[Fixed drug combinations in hypertension: a budget impact analysis for the Spanish Health System on the marketing of a fixed combination of olmesartan/amlodipine]. / Las combinaciones fijas en hipertensión: análisis de impacto presupuestario para el Sistema Nacional de Salud Español de la comercialización de la combinación fija de olmesartan/amlodipino.

OBJECTIVE: To carry out a budget impact analysis (BIA) of olmesartan/amlodipine (20/5, 40/5 and 40/10mg) marketed as a fixed combination (FC) in its approved indication for the National Health System (NHS). DESIG: We developed a decision tree model in order to estimate usual hypertension treatment algorithm in Spanish clinical practice. SETTINGS: The BIA has been developed from the perspective of the NHS for a period of 3 years (years 2010-2012). PARTICIPANTS: Spanish hypertensive population ≥ 35 years old. INTERVENTIONS: Introduction into the market of a fixed combination (FC) olmesartan/amlodipine in Spain. PRIMARY MEASURES: Expected costs to be assumed by the Spanish NHS (RRP-VAT) for hypertensive population able to be treated with the FC versus currently assumed costs by the NHS with free combination olmesartan and amlodipine. RESULTS: Estimated pharmaceutical costs in hypertensive population treated with olmesartan and amlodipine (2 pills) would be €25.2M (1(st) year), €26.4M (2011), €27.6M (2012), with a total 3-year period of €79.2M. According to patient tree model, the population able to be treated with FC would be 71,283 patients (2010), with a growth rate of 4.8% in the successive years, which supposes an annual cost of €21.2M (2010), €21.8M (2011) and €22.4M (2012), with a total 3-year period of €65.4M. The BIA shows savings of €13.8M in a total 3-year period. CONCLUSION: The BIA of FC olmesartan/amlodipine could generate net savings of €13.8M for the NHS in the period ranging from years 2010 to 2012.

[Prevalence of target organ damage and factors associated with cardiovascular events in subjects with refractory hypertension]. / Prevalencia de lesión de órganos diana y factores asociados a la presencia de episodios cardiovasculares en sujetos con hipertensión arterial refractaria.

OBJECTIVES: To asses the prevalence of target organ damage (TOD) and factors associated with cardiovascular events in subjects with refractory hypertension. PATIENTS AND METHODS: Cross-sectional study of 146 patients with clinical diagnosis of refractory hypertension. TOD was defined as the presence of microalbuminuria (MA), renal failure (RF), left ventricular hypertrophy (LVH) or left atrial enlargement (LAE). Cardiovascular events were defined as the antecedent of stroke, coronary heart disease, heart failure or peripheral arterial disease. 24-h ambulatory blood pressure monitoring was (ABPM) performed with a validated Spacelabs 90207. RESULTS: The prevalence of LVH was 62.3%, and LAE was observed in 27.7% of the subjects. The prevalence of RF was 28.1% and MA was found in 41,4%. An association between MA and LVH was observed. After adjusting by age, the urinary albumin excretion (UAE) correlated with clinical blood pressure (BP) and BP during 24-h ABPM, whereas LVMI correlated with ambulatory BP but not with clinical BP. The prevalence of previous cardiovascular events was 22% and in the multivariate regression analysis, UAE was the only independent factor associated with the antecedent of cardiovascular events. CONCLUSION: In subjects with refractory hypertension, the prevalence of TOD was high, and an association between heart and renal organ damage was observed. UAE was independently associated with the antecedent of cardiovascular disease.

Putative endothelial progenitor cells are associated with flow-mediated dilation in refractory hypertensives.

