Similar Reductions In Blood Pressure Research Articles

Risk of Hyponatremia with Diuretics: Chlorthalidone versus Hydrochlorothiazide

BackgroundChlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. MethodsTo investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. ResultsA total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. ConclusionsThis is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose.

Collaborative hypertension case management by registered nurses and clinical pharmacy specialists within the Patient Aligned Care Teams (PACT) model.

Clinical Pharmacy Specialists (CPSs) and Registered Nurses (RNs) are integrally involved in the Patient Aligned Care Teams (PACT) model, especially as physician extenders in the management of chronic disease states. CPSs may be an alternative to physicians as a supporting prescriber for RN case management (RNCM) of poorly controlled hypertension. To compare CPS-directed versus physician-directed RNCM for patients with poorly controlled hypertension. Non-randomized, retrospective comparison of a natural experiment. A large Midwestern Veterans Affairs (VA) medical center. Utilizing CPSs as alternatives to physicians for directing RNCM of poorly controlled hypertension. All 126 patients attended RNCM appointments for poorly controlled hypertension between 20 September 2011 and 31 October 2011 with either CPS or physician involvement in the clinical decision making. Patients were excluded if both a CPS and a physician were involved in the index visit, or they were enrolled in Home Based Primary Care, or if they displayed non-adherence to the plan. All data were obtained from review of electronic medical records. Outcomes included whether a patient received medication intensification at the index visit, and as the main measure, blood pressures between the index and next consecutive visit. All patients had medication intensification. Patients receiving CPS-directed RNCM had greater decreases in systolic blood pressure compared to those receiving physician-directed RNCM (14 ± 13 mmHg versus 10 ± 11 mmHg; p = 0.04). After adjusting for the time between visits, initial systolic blood pressure, and prior stroke, provider type was no longer significant (p = 0.24). Change in diastolic blood pressure and attainment of blood pressure < 140/90 mm Hg were similar between groups (p = 0.93, p = 0.91, respectively). CPS-directed and physician-directed RNCM for hypertension demonstrated similar blood pressure reduction. These results support the utilization of CPSs as prescribers to support RNCM for chronic diseases.

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

ObjectiveThe aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg.MethodsThis was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring.ResultsThe mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%).ConclusionCoadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Arterial Stiffness as a Risk Factor for Coronary Artery Disease

Hypertension is a major modifiable risk factor, and clinical trials have demonstrated that successful reduction of elevated blood pressure to target levels translates into decreased risk for the development of coronary artery disease, stroke, heart failure, and renal failure. The arterial system had previously been regarded as a passive conduit for the transportation of arterial blood to peripheral tissues. The physiologic role the arterial system was greatly expanded by the recognition of the central role of the endothelial function in a variety of physiologic processes. The role of arterial function and structure in cardiovascular physiology was expanded with the development of a variety of parameters that evaluate arterial stiffness. Markers of arterial stiffness have been correlated with cardiovascular outcomes, and have been classified as an emerging risk factor that provides prognostic information beyond standard stratification strategies involving hypertension, diabetes, obesity, dyslipidemia and smoking. Multiple epidemiologic studies have correlated markers of arterial stiffness such as pulse-wave velocity, augmentation index and pulse pressure with risk for the development of fatal and nonfatal cardiovascular events. Additionally, measurements of arterial stiffness had clarified the results of clinical trials that demonstrated differing impacts on clinical outcomes, despite similar reductions in blood pressure, as measured by brachial and sphygmomanometry.

Nebivolol reduces central blood pressure in stage I hypertensive patients: experimental single cohort study.

