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.

A comparative review of the efficacy of antihypertensive agents on 24 h ambulatory blood pressure.

BACKGROUND: Ambulatory blood pressure (ABP) monitoring has contributed significantly to the diagnosis, prognosis and treatment of hypertension. However, most of the published reviews have not focused on the 24 h efficacy of conventional and new antihypertensive agents as measured by ABP monitoring. OBJECTIVES: To discuss the importance of 24 h blood pressure control, and to review the antihypertensive efficacy of conventional antihypertensive agents and of angiotensin II type I receptor (AT1R) blockers as assessed by ABP monitoring. PATIENTS AND METHODS: The 24 h antihypertensive efficacy of the different classes of agents was reviewed based on clinical, randomized, double-blind trials published in peer review journals. These trials were mainly performed in the authors' research unit but were performed in other centres as well. RESULTS AND CONCLUSIONS: Most antihypertensive agents provided 24 h ABP control. However, in the authors' experience, hydrochlorothiazide, some angiotensin converting enzyme inhibitors and low dosages of the calcium antagonist diltiazem did not permit satisfactory blood pressure reduction as assessed by ABP monitoring in truly hypertensive patients. AT1R blockers and especially those of the new generation characterized by tight and long lasting AT1-receptor binding produced adequate 24 h ABP control and continued effectiveness during the high risk early morning hours.

Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy.

BACKGROUND: The objectives of this study were to compare the effects of the angiotensin II receptor blocker, losartan, to those of the angiotensin-converting enzyme inhibitor, enalapril, on albuminuria and renal function in relationship to clinic and ambulatory blood pressure (ABP) in hypertensive type 2 diabetic subjects with early nephropathy. The tolerability of these agents and their effect on the metabolic profile were also evaluated. METHODS: The study was a one-year prospective, double-blind trial with losartan and enalapril administered alone or in combination with hydrochlorothiazide and other antihypertensive agents. ABP and renal and biochemical parameters were measured at baseline and after 12, 28, and 52 weeks of active treatment. Ninety-two hypertensive type 2 diabetics with early nephropathy completed the study. RESULTS: Both losartan and enalapril administered alone or in combination with other agents induced significant reductions in sitting clinic (P < 0.05) and ABP (P < 0.002) without a statistical difference between groups. Geometric means for urinary albumin excretion (UAE) decreased significantly (P < 0.001) in patients treated with losartan from 64. 1 to 41.5 microg/min and in those treated with enalapril from 73.9 to 33.5 microg/min after 52 weeks of therapy. A significant relationship (P < 0.05) between changes in systolic and diastolic ABP and the decrease in UAE at 52 weeks was seen in both groups. The decline in glomerular filtration rate (GFR) was stabilized at the end of therapy and was identical in both treatment groups. Treatment with enalapril was associated with a significantly higher incidence of cough (P = 0.006) and a rise in serum uric acid (P = 0.002) compared with losartan. CONCLUSIONS: Our results indicate that a one-year course of antihypertensive therapy with either losartan or enalapril significantly reduces UAE in hypertensive type 2 diabetic patients with early nephropathy. The reduction in UAE with each treatment is similarly related to decrements in ABP. In addition, the rate of decline in GFR is similar in both treatment groups.

ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension.

The antihypertensive efficacy and tolerability profiles of the selective AT1 receptor antagonists telmisartan and losartan were compared with placebo in a 6-week, multinational, multicentre, randomised, double-blind, double-dummy, parallel-group study of 223 patients with mild-to-moderate hypertension, defined as clinic diastolic blood pressure (DBP) >/=95 and /=140 and /=85 mm Hg. After a 4-week single-blind placebo run-in, eligible patients were randomised to receive telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, or placebo. Ambulatory blood pressure monitoring (ABPM) after 6 weeks of double-blind therapy showed that all active treatments produced significant (P < 0.01) reductions from baseline in 24-h mean SBP and DBP compared with placebo. During the 18-to-24 h period after dosing, the reductions in SBP/DBP with telmisartan 40 mg (10.7/6.8 mm Hg) and 80 mg (12.2/7. 1 mm Hg) were each significantly (P <0.05) greater than those observed for losartan 50 mg (6.0/3.7 mm Hg), and losartan was no better than placebo. Also for the 24-h mean blood pressure, telmisartan 40 mg and 80 mg were significantly (P< 0.05) better than losartan 50 mg. Compared with losartan, telmisartan 80 mg produced significantly (P < 0.05) greater reductions in both SBP and DBP during all monitored periods of the 24-h period, while telmisartan 40 mg produced significantly greater reductions in SBP and DBP in the night-time period (10.01 pm to 5.59 am) (P < 0.05) and in DBP in the morning period (6.00 am to 11.59 am) (P < 0.05). All treatments were comparably well tolerated. Telmisartan 40 mg and 80 mg once daily were effective and well tolerated in the treatment of mild-to-moderate hypertension, producing sustained 24-h blood pressure control which compared favourably with losartan.

