24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension.

To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8-24.1/11.7-15.5, 19.0-25.1/12.0-16.0 and 18.3-22.6/11.1-14.3 mm Hg (P≤0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were ≤130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.

Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials.

Cardiovascular risk is subject to circadian variation, with peak morning incidence of myocardial infarction and stroke correlating with the early morning blood pressure (BP) surge (EMBPS). Ideally, antihypertensive therapy should maintain control of BP throughout the 24-h dosing cycle. In two sister studies, Prospective, Randomized Investigation of the Safety and efficacy of Micardis vs Ramipril Using ABPM (ambulatory BP monitoring) (PRISMA) I and II, BP control was compared in patients with essential hypertension (24-h mean baseline ambulatory BP approximately 148/93 mm Hg) randomized to the angiotensin receptor blocker, telmisartan (80 mg; n=802), or the angiotensin-converting enzyme inhibitor, ramipril (5 or 10 mg; n=811), both dosed in the morning. The primary end point was the change from baseline in mean ambulatory systolic BP (SBP) and diastolic BP (DBP) during the final 6 h of the 24-h dosing cycle. The adjusted mean treatment differences in the last 6-h mean ambulatory SBP/DBP were -5.8/-4.2 mm Hg after 8 weeks and -4.1/-3.0 mm Hg after 14 weeks, in favour of telmisartan (P<0.0001 for all four comparisons). Secondary end point results, including the mean 24-h ambulatory BP monitoring, day- and night-time BP and 24-h BP load, also significantly favoured telmisartan (P<0.0001). Both treatments were well tolerated; adverse events, including cough, were less common with telmisartan. These findings suggest that telmisartan is more effective than ramipril throughout the 24-h period and during the EMBPS; this may be attributable to telmisartan's long duration of effect, which is sustained throughout the 24-h dosing period.

Magnitude of the early morning blood pressure surge in untreated hypertensive patients: a pooled analysis.

OBJECTIVES: A post hoc analysis was performed to assess the magnitude of the early morning blood pressure surge (EMBPS), which is associated with peak cardiovascular risk, in untreated hypertensive patients enrolled in two sister studies (Prospective, Randomised Investigation of the Safety and efficacy of MICARDIS vs. ramipril using ambulatory blood pressure monitoring I and II) with identical design. METHODS: In adults with a mild-to-moderate primary hypertension and no significant comorbidities, 24-h ambulatory blood pressure monitoring was conducted after a 2- to 4-week placebo run-in period and before treatment initiation. Individual blood pressure measurements at 20-min intervals were analysed. RESULTS: In 1419 hypertensive patients with normal sleeping times, blood pressure displayed a typical circadian rhythm, with a mean EMBPS of 29/24 mmHg. An EMBPS of >or= 25 mmHg was observed in around 60% of patients. The surge was significantly increased with smoking, alcohol consumption, longer sleep, later waking times, and increased blood pressure variability during waking and sleeping. The magnitude of the EMBPS was significantly reduced in Black vs. White patients. The surge was not affected by gender, body mass index or duration of hypertension. Further analysis showed that ethnicity, alcohol consumption and smoking were all found to have a significant impact on surge around waking and age, sleep duration and sleep blood pressure variability were all found to have an effect on the prewake surge. CONCLUSIONS: In untreated hypertensive patients, the magnitude of the EMBPS is significant when compared with the 24-h mean and is affected by individual patient characteristics. In light of these findings, physicians should understand the importance of 24-h blood pressure control and the modification of certain lifestyle factors as ways of reducing the EMBPS.

Efficacy and tolerability of fixed-dose combinations of telmisartan plus HCTZ compared with losartan plus HCTZ in patients with essential hypertension.

