Health-related quality of life during treatment of elderly patients with hypertension: results from the Study on COgnition and Prognosis in the Elderly (SCOPE).

The Study on COgnition and Prognosis in the Elderly (SCOPE) was a multinational, randomised, double-blind study to assess the effects of candesartan 8-16 mg daily on cardiovascular events and cognitive function in elderly patients (aged 70-89 years) with mild to moderate hypertension. A total of 4937 patients were randomised to candesartan or placebo with other antihypertensive drugs (mostly diuretics, beta-blockers, and calcium antagonists) added as needed to control blood pressure. Only 16% of the patients in the control group received placebo alone. The mean follow-up was 3.7 years. The aim of this health-related quality of life (HRQL) substudy analysis was to investigate changes in HRQL during antihypertensive treatment, and possible differences in patients receiving candesartan-based or other antihypertensive treatment. Three validated HRQL instruments were used: the Psychological General Well-being (PGWB) Index, the Subjective Symptoms Assessment Profile (SSA-P), and the EuroQoL Health Utility Index (EuroQoL). The HRQL was generally good at baseline and well preserved during follow-up in the presence of substantial blood pressure reductions in both treatment groups. Several of the observed changes in score from baseline to last visit favoured candesartan-based compared to control treatment, particularly the changes in PGWB Anxiety (-0.5 vs -1.0, P=0.01), PGWB Positive well-being (-0.8 vs -1.1, P=0.04), SSA-P Cardiac symptoms (0.03 vs 0.10, P=0.03), and EuroQoL Current health (-3.1 vs -5.3, P=0.008). This favourable result may be related to the somewhat lower blood pressure associated with candesartan-based treatment. In conclusion, there should be no reason to withhold modern antihypertensive therapy in elderly patients due to concerns for a negative effect on HRQL.

Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group.

BACKGROUND: The Hypertension Optimal Treatment (HOT) Study has provided information about cardiovascular events in 18790 hypertensives, subjected to pronounced blood pressure (BP) lowering for a mean of 3.8 years. The HOT study data have subsequently been analysed after stratification of the patients according to global cardiovascular risk, and it has been found that, despite intensive blood pressure lowering in all risk strata, morbid event rates increased with increasing risk stratum. OBJECTIVES: Previously analysed global risk strata were based on combinations of risk factors. The analyses presented here were intended to provide information on the relative role that the presence of each individual factor may have in increasing cardiovascular risk, despite good BP control. METHODS: Risk ratios (RR) for patients with and those without a risk factor were calculated with 95% confidence intervals (CI) using a Cox proportional hazard model, and adjusted for all variables except the one under examination. RESULTS: For all risk factors considered and for all types of event, RR were always greater than 1, indicating a greater risk in the presence, compared with that in the absence of each factor. The male gender was a statistically significant risk for cardiovascular (CV) events, CV and total mortality and particularly for myocardial infarction (MI); age > or = 65 years for CV events, stroke, CV and particularly total mortality; smoking for all events analysed, but particularly for total mortality (twice higher in smokers than in non-smokers); high serum cholesterol (> 6.8 mmol/l) for CV events, MI and CV mortality; high serum creatinine (> 155 micromol/l) for CV events, stroke, CV and total mortality; diabetes for CV events, stroke, total mortality and particularly CV mortality; and ischaemic heart disease for all events analysed. Adjusted RR were often close to or greater than 2. CONCLUSIONS: Each of the risk factors considered was found to be an important cause of residual risk, despite good BP control. These findings emphasize the importance of addressing other correctable risk factors, e.g. smoking, hypercholesterolaemia and diabetes, as well as rigorous control of blood pressure, and of initiating antihypertensive therapy before cardiovascular and renal damage becomes manifest.

The relationship between age, gender, well-being and symptoms, and the use of pharmaceuticals, herbal medicines and self-care products in a Swedish municipality.