BACKGROUND: Hypertension has been related to endothelial dysfunction. Patients with refractory hypertension (RH) have a reduced number of endothelial progenitor cells (EPCs). AIM: To evaluate if blood EPC levels relate to endothelium-dependent vasodilation (ED-VD) in RH. METHODS: We analyzed 29 RH confirmed by 24-h ambulatory blood pressure monitoring and assessed complete clinical and laboratory evaluation. EPCs were isolated from peripheral mononuclear cells (MNC) by flow cytometry. ED-VD was determined measuring flow-mediated dilation (FMD) by venous occlusion plethysmography. Results. Circulating EPCs/10(5) MNC (median [Q1-Q3]): 23.0 [4.5-53.8]. FMD (median [Q1-Q3]): 211.7 [79.5-365.8]%. Significant correlations with log-FMD: EPCs (r = 0.469; p = 0.018) and homocysteine (r = -0.414; p = 0.045). There was no collinearity between EPCs and homocysteine. FMD did not correlate with age, gender, office BP, 24-h systolic blood pressure or 24-h diastolic blood pressure, laboratory parameters, C-reactive-protein, left ventricular-mass index, dyslipidaemia, smoking habit and statin or angiotensin system blockers treatment. Multiple linear regression analysis showed that after age-adjustment, EPC (p = 0.027) and homocysteine (p = 0.004) were the only variables that predicted FMD (R = 0.740). After dividing patients according to EPC number, patients in the lower tertile showed a significantly reduced FMD compared with those in the group of the two upper tertiles of EPC: log-FMD (mean+/-SD): 4.7+/-0.9 vs 5.6+/-0.8, respectively (p = 0.031). CONCLUSIONS: ED-VD independently correlates with circulating EPCs in RH. Homocysteine is also an independent predictor of lower FMD in such patients.

Factors associated with the reduction of albumin excretion in diabetic hypertensive patients: differential effect of manidipine versus amlodipine.

AIMS: In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed. METHODS: For this purpose, a multivariable analysis was performed. RESULTS: Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE. CONCLUSION: The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

Antihypertensive effect of manidipine.

Manidipine is a lipophilic, third-generation, highly vasoselective, dihydropyridine (DHP) calcium channel antagonist, which, when given on a once-daily basis, effectively reduces blood pressure (BP) in patients with mild-to-moderate essential hypertension. Manidipine has a gradual onset and a long duration of action, effectively maintaining reduced BP levels throughout the 24-hour dosing period, and is effective in the long term with no evidence of intolerance. The BP-lowering capacity of manidipine is similar to that of other established DHPs and of angiotensin-converting enzyme inhibitors. Diabetic patients and very elderly patients with mild-to-moderate hypertension also respond favourably to treatment with manidipine. Manidipine has neutral effects on glucose and lipid metabolism and is generally well tolerated. Manidipine thus represents a first-line option for lowering BP in patients with mild-to-moderate hypertension.

[Differences in the reduction of blood pressure according to drug administration at activity hours or rest hours]. / Diferencias en la reducción de la presión arterial en función de la toma de la medicación en horario diurno o nocturno.

BACKGROUND AND OBJECTIVE: In this study, 123 recordings of blood pressure (BP) obtained by ambulatory BP monitoring were analyzed. These recordings were measured in 2011 in patients from a Spanish tertiary university hospital. All participating patients were treated with 2, 3 or 4 anti-hypertensive drugs. The main aim of this study was to determine differences in BP control, if any, depending on the medication schedule. Thus, BP levels were studied at 3 periods of the day: activity hours, rest hours and 24h. PATIENTS AND METHOD: We compared subjects taking all anti-hypertensive agents during the day (n=70, group 1) with those taking at least one at night (n=53, group 2). RESULTS: Significant differences were found on diastolic BP, where group 2 patients had lower levels at activity, 24h periods and sleep-time. Even if it was not statistically significant, lower levels of systolic BP from group 2 were also observed at activity and 24h periods as well as lower levels of systolic, diastolic and mean BP at rest hours periods. There were also significant group differences in relation to the number of prescribed agents (with the mean being higher for group 2) and the type of agent (beta-blockers and calcium antagonists were more prevalent in group 2). Nevertheless, the multivariate regression analysis done taking into account these variables did not change the observed statistical significance. CONCLUSION: The administration of anti-hypertensive drugs at night could be associated with lower BP levels.