Lifestyle modifications to prevent and control hypertension. 3. Recommendations on alcohol consumption. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada.

OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of alcohol consumption on the prevention and control of hypertension in otherwise healthy adults (except pregnant women). OPTIONS: There are 2 main options for those at risk for hypertension: avert the condition by limiting alcohol consumption or by using other nonpharmacologic methods, or maintain or increase the risk of hypertension by making no change in alcohol consumption. The options for those who already have hypertension include decreasing alcohol consumption or using another nonpharmacologic method to reduce hypertension; commencing, continuing or intensifying antihypertensive medication; or taking no action and remaining at increased risk of cardiovascular disease. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 with the terms ethyl alcohol and hypertension. Other relevant evidence was obtained from the reference lists of articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design, and graded according to the level of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: A reduction in alcohol consumption from more than 2 standard drinks per day reduces the blood pressure of both hypertensive and normotensive people. The lowest overall mortality rates in observational studies were associated with drinking habits that were within these guidelines. Side effects and costs were not measured in any of the studies. RECOMMENDATIONS: (1) It is recommended that health care professionals determine how much alcohol their patients consume. (2) To reduce blood pressure in the population at large, it is recommended that alcohol consumption be in accordance with Canadian low-risk drinking guidelines (i.e., healthy adults who choose to drink should limit alcohol consumption to 2 or fewer standard drinks per day, with consumption not exceeding 14 standard drinks per week for men and 9 standard drinks per week for women). (3) Hypertensive patients should also be advised to limit alcohol consumption to the levels set out in the Canadian low-risk drinking guidelines. VALIDATION: These recommendations are similar to those of the World Hypertension League, the National High Blood Pressure Education Program Working Group on Primary Prevention of Hypertension and the previous recommendations of the Canadian Coalition for High Blood Pressure Prevention and Control and the Canadian Hypertension Society. They have not been clinically tested. The low-risk drinking guidelines are those of the Addiction Research Foundation of Ontario and the Canadian Centre on Substance Abuse. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada. The low-risk drinking guidelines have been endorsed by the College of Family Physicians of Canada and several provincial organizations.

The incidence of cough: a comparison of lisinopril, placebo and telmisartan, a novel angiotensin II antagonist. Telmisartan Cough Study Group.

Dry cough is a troublesome side-effect associated with certain antihypertensive agents that act by modulating aspects of the renin-angiotensin-aldosterone system. The incidence of dry cough associated with two of these therapies, the novel All receptor antagonist telmisartan and the ACE inhibitor lisinopril, was assessed in a multicentre, randomised, parallel-group, double-blind, placebo-controlled, 8-week study of 88 patients with mild to moderate hypertension who previously demonstrated ACE inhibitor-related cough. Patients received either telmisartan 80 mg, lisinopril 20 mg, or placebo once daily. Cough incidence, measured at each visit by a self-administered symptom assessment questionnaire, was significantly higher with lisinopril (60%) than with telmisartan (15.6%) or placebo (9.7%). A visual analogue scale demonstrated a similar trend for cough frequency. Thus the incidence of cough with telmisartan 80 mg is significantly less than that seen with lisinopril 20 mg and is comparable to placebo.

A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebo-controlled, forced titration study. Candesartan/Losartan study investigators.

The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a longlasting binding to the human AT1-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose intake. After a 4-week placebo lead-in period, 268 patients with sitting diastolic BP 95 to 110 mm Hg and mean awake ambulatory DBP > or =85 mm Hg were randomized to receive either 8 mg of candesartan, 50 mg of losartan, or placebo for a 4-week period. Thereafter, the doses were doubled in all patients for an additional 4-week period. Ambulatory BP monitoring was performed for 36 h after dosing and clinic BP measured 48 h after dosing. Candesartan cilexetil (16 mg) reduced ABP to a significantly greater extent than 100 mg of losartan, particularly for systolic ABP during daytime (P<.05), nighttime (P<.05), and 24-h (P<.01) periods, systolic (P<.01) and diastolic (P<.05) ABP between 0 and 36 h, and both systolic (P<.001) and diastolic (P<0.001) ABP during the day of a missed dose. Clinic BP at 48 h after dosing was significantly reduced exclusively with 16 mg of candesartan. The differences in BP reduction between 8 mg of candesartan and 50 mg of losartan were statistically significant for systolic ABP during daytime (P<.01), nighttime (P<.05), 24-h (P<.01), 0 to 36 h (P<.05) and during the day of missed dose (P<.05). Moreover, although losartan did not significantly reduce ambulatory BP in a dose-related manner, ambulatory systolic and diastolic BP reductions with 16 mg of candesartan were significantly greater (P<.01 and <.001) than those seen with 8 mg of candesartan during every period at the ABP supporting a dose-response relationship. In conclusion, this forced titration study in ambulatory hypertensive patients demonstrates that candesartan cilexetil provides significant dose-dependent reduction in both clinic and ambulatory BP in doses ranging from 8 to 16 mg once daily. Furthermore, candesartan cilexetil is superior to losartan in reducing systolic ABP and in controlling both systolic and diastolic ABP on the day of a missed dose. The differences observed between both agents are most likely attributable to a tighter binding to, and a slower dissociation from, the receptor binding site with candesartan cilexetil.