Assessment of central blood pressure (BP) has grown substantially over recent years because evidence has shown that central BP is more relevant to cardiovascular outcomes than peripheral BP. Thus, different classes of antihypertensive drugs have different effects on central BP despite similar reductions in brachial BP. The aim of this study was to investigate the effect of nebivolol, a β-blocker with vasodilator properties, on the biochemical and hemodynamic parameters of hypertensive patients. Experimental single cohort study conducted in the outpatient clinic of a university hospital. Twenty-six patients were recruited. All of them underwent biochemical and hemodynamic evaluation (BP, heart rate (HR), central BP and augmentation index) before and after 3 months of using nebivolol. 88.5% of the patients were male; their mean age was 49.7 ± 9.3 years and most of them were overweight (29.6 ± 3.1 kg/m2) with large abdominal waist (102.1 ± 7.2 cm). There were significant decreases in peripheral systolic BP (P = 0.0020), diastolic BP (P = 0.0049), HR (P < 0.0001) and central BP (129.9 ± 12.3 versus 122.3 ± 10.3 mmHg; P = 0.0083) after treatment, in comparison with the baseline values. There was no statistical difference in the augmentation index or in the biochemical parameters, from before to after the treatment. Nebivolol use seems to be associated with significant reduction of central BP in stage I hypertensive patients, in addition to reductions in brachial systolic and diastolic BP.

Family history of premature cardiovascular disease: blood pressure control and long-term mortality outcomes in hypertensive patients

Current guidelines recommend early referral and initiation of intensive cardiovascular (CV) risk reduction in individuals with a positive family history of coronary heart disease (CHD). We hypothesized that a family history of premature CHD and stroke [CV disease (CVD)] would lead to earlier referral of hypertensive patients to secondary care clinic, leading to better control of risk factors, mitigating the excess risk seen in these individuals. We studied the association of a positive family history of CVD in 10 787 individuals with longitudinal changes in risk factors and long-term cause-specific mortality in the Glasgow Blood Pressure Clinic using generalized estimating equations and the Cox proportional hazard models, respectively. The total time at risk was 193 756 person-years with a median survival time of 29.2 years. A positive family history of CVD was associated with an earlier presentation to the clinic, a lower burden of traditional CV risk factors, and similar longitudinal blood pressure reduction and drug adherence compared with those without. But despite these positive features, all-cause [hazard ratio (HR) = 1.12, 95% confidence interval 1.01-1.25] and CV (HR = 1.20, 1.04-1.38) mortality independent of baseline risk factors were worse. Consistent results were observed in propensity score-matched analysis. Inclusion of family history of CVD did not improve mortality risk discrimination over and above traditional risk factors. Our study suggests that despite earlier referral and treatment of individuals with a positive family history of premature CVD, excess risk persists, indicating the need for continued and sustained efforts to reduce risk factors and drug adherence in these individuals.

Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors

Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n = 7), or a diuretic, hydrochlorothiazide (n = 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P = 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)(-1) pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)(-1); P = 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)(-1)), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)(-1); P = 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P = 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r = 0.74, P = 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients.

Effects of renin-angiotensin-aldosterone system inhibitors and beta-blockers on markers of arterial stiffness

Antihypertensive agents may, even within the same class, exert variable effects on arterial stiffness variables. Nebivolol could have a better impact than atenolol on arterial stiffness, by increasing the bioavailability of endothelium-derived nitric oxide. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase plasma renin activity (enhancing the production of angiotensin II via non-ACE-related pathways) whereas aliskiren does not, potentially affecting central hemodynamics differently. We compared the effects of two renin-angiotensin-aldosterone system (RAAS) inhibitors (quinapril and aliskiren) and 2 beta-blockers (atenolol and nebivolol) on arterial stiffness variables. Treatment-naïve patients (n = 72; 68.1% males; age, 47.6 ± 10.6 years) with uncomplicated stage I-II essential hypertension were randomly assigned to quinapril, aliskiren, atenolol, or nebivolol for 10 weeks. Central systolic and diastolic blood pressure (BP), central pulse pressure (PP), augmentation index (AIx), and pulse wave velocity (PWV) were measured at baseline, 2, and 10 weeks. The same measurements were performed in 20 normotensive subjects (65.0% males; age, 40.0 ± 8.9 years). Peripheral and central systolic and diastolic BP, peripheral PP, and PWV were significantly and similarly reduced by all agents. However, PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol. Central PP and AIx decreased in patients on quinapril, aliskiren, and nebivolol but did not change in those taking atenolol. The decrease in central PP and AIx did not differ between patients on quinapril, aliskiren, and nebivolol. Despite similar reductions in peripheral BP, atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics. Aliskiren exerts similar effects on markers of arterial stiffness as quinapril. The clinical relevance of these differences remains to be established.