BACKGROUND: A relatively small proportion of the population accounts for a substantial part of the public drug cost. Therefore, identifying the characteristics of high users of drugs is an important step towards limiting the cost of drugs. The aim of this study was to assess the relationship between age, gender, well-being and symptoms, and the use of pharmaceutical specialities, herbal medicines and self-care products. METHODS: A postal questionnaire was sent to a representative population sample (n = 1.312) from a small Swedish municipality. The relationship between age, gender, well-being and symptoms, and the use of drugs and self-care products was tested using multivariate analysis. RESULTS: The questionnaire was answered by 827 subjects. The use of prescribed pharmaceuticals increased with age in both genders. Women used prescribed and non-prescribed pharmaceuticals as well as herbal medicines and self-care products more than men. Subjects who reported low scores for well-being had significantly higher odds of having used prescribed pharmaceuticals than subjects with high scores. Bad perceived health was the only well-being measure that was associated with high odds for the use of herbal medicines. Most symptoms occurred more frequently in users than in nonusers of pharmaceuticals. Subjects with many symptoms (six or more) had higher odds of having used pharmaceuticals and self-care products than those with few symptoms. CONCLUSION: High age, female gender and low perceived well-being significantly increased the use of drugs, particularly prescribed pharmaceuticals. Subjects with many symptoms used pharmaceuticals and self-care products more than those with few symptoms.

Study on COgnition and Prognosis in the Elderly (SCOPE): baseline characteristics.

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multi-centre, prospective, randomized, double-blind, parallel-group study. The primary objective of SCOPE is to assess the effect of the angiotensin II type 1 (AT1) receptor blocker, candesartan cilexetil 8-16 mg once daily, on major cardiovascular events in elderly patients (70-89 years of age) with mild hypertension (DBP 90-99 and/or SBP 160-179 mmHg). The secondary objectives of the study are to test the hypothesis that antihypertensive therapy can prevent cognitive decline (as measured by the Mini Mental State Examination, MMSE) and dementia, and to assess the effect of therapy on total mortality, myocardial infarction (MI), stroke, renal function, and hospitalization. A total of 4964 patients from 15 participating countries were recruited during the randomization phase of SCOPE, exceeding the target population of 4000. The mean age of the patients at enrolment was 76 years, the ratio of male to female patients was approximately 1:2, and 52% of patients were already being treated with an antihypertensive agent at enrolment. The majority of patients (88%) were educated to at least primary school level. At randomization, mean sitting blood pressure values were SBP 166 mmHg and DBP 90 mmHg, and the mean MMSE score was 28. Previous cardiovascular disease in the study population included myocardial infarction (4%), stroke (4%) and atrial fibrillation (4%). Men, more often than women, had a history of previous MI, stroke and atrial fibrillation. A greater percentage of men were smokers (13% vs 6% in women) and had attended university (11% vs 3% of women). Of the randomized patients, 21% were 80 years of age. In this age group smoking was less common (4% vs 10% for 70-79-year-olds) and fewer had attended university (4% vs 7% for 70-79-year-olds). The incidence of MI was similar in both age groups. However, stroke and atrial fibrillation had occurred approximately twice as frequently in the older patients. The patients' mean age at baseline was similar in the participating countries, and most countries showed the approximate 1:2 ratio for male to female patients. There was also little inter-country variation in terms of mean SBP, DBP or MMSE score. However, there was considerable regional variation in the percentage of patients on therapy prior to enrolment.

Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT study. Hypertension Optimal Treatment.