Validation of the short form of the Spanish Hypertension Quality of Life Questionnaire (MINICHAL).

BACKGROUND: The finding that low health-related quality of life (HRQoL) can be a risk factor for future cardiovascular events in patients with hypertension emphasizes the need for disease-specific HRQoL assessment tools in this population. OBJECTIVE: This study evaluated the feasibility and psychometric properties of the short form of the Spanish Hypertension Quality of Life Questionnaire (MINICHAL). METHODS: An observational, prospective, multicenter study was carried out among patients with hypertension, stratified by sex and disease stage. The feasibility and validity of the MINICHAL were evaluated at baseline. Two follow-up visits were conducted at 1 and 6 months after the initial visit, during which the test-retest reliability and responsiveness to change of the MINICHAL were assessed, respectively. RESULTS: A total of 736 consecutive patients with hypertension were included. Mean (SD) administration time for the MINICHAL was 7.2 (6.5) minutes. In the validation process, factor analysis showed 2 dimensions: "State of mind" (StM) and "Somatic manifestations" (SM). The response level was high, with 94.3% of patients answering all items. Patients with a higher disease stage (ie, stage II/III hypertension) had a worse HRQoL than those with a lower disease stage (P < 0.01). Internal consistency was 0.87 for StM and 0.75 for SM. Test-retest reliability was 0.82 and 0.75 for the StM and SM dimensions, respectively. Among patients who reported experiencing a positive change in their overall health status 6 months after treatment initiation or treatment change, responsiveness to change ranged from 0.52 (better) to 1.14 (much better). CONCLUSIONS: The MINICHAL questionnaire could be administered in a short time with a high response level and was found to have acceptable psychometric properties. The MINICHAL is a potentially useful tool for the evaluation of HRQoL among patients with hypertension in the routine clinical setting.

Uncontrolled early morning blood pressure in medicated patients: the ACAMPA study. Analysis of the Control of Blood Pressure using Abulatory Blood Pressure Monitoring.

BACKGROUND: A blood pressure surge during the early morning may help to precipitate cardiovascular events. The objective of this study was thus to assess the blood pressure behaviour profile of early morning blood pressure in patients receiving antihypertensive treatment. DESIGN: The ACAMPA study is a multi-center, open, prospective, observational study that was carried out by 24 investigators in Spain. METHODS: Two hundred and ninety patients with essential hypertension who had been receiving the same antihypertensive treatment for at least 2 months were included in the study. Office blood pressure was measured before taking medication in the morning, and 24-h ambulatory blood pressure monitoring was performed. In addition to the automatic measurements, patients were instructed to take a blood pressure measurement after waking. RESULTS: The group analysis used 240 patients (mean age 54 years, including 101 males). Good clinical control (a blood pressure of less than 140/90 mmHg) was found in 53 cases (22%). The differences between the clinical and ambulatory readings during the period of activity were minimal in the group with good control (127 +/- 9/81 +/- 7 versus 127 +/- 10/81 +/- 7 mmHg; non-significant) but were significant in the group with poor control (155 +/- 16/93 +/- 10 versus 138 +/- 14/86 +/- 11 mmHg; P < 0.001). The blood pressure values were synchronized according to the moment of awakening. In almost half of the patients with good control, systolic and diastolic blood pressure values were higher than normal (135/85 mmHg); in those patients with poor control, this fraction rose to over 70%. The proportion of patients presenting high blood pressure values became even greater during the second hour after waking (62% in patients with good blood pressure control and 82% in those with poor control). CONCLUSIONS: In a large number of antihypertensive patients receiving treatment, blood pressure values remain high during the early-morning hours. At least half of those patients with an apparently well-controlled office blood pressure do not have their blood pressure under control for the period shortly after waking.

[Relationship between clinical and therapeutic variables and health-related quality of life in patients with hypertension. MINICHAL Study]. / Relación entre variables clínicas y terapéuticas y calidad de vida relacionada con la salud en pacientes con hipertensión arterial. Estudio MINICHAL.

