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.

Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations.

For the general practitioner to be able to prescribe optimal therapy to his individual hypertensive patients, he needs accurate information on the therapeutic agents he is going to administer and practical treatment strategies. The information on drugs and drug combinations has to be applicable to the treatment of individual patients and not just patient study groups. A basic requirement is knowledge of the dose-response relationship for each compound in order to choose the optimal therapeutic dose. Contrary to general assumption, this key information is difficult to obtain and often not available to the physician for many years after marketing of a drug. As a consequence, excessive doses are often used. Furthermore, the physician needs comparative data on the various antihypertensive drugs that are applicable to the treatment of individual patients. In order to minimize potential side effects due to unnecessary combinations of compounds, the strategy of sequential monotherapy is proposed, with the goal of treating as many patients as possible with monotherapy at optimal doses. More drug trials of a crossover design and more individualized analyses of the results are badly needed to provide the physician with information that he can use in his daily practice. In this time of continuous intensive development of new antihypertensive agents, much could be gained in enhanced efficacy and reduced incidence of side effects by taking a closer look at the drugs already available and using them more appropriately in individual patients.

Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study.

Objective The goal of this study was to investigate whether increasing the dose of an angiotensin II receptor blocker (ARB) provides as much benefits as combining the ARB with an angiotensin-converting enzyme inhibitor (ACEI) in terms of blood pressure (BP) control and urinary albumin excretion (UAE) in hypertensive patients with a proteinuria.Methods We enrolled 20 hypertensive patients with proteinuric nephropathies and a reduced renal function in a randomized, 12-month, triple-crossover, prospective, open-label study to compare the effects of a regular dose of losartan (Los 100mg q.d., LOS100) vs. a high dose of losartan (Los 100mg b.i.d., LOS200) vs. losartan 100mg q.d. associated with lisinopril 20 mg q.d. (LOS100 + LIS20). Each treatment was given for 8 weeks with a 4-week initial run-in period and 2 weeks of washout between each treatment phases. 24 h UAE and ambulatory BP were measured during the running phase and at the end of each treatment period.Results Compared to pretreatment, 24 h SBP and DBP were reduced by 10/5 +/- 7/4 mmHg with LOS100 (P=0.023 vs. baseline) and, respectively, 13/6 +/- 12/5 mmHg with LOS200 (P=0.011) and 19/9 +/- 15/8 mmHg with LOS100+LIS20 (P < 0.01). UAE decreased significantly with LOS100 and to an even greater degree with LOS200 and LOS100+LIS20 (P < 0.01 vs. baseline for both and P=0.032, LOS100+LIS20 vs. LOS200). The combination had a greater impact in patients with a high baseline proteinuria as suggested by a nonparallel leftward shift of the relationship between the changes in UAE induced by the combination and those induced by LOS200. The high dose of losartan was better tolerated than the combination.Conclusion Increasing the dose of losartan from 100mg once daily to 100mg twice a day enables to obtain a greater decrease in BP and proteinuria and is better tolerated than combining the ARB with lisinopril, though the high dose appears to be slightly less effective than the combination in patients with a marked proteinuria. J Hypertens 29: 1228-1235 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Ambulatory blood pressure monitoring in the elderly hypertensive patient.

In this retrospective analysis, we assessed the usefulness of ambulatory blood pressure monitoring in the evaluation of elderly hypertensive patients. Thirty-eight untreated and 31 treated hypertensives aged 70 years or more had a systolic blood pressure greater than or equal to 160 mmHg and/or a diastolic blood pressure greater than or equal to 95 mmHg in the clinic. All 69 patients underwent blood pressure monitoring during their customary daily activities using a portable semi-automatic blood pressure recorder (Remier M2000). The mean of all blood pressures obtained with this device was taken as the ambulatory recorded blood pressure. Recorded blood pressures were greater than or equal to 160 mmHg systolic and greater than or equal to 90 mmHg diastolic in 17 untreated and 17 treated patients. In these patients, the introduction of antihypertensive therapy, or its modification, markedly reduced blood pressure during a 4-8 month follow-up. A further 21 untreated and 14 treated patients had recorded blood pressures of less than 160/90 mmHg. The treatment status of these patients was left unchanged for 4-8 months of follow-up. Nevertheless, office blood pressure in these groups, with no change in treatment, decreased significantly during the observation period. At the last visit to the outpatient clinic, there was no significant difference in blood pressure between the four subgroups of patients. Thus, ambulatory blood pressure monitoring appears to be useful in the elderly hypertensive patient in detecting those patients whose blood pressure is elevated only in the clinic. Blood pressure profiles obtained outside the clinic may therefore be useful in making therapeutic decisions in the aged hypertensive.