OBJECTIVE: We have assessed the influence of gender and age on the main outcome results of the Hypertension Optimal Treatment (HOT) study. DESIGN AND INTERVENTIONS: The aims of the HOT study were to study the relationship between three levels of target office diastolic blood pressure (BP) (< or = 90, < or = 85 or < or = 80 mmHg) and cardiovascular (CV) events in hypertensive patients, and to examine the effects of 75 mg acetylsalicylic acid (ASA) daily versus placebo. SETTING: Outpatient clinical trial in 26 countries. PATIENTS: A total of 18790 patients (mean age 61.5 years, range 50-80) were randomized and followed for an average of 3.8 years until 71051 patient-years and 683 events had occurred. MAIN OUTCOME MEASURES: CV death, myocardial infarction (MI) and stroke. RESULTS: There were significantly fewer MIs in those in the lower diastolic BP target groups (3.0 versus 1.2 and 1.7 MIs/1000 patient-years, P for trend = 0.034) in women (n = 8883), whereas the similar but smaller trend (4.1 versus 4.1 and 3.4 MIs/1000 patient-years) was not statistically significant in men nor in the subgroup analysis of younger and older subjects. The effect of ASA on preventing MI was not influenced by age < 65 years (P= 0.02) or age > or = 65 years (P = 0.04) but was influenced by gender (P = 0.38 in women and P = 0.001 in men, lowered by 42% corresponding to a reduction from 5.0 to 2.9 MIs/1000 patient-years). CONCLUSIONS: The data of this HOT study sub-analysis suggest somewhat differentiated optimal gender- and age-dependent effects of anti-hypertensive and anti-platelet therapies; lowering of diastolic BP to about 80 mmHg in hypertensive women and, in addition, the administration of 75 mg of ASA to well-treated hypertensive men appear to effectively reduce the most common cardiovascular complication, i.e. myocardial infarction, in patients with essential hypertension.

Does hypertension or a previous myocardial infarction influence the blood pressure and heart rate responses to changes in body position? Results from a study with serial measurements in the supine and standing positions in 60-year-old men.

An age-related attenuation of the normal increase in diastolic blood pressure and heart rate upon standing has previously been observed in man. Whether this is due to ageing as such, or a consequence of a higher prevalence of cardiovascular disease in older compared to younger subjects, is unclear. This population-based study was conducted to address this question. It was carried out in three groups of 60-year-old men: (i) with hypertension (n = 75), (ii) with a previous myocardial infarction (n = 39), and (iii) without any of these diseases, thus constituting a control group (n = 41). Blood pressure and heart rate were assessed during three 7-min periods (supine-standing-supine), using an unbiased non-invasive method. The cardiovascular responses were both qualitatively and quantitatively similar in all three groups, i.e. the increases in diastolic blood pressure and heart rate upon standing, and decreases upon laying down, were of a similar magnitude. In conclusion, 60-year-old men with hypertension or a previous myocardial infarction had blood pressure and heart rate responses similar to those of men of the same age who did not have these diseases. This indicates that the attenuated response previously reported in older compared to younger people is not explained by the higher prevalence of these cardiovascular diseases in the elderly, but is merely an age-dependent characteristic.

Candesartan Cilexetil, a Novel Angiotensin II Antagonist, Provides Dose-dependent Antihypertensive Effect with Maintained Tolerability.