Chronotherapeutics: are there meaningful differences among antihypertensive drugs?

In the past decade, many publications have dealt with the possible relationship between biological rhythms and the incidence of cardiovascular events. A high proportion of treated hypertensive patients have cardiovascular complications, and chronotherapy, which permits the use of drugs that are maximally effective at different points in the circadian cycle, may be an interesting and valuable approach to decreasing morbidity and mortality in these patients. This article summarizes current knowledge on the new science of chronopharmacology, as demonstrated in several clinical studies that have used conventional agents administered at various points in the circadian cycle as well as new chronotherapeutic agents, such as controlled onset extended release (COER)-verapamil. In addition, emphasis is given to a rigorous evaluation of antihypertensive agents in terms of efficacy and duration of effect to obtain adequate and sustained lowering of blood pressure over the 24-hour period.

The antihypertensive efficacy of losartan and amlodipine assessed with office and ambulatory blood pressure monitoring. Canadian Cozaar Hyzaar Amlodipine Trial Study Group.

BACKGROUND: Losartan potassium is a recently marketed angiotensin II receptor antagonist. Previous studies have suggested that its full antihypertensive efficacy may be delayed for up to 12 weeks. The authors compared the antihypertensive efficacy and tolerability of losartan at 6 and 12 weeks with those of amlodipine besylate, a commonly used calcium antagonist. METHODS: This multicentre, randomized, double-blind clinical trial studied 302 patients with mild or moderate hypertension in 1995. Of the 302, 97 also underwent ambulatory blood pressure monitoring (ABPM). After a 4-week placebo run-in period, the patients were randomly assigned to group A, B or C for 12 weeks. Those in groups A and B began treatment with losartan at 50mg/d, and those in group C began with amlodipine at 5 mg/d. If the blood pressure remained uncontrolled after 6 weeks, subjects in group A had their losartan dose doubled (to 100 mg/d), those in group B were given hydrochlorothiazide (12.5 mg/d) in addition to the losartan, which remained at 50 mg/d, and patients in group C had their amlodipine dose doubled (to 10 mg/d). RESULTS: At 12 weeks all 3 regimens reduced office-recorded diastolic blood pressure (DBP) with the patient sitting. The mean reduction in group A was 8.7 mm Hg (95% confidence interval [CI] 7.3 to 10.1) (p < 0.001), in group B 12.5 mm Hg (95% CI 11.0 to 14.0) (p < 0.001) and in group C 12.9 mm Hg (95% CI 11.4 to 14.5) (p < 0.001). Losartan alone lowered sitting DBP to a lesser degree than the other 2 treatments (p < 0.01). In contrast, ABPM readings, whether 24-hour, daytime or nighttime, were not different among the regimens. Comparison of the results at 6 weeks yielded similar findings. Adverse effects were uncommon and were not different among the groups, with the exception of ankle edema, which was more frequent in group C. INTERPRETATION: Losartan alone reduces both office and ABPM readings. The observed changes in office-recorded sitting DBP suggest that losartan is less effective than amlodipine or the combination of losartan and hydrochlorothiazide, but ABPM did not confirm this difference. Perhaps changes in office readings measure different attributes of a drug than does ABPM.

Vascular structure in the forearm and calf after 6 months of angiotensin converting enzyme inhibition in elderly hypertensive subjects with left ventricular hypertrophy.

