective of this study was the evaluation of the arterial stiffness, which changed after adding statins to the guidelines recommended dual or triple fixed combination antihypertensive therapy in patients with moderate to severe arterial hypertension. Materials and methods: It was included 99 patients in total being diagnosed with moderate and severe arterial hypertension (2nd and 3rd stages of arterial hypertension) without diabetes. Those patients were divided into 2 groups. The first group (n = 59) was assigned to the dual or triple fixed combination antihypertensive therapy plus including statins.Patients in the second group (n = 40) received only the dual or triple fixed combination antihypertensive treatment following the recommended guidelines without any statins. The CAVI index was performed in order to measure in all participants before and at the end of the follow-up period. Furthermore, the Office (Clinic BP) Blood Pressure (BP) was monitored in assigned participants as well as the Ambulatory Blood Pressure Monitoring (ABPM). The laboratory investigations also took place such as the standard blood test, the urine and biochemistry analysis and the estimated Carotid Intima-Media Thicknesses with Ultrasound. The study-duration was 6 months. Results: Office BP and ABPM had decreased significantly and equally in both treatment groups. The total cholesterol (TC) and LDL cholesterol had decreased significantly in the statin group on 1,76 mmol/l (30%, p < 0,05) and 1,51 mmol/l (41%, p < 0,05) respectively. In the group without statin therapy, there was no changes in the level of TC and LDL cholesterol. In the group without statins, it was noted a significant decrease in the level of BP, however, the CAVI index level was shown the growth to +0,9 units on the right side and +1,0 units on the left.In the group without statin's treatment, the CAVI index was changed from 7.73 ± 0.17/7.62 ± 0.19 units to 8.63 ± 0.22/8.62 ± 0.12 units on the right/left site after treatment (p < 0,05). It means there was an increase in the stiffness of the arterial wall in terms of cardio-vascular index CAVI in the group without added statin after 6 months of the therapy. In the group with added statin after 6 months of the therapy, the CAVI had not have any changes. It can be seen from the observed figures: the CAVI on the right/left site was 8.32 ± 0.16/8.33 ± 0.19 initially and 8.44 ± 0.16/8.24 ± 0.15 units treatment (p > 0,05) afterwards.We did not note any impact of statin therapy on the BP level. However, a significant correlations was found between the CAVI index with age and the serum level of blood Triglycerides before treatment, including LDL Cholesterol and HDL Cholesterol, duration of hypertension, the blood glucose level, the Potassium level and the Maximum Thickness of Intima-Media of Carotid Arteries in the statins group. Conclusion: The adding of the statin to the current fixed dual or triple combination of the antihypertensive therapy could prevent the progression of arterial stiffness in patients with 2nd and 3rd stages of arterial hypertension.

Pulmonary Vascular Research Institute GoDeep: A meta-registry merging deep phenotyping datafrom international PH reference centers.

The Pulmonary Vascular Research Institute GoDeep meta-registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta-registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty-nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface-based automated retrospective and prospective data transfer, GoDeep aims to provide in-depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Ventricular Function and Cardio-Ankle Vascular Index in Patients With Pulmonary Artery Hypertension.

Aim: This study aims to evaluate the left ventricle (LV) systolic and diastolic function in patients with idiopathic pulmonary arterial hypertension (IPAH) and its correlation with systemic arterial stiffness assessed by cardio-ankle vascular index (CAVI). Patient and methods: We included 37 patients with IPAH and 20 healthy people matched by age. All patients were assessed: vital signs, 6-minute walk test, NT-proBNP level, the CAVI, the right ventricular (RV) and LV function parameters, including ejection time (ET), tissue speckle-tracking values - global longitudinal strain (GLS) and strain rate (SR). Results: The groups were matched by age, gender, BMI, office SBP and DBP. Patients with IPAH had higher heart rate, NT-proBNP level and lower ferritin level, GFR (CKD-EPI), SaO2 than healthy people. The mean CAVIleft was higher in IPAH patients than in the control group- 8.7±1.1 vs 7.5±0.9, P=0.007. Healthy people had significantly less E/e' and lower IVRT. LVET and RVET were shorter in IPAH patients. Patients with IPAH had mean LVGLS -(-17.6±4.8%) and 35.1% of them were with LVGLS ≤16% compared to healthy people -(-21.8±1.4%) and 0%, respectively. LVSR was significant less in IPAH patients, but in the normal range. We found significant correlations of CAVI with age, history of syncope, bilirubin, uric acid, total cholesterol, cardiac output, cardiac index, RVET, LVET and E/A. Multiple linear regression confirmed the independent significance for age (ß=0.083±0.023, CI 0.033-0.133) and RVET (ß=-0.018±0.005, CI -0.029 to -0.008) only. The risk to have CAVI ≥8 increased in 5.8 times in IPAH patients with RVET <248 ms (P=0.046). CAVI did not correlate with LVGLS and LVSR. Conclusion: Significant worse systolic and diastolic LV functions were stated in pulmonary hypertensive patients compared to the control group. No LV GLS, no LV SR had significant associations with arterial stiffness evaluated by CAVI.