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker that binds tightly to and dissociates slowly from the AT 1 -receptor. It is administered as a prodrug, candesartan cilexetil, which is completely converted to the active compound, candesartan, during absorption in the gastrointestinal tract. Placebo-controlled studies have shown that candesartan cilexetil is an effective antihypertensive drug. The individual studies, however, lacked the statistical power to assess the dose-response relationship with high precision. A more precise estimate of the effect of different doses may be achieved by pooling similar studies in a meta-analysis. The primary objective of this meta-analysis was to determine the dose-response relationship for the antihypertensive effect of candesartan cilexetil. Six European randomized, double-blind, placebo-controlled, dose-response studies with candesartan cilexetil were reported by 30 September 1996. These studies enrolled similar patients (primary hypertension with a sitting diastolic blood pressure [DBP] of 95-114 mmHg after a placebo run-in period) and had a similar design (parallel groups and fixed doses). The doses investigated ranged from 2 to 16 mg once daily. All doses were not given in every study, but all studies investigated at least two different doses of candesartan cilexetil. The duration of the double-blind phase varied between studies, but was at least 4 weeks (range: 4-12 weeks). The variable of primary interest was sitting DBP measured 24 h after dose (trough effect). Each dose of candesartan was analysed separately, and compared with placebo data only from those studies in which that dose was given. The analysis was performed using an analysis of covariance model. Placebo-corrected estimated mean blood pressure reductions from baseline (randomization) to the end of the study and the 95% confidence intervals for the true mean reductions were calculated for each dose. In total, 1498 hypertensive patients were randomized, of whom 1482 provided efficacy data and were included in the analysis. The vast majority of patients (99%) were of Caucasian origin. The placebo-corrected reductions in sitting DBP and sitting systolic blood pressure (SBP) achieved with the different doses of candesartan cilexetil are shown in the Table. Reductions in blood pressure were dose-related, and age or gender did not influence the antihypertensive effect of candesartan cilexetil. Furthermore, blood pressure reductions achieved in the standing position were similar to those in the sitting position, i.e. there was no indication of an abnormal orthostatic response during treatment with candesartan cilexetil. Heart rate was not significantly influenced by candesartan cilexetil. Adverse events occurred in a similar proportion of patients treated with placebo or candesartan cilexetil and did not increase with the dose. Candesartan cilexetil was equally well tolerated in young and elderly patients and in men and women. Thus, in European patients with mild to moderate hypertension, candesartan cilexetil provides a clinically significant, dose-dependent, antihypertensive effect in doses ranging from 4 to 16 mg once daily. The optimal maintenance doses of candesartan cilexetil appear to be 8 or 16 mg once daily in most patients.

Study on COgnition and Prognosis in the Elderly (SCOPE).

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

The influence of sociodemographic characteristics on well-being and symptoms in a Swedish community. Results from a postal questionnaire survey.

STUDY OBJECTIVE: To assess the influence of sociodemographic characteristics on self-reported well-being and symptoms. DESIGN: A postal questionnaire was sent to a representative population sample drawn from the population census. SETTING: The municipality of Håbo, Sweden. PARTICIPANTS: Out of 1312 subjects in the population sample, 827 (63%) participated in the study, i.e. answered the questionnaire. RESULTS: Sociodemographic characteristics significantly influenced most well-being variables and symptoms. The prevalence of symptoms in the categories depression and tension, as well as headache, decreased while most other symptoms increased with age. Women had more symptoms than men. Married subjects, compared to others, had higher social and mental but lower physical well-being. Subjects from households with up to three persons, and subjects with comprehensive school only, had lower physical well-being than other subjects. Working subjects generally had a higher well-being than non-working subjects. CONCLUSION: Sociodemographic characteristics had a significant influence on most well-being variables and symptoms.

Age-related differences in blood pressure and heart rate responses to changes in body position: results from a study with serial measurements in the supine and standing positions in 30-, 50- and 60-year-old men.

This population-based study presents the blood pressure and heart rate responses to sudden changes in body position in representative groups of men aged 30 (n = 50), 50 (n = 44) and 60 (n = 69) years, using an unbiased method for non-invasive blood pressure measurements. Blood pressure and heart rate were measured every minute during three 7-min periods in the supine, standing and again supine positions. Whereas there was an initial decrease in systolic blood pressure upon standing in men aged 50 and 60 years, an increase was seen in the 30-year-olds. The diastolic blood pressure increased in all age groups, but less in the older compared to the younger men. In all age groups, the changes in systolic blood pressure upon standing were transient, while the changes in the diastolic blood pressure lasted during the entire observation period. The heart rate increased to a similar extent upon standing in all age groups. No symptomatic hypotension was observed. After resuming the supine position, both blood pressure and heart rate returned towards the levels initially recorded. This population-based study confirms previous observations in selected subjects of age-related attenuation in blood pressure response to change in body position. The study also shows that blood pressure and heart rate are rapidly stabilized upon standing up.

Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.

BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Candesartan cilexetil, a new generation angiotensin II antagonist, provides dose dependent antihypertensive effect.

Candesartan is a new generation angiotensin II type 1 receptor blocker, characterised by tight binding to and slow dissociation from the receptor. In order to delineate the dose-response curve for candesartan cilexetil (the orally administered prodrug), results from six European placebo-controlled, dose-response studies were pooled. These were of a double-blind, randomised, parallel group design, with a treatment duration of 4-12 weeks. A total of 1482 patients with mild to moderate primary hypertension were treated with candesartan cilexetil 2 mg (n = 80), 4 mg (n = 216), 8 mg (n = 455) or 16 mg (n = 294), or with placebo (n = 437). Blood pressure (BP) measurements were performed 24 h after dose. The differences in BP change (baseline vs end of the studies) between the placebo group and the groups treated with candesartan cilexetil were assessed using analysis of covariance and dose response curves were estimated by fitting the data to an Emax model. The placebo-corrected mean reductions in sitting diastolic BP were approximately 2.5 mm Hg with 2 mg, 4.5 mm Hg with 4 mg, 6 mm Hg with 8 mg, and 8 mm Hg with 16 mg of candesartan cilexetil. For sitting systolic BP, the placebo-corrected mean reductions were in the order of 5, 7, 10 and 12 mmHg, respectively, with 2, 4, 8 and 16 mg of candesartan cilexetil. The BP reductions were similar in the standing position with no indication of postural hypotension. Age or gender did not influence the BP response to candesartan cilexetil. In conclusion, candesartan cilexetil provides a clinically significant, dose-dependent antihypertensive effect in doses ranging from 4-16 mg once daily.

Candesartan cilexetil: safety and tolerability in healthy volunteers and patients with hypertension.

The tolerability and safety of candesartan cilexetil has been evaluated in over 5000 subjects enrolled into double-blind or open-label clinical studies. In double-blind clinical trials in patients with primary hypertension, candesartan cilexetil 2-16 mg once-daily was associated with a low incidence of adverse events and drug-related withdrawals, similar to placebo. The drug showed no evidence of dose-dependent adverse events and it was equally well tolerated by men and women and by elderly (> or =65 years) and younger (<65 years) patients alike. Candesartan cilexetil had no effect on blood glucose control or serum lipid profile in patients with type II diabetes. It was very well tolerated also when given in combination with hydrochlorothiazide or amlodipine and during long-term open-label therapy (up to 1 year). Candesartan cilexetil therefore possesses an excellent tolerability profile that extends to a wide variety of patients including the elderly and it does not aggravate co-existing risk factors such as hyperlipidaemia or glucose intolerance. It therefore appears to offer a better tolerated alternative to other commonly used antihypertensive agents.

Overview of the safety of felodipine based on clinical trials in patients with hypertension.

All clinical studies of at least 1 week's duration with felodipine in patients with hypertension were included in a safety analysis. The major finding was that felodipine does not increase mortality or the incidence of major cardiovascular events and that the data indicate a favorable effect.

Effects of felodipine, metoprolol and their combination on blood pressure at rest and during exercise and on volume regulatory hormones in hypertensive patients.