BACKGROUND AND OBJECTIVE: Our objective was to evaluate, through the health related quality of life (HRQoL) questionnaire MINICHAL, the influence of socio-demographic, clinical and therapeutic variables on health related quality of life of hypertensive patients. PATIENTS AND METHOD: An observational, prospective and multi-center study was carried out in hypertensive patients who were either starting or undergoing a modification of antihypertensive treatment. A total of three visits was done: a baseline visit and two follow-up visits at one and six months. At all three visits, several socio-demographic, clinical and therapeutic variables were recorded and HRQoL was measured using the MINICHAL questionnaire, the Spanish version of the Psychological General Well-Being Index, and a single question about the change in general health status. The objective was to evaluate the impact of these variables on HRQoL. RESULTS: 736 patients with hypertension were evaluated. In the multivariate analysis, gender, number of concomitant diseases, degree of hypertension, organ damage and educational level were all variables displaying a relation with HRQoL. After 6 months of treatment intensification, an improvement of HRQoL was observed. Moreover, a positive correlation was observed between the degree of reduction of blood pressure (BP) and heart rate and HRQoL improvement, especially in the State of mind dimension. CONCLUSIONS: In hypertension, a better BP control has a positive influence on HRQoL. As several clinical variables are negatively correlated with HRQoL, specific interventions are needed to correct modifiable factors.

[Vascular risk in outpatient from Internal Medicine departments. MICARE Study]. / Riesgo vascular en las consultas de Medicina Interna. Estudio MICARE.

BACKGROUND AND OBJECTIVES: The population attended in the Spanish Internal Medicine departments is of increasing age, but the prevalence of vascular risk factors and its degree of control are unknown, as well as the differences by type of hospital or consulting room. PATIENTS AND METHODS: Epidemiologic, transversal and metacentric study in patients ≥ 18 years treated in outpatient Internal Medicine hospital. Two-hundred and ninety physicians from 17 Autonomic Communities participated in the study. The type of hospital or consulting room was also recorded. Blood pressure control was defined as <140/90 mm Hg (<130/80 mm Hg in diabetics or patients with vascular disease), LDL-cholesterol control when<130 mg/dl (<100mg/dl in diabetic or vascular disease) and diabetes control if glycated hemoglobin was<7%. RESULTS: Data from 2,704 patients was collected (54% men) mean age (SD) 64,1 (14,5) years. Ninety-three percent of them had at least one cardiovascular risk factor: hypertension 73.9%, dyslipidemia 59.5%, abdominal obesity 43.4%, diabetes 39.5%. Fifty percent had some target organ damaged, 46.7% showed vascular disease and 71.2% a high or very high vascular risk. Control over risk factors was: hypertension 33.8%, cholesterol-LDL 40.8% and diabetes 50.7%. There were no differences between type of hospital or type of outpatient consultancy. CONCLUSIONS: Over 90% of patients treated in outpatient consultancies of Internal Medicine departments present vascular risk factors, regardless of the type of hospital or type of consulting room. Risk factors control was poor.

Isolated clinic hypertension: diagnostic criteria based on 24-h blood pressure definition.