Efficacy of losartan and carvedilol on central hemodynamics in hypertensives: a prospective, randomized, open, blinded end point, multicenter study

Renin-angiotensin system (RAS) blockers have shown clinical outcomes superior to those of the beta (β)-blocker atenolol, despite similar reductions in the peripheral blood pressure (BP), perhaps because of different impacts on central hemodynamics. However, few comparative studies of RAS blockers and newer vasodilating β-blockers have been performed. We compared the central hemodynamic effects of losartan and carvedilol in a prospective, randomized, open, blinded end point study. Of the 201 hypertensive patients enrolled, 182 (49.6±9.9 years, losartan group=88 and carvedilol group=94) were analyzed. Carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), AIx corrected for a heart rate (HR) of 75 beats per minute (AIx@HR75) and central BP were measured noninvasively at baseline and after a 24-week treatment regimen with losartan or carvedilol. After 24 weeks, there were no between-group differences in the brachial BP, cfPWV, AIx@HR75 or central BP changes, except for a more favorable AIx effect with losartan. The changes in all measured metabolic and inflammatory parameters were also not significantly different between the two groups, except for uric acid. Losartan and carvedilol showed generally comparable effects on central hemodynamic indices, metabolic profile, inflammatory parameters and peripheral arterial pressure with a 24-week treatment.

Abstract 528: Response of Muscle Sympathetic Nerve Activity to Heat Stress is Attenuated in Chronic Heart Failure

Cutaneous vascular conductance (CVC) rises during heat stress in normal humans. Recently, we showed that this response is attenuated in chronic heart failure (CHF), even though the skin sympathetic nerve activity response to heat stress was not attenuated. Of note, heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. This effect may allow flow to be distributed to other tissues. The MSNA response to heat stress in CHF has not been reported. We postulated that in CHF the MSNA response to heat stress is attenuated. Passive whole body heating was applied with water-perfused suits on 9 male (60 ± 3 yrs) patients with stable class II-III CHF and 9 age-matched male healthy subjects. Whole body heating induced similar increases in skin temperature (~4 °C), internal temperature (~0.6 °C), similar reduction in blood pressure, and similar increase in heart rate. The elevation in forearm CVC in CHF patients was significantly lower than that in healthy control subjects (102 ± 29 vs. 312 ± 54 units, P &lt; 0.001). While baseline MSNA in CHF was higher than in controls ( P &lt; 0.05); heat stress increased MSNA in the controls (33.2 ± 3.8 to 47.3 ± 4.4 bursts/min; 618 ± 74 to 934 ± 93 units/min, both P &lt; 0.001, N = 9), but not in CHF (43.4 ± 5.7 to 49.6 ± 7.0 bursts/min; 996 ± 104 to 1039 ± 108 units/min, both P &gt; 0.15, N = 6; two-factor ANOVA with repeated measure on one factor). Moreover, the MSNA change by heating in CHF was significantly lower than that in the controls (6.2 ± 2.6 to 14.1 ± 1.5 bursts/min; 43 ± 45 to 316 ± 34 units/min; both P &lt; 0.01, unpaired t-test). The attenuated MSNA response to heating was not due to a ceiling effect as that static fatiguing handgrip in CHF in a control trial evoked significant increases in MSNA. These data show that the MSNA response to heat stress is attenuated in CHF patients. We postulate that the attenuated MSNA response contributes to an impaired re-distribution of blood low to the skin during heat stress in CHF.