Prognostic Significance of Systemic Arterial Stiffness Evaluated by Cardio-Ankle Vascular Index in Patients with Idiopathic Pulmonary Hypertension.

BACKGROUND: In a previous study, the cardio-ankle vascular index (CAVI) was increased significantly in idiopathic pulmonary arterial hypertension (IPAH) patients compared to the healthy group and did not much differ from one in systemic hypertensives. In this study the relations between survival and CAVI was evaluated in patients with IPAH. PATIENTS AND METHODS: We included 89 patients with new-diagnosed IPAH without concomitant diseases. Standard examinations, including right heart catheterization (RHC) and systemic arterial stiffness evaluation, were performed. All patients were divided according to CAVI value: the group with CAVI ≥ 8 (n = 18) and the group with CAVI < 8 (n = 71). The mean follow-up was 33.8 ± 23.7 months. Kaplan-Meier and Cox regression analysis were performed for the evaluation of our cohort survival and the predictors of death. RESULTS: The group with CAVI≥8 was older and more severe compared to the group with CAVI< 8. Patients with CAVI≥8 had significantly reduced end-diastolic (73.79±18.94 vs 87.35±16.69 mL, P<0.009) and end-systolic (25.71±9.56 vs 33.55±10.33 mL, P<0.01) volumes of the left ventricle, the higher right ventricle thickness (0.77±0.12 vs 0.62±0.20 mm, P < 0.006), and the lower TAPSE (13.38±2.15 vs 15.98±4.4 mm, P<0.018). RHC data did not differ significantly between groups, except the higher level of the right atrial pressure in patients with CAVI≥ 8-11.38±7.1 vs 8.76±4.7 mmHg, P<0.08. The estimated overall survival rate was 61.2%. The CAVI≥8 increased the risk of mortality 2.34 times (CI 1.04-5.28, P = 0.041). The estimated Kaplan-Meier survival in the patients with CAVI ≥ 8 was only 46.7 ± 7.18% compared to patients with CAVI < 8 - 65.6 ± 4.2%, P = 0.035. At multifactorial regression analysis, the CAVI reduced but saved its relevance as death predictor - OR = 1.13, CI 1.001-1.871. SUMMARY: We suggested the CAVI could be a new independent predictor of death in the IPAH population and could be used to better risk stratify this patient population if CAVI is validated as a marker in a larger multicenter trial.

Systemic Arterial Stiffness in New Diagnosed Idiopathic Pulmonary Arterial Hypertension Patients.