Assessment of drug compliance in patients with high blood pressure resistant to antihypertensive therapy.

The persistence of high blood pressure under antihypertensive treatment (resistant hypertension) entails an increased cardiovascular risk. It occurs in three of ten treated hypertensive patients, and has several possible contributing factors, notably insufficient therapeutic adherence. There are a number of ways to evaluate whether patients take their medication as prescribed. These include interviewing the patient, pill counting, prescription follow-up, assay of drugs in blood or urine, and use of electronic pill dispensers. None is perfect. However, the essential is to discuss with the patient the importance of complying with the treatment as soon as it is prescribed for the first time, and not waiting for the appearance of resistant hypertension. The measurement of blood pressure outside the medical office and the monitoring of adherence may help to identify patients in whom hypertension is truly resistant and so to tailor the measures required to improve the control of blood pressure in the most appropriate manner.

Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.

AIM: To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients. METHODS: Prospective randomized 2-way cross over study; T2DM patients with (micro)albuminuria and/or hypertension underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) at baseline, after one month of enalapril (20mgqd), and after one month of candesartan (16mgqd). Each BOLD-MRI was performed before and after the administration of furosemide. The mean R2* (=1/T2*) values in the medulla and cortex were calculated, a low R2* indicating high tissue oxygenation. RESULTS: Twelve patients (mean age: 60±11 years, eGFR: 62±22ml/min/1.73m(2)) completed the study. Neither chronic enalapril nor candesartan intake modified renal cortical or medullary R2* levels. Furosemide significantly decreased cortical and medullary R2* levels suggesting a transient increase in renal oxygenation. Medullary R2* levels correlated positively with urinary sodium excretion and systemic blood pressure, suggesting lower renal oxygenation at higher dietary sodium intake and blood pressure; cortical R2* levels correlated positively with glycemia and HbA1c. CONCLUSION: RAS blockade does not seem to increase renal tissue oxygenation in T2DM hypertensive patients. The response to furosemide and the association with 24h urinary sodium excretion emphasize the crucial role of renal sodium handling as one of the main determinants of renal tissue oxygenation.

Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Percutaneous 17ß-estradiol replacement therapy in hypertensive postmenopausal women

The present study evaluated the short-term effects of percutaneous 17ß-estradiol on blood pressure, metabolic profile and hormonal levels in postmenopausal women with systemic arterial hypertension. After a wash-out period of 15 days, 10 hypertensive patients were treated with guanabenz acetate to control blood pressure, followed by 17ß-estradiol in the form of hydroalcoholic gel administered for 21 of 28 days of each cycle, for 3 cycles. Patients were evaluated before, during and 2 months after estrogen administration. Systolic and diastolic blood pressure or heart rate did not present any significant change in any patient when compared to those periods with the antihypertensive drug only (pretreatment period and 60 days after estrogen therapy was discontinued). Plasma biological markers of hepatic estrogenic action (plasma renin activity, antithrombin III, triglycerides, total cholesterol and lipoproteins) also remained unchanged during the study. Hormone treatment was effective, as indicated by the relief of menopausal symptoms, a decrease in FSH levels (73.48 ± 27.21 to 35.09 ± 20.44 IU/l, P<0.05), and an increase in estradiol levels (15.06 ± 8.76 to 78.7 ± 44.6 pg/ml, P<0.05). There was no effect on LH (18.0 ± 9.5 to 14.05 ± 8.28 IU/l). Hormone levels returned to previous values after estrogen treatment was discontinued. The data indicate that short-term percutaneous 17ß-estradiol replacement therapy, at the dose used, seems to be a safe hormone therapy for hypertensive menopausal women. Nevertheless, a controlled, prospective, randomized clinical assay with a larger number of subjects is needed to definitely establish both the beneficial and harmful effects of hormone replacement therapy in hypertensive women

Nitric oxide, cholesterol oxides and endothelium-dependent vasodilation in plasma of patients with essential hypertension