Effects of Antihypertensive Drugs on Central Blood Pressure in Humans: A Preliminary Observation

Central blood pressure (BP) is considered a better predictor of cardiovascular events than brachial BP. Modifications of central, beyond brachial BP, can be assessed by pressure amplification, a potential new cardiovascular risk factor. Comparison between drugs' effect on central hemodynamics has been poorly studied. Our aim was to assess the hemodynamic effect of a 12-week treatment with amlodipine 5mg, or candesartan 8mg, or indapamide sustained-release 1.5mg, in comparison with placebo. We analyzed 145 out-patients with essential hypertension in primary prevention enrolled in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) study, a multicenter, randomized, double-blinded, placebo-controlled trial. Arterial stiffness, central BP, pressure amplification, and wave reflection were measured by applanation tonometry. Baseline characteristics of patients were homogeneous between groups. After treatment, we found that active drugs produced similar reduction of both central and peripheral BPs, with no significant interdrug differences (all P < 0.05; excluded peripheral pulse pressure, compared with placebo). Second, amlodipine (1.9% ± 15.3%), candesartan (3.0% ± 14.6%) and indapamide (4.1% ± 14.4%) all increased pulse pressure amplification, but only indapamide was statistically different from placebo (P = 0.02). Finally, no significant changes were observed on pulse wave velocity, heart rate, and augmentation index. The 3 antihypertensive drugs similarly reduced peripheral and central BP, as compared with placebo, but a significant increase in pulse pressure amplification was obtained only with indapamide, independently of arterial stiffness modifications. 3283161 by BIOPHARMA.

Comparison of Benazepril Plus Amlodipine or Hydrochlorothiazide in High-Risk Patients With Hypertension and Coronary Artery Disease

Combination therapy with benazepril 40 mg and amlodipine 10 mg (B+A) has been shown to be more effective than benazepril 40 mg and hydrochlorothiazide (HCTZ) 25 mg (B+H) in reducing cardiovascular (CV) events in high-risk patients with stage 2 hypertension with similar blood pressure reductions. In the present post hoc analysis, we evaluated whether B+A is more effective than B+H for reducing CV events in patients with known coronary artery disease (CAD) at baseline in a subgroup analysis of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study. The main trial randomized 11,506 patients. Of those, 5,744 received B+A and 5,762 received B+H. Of the 11,506 patients, 5,314 (46%) were classified as having CAD at baseline. The mean patient follow-up period was 35.7 months for the B+A group and 35.6 months for the B+H group. The primary end point was the interval to the first event of composite CV morbidity and mortality. At baseline, significant differences were present between the 5,314 with CAD and the 6,192 without CAD. The patients with CAD had a lower systolic blood pressure and heart rate, a lower incidence of diabetes, and greater incidence of dyslipidemia. However, no baseline differences were found between the randomized B+A and B+H groups. In the patients with CAD, an 18% reduction occurred in the hazard ratio for CV events (primary end point) with B+A versus B+H (p= 0.0016). In a prespecified secondary analysis of the composite end point, including only CV death, myocardial infarction, and stroke, the hazard ratio in the patients with CAD was reduced by 25% (p= 0.0033) in the B+A group compared with the B+H group. B+A was more effective than B+H at comparable blood pressure reductions for reducing CV events in patients, regardless of the presence of CAD. In conclusion, our findings suggest that the combination of B+A should be preferentially used for older patients with high-risk, stage 2 hypertension.

Angiotensin II (Ang II)‐pretreated female but not male rats are protected from pressor response and sympathetic activation to 2% saline drinking

Growing evidence suggests sex differences in the development of hypertension. Previous work in our lab indicated male rats display a greater pressor response to 2% saline when sensitized with Ang II, so‐called “induced salt sensitivity”. In the current study, we hypothesized female rats are resistant to induced salt sensitivity. To test this hypothesis, blood pressure (BP) of female rats was monitored continuously with telemetry devices. Following an Induction‐Delay‐Expression (I‐D‐E) design, after one week recovery and one week baseline recording (B), rats received a subpressor dose of Ang II (10ng/kg/min, sc) via osmotic pumps for 7 days (I) and were then rested an additional 7 days to metabolize any exogenous Ang II (D). No difference in BP was detected during B, I, or D in these animals. During E, with 2% saline as the sole drinking fluid, no change in BP was detected in either control (97±2 mmHg, B, vs. 100±3 mmHg, E) or Ang II‐pretreated rats (99±2 mmHg, B, vs. 102±3 mmHg, E). To determine the influence of sympathetic tone on baseline BP, ganglionic blocker hexamethonium (30 mg/kg, ip) elicited similar reductions in BP in both control and pre‐treated Ang II female rats throughout the course of the study (B,I,D,E). These results suggest that female rats are protected from induced salt sensitivity, possibly through a resistance to sympathetic activation.