OBJECTIVE: We suggested: 1) patients with idiopathic pulmonary hypertension (IPAH) have active factors which could damage not only the pulmonary but systemic arteries too as in arterial hypertensive patients; 2) if these changes were present, they might correlate with other parameters influencing on the prognosis. This study is the first attempt to use cardio-ankle vascular index (CAVI) for the evaluation of systemic arterial stiffness in patients with IPAH. METHODS: A total of 112 patients were included in the study: group 1 consisted of 45 patients with new diagnosed IPAH, group 2 included 32 patients with arterial hypertension, and in the control group were 35 healthy persons adjusted by age. Right heart catheterization, ECG, a 6-minute walk test (6MWT), echocardiography, blood pressure (BP) measurement and ambulatory BP monitoring, pulse wave elastic artery stiffness (PWVe; segment carotid-femoral arteries) and muscular artery stiffness (PWVm; segment carotid-radial arteries), CAVI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level were provided. The Spearman correlation, a linear regression and multivariable binary logistic analysis were performed to indicate the predictors associated with PWV and CAVI. RESULTS: The groups were adjusted for principal characteristics influenced on arterial stiffness. IPAH patients had significantly (P<0.001 for all) shorter 6MWT distance and higher Borg dyspnea score than the patients with arterial hypertension (systolic/diastolic BP = 146.1±10.7/94.2±9.8 mmHg) and the control group = 330.2±14.6 vs 523.8±35.3 and 560.9±30.2 m respectively and 6.2±1.8 vs 1.2±2.1 and 0.9±2.8 points. The PWVm and PWVe were the highest in hypertensive patients (10.3±1.5 and 11.42±1.70 m/s). The control group and IPAH did not have significant differences in aorta BP, but PWVm/PWVe values were significantly (P<0.003/0.008) higher in IPAH patients than in the control group (8.1±1.9/8.49±1.92 vs 6.63±1.34/7.29±0.87 m/s). The CAVIs on both sides were significantly lower in the healthy subjects (5.91±0.99/5.98±0.87 right/left side). Patients with IPAH did not differ from the arterial hypertension patients by CAVIs in comparison with the control group (7.40±1.32/7.22±1.32 vs 7.19±0.78/7.2±1.1 PWVe) did not correlate with any parameters except uric acid. PWVm correlated with uric acid (r=0.58, P<0.001), NT-proBNP (r=0.33, P=0.03) and male gender (r=0.37, P=0.013) at Spearman analysis, but not at multifactorial linear regression analysis. The CAVI correlated with age and parameters characterized functional capacity (6MWT distance) and right ventricle function (NT-proBNP, TAPSE) at Spearman analysis and with age and TAPSE at multifactorial linear regression analysis. At binary logistic regression analysis CAVI > 8.0 at right and/or left side had a correlation with age, 6MWT distance, TAPSE, but an independent correlation was only with age (ß=1.104, P=0.008, CI 1.026-1.189) and TAPSE (ß=0.66, P=0.016, CI 0.474-0.925). CONCLUSION: In spite of equal and at normal range BP level, the age-adjusted patients with IPAH had significantly stiffer arteries than the healthy persons and they were comparable with the arterial hypertensive patients. Arterial stiffness evaluated by CAVI correlated with age and TAPSE in IPAH patients. Based on our results it is impossible to conclude the pathogenesis of arterial stiffening in IPAH patients, but the discovered changes and correlations suggest new directions for further studies, including pathogenesis and prognosis researches.

Analysis of pulmonary hypertension patient survival after treatment in referral center (data of first Ukrainian register).

The aims of the study were: (1) to evaluate the Ukrainian reality of survival in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH); and (2) to determine predictors of death. A total of 281 patients were enrolled (52 [18.5%] with CTEPH, 229 [81.5%] with PAH). Long-term survival (Kaplan-Meier) and its predictors (Stepwise binary logistic regression and Cox's proportional hazards analyses) were evaluated in adult patients with PH (diagnosed by right heart catheterization [RHC]) within a prospective registry at a single referral center in Kyiv, Ukraine. Follow-up period was up to 51 months. The Kaplan-Meier survival rate for the total cohort was 93.3%, 86.8%, and 81.5% at one, two, and three years, respectively. Survival was better in patients with congenital heart diseases (CHD) in comparison with idiopathic PAH (long rank P = 0.002), connective tissue diseases (CTD; long rank P = 0.001) and CTEPH (long rank P = 0.04). Univariate Cox's predictors of death were: functional class IV (odds ratio [OR] = 4.94; 95% confidence interval [CI] = 2.12-11.48), presence of ascites (OR = 4.52; 95% CI = 2.21-9.24), PAH-CTD (OR = 3.07; 95% CI = 1.07-8.87), PAH-CHD (OR = 0.28; 95% CI = 0.11-0.68), HR on treatment > 105 beats per min (OR = 7.85; 95% CI = 1.83-33.69), office systolic BP < 100 mmHg (OR = 2.78; 95% CI = 1.26-6.1), 6MWT on treatment < 340 m (OR = 3.47; 95% CI = 1.01-12.35), NT-proBNP > 300 pg/mL (OR = 4.98; 95% CI = 1.49-16.6), right atrium square > 22 cm2 (OR = 14.2; 95% CI = 1.92-104.89), right ventricular square in diastole (OR = 1.08; 95% CI = 1.03-1.14), right ventricular square in systole (OR = 1.08; 95% CI = 1.02-1.11), mean pressure in right atrium per each 1-mmHg increase (OR = 1.02; 95% CI = 1.02-1.19). In multivariate Cox regression analyses only presence of ascites, office systolic BP < 100 mmHg, CHD etiology of PH, and NT-proBNP > 300 pg/mL were associated with survival.