Telmisartan, an angiotensin II receptor blocker, is an effective once-daily antihypertensive agent available either alone or in fixed-dose combination with hydrochlorothiazide (HCTZ). This multicentre, prospective, randomised, open-label, blinded-endpoint (PROBE) study assessed the efficacy and safety of six weeks' treatment with telmisartan 40 mg/HCTZ 12.5 mg (n = 199) and telmisartan 80 mg/HCTZ 12.5 mg (n = 200) versus losartan 50 mg/HCTZ 12.5 mg (n = 198) in patients with mild to moderate essential hypertension. During the last six hours of the dosing interval, telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg reduced mean ambulatory diastolic blood pressure (DBP) to a greater extent than losartan 50 mg/HCTZ 12.5 mg (treatment differences 1.8 mmHg [p < 0.05] and 2.5 mmHg [p < 0.001], respectively). Telmisartan 80 mg/HCTZ 12.5 mg also lowered mean 24-hour DBP by 2.3 mmHg more than losartan 50 mg/HCTZ 12.5 mg (p < 0.001). Telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg produced greater reductions in ambulatory systolic blood pressure versus losartan 50 mg/HCTZ 12.5 mg of 2.5 mmHg and 3.4 mmHg, respectively, during the last six hours of the dosing interval (p < 0.05), and of 2.1 mmHg and 3.4 mmHg, respectively, over the entire 24-hour dosing interval (p < 0.05). All treatments were well tolerated.

A new fixed-dose combination for added blood pressure control: telmisartan plus hydrochlorothiazide.

Population surveys on hypertension management reveal worrying deficiencies in the awareness and treatment of high blood pressure. Many patients with hypertension will require two or more drugs with complementary mechanisms of action (which generally have additive effects, producing greater blood pressure reductions than either agent alone) to attain the blood pressure goals specified in internationally accepted guidelines. Nevertheless, physicians are often reluctant to prescribe multiple anti-hypertensive drugs due to concerns over side-effects, inconvenient dosing regimens and costs. Fixed-dose formulations combining two agents from different classes in a single tablet should help to allay these concerns. A fixed-dose combination containing telmisartan (an angiotensin II receptor blocker) and hydrochlorothiazide (a thiazide diuretic) has recently been developed. Telmisartan/hydrochlorothiazide provides additional anti-hypertensive efficacy compared with the respective monotherapies in a wide range of patients, including black patients, requires once-daily dosing, is cost-effective, well tolerated and is associated with less potassium depletion than hydrochlorothiazide administered alone.

Efficacy and tolerability of a fixed-dose combination of telmisartan plus hydrochlorothiazide in patients uncontrolled with telmisartan monotherapy.

The antihypertensive effects of a telmisartan 80 mg/hydrochlorothiazide (HCTZ) 12.5 mg fixed-dose combination and telmisartan 80 mg monotherapy were compared in patients with a history of mild-to-moderate essential hypertension and inadequate BP control (DBP > or = 90 mm Hg) following 8 weeks of telmisartan monotherapy. At the end of this period, 491 patients (62.9% men; mean age 55.3 years) whose DBP was > or = 90 mm Hg were double-blind randomised to once-daily telmisartan 80 mg/HCTZ 12.5 mg (n = 246) or telmisartan 80 mg (n = 245). Trough (24 h post-dose) clinic BP was measured after 4 and 8 weeks of double-blind therapy. At the end of double-blind treatment, patients receiving telmisartan 80 mg/HCTZ 12.5 mg had significant additional decrements in clinic SBP/DBP over telmisartan 80 mg of -5.7/-3.1 mm Hg (P < 0.01). Most of the additional effect occurred during the first 4 weeks of treatment. The proportion of patients with normalised BP (SBP < 140 mm Hg and DBP < 90 mm Hg) was significantly greater in the telmisartan 80 mg/HCTZ 12.5 mg group than the telmisartan 80 mg group (41.5%vs 26.1%;P < 0.05). Both treatments were well tolerated. The incidence of adverse events was similar except for diarrhoea, which occurred more frequently in the telmisartan 80 mg/HCTZ 12.5 mg group, and oedema, which occurred more frequently in the telmisartan group. Our results indicate that a telmisartan 80 mg/HCTZ 12.5 mg fixed-dose combination confers significant additional BP reductions compared with continuation of telmisartan monotherapy in non-responders.

Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients.