The objective of the present study was to identify disturbances of nitric oxide radical (·NO) metabolism and the formation of cholesterol oxidation products in human essential hypertension. The concentrations of·NO derivatives (nitrite, nitrate, S-nitrosothiols and nitrotyrosine), water and lipid-soluble antioxidants and cholesterol oxides were measured in plasma of 11 patients with mild essential hypertension (H: 57.8 ± 9.7 years; blood pressure, 148.3 ± 24.8/90.8 ± 10.2 mmHg) and in 11 healthy subjects (N: 48.4 ± 7.0 years; blood pressure, 119.4 ± 9.4/75.0 ± 8.0 mmHg).Nitrite, nitrate and S-nitrosothiols were measured by chemiluminescence and nitrotyrosine was determined by ELISA. Antioxidants were determined by reverse-phase HPLC and cholesterol oxides by gas chromatography. Hypertensive patients had reduced endothelium-dependent vasodilation in response to reactive hyperemia (H: 9.3 and N: 15.1% increase of diameter 90 s after hyperemia), and lower levels of ascorbate (H: 29.2 ± 26.0, N: 54.2 ± 24.9 µM), urate (H: 108.5 ± 18.9, N: 156.4 ± 26.3 µM), ß-carotene (H: 1.1 ± 0.8, N: 2.5 ± 1.2 nmol/mg cholesterol), and lycopene (H: 0.4 ± 0.2, N: 0.7 ± 0.2 nmol/mg cholesterol), in plasma, compared to normotensive subjects. The content of 7-ketocholesterol, 5alpha-cholestane-3ß,5,6ß-triol and 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol in LDL, and the concentration of endothelin-1 (H: 0.9 ± 0.2, N: 0.7 ± 0.1 ng/ml) in plasma were increased in hypertensive patients. No differences were found for ·NO derivatives between groups. These data suggest that an increase in cholesterol oxidation is associated with endothelium dysfunction in essential hypertension and oxidative stress, although ·NO metabolite levels in plasma are not modified in the presence of elevated cholesterol oxides.

Nursing consultation applied to hypertensive clients: application of orem's self-care theory

O objetivo foi implantar a Consulta de Enfermagem para indivíduos hipertensos, utilizando-se a teoria do autocuidado de Orem e sistematizar a assistência de enfermagem. Foram entrevistados 56 pacientes, sendo 58,9% mulheres, 75% na faixa etária de 50 a 80 anos, 76,4% casados, 42,9% donas de casa, 47,2% aposentados e 67,3% com ensino fundamental completo. Utilizou-se instrumento estruturado abordando os requisitos de autocuidado universal, de desenvolvimento e de desvios de saúde. A análise dos dados possibilitou avaliar os requisitos de autocuidado alterados. No planejamento da assistência, as ações de apoio-educação foram prioridades. A teoria do autocuidado possibilitou identificar aspectos importantes para serem trabalhados pelo enfermeiro.

Systemic hypertension in patients with glomerulonephritis

Although systemic hypertension is very common in patients with glomerulonephritis there is a dispute if this alteration is consequence of the glomerulonephritis per se or is a consequence of the renal failure secondary to the glomerular lesion. With the aim to analyze the factors associated with systemic hypertension, 196 patients with different forms of nephritis were studied. The systemic arterial pressure was measured by standard sphygmomanometer, renal function was evaluated by the determination of the serum creatinine concentration or creatinine clearance. The diagnosis of the type of glomerulonephritis was made on the basis of an examination of kidney biopsy specimens. The prevalence of arterial hypertension among patients with glomerulonephritis was 62.7%. The hypertensive patients were older (hypertensive = 30.6 ± 12.8; normotensive = 25.4 ± 1.6 years; P = 0.03). The prevalence of arterial hypertension was lower in patients with minimal glomerular lesion (12.5%), though their ages were also lower (18.1 ± 3.6 and 29.1 ± 1.03 years; P = 0.03). Arterial hypertension did not correlate with the serum levels of creatinine and albumin; creatinine clearance and 24-h proteinuria. In conclusion: In the patients with glomerulonephritis, the presence of arterial hypertension was associated with a higher mean age whereas the intensity of proteinuria, the level of renal function or the type of glomerulonephritis was not different between the two groups.

Efficacy and Tolerability of the Combination Valsartan/Hydrochlorothiazide Compared with Amlodipine in a Mild-to-moderately Hypertensive Brazilian Population