Influence of fixed-dose combination perindopril/amlodipine on target organ damage in patients with arterial hypertension with and without ischemic heart disease (results of EPHES trial).

BACKGROUND: The EPHES trial (Evaluation of influence of fixed dose combination Perindo-pril/amlodipine on target organ damage in patients with arterial HypErtension with or without iSchemic heart disease) compared the dynamics of target organ damage (TOD) in hypertensive patients with and without ischemic heart disease (IHD) treated with the fixed-dose combination (FDC) perindopril + amlodipine. METHODS: The analysis included 60 hypertensive patients (aged >30 years): 30 without IHD and 30 with IHD. At randomization, FDC was administered at a daily baseline dose of 5/5 mg with uptitration to 10/10 mg every two weeks. If target blood pressure (BP<140/90 mmHg) was not achieved after six weeks, indapamide 1.5 mg was added to the regimen. All patients underwent body mass index measurements, office and ambulatory BP measurements, pulse wave velocity (PWVe) and central systolic BP evaluation, augmentation index adjusted to heart rate 75 (Aix@75) evaluation, biochemical analysis, ECG, echocardiography with Doppler, ankle-brachial index measurement, and intima-media thickness measurement. The follow-up period was 12 months. RESULTS: Therapy based on FDC perindopril/amlodipine was effective in lowering BP (office, ambulatory, central) in both groups. We noted significant decrease in Aix@75 with the therapy in both groups, but ΔAix@75 was lesser in the group with IHD than the group without IHD. FDC provided significant improvement in PWVe and left ventricular diastolic function, and decrease in albuminuria, left ventricular hypertrophy (LVH), and left atrium size. ΔPWVe was significantly (P<0.005) less in patients without IHD than those with IHD (2.5±0.2 vs 4.4±0.5 m/s, respectively). In spite of almost equal LVH regression, the positive dynamics of ΔE/A and ΔE/E´ were more in patients with IHD than those without IHD (64.4% and 54.1% vs 39.8 and 23.2%, respectively; P<0.05 for both comparisons). Adverse reactions were in 2 (6.5%) patients without IHD and 3 (10%) with IHD (P=NS). In the group with IHD, we noted significant decrease in angina episode rate - from 2.5±0.4 to 1.2±0.2 (P<0.01) per week. CONCLUSION: Thus, treatment based on FDC was effective in decreasing BP and TOD regression in both patients with and without IHD. However, the dynamics of changes in TOD were different between the two groups, which should be taken into consideration during management of patients with and without IHD.

Effects of metabolic syndrome on arterial function in different age groups: the Advanced Approach to Arterial Stiffness study.

OBJECTIVE: The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. METHODS: This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health & Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. RESULTS: Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P < 0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r = 0.06, P < 0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57 ±â€Š0.06 vs. 8.65 ±â€Š0.10, P < 0.001; CAVI: 8.34 ±â€Š0.03 vs. 8.29 ±â€Š0.04, P = 0.40; mean ±â€ŠSEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. CONCLUSION: This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF-PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study.

The efficacy and safety of valsartan and a combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension: a subgroup analysis of the effect of valsartan and its combination with .

BACKGROUND AND AIM: The aim of the study was to establish the effect of valsartan and combination of valsartan and hydrochlorothiazide (HCTZ) on pulse wave velocity (PWV) and central blood pressure (CBP) in a large population of patients with mild to moderate arterial hypertension. METHODS: This was an international, multicentre, open-label, prospective trial. After one week of washout in previously treated patients, 74 subjects were treated with valsartan or valsartan combined with HCTZ for 16 weeks according to the protocol. Naïve patients received the treatment immediately. During the active treatment, four visits were planned for each patient to obtain data for the primary and secondary efficacy. At the beginning and at the end of the study PWV and CBP were determined with central arterial pressure waveform analysis (SphygmoCor®, Atcor Medical). This study is registered with clinicaltrialsregister.eu, EudraCT number 2012-005129-57. RESULTS: The results of the present VICTORY trial showed that valsartan and combination of valsartan and HCTZ effectively reduced the brachial blood pressure in patients with mild to moderate arterial hypertension as well as PWV, central systolic blood pressure and central diastolic blood pressure. The effects on the augmentation index were not statistically significant. CONCLUSIONS: Valsartan and valsartan/HCTZ improve arterial stiffness in patients with mild to moderate hypertension.