Differential Effects of Nebivolol Versus Metoprolol on Functional Sympatholysis in Hypertensive Humans

In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

The Effects of Telmisartan and Amlodipine in Treatment-Naïve and Previously Treated Hypertensive Patients: A Subanalysis from a 4 × 4 Factorial Design Study

The subanalysis of a 4 × 4 factorial, 8-week study to evaluate the efficacy and tolerability of telmisartan (T) 40–80 mg/amlodipine (A) 5–10 mg used in treatment-naïve patients (n = 231) and patients previously treated with antihypertensive agents (n = 880). Similar blood pressure (BP) reductions were achieved with T + A, regardless of their pretreatment status. Highest reductions were achieved with T80 + A10 (treatment-naïve −26.5/−18.2 mm Hg and previously treated −25.6/−19.9 mm Hg). Most patients (treatment-naïve 72.4% and previously treated 77.6%), including those with added risk, achieved BP goal (<140/90 mm Hg) with T80 + A10. Tolerability was comparable in both groups.Trial registration: ClinicalTrials.gov identifier: NCT00281580.

Ambulatory Blood Pressure Values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)

In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, telmisartan (T; 80 mg daily) and ramipril (R; 10 mg daily) caused similar clinic blood pressure (BP) reductions, with a similar incidence of cardiovascular and renal events. The R+T combination lowered clinic BP somewhat more with no further cardiovascular or renal protection. The aim of this substudy was to see whether these clinic BP changes reflected the changes of 24-hour BP, a BP with a better prognostic value. In 422 patients in whom 24-hour BP monitoring was performed either before or after 6 to 24 months of treatment, demographic and clinical characteristics were similar in the 3 treated groups. Twenty-four-hour systolic BP was similarly reduced by R (-2.0 mm Hg) and T (-2.1 mm Hg), whereas the reduction was more than twice as large in the T+R group (-5.3 mm Hg), which showed a lower on-treatment 24-hour BP also in additional patients (n=408) in whom ambulatory BP was performed only on-treatment. Twenty-four-hour systolic BP was ≈ 14 mm Hg lower than clinic systolic BP at baseline, whereas during treatment the 2 values became progressively closer as clinic systolic BP was more tightly controlled and superimposable when clinic systolic BP was <120 mm Hg. Similar results were obtained for diastolic BP. These findings provide evidence on the relationship of clinic and ambulatory BP target drug treatment. They also show that in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, failure of the R+T combination to enhance cardiovascular and renal protection was not because of inability to more effectively control daily life BP.

Hypertensive left ventricular hypertrophy

Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not. Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM). All BP indices were highly comparable at the start and end of the trial (P > 0.6 between groups). BP was reduced (always P < 0.0001) by 37/17 mmHg in the valsartan and moxonidine group and 38/19 mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P < 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9 g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3 g; -23.3 to -13.4) (P < 0.05). The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH.

How much effect of different antihypertensive medications on cardiovascular outcomes is attributable to their effects on blood pressure?

The debate over whether certain antihypertensive medications have benefits beyond what would be expected from their blood pressure lowering spurred the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, which randomized 42,418 participants to chlorthalidone (15,255), amlodipine (9048), lisinopril (9054), or doxazosin (9061). We compared chlorthalidone, the active control, with each of the other three agents with respect to the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, and several other clinical endpoints. The arms were similar with respect to the primary endpoint, although some differences were found for other endpoints, most notably heart failure. Although the desire was to achieve similar blood pressure reductions in the four arms, we found some systolic blood pressure and diastolic blood pressure differences. A natural question is to what degree can observed treatment group differences in cardiovascular outcomes be attributed to these blood pressure differences. The purpose of this paper was to delineate the problems inherent in attempting to answer this question, and to present analyses intended to overcome these problems.

936 EFFECTS OF OLMESARTAN PLUS AZELNIDIPINE VERSUS DIURETIC ON URINE ALBUMIN IN HYPERTENSIVE PATIENTS WITH DIABETES

Background: In the GUARD study, an angiotensin converting enzyme inhibitor combined with a diuretic is superior to a combination of an angiotensin converting enzyme inhibitor and a calcium channel blocker (CCB), amlodipine, in reducing urine albumin. However, CCBs have diverse characteristics and azelnidipine exerts renoprotective effects. This study tested the hypothesis that combining an angiotensin receptor blocker with either azelnidipine or a diuretic will cause similar reduction in blood pressure and albuminuria in patients with hypertension and diabetes mellitus. Design and Methods: Hypertensive patients with type 2 diabetes mellitus and albuminuria with clinic blood pressure >130/80mmHg under a monotherapy with a standard dose of an inhibitor of the renin-angiotensin system were enrolled. After a 12-week run-in period under a combination therapy with olmesartan (20 mg/day) plus amlodipine (5 mg/day), baseline data were obtained and patients were randomly assigned to receive either olmesartan (20 mg/day) plus azelnidipine (16 mg/day) (CCB group) or olmesartan (20 mg/day) plus trichlormethiazide (1 mg/day) (D group) for another 24-week. Changes in urine albumin from baseline to week 24 were assessed. Results: Blood pressure was not altered after replacing amlodipine with azelnidipine or trichlormethiazide and was similar throughout the study period in the CCB (from 136.5/75.3 to 134.8/75.4mmHg) and D groups (from 131.2/73.7 to 133.8/73.8mmHg; NS in 2-way ANOVA). In contrast, both regimens effectively reduced urinary excretion of albumin (p < 0.0001) to a similar extent (median value: CCB group, from 141.0 to 81.1 mg/g creatinine; D group from 96.4 to 69.4). Conclusions: Olmesartan combined with azelnidipine or trichlormethiazide exerts similar kidney protective effects.

The Effect of Valsartan versus Non-RAAS Treatment on Autoregulation of Cerebral Blood Flow

Background: Cerebral autoregulation (CA) is a protective mechanism which maintains the steadiness of the cerebral blood flow (CBF) through a broad range of systemic blood pressure (BP). Acute hypertension has been shown to reduce the cerebrovascular adaptation to BP variations. However, it is still unknown whether CA is impaired in chronic hypertension. This study evaluated whether a strict control of BP affects the CA in patients with chronic hypertension, and compared a valsartan-based regimen to a regimen not inhibiting the renin-angiotensin-aldosterone system (non-RAAS). Methods: Eighty untreated patients with isolated systolic hypertension were randomized to valsartan 320 mg or to a non-RAAS regimen during 6 months. The medication was upgraded to obtain BP <140/90 mm Hg. Continuous recordings of arterial BP and CBF velocity (transcranial Doppler) were performed during periods of 5 minutes, at rest, and at different levels of alveolar CO₂ pressure provided by respiratory maneuvers. The dominant frequency of CBF oscillations was determined for each patient. Dynamic CA was measured as the mean phase shift between BP and CBF by cross-spectral analysis in the medium frequency and in the dominant CBF frequency. Results: Mean ambulatory 24-hour BP fell from 144/87 to 127/79 mm Hg in the valsartan group and from 144/87 to 134/81 mm Hg in the non-RAAS group (p = 0.13). Both groups had a similar reduction in the central BP and in the carotido-femoral pulse wave velocity. The average phase shift between BP fluctuations and CBF response at rest was normal at randomization (1.82 ± 0.08 s), which is considered a preserved autoregulation and increased to 1.91 ± 0.12 s at the end of study (p = 0.45). The comparison of both treatments showed no significant difference (–0.01 ± 0.17 s vs. 0.16 ± 0.16 s, p = 0.45) for valsartan versus non-RAAS groups. The plasmatic level of glycosylated hemoglobin decreased in the valsartan arm compared to the non-RAAS arm (–0.23 ± 0.06 vs. –0.08 ± 0.07%, p = 0.07). Conclusions: In elderly hypertensive men with isolated chronic systolic hypertension, CA seems efficient at baseline and is not significantly affected by 6 months of BP-lowering treatment. This suggests that the preventive effects of BP medication against stroke are not mediated through a restoration of the CA.