Most hypertensive patients need more than one drug to reach recommended blood-pressure targets. We investigated the effects on 24-h ambulatory blood pressure (ABP) of the angiotensin-receptor blocker, valsartan, in combination with hydrochlorothiazide (HCTZ), compared with the calcium-channel blocker amlodipine in a Brazilian population in a multicentre, double-blind, double-dummy, parallel group, controlled study in 373 patients with essential hypertension. After a 2-week washout period, patients with a mean sitting systolic blood pressure (SBP) of 160-190 mmHg were randomized to receive either valsartan 160 mg o.d., or amlodipine 5 mg o.d. for 2 weeks and subsequently force-titrated to valsartan 160 mg/HCTZ 25 mg o.d. or amlodipine 10 mg o.d. This regimen was continued until the end of the study at week 8. The primary efficacy parameter was the change from baseline to week 8 in mean 24-h SBP. Secondary endpoints were change in mean 24-h diastolic blood pressure (DBP), tolerability and safety of treatments. Valsartan/HCTZ achieved a mean reduction in systolic ABP of -19.1 ± 11.3 mmHg compared with -20.7 ± 12.0 mmHg with amlodipine (p = 0.324 for the comparison) and in diastolic ABP by -11.1 ± 7.4 mmHg vs -11.6 ± 7.2 mmHg by amlodipine (p = 0.853 for the comparison). The valsartan/HCTZ group exhibited markedly lower rates of adverse events and discontinuations than the amlodipine group. Peripheral oedemas were far more frequent with amlodipine than with valsartan/HCTZ (1.6% with valsartan/HCTZ; 16.8% with amlodipine). Thus, the valsartan 160 mg/HCTZ 25 mg combination appears to be as efficacious as amlodipine 10 mg in this patient population but better tolerated.

Comparison of epinephrine and felypressin pressure effects in 1K1C hypertensive rats treated or not with atenolol

Epinephrine is considered the gold standard vasoconstrictor for hypertensive patients, but few studies report felypressin’s effects. The present study aimed to analyze and compare the effects of these two vasoconstrictors, injected by the intravenous route, on the arterial pressure of normotensive, hypertensive and atenolol-treated hypertensive rats. Method The hypertension model was one-kidney-one-clip (1K1C): the main left renal artery was partially constricted and the right kidney was surgically removed in 45-day-old male Wistar rats. 1K1C hypertensive rats received atenolol (90 mg/kg/day) by gavage for 2 weeks. 28–35 days after hypertension induction, a catheter was inserted into the left carotid artery to record direct blood pressure values. The following parameters were recorded: minimal hypotensive response, maximal hypertensive response, response duration and heart rate. Results Epinephrine, but not felypressin, exerted an important hypotensive action; non-treated hypertensive rats showed more pronounced vasodilation. Treated and non-treated rats showed hypertensive responses of the same magnitudes in all groups; 1K1C atenolol rats showed reduced hypertensive responses to both vasoconstrictors. Felypressin’s response duration was longer than that of epinephrine in all groups. Epinephrine increased heart rate while felypressin reduced this parameter only in the normotensive group. Conclusions Our results suggest that felypressin has equipotent pressure responses when compared with epinephrine, showing a greater extent of action. Atenolol’s reduction of hypertensive effects surprisingly suggests that atenolol β-blockade may also be important for felypressin’s cardiovascular effect, as is widely known for epinephrine. Our data suggest that felypressin is safe for hypertensive subjects, in particular those receiving atenolol.

Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats

Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1 h) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120 mm Hg, group 1, n=6) or hypertension (160-170 mm Hg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 vs. group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke. Published by Elsevier B.V.

Diastolic function parameters are improved by the addition of simvastatin to enalapril-based treatment in hypertensive individuals

Objective: Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigate in a prospective, double-blinded, placebo-controlled randomized design the additive effect of simvastatin on DD in enalapril-treated hypertensive patients with average cholesterol levels. Methods: Hypertensive patients with DD and LDL-cholesterol <160 mg/dL underwent a run-in phase to achieve a systolic blood pressure (SBP) <135 mmHg and diastolic blood pressure (DBP) <85 mmHg with enalapril. Hydrochlorothiazide was added when need to achieve blood pressure control. Four weeks after reaching the optimum anti-hypertensive regimen patients were randomized to receive 80 mg simvastatin (n = 27) or placebo (n = 28) for a period of 20 weeks. Echocardiograms were performed before and after treatment with measurement of maximum left atrial volume (LAV), conventional and tissue Doppler velocities in early diastole (E, e') and late diastole (A, a'). Results: After 20 weeks, the simvastatin group presented reduction in SBP (-4 +/- 2 mmHg, p = 0.02), increase in E/A ratio (1.0 +/- 0.05 to 1.2 +/- 0.06, p = 0.03) and decrease of LAV indexed to body surface area (24.5 +/- 0.9 to 21.1 +/- 0.8 ml/m(2), p = 0.048), as compared with placebo arm. No change in systolic function and no correlation between the E/A ratio, LAV and changes in blood pressure or lipid profile were observed. Conclusions: The addition of simvastatin to enalapril in hypertensive patients with average cholesterol levels improves parameters of diastolic function independently of changes in blood pressure or cholesterol. (C) 2012 Elsevier Ireland Ltd. All rights reserved.