Impact of Statin Therapy on the Blood Pressure-Lowering Efficacy of a Single-Pill Perindopril/Amlodipine Combination in Hypertensive Patients with Hypercholesterolemia.

INTRODUCTION: Several lines of research indicate that statins can lower blood pressure (BP) independently of their lipid-lowering effects when used as monotherapy and in combination with antihypertensive agents. AIM: This short-term, open-label study examined whether statin therapy had a synergistic effect on the BP-lowering efficacy of perindopril/amlodipine in a subgroup of patients in the PERSPECTIVA study with concomitant hypertension and hypercholesterolemia, with or without statin at baseline. METHODS: The PERSPECTIVA study recruited 732 adults with untreated or uncontrolled hypertension. This subgroup analysis of PERSPECTIVA included 587 patients with concomitant hypertension and hypercholesterolemia (mean age 56.7 years) of whom 226 were receiving a statin at baseline (statin [+] group) and 361 were not (statin [-] group). All patients received treatment with single-pill combination perindopril/amlodipine at a dose of 5/5, 10/5 or 10/10 mg/day. The study duration was 60 days with follow-up visits for BP monitoring at 7, 15, 30 and 60 days. RESULTS: At day 60, BP control (<140/90 mmHg) was significantly greater in the statin [+] vs statin [-] group: 73 vs 64% respectively (+14%, P < 0.05). In the statin [+] group, the single-pill perindopril/amlodipine combination significantly reduced BP in patients previously untreated (n = 18), or treated with monotherapy (n = 97), dual therapy (n = 93), or triple therapy (n = 18): -38.8/-20.0, -39.1/-20.1, -38.0/-19.4, -39.9/-18.3 mmHg respectively (P < 0.001 vs baseline BP). The greatest BP reductions were observed in the first 7 days. Treatment was well tolerated with a similar rate of adverse events in the statin [+] group (0.9%) vs the statin [-] group (2.5%). CONCLUSION: BP control rates in patients with uncontrolled hypertension and concomitant hypercholesterolemia are significantly improved with a treatment regimen that combines perindopril/amlodipine with statin therapy, regardless of previous antihypertensive therapy. This subanalysis of the PERSPECTIVA study supports the synergistic BP-lowering effect of statins and perindopril/amlodipine.

The efficacy and safety of valsartan and combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension - the VICTORY trial.

BACKGROUND AND AIM: The aim of the trial was to establish the efficacy and safety of Valsacor® (valsartan) and Valsacombi® (combination of valsartan and hydrochlorothiazide) in a wide variety of patient populations with mild to moderate arterial hypertension. METHODS: We performed an international, multicentre, open-label, prospective trial. After one week of washout in previously treated patients, the patients were treated for 16 weeks according to the protocol. Naïve patients entered the treatment period immediately. During the active treatment, four visits were planned for each patient to obtain the data for the primary and secondary efficacy endpoints analysis. The principal methods were blood pressure (BP) measurement, additionally in a subgroup of patients, assessment of erectile function. The initial dosage of valsartan 80 mg/day was titrated up to 320 mg/day to achieve the BP goal, with the addition of hydrochlorothiazide (HCTZ) in a fixed-dose combination (FDC), if needed. RESULTS: Mean ± standard deviation changes from baseline at week 16 were -26.6 ± 10.4 mm Hg (systolic BP) and -14.8 ± 7.6 mm Hg (diastolic BP). A total of 91% of the patients treated with either valsartan or valsartan FDC achieved the BP goal. Adverse reactions were experienced by 7.1% of the patients, with the most common being headache (1.9%), palpitation (1.6%), dizziness (1.6%), and fatigue (1.6%), during the whole trial. CONCLUSIONS: The results of the VICTORY trial show that valsartan and valsartan FDC effectively reduce the BP in patients with mild to moderate arterial hypertension and have a good tolerability profile.

Randomized evaluation of a novel, fixed-dose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a first-step treatment in hypertension.