The effects on blood pressure (BP) and heart rate (HR), at rest and during bicycle exercise, of the vascular selective calcium antagonist felodipine, the cardio-selective beta-blocker metoprolol, and of the two drugs in combination, were assessed in a double-blind, three-way cross-over study comprising 23 patients with essential, mild to moderate hypertension. All three treatment regimens were given to each patient in randomised order for 4 weeks after a 4 week placebo run-in period. Felodipine 10-20 mg daily, metoprolol 100-200 mg daily and the combination of felodipine 10-20 mg plus metoprolol 100 mg daily were all effective antihypertensive treatments both at rest and during exercise. The two drugs seemed to have additive effects and the effect on BP of the combination was greater than that of either drug given as monotherapy. The mean sitting BP was 148/103 mmHg at randomisation, after 4 weeks of placebo treatment, and 134/88, 134/94 and 121/84 mmHg, respectively, after 4 weeks' treatment with felodipine, metoprolol and the combination. Maximal exercise capacity was similar irrespective of treatment regimen, and the normal response to exercise BP and HR was maintained during all active treatments. Changes observed in volume regulatory hormones (PRA, aldosterone and ANP) were consistent with a direct tubular natriuretic-diuretic effect of felodipine and of beta-blocker attenuated release of renin. All treatment regimens were well tolerated and adverse events reported were usually mild and transient.

Improving the therapeutic balance between efficacy and tolerability in antihypertensive drugs--the rationale and benefits of combining felodipine and metoprolol.

Several studies, most recently the Starnberg Study on Epidemiology of Parkinsonism and Hypertension in the Elderly (STEPHY), have shown that BP is not adequately controlled in a substantial proportion of treated hypertensive patients. This finding highlights the need for new treatment strategies that are sufficiently effective throughout the dosing interval, well tolerated, and available in a convenient, once-daily regimen. Monotherapy with any individual drug class is often unable to fulfil all of these criteria in more than a minority of patients. In contrast, once-daily therapy with rational combinations of antihypertensive drugs offers a promising approach to improving treatment of hypertension. The highly vascular selective calcium antagonist felodipine and the cardioselective beta-blocker metoprolol have complementary mechanisms of action, making them appropriate for use together in the management of hypertension. A new extended-release (ER) formulation, combining felodipine, 5 mg, and metoprolol, 50 mg*, has therefore been developed. This formulation has been shown to provide significantly greater reductions and higher antihypertensive response rates than either agent used alone. This high efficacy is achieved with maintained good tolerability. In comparative trials, felodipine-metoprolol has also been shown to be more effective than combination treatment with nifedipine and atenolol, or captopril and hydrochlorothiazide. It is concluded that the felodipine-metoprolol ER tablet offers predictably high 24 h antihypertensive response rates from a convenient and well-tolerated once-daily dose.

Clinical equivalence of two tablet formulations of felodipine. A placebo-controlled study of 24-hour blood pressure control and tolerability.

OBJECTIVE: This study was performed to assess whether a new formulation of felodipine extended release (FER) tablets with a 9 mm diameter is similar to the presently used 11 mm diameter FER formulation with respect to antihypertensive effect and tolerability in patients with essential hypertension. A randomised, double-blind, placebo controlled, three-way cross-over study design was used. PATIENTS: Twenty-four patients with a supine diastolic blood pressure (DBP) of 95-115 mmHg after a 4-week placebo run-in period were given FER 5 mg 9 mm tablets, FER 5 mg 11 mm tablets and placebo in randomised order. The tablets were given once daily and each double-blind treatment period lasted for two weeks. METHODS: Twenty-four hour ambulatory blood pressure monitoring was performed at the end of each treatment period. The primary effect variable was mean DBP over 24 hours. Nineteen patients had 24-hour blood pressure data valid for analysis using an analysis of variance with patient, treatment, period and carry-over as factors. RESULTS: Both formulations of FER 5 mg tablets significantly reduced the mean 24-hour DBP compared to placebo. The 9 and 11 mm tablets resulted in, on average, 4.7 and 3.4 mmHg lower mean 24-hour DBP than placebo. There was, however, no significant difference between the two different FER formulations. Both FER formulations were well tolerated and similar to placebo in this respect. CONCLUSION: Both FER 5 mg tablet formulations (9 and 11 mm diameter), given once daily, were clinically equivalent with respect to antihypertensive effect and tolerability in patients with mild to moderate essential hypertension.

Relevance of plasma noradrenaline concentrations to estimate autonomic effects of antihypertensive drugs.