OBJECTIVE: The use of diagnostic criteria based on 24-h ambulatory blood pressure (BP) values could improve prognostic value by incorporating night BP, minimize biases and improve the diagnostic reproducibility of isolated clinic hypertension (ICH). We estimate the 24-h BP cut-off points that best discriminate and predict the two diagnostic thresholds of mean daytime BP for ICH (135/85 and 130/80 mmHg). METHODS: Cross-sectional, comparative, multicentre study in 6176 untreated hypertensive patients, whose BP was measured by ambulatory BP monitoring. ICH was defined with an office BP of ≥140/≥90 mmHg and a daytime BP of <135/<85 mmHg (ICH1) or <130/80 mmHg (ICH2). Sensitivity, specificity, positive likelihood ratio (LR+), odds ratio (OR), error rate, predictive values, κ values and 95% confidence interval were calculated for each possible cut-off point for ICH1 and ICH2. RESULTS: One thousand eight hundred and seven patients (29.2%) and 960 patients (15.5%) met ICH1 and ICH2 criteria, respectively. The 24-h BP cut-off points that best predict ICH1 and ICH2 are less than 132/82 mmHg (sensitivity: 93.6%, specificity: 94.3%, LR+: 16.6, OR: 1367.1, error rate: 5.9, κ 0.86) and less than 127/77 mmHg (sensitivity: 90.8%, specificity: 97.4%, LR+: 34.6, OR: 1041.5, error rate: 3.6,κ 0.86), respectively. These values achieved the best balance of sensitivity and specificity, together with the highest values of LR+ and OR and the lowest error rate. CONCLUSION: The 24-h BP cut-off point that best predicts the daytime criterion of less than 135/85 and less than 130/80 mmHg are 132/82 and 127/77 mmHg, respectively. These 24-h cut-off points may add value to ambulatory blood pressure monitoring for both diagnostic and management future decisions.

Discrepancies between office and ambulatory blood pressure: clinical implications.

BACKGROUND: Recent trials have documented no benefit from small reductions in blood pressure measured in the clinical office. However, ambulatory blood pressure is a better predictor of cardiovascular events than office-based blood pressure. We assessed control of ambulatory blood pressure in treated hypertensive patients at high cardiovascular risk. METHODS: We selected 4729 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry. Patients were aged >/=55 years and presented with at least one of the following co-morbidities: coronary heart disease, stroke, and diabetes with end-organ damage. An average of 2 measures of blood pressure in the office was used for analyses. Also, 24-hour ambulatory blood pressure was recorded at 20-minute intervals with a SpaceLabs 90207 device. RESULTS: Patients had a mean age of 69.6 (+/-8.2) years, and 60.8% of them were male. Average time from the diagnosis of hypertension to recruitment into the Registry was 10.9 (+/-8.4) years. Mean blood pressure in the office was 152.3/82.3 mm Hg, and mean 24-hour ambulatory blood pressure was 133.3/72.4 mm Hg. About 60% of patients with an office-pressure of 130-139/85-89 mm Hg, 42.4% with office-pressure of 140-159/90-99 mm Hg, and 23.3% with office-pressure > or =160/100 mm Hg were actually normotensive, according to 24-hour ambulatory blood pressure criteria (<130/80 mm Hg). CONCLUSION: We suggest that the lack of benefit of antihypertensive therapy in some trials may partly be due to some patients having normal pressure at trial baseline. Ambulatory monitoring of blood pressure may allow for a better assessment of trial eligibility.

Clinical effects of torasemide prolonged release in mild-to-moderate hypertension: a randomized noninferiority trial versus torasemide immediate release.

The efficacy of a new torasemide prolonged release (PR) formulation to torasemide immediate release (IR) was compared in a randomized noninferiority double-blind trial. Patients with newly diagnosed mild-to-moderate hypertension or unresponsive or poor tolerability to previous antihypertensive monotherapy received 5 mg/day of torasemide-PR (n = 219) or torasemide-IR (n = 223) for 12 weeks (uptitration to 10 mg/day if no response at 4 or 8 weeks). Mean diastolic blood pressure (DBP) reduction in the torasemide-PR group (11.6 +/- 7.1 mmHg, 95% confidence interval [CI] 10.6-12.5) versus torasemide-IR (11.3 +/- 7.5 mmHg, 95% CI 10.2-12.3) met the noninferiority criterion of a nonsided 97.5% CI lower than the preestablished margin of 2 mmHg. A significantly higher percentage of patients in the torasemide-PR group achieved adequate BP control after 8 and 12 weeks. Ambulatory 24-h BP monitoring (ABPM) measurements in a subset of 100 patients showed greater daytime SBP reductions in the torasemide-PR group (128.4 +/- 9.9 mmHg vs. 133.5 +/- 10.4 mmHg, P < 0.05). Safety and tolerability of both formulations were similar.