OBJECTIVE: To evaluate perindopril 3.5 mg/amlodipine 2.5 mg once daily, a novel fixed-dose combination adapted for first-step treatment in patients with hypertension. This fixed dose had to be equivalent to amlodipine 5 mg in terms of blood pressure efficacy, but with an expected better tolerability profile. We selected two drugs with complementary modes of action, with doses chosen so that each drug would contribute similarly to the overall blood pressure-lowering effect METHODS: : An international, randomized, double-blind, placebo-controlled study with six equal parallel treatment arms and an 8-week randomized treatment period, whose design, clinical significance and non-inferiority criteria were in accordance with European guidelines. RESULTS: In all, 1581 patients with mild-to-moderate uncomplicated hypertension (mean age 51.7 years) were randomized and 94.7% completed the study. The combination was statistically and clinically superior to placebo (between-group differences: SBP: -7.22 mmHg, DBP: -4.12 mmHg, P < 0.001 for both). Rates of response and normalization of blood pressure were greater with the combination (P < 0.001 for both) and numerical differences relative to placebo were apparent at 2 weeks. The combination was superior to either component given singly (P < 0.001 for both drugs, for SBP and DBP), and was non-inferior to both component drugs given singly at their lowest clinically-approved doses. The components of the combination had similar effects on SBP (perindopril 3.5 mg: -16.3 mmHg; amlodipine 2.5 mg: -16.0 mmHg). Adverse events relating to peripheral oedema were less frequent with the combination than with amlodipine 5 mg. CONCLUSIONS: The observed blood pressure-lowering efficacy, rapidity of onset of effect and favourable safety profile of the combination perindopril 3.5 mg/amlodipine 2.5 mg indicate its potential suitability for use as first-step treatment in hypertension.

Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence.

BACKGROUND AND OBJECTIVES: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke. RESULTS: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak. CONCLUSION: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.

Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial.

BACKGROUND AND OBJECTIVES: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design. PROTOCOL DESIGN: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125  mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8  mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly. OUTCOMES: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety. SAMPLE SIZE CALCULATION: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

Current and future initiatives for vascular health management in clinical practice.

Central arterial structure and function comprise a primary determinant of vascular health, and are integral to the important concept of ventriculo-vascular coupling or interaction. Central aortic stiffening is a major influence on central blood pressure, and directly relates to coronary perfusion. The joint session of the International Society of Vascular Health (Eastern Region) and the Ukrainian Congress of Cardiology was held in Kiev, Ukraine, on September 23, 2011; it provided an expert forum to discuss arterial evaluations, clinical applications, and progress toward translating arterial protection into cardiovascular benefits. The conclusions of the expert panel were: 1. Aortic stiffness is not presently a treatment target but may be useful for substratifying cardiovascular risk in individuals in order to better target the intensity of conventional therapy, and it may be useful in assessing response to treatment. 2. Crosstalk between macro- and microcirculation in hypertension has important implications for pharmacological treatment. An antihypertensive regimen should abolish the vicious cycle between the increased resistance in the microcirculation and the increased stiffness of the larger arteries. Such treatment should be based on drugs with multiple actions on the vascular tree, or on drug combinations that target the various segments of the arterial system. 3. Several blood pressure-independent mechanisms of large artery stiffness exist. Future considerations for clinical understanding of large artery stiffness should involve new drugs and new evaluation methods - with a focus on vascular health, for the initiation of cardiovascular prevention, for newly designed studies for treatment evaluation, and for new studies of drug combinations. 4. Arterial stiffening is a sign of cardiovascular aging and is a major factor affecting the biomechanics of large arteries. Arterial stiffness is an attractive therapeutic target in terms of vascular aging. Healthy lifestyle, physical exercise, and smoking cessation are the most effective ways of preventing and treating early vascular aging. Long-term effects of cardiovascular drugs on arterial stiffness need to be further investigated. 5. The emerging clinical data on the cardio ankle vascular index (CAVI) technique of arterial health assessment is presented, showing that the CAVI is elevated in aging, coronary artery diseases, chronic kidney disease, hypertension, diabetes mellitus, smoking, and stress. The CAVI decreased with the administration of statins, angiotensin II receptor blocking agents, and calcium channel blockers. The CAVI is suggested as an important predictor of cardiovascular diseases. Future development of a clinical understanding of large artery stiffness is important and should include consideration of new drugs and new evaluation methods, with a focus on vascular health aimed at cardiovascular prevention.

Modeling and analysis of transients in periodic gratings. I. Fully absorbing boundaries for 2-D open problems.

Frequency domain methods allow us to simulate and study efficiently only some of the periodic structures that are widespread in optics and spectroscopy. Time domain approaches could be more effective, but their deployment is held back by a number of unsolved problems associated mainly with a proper truncation of the computation space in the so-called open problems. This paper is devoted to analysis of these problems in the 2-D case (infinite one-dimensionally periodic semitransparent and reflecting gratings in the field of pulsed E- and H-polarized waves).