The sympathetic nervous system is important in regulating cardiovascular function. It is therefore of interest to study the influence of antihypertensive drugs on sympathetic nerve activity. For this purpose, measurements of noradrenaline concentrations in forearm venous plasma have often been used. For several reasons, this provides limited information: i) the sympathetic nervous system is highly differentiated, i.e. activity may be high in some organs and low in others; ii) noradrenaline in forearm venous plasma is largely derived from sympathetic activity to the forearm skeletal muscle; iii) plasma noradrenaline concentrations are determined not only by noradrenaline spillover from sympathetic nerve endings, which is related to sympathetic nerve activity, but also by noradrenaline clearance. Under most circumstances plasma noradrenaline concentrations are not high enough to produce hormonal effects. Many types of antihypertensive drugs may cause acute and long-term increases in forearm venous noradrenaline concentrations. The mechanisms underlying these increases are not fully understood but seem to differ between drug classes: Diuretics increase renal noradrenaline spillover; beta-blockers do not affect spillover but reduce total noradrenaline clearance; calcium antagonists and alpha-blockers probably increase noradrenaline spillover, but it is not known which organs are involved, particularly during long-term treatment. ACE inhibitors seem to have a sympatholytic action, which counteract reflex increases in sympathetic nerve activity during blood pressure reduction, and plasma noradrenaline concentrations are generally not affected. To be able to judge the possible clinical consequences of changes in plasma noradrenaline concentrations during chronic antihypertensive treatment, assessments of noradrenaline spillover from individual organs are needed.

Plasma concentration--effect relationships for felodipine: a meta analysis.

The plasma concentration versus antihypertensive effect relationship for the calcium antagonist felodipine was investigated in 67 patients with hypertension and 21 healthy subjects by use of the Emax model. No consistent effect of felodipine on blood pressure was observed in the healthy subjects. In patients with hypertension the plasma drug concentration and blood pressure versus time curves mirrored each other, indicating a close relationship between concentration and effect. The maximum effect (Emax) model fitted the diastolic blood pressure data of most patients, but the model was less often applicable in patients with low initial diastolic blood pressure levels. The average Emax values and the plasma felodipine concentration needed to obtain 50% of Emax for the patients with hypertension were 29 mm Hg and 8 nmol/L, respectively. The Emax values increased with increasing initial diastolic blood pressure levels but were similar in patients with high and low plasma felodipine concentrations. Age had negligible influence on the antihypertensive response to felodipine when compensation was made for the plasma concentrations.

Renal effects of felodipine--a review.

Felodipine is a dihydropyridine calcium antagonist which lowers total peripheral resistance and blood pressure in doses which have no effect on cardiac conduction and contractility. It increases the urinary excretion of sodium and water due to decreased renal tubular reabsorption from the glomerular ultrafiltrate. This is observed at low doses which do not affect blood pressure, renal blood flow (RBF) or glomerular filtration rate (GFR). Felodipine decreases total renal vascular resistance and causes a transient increase in RBF in patients with normal RBF. In patients with low pretreatment values, RBF is increased during chronic treatment. Felodipine does not affect normal GFR. Thus filtration fraction may decrease. In patients with severe hypertension and reduced GFR, felodipine treatment results in good blood pressure control and increased GFR. In animal models of progressive renal disease due to hyperfiltration, felodipine has no negative effect on GFR, glomerulosclerosis or survival although proteinuria may increase. In salt-sensitive rats given high salt diet, resulting in hypertension, hypoperfused kidneys and progressive renal damage, felodipine treatment results in reduced blood pressure, increased RBF and GFR, and reduced proteinuria and glomerulosclerosis. In patients with previously refractory hypertension and progressive impairment of renal function, felodipine treatment results in good blood pressure control and a reduced rate of progression. In animals, felodipine limits the extent of renal damage after ischemia and reperfusion.