OBJECTIVE: To investigate the effects of angiotensin converting enzyme inhibition on the structure of resistive arteries assessed from minimal vascular resistance in the forearm and the calf and on left ventricular mass index of elderly hypertensive subjects with left ventricular hypertrophy. DESIGN AND METHODS: We evaluated 23 elderly patients [12 women and 11 men, aged 70 +/- 1 years (mean +/- SEM)] with essential hypertension assessed with ambulatory blood pressure monitoring and left ventricular hypertrophy before and at the end of 6 months' treatment with quinapril. Minimal vascular resistance was calculated as the ratio of mean arterial pressure to regional blood flow measured upon restoration of circulation after 13 min of ischaemia combined with exercise and taken as an index of resistive vessel structure (i.e. media:lumen ratio). RESULTS: Daytime ambulatory blood pressure had decreased from 164 +/- 2/95 +/- 1 to 147 +/- 3/86 +/- 2 mmHg (P < 0.001) and left ventricular mass index decreased from 138 +/- 4 to 120 +/- 5 g/m2 (P < 0.001) at the end of treatment. Minimal vascular resistance in the forearm had decreased from 3.1 +/- 0.3 to 2.4 +/- 0.2 mmHg/ml per 100 ml per min (P < 0.01) whereas we observed no change in minimal vascular resistance in the calf after treatment (4.6 +/- 0.7 versus 4.2 +/- 0.4 mmHg/ml per 100 ml per min, NS). The decrease in minimal vascular resistance in the forearm was correlated significantly to the fall in 24 h ambulatory mean arterial pressure (r = 0.58, P < 0.01). Changes in left ventricular mass index were not correlated to those in ambulatory blood pressure or to those in minimal vascular resistance in the forearm. CONCLUSIONS: A 6-month reduction in blood pressure under quinapril treatment was associated with decreases in left ventricular hypertrophy and in minimal vascular resistance in the forearm of elderly hypertensive patients. Absence of structural changes in leg vasculature could be related to the greater arterial pressure prevalent in the lower limbs while patients stood upright and, consequently, a proportionately smaller decrease in blood pressure, as well as greater structural changes and fibrous damage than those of the upper limbs.

Comparative effects of felodipine ER, amlodipine and nifedipine GITS on 24 h blood pressure control and trough to peak ratios in mild to moderate ambulatory hypertension: a forced titration study.

OBJECTIVE: To evaluate the 24 h antihypertensive efficacy and duration of action of felodipine extended release (ER) in comparison with two other long acting dihydropyridine calcium antagonists, amlodipine and nifedipine gastrointestinal therapeutic system (GITS), in patients with mild to moderate essential hypertension substantiated by ambulatory blood pressure (BP) monitoring. DESIGN: Randomized, forced titration, parallel group study. Clinic BP was measured at every patient's visit, and 24 h ambulatory BP was monitored at baseline and at the end of each dose-titration period. SETTING: Single centre: hypertension research unit in Quebec City, Quebec. PATIENTS: There were 89 patients enrolled into the study. Eighty-four eligible patients were randomized, and 83 completed the study and were included in the final efficacy analysis. INTERVENTIONS: Following a two-to four-week washout period (baseline), patients were randomly allocated to receive felodipine ER 5 mg, amlodipine 5 mg or nifedipine GITS 30 mg for four weeks (low dose). All study patients had their daily dose doubled to felodipine ER 10 mg, amlodipine 10 mg or nifedipine GITS 60 mg for a further four weeks (high dose). MAIN RESULTS: Significant (P < 0.001) and similar changes from baseline in clinic BP were observed in all treatment groups for low and high doses. Ambulatory BP profiles showed comparable blood pressure reductions with felodipine ER and amlodipine, and a trend towards a lesser reduction with nifedipine GITS during 24 h, daytime and night-time periods. BP loads were similarly reduced with the three treatments. Trough to peak ratios (T:Ps) were calculated from 24 h ambulatory BP curves according to two different approaches: for diastolic and systolic BP, respectively, the global approach produced T:Ps of 0.49 and 0.50 with felodipine ER 5 mg; 0.50 and 0.34 with felodipine ER 10 mg; 0.70 and 0.60 with amlodipine 5 mg; 0.88 and 0.82 with amlodipine 10 mg; 0.65 and 0.55 with nifedipine GITS 30 mg; 0.68 and 0.53 with nifedipine GITS 60 mg. T:Ps in the individual approach were 0.07 and 0.10 with felodipine ER 5 mg; 0.23 and 0.31 with felodipine ER 10 mg; 0.22 and 0.31 with amlodipine 5 mg; 0.45 and 0.58 with amlodipine 10 mg; 0.27 and 0.31 with nifedipine GITS 30 mg; and 0.24 and 0.40 with nifedipine GITS 60 mg. CONCLUSION: There was no evidence in this study of a difference among felodipine ER, amlodipine and nifedipine GITS in lowering ambulatory or clinic BP. Treatment based on ambulatory BP may be preferable to treatment guided by T:Ps because ambulatory BP is firmly established as a predictor of cardiovascular risk. Furthermore, there is no consensus on how to calculate T:Ps, and different methods of calculation may give divergent results.