OBJECTIVES: To compare the effects of nebivolol and atenolol in 25 ambulatory hypertensive patients with impaired glucose tolerance. DESIGN: Clinic and ambulatory blood pressure, insulin sensitivity (euglycemic-hyperinsulinemic clamp), glucose tolerance (intravenous glucose tolerance test), systemic and regional haemodynamics were measured after 4 weeks of placebo and after each 16-week treatment period in a double-blind, crossover fashion. RESULTS: Nebivolol and atenolol similarly reduced (P< 0.001) clinic and ambulatory blood pressure by approximately 15/10 mmHg, systolic and diastolic. Clinic and ambulatory heart rate was reduced to a greater extent (P < 0.01) by atenolol than nebivolol. Atenolol was associated with an approximately 20% reduction in insulin sensitivity (insulin-induced glucose disposal rate/mean insulin concentration ratio, P < 0.01) and an approximately 10% reduction in glucose disappearance rate (K-value, P < 0.05), whereas these variables were not significantly modified with nebivolol. Cardiac output was reduced similarly (P < 0.05) by both drugs at rest but forearm blood flow, forearm vascular resistance or total peripheral resistance were unaffected. A significant inverse correlation coefficient between cardiac output and insulin sensitivity was found at baseline, suggesting that a compensatory increase in systemic blood flow occurs in hypertensive patients with progressively more marked insulin resistance. This relationship was unaffected by nebivolol but was lost with atenolol. CONCLUSIONS: These results indicate that insulin sensitivity was not modified significantly by nebivolol, whereas it was reduced by atenolol, although blood pressure was decreased to the same extent by both drugs. Neither drug induced systemic or forearm vasodilatation but the inverse relationship between cardiac output and insulin sensitivity was preserved with nebivolol but not with atenolol.

Paget disease of bone: mapping of two loci at 5q35-qter and 5q31.

Paget disease of bone is characterized by focal increases of the bone-remodeling process. It is the second most common metabolic bone disease after osteoporosis. Genetic factors play a major role in the etiology of Paget disease of bone, and two loci have been mapped for the disorder: PDB1 and PDB2. The gene(s) causing the typical form of the disorder remains to be characterized. To decipher the molecular basis of Paget disease of bone, we performed genetic linkage analysis in 24 large French Canadian families (479 individuals) in which the disorder was segregating as an autosomal dominant trait. After exclusion of PDB2, a genomewide scan was performed on the three most informative family nuclei. LOD scores >1.0 were observed at seven locations. The 24 families were then used to detect strong evidence for linkage to chromosome 5q35-qter. Under heterogeneity, a maximum LOD score of 8.58 was obtained at D5S2073, at straight theta= .1. The same characteristic haplotype was carried by all patients in eight families, suggesting a founder effect. A recombination event in a key family confined the disease region within a 6-cM interval between D5S469 and the telomere. The 16 other families, with very low conditional probability of linkage to 5q35-qter, were further used, to map a second locus at 5q31. Under heterogeneity, a maximum LOD score of 3.70 was detected at D5S500 with straight theta=.00. Recombination events refined the 5q31 region within 12.2 cM, between D5S642 and D5S1972. These observations demonstrate the mapping of two novel loci for Paget disease of bone and provide further evidence for genetic heterogeneity of this highly prevalent disorder. It is proposed that the 5q35-qter and 5q31 loci be named "PDB3" and "PDB4," respectively.

A multicenter, randomized, double-blind study of the antihypertensive efficacy and tolerability of irbesartan in patients aged > or = 65 years with mild to moderate hypertension.

BACKGROUND: Blockade of the renin-angiotensin-aldosterone system (RAAS) is the preferred mechanism of action for controlling hypertension in select groups of patients, including those with diabetic nephropathy and heart failure. Currently, 2 classes of drugs work by blocking the RAAS, albeit by differing mechanisms: angiotensin-converting enzyme (ACE) inhibitors and angiotensin II angiotensin type 1 receptor blockers (ARBs). OBJECTIVE: The goal of this study was to assess the comparative efficacy and tolerability of the ARB irbesartan and the ACE inhibitor enalapril in patients > or = 65 years of age with mild to moderate hypertension (sitting diastolic blood pressure [DBP], 95 to 110 mm Hg). METHODS: Elderly (> or = 65 years of age) patients were recruited from 26 Canadian study centers for a randomized, double-blind, 8-week clinical trial. Exclusion criteria included sitting DBP >110 mm Hg or sitting systolic blood pressure (SBP) >200 mm Hg, angina pectoris, myocardial infarction, cardiac procedure, stroke, or transient ischemic attack within 6 months of randomization, as well as other preexisting or present severe medical or psychologic conditions. Patients were randomly assigned to receive a single daily dose of irbesartan 150 mg (n = 70) or enalapril 10 mg (n = 71) with treatment doses of study drugs doubled at week 4 for sitting DBP > or = 90 mm Hg. Reductions from baseline blood pressure measurements at trough (24 +/- 3 hours after the last dose of medication) were assessed for sitting DBP and sitting SBP. Comparative tolerability to study drugs was also assessed. RESULTS: The intent-to-treat analysis demonstrated similar reductions at week 8 in both DBP and SBP for both groups. For the primary efficacy analysis of sitting DBP, there was a mean reduction from baseline of 9.6 mm Hg and 9.8 mm Hg for the irbesartan and enalapril groups, respectively (P = 0.93). The mean reduction from baseline in sitting SBP was 10.1 mm Hg and 11.6 mm Hg for the irbesartan and enalapril groups, respectively (P = 0.54). Normalization rates (sitting DBP <90 mm Hg) at week 8 did not differ between groups (52.9% in the irbesartan group and 54.9% in the enalapril group; P = 0.81). No statistical difference existed between the 2 groups with respect to serious adverse events or discontinuations due to adverse events. Irbesartan was associated with a significantly lower incidence of cough than was enalapril (4.3% vs 15.5%, respectively; P = 0.046). CONCLUSIONS: Irbesartan is an effective and well-tolerated antihypertensive for elderly patients with mild to moderate hypertension. This study establishes that irbesartan has better tolerability than enalapril with respect to cough and suggests that irbesartan is as effective at lowering blood pressure but better tolerated than an ACE inhibitor in hypertensive patients > or = 65 years of age.

A new approach to assessing antihypertensive therapy: effect of treatment on pulse pressure. Candesartan cilexetil in Hypertension Ambulatory Measurement of Blood Pressure (CHAMP) Study Investigators.

BACKGROUND: A high pulse pressure is an independent cardiovascular risk factor. It has therefore been suggested that antihypertensive treatment should not only reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP), but should also decrease pulse pressure (SBP minus DBP). In a previous analysis, we showed that two angiotensin II type 1 (AT1)-receptor blockers, candesartan cilexetil and losartan, differed in their effects in reducing SBP and DBP. OBJECTIVE: To compare the efficacy of candesartan cilexetil and losartan according to a new approach--their effect on pulse pressure--and to describe the dose-effect relationship for SBP, DBP and pulse pressure, in a placebo-controlled study. METHODS: After a 4-week placebo run-in period, 268 patients with mild-to-moderate hypertension were allocated randomly to groups to receive placebo, candesartan cilexetil (8 mg once daily) or losartan (50 mg once daily), for 4 weeks. The doses were then doubled to 16 and 100 mg, respectively, for the final 4 weeks of the study. Clinic blood pressure was measured 24 and 48 h after each dose of drug or placebo, and ambulatory blood pressure was monitored from 0 to 36 h after each dose, at baseline and after 4 and 8 weeks of treatment. RESULTS: Candesartan cilexetil decreased ambulatory pulse pressure significantly (P < 0.05) more than did losartan during both daytime and night-time, and over the 24 h period after the previous dose. A different dose-effect relationship on SBP, DBP and pulse pressure was observed. The duration of action of candesartan cilexetil was greater than that of losartan. After a missed dose (i.e. approximately 24-36 h after the previous dose), mean ambulatory pulse pressure values after 4 and 8 weeks of treatment with candesartan cilexetil were lower than those observed with losartan (P < 0.005). Clinic pulse pressure measurements were consistent with these ambulatory measurements. CONCLUSIONS: AT1 -receptor blockers differ both in their ability to reduce pulse pressure and in their duration of effect, candesartan cilexetil having a greater and more sustained effect than losartan. Different dose-effect relationships on SBP, DBP or pulse pressure were observed. Further prospective studies based on pulse pressure are needed to analyse the mechanism of reduction of pulse pressure and to determine its